Fast achievement and/or completion of substantial stable drug delivery

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to therapy and endocrinology, and can be used in treating patients suffering type 2 diabetes mellitus. That is ensured by a continuous exenatide delivery by implanting into a patient into an osmotic delivery device comprising an impermeable container, a semi-permeable membrane, an osmotic mechanism integrated into the container and adjoining the semi-permeable membrane, a piston adjoining the above osmotic mechanism; the above piston forms a movable seal with an inner surface of the container and divides the container into a first chamber comprising the osmotic mechanism, and a second chamber comprising a suspension formulation, and a diffusion adjustor. The suspension formulation contains a particle formulation containing exenatide particles having a diameter of less than 10 to 30 mcm. The delivery formulation contains a solvent specified in a group consisting of benzyl benzoate, lauryl lactate and lauryl alcohol, and polyvinylpyrrolidone polymer. The delivery formulation has a viscosity of approximately 10,000 poise to approximately 20,000 poise at 37°C. The continuous exenatide delivery in the therapeutic concentration is ensured for 5 days or less. The continuous exenatide delivery from the osmotic delivery device in a dose of exenaide of 10 mcg/day, 20 mcg/day, 30 mcg/day, 40 mcg/day, 60 mcg/day, and 80 mcg/day can be effected through at least three months.

EFFECT: method enables the effective treatment of the given pathology by the fast achievement and long maintenance of the exenatide concentration to be completed rapidly with no constant injections or oral administration.

15 cl, 20 tbl, 21 dwg, 4 ex

 

Cross-reference to related applications

[0001] the Present application claims priority on the basis of the provisional application for U.S. patent No. 61/277724, filed September 28, 2009, is currently in the review process, and provisional application for U.S. patent No. 61/358112, filed on 24 June 2010, is currently in the review process, the full contents of which are incorporated into this description by reference.

Area of technology

[0002] the Present invention relates to organic chemistry, chemistry of formulation preparation and chemistry of the peptides, pharmaceutical research and development. Aspects of the present invention include, but are not limited to, methods of treating a disease or condition in a subject in need of such treatment. In one embodiment, the implementation of the specified disease is a diabetes mellitus type 2.

The level of technology

[0003] there is a variety of dosage forms and routes of administration for drug delivery mammals, in particular, for drug delivery (see, e.g., Merck Manual of Diagnosis and Therapy, 18thedition, Published by Merck Sharp & Dohme Corp., Whitehouse Station, NJ). These dosage forms include, for example, use the following routes of administration: oral; injectable (e.g., votive�but intramuscularly, intrathecally, or subcutaneously); implantation (e.g., subcutaneously); and the introduction through the skin or mucous membranes (for example, sublingually, rectal, vaginal, intraocular, nasal, by inhalation into the lungs, topical or transdermal). Each route of administration has a specific purpose, advantages and disadvantages.

[0004] the Oral route of administration is the most common and generally considered the most convenient. However, oral administration imposes some constraints because of the drug, the input data path, are exposed to harsh conditions in the digestive system. When oral path cannot be used, may require other routes of administration.

[0005] When drugs are prepared for administration by injection (e.g., subcutaneous, intramuscular, intravenous or intrathecal), a medicament can be prepared in various ways, including lineups, prolonging the absorption of the drug from the injection site for hours, days or longer. Such compositions are typically used for subcutaneous injection. Products for injection, prepared in the form for the prolonged delivery, usually not administered as often as drugs for injection that has a more rapid absorption. �odbornoe injection is used for many protein or peptide drugs, since these medicines when taken orally, usually disintegrate in conditions of the digestive system in an inactive form. Subcutaneous administration of the drug, as a rule, requires frequent self-injections, such as injections one or more times a day, or once a week.

[0006] When a large amount of the medicinal product, intramuscular administration in General is the preferred route of administration. Generally intramuscular administration of medicines is carried out by injection into the muscle of the shoulder, hip or buttocks. The speed of absorption of the drug into the bloodstream largely depends on the blood supply of the muscles, i.e. the larger the circulation, the faster absorbed drug.

[0007] For intravenous administration of the drug requires that the needle was inserted directly into the vein. The drug can be administered in a single dose or by continuous infusion. For infusion of the drug solution is delivered either using gravity (for example, of a collapsible plastic bag), or by using an infusion pump via a tube inserted into a vein, usually in the forearm. Intravenous injection may be more difficult to introduce than, for example, subcutaneous and�and intramuscular injection, because it may be difficult the introduction of a needle or catheter into a vein, the drug typically needs to be mixed in a relatively short period of time prior to the introduction, there is an increased risk of infection (e.g., purulent infections at the injection site, caused by lack of hygiene and/or lack of proper aseptic technology), and over time there is a damage to the peripheral veins in the form of scarring.

[0008] When drugs are administered by intravenous injection, medical personnel often need to carefully observe the subjects to identify indications that the drug was effective and the medicine does not cause unwanted side effects. As a rule, the action of drugs injected intravenously lasts for shorter periods of time than drugs, introduced by subcutaneous injection or intramuscular injection. Therefore, some drugs must be administered by continuous infusion to provide appropriate therapeutic effect. Due to the difficulties associated with intravenous administration of drugs, it is most often used in hospitals or skilled care; it is rarely used for long-term treatment�th self-treatment.

[0009] a Number of difficulties negatively affect adherence to treatment by injection, including, by not limited to, the following complications. The subject may experience the fear of injections, which is especially problematic for the subject where the drug must be administered by injection for long periods of time. Adherence also may be complicated by the inconvenience of introducing the drug by injection, for example, when subjects are surrounded by people or busy daily activities. Also frequent self-introduction of the drug reminds the actors of the painful condition and causes psychological discomfort associated with the disease and/or treatment.

[0010] an Implantable osmotic device for drug delivery according to the present invention and the application of these osmotic delivery devices in the treatment of diseases or conditions in subjects in need of treatment, uniquely aimed at addressing unfulfilled needs related to previously described formulations and methods of treatment. For example, according to the present invention proposed the treatment of subjects with a target dose of the drug, which is continuously administered over time, with the ability t�STU quickly achieve and maintain for some time a substantial stable of the drug delivery while providing opportunities for the rapid termination of drug administration funds. To date, the introduction of medicines through injections, as a rule, could not provide the rapid achievement and long-term maintenance (e.g., three months or more) stable drug delivery, and even if it were possible, treatment with medicines, administered by injection (for example, medicines prepared in the form for the prolonged delivery), it was impossible to quickly stop. The present invention also provides an improved tolerability subjects of increasing doses of the drug compared with increasing the dose, carried out by introducing the drug by injection.

Brief description of the invention

[0011] the Present invention generally relates to improved methods of treatment of diseases or conditions in subjects in need of treatment, wherein said methods according to the present invention provide rapid achievement and/or fast termination of substantial steady delivery of the drug. In addition, the present invention relates to methods of increasing the dose of medicines that provide improved tolerability subjects of elevated levels of doses of the drug compared with increasing the dose standard.�AMI injection of the drug. Preferred subjects for methods according to the present invention represent the people.

[0012] In accordance with the first aspect of the present invention relates to methods of treatment of diabetes mellitus type 2 in a subject in need of treatment. The method comprises providing a continuous delivery of mimetica of incretin from the osmotic delivery device, wherein substantial steady delivery of mimetica of incretin in therapeutic concentrations is achieved within a time period of approximately 7 days or less after implantation of the specified osmotic delivery device to a subject. Significant stable delivery of mimetica of incretin from the osmotic delivery device, as a rule, is continuous for a period of at least about 3 months. In some embodiments, implementation of the present invention a substantial stable delivery of mimetica of incretin in therapeutic concentrations achieved after implantation of the osmotic delivery device to a subject during a time period selected from the group consisting of about 5 days or less, about 4 days or less, about 3 days or less, about 2 days or less, or about 1 day or less.

[0013] a Significant stable delivery of mimetica of incretin from OSMO�quarter delivery device is continuous over the period of the introduction, constituting, for example, from at least about 3 months to about a year, from at least about 4 months to about a year, from at least about 5 months to about a year, from at least about 6 months to about a year, from at least about 8 months to about a year or from at least about 9 months to about a year.

[0014] the Proposed method may additionally include providing a significant reduction of glucose concentration in the blood plasma of a subject on an empty stomach after implantation of the osmotic delivery device to a subject, compared to the concentration of glucose in the blood plasma of a subject on an empty stomach prior to implantation of the osmotic delivery device. This decrease, as a rule, reach within, for example, about 7 days or less, about 6 days or less, about 5 days or less, about 4 days or less, about 3 days or less, about 2 days or less, or about 1 day or less. Usually a significant decrease in plasma glucose blood glucose is maintained during the period of administration.

[0015] the proposed method may additionally include the possibility of termination of continuous delivery of mimetica of incretin so that the concentration of mimetica of incretin becomes essentially netdetective in the blood sample of the subject for about 6 period�in half-life or less, about 5 half-lives or less, about 4 half-lives or less, or about 3 half-lives or less of mimetica of incretin after termination of continuous delivery. In the case when exenatide (exenatide) is a mimetic of incretin, the method may also include the possibility of termination of continuous delivery so that the concentration èksenatida becomes essentially netdetective in the blood sample of the subject after termination of continuous delivery through the number of hours, selected from the group consisting of less than about 72 hours, less than about 48 hours, less than about 24 and less than about 12 hours. In one embodiment, the implementation of the cessation of continuous delivery is carried out by extracting the osmotic delivery device from the subject. A mimetic of incretin detects, for example, by radioimmunoassay.

[0016] the Osmotic delivery device for use in the methods according to the present invention may contain the components described in this application, including, but not limited to, a reservoir, a semi-permeable membrane, osmotic mechanism, the piston, the composition in the form of a suspension and a diffusion controller.

[0017] the Compositions in the form of a slurry for use in the present invention usually contain the composition in the form of particles containing a mimetic of incretin,and the composition of the carrier. Examples of mimetics incretin suitable for implementing the present invention, include, but are not limited to, peptides èksenatida, analogues of peptides èksenatida derived peptides èksenatida, peptides GLP-1, analogs of the peptides GLP-1 or derived peptides GLP-1. Examples of preferred mimetics incretin suitable for implementing the present invention, include exenatide containing the amino acid sequence of Bloomington: Indiana-4, licesence (lixisenatide), GLP-1 (7-36), liraglutide (liraglutide), albiglutide (albiglutide) and taspoglutide (taspoglutide). In some embodiments, the implementation of the composition-the media contains a solvent (e.g., benzyl, laurolactam and/or lauryl alcohol) and a polymer (e.g., polyvinylpyrrolidone).

[0018] In some embodiments, implementation of the present invention for continuous delivery provides the subject a dose of èksenatida in µg/day, selected from the group consisting of about 10 mcg/day; about 20 mcg/day, about 30 mcg/day; about 40 mcg/day, about 60 mg/day and about 80 mg/day.

[0019] In another embodiment of the present invention, the proposed method additionally includes the first period of continuous introduction of mimetica of incretin the first dose in mcg/day followed by a second period of continuous injection, resulting in an increased dose of mimetica of incretin doctoral dose ág/day, wherein said second dose in mcg/day more than the first dose ág/day. The first dose in mcg/day deliver, for example, by first osmotic delivery device, and a second dose in mcg/day delivered by a second osmotic delivery device, and delivery of mimetica of incretin from at least the first or second osmotic delivery device is continuous for a period of at least about 3 months. In one embodiment, the implementation of the second dose ág/day at least twice the first dose in mg/day. The method may further include at least one period of continuous injection, resulting in an increased dose of mimetica of incretin up to a higher dose ág/day, compared to the second dose in mg/day.

[0020] Typical dose for èksenatida are as follows: about 10 mcg/day followed about 20 mcg/day; about 10 mcg/day followed about 40 mcg/day; about 10 mcg/day followed about 60 mcg/day; about 10 mcg/day followed about 80 mcg/day; about 20 mcg/day followed about 40 mcg/day; about 20 mcg/day followed about 60 mcg/day; about 20 mcg/day followed about 80 mcg/day; about 40 mcg/day followed�mi about 60 mcg/day; about 40 mcg/day followed about 80 mcg/day; or about 60 mcg/day followed about 80 mcg/day.

[0021] In accordance with a second aspect of the present invention relates to a method of treating a disease or condition in a subject in need of treatment. This method usually involves providing continuous delivery of the drug from the osmotic delivery device, wherein substantial steady delivery of the specified drugs in therapeutic concentrations is achieved within a time period of approximately 7 days or less after implantation of the specified osmotic delivery device to a subject. Significant stable delivery of the drug from the osmotic delivery device, as a rule, is continuous for a period of at least about 3 months, this drug has a half-life. In one embodiment, the implementation of this method includes a condition that the specified disease or condition is a cancer of the prostate.

[0022] the method may further include the possibility of termination of continuous delivery so that the concentration of the drug becomes essentially netdetective in the blood sample in tech�of about 6 half-lives or less, about 5 half-lives or less, about 4 half-lives or less, or about 3 half-lives or less of the drug after termination of continuous delivery. In one embodiment, the implementation of the cessation of continuous delivery is carried out by extracting the osmotic delivery device from the subject. The drug detects, for example, by radioimmunoassay or chromatography.

[0023] In another embodiment of the present invention the method additionally includes the first period of continuous administration of the drug in the first dose/day, followed by a second period of continuous injection, resulting in an increased dose of the medication until the second dose/day, wherein said second dose/day more than the first dose/day. The first dose/day deliver, for example, by first osmotic delivery device, and the second dose/day delivered by a second osmotic delivery device, and the delivery of the drug from at least the first or second osmotic delivery device is continuous for a period of at least about 3 months. The method may further include at least one period of continuous BB�Denia, providing an increase in the dose of the medication to a higher dose/day, compared with the second dose/day.

[0024] the Osmotic delivery device for use in the methods according to the present invention may contain the components described in this document, including, but not limited to, a reservoir, a semi-permeable membrane, osmotic mechanism, a piston, a medicinal composition or the composition in the form of a slurry and a diffusion controller. Drug formulations usually contain the drug and the composition of the carrier.

[0025] the Compositions in the form of a slurry for use in the present invention usually contain the composition in the form of particles containing a medicament, and a composition of the carrier. In some embodiments, the implementation of the specified drug is a polypeptide, e.g., a recombinant antibody, an antibody fragment, a humanized antibody, single-chain antibody, monoclonal antibody, avimer (avimer), human growth hormone, epidermal growth factor, fibroblast growth factor, platelet derived growth factor, transforming growth factor, nerve growth factor, a cytokine or an interferon. In some embodiments, the implementation of the composition-the media contains a solvent (e.g., benzyl, laurolactam and/or lauryl alcohol) and a polymer (e.g. gender�vinylpyrrolidone).

[0026] These and other embodiments of the present invention will be obvious to a person skilled in the art given the descriptions given in this application.

Brief description of the drawings

[0027] Fig.1 presents results of a randomized, open-29-day study of continuous subcutaneous delivery èksenatida with the use of osmotic delivery device. This figure shows the concentration of glucose in the blood plasma on an empty stomach depending on time within 28 days of treatment. In this figure the vertical axis represents the Average glucose concentration in the blood plasma of fasting (mg/DL), and the horizontal axis represents Days of treatment. Shaded circles indicate the base point for the osmotic device for delivering 10 mcg/day. The shaded triangles indicate the base point for the osmotic device for delivering 20 mcg/day. The shaded rhombuses show the base point for the osmotic device that delivers 40 mcg/day. The shaded squares show the base point for the osmotic device that delivers 80 mcg/day.

[0028] Fig.2 shows results of a randomized, open-29-day study of continuous subcutaneous delivery èksenatida with the use of osmotic delivery device. At this shape PR�dstanley pharmacokinetic data associated with concentration èksenatida of glucose in blood plasma depending on time within 28 days of treatment, ending on day 29, and 7 days after extraction. In this figure the vertical axis represents the Concentration èksenatida (PG/ml), and the horizontal axis represents Time (days). The shaded rhombuses show the base point for the osmotic device for delivering 10 mcg/day. The shaded squares show the base point for the osmotic device for delivering 20 mcg/day. The shaded triangles indicate the base point for the osmotic device that delivers 40 mcg/day. "X" indicate the base point for the osmotic device that delivers 80 mcg/day. On day 29, the extraction of the osmotic delivery device and a concomitant decrease in the concentration of èksenatida in plasma indicated by the vertical arrow.

[0029] Fig.3 presents data from a randomized, open-29-day study of continuous subcutaneous delivery èksenatida with the use of osmotic delivery device. This figure shows the manifestation of nausea, depending on the time of individual subjects osmotic device for delivering 10 mcg/day, 20 mcg/day 40 mcg/day 80 mcg/day. The vertical axis represents the Number of patients (sub�projects), nauseous, the horizontal axis for each of the delivered concentration èksenatida presented in Weeks. The degree of sickness is shown below figure in the form of absence of nausea (marks without hatching), mild nausea (vertical line), mild nausea (horizontal line) and severe nausea (hatch in the cell).

[0030] Fig.4 is a partial view in cross section of one of the variants of the osmotic delivery device suitable to implement the present invention.

[0031] Fig.5 presents an overview of the design of clinical studies in phase 2. In this figure the upper line shows the timeline of the study Phase 2 (12 weeks) and 12-Adelino extended phase. Extended phase represents weeks 13-24, and the group was randomizable 1:1 for continuous delivery èksenatida, as shown the figure. Group 3, exenatide, administered by injection, is the second line. The splitting of the line indicates the randomization group and the transition to continuous delivery in the amount of 40 mcg/day and 60 mcg/day. Group 1, exenatide, administered with the use of osmotic delivery device for the continuous delivery of 20 mcg/day, represents the third line. The splitting of the line indicates the randomization group to continue 20 mg/day or increased to a value� dose equal to 60 mg/day. Group 2, exenatide, administered with the use of osmotic delivery device for continuous delivery in the amount of 40 µg/day, represents the fourth line. The splitting of the line indicates the randomization group to continue 40 mg/day or increased to a high dose, equal to 80 mg/day.

[0032] Fig.6 presents data on the incidence of nausea over time for the treatment by continuous delivery èksenatida (Groups 1 and 2) compared with treatment by injection èksenatida twice a day (Group 3). The vertical axis represents the Number of cases of sickness per week (%), and the horizontal axis represents the time of treatment in Weeks. In this figure, Group 1, treatment by continuous delivery of 20 mcg/day èksenatida, represented by diamonds; Group 2, treatment by continuous delivery 40 mg/day èksenatida, represented by squares; and Group 3, treatment by injection of 5 µg twice a day (injection twice a day) for 4 weeks (arrow shows approximately the start time point) followed by 10 mcg twice a day for 8 weeks (arrow shows approximately the start time point), represented by triangles.

[0033] Fig.7 presents data demonstrating the percentage change relative to baseline in the overall assessment of the Ka�society of life (QOL) in week 8. In this figure the numbers above the columns in the histogram indicate the following: n improved QOL indicator/n with stable QOL indicator/n with reduced QOL index, respectively; for Group 3, 36/0/15; for Group 1, 35/3/9; and for Group 2, 40/1/7. The vertical axis represents the Change relative to baseline in rates (%; the overall QOL index). The group is located at the horizontal axis and the size of the groups listed under each group: Group 3, n=51; Group 1, n=47; Group 2, n=48.

[0034] Fig.8 presents the data analysis of QOL using Pascal held in week 8. The vertical axis represents the Change relative to baseline indicators in percent for each of the four Pascal QOL: Health, Medical care, lifestyle and Convenience. These four podskalny QOL are located on the horizontal axis. In this figure each column of the graph indicated by the Group number. Within each podskalny columns of the graph are arranged in the following order: Group 3, Group 1 and Group 2.

[0035] Fig.9 presents an overview of the extended phase for subject status at week 20. At this shape continuous delivery èksenatida at the indicated doses marked "CD". The size of the groups represented by a number of dose extended phase. In the extended phase for weeks 13-24 of subjects from each treatment group randomizer�Ali to obtain continuous delivery èksenatida 20, 40, 60 or 80 mcg/day. In this figure, Group 1 represents treatment by continuous delivery of 20 mcg/day èksenatida within the first 12 weeks; Group 2 represents treatment by continuous delivery 40 mg/day èksenatida within the first 12 weeks; and Group 3 represents treatment by injection of 5 µg twice a day (twice a day) for 4 weeks followed by 10 mcg twice a day for 8 weeks during the first 12 weeks. The splitting of the group means the randomization groups at week 12, and the squares show the dose to increase the dose after 12 weeks. The number in each group at week 20 marked "n".

[0036] Fig.10 presents data extended phase (weeks 13-24) on the incidence of nausea over time. The first point (-1 Week) shows the number of cases of nausea a week before randomization and start of treatment Protocol extended phase. The vertical axis represents the Number of cases of sickness per week percentage (%), and the horizontal axis represents the time of treatment in Weeks. At this shape continuous data delivery using implantable osmotic device that delivers 20 mcg/day èksenatida, represented as shaded triangles; data continuous delivery with the use of an implantable osmotic device that delivers 20 mcg/day� èksenatida, while the subjects were then included in an extended phase for continuous delivery with the use of an implantable osmotic device that delivers 60 mg/day èksenatida represented as squares; and data for injection twice a day èksenatida, with subjects included in an extended phase for continuous delivery with the use of an implantable osmotic device that delivers 60 mg/day èksenatida, represented as shaded circles.

[0037] Fig.11 shows data extended phase, showing the percentage change relative to baseline in the overall assessment of QOL at week 20. On this figure the number in each histogram bar indicate which week (8 week or 20 week) evaluated QOL. The group is located at the horizontal axis to the left as follows: Group 3 (8 week), translated into continuous delivery èksenatida in the amount of 40 mg/day (40 µg CD/day); and Group 3 (8 week), translated into continuous delivery èksenatida in the amount of 60 µg/day (CD 60 mg/day). The vertical axis represents the % Change relative to baseline on overall QOL.

[0038] Fig.12 presents additional data extended phase, showing the percentage change relative to baseline in the overall assessment of QOL at week 20. On this Fig�re numbers in each column of the histogram to indicate which week (8 week or 20 week) evaluated QOL. The group is located at the horizontal axis to the left as follows: Group 1 (8 weeks), translated into continuous delivery èksenatida in the amount of 60 µg/day (CD 60 mg/day); and Group 2 (8 weeks), translated into continuous delivery èksenatida in the amount of 80 mcg/day (CD 80 mcg/day). The vertical axis represents the % Change relative to baseline on overall QOL.

[0039] Fig.13 presents a competitive profile among subjects with a background treatment of Metformin (metformin) in combination with many types of treatment of diabetes mellitus type 2. The vertical axis represents the % HbA1c. These types of treatment shown on the horizontal axis as follows: exenatide, administered by injection twice a day (Treatment A); exenatide, administered by injection once a week (Treatment B); liraglutide administered by injection once a day (Treatment C); taspoglutide, administered by injection once a week (Treatment D); and treatment using the methods and osmotic delivery devices according to the present invention for continuous delivery of èksenatida 20 mcg/day and 60 mcg/day (Treatment E). The number inside and at the top of the column histogram with vertical lines associated with each treatment, shows the source of % HbA1c (e.g., Treatment A, and 8.2). The number inside and in ver�parts of the histogram bars with diagonal lines, associated with each treatment, shows end % HbA1c for the study (e.g., Treatment A, 7,4). The number inside and closer to the horizontal axis of the histogram bars with diagonal lines associated with each treatment, shows the change in HbA1c for the study (e.g., Treatment, and 0.8).

[0040] Fig.14 presents a competitive profile among subjects with background Metformin treatment only in combination with many types of treatment of diabetes mellitus type 2. The vertical axis represents the %1. These types of treatment shown on the horizontal axis as follows: treatment with sitagliptin (sitagliptin) (Treatment F); and treatment with the use of pioglitazone (pioglitazone) (Treatment G); exenatide, administered by injection once a week (Treatment); treatment using the methods and osmotic delivery devices according to the present invention for continuous delivery of èksenatida 20 mcg/day and 60 mcg/day (Treatment E). The number inside and at the top of the column histogram with vertical lines associated with each treatment, shows the source of % HbA1c (e.g., Treatment F, 8,5). The number inside and in the upper part of the histogram bars with diagonal lines associated with each treatment, shows end % HbA1c for the study (e.g., Treatment F, and 7.6). The number inside and closer to the horizontal axis of the column GIS�of Grammy with diagonal lines, associated with each treatment, shows the change in HbA1c for the study (e.g., Treatment F, -0,9).

[0041] Fig.15 presents a competitive profile among subjects with background Metformin treatment only in combination either with continuous delivery of èksenatida or injection èksenatida once a week. The vertical axis represents the % HbA1c. These types of treatment shown towards the top of the figure as follows: treatment using the methods and osmotic delivery devices according to the present invention for continuous delivery of èksenatida 20 mcg/day and 60 mcg/day (Treatment E), which includes the first three columns of the histogram; and treatment with èksenatida, administered by injection once a week (Treatment B), which is separated by a frame surrounded by a dashed line. On the horizontal axis of the actors for the treatment of E divided into groups based on baseline HbA1c as follows: All subjects; Baseline HbA1c greater than about 7.0; and Baseline HbA1c greater than or equal to 7.5. The number inside and at the top of the column histogram with vertical lines associated with each treatment, shows the source of % HbA1c (for example, Treatment In, or 8.6). The percentage marked with an asterisk inside the column of the histogram with vertical lines associated with each treatment, shows the percentage of subjects, dost�GSA HbA1c, equal to 7% or less (for example, Treatment In, 58%*). The number inside and in the upper part of the histogram bars with diagonal lines associated with each treatment, shows end % HbA1c for the study (e.g., Treatment and 7.1). The number inside and closer to the horizontal axis of the histogram bars with diagonal lines associated with each treatment, shows the change in HbA1c for the study (e.g., Treatment In, -1,5).

[0042] In Fig.16 presents a competitive profile among subjects with background Metformin treatment only in combination either with continuous delivery of èksenatida or injection èksenatida once a week, with source levels were normalized. The vertical axis represents the % HbA1c. These types of treatment shown towards the top of the figure as follows: treatment using èksenatida, administered by injection once a week (Treatment B); and treatment using the methods and osmotic delivery devices according to the present invention for continuous delivery of èksenatida 20 mcg/day and 60 mcg/day (Treatment E). This figure is divided vertically into two regions as follows: on the left side and labeled on the horizontal axis is data for subjects with baseline HbA1c less than 9,0; and on the right side and labeled on the horizontal axis ol�entered data for subjects with baseline HbA1c greater than or equal to 9.0. The asterisk after "Subjects with baseline HbA1c≥9,0*" indicates that approximately one third of subjects in the Treatment had baseline HbA1c greater than or equal to 9.0; but only one subject of Treatment E had a baseline HbA1c greater than or equal to 9.0. The number inside and at the top of the column histogram with vertical lines associated with each treatment, shows the source of % HbA1c (for example, Treatment In, left the area, and 7.8). The number inside and in the upper part of the histogram bars with diagonal lines associated with each treatment, shows end % HbA1c for the study (e.g., Treatment In, left pane, 6,7). The number inside and closer to the horizontal axis of the histogram bars with diagonal lines associated with each treatment, shows the change in HbA1c for the study (e.g., Treatment In, left pane, -1,1).

[0043] Fig.17 presents a competitive profile among subjects with background Metformin treatment only in combination either with continuous delivery of èksenatida or sitagliptin. The vertical axis represents the % HbA1c. These types of treatment shown towards the top of the figure as follows: treatment using the methods and osmotic delivery devices according to the present invention for continuous delivery of èksenatida 20 mcg/day and 60 mcg/day (Treatment E), which includes the first three GRU�PY column of the histogram; and treatment with sitagliptin (Treatment F), which is separated by a frame surrounded by a dashed line. On the horizontal axis of the actors for the treatment of E divided into groups based on baseline HbA1c as follows: All subjects; Baseline HbA1c greater than about 7.0; and Baseline HbA1c greater than or equal to 7.5. The number inside and at the top of the column histogram with vertical lines associated with each treatment, shows the source of % HbA1c (e.g., Treatment F, 8,5). The percentage marked with an asterisk inside the column of the histogram with vertical lines associated with each treatment, shows the percentage of subjects who reached HbA1c to 7% or less (e.g., Treatment F, 31%*). The number inside and in the upper part of the histogram bars with diagonal lines associated with each treatment, shows end % HbA1c for the study (e.g., Treatment F, and 7.6). The number inside and closer to the horizontal axis of the histogram bars with diagonal lines associated with each treatment, shows the change in HbA1c for the study (e.g., Treatment F, -0,9).

[0044] Fig.18 presents a competitive profile among subjects with background Metformin treatment only in combination either with continuous delivery of èksenatida or sitagliptin, with source levels were normalized. The vertical axis represents the % HbA1c. These types of treatment is shown in direction�attachment to the upper part of the figure as follows: treatment with sitagliptin (Treatment F); and treatment using the methods and osmotic delivery devices according to the present invention for continuous delivery of èksenatida 20 mcg/day and 60 mcg/day (Treatment E). This figure is divided vertically into two regions as follows: on the left side and labeled on the horizontal axis is data for subjects with baseline HbA1c less than 9,0; and on the right side and labeled on the horizontal axis is data for subjects with baseline HbA1c greater than or equal to 9.0. The asterisk after "Subjects with baseline HbA1c≥9,0*" indicates that approximately one third of subjects in the Treatment F had a baseline HbA1c greater than or equal to 9.0; only one subject of Treatment E had a baseline HbA1c greater than or equal to 9.0. The number inside and at the top of the column histogram with vertical lines associated with each treatment, shows the source of % HbA1c (e.g., Treatment F, the left area of 7.7). The number inside and in the upper part of the histogram bars with diagonal lines associated with each treatment, shows end % HbA1c for the study (e.g., Treatment F, the left area of 7.2). The number of B1 inside and closer to the horizontal axis of the histogram bars with diagonal lines associated with each treatment, shows the change in HbA1c for the study (e.g., Treatment F, the left pane, -0,5).

[0045] Fig.19 shows competition�entry profile among subjects with background Metformin treatment only in combination either with continuous delivery of èksenatida, or with pioglitazone. The vertical axis represents the % HbA1c. These types of treatment shown towards the top of the figure as follows: treatment using the methods and osmotic delivery devices according to the present invention for continuous delivery of èksenatida 20 mcg/day and 60 mcg/day (Treatment E), which includes the first three columns of the histogram; and treatment with the use of pioglitazone (Treatment G), which is separated by a frame surrounded by a dashed line. On the horizontal axis of the actors for the treatment of E divided into groups based on baseline HbA1c as follows: All subjects; Baseline HbA1c greater than about 7.0; and Baseline HbA1c greater than or equal to 7.5. The number inside and in the upper part of a continuous column of the histogram associated with each treatment, shows the source of % HbA1c (e.g., Treatment G, 8,5). The percentage marked with an asterisk inside the column of the histogram with vertical lines associated with each treatment, shows the percentage of subjects who reached HbA1c to 7% or less (e.g., Treatment G, 43%*). The number inside and in the upper part of the histogram bars with diagonal lines associated with each treatment, shows end % HbA1c for the study (e.g., Treatment G, 7,3). The number inside and closer to the horizontal axis of the histogram bars with diagonal lines associated with each Leche�education, shows the change in HbA1c for the study (e.g., Treatment G, -1,2).

[0046] In Fig.20 presents a competitive profile among subjects with background Metformin treatment only in combination either with continuous delivery of èksenatida or pioglitazone, with source levels were normalized. The vertical axis represents the % HbA1c. These types of treatment shown towards the top of the figure as follows: treatment using pioglitazone (Treatment G); and treatment using the methods and osmotic delivery devices according to the present invention for continuous delivery of èksenatida 20 mcg/day and 60 mcg/day (Treatment E). This figure is divided vertically into two regions as follows: on the left side and labeled on the horizontal axis is data for subjects with baseline HbA1c less than 9,0; and on the right side and labeled on the horizontal axis is data for subjects with baseline HbA1c greater than or equal to 9.0. The asterisk after "Subjects with baseline HbA1c≥9,0*" indicates that approximately one third of subjects in the Treatment G had a baseline HbA1c greater than or equal to 9.0; but only one subject of Treatment E had a baseline HbA1c greater than or equal to 9.0. The number inside and at the top of the column histogram with vertical lines associated with each treatment, shows and�initial % HbA1c (e.g., Treatment G, the left pane, and 7.8). The number inside and in the upper part of the histogram bars with diagonal lines associated with each treatment, shows end % HbA1c for the study (e.g., Treatment G, the left pane, 6,9). The number inside and closer to the horizontal axis of the histogram bars with diagonal lines associated with each treatment, shows the change in HbA1c for the study (e.g., Treatment G, the left pane, -0,9).

[0047] In Fig.21 presents a comparison of weight loss among the subjects with background Metformin treatment only in combination with many types of treatment of diabetes mellitus type 2. The vertical axis represents the % of weight Loss. These types of treatment shown on the horizontal axis as follows: treatment using pioglitazone (Treatment G); treatment with sitagliptin (Treatment F); exenatide, administered by injection once a week (Treatment B); and treatment using the methods and osmotic delivery devices according to the present invention for continuous delivery of èksenatida 20 mcg/day and 60 mcg/day (Treatment E). The number inside the column of the histogram associated with each treatment, shows an increase or loss of weight during the study (e.g., Treatment G,+2.8 kg).

Detailed description of the invention

[0048] the Content of all patents, publications and forms�to patent herein, are incorporated in this application by reference as if each individual patent, publication, or patent application was specifically included fully separately for all purposes.

1.0.0 Definition

[0049] it Should be understood that the terminology used in this application are only for the purpose of describing the implementation details and is not limiting. In this description and the attached claims, the singular form include many objects, unless the context explicitly States otherwise. Thus, for example, reference to "a solvent" includes a combination of two or more such solvents, reference to "a peptide" includes one or more peptides or mixtures of peptides, reference to "a drug" includes one or more drugs, reference to "an osmotic device" includes one or more osmotic devices, etc.

[0050] If not defined otherwise, all technical and scientific terms used in this description have the same meaning as that usually understood by the expert in the field of the present invention. Despite the fact that in the implementation of the present invention can use other methods and materials similar or equivalent to those in astashevskiy, here is described the preferred materials and methods.

[0051] In the description and preparation of claims, will be used the following terminology in accordance with the definitions given below.

[0052] the Terms "drug", "therapeutic agent" and "beneficial agent" are used interchangeably and refer to any therapeutically active substance which is delivered to a subject to provide the desired beneficial effect. In one variant of implementation of the present invention the medicament is a polypeptide. In another embodiment of the invention implementation of the present invention, the drug is a small molecule, for example, hormones such as androgens or estrogens. Devices and methods according to the present invention are well suited for the delivery of proteins, small molecules, and combinations thereof.

[0053] In the present description, the terms "peptide", "polypeptide" and "protein" are used interchangeably and generally refer to a molecule containing a chain of two or more amino acids (for example, mostly L-amino acids, but also including, for example, D-amino acids, modified amino acids, analogues amino acids and/or amino acid mimetic). The peptides may be naturally occurring, synthesized or expressed recombinant methods. �eptide may also contain additional groups, modifying the amino acid chain, for example, a functional group that is attached through posttranslational modifications. Examples of post-translational modifications include, but are not limited to, acetylation, alkylation (including methylation), biotinylation, glutaminovaya, pilleriana, glycosylation, isoprenylation, liparitovna, phosphopantetheine, phosphorylation, selenitovyj and C-terminal amidation. The term "peptide" also includes peptides containing modifications of aminocore and/or carboxylic. Modifications of the terminal amino group include, but are not limited to, detainee modification, modification with the formation of N-lower alkyl, N-di-lower-alkyl and N-acyl. Modifications endnote carboxypropyl include, but are not limited to, modification with the formation of amide, lower alkylamide, dialkylamide and lower alkylamine (for example, where lower alkyl is a C1-C4alkyl). The term "peptide" also includes modifications such as described above, but not limited to, amino acids located between amino - and carboxybenzene. In one embodiment, the implementation of a peptide can be modified by attaching small molecule drugs.

[0054] the terminal amino acid at one end of the peptide chain, as a rule, sod�RIT free amino group (i.e., aminocore). Limit the amino acid at the other end of this circuit usually contains a free carboxyl group (i.e. carboxysomes). Typically, the amino acids constituting the peptide are numbered in order, starting with aminocore and increasing in the direction of carboxylic peptide.

[0055] In the present description, the term "amino acid residue" refers to amino acids included in the peptide through an amide bond or mimetica amide bond.

[0056] In the present description, the term "mimetics incretin" includes, but is not limited to, glucagon-like peptide 1 (GLP-1) and its peptide derivatives and peptide analogs; and exenatide, as well as its peptide derivatives and peptide analogs. Look incretin also known in the literature as "the insulinotropic peptide or receptor agonists GLP-1".

[0057] In the present description, the term "insulinotropic" as a rule, refers to the ability of a compound, such as a peptide to stimulate or influence the production and/or insulin activity (e.g., insulinotropic hormone). These compounds, generally, stimulate the secretion or biosynthesis of insulin in a subject.

[0058] In the present description, the term "carrier" refers to a medium used for the conclusion in connection, for example, medicines. The media according to the present invention,as a rule, contain components such as polymers and solvents. The medium in the form of a suspension according to the present invention, generally contain solvents and polymers, which are used to prepare compositions in the form of a suspension, optionally containing pharmaceutical compositions in the form of particles.

[0059] In the present description, the term "phase separation" refers to the formation of several phases (e.g., liquid or gel phase) to a carrier in the form of a suspension, such as when the contact carrier in the form of a slurry with the aqueous medium. In some embodiments, the implementation of the present invention, the carrier in the form of suspension include the composition for the existence of phase separation upon contact with an aqueous medium containing less than about 10% water.

[0060] In the present description, the term "single phase" refers to solid, semi-solid or liquid homogeneous system, which is fully physically and chemically homogeneous.

[0061] In the present description, the term "dispersed" refers to the dissolution, dispersion, suspendirovanie or another distribution of compounds, for example, a medicinal composition in the form of particles in a carrier in the form of a suspension.

[0062] In the present description, the term "chemically stable" refers to education as part of the allowed percentage of degradation products produced during a certain time period chem�ical ways, such as desametasone (usually by hydrolysis), aggregation or oxidation.

[0063] In the present description, the term "physically stable" refers to education as part of the allowed percentage of aggregates (e.g., dimers and other products with higher molecular weight). In addition, physically stable composition does not change its physical state, such as from a liquid to a solid substance or from amorphous to crystalline form.

[0064] In the present description, the term "viscosity" as a rule, refers to the value determined from the ratio of shear stress to shear rate (see, e.g., Considine, D. M. &Considine, G. D., Encyclopedia of Chemistry, 4th Edition, Van Nostrand, Reinhold, NY, 1984) essentially as follows:

[0065] F/A=μ*V/L (Equation 1)

where F/A=shear stress (force per unit area),

µ=constant of proportionality (viscosity), and

V/L=the velocity in the layer thickness (shear rate).

[0066] From this relation, the ratio of shear stress to shear rate determines the viscosity. Measurements of shear stress and shear rate, as a rule, is carried out using reometry with parallel plates is performed in the selected conditions (e.g., temperature of about 37°C). Other methods of determining the viscosity include measurement of kinematic viscosity using viscometer, for example, viscose�meter cannon-Fenske (Cannon-Fenske), viscometer Ubbelohde (Ubbelohde) for opaque mortar cannon-Fenske or Ostwald viscometer. In General, the medium in the form of a suspension according to the present invention have a viscosity sufficient to prevent deposition of the composition in the form of particles suspended in them during storage and use in the method of delivery, for example, in an implantable device of the drug delivery.

[0067] In the present description, the term "non-aqueous" refers to the total moisture content, for example, the composition in the form of suspension, normally less than or equal to about 10 wt.%, preferably, less than or equal to about 7 wt.%, more preferably, less than or equal to about 5 wt.% and, more preferably, less than about 4 wt.%.

[0068] In the present description, the term "subject" refers to any member of the subtype of Chordates (Chordata), including, without limitation, humans and other primates, including apes, not the humans, such as rhesus and other monkeys, and chimpanzees, and other apes; farm animals such as cattle, sheep, pigs, goats and horses; domestic mammals such as dogs and cats; laboratory animals including rodents such as mice, rats and Guinea pigs; birds, including domestic, wild and game birds such as chickens, turkeys and other� birds gallinaceous, ducks, geese, etc. This term does not indicate a specific age or gender. Thus, it includes both the adult and newborn individuals.

[0069] In the present description, the term "osmotic delivery device", usually refers to the device used to deliver drugs (e.g., mimetica of incretin) to a subject, wherein the specified device contains, for example, a reservoir (made, for example, of a titanium alloy) having a cavity containing a composition in the form of a suspension containing a drug (e.g., a mimetic of incretin), and the composition of the osmotic agent. A piston Assembly located in said cavity, isolates the composition in the form of suspension from the composition of the osmotic agent. Semi-permeable membrane is located on the first distal end of the reservoir adjacent the osmotic composition of the agent, and the diffusion controller (which contains the hole for delivery through which the composition is in the form of a slurry exits the device) is located at the second distal end of the reservoir adjacent to the composition in the form of suspension. Typically, the osmotic delivery device is implanted in the subject, for example, subcutaneously (e.g., in inner, outer or back of the shoulder; or in the abdomen). Typical osmotic delivery device is a delivery device DROS® (ALZA Corporation, Mountain View, CA).

[0070] In the present description, the term "continuous delivery", generally refers to essentially a continuous drug release from the osmotic delivery device. For example, the delivery device DUROS® releases the drug at a substantially predetermined speed based on the principle of osmosis. Extracellular fluid enters the device DUROS® through a semi-permeable membrane directly to the osmotic mechanism, which expands and moves the piston with a slow and consistent speed. The movement of the piston causes the medicinal composition to be released through the hole diffusion controller. Thus, drug release from osmotic delivery device occurs with a slow, controlled, consistent rate.

[0071] In the present description, the term "substantial stable delivery" usually refers to the delivery of the drug concentration in the target or close to it within a certain period of time, wherein the amount of drug delivered from an osmotic device is essentially a zero-order delivery. Substantial delivery of active agent (e.g., èksenatida) zero order means that the speed delivered by Lekarstvo�th means constant and does not depend on medicines available in the delivery system; for example, zero-order delivery if you build a graph of the speed of the delivered drug to the time to build a line, this line has an angle of inclination approximately equal to zero, as defined by standard methods (e.g., linear regression).

[0072] In the present description, the term "half-life of the drug" refers to how much time is required for the excretion of the drug from plasma to half of its concentration. The half-life of the drug is usually measured by monitoring the way breaks up the drug when it is administered by injection or intravenously. The drug is usually detected using, for example, radioimmunoassay method or chromatography.

2.0.0 General overview of the invention

[0073] Before a detailed description of the present invention it should be understood that the invention is not limited to specific types of devices for drug delivery, specific sources of medicines, specific solvents, polymers, etc., because the application of these elements can be selected in the light of the ideas of the present description. It should also be understood that the terminology among�aleema in the present description, is intended only to describe specific variants of implementation of the present invention and is not limiting.

[0074] according To the first aspect, the present invention relates to a method for the treatment of diabetes mellitus type 2 in a subject in need of treatment. The method comprises providing a continuous delivery of mimetica of incretin from the osmotic delivery device, wherein substantial steady delivery of the specified mimetica of incretin in therapeutic concentrations is achieved within a time period of approximately 7 days or less after implantation of the specified osmotic delivery device to a subject. Significant stable delivery of mimetica of incretin from the osmotic delivery device is continuous during the period of administration. People are the preferred entities for the implementation of the present invention. The present invention includes a mimetic of incretin (e.g., exenatide), and the osmotic device comprising a mimetic of incretin (e.g., exenatide), for use in methods of treatment of diabetes mellitus type 2 according to the present invention the subject in need of treatment.

[0075] In some embodiments, the implementation of the present invention, the period of the introduction is, for example, at least about 3 months�and, from at least about 3 months to about one year, from at least about 4 months to about one year, from at least about 5 months to about one year, from at least about 6 months to about one year, from at least about 8 months to about one year, from at least about 9 months to about one year, or from at least about 10 months to about one year.

[0076] In some embodiments, implementation of the present invention a substantial stable delivery of mimetica of incretin in therapeutic concentrations is achieved within about 5 days or less after implantation of the osmotic delivery device in the subject, within about 4 days or less after implantation of the osmotic delivery device in the subject, within about 3 days or less after implantation of the osmotic delivery device in the subject, within about 2 days or less after implantation of the osmotic delivery device to a subject, or within about 1 day or less after implantation of the osmotic delivery device to a subject. In preferred embodiments, the implementation of the present invention a substantial stable delivery of mimetica of incretin in therapeutic concentrations is achieved within about 2 days or less before�occhialino for about 1 day or less after implantation of the osmotic delivery device to a subject.

[0077] In other embodiments, implementation of the methods of treatment according to the present invention provide a significant reduction of glucose concentration in the blood plasma of a subject on an empty stomach after implantation of the osmotic delivery device to the subject (compared to the concentration of glucose in the blood plasma of a subject on an empty stomach prior to implantation of the osmotic delivery device), which is reached in about 7 days or less after implantation of the osmotic delivery device to a subject for about 6 days or less after implantation of the osmotic delivery device in the subject, within about 5 days or less after implantation of the osmotic delivery device to a subject, for about 4 days or less after implantation of the osmotic delivery device in the subject, within about 3 days or less after implantation of the osmotic delivery device in the subject, within about 2 days or less after implantation of the osmotic delivery device to a subject, or within about 1 day or less after implantation of the osmotic delivery device to a subject. In preferred embodiments, the implementation of the present invention indicated a significant decrease in the glucose concentration in the blood plasma of a subject on an empty stomach after implantation of the osmotic device, compared to a concentration of HL�goats in the blood plasma of a subject on an empty stomach prior to implantation, reach for about 2 days or less, preferably within about 1 day or less after implantation of the osmotic delivery device to a subject, or more preferably within about 1 day after implantation of the osmotic delivery device to a subject. A significant decrease in the glucose concentration in the blood plasma on an empty stomach, as a rule, is statistically significant, as shown by the use of an appropriate statistical test, doctor or deemed significant for the subject. A significant decrease in the glucose concentration in the blood plasma on an empty stomach compared to the original, usually retained during the period of administration.

[0078] In other embodiments, implementation of the first aspect of the present invention, the treatment methods further include the possibility of termination of continuous delivery of mimetica of incretin so that the concentration of mimetica of incretin becomes essentially netdetective in the blood sample of a subject within about 6 half-lives or less of mimetica of incretin after termination of continuous delivery, within about 5 half-lives or less of mimetica of incretin after termination of continuous delivery, within about 4 half-lives or less of mimetica of incretin after termination of continuous delivery, or within approx�RNO 3 half-lives or less of mimetica of incretin after termination of continuous delivery. Examples: the half-lives of mimetica of incretin: exenatide - approximately 2.5 hours, and GLP-1 - approximately 2 minutes. A mimetic of incretin can be detected, for example, by radioimmunoassay. Termination of continuous delivery may be effected, for example, by extracting the osmotic delivery device from the subject.

[0079] In the respective embodiments, the implementation of the present invention, the treatment methods further include the possibility of termination of continuous delivery èksenatida so that the concentration èksenatida becomes essentially netdetective in the blood sample of a subject using less than approximately 72 hours after termination of continuous delivery, using less than about 48 hours after termination of continuous delivery, using less than about 24 hours after termination of continuous delivery, using less than about 18 hours after termination of continuous delivery, using less than about 14 hours after termination of continuous delivery, using less than about 12 hours after termination of continuous delivery, using less than about 6 hours after termination of continuous delivery, or through less than about 4 hours after termination of continuous delivery. In preferred embodiments, the implementation of exenatide essentially redetection in the blood sample of a subject using less che� about 24 hours after termination of continuous delivery, using less than about 18 hours after termination of continuous delivery, or more preferably from less than about 14 hours after termination of continuous delivery.

[0080] In preferred embodiments, the implementation of the first aspect of the present invention, a mimetic of incretin includes peptide èksenatida, a peptide analogue of the specified peptide or peptide derivative of the indicated peptide; the peptide GLP-1 (e.g., a peptide GL-1(7-36)amide), a peptide analogue of the specified peptide or peptide derivative of the indicated peptide. Specific examples of preferred mimetics incretin appropriate in the implementation of the present invention include exenatide containing the amino acid sequence of Bloomington: Indiana-4, sixestate, GLP-1 (7-36), liraglutide, albiglutide and taspoglutide.

[0081] In some embodiments, the implementation of the first aspect of the present invention, in which a mimetic of incretin represents exenatide, continuous delivery can provide the subject a dose of èksenatida in µg/day, for example, of approximately 10 μg/day, about 20 μg/day, about 30 mcg/day; about 40 mcg/day, about 60 mg/day or about 80 mg/day.

[0082] In some embodiments, the implementation of the first aspect of the present invention, in which a mimetic of incretin exenatide is a method for the treatment Saharna� type 2 diabetes additionally includes the possibility of termination of continuous delivery, the concentration of èksenatida becomes essentially netdetective in the blood sample of the subject after termination of continuous delivery through, for example, less than about 72 hours, less than about 48 hours, less than about 24 hours or using less than about 12 hours.

[0083] In additional embodiments, the implementation of the first aspect of the present invention a method for the treatment of diabetes mellitus type 2 additionally includes the first period of continuous introduction of mimetica of incretin the first dose in mcg/day followed by a second period of continuous injection, resulting in an increased dose of mimetica of incretin to the second dose in mcg/day, wherein said second dose in mcg/day more than the first dose in mg/day. In some embodiments, the implementation of the first dose in mcg/day delivered via the first osmotic delivery device, and a second dose in mcg/day delivered by a second osmotic delivery device, and delivery of mimetica of incretin from at least the first or second osmotic delivery device is continuous for a period of at least about 3 months. In one embodiment, the implementation of the second dose in mcg/day at least twice the first dose ág/day. In addition, the method may include at least �to give you one continuous period of administration, providing increasing doses of mimetica of incretin to a higher dose in mcg/day, compared with the second dose ág/day. Increasing the dose may be effected, for example, by extracting the first osmotic device for the delivery and implantation of a second osmotic delivery device, or by implantation of a second or more osmotic delivery device, wherein the total dose delivered by the first and second osmotic delivery device, provides the necessary dose increase.

[0084] In a preferred embodiment of the present invention, including the increasing doses, a mimetic of incretin represents exenatide and the first dose in mcg/day followed by second dose in mcg/day for continuous delivery selected from the group consisting of: about 10 mcg/day followed about 20 mcg/day; about 10 mcg/day followed about 40 mcg/day; about 10 mcg/day followed about 60 mcg/day; about 10 mcg/day followed about 80 mcg/day; about 20 mcg/day followed about 40 mcg/day; about 20 mcg/day followed about 60 mcg/day; about 20 mcg/day followed about 80 mcg/day; about 40 mcg/day followed about 60 mcg/day; about 40 mcg/day followed about 80 mcg/day; etc�about 60 mcg/day followed about 80 mcg/day.

[0085] In accordance with a second aspect of the present invention relates to a method for the treatment of diabetes mellitus type 2 in a subject in need of treatment. The method comprises providing a continuous delivery of mimetica of incretin (e.g. èksenatida) of the implanted osmotic delivery device, wherein (i) a significant decrease in the glucose concentration in the blood plasma on an empty stomach reach after implantation of the osmotic device to a subject compared to the glucose concentration in the blood plasma on an empty stomach prior to implantation, for about 7 days after implantation of the osmotic delivery device to a subject, (ii) delivery of mimetica of incretin is uninterrupted during the period, and (iii) a significant decrease in the glucose concentration in the blood plasma on an empty stomach continues during this period. A significant decrease in the glucose concentration in the blood plasma on an empty stomach, as a rule, is statistically significant, as shown using an appropriate statistical test is considered significant for the subject on the doctor's decision.

[0086] In accordance with a third aspect of the present invention relates to a method for the treatment of diabetes mellitus type 2 in a subject in need of treatment, including the possibility of termination of continuous delivery of mimetica of incretin so that the concentration�I mimetica of incretin becomes essentially netdetective in the blood sample of a subject within about 6 half-lives or less of mimetica of incretin after termination of continuous delivery, within about 5 half-lives or less of mimetica of incretin after termination of continuous delivery, within about 4 half-lives or less of mimetica of incretin after termination of continuous delivery, or within about 3 half-lives or less of mimetica of incretin after termination of continuous delivery. Examples of half-lives of mimetica of incretin include exenatide, approximately 2.5 hours, and GLP-1, about 2 minutes.

[0087] In accordance with a fourth aspect of the present invention relates to a method for the treatment of diabetes mellitus type 2, including the first period of continuous introduction of mimetica of incretin the first dose in mcg/day followed by a second period of continuous injection, resulting in an increased dose of mimetica of incretin to the second dose in mcg/day, wherein said second dose ág/day over the first dose in mg/day. In some embodiments, the implementation of the first dose in mcg/day delivered via the first osmotic delivery device, and a second dose in mcg/day delivered by a second osmotic delivery device, and delivery of mimetica of incretin from at least the first or second osmotic delivery device is continuous for a period of at least about 3 months�CA. In one embodiment, the implementation of the second dose in mcg/day at least twice the first dose in mg/day. In addition, the method may include at least one additional period of continuous injection, resulting in an increased dose of mimetica of incretin up to a higher dose ág/day, compared with the second dose ág/day. Increasing the dose may be effected, for example, by extracting the first osmotic device for the delivery and implantation of a second osmotic delivery device, or by implantation of a second or more osmotic delivery device, wherein the total dose delivered by the first and second (or additional) of the osmotic delivery device, provides the necessary increase in dose. This aspect of the present invention (comprising numerous, successive periods of continuous introduction of increasing doses of mimetica of incretin) provides enhanced flexibility with respect to increasing doses of mimetica of incretin compared with increasing the dose based on injections of mimetica of incretin.

[0088] In embodiments, the implementation of all aspects of the present invention relating to methods of treatment of diabetes mellitus type 2, a typical osmotic delivery device contains the following: an impermeable reservoir containing EXT�internal and external surfaces, and first and second open ends; a semipermeable membrane that is installed with the seal relative to the first open end of the reservoir; an osmotic mechanism within the tank and adjacent to the semipermeable membrane; a piston adjacent to the specified osmotic mechanism, and the said piston forms a movable seal with the inner surface of the reservoir, wherein the piston divides the reservoir for the first chamber and the second chamber where the first chamber contains an osmotic mechanism; the composition in the form of a suspension, wherein the second chamber contains a composition in the form of a slurry and said composition is in the form of suspension is fluid and contains a mimetic of incretin; and a diffusion controller, built in the second open end of the tank, and the specified controller is adjacent to the diffusion of the composition in the form of suspension. In preferred embodiments, the implementation of the reservoir contains titanium or titanium alloy.

[0089] In embodiments, the implementation of all aspects of the present invention relating to methods of treatment of diabetes mellitus type 2, the compositions in the form of a slurry for use in these methods can include, for example, the composition in the form of particles containing a mimetic of incretin, and the composition of the carrier. Examples of mimetics incretin include, but are not limited to, a peptide èksenatida, a peptide analogue of the specified peptide or peptide production�the ne of the specified peptide; peptide GLP-1 peptide analogue of the specified peptide or peptide derivative of the indicated peptide. Specific examples of preferred mimetics incretin include exenatide containing the amino acid sequence of axendia-4, sixestate, GLP-1 (7-36), liraglutide, albiglutide and taspoglutide. The compositions of the carrier for application to obtain compositions in the form of a suspension according to the present invention can, for example, contain the solvent and the polymer. Examples of solvents include, but are not limited to, benzyl benzoate, laurinlactam, lauryl alcohol, or combinations thereof. An example of the polymer is polyvinylpyrrolidon. In a preferred embodiment the medium is in the form of a slurry essentially consists of one solvent and one polymer, for example, the solvent of benzyl benzoate and the polymer is polyvinylpyrrolidone.

[0090] the Reservoir of the osmotic delivery devices may, for example, contain titanium or titanium alloy.

[0091] In accordance with a fifth aspect of the present invention relates to a method of treating a disease or condition in a subject in need of treatment. The method comprises providing a continuous delivery of the drug from the osmotic delivery device, wherein substantial steady delivery of a specified drug in therapeutic to�ncentrated achieved within a time period approximately 7 days or less after implantation of the specified osmotic delivery device to a subject. Significant stable delivery of the drug from the osmotic delivery device is continuous for a period of at least about 3 months. The drug has a known or determined the half-life for a typical subject. People are the preferred entities to implement the present invention in practice. The present invention includes a drug effective to treat a disease or condition, as well as the osmotic device containing a specified medicament, for use in methods of treating a disease or condition according to the present invention the subject in need of treatment. The advantages of the present invention include reducing the toxicity of drugs related to peak concentrations, and a decrease in non-optimal drug therapy associated with minimal concentrations.

[0092] In some embodiments, the implementation of the present invention, the period of the introduction is, for example, at least about 3 months, at least about 3 months to about one year, from at least about 4 months before the example�about one year, from at least about 5 months to about one year, from at least about 6 months to about one year, from at least about 8 months to about one year, from at least about 9 months to about one year, or from at least about 10 months to about one year.

[0093] In one embodiment, the implementation of this aspect of the present invention a method of treating a disease or condition includes a condition that the specified disease or condition is a cancer of the prostate.

[0094] In some embodiments, the implementation of this aspect of the present invention a substantial stable delivery of the drug at therapeutic concentrations is achieved within a time period of approximately 7 days or less after implantation of the osmotic delivery device to a subject, about 5 days or less after implantation of the osmotic delivery device to a subject, about 4 days or less after implantation of the osmotic delivery device to a subject, about 3 days or less after implantation of the osmotic delivery device to a subject, about 2 days or less after implantation of the osmotic delivery device to a subject, or about 1 day or less after implantation of the osmotic delivery device to a subject.

[0095] In some embodiments, the implementation of this aspect of the present invention, the installation of a substantial stable of the drug delivery in therapeutic concentrations after implantation of the osmotic delivery device to a subject may take a longer period of time, for example, a period of approximately 2 weeks or less, or within about 6 half-lives of the drug in the subject after implantation of the device.

[0096] In other embodiments, implementation of the fifth aspect of the present invention methods of treating a disease or condition also includes the possibility of termination of continuous delivery of the drug so that the concentration of the drug becomes essentially netdetective in the blood sample of a subject within about 6 half-lives or less of the drug after termination of continuous delivery, within about 5 half-lives or less of the drug after termination of continuous delivery, within about 4 half-lives or less of the drug after termination of continuous delivery, or within about 3 half-lives or less of the drug after termination of continuous delivery. Some of primeramente half-life of medicines are as follows: exenatide - approximately 2.5 hours; GLP-1 is approximately 2 minutes; GIP - about 5 minutes; PYY - approximately 8 minutes; glucagon - approximately 6 minutes; acceptable - approximately 6 minutes; and GLP-2 - approximately 6 minutes. In the case when injected more than one drug, the possibility of ending the continuous delivery of more than one drug is such that more than one concentration of the drug becomes essentially netdetective in the blood sample of a subject within about 6 half-lives or less more than one drug with the longest half-life period, after termination of continuous delivery. Termination of continuous delivery may be effected, for example, by extracting the osmotic delivery device from the subject. In some embodiments, the implementation of the drug detected in the blood sample by radioimmunoassay or chromatography.

[0097] In preferred embodiments, the implementation of the fifth aspect of the present invention the specified drug includes the polypeptide, for example, chosen from the following: recombinant antibodies, fragments of antibodies, humanized antibodies, single-chain antibodies, monoclonal antibodies and aimery; human growth hormone, epidermal growth factor, the factor of rastapopoulos, platelet derived growth factor, transforming growth factor and nerve growth factor; cytokines and interferons. In other embodiments, the implementation of a drug comprises a small molecule.

[0098] In additional embodiments, the implementation of the fifth aspect of the present invention a method of treating a disease or condition further includes the first period of continuous administration of the drug in the first dose/day, followed by a second period of continuous injection, resulting in an increased dose of the medication until the second dose/day, wherein said second dose/day more than the first dose/day. In some embodiments, the implementation of the first dose/day delivered via the first osmotic delivery device, and the second dose/day delivered by a second osmotic delivery device, and the delivery of the drug from at least the first or second osmotic delivery device is continuous for a period of at least about 3 months. In one embodiment, the implementation of the second dose/day at least twice the first dose/day. In addition, the method may include at least one period of continuous injection, resulting in an increased dose of the medication to a higher dosushki, compared to the second dose/day. Increasing the dose may be effected, for example, by extracting the first osmotic device for the delivery and implantation of a second osmotic delivery device, or by implantation of a second or more osmotic delivery device, wherein the total dose delivered by the first and second osmotic delivery device, provides the necessary dose increase.

[0099] In accordance with the sixth aspect of the present invention relates to a method of treating a disease or condition in a subject in need of treatment, including the possibility of termination of continuous delivery of the drug so that the concentration of the specified medicines is becoming essentially netdetective in the blood sample of a subject within about 6 half-lives of the drug after termination of continuous delivery, within about 5 half-lives of the drug after termination of continuous delivery, within about 4 half-lives of the drug after termination of continuous delivery, or for about 3 half-lives of the drug after termination of continuous delivery. Some examples of frames on�of vyvedenija medicines are as follows: exenatide - approximately 2.5 hours; GLP-1 is approximately 2 minutes; GIP - about 5 minutes; PYY - approximately 8 minutes; glucagon - approximately 6 minutes; oxyntomodulin - approximately 6 minutes; and GLP-2 - approximately 6 minutes. In some embodiments, the implementation of the cessation of continuous delivery includes extraction of the osmotic delivery device from the subject. In some embodiments, the implementation of the drug detected in the blood sample by radioimmunoassay or chromatography.

[00100] In accordance with the seventh aspect of the present invention relates to a method of treating a disease or condition in a subject in need of treatment comprising the first period of continuous administration of the drug in the first dose/day, followed by a second period of continuous injection, resulting in an increased dosage of a specified drug before the second dose/day, wherein said second dose/day more than the first dose/day. In some embodiments, the implementation of the first dose/day delivered via the first osmotic delivery device, and the second dose/day delivered by a second osmotic delivery device, and the delivery of the drug from at least the first or second osmotic delivery device is continuous during the period of administration, the composition of the�accounting for at least about 3 months. In one embodiment, the implementation of the second dose/day at least twice the first dose/day. In addition, the method may include at least one additional period of continuous injection, resulting in an increased dose of the medication to a higher dose/day, compared with the second dose/day. Increasing the dose may be effected, for example, by extracting the first osmotic device for the delivery and implantation of a second osmotic delivery device, or by implantation of a second or more osmotic delivery device, wherein the total dose delivered by the first and second (or additional) of the osmotic delivery device, provides the necessary increase in dose. This aspect of the present invention (comprising numerous, successive continuous periods of introduction of increasing doses of the drug) provides enhanced flexibility with respect to increasing doses of the drug compared to, for example, with increasing doses of PA-based injection of the drug.

[00101] In embodiments, the implementation of all aspects of the present invention related to methods of treating a disease or condition in a subject, the typical osmotic delivery device contains the following: impervious� tank includes inner and outer surfaces, and first and second open ends; a semipermeable membrane that is installed with the seal relative to the first open end of the reservoir; an osmotic mechanism within the tank and adjacent to the semipermeable membrane; a piston adjacent to the specified osmotic mechanism, wherein said piston forms a movable seal with the inner surface of the tank, the piston divides the reservoir for the first chamber and the second chamber, the first chamber contains an osmotic mechanism; a medicinal composition or the composition in the form of a suspension containing a drug, wherein the second chamber contains a medicinal composition or the composition in the form of a suspension, and said medicinal composition or the composition in the form of a slurry is flowable; and a diffusion controller, built-in to the second open end of the reservoir, the diffusion controller is adjacent to a composition in the form of suspension. In preferred embodiments, the implementation of the reservoir contains titanium or titanium alloy.

[00102] In embodiments, the implementation of all aspects of the present invention related to methods of treating a disease or condition in a subject, the pharmaceutical composition may contain a drug and the composition of the carrier. Alternatively, the compositions in the form of suspension used in these methods and they can �of primer, to contain the composition in the form of particles containing a medicament, and a composition of the carrier. The compositions of media for use in the formation of compounds in the form of a suspension according to the present invention can, for example, contain the solvent and the polymer. Examples of solvents include, but are not limited to, benzyl benzoate, laurinlactam, lauryl alcohol, or combinations thereof. An example of the polymer is polyvinylpyrrolidone. In a preferred embodiment the composition of the carrier essentially consists of one solvent and one polymer, for example, the solvent of benzyl benzoate and the polymer is polyvinylpyrrolidone.

[00103] the Reservoir of the osmotic delivery devices may, for example, contain titanium or titanium alloy.

[00104] In embodiments, the implementation of all aspects of the present invention implanted osmotic delivery device can be applied to ensure subcutaneous delivery.

[00105] In embodiments, the implementation of all aspects of the present invention for continuous delivery may be, for example, a controlled continuous delivery of order zero.

3.0.0 and composition

[00106] Medicines for use to implement the present invention in practice, usually uniformly suspended, dissolved or dispersed in a carrier in the form of a suspension with educational�amount of force composition in the form of suspension.

3.1.0 Medicinal agents in the form of particles

[00107] In accordance with one aspect of the present invention proposed pharmaceutical composition in the form of particles for pharmaceutical applications. The composition in the form of particles, usually contain a medicament and contains one or more stabilizing components. Examples of stabilizing components include, but are not limited to, carbohydrates, antioxidants, amino acids, buffers, inorganic compounds and surfactants.

3.1.1 Typical medicines

[00108] the Pharmaceutical compositions in the form of particles that contain a drug. Specified medicinal agent may be any physiologically or pharmacologically active substance, in particular, are known for delivery to the human or animal body. Drugs that can be delivered by the osmotic delivery system according to the present invention, include, but are not limited to, drugs that act on the peripheral nerves, adrenergic receptors, cholinergic receptors, skeletal muscles, cardiovascular system, smooth muscles, the blood circulatory system, SYNOPTIC sites, neuroeffector atrioventricular sites, endocrine and hormone system, immune�logical system, reproductive system, skeletal system, system of physiologically active substances, digestive and excretory systems, the histamine system or the Central nervous system. Moreover, drugs that can be delivered by the osmotic delivery system according to the present invention, include, but are not limited to, a drug used for the treatment of infectious diseases, chronic pain, diabetes, autoimmune diseases, endocrine disorders, metabolic disorders, and rheumatologic disorders.

[00109] Suitable drugs include, but are not limited to, the following ingredients: peptides, proteins, polypeptides (e.g., enzymes, hormones, cytokines), polynucleotides, nucleoproteins, polysaccharides, glycoproteins, lipoproteins, steroids, analgesics, local anesthetics, antibiotic agents, anti-inflammatory corticosteroids, drugs for eyes, or other small molecules for pharmaceutical applications (e.g., ribavirin) or synthetic analogues of these substances, and mixtures thereof.

[00110] In one embodiment, the implementation of the preferred drugs include macromolecule. These macromolecules include, but are not limited to, pharmacologically active peptides, Bel�and, polypeptides, genes, gene products, other agents for gene therapy or other small molecules. In a preferred embodiment of the macromolecule constitute peptides, polypeptides or proteins. Numerous peptides, proteins or polypeptides that are suitable in the implementation of the present invention described herein. In addition to the described peptides, proteins or polypeptides, modifications of the peptides, proteins or polypeptides are also known to those skilled in the art and can be used in implementing the present invention in accordance with the guidance provided in the present description. These modifications include, but are not limited to, analogs, amino acid mimetics of amino acids, analog polypeptides or derivatives of the polypeptides. Moreover, medicines, described herein, can be incorporated or introduced separately or in combination (e.g., with the use of mixtures of drugs or devices; patent publication US 2009/0202608).

[00111] Examples of proteins that can be included in pharmaceutical compositions in the form of particles according to the present invention, include, but are not limited to the following substances: human growth hormone; somatostatin; somatropin, somatotropin, analogues somatotropin, comatosed�h-C, somatotropin plus an amino acid, somatotropin plus a protein; follicle stimulating hormone; luteinizing hormone, a hormone releasing luteinizing hormone (LHRH), LHRH analogues such as leuprolide or leuprolide, nafarelin and goserelin, agonists or LHRH antagonists; factor in the release of growth hormone; calcitonin; colchicine; gonadotropin releasing hormone; gonadotropins such as chorionic gonadotropin; oxytocin, octreotide; vasopressin; adrenocorticotropic hormone; epidermal growth factor; fibroblast growth factor; platelet-growth factor; transforming growth factor; nerve growth factor; prolactin; jintropin; depressieve polypeptides, such as the thyrotropin-releasing hormone; a hormone that stimulates the thyroid gland; secretin; pankreozimin; enkephalin; glucagon; mimetics incretin; endocrine agents that are excreted within and distributed through the bloodstream, etc.

[00112] Additional proteins that can be included in pharmaceutical compositions in the form of particles include, but are not limited to the following substances: alpha-antitrypsin; factor VII; factor VIII; factor IX and other coagulation factors; insulin and the related insulin compounds (for example, suspension isophane-insulin suspension Protamine-zinc-insulin, globin zinc insulin, a suspension of zinc-insulin �inflammatory action); peptide hormones; adrenocorticosteroid hormone, the hormone that stimulates the thyroid gland, and other pituitary hormones; erythropoietin; growth factors such as grapholitini colony stimulating factor; granulocyte macrophage-colony stimulating factor; insulin-like growth factor 1; tissue plasminogen activator; CD4; 1 deamino-8-D-organisatorisches; receptor antagonist interleukin-1; tumor necrosis factor, a receptor of tumor necrosis factor; proteins-suppressors of tumor growth; pancreatic enzymes; lactase; cytokines, including lymphokines, chemokines or interleukins such as interleukin-1, interleukin-2; cytotoxic proteins; superoxide dismutase; endocrine agents that are excreted inside and distribute the animal through the bloodstream; recombinant antibodies, fragments of antibodies, humanized antibodies, single-chain antibodies, monoclonal antibodies; Avineri, etc.

[00113] Some variants of implementation of the present invention include the use of peptide hormones, for example, mimetics incretin (e.g., GLP-1 or èksenatida), as well as peptide analogs of the aforementioned peptides and peptide derivatives of the aforementioned peptide; PYY (also known as peptide YY, peptide tyrosine-tyrosine), as well as peptide analogs of the indicated peptide and peptide derivatives of the above mentioned Pat�Yes, for example, PYY(3-36); oxyntomodulin, as well as peptide analogs of the indicated peptide and peptide derivatives of the indicated peptide; and gastric inhibitory peptide (GIP), and peptide analogs of the indicated peptide and peptide derivatives of the indicated peptide.

[00114] Other options for implementation include the use of peptides of interferon (e.g., alpha, beta, gamma, lambda, omega, Tau, consensus and variant interferons, as well as analogues of these peptides or derivatives of these peptides, such as pegylated forms, and their mixtures; see, for example, The Interferons: Characterization and Application, by Anthony Meager (Editor), Wiley-VCH (May 1, 2006)).

[00115] it Was shown that GLP-1, including three forms of the indicated peptide GLP-l(l-37), GLP-1 (7-37) and GLP-1 (7-36)amide and peptide analogs of GLP-1 stimulate insulin secretion (i.e., are insulinotropic, which induces glucose uptake by cells leads to the decrease of serum concentrations of glucose (see, e.g., Mojsov, S., Int. J. Peptide Protein Research, 40:333-343 (1992)).

[00116] Many peptide derivatives and peptide analogs of GLP-1, demonstrating insulinotropic action are known in the art (see, e.g., U.S. patents 5118666; 5120712; 5512549; 5545618; 5574008; 5574008; 5614492; 5958909; 6191102; 6268343; 6329336; 6451974; 6458924; 6514500; 6593295; 6703359; 6706689; 6720407; 6821949; 6849708; 6849714; 6887470; 6887849; 6903186; 7022674; 7041646; 7084243; 7101843; 7138486; 7141547; 7144863; and 7199217), and also� from clinical trials (for example, taspoglutide and albiglutide). One example of a peptide derivative of GLP-1, suitable for implementing the present invention in practice, is Victoza Victoza® (Novo Nordisk A/S, Bagsvaerd (DK) (liraglutide; U.S. patent 6268343, 6458924, 7235627). Victoza (liraglutide) injection once a day commercially available in the United States, Europe and Japan. In the present description, for convenience, a family of peptides GLP-1 derived peptides GLP-1 and analogues of the peptides of GLP-1 having insulinotropic activity, is a common name of "GLP-1".

[00117] the Molecule èksenatida contains the amino acid sequence of Bloomington: Indiana-4 (Kolterman O. G., et al., J. Clin. Endocrinol. Metab. 88(7):3082-9 (2003)), and it is obtained by chemical synthesis or recombinant expression. Exenatide for injection twice a day commercially available in the United States and Europe, and is sold under the trade name Byetta® (Byetta®) (Amylin Pharmaceuticals, Inc., San Diego, CA). Bloomington: Indiana-3 and Bloomington: Indiana-4 is known in the art and was originally isolated from Heloderma spp.(Eng, J., et al., J. Biol. Chem., 265:20259-62 (1990); Eng., J., et al., J. Biol. Chem., 267:7402-05 (1992)). It was suggested that the application of Bloomington: Indiana-3 and Bloomington: Indiana-4 for the treatment of diabetes mellitus type 2 and prevention of hyperglycemia (see, e.g., U.S. patent 5424286). In the art, many known peptide derivatives and peptide analogs èksenatida (including, for example, agonis�s of Bloomington: Indiana-4) (see, for example, U.S. patents 5424286; 6268343; 6329336; 6506724; 6514500; 6528486; 6593295; 6703359; 6706689; 6767887; 6821949; 6849714; 6858576; 6872700; 6887470; 6887849; 6924264; 6956026; 6989366; 7022674; 7041646; 7115569; 7138375; 7141547; 7153825; and 7157555). One example of a derived èksenatida, in a suitable implementation of the present invention is licesence (also known as ZP10, AVE0010) (see, e.g., U.S. patent 6528486), which is at the stage of clinical trials. In the present description, for convenience, a family of peptides èksenatida (for example, including Bloomington: Indiana-3, Bloomington: Indiana-4 and Bloomington: Indiana-4-amide), peptide derivatives èksenatida and peptide analogues èksenatida is the common name of "exenatide".

[00118] PYY is an amide of peptide consisting of 36 amino acid residues. PYY slows down gut motility and blood flow (Laburthe, Trends Endocrinol Metab. 1 (3): 168-74 (1990), mediates intestinal secretion (Cox, N. M. et al., Br J Pharmacol 101(2):247-52 (1990); Playford, R. J., et al., Lancet 335(8705): 1555-7 (1990)) and stimulate net absorption (MacFayden, R. J., et al., Neuropeptides 7(3):219-27 (1986)). There were identified two main variants in vivo, PYY(l-36) and PYY(3-36) (e.g., Eberlein, G. A., et al., Peptides 10(4), 797-803 (1989)). The sequence of PYY and its peptide analogs and peptide derivatives are known in the art (e.g., U.S. patent 5574010 and 5552520).

[00119] Oxyntomodulin is a naturally occurring peptide hormone composed of 37 amino acids, soteriades� in the colon, which, as it was discovered, suppresses appetite and promotes weight loss (Wynne K, et al., Int J Real Trap (Lond) 30(12): 1729-36(2006)). The sequence of oxyntomodulin and its peptide analogs and peptide derivatives are known in the art (e.g., Bataille D, et al., Peptides 2(Suppl 2):41-44 (1981); and patent publication U.S. 2005/0070469 and 2006/0094652).

[00120] GIP is an insulinotropic peptide hormone (Efendic, S., et al., Horm Metab Res. 36:742-6 (2004)), it is secreted by the mucous membrane of the duodenum and jejunum in response to the absorbed fat and carbohydrate, which stimulates insulin secretion by the pancreas. GIP circulates as a biologically active peptide consisting of 42 amino acids.GIP is also known as glucose-dependent insulinotropic protein. GIP is a regulatory peptide in the gastrointestinal tract, consisting of a 42-amino acid, which stimulates the secretion of insulin from the beta cells of the pancreas in the presence of glucose (Tseng, S., et al., PNAS 90:1992-1996 (1993)). The sequence of GIP and its peptide analogs and peptide derivatives are known in the art (e.g., Meier J. J., Diabetes Metab Res Rev. 21(2):91-117 (2005); Efendic S., Horm Metab Res. 36(11-12):742-6 (2004)).

[00121] Examples of half-lives of some of these peptides are as follows: exenatide - approximately 2.5 hours; GLP-1, approximately 2 minutes�; GIP-about 5 minutes; PYY - approximately 8 minutes; glucagon - approximately 6 minutes; oxyntomodulin - approximately 6 minutes; and GLP-2 - about 6 minutes.

[00122] Examples of pharmaceutical compositions in the form of particles for use in the implementation of the present invention is exenatide. These examples are not limiting.

[00123] In another embodiment preferred drugs include small molecules. Examples of medicines that can be used to implement the present invention into practice include, but are not limited to the following drugs: chemotherapeutic agents; hypnotics and sedatives such as pentobarbital sodium, phenobarbital, secobarbital (secobarbital), thiopental (thiopental), amides and urea, examples of which are diethylethanamine and alpha-bromo-isovalerylglycine, urethanes or disulfide; heterocyclic hypnotics such as dioxopiperidin and glutarimide; antidepressants such as isocarboxazid (isocarboxazid), nialamide (nialamide), phenelzine (phenelzine), imipramine (imipramine), tranylcypromine (tranylcypromine), pargyline (pargyline); tranquilizers, such as chlorpromazine (chloropromazine), promazine (promazine), fluphenazine (fluphenazine), reserpine (reserpine), deserpidine (deserpidine), meprobamate (meprobamate), benzodiazepines, such as Hardies�of oxid (chlordiazepoxide); anticonvulsants such as primidone (primidone), diphenylhydantoin (diphenylhydantoin), ethotoin (ethltoin), featured (pheneturide), ethosuximide (ethosuximide; muscle relaxants and anti-disease Parkinsona, such as mephenesin (mephenesin), Methocarbamol (methocarbomal), trihexyphenidyl (trihexyphenidyl), biperiden (biperiden), l-DOPA (levo-dopa), also known as L-DOPA and L-beta-3-4-DOPA; analgesics, such as morphine, codeine (codeine), meperidine (meperidine), nalorphine (nalorphine); antipyretics and anti-inflammatory agents such as aspirin, salicylamide, sodium salicylamide, naproxen (naproxin), ibuprofen (ibuprofen); local anesthetics, such as procaine (procaine), lidocaine (lidocaine), nephin (naepaine), piperocaine (piperocaine), tetracaine (tetracaine), dibucaine (dibucane); antispasmodics and antiulcer agents such as atropine (atropine), scopolamine (scopolamine), methscopolamine (methscopolamine), oxepanone (oxyphenonium), papaverine (papaverine), prostaglandins such as PGE1, PGE2That PGF1-alphaThat PGFAlpha, PGA; anti-microbials such as penicillin (penicillin), tetracycline (tetracycline), oxytetracycline (oxytetracycline), chlortetracycline (chlorotetracycline), chloramphenicol (chloramphenicol), sulfonamides, tetracycline, bacitracin (bacitracin), chlortetracycline, erythromycin (erythromycin), isoniazid (isoniazid), rifampin (rifampin), ethambutol (ethambutol), pyrazinamide (pyrazinamide), rifabutin (rifabutin), rifapentine (rifapetine), cycloserine (cycloserine), ethionamide (ethionamide), streptomycin (streptomycin), amikacin/kanamycin (amikacin/kanamycin), capreomycin (capreomycin), p-aminosalicylic acid, levofloxacin (levofloxacin), moxifloxacin (moxifloxacin and Gatifloxacin (gatifloxacin); antimalarial agents such as 4-aminoquinoline, 8-aminoquinoline, pyrimethamine (pyrimethamine), chloroquine (chloroquine), sulfadoxine-pyrimethamine; mefloquine (mefloquine); atovaquone-proguanil (atovaquone-proguanil); quinine (quinine); doxycycline (doxycycline); artemisinin (artemisinin) (sesquiterpene lactone) and derivatives; anti-leishmaniasis (e.g., Melodiya antimoniate (meglumine antimoniate), sodium stibogluconate (sodium stibogluconate), amphotericin (amphotericin), miltefosine (miltefosine and paromomycin (paromomycin)); means for trypanosomiasis (e.g., disease, benznidazole and nifurtimox); anti-amebiasis (for example, metronidazole (metronidazole), tinidazole (tinidazole) and diloxanide furoate (diloxanide furoate)); Antiprotozoal drugs (e.g., eflornithine (eflornithine), furazolidone (furazolidone), melarsoprol (melarsoprol), metronidazole, Ornidazole (ornidazole, paromomycin sulfate, pentamidine (pentamidine), pyrimethamine and tinidazole); hormonal agents such as prednisolone (prednisolone), cortisone (cortisone), cortisol (Cortisol) and triamcinolone (triamcinolone), hydrogene steroids (for example, methyltestosterone (methyltestosterone), fluoxymesterone (fluoxmesterone)); estrogenic steroids (e.g., 17-alpha stages�ol and etinilestradiol (thinyl estradiol)); progestagenic steroids (e.g., 17-alpha-hydroxyprogesterone acetate, 19-nor-progesterone, norethindrone (norethindrone)); sympathomimetic drugs such as epinephrine (epinephrine), amphetamine (amphetamine), ephedrine (ephedrine), norepinephrine (norepinephrine); cardiovascular drugs such as procainamide (procainamide), amylnitrate (amyl nitrate), nitroglycerin, dipyridamole (dipyridamole), sodium nitrate, mannitol nitrate; diuretics such as acetazolamide (acetazolamide), chlorothiazide (chlorothiazide), flumethiazide (flumethiazide); antiparasitic agents, such as bephenium hydroxynaphthoate (bephenium hydroxynaphthoate), dichlorophen (dichlorophen), antabus (enitabas), Dapsone (dapsone); antineoplastic agents, such as mechlorethamine (mechlorethamine), uramustine (uracil mustard), 5-fluorouracil, 6-thioguanine and procarbazine (procarbazine); hypoglycemic drugs such as tolbutamide (tolbutamide), acetohexamide (acetohexamide), tolazamide (tolazamide), chlorpropamide (chlorpropamide); nutritional agents such as vitamins, essential amino acids and essential fats; medicines for eyes, such as pilocarpine base (pilocarpine base, pilocarpine hydrochloride, pilocarpine nitrate; antiviral medicines such as disoproxil fumarate (disoproxil fumarate), acyclovir (aciclovir), cidofovir (cidofovir), docosanol (docosanol), famciclovir (famciclovir), fomivirsen (fomivirsen), foscarnet (foscarnet), �of ganciclovir (ganciclovir), idoxuridine (idoxuridine), penciclovir (penciclovir), trifluridine (trifluridine), tromantadine (tromantadine), valacyclovir (valaciclovir), valganciclovir (valganciclovir), vidarabine (vidarabine), amantadine (amantadine), Arbidol (Arbidol have), oseltamivir (oseltamivir), as peramivir (peramivir), rimantadine (rimantadine), zanamivir (zanamivir), abacavir (abacavir), DDI (didanosine), emtricitabine (emtricitabine), lamivudine (lamivudine), stavudine (stavudine), zalcitabine (zalcitabine), AZT (zidovudine), tenofovir (tenofovir), efavirenz (efavirenz), delavirdine (delavirdine), nevirapine (nevirapine), lowered (loviride), amprenavir (amprenavir), atazanavir (atazanavir), darunavir (darunavir), fosamprenavir (fosamprenavir), indinavir (indinavir), LPV (lopinavir), nelfinavir (nelfinavir), ritonavir (ritonavir), saquinavir (saquinavir are), tipranavir (tipranavir), enfuvirtide (enfuvirtide), adefovir (adefovir), fomivirsen (fomivirsen), imiquimod (imiquimod), inosine (inosine), podophyllotoxin (podophyllotoxin), ribavirin, viramidine (viramidine), hybrid blockers, specific targeted influencing of viral surface proteins or viral receptors (e.g., an inhibitor of gp-41 inhibitor (T-20), an inhibitor of CCR-5); anti-sickness, such as scopolamine, dimenhydrinate (dimenhydrinate); idoxuridine (iodoxuridine), hydrocortisone, eserine (eserine), phospholine iodide (phospholine iodide), and many other useful medicines.

[00124] These drugs can be in various forms, including, but not limited to, the following forms: Nezar�conjugated molecules; components of molecular complexes, and pharmacologically acceptable salts such as hydrochloride, hydrobromide, sulfate, laurate, palmitate, phosphate, nitrate, borate, acetate, maleate, tartrate, oleate or salicylates. For acidic drugs can be used salts of metals, amines or organic cations, for example Quaternary ammonium. Furthermore, simple derivatives of the drugs such as esters, ethers, amides, etc., have solubility characteristics suitable for the purpose of the present invention, can also be used in the present invention.

[00125] the Above drugs and other drugs that are known to those skilled in the art, are suitable for methods of treatment of various conditions, including, but not limited to, the following conditions: chronic pain, hemophilia and other blood disorders, endocrine disorders, metabolic disorders, rheumatologic disorders, diabetes (including diabetes mellitus type 1 and type 2), leukemia, hepatitis, renal failure, infectious diseases (including bacterial infection, viral infection (e.g., infection caused by the human immunodeficiency virus, hepatitis C virus, hepatitis b virus, the yellow fever virus, West Nile virus, Dengue virus, the virus M�rburg, the Ebola virus, etc.) and parasitic infection), hereditary diseases (such as shortage of cerebrosidase and deficiency of adenosine deaminase), hypertension, septic shock, autoimmune diseases (e.g., graves disease, systemic lupus erythematosus, multiple sclerosis and rheumatoid arthritis), shock and causing depletion disorders, cystic fibrosis, lactose intolerance, Crohn's disease, inflammatory bowel disease, cancer of the gastrointestinal tract (including colon cancer and rectal cancer), breast cancer, leukemia, lung cancer, bladder cancer, kidney cancer, nahodkinskuju lymphoma, pancreatic cancer, thyroid cancer, endometrial cancer and other cancers. Moreover, some of the above agents are suitable for the treatment of infectious diseases requiring long-term treatment, including, but not limited to, tuberculosis, malaria, leishmaniasis, trypanosomiasis (sleeping sickness and Chagas disease), and parasitic worms.

[00126] the Amount of drug in pharmaceutical formulations in the form of particles represents the amount necessary to deliver a therapeutically effective amount of the agent to achieve the desired therapeutic effect in a subject, which deliver the specified drug. In practice this number�the amount will vary depending on such variable factors how, for example, a particular agent, severity of the condition and the desired therapeutic effect. Useful agents and their dosing units known from the prior art in Goodman & Gilman''s The Pharmacological Basis of Therapeutics, 11th Ed., (2005), McGraw Hill; Remington's Pharmaceutical Sciences, 18th Ed., (1995), Mack Publishing Co.; and Martin's Physical Pharmacy and Pharmaceutical Sciences, edition 1.00 (2005), Lippincott Williams & Wilkins. Moreover, particles of highly concentrated medicines described in patent publication U.S. 2010/0092566. Typically, for an osmotic delivery system enclosure volume containing medicinal composition, is from about 100 μl to about 1000 μl, more preferably from about 140 μl to about 200 μl. In one embodiment, the implementation volume of the chamber containing the medicinal composition is about 150 μl.

[00127] the Pharmaceutical compositions in the form of particles according to the present invention are preferably chemically and physically stable for at least 1 month, preferably at least 3 months, more preferably at least 6 months, more preferably at least 12 months at delivery temperature. The temperature of delivery, usually, is a normal human body temperature, e.g., about 37°C or slightly above, for example, about 40°C. moreover, the pharmaceutical compositions in the form of particles according to the present invention preferred�Stateline chemically and physically stable for at least 3 months, preferably at least 6 months, more preferably at least 12 months at storage temperature. Examples of the storage temperature include cooling temperature, e.g., about 5°C. or room temperature, e.g., about 25°C.

[00128] the Medicinal composition in the form of particles can be considered chemically stable if less than about 25%, preferably less than about 20%, more preferably, less than about 15%, more preferably less than about 10% and, more preferably, less than about 5% breakdown products of the drug particles are formed after about 3 months, preferably after about 6 months, preferably after about 12 months at delivery temperature and after about 6 months, after about 12 months, and preferably after about 24 months at storage temperature.

[00129] the Medicinal composition in the form of particles can be considered physically stable if less than about 10%, preferably less than about 5%, more preferably, less than about 3%, more preferably less than about 1% of units of the drug is formed after about 3 months, preferably after about 6 months at delivery temperature and after approximately 6 months, preferably about 12 months, at storage temperature.

[00130] In case when the drug in the pharmaceutical composition in the form of particles is a protein, a solution of the specified protein is stored in a frozen state and lyophilizers or spray dried to solid state. Tg (glass transition temperature) may be one of the factors that must be considered when obtaining stable compositions of protein. Not wishing to be bound by any particular theory, in the pharmaceutical industry was used in theory of formation of amorphous solids with high Tg for the stabilization of peptides, polypeptides or proteins. In General, if an amorphous solid has a higher Tg, such as 100°C, peptide products will not have mobility during storage at room temperature or even at 40°C as the storage temperature below Tg. Calculations using molecular information has shown that if the glass transition temperature above the storage temperature of 50°C, there is zero mobility of the molecules. Zero mobility of molecules correlates with greater stability. Tg also depends on the concentration of moisture in the product. In General, the higher the humidity, the lower the Tg of the composition.

[00131] Accordingly, according to some aspects of the present invention, the fillers with a higher Tg may be included in protein composition for higher�Oia stability, for example, sucrose (Tg=75°C) and trehalose (Tg=110°C). Preferably, the compositions in the form of particles is formed into particles using methods such as spray drying, lyophilization, dewatering, drying by sublimation, grinding, granulation, ultrasonic drop formation, crystallization, deposition, or other techniques available in the art for forming particles from a mixture of components. In one variant of implementation of the present invention the particles are spray dried. Preferably, the particles are essentially identical in shape and size.

[00132] the Particles are typically adjusted to size so that they can be delivered through an implantable osmotic delivery device of the medicine. Same shape and size of the particles, as a rule, helps to ensure consistent and uniform rate of release of said device delivery; however, it is also possible to use the composition in the form of particles having non-normal distribution characteristics of particle size. For example, in a typical implantable osmotic delivery device having an aperture for delivery, the particle size is less than about 30%, more preferably is less than about 20%, more preferably is less than about 10% of dia�of ETP specified openings for delivery. In one embodiment of the composition in the form of particles for use with an osmotic delivery system, wherein the diameter of the holes for delivery of the specified implant is approximately 0.5 mm, the particle size can be, for example, from less than about 150 microns to about 50 microns. In one embodiment of the composition in the form of particles for use with an osmotic delivery system, wherein the diameter of the holes for delivery of the specified implant is approximately 0.1 mm, the particle size can be, for example, from less than about 30 microns to about 10 microns. In one embodiment, the implementation of said hole is about 0.25 mm (250 microns), and the particle size is from about 2 microns to about 5 microns.

[00133] typically, the particles of the compositions in the form of particles, when included in the media in the form of a suspension do not settle through the less than about 3 months, preferably not settle through the less than about 6 months, more preferably not settle through the less than about 12 months, more preferably not settle through the less than about 24 months at a temperature of delivery and most preferably do not settle through the less than about 36 months at a temperature of delivery. Media in suspension, generally have a viscosity of from about 5,000 to about 30,000 poise, preferably from about 8,000 to prima�but 25000, poise, more preferably from about 10,000 to about 20,000 poise. In one embodiment, the implementation of the media in the form of a slurry has a viscosity of about 15,000 poise plus or minus about 3000 poises. In General, smaller particles generally have a lower sedimentation rate in the media in the form of a viscous suspension than larger particles. Accordingly, particles with sizes from microns to nanometers, as a rule, are preferred. In the composition in the form of a viscous slurry of particles of from about 2 microns to about 7 microns according to the present invention will not settle for at least 20 years at room temperature on the basis of simulation studies. In one embodiment of the composition in the form of particles according to the present invention for use in an implantable osmotic delivery device included particles with sizes less than about 50 microns, more preferably less than about 10 microns, more preferably in the range from about 2 microns to about 7 microns.

[00134] In one embodiment, the implementation of the pharmaceutical composition in the form of particles contains a medicament, as described above, one or more stabilizers and possibly a buffer. The specified stabilizer may be, for example, carbohydrate, antioxidant, amino acid, buffer, inorganic compound Il� surfactant. The number of stabilizers and buffer in the composition is in the form of particles can be determined experimentally on the basis of activity of the indicated stabilizers and buffers and the desired characteristics of the composition in the light of the ideas presented in this description. Typically, the amount of carbohydrate in the composition is determined based on the problems of aggregation. In General, the amount of carbohydrate should not be too large, in order to avoid contribute to the growth of crystals in the presence of water due to excess carbohydrate, unbound drug. Typically, the amount of antioxidant in the composition is determined based on the problems of oxidation, whereas the number of amino acids in the composition is determined based on the problems of oxidation and/or the moldability of the particles during spray drying. Typically, the amount of buffer in the composition is determined based on the problems pre-treatment, problems of stability and moldability of the particles during spray drying. The buffer may be needed to stabilize the drug during processing, for example, solution preparation and spray drying, when all the fillers solubilizers.

[00135] Examples of carbohydrates that can be included in the composition in the form of particles include, but are not limited to, monosaccharides (e.g., fructose, maltose, galactose, glucose, D-mannose and sorbose), di�charity (for example, lactose, sucrose, trehalose and cellobiose), polysaccharides (e.g., raffinoses, melezitose, maltodextrins, dekstrana and starches) and alditol (acyclic polyols; e.g., mannitol, xylitol, maltitol, lactitol, xylitol, sorbitol, piranozidei and monoset). Preferred carbohydrates include disaccharides and/or nevosstanovlenie sugar, such as sucrose, trehalose and raffinoses.

[00136] Examples of antioxidants that can be included in the composition in the form of particles include, but are not limited to, methionine, ascorbic acid, sodium thiosulfate, catalase, platinum, ethylenediaminetetraacetic acid (EDTA), citric acid, cysteines, thioglycerol, thioglycolic acid, toorbit, butilirovaniya hydroxyanisole, butylated hydroxytoluene and propylgallate. In addition, amino acids that are easily oxidized, can be used as antioxidants, for example, cysteine, methionine and tryptophan. The preferred antioxidant is a methionine.

[00137] Examples of amino acids that can be included in the composition in the form of particles include, but are not limited to, arginine, methionine, glycine, histidine, alanine, L-leucine, glutamic acid, isoleucine, L-threonine, 2-phenylamine, valine, Norvaline, Proline, phenylalanin, tryptophan, serine, asparagines, cysteine, tyrosine, lysine, and norleucine. Preferred and�of inability include those amino acids, easily oxidized, for example, cysteine, methionine and tryptophan.

[00138] Examples of buffers that may be included in the composition in the form of particles include, but are not limited to, citrate, histidine, succinate, phosphate, maleate, Tris, acetate, carbohydrate and gly-gly. Preferred buffers include citrate, histidine, succinate, and Tris.

[00139] Examples of inorganic compounds that can be included in the composition in the form of particles include, but are not limited to, NaCl, Na2SO4, NaHCO3, Kl, KH2PO4, l2and MgCl2.

[00140] in addition, the composition in the form of particles may contain other excipients, such as surfactants and salts. Examples of surfactants include, by are not limited to, Polysorbate 20, Polysorbate 80, PLURONIC® (PLURONIC®) (BASF Corporation, Mount Olive, NJ) F68 and sodium dodecyl sulfate (SDS). Examples of salts include, but are not limited to, sodium chloride, calcium chloride and magnesium chloride.

[00141] All of the components included in the composition in the form of particles, as a rule, are acceptable for pharmaceutical use in mammals, particularly in humans.

[00142] Thus, the selected drug or combination of drugs included in the dried powders in the solid state, which retain maximum chemical and biological hundred�innosti medicines. The composition in the form of particles provides stability during prolonged storage at high temperature and, therefore, allows us to deliver to a subject a stable and biologically effective drug for long periods of time.

3.2.0 Trains-carriers and formulations as suspensions

[00143] In accordance with one aspect of the media in the form of suspension provides a stable environment in which drug is dispersed composition in the form of particles. Pharmaceutical compositions in the form of particles chemically and physically stable (as described above) on the substrate in the form of a suspension. The media in the form of a slurry typically contains one or more polymers and one or more solvents to form a solution of sufficient viscosity for uniform suspension of particles containing a medicament. The media in the form of suspension may contain additional components, including, but not limited to, surfactants, antioxidants and/or other compounds soluble in the specified media.

[00144] the Viscosity of the carrier in the form of suspension, as a rule, sufficient to prevent sedimentation of the medicinal composition in the form of particles during storage and use in the method of delivery, for example, in an implantable osmotic delivery device. The media in the form of a suspension is lioresla�recovery in that regard, that the specified media in the form of a slurry decomposes or disintegrates during the period of time in response to the biological environment, whereas the particle of the drug dissolved in the biological environment, and active pharmaceutical ingredient (i.e., drug) within the specified particle absorbed.

[00145] the Solvent in which the dissolved polymer can affect the characteristics of the composition in the form of a suspension, such as the behaviour of the medicinal composition in the form of particles during storage. The solvent may be selected in combination with the polymer so that the resulting carrier in the form of suspension showed phase separation upon contact with an aqueous environment. In some embodiments, the implementation of the present invention, the solvent may be selected in combination with the polymer so that the resulting carrier in the form of suspension showed phase separation upon contact with an aqueous medium containing less than about 10% water.

[00146] the Solvent may be an acceptable solvent that is not miscible with water. The solvent can also be selected so that the polymer was soluble in a specified solvent at high concentrations, for example, when the concentration of polymer is increased by approximately 30%. Examples of solvents suitable in the implementation of the present invention include, but are not limited�Xia them lauryl alcohol, benzyl benzoate, benzyl alcohol, laurinlactam, decanol (also called decyl alcohol), Ethylhexylglycerin and clinocerinae (C8to p24aliphatic alcohols, ethers or mixtures thereof. The solvent used in the media in the form of a suspension, may be "dry" in the sense that it has a low moisture content. Preferred solvents for use in the preparation of the carrier in the form of suspension include laurinlactam, lauryl alcohol, benzyl benzoate, and mixtures thereof.

[00147] Examples of polymers for the preparation of carriers in the form of a suspension according to the present invention include, but are not limited to, polyester (e.g., polylactic acid or polylactic-acid polyglycol), the polymer containing pyrrolidone (for instance, polyvinylpyrrolidone having a molecular weight in the range from about 2000 to about 1000000), an ester or ether of unsaturated alcohol (e.g., vinyl acetate), a block copolymer of polyoxyethylene-polyoxypropylene or mixtures thereof. Polyvinylpyrrolidone can be characterized by its K-value (for example, K-17), which represents the viscosity index. In one variant of implementation, the polymer is a polyvinylpyrrolidone having a molecular weight of 2000 to 1000000. In a preferred embodiment, the polymer p�establet a polyvinylpyrrolidone K-17 (usually having an approximate average molecular weight in the range of 7900 - 10800). The polymer used in the media in the form of a suspension, may include one or more different polymers or may include different varieties of the same polymer. The polymer used in the media in the form of a slurry, may also be dry or have a low moisture content.

[00148] In General, the media in the form of a slurry for use in the present invention may vary in composition based on the desired operating characteristics. In one embodiment, the implementation of the media in the form of suspension may contain from about 40 wt.% up to about 80 wt.% polymer (polymers) and from about 20 wt.% to about 60 wt.% solvent (solvents). Preferred embodiments of the carrier in the form of suspension include the media formed of a polymer (polymer) and solvent (solvents), combined in the following ratios: about 25 wt.% solvent and about 75 wt.% polymer; about 50 wt.% solvent and about 50 wt.% polymer; about 75 wt.% solvent and about 25 wt.% polymer. Accordingly, in some embodiments, the implementation of the media in the form of suspension may include selected components, and in other embodiments, the implementation essentially consist of selected components.

[00149] the media in the form of suspension may demonstrirov�ü Newtonian behavior. The media in the form of a suspension, usually made with the viscosity that support homogeneous dispersion of the composition in the form of particles within a predetermined period of time. This helps to facilitate the obtaining of a composition in the form of a suspension designed to provide controlled delivery of the drug contained in the pharmaceutical composition in the form of particles. The viscosity of the carrier in the form of suspension may vary depending on the desired application, the size and type of the composition in the form of particles and loading the composition in the form of particles in a carrier in the form of a suspension. The viscosity of the carrier in the form of a suspension can be varied by changing the type or relative amount of the used solvent or polymer.

[00150] the media in the form of a slurry can have a viscosity in the range from about 100 poise to about 1,000,000 poise, preferably from about 1000 poise to about 100,000 poise. In preferred embodiments, the implementation of the medium in the form of a slurry, typically have a viscosity at 33°C, component from about 5,000 to about 30,000 poise, preferably from about 8,000 to about 25,000 poise, more preferably from about 10,000 to about 20,000 poise. In one embodiment, the implementation of the media in the form of a slurry has a viscosity, which is approximately 15000 poise plus or minus about 3000 poise at 33°C. Elm�ity can be measured at 33°C, at a shear rate of 10-4/h with use of a rheometer with parallel plates.

[00151] the media in the form of suspension may exhibit phase separation upon contact with an aqueous environment; however, as a rule, the media in the form of a slurry essentially demonstrates the separation of the phases, depending on temperature. For example, at a temperature in the range from approximately 0°to approximately 70°C and with temperature Cycling, such as Cycling from 4°C to 37°C to 4°C, the medium in the form of suspension, as a rule, does not show phase separation.

[00152] the media in the form of a suspension can be obtained by combining polymer and solvent in dry conditions, for example, in a dry box. The polymer and solvent can be combined at an elevated temperature, for example, from approximately 40°to approximately 70°C, and leave for liquefaction and formation of a uniform phase. These ingredients may be mixed under vacuum to remove air bubbles formed from the dry ingredients. The ingredients can be combined using conventional mixer, such as mixer with double spiral blades, or similar mixer set at speed of approximately 40 rpm, However, can also be used over a high speed to mix ingredients. After receive the goods� liquid solution of ingredients the media in the form of a suspension can be cooled to room temperature. You can apply differential scanning calorimetry (DSC) in order to make sure that the carrier is in the form of suspension represents one phase. Moreover, media components (e.g., solvent and/or polymer) can be treated with essentially reduce or essentially remove peroxides (for example, by treatment with methionine; see, for example, the publication of the patent application U.S. 2007-0027105).

[00153] the Medicinal composition in the form of particles added to the medium in the form of a suspension with the formation of the composition in the form of a suspension. In some embodiments, the implementation of the composition in the form of suspension may contain a medicinal composition in the form of particles and a carrier in the form of a suspension, and in other embodiments, the implementation essentially consist of a medicinal composition in the form of particles and the carrier in the form of suspension.

[00154] the Composition in the form of suspension can be obtained by dispersing the composition in the form of particles in a carrier in the form of a suspension. The media in the form of a slurry can be heated to the specified media in the form of a slurry to add the composition in the form of particles in dry conditions. The ingredients may be mixed under vacuum at an elevated temperature, e.g. from about 40°to about 70°C. the Ingredients may be mixed at a sufficient speed, such as from approx�RNO 40 rpm to about 120 rpm, and for sufficient time, e.g. about 15 minutes, to obtain a homogeneous dispersion of the composition in the form of particles in a carrier in the form of a suspension. The mixer may be a mixer with double spiral blades or other suitable mixer. The resulting mixture can be removed from the mixer, sealed in a dry container to prevent contamination of the composition in the form of a slurry with water, and leave to cool to room temperature before further use, for example, loading in implantable drug delivery device means, a container for single doses or container for multiple doses.

[00155] the Composition in the form of suspension, as a rule, has a total moisture content less than about 10 wt.%, preferably less than about 5 wt.% and more preferably less than about 4 wt.%.

[00156] In preferred embodiments, the implementation of the compositions in the form of a suspension according to the present invention are essentially homogeneous and flowable to enable delivery of the drug compound in the form of particles of the osmotic delivery device to a subject.

[00157] Thus, the media components in the form of a suspension provide biocompatibility. Media components in the form of suspension provides a suitable physico-chemical properties to obtain stability�x suspensions of pharmaceutical compositions in the form of particles. These properties include, but are not limited to the following properties: viscosity of the suspension; the purity of the carrier; the residual moisture of the carrier; carrier density; compatibility with dry powders; compatible with implantable devices; molecular weight of the polymer; the stability of the vehicle; and the hydrophobic and hydrophilic nature of carrier. These properties can be managed and controlled, for example, by varying the composition of the carrier and control the ratio of the components used in the carrier in the form of suspension.

4.0.0 delivery compositions in the form of suspensions

[00158] the Compositions in the form of a suspension, is described in the present application, can be used in an implantable osmotic device of the drug delivery with controlled and prolonged delivery of zero-order connections over a long period of time, for example, in the weeks, months, or up to about one year or more. Specified implantable osmotic drug delivery device means, as a rule, capable of delivering the composition in the form of a suspension containing a drug, the desired rate of flow within the desired time period. The composition in the form of a suspension can be loaded into an implantable osmotic delivery device of the drug through t�Edizioni technologies.

[00159] the Dose and speed of delivery can be selected to achieve the desired concentration of the drug in the blood, in General, in less than about 6 half-lives of the specified drug in a subject after implantation of the device. The concentration of the drug in the blood is chosen to achieve optimal therapeutic effects of the drug, while avoiding the undesirable side effects that may be induced by excessive concentration of the drug, while avoiding the peaks and lows, which can induce side effects associated with peak or minimum concentrations of the drug in the blood plasma.

[00160] an Implantable osmotic delivery device of the drug, typically comprises a reservoir having at least one opening through which the composition is delivered in the form of suspension. The composition in the form of a suspension can be stored in the specified tank. In a preferred embodiment, an implantable drug delivery device means is an osmotic delivery device in which drug delivery is driven by the phenomenon of osmosis. Have been described by some osmotic delivery device and its components, for example, the device is sufficient�Ki DUROS®, or similar device (see, for example, U.S. patents 5609885; 5728396; 5985305; 5997527; 6113938; 6132420; 6156331; 6217906; 6261584; 6270787; 6287295; 6375978; 6395292; 6508808; 6544252; 6635268; 6682522; 6923800; 6939556; 6976981; 6997922; 7014636; 7207982; 7112335; 7163688; patent publication US 2005/0175701, 2007/0281024, 2008/0091176 and 2009/0202608).

[00161] the delivery Device DUROS®, as a rule, consists of a cylindrical reservoir, which contains an osmotic mechanism, piston and medicinal composition. The said reservoir is closed at one end by a semi-permeable membrane at a controlled rate and closed at the other end of the diffusion controller, through which the composition is in the form of a suspension containing a drug is released from the reservoir of the drug. The piston separates the drug from an osmotic mechanism and the use of an insulating layer to prevent the ingress of water into the compartment of an osmotic mechanism to the reservoir of the drug. The diffusion controller is designed, in conjunction with medical staff, to prevent the ingress of body fluids into the reservoir of the drug through the hole.

[00162] the Device DUROS® releases the drug with a pre-determined speed based on the principle of osmosis. Extracellular fluid enters the device DUROS® through a semi-permeable membrane directly into a saline mechanism that expands and moves the piston to slow odinakovoi speed of delivery. The movement of the piston causes the medicinal composition to be released through the opening or outlet with a predetermined absolute speed. In one embodiment, the implementation of the present invention, the reservoir device DUROS® load composition in the form of a suspension, wherein the device capable of delivering said composition is in the form of a suspension to a subject over a long period of time (e.g., about 1, about 3, about 6, about 9, about 10, or about 12 months) with a predetermined therapeutically effective delivery rate.

[00163] the Rate of release of the drug from the osmotic delivery device, typically provides the subject a predetermined target dose of drug, for example, a therapeutically effective daily dose is delivered during the day; i.e. the rate of release of the drug from the device provides a significant sustained delivery of the drug at therapeutic concentrations to the subject.

[00164] typically, for an osmotic delivery device chamber volume with a helpful agent containing composition useful agent ranges from about 100 μl to about 1000 μl, more preferably from about 120 μl to about 500 μl, more preferably from about 150 μl to about 200 μl.

[00165] the osmotic delivery device is implanted in a subject, for example, subcutaneously with the provision of subcutaneous drug delivery. Device (s) can be implanted subcutaneously in either one or both hands (for example, in inner, outer or back of the shoulder) or in the abdomen. Preferred areas in the abdomen under the skin of the abdomen in the region extending below the ribs and above the belt line. To provide several sites for implantation of one or more osmotic delivery devices in the abdomen, the abdominal wall can be divided into 4 quadrants as follows: right upper quadrant extending 5-8 centimeters below the right ribs and about 5-8 centimeters to the right from the middle line, right lower quadrant extending 5-8 centimeters above the belt line and 5-8 centimeters to the right from the middle line, the upper left quadrant extending 5-8 centimeters below the left ribs and about 5-8 centimeters to the left of the midline, and the left lower quadrant, extending 5-8 centimeters above the belt line and 5-8 centimeters to the left from the middle line. This provides more available sites for implantation of one or more devices once or repeatedly. The implantation and extraction of osmotic delivery devices, as a rule, exercise� health workers using local anesthesia (e.g., lidocaine).

[00166] the treatment by extracting the osmotic delivery device from the subject is simple and gives the important advantage of immediate stopping of the drug delivery to a subject.

[00167] the Compositions in the form of suspension can also be used in infusion pumps, for example, osmotic pumps ALZET® (DURECT Corporation, Cupertino CA), which is a miniature infusion pumps for continuous administration of doses to laboratory animals (e.g. mice and rats).

5.0.0 Typical advantage of some aspects of the present invention

[00168] In accordance with one aspect of the present invention relates to methods of treatment using continuous delivery mimetics incretin (e.g. èksenatida), for example, through the use of an implantable osmotic delivery device. The experiments described in the present application, showed that continuous delivery èksenatida with the use of an implantable osmotic delivery device provided the following useful effects for subjects needing treatment: treatment of diabetes type 2 diabetes, improved glycemic control (as measured, for example, levels of glucose, HbA1c and/or fructosamine), the decrease in HbA1c, a decrease in the glucose concentration in the blood plasma on an empty stomach, lowering levels of blood glucose after meals, reduced�Linux unwanted effects in the gastrointestinal tract (e.g., nausea and vomiting) compared with injections twice a day, weight loss, lowering cholesterol low-density lipoprotein (LPNP), systolic blood pressure, treatment of hypertension, decreased levels of fructosamine and improving the quality of life of subjects treated.

[00169] in addition, continuous delivery mimetics incretin (e.g. èksenatida) can be used when implementing in practice the following methods: obesity treatment, control appetite, decrease calorie consumption, the reduction of food intake, appetite suppression, induction of anorexia, the treatment of impaired glucose tolerance, treatment of postprandial hyperglycemia, the treatment of postprandial dumping syndrome, the treatment of hyperglycemic conditions, reduction of triglycerides, reduction of cholesterol, increasing urine output, reducing the concentration of potassium in the urine, weakening of hypovolemia toxic, inducing rapid diuresis, preoperative preparation of the patient, the postoperative treatment of the patient, increase in renal plasmatica and glomerular filtration rate, treatment of pre-eclampsia or eclampsia during pregnancy, the increase in cardiac contractility, kidney failure treatment, treatment congestive heart failure treatment nephrotic syndrome treatment edema l�gcih, the treatment of systemic edema, treatment of cirrhosis, treatment of impaired glucose tolerance, treatment of pre-diabetes (glucose levels in the blood are higher than normal but not yet high enough to be diagnosed with diabetes), treatment of diabetes mellitus type 1 (e.g., in combination with insulin), reducing the risk of cardiovascular phenomena due to impaired glucose tolerance, reducing the risk of cerebrovascular disease due to impaired glucose tolerance, delay of progression of diabetes, the diabetes relief, delay the development of diabetes, induction of regeneration of β-cells, restoration of normoglycemia, ensuring applicationscope control, treatment of peripheral vascular disease, treatment of acute coronary syndrome, treatment of cardiomyopathy, treatment of gestational diabetes, treatment of polycystic ovary syndrome, treatment or prevention of nephropathy and diabetes induced by various diseases or conditions (e.g., steroid-induced diabetes, diabetes induced by treatment of human immunodeficiency virus, latent autoimmune diabetes in adults, nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, tolerance to impending hypoglycemia, restrictive lung disease, chronic�wow obstructive pulmonary disease, lipoatrophy and metabolic syndrome).

[00170] According to the present invention also proposed treatments for delivery of mimetica of incretin has the following advantages. Continuous delivery, for example, from the osmotic delivery device provides 100% adherence for subjects and eliminates the need for injections twice a day, every day, every week or even every month because the devices described in the present application, can deliver a mimetic of incretin for periods of time up to about one year or more. Avoidance of self-injection is of particular benefit to the subject suffering from fear of needles. Moreover, the use of implantable devices for continuous delivery provides the convenience of treatment and avoids scheduling conflicts, for example, with food, and also eliminates the inconvenience of administration of the drug by injection, for example, when subjects are people or busy daily activities. Also frequent self-introduction of the drug reminds the subjects of a disease state and contributes to the stigma associated with the disease and/or treatment; while the continuous delivery of drug from an implanted osmotic device mo�et to ensure that operators some relief from these reminders and stigma.

[00171] According to the present invention also proposed methods of treatment of subjects at dose levels mimetics incretin previously considered higher tolerated dose levels. For example, the herein described continuous delivery èksenatida for tolerated doses of at least 80 mg/day.

[00172] In accordance with another aspect of the present invention proposed methods of increasing the dose. In one embodiment, the implementation of the proposed multiple devices for continuous delivery of the drug, for example, mimetica of incretin. Each device can deliver a specific dose of drug per day. First implanted device with a low dose, after which it is removed and the implanted device with a higher daily dose. Alternatively, the first device may remain in place and can be implanted in a second device with increasing daily dose. According to another alternative, you can start introducing doses to a subject with an injectable form of the drug (for example, injections twice a day, once a day, once a week or once or twice a month) and move to the implantable device, thereby achieving continuous delivery after an initial period. The specified transition from the injectable form to implanter�the reception device, for example, can allow the actors or doctors to try a drug and may be monitored for any immediate adverse effects prior to implantation of the device. Transitions from injecting to form the implantable device can also be useful for treatment of subjects who are particularly worried about the possible side effects of the drug. Furthermore, the introduction of drugs by injection or by continuous delivery in low dose can provide adaptability in relation to medicines in low dose before changing to a higher and more effective therapeutic dose.

[00173] the Optimum time periods to determine the drug on how long the initial device remains in place until replacement by a delivery device with a higher dose. Similarly determine the optimal time periods of the continuation of the initial phase of treatment by injection prior to implantation of the osmotic delivery device. For example, the treatment is started at a low dose with a low incidence of side effects (e.g., within about 2 weeks, about 3 months, about 6 months, about 9 months, about one year). The subject adapts to this dose and then implanted device d�rates with the higher dose, providing a dose increase. Alternatively, the subject being treated with injectable form, increasing the dose occurs via implantable osmotic delivery device. Based on the data presented in the present description, it has been shown that the increasing doses provide additional beneficial effects in the regulation of glucose and weight loss. The initial examples of doses include, but are not limited to, delivery of from about 1 μg/day to about 20 mg/day with subsequent dose increase to values from about 5 μg/day to about 1000 μg/day. Preferably, the increasing doses of mimetica of incretin includes, but is not limited to, the following: about 10 mcg/day followed about 20 mcg/day; about 10 mcg/day followed about 40 mcg/day; about 10 mcg/day followed about 60 mcg/day; about 10 mcg/day followed about 80 mcg/day; about 20 mcg/day followed about 40 mcg/day; about 20 mcg/day followed about 60 mcg/day; about 20 mcg/day followed about 80 mcg/day; about 40 mcg/day followed about 60 mcg/day; about 40 mcg/day followed about 80 mcg/day; and about 60 mcg/day followed about 80 mcg/day. In one embodiment, the implementation of the present invented�e includes kits and methods of making sets, containing one or more osmotic delivery devices with a lower dose and one or more osmotic delivery devices with a higher dose (data of lower or higher doses are relative to other devices in the kit). These kits can further contain implanter, lidocaine and sterile region/auxiliary materials.

[00174] In General, increasing the dose is carried out from low-dose mimetica of incretin, for example, from about 1 μg/day to about 30 μg/day, high dose, which is longer than the specified low-dose, up to about 80 mcg/day.

[00175] In accordance with another aspect according to the present invention a method of treating diabetes without a significant increase of insulin secretion using mimetica of incretin. In a preferred embodiment of this aspect of the present invention the specified mimetic of incretin is a exenatide. The data obtained in the studies described herein showed that higher doses of continuous delivery èksenatida (for example, 20 mcg/day 40 mcg/day 80 mcg/day) was achieved for effective treatment of diabetes in the absence of an increase in insulin production. Insulin levels were determined by radioimmunoassay.

[00176] In accordance with another aspect of the methods according to the present�the invention provide for the administration of the drug, for example, mimetica of incretin without a substantial initial release of the drug, which usually occurs with depot injections (for example, the initial drug release from about 5% of the total drug in the depot composition to about 1% of the drug in depot-part) that ensure the continuous delivery within a certain time period (for example, depot injection, obtained using poly(lactides), poly(glycolide), copolymers of lactide with glycolide, poly(milk acid), poly(glycolic acid), copolymers of lactic and glycolic acids and their mixtures, and copolymers).

[00177] In accordance with another aspect of the present invention relates to methods of providing a more significant decrease in the concentration of glucose in plasma in a shorter period of time (e.g., 1-5 days), which can be achieved using injections twice a day, including ensuring continuous delivery of mimetica of incretin, for example, èksenatida. In one embodiment, the implementation of continuous delivery reach through the use of an implantable osmotic delivery device.

[00178] Another advantage of the present invention is the ability to remove the delivery device, provide�future continuous delivery of the drug, and to ensure a rapid termination of drug delivery, for any reason, for example, in the case of myocardial infarction, pregnancy, pancreatitis or suspected pancreatitis, a medical emergency (for example, discontinuation of drug therapy) or adverse reaction to the medication.

[00179] the Present invention uniquely aimed at addressing unfulfilled needs regarding mimetics incretin for injection. For example, one of the drawbacks of èksenatida for injections twice a day is that more than 65% of the subjects do not heal or are not supported on the target to ensure the level of HbA1c. Another disadvantage èksenatida for injections twice a day is that more than 65% of these subjects cease to comply with the treatment between 6-12 months when trying to comply with the treatment regimen by injection. Also 65% of subjects being treated with èksenatida for injections twice a day, are overweight and require long-term weight loss.

[00180] the Experiments described in the present application (e.g., Example 3) showed that the methods of and osmotic devices containing a mimetic of incretin, for use in methods of treating diabetes type 2 diabetes mellitus by continuous delivery according to the present invention provide long-term treatment of subjects � target doses full compliance with the subject's treatment regimen and long-term weight loss. Target dose usually provides significant sustained delivery of mimetica of incretin in therapeutic concentrations to the subject.

[00181] the Data presented in the section "Experiments" of the present description, show that according to the present invention proposed methods of and osmotic devices containing mimetics of incretin, for use in methods of treating diabetes type 2 diabetes mellitus by continuous delivery, with substantial stable delivery of mimetica of incretin in therapeutic concentrations is achieved within a time period of approximately 7 days or less, about 6 days or less, about 5 days or less, about 4 days or less, about 3 days or less, preferably about 2 days or less and more preferably about 1 day or less after implantation of the osmotic delivery device to a subject.

[00182] the data also show that according to the present invention proposed methods of and osmotic devices containing mimetics of incretin, for use in methods of treating diabetes type 2 diabetes mellitus by continuous delivery, with a significant decrease of glucose concentration in the blood plasma on an empty stomach, compared to the concentration of glucose in plasma NATOs�to before implantation, reach after implantation of the osmotic delivery device in the subject over a time period of approximately 7 days or less, about 6 days or less, about 5 days or less, about 4 days or less, about 3 days or less, preferably about 2 days or less and more preferably about 1 day or less after implantation of the osmotic delivery device to a subject.

[00183] the Data also show that according to the present invention proposed the possibility of termination of continuous delivery so that the concentration of mimetica of incretin becomes essentially netdetective in the blood sample of the subject after termination of continuous delivery, less than about 6 half-lives of the drug after termination of continuous delivery, using less than about 5 half-lives of the drug after termination of continuous delivery, using less than about 4 half-lives of the drug after termination of continuous delivery, or through less than approximately 3 half-lives of the drug after termination of continuous delivery. Moreover, the data show that treatment by continuous delivery of mimetica of incretin provided greater reductions in HbA1c than treatment by injection.

[00184] the Data also show�t, what methods of and osmotic devices containing a mimetic of incretin, for use in methods of treating diabetes type 2 diabetes mellitus by continuous delivery that are described herein provide improved adaptability with respect to increasing doses of the indicated mimetica of incretin, compared with injection of mimetica of incretin.

[00185] in addition, the data presented in the present description, show a significant advantage of the implanted osmotic delivery device according to the present invention before the introduction of mimetica of incretin through injections from the point of view of the received data on the quality of life for cure of subjects.

[00186] the Comparative data described below show the excellent results of treatment using the methods and osmotic devices containing a mimetic of incretin, for use in methods of treating diabetes type 2 diabetes mellitus by continuous delivery according to the present invention, in combination with Metformin treatment compared to other treatment modalities. These other treatments include injections èksenatida twice a day, an injection èksenatida once a week injection of liraglutide once a day, the injection taspoglutide once a week, orally administered once a day sitagliptin and oral �injected once a day pioglitazone.

[00187] Thus, the methods of and osmotic devices containing a mimetic of incretin, for example, exenatide, for use in methods of treating diabetes type 2 diabetes mellitus by continuous delivery described in this paper provide a new standard of effective treatment. The present invention provides a superior reduction in HbA1c, improved weight loss and full compliance with the treatment and long-term glycemic control compared with inhibitors of dipeptidyl peptidase-4 (DPP-4) (e.g., sitagliptin), thiazolidinedione (TZDs) (e.g., pioglitazone), other mimetics incretin for injection (e.g., liraglutide and taspoglutide) and injection èksenatida twice a day or once a week. Moreover, the present invention provides better tolerability of treatment of mimetic incretin because it is not necessary to self-inject, and methods of and osmotic devices containing a mimetic of incretin, for use in methods of treating diabetes type 2 diabetes mellitus by continuous delivery provide an improved tolerability gastro-intestinal tract.

Experiments

[00188] the Following examples are presented to provide the specialist in the art a complete disclosure and description of how to implement the present invention on the PRA�tick but these examples are not intended to limit the scope of what the authors regard as the invention. Attempts have been made to ensure accuracy in terms of numerical values (e.g., amounts, concentrations, percentage change, etc.), but should take into account some experimental errors and deviations. Unless otherwise stated, temperatures are given in degrees Celsius and pressure is atmospheric or close to it.

[00189] the Compositions used to implement the methods according to the present invention, conform to the specifications for content and purity of pharmaceutical products. Additional examples of compositions in the form of a suspension containing mimetics of incretin can be found in patent publications U.S. 2006/0193918, 2008/0260840 and 2010/0092566.

Example 1

Description of a typical osmotic delivery device

[00190] Were developed formulations in the form of a suspension containing particles èksenatida suspended in media solvent/polymer for the treatment of diabetes mellitus type 2. Compositions in the form of suspension was loaded into the device DUROS® for subcutaneous implantation for delivery èksenatida with a constant and consistent speed.

[00191] Fig.4 shows an example of a delivery system DUROS®, suitable for implementing the present invention. Fig.4 p�shown the osmotic delivery device 10, containing reservoir 12. The piston Assembly 14 is in the cavity of the tank and divides the specified cavity into two chambers. In this example, the chamber 16 contains a composition useful agent, and the chamber 20 contains an osmotic agent. Semi-permeable membrane 18 is located on the first distal end of the reservoir adjacent to the chamber 20 containing the composition of the osmotic agent. The diffusion controller 22 is located, docking connection, the second distal end of the vessel 12 adjacent to the chamber 16 containing the composition in the form of a suspension containing a drug. The diffusion controller 22 contains a hole for the delivery of 24. The diffusion controller 22 may be any suitably in-line device having an opening for delivery. In this embodiment the flow path 26 is formed between the diffusion controller with thread 22 and the pitch of thread 28 formed on the inner surface of the tank 12. In alternative embodiments, the implementation of the diffusion controller may, for example, (i) to be pressed (or preterm) through the hole and may come in contact with the smooth inner surface of the vessel or (ii) contain two pieces the outer casing is created and arranged for positioning in the bore, the inner core that is embedded in the outer shell, and a channel for liquids, having a spiral shape defined between the outer sheath�and the inner core (e.g., patent publication US 2007/0281024).

[00192] the Liquid drawn into the chamber 20 through the semi-permeable membrane 18. The composition of the useful agent is distributed from the chamber 16 through the opening for the delivery of 24 in the diffusion controller 22. The piston Assembly 14 is in contact and is tightly on the inner wall of the tank 12, thus isolating the composition of the osmotic agent in the chamber 20 and the liquid sucked through the semi-permeable membrane 18, the composition of a useful agent in the chamber 16. In equilibrium composition in the form of suspension is released through the opening for the delivery of 24 in the diffusion controller 22 at a speed corresponding to the speed at which the external fluid is drawn into the chamber 20 through the semi-permeable membrane 18. That is, the delivery device DUROS® releases the drug with a pre-determined speed based on the principle of osmosis. Extracellular fluid enters the delivery device DUROS® through a semi-permeable membrane directly to the osmotic mechanism, which expands and moves the piston with a slow and consistent speed. The movement of the piston causes the medicinal composition to be released through the hole diffusion controller.

[00193] a Semi-permeable membrane 18 may be in the form of a tube, which is flexibly mounted seal relative to the inner surface of the tank 12. N� Fig.4 shows she has ribs that are used for the semipermeable membrane 18 in contact by friction with the inner surface of the tank 12.

[00194] the Data delivery device DUROS® provide a continuous and controlled subcutaneous delivery èksenatida zero order with consistent velocity, which gives some advantages, such as the treatment of diabetes mellitus type 2; for example, relatively constant therapeutic concentrations èksenatida in the blood allow better control of glucose concentration in the blood and can reduce the risk of secondary disease, is otherwise associated with poorly controlled diabetes mellitus type 2. The data delivery device DUROS® provide the treatment duration of approximately 3 to approximately 12 months in a wide range of doses while maintaining the stability èksenatida.

[00195] In contrast to injections èksenatida once a day or twice a day, the delivery device DUROS® support consistent concentration èksenatida in the blood. This is particularly important during all meal periods and throughout the night. Device delivery DUROS® does not require any action by the entity to ensure compliance with the treatment regimen.

[00196] in addition, the data delivery device DUROS® may have advantages from the point of view of safety�reports compared with injections èksenatida once a day or twice a day, or depot formulations èksenatida. Shipping excludes zero-order peak concentrations èksenatida in the blood, usually observed in the case of injections, once a day or twice a day, which, apparently, are associated with adverse reactions, for example, frequent nausea, and the minimum concentration that can be associated with reduced efficacy. Another desired feature of the devices of delivery DUROS® is that they can be quickly and easily removed in the doctor's office to stop the introduction of the drug in the event of adverse reactions to the medication or any event requiring stopping treatment.

Example 2

Data from clinical studies in phase 1b for continuous delivery èksenatida

[00197] Clinical trial phase 1b is planned as a multicenter, randomized, open study with three malls and a total of 44 subjects. Specified clinical trial phase 1b is planned and conducted to evaluate the safety and tolerability of continuous subcutaneous delivery of unmodified synthetic èksenatida containing the amino acid sequence of axendia-4, by means of the delivery devices DUROS® (ITCA 650) in subjects with poorly controlled diabetes type 2 diabetes. In this study, the osmotic device for the delivery and�was planirovanie subcutaneously in the abdomen under the skin of the abdomen.

[00198] In the study of subjects randomizable to receive doses of 10 mcg/day, 20 mcg/day 40 mcg/day 80 mcg/day of ITCA 650. Each group consisted of 10-12 subjects for each of the four dose groups. The treatment was performed within 28 days with 7-day follow-up period. Thus, this study was a 29-day study, which tallied just 28 days of treatment.

[00199] A. Demographic data of the group for the study

[00200] the Criteria for inclusion/exclusion were as follows: subjects were 30-70 years of age, and diabetes mellitus type 2 was diagnosed more than 6 months prior to screening. The subjects were insufficiently controlled diabetes mellitus type 2, but they followed a stable therapeutic regimens diet and exercise alone or in combination monotherapy with Metformin, TZD monotherapy or combination therapy with Metformin plus TZD. The subjects levels of hemoglobin A1c (HbA1c) were greater than or equal to 6.5% and less than or equal to 10%. The subjects of the glucose concentration in the blood plasma on an empty stomach was less than 270 mg/DL and the concentration of C-peptide fasting was more than 0.8 ng/ml.

[00201] Studied the following 4 dose groups: Group 1, 10 μg/day èksenatida delivered through delivery devices DUROS®; Group 2, 20 mg/day èksenatida, zastavlyavhsim delivery devices DUROS®; Group 3, 40 mcg/day èksenatida delivered through delivery devices DUROS®; and Group 4, 80 mcg/day èksenatida delivered through delivery devices DUROS®.

[00202] the Demographic data for the study are presented in Table 1.

[00203]

Average
Table 1
Group 1Group 2Group 3Group 4
Age (years)
Average56,457,452,156,7
Range44-6847-7037-6749-63
Gender (M/F)8/47/44/67/4
Weight (kg)
95,794,388,589,5
Range75,5-130,255,7-to 120.456,1 is 125.8to 58.1-130,3
HbA1c (%)
Average7,7%7,9%7,4%7,4%
Range6,5-10,26,7-9,86,5-9,46,6-9,4
Preceding
treatment:
Diet and physical8,3%20,0%by 36.4%
exercise
Metformin91,7%of 90.9%80,0%45,4%
Metformin + TZD9,1%18,2%

[00204] the Distribution of subjects in the study are presented in Table 2.

[00205]

Table 2
Group 1Group 2Group 3Group 4
n12111011
Completed11 (92%)11 (100%)10(100%)7 (64%)
research
The retired actors1 (8%) 0 (0%)0 (0%)4 (36%)
Undesirable1001
phenomena
Withdrew0003
informed
consent

[00206] V. pharmacodynamics Data

[00207] the Following measurement data pharmacodynamics received in the result of the study èksenatida delivered through the delivery devices DUROS®.

[00208] the Concentration of glucose in the blood plasma on an empty stomach (defined by standard methods) was reduced within 24 hours (Fig.1) after the start of treatment (i.e., implanted delivery devices DUROS®) and differed significantly from baseline to endpoint in the group of 20 m�g/day, the group of 40 mg/day and 80 mcg/day, as shown in Table 3. Table 3 shows the results of a randomized, open-29-day study of continuous subcutaneous delivery èksenatida with the use of osmotic delivery device. The table shows the change in glucose concentrations in the blood plasma on an empty stomach at the end of the 28 day treatment osmotic device for delivering 10 mcg/day, 20 mcg/day 40 mcg/day 80 mcg/day. Average values in the table are given in units of mg/DL. Reduce concentrations of plasma glucose fasting blood osmotic device for delivering 20 mcg/day 40 mcg/day 80 mcg/day were statistically significant.

[00209] Accordingly, in one embodiment implementing the present invention relates to methods of and osmotic devices containing exenatide, for use in methods of treating diabetes type 2 diabetes mellitus by continuous delivery èksenatida, with significant stable delivery èksenatida in therapeutic concentrations is achieved within a time period of approximately 7 days or less, preferably about 2 days or less and more preferably about 1 day or less after implantation of the osmotic delivery device to a subject. In a related embodiment the present invention provides considerable�e reduction of glucose concentration in the blood plasma on an empty stomach compared with the glucose concentration in the blood plasma on an empty stomach prior to implantation achieved after implantation of the osmotic delivery device in the subject over a time period of approximately 7 days or less, preferably about 2 days or less and more preferably about 1 day or less after implantation of the osmotic delivery device to a subject.

[00205]

Table 3
Mean ± S. D.p-value
10 µg/day-5,6±34,330,5175
20 mg/day-31,2±24,20of 0.0039
40 mg/day-42,0±33,160,0003
80 mg/day-28,8±overall 32.250,0014

[00211] the Treatment èksenatida delivered through delivery devices DUROS® 20 mcg/day 40 mcg/day and 80 mg/day resulted in clinically significant decreases in the average glucose concentration two hours after meals from pre-treatment to end�th point, as shown in Table 4. Observed apparent dose-response. Dimension reduction of glucose concentration two hours after food intake was performed by standard methods. In Table 4 data show a change in glucose concentrations two hours after the meal at the end of the 28 day treatment osmotic device for delivering 10 mcg/day, 20 mcg/day 40 mcg/day 80 mcg/day. Average values in the table are given in units of mg/DL. Reduce concentrations of glucose two hours after meals as an osmotic device that delivers 20 mcg/day 40 mcg/day 80 mcg/day were statistically significant.

[00212]

Table 4
Mean±S. D.p-value
10 µg/day-16,3±24,780,1699
20 mg/day-34,7±32,390,0135
40 mg/day-47,1±70,450,0012
80 mg/day-69,6±44,35<0,0001

[00213] the area under the crooked� (AUC) of glucose and the ratio of the endpoint prior to treatment was significantly different from baseline AUC in the group of 20 mcg/day, the group of 40 mg/day and 80 mcg/day; observed decreasing trend of these indicators in the dose of 10 mg/day. The AUC calculations were performed by standard methods.

[00214] After implantation of the delivery devices DUROS® concentration èksenatida in plasma was increased to affecting equilibrium concentration within 24-48 hours and persisted throughout the treatment period (Fig.2). After extraction device delivery DUROS® concentration èksenatida fell to nedetectabile concentrations over 24 hours (Fig.2). Exenatide were detected using radioimmunoassay. Accordingly, in one embodiment implementing the present invention relates to methods of and osmotic devices containing exenatide, for use in methods of treating diabetes type 2 diabetes mellitus by continuous delivery èksenatida that provide the possibility of termination of continuous delivery so that the concentration èksenatida becomes essentially netdetective in the blood sample of the subject after termination of continuous delivery using less than about 72 hours, preferably less than about 24.

[00215] the HbA1c Levels (as shown in Table 5) and fructosamine differed significantly from baseline to endpoint in all treatment groups. Determine HbA1c and fructosamine was performed by standard methods. In Table 5 the following�NY data of a randomized, open-29-day study of continuous subcutaneous delivery èksenatida with the use of osmotic delivery device. The table shows the change in HbA1c at day 29 (relative to day 1 of the study; i.e., the beginning of continuous delivery) osmotic device for delivering 10 mcg/day, 20 mcg/day 40 mcg/day 80 mcg/day. Average values in the table represent changes of HbA1c plus or minus the standard deviation (S. D.). Reducing HbA1c for all osmotic device (i.e. delivering 10 mcg/day, 20 mcg/day 40 mcg/day 80 mcg/day) were statistically significant.

[00216]

Table 5
DoseMean change in HbA1c±S. D.p-value
10 µg/day-0,54±0,39is 0.0010
20 mg/day-0,62±0,31<0,0001
40 mg/day-0,45±0,31with 0.0013
80 mg/day-0,73±0,360,0018

[00217] the body Weight decreased in all treatment groups and was significantly different from baseline to endpoint in the group of 80 mcg/day (table 6). Table 6 shows the data randomized�wow open 29-day study of continuous subcutaneous delivery èksenatida with the use of osmotic delivery device. The table shows the change in body weight at the end of the 28 day treatment osmotic device for delivering 10 mcg/day, 20 mcg/day 40 mcg/day 80 mcg/day. Average values in the table are given in kilograms (kg).

[00218]

Table 6
DoseMean±S. D.p-value
10 µg/day-0,27±,910,3415
20 mg/day-0,28±1,510,5485
40 mg/dayof 1.13±1,600,0524
80 mg/day-3,09±2,130,0086

[00219] while the observed apparent dose-response in relation to unwanted effects in the gastrointestinal tract (nausea and vomiting), these phenomena occurred in the early period after implantation of the device (s) and decreased in the first week for most actors. These symptoms of nausea, depending on the time of individual subjects is shown in Fig.3.

[00220] in affect�, treatment èksenatida delivered using delivery devices DUROS® at doses of 10, 20 and 40 mg/day were well tolerated within 28 days of treatment. Equilibrium concentration èksenatida quickly achieved and maintained during the entire course of treatment. Remove hardware delivery DUROS® led to the rapid cessation of treatment, and the concentration of èksenatida fell to nedetectabile concentrations within 24 hours. A significant decrease in the concentration of glucose in plasma fasting glucose concentration two hours after food intake were observed for 1-5 days and they persisted throughout the 28 day treatment period in the dose groups of 20, 40, 80 mcg/day. A significant reduction in HbA1c was observed in all treatment groups. Body weight decreased in all treatment groups.

[00221] the Treatment of subjects with diabetes mellitus type 2 using delivery devices DUROS®, providing 10 μg/day, 20 mcg/day 40 mcg/day 80 mcg/day, was safe and well tolerated; for treatment of clinically significant changes in terms of safety, the main indicators of the condition of the body or data of the medical examination were not observed. While the observed apparent dose-response in relation to unwanted effects in the gastrointestinal tract (nausea and vomiting), these phenomena have any�in the early stages (within the first week) after implantation of the device (s) and tended to decrease with time.

[00222] the data showed that the delivery device DUROS®, which provides continuous delivery of èksenatida, had the following advantages: highly effective glucose control; a reduction in the frequency, severity and duration of side effects; elimination of the need to self-inject; significant weight loss; and 100% compliance with the prescribed treatment. Additional benefits treatment of diabetes mellitus type 2 with the help of these devices was the ability to quickly reach equilibrium therapeutic concentrations èksenatida the subject after implantation; the ability to ensure long-term stable delivery èksenatida; the ability to provide a significant decrease in the glucose concentration in the blood plasma on an empty stomach (compared to glucose concentration in the blood plasma on an empty stomach prior to implantation of the osmotic device); and the ability to quickly stopping treatment if necessary.

Example 3

Data from clinical studies in phase 2 for continuous delivery èksenatida

[00223] the Clinical study phase 2 was planned as a multicenter, randomized, open study has 50 centers in total of 155 subjects. The specified phase 2 study planned and conducted to compare the efficacy, safety and tolerability of treatment with continuous on�cutaneous delivery of unmodified synthetic èksenatida, containing the amino acid sequence of Bloomington: Indiana-4, by means of the delivery devices DUROS® (ITCA 650) with injections twice a day unmodified synthetic èksenatida containing the amino acid sequence of Bloomington: Indiana-4, the subjects with poorly controlled Metformin cure diabetes type 2 diabetes. In this study, subjects first randomizable to receive either 20 or 40 mcg/day ITCA 650 for 12 weeks or injections èksenatida twice a day in an amount of 5 μg twice a day for 4 weeks followed by 10 mcg twice a day for 8 weeks. Then the subjects randomizable to obtain 20, 40, 60 or 80 mcg/day ITCA 650 for another 12 weeks. In this study, the osmotic delivery device (ITCA 650) implanted subcutaneously in the abdomen under the skin of the abdomen.

[00224] In each group included approximately 50 subjects for each of the three groups as follows: Group 1, the group treated with implanted osmotic delivery devices according to the present invention, which brought 20 mcg/day; Group 2, the group treated with implanted osmotic delivery devices according to the present invention, which brought 40 μg/day; and Group 3, group treated with injections of e�Sentido twice a day in an amount of 5 μg twice a day for 4 weeks followed by 10 mcg twice a day for 8 weeks. Overview of the study design is shown in Fig.5. Extended phase consisted weeks 13-24 and group repositional 1:1 for continuous delivery èksenatida, as shown in this figure. At the beginning of the extended phase for each subject was extracted any implanted osmotic delivery device and an implanted osmotic delivery device that provides continuous delivery of èksenatida at a given dose. For example, if the subject was originally in Group 1 treated by continuous delivery of èksenatida 20 mcg/day, and received an increase to a dose of 60 mg/day, at the beginning of the extended phase was extracted osmotic device that delivers 20 mcg/day, and implanted a new device that delivers 60 mg/day. For subjects initially treated by injection, the injection was stopped and implanted osmotic delivery device at the beginning of the extended phase. The study was completed on 15 July 2010.

[00225] Accordingly, the results of phase 2 study allow to evaluate the safety and efficacy of treatment using continuous delivery èksenatida compared with injections èksenatida twice a day, diabetes mellitus type 2 for 13 to 24-week treatment period. Moreover, this study allows to evaluate stole�the radiation dose of treatment by continuous delivery èksenatida and the possibility of transition of subjects from treatment èksenatida injecting èksenatida twice a day to treatment by continuous delivery.

[00226] Demographic data of the group for the study

[00227] the Criteria for inclusion/exclusion were as follows: subjects were 18-70 years of age, and diabetes mellitus type 2 was diagnosed more than 6 months prior to screening. The subjects were insufficiently controlled diabetes mellitus type 2, but they followed a stable therapeutic regimens diet and exercise alone or in combination with Metformin monotherapy. The subjects HbA1c levels were greater than or equal to 7.0% and less than or equal to 10%. The subjects of the glucose concentration in the blood plasma on an empty stomach was less than 240 mg/DL and body mass index (BMI) was less than or equal to 40 kg/m2.

[00228] the Personal data of the study groups are presented in Table 7.

[00229]

Table 7
Group 1Group 2Group 3
N (sample size)515153
Age (years)54,053,353,8
Gender (M/F)25/2623/28 29/24
Duration of diabetes (years)6,28,45,2
HbA1c (%)7,98,08,0
Weight (kg)93,591,593,4
BMI (kg/m2)of 33.531.8 mm33,0

[00230] the Distribution of subjects in the study after 12 weeks are presented in Table 8.

[00231]

Table 8
Group 1Group 2Group 3Total
N (%)N (%)N (%)N (%)
Randomized and treated515153155
Completed research�R 47 (92,2)48 (94,1)47 (88,7)142 (91,6)
Early dismissal4 (7,8)3 (5,9)6(11,3)13(8,4)
Withdrew informed consent2 (3,9)1 (2,0)2 (3,8)5 (3,2)
Adverse event1 (2,0)2 (3,9)2 (3,8)5 (3,2)
1 (2,0)0 (0,0)2 (3,8)3(1,9)

[00232] V. pharmacodynamics Data

[00233] (i) Data at week 12

[00234] the Following measurement data pharmacodynamics received as a result of this clinical study èksenatida phase 2.

[00235] Change in HbA1c after 12 weeks of treatment are presented in Table 9.

[00236]

Table 9
Volume SourceHbA1c%Change
sampleb1%Week 12HbA1c
Group 1n=477,906,94-0,96*
Group 2n=478,006,96-1,04*
Group 3n=478,01of 7.19-0,82*
*p<0,001 relative to the initial level

[00237] the Data showed that after 12 weeks of treatment, all groups showed a decrease in HbA1c from baseline to final. Treatment èksenatida by continuous delivery (Group 1 and 2) provided greater HbA1c reduction than treatment with èksenatida by injection (Group 3). All reduce HbA1c were statistically great in 12 weeks, compared with baseline, but not among themselves. This study does not serve to identify differences between groups.

[00238] Dal�achi analysis of the data showed that a higher percentage of subjects achieved HbA1c less than or equal to 7% and less than or equal to 6.5% after 12 weeks in the treatment in accordance with the methods according to the present invention using a continuous delivery èksenatida from the osmotic delivery device, compared with the injection, twice a day (table 10).

[00239]

Table 10
Subjects (at 7% or below of all)PercentageThe subjects (at the level of 6.5% or below of all)Percentage
Group 130 of 476415 of 4732
Group 232 of 476812 of 4726
Group 324 of 47518 of 4717

[00240] the body Weight decreased in all treatment groups and was significantly different from baseline to endpoint after 12 weeks of treatment in all GRU�groin (table 11).

[00241]

Table 11
EntitiesThe average loss of weight (in kg)Percentage change (%)
Group 1n=47-0,8±2,4**-0,9±2,7 5
Group 2n=48of -2.0±3,0*of -2.6±3,5
Group 3n=47-1,3±2,5*of -1.5±2,8
*p<0001, relative to the initial level
**p<0,05 relative to the initial level

[00242] while the observed apparent dose-response in relation to unwanted effects in the gastrointestinal tract (nausea and vomiting), these phenomena occurred in the early period after implantation of the device (s) and generally decreased in the past several weeks the majority of the subjects (Fig.6). Fig.6 shows that when the dose of the injections twice per day increased from 5 mg/day to 10 mg/day, the incidence of nausea Uwe�was icials and remained higher than with the initial dose level of treatment. This result was opposite to the data observed in continuous delivery, in which the General trend was aimed to decrease the incidence of nausea over time.

[00243] Referring To Fig.6, the initial frequency of nausea in the case of injections èksenatida was above 20% at a dose of 5 mcg twice a day. After four weeks, when the dose increased to 10 mcg twice a day, the frequency of nausea was again increased to over 20% and remained at this level during the remainder of the 12-week period.

[00244] In the case of treatment at 20 mg/day by continuous delivery of primary frequency of nausea was approximately 25% and gradually decreased every week. During the first four weeks, the incidence of nausea was similar with injections èksenatida, although delivered twice the number of èksenatida. With 6 weeks and then the frequency of nausea continued to fall and was below 10% at the end of 12 weeks. The duration of nausea was significantly lower in the group of continuous delivery of 20 mcg/day with an average duration of nausea 17 days compared from 47.7 days in the case of injections èksenatida.

[00245] In a higher dose, of 40 mg/day, administered by continuous delivery, the incidence of nausea was higher, but dropped to a similar level compared to the injections� èksenatida from 6 weeks onward, although the number of èksenatida that retrieved the subject, was twice the number of injections èksenatida. In most cases, the nausea was mild to moderate.

[00246] the Data in Fig.6 show that the delivery of 20 mcg/day by continuous delivery from an osmotic delivery device resulted in permanent relief of symptoms of nausea during the 12-week treatment period. Moreover, the data show that over time, the delivery of 40 µg/day by continuous delivery from an osmotic delivery device does not lead to more nausea than injection èksenatida at a lower dose twice a day. These data show improved tolerability of treatment with èksenatida using a continuous delivery compared with injections èksenatida twice a day. Accordingly, in one embodiment implementing the present invention relates to methods of and osmotic devices containing exenatide, for use in methods of treating diabetes type 2 diabetes mellitus by continuous delivery èksenatida that provide improved adaptability in increasing doses èksenatida.

[00247] in addition, evaluated the quality of life among the study subjects at baseline and 8 weeks using a validated survey of quality of life DM-SAT (Anderson, RT, et al., Diabetes Care 32:51 (2009)). Studies�mended sixteen criteria and their subjects were independently rated on a scale of 0-10. Was performed comparing the change relative to baseline values among the treatment groups (n ~ 50 subjects/group) and received an overall assessment on the basis of 16 criteria. In addition, these 16 criteria grouped in four podskalan health, lifestyle, medical, control and comfort.

[00248] the Data presented in Fig.7, showing the percentage change relative to baseline in overall QOL assessment in week 8. In this figure the numbers above the columns in the histogram indicate the following: n improved indicator QOL/n with stable QOL indicator/n, with a reduced rate, QOL, respectively; for Group 3, 36/0/15; for Group 1, 35/3/9; and for Group 2, 40/1/7. The data showed that, on average, subjects gave an overall higher QOL assessment treatment èksenatida when said treatment provided by continuous delivery of 20 mcg/day (Group 1) and 40 mg/day (Group 2) using the implanted osmotic delivery device in comparison with when exenatide was administered by injection twice a day (Group 3). For injection èksenatida (Group 3) improved QOL was slightly more than 10%. For Groups 1 and 2 improved QOL was more from 20-30%. The majority of subjects receiving injections èksenatida (Group 3) reported lower QOL than any of the groups continuously�Noah shipping (Group 1 and 2). These data demonstrated a significant advantage of the implanted osmotic delivery device before the introduction of èksenatida through injections from the point of view of the received data on the quality of life for cure of subjects.

[00249] moreover, in analysing QOL using Pascal in week 8, and the percentage change relative to baseline is shown in Fig.8. In this figure, the columns indicated by the Group number, i.e. Groups 3, 1 and 2 respectively. The data showed that subjects were evaluated by continuous delivery èksenatida with the use of an osmotic pump providing a consistently higher QOL than exenatide, administered by injection, for each of the four podsol of health, health monitoring, lifestyle and convenience. These data demonstrated a significant advantage of the implanted osmotic delivery device before the introduction of èksenatida through injections from the point of view of the received data on the quality of life in each of the four Pascal cure for entities.

[00250] the Treatment èksenatida by continuous delivery has led to a possible beneficial changes in the other parameters compared to treatment with injections èksenatida at 12 weeks. For example, the values of cholesterol low-density lipoprotein (HLPP)�relative baseline to the 8 week was so, as shown in Table 12.

[00251]

Table 12
The change in LDL cholesterol relative to baselinePercentage change
Group 1-4,8 mg/DL-1,63
Group 2-5,4 mg/DL-4,33
Group 3+1.2 mg/DL15,26

[00252] HPNP decreased by 4.8 and 5.4 mg/DL in the treatment èksenatida by continuous delivery in 20 and 40 mcg/day, respectively, while it increased by 1.2 mg/DL in the treatment èksenatida by injection. These data showed a more favorable effect on the reduction HPNP by treatment using continuous delivery èksenatida compared with the injection, twice a day.

[00253] moreover, the change of systolic blood pressure in the sitting position relative to baseline to 8 weeks was as shown in Table 13.

[00254]

Table 13
Group 1-3,6 mm Hg.PT.
Group 2-6,8 mm Hg.PT.
Group 3RUR 4.2 mm Hg.PT.

[00255] Systolic blood pressure decreased by 3.6 and 6.8 mm Hg.PT. when treating èksenatida by continuous delivery in 20 and 40 mcg/day, respectively, and decreased by 4.2 mm Hg.PT. when treating èksenatida by injection. These data showed that all treatments had a similar beneficial effect on reducing systolic blood pressure by treatment with application of continuous delivery èksenatida and injections twice a day.

[00256] (ii) Data on the 20 week

[00257] extended Data phase to the status of the subject at week 20 shown in Fig.9. In the extended phase for weeks 13-24 of subjects from each treatment group randomizable to obtain continuous delivery èksenatida 20, 40, 60 or 80 mcg/day. Changes of HbA1c percentage at week 20 of treatment are presented in Table 14.

[00258]

Table 14
The dose delivered by a continuous delivery randomized groupsSample size Baseline HbA1c%Hb1% at week 20The change of HbA1c
20 mg/dayn=17of 7.88of 7.03-0,85
40 mg/dayn=397,83was 6.77-1,06
60 mg/dayn=358,06of 6.79-1,27
80 mg/dayn=17of 8.076,68-1,39

[00259] the data showed that increasing the dose for continuous delivery in higher doses of 60-80 mg/day, resulted in a further reduction in HbA1c relative to baseline. In addition, observed the continuation of weight loss.

[00260] the Data presented in Table 15, show of subjects reaching treatment goals HbA1c after 20 weeks. These data showed a continuous decrease in HbA1c in the randomized groups. Moreover, data showed that increasing the dose resulted in a greater number of subjects reaching treatment goals HbA1c./p>

[00261]

Table 15
Subjects (at 7% or below of all)PercentageThe subjects (at the level of 6.5% or below of all)Percentage
20 mg/day10 of 2050%4 of 2020%
40 mg/day31 of 3979%18 of 3946%
60 mg/day28 of 3874%18 of 3847%
80 mg/day13 of 1776%9 of 1753%

[00262] Thus, treatment with èksenatida by continuous delivery with the use of an implantable osmotic delivery device in the doses of 20 and 40 mg/day was well tolerated for 12 weeks with strong activity in lowering glucose. HbA1c decreased by 0.96% and 1.04% in the treatment of AIX�Atidim by continuous delivery at doses of 20 and 40 µg/day, respectively, compared with a decline of 0.82% with injections èksenatida. A larger number of subjects achieved treatment goals HbA1c 7% or 6.5% in the treatment èksenatida by continuous delivery compared with injections èksenatida. The mass loss was observed in all treatment groups. Despite receiving twice èksenatida during the first 4 weeks of treatment, nausea gradually decreased during the first six weeks in the treatment èksenatida by continuous delivery of 20 mcg/day compared with treatment with injections of èksenatida, when the nausea lasted from weeks 4-12 with the number of cases per week ≥20%. Both doses of treatment èksenatida by continuous delivery performed better than injections èksenatida overall and in all four podskalak (health, medical care, way of life, convenience) QOL survey conducted after 8 weeks of treatment.

[00263] in addition, to increase the dose when treating èksenatida by continuous delivery 13 weeks resulted in further reduction of HbA1c after 8 weeks of treatment. Subjects treated èksenatida by continuous delivery in the amount of 60 µg/day from 13-20 weeks, showed a reduction of HbA1c by 1.27% compared to baseline. Subjects treated èksenatida by continuous delivery in an amount of 80 mg/day from weeks 13 to 20, have demonstrated�Eisenia HbA1c 1.39% relative to baseline.

[00264] (iii) Final data NDT completion of the study phase 2

[00265] the Overall distribution of subjects at the completion of the study are presented in Table 16.

[00266]

Table 16
Groups 1 and 2Group 3
Weeks 1-1210
The percentage of completion93%89%
Exception due to nausea3,9%the 5.7%
The exception before re-randomization8,4%6,4%
Weeks 13-24
The percentage of completion95%NA* 15
Exception due to nausea<1%NA*
*NA - not applicable

[00267] In Table 16, column "Week 1-12" shows the distribution issledovania the first period of treatment. Was a very high completion percentage, 93%, treatment groups, providing continuous delivery (Group 1 and 2). Groups 1 and 2 each consisted of two subjects excluded due to nausea, and Group 3 included three subjects excluded due to nausea. In the table column "Exception before re-randomization" represents subjects who completed the first 12 weeks of treatment, but decided not to continue the treatment period 12-week extended phase. The specific cause of this exception have not been explained.

[00268] In Table 16 for "Weeks 13-24" all subjects treated with the use of continuous delivery from implanted osmotic delivery devices. The period of treatment in the study had a very high completion percentage. Only one subject was excluded due to nausea. The subject received injections of èksenatida, and then were treated by continuous delivery in the amount of 60 mg/day. The subject was marked by nausea for five days, and this subject was excluded from the study.

[00269] to change the percentage of HbA1c for weeks 13-24 treatment are presented in Table 17.

[00270]

Table 17
Dose delivered
by continuous delivery
Weeks 13-24 (µg/day)
Sample sizeBaseline HbA1c, %HbA1c, %, week 12HbAlc, %, at week 24The change of HbA1cThe percentage of subjects who reached HbA1c:≤7%≤6,5%
20n=207,967,107,07-0,89*60%20%
40n=427,797,076,93-0,86*71%43%
60n=418,057,086,67-1,38*73%49%
80n=198,036,836,67-1,36*79%63%
*p<0,0001 relative to baseline

[00271] In Table 17, the data for 12 weeks, indicate the average change in HbA1 values from the start of treatment (baseline) to 12 weeks (end of treatment) for subjects after randomization and prior to the entry into the period of extended treatment phase (weeks 13-24) (see Fig.5). The data given for 24 weeks, and the improvements in HbA1c associated with each dose at the end of treatment by continuous delivery at the indicated doses. After treatment with èksenatida by continuous delivery at 24 weeks was observed further reduction in HbA1c in all treatment groups. All of these reduce HbA1c statistically significant relative to baseline and demonstrate what can be achieved, a further decrease in HbA1c using a continuous delivery èksenatida. For the two highest doses (i.e., 60 mg/day and 80 mcg/day) in both groups observed a change of more than 1.3%, which shows that increasing the dose èksenatida, administered by continuous delivery, provided further decrease in HbA1c during the treatment period. The percentage of subjects with HbA1c of 7% or less showed a good result of treatment for all groups, with the largest improvements observed at higher doses (60 mg/day, 73%; and 80 mcg/day, 79%). This study does not serve to identify differences between groups.

[00272 Reduce HbA1c and percentage of subjects reached HbA1c less than 7%, demonstrating the clinical value of treatment of subjects with diabetes mellitus type 2 using a continuous delivery èksenatida in a range of different doses.

[00273] Further analysis of the data HbA1c weeks 13-24 for subjects receiving continuous delivery 60 mg/day èksenatida showed that the higher the initial level of HbA1c at the beginning of the extended period of treatment phase, the greater the reduction in HbA1c was observed at the end of the period of extended treatment phase (table 18).

[00274]

Table 18
The subjects treated by continuous delivery 60 mg/daySample sizeBaseline HbA1cHbA1c at week 24The change of HbA1cThe percentage of subjects who reached HbA1c is 7% or less
All subjectsn=418,056,67-1,38*73%
Subjects with baseline HbA1c > 7,0n=368,226,73-1,49* 69%
Subjects with baseline HbA1c≥7.5 ton=278,54was 6.77-1,77*63%
*p<0,0001 relation to the initial level

[00275] In Table 18, column "Original" represents the average HbA1c for subjects at the beginning of treatment in early clinical studies. For 41 of the subject treated by continuous delivery 60 mg/day èksenatida from weeks 13-24, the average HbA1c was 8,05% fall by 1.38% after treatment. Data from 41 provinces, 36 subjects whose baseline HbA1c was greater than 7, showed an average HbA1c 8,22% with the fall 1.49% after treatment. Of the 41 provinces, 27 subjects whose baseline HbA1c was greater than or equal to 7.5, showed an average HbA1c 8,54% with an even greater decline, amounting to 1.77%, after treatment. These results also show that treatment of subjects with diabetes mellitus type 2 using a continuous delivery èksenatida gives the desired result of the treatment, as observed further improvement in HbA1c during the treatment period and subjects with higher initial levels at the beginning of the treatment period showed the desired result of large reductions in HbA1c than subjects with lower outcome�bubbled levels.

[00276] the body Weight was decreased in all treatment groups and was significantly different from baseline to endpoint after 24 weeks of treatment in all groups (table 19).

[00277]

Table 19
The dose delivered by a continuous delivery
Weeks 13-24 (µg/day)
Sample sizeThe average loss of weight (in kg)Percentage change (-%)
20n=20-0,8-0,85
40n=42-3,6*-4,0
60n=41-3,1*-3,4
80n=19is -3.5**-3,8 10
*p<0,0001 relation to the initial level
**p<0.01 relative to baseline

[00278] the lowest dose of 20 mcg/day led to an average weight loss of constituting 0.8 kg. higher doses leads to�or loss of mass, component greater than 3 kg; these values were also statistically significant.

[00279] the Data presented in Fig.10 show the number of cases of sickness during the period of treatment, weeks 13-24. On this figure the first temporal point (-1 week) shows the incidence of nausea in the week prior to randomization of subjects for administration of doses in the extended phase. For continuous delivery of 20 mcg/day èksenatida the number of cases of nausea remained very low throughout the treatment period. When you increase the dose continuous delivery of 20 mcg/day and 60 mcg/day èksenatida observed an increase in the number of cases of nausea; but the treatment was well tolerated, as described below. When subjects receiving 20 mg/day èksenatida by injection twice a day, treated in the extended phase using a continuous delivery 60 mg/day èksenatida, the incidence of nausea was much higher, reaching 50% within the fourth week after the dose. Thus, treatment with injections of èksenatida twice a day did not contribute to the adaptability of the subjects in relation to side effects from the gastrointestinal tract increased doses èksenatida, while treatment with continuous delivery èksenatida really provide conformability of the subjects in relation to side effects with�parties gastrointestinal tract increased doses èksenatida. Accordingly, in one embodiment implementing the present invention relates to methods of and osmotic devices containing exenatide, for use in methods of treating diabetes type 2 diabetes mellitus by continuous delivery èksenatida that provide improved conformability with respect to increasing dose èksenatida.

[00280] In relation to well acceptable treatment for subjects who received treatment with continuous delivery from 20 to 60 mg/day èksenatida, there were no exceptions to treatment, six subjects reported nausea during weeks 13-24, and four reported nausea during weeks 1-12. There were no reports of vomiting. Four of these subjects were in the centres participating in the continuation phase, providing treatment with weeks 25-48, and all four chose to continue treatment with the use of continuous delivery. Moreover, 85% of all eligible subjects in all treatment groups chose to continue treatment in the continuation phase.

[00281] in addition, the changes of QOL index of subjects in the extended phase of the study was assessed essentially as described above. According To Fig.9, the data presented in Fig.11, showing the changes relative to the initial level for indicators of QOL, based on a subsequent randomization into two groups of treatment (i.e., continuous delivery or 40 mcg/day, or 60 �kg/day èksenatida) in the extended phase of the initial subjects in Group 3 (injection èksenatida twice a day). QOL original subjects of Group 3, which randomizable for continuous delivery of 40 mcg/day, was compared using data from their 8 weeks QOL and QOL data obtained at week 20. These initial QOL of the subjects of Group 3, which randomizable for continuous delivery 60 mg/day, was compared using data from their 8 weeks QOL and QOL data obtained at week 20. As can be seen from the data in Fig.11, subjects who switched from the injections èksenatida twice a day (Group 3) to a continuous delivery from implanted osmotic device (in doses of 40 mg/day or 60 mcg/day èksenatida) reported a significant improvement in QOL indicators.

[00282] According To Fig.9, the data presented in Fig.12, showing the changes relative to the initial level for QOL indicators taking into account initial data of subjects of Group 1 (continuous delivery of 20 mcg/day èksenatida), which then randomizable for continuous delivery 60 mg/day in the extended phase, and the initial subjects of Group 2 (continuous delivery 40 mg/day èksenatida), which then randomizable for continuous delivery 80 mg/day in the extended phase. These QOL data of subjects were compared using data from their 8 weeks QOL and QOL data obtained at week 20. As can be seen from the data presented in Fig.12, in respect of� indicators of QOL for subjects, treated by continuous delivery, in whom the dose was increased 2-3 times in the extended phase, remained higher values of QOL indicators (in comparison with the performance of those subjects who were treated by injection twice a day, in comparison with Fig.7 and Fig.8) even in higher doses. Thus, according to the present invention proposed methods of and osmotic devices containing exenatide, for use in methods of treating diabetes type 2 diabetes mellitus by continuous delivery èksenatida that provide improved QOL subjects receiving treatment with èksenatida.

[00283] Thus, treatment of diabetes mellitus type 2 using a continuous delivery èksenatida from implanted osmotic device provides glycemic control in all doses. Subjects who started with continuous delivery of 20 mcg/day with subsequent dose increase to 60 mg/day, showed excellent tolerance, and reduction of HbA1c and weight. In addition, the improvement reported by the subjects of QOL was observed in all doses èksenatida, administered by continuous delivery, compared with injection èksenatida twice a day. More significant improvement of QOL was observed in subjects treated by continuous delivery of èksenatida, compared with injection èksenatida twice a day. Also W�significant improvement in QOL was observed in the subjects, coming from injections èksenatida twice per day for continuous delivery with application of the implanted osmotic delivery devices.

[00284] the Methods and implantable osmotic delivery device according to the present invention provide a unique possibility of long-term optimal treatment of diabetes mellitus type 2, since this treatment is a first treatment of mimetic incretin ensuring adherence actors and reducing the need to self-inject.

[00285] S. Comparative data treatment

[00286] In this example, we consider the comparison of different therapeutic approaches to the treatment of diabetes type 2 among the subjects on background Metformin treatment only. The data described above, clinical studies phase 2 treatment using continuous delivery from implanted osmotic delivery devices were compared with the results of treatment for injection èksenatida twice a day, once a week, as well as oral antidiabetic drugs.

[00287] In the figures 13 to 21 presents a comparison of treatment for medicines and medical treatment as indicated in Table 20.

[00288]

Table 20
Designation of treatment PA figuresDrug/ treatment Regime dosesData source/Study
Treatment AndExenatide, injection twice a day (each injection 5 µg)DeFronzo RA, et al., Diabetes Care 28(5): 1092-1100 (2005)
TreatmentExenatide, injection once weekly (2 mg/week)Bergenstal RM, et al., Lancet 376(9739):431-439 (2010)
Treatment WithLiraglutide injection once a day (1.2 or 1.8 mg/day)Pratley RE, et al., Lancet 375(9724):1447-1456(2010)
Treatment DTaspoglutide, the injection once a week (10 or 20 mg/week)Rosenstock J, et al., American Diabetes Association (ADA) 70th Scientific Sessions, Orlando FL, Abstract 62-OR (2010); Nauck M, et al., American Diabetes Association (ADA) 70th Scientific Sessions, Orlando FL, Abstract 60-OR (2010); Bergenstal R, et al., American Diabetes Association (ADA) 70th Scientific Sessions, Orlando FL, Abstract 58-OR (2010).
Treatment EExenatide, continuous delivery of 20 mcg/day or 60 mcg/day with the use of an implantable osmotic device (i.e. variants of implementation of the present invention)Clinical research�a lo g phase 2, described in this application
Treatment FSitagliptin taken orally once a day (100 mg/day)Bergenstal RM, et al., Lancet 376(9739):431-439 (2010)
Treatment GPioglitazone, taken orally once daily (15 mg, 30 mg or 45 mg)Bergenstal RM, et al., Lancet 376(9739):431-439 (2010)

[00289] Liraglutide and taspoglutide both represent the peptides and mimetics incretin. Sitagliptin is an inhibitor of DPP-4 with a small molecule. Pioglitazone is a TZD and a strong agonist of gamma receptor proliferator-activated the peroxisome.

[00290] the Comparative data shown in Fig.13, demonstrate that treatment using the methods and osmotic delivery devices according to the present invention for continuous delivery of èksenatida (Treatment E) provided the best reduction in HbA1c during the periods of treatment of research data. Accordingly, continuous delivery èksenatida described herein, provided superior reduction in HbA1c compared with èksenatida, administered by injection either twice a day (Treatment A), or once a week (Treatment B), and superior HbA1c reduction compared with treatment with two R�EIT mimic incretin, liraglutide (injection once a day; Treatment C) and taspoglutide (injection once a week; Treatment D).

[00291] the Comparative data shown in Fig.14, demonstrate that treatment using the methods and osmotic delivery devices according to the present invention for continuous delivery of èksenatida (Treatment E) provided a great drop in HbA1c despite the lower initial level at baseline than the treatment with sitagliptin (Treatment F), pioglitazone (Treatment G) or injections èksenatida once a week (Treatment B). In the study, Bergenstal RM, et al. approximately one third of the subjects showed a HbA1c greater than 9%; however, in the experiments described herein, using a continuous delivery of 20 mcg/day or 60 mcg/day èksenatida was only one subject showing HbA1c above 9. This explains the difference in the mean baseline HbA1c.

[00292] the Comparative data shown in Fig.15, demonstrate that treatment using the methods and osmotic delivery devices according to the present invention for continuous delivery of èksenatida (Treatment E) provided greater reduction in HbA1c despite the lower baseline levels, compared with the introduction of èksenatida once a week. Unlike clinical studies phase 2 described in the present application, filed�e conducted exclusively in the United States, the study Bergenstal RM, et al. conducted in the United States, Mexico, and India. This geographical distribution has led to the registration of entities which are less controlled with Metformin monotherapy, and who entered the study with higher initial HbA1c levels. Baseline average HbA1c among subjects who were treated with injections èksenatida once a week (Treatment) from the study Bergenstal RM, et al., and one third of the subjects registered in the study Bergenstal RM, et al., demonstrated baseline HbA1c levels above 9%. The analysis only subjects from Treatment E, which showed higher initial levels of HbA1c, showed that the absolute drop in HbA1c is higher among the subjects in the treatment with application of the methods and osmotic delivery devices according to the present invention for continuous delivery of èksenatida (Treatment E). This shows that continuous delivery èksenatida described according to the present invention, can surpass the injection èksenatida once a week in similar study populations, showing high baseline HbA1c.

[00293] the Comparative data shown in Fig.16, show that treatment using the methods and osmotic delivery devices according to the present invention for continuous delivery of èksenatida (Treatment E) provided strong�s reducing HbA1c compared with treatment with injections of èksenatida once a week (Treatment B). Change of HbA1c from the study Bergenstal RM, et al. additionally analyzed between subjects with baseline HbA1c less than 9% of subjects with baseline HbA1c greater than or equal to 9%. Comparison of results of treatment with èksenatida by continuous delivery according to the present invention (Treatment E) with treatment using injections èksenatida once a week (Treatment b) In accordance with one and the same analysis showed that the reduction in HbA1c as a result of the methods of treatment according to the present invention are the same or better than the reduction observed with the use of injections èksenatida once a week.

[00294] the same comparison, the results from the implementation of the methods of treatment according to the present invention (Treatment E) with the results for subjects in the treatment of sitagliptin studies Bergenstal RM, et al. showed an even greater advantage continuous delivery èksenatida to ensure a more preferred reductions in HbA1c compared with sitagliptin (Fig.17). These results led to the use of osmotic delivery devices according to the present invention for the treatment, ensuring continuous delivery as a preferred additional treatment to Metformin treatment, compared with inhibitors of DPP-4 (e.g., sitagliptin). Moreover, when comparing subjects with HbA1c less than or equal to 9% of �direction Bergenstal RM, et al. with similar subjects from clinical studies phase 2 described in the present application, it was evident that the methods of treatment and osmotic devices according to the present invention provide a much more significant reduction in HbA1c (Fig.18).

[00295] likewise, a similar comparison of the results of the implementation of the methods of treatment according to the present invention (Treatment E) with the results for subjects in the treatment pioglitazon from the study Bergenstal RM, et al. showed that continuous delivery èksenatida provides a more significant reduction in HbA1c compared with pioglitazone (Fig.19). These results led to the use of osmotic delivery devices according to the present invention for the treatment, ensuring continuous delivery as a preferred additional treatment to Metformin treatment, compared to TZDs (e.g., pioglitazone). Moreover, when comparing subjects with HbA1c less than or equal to 9% of research Bergenstal RM, et al. with similar subjects from clinical studies phase 2 described in the present application, it was evident that the methods of treatment and osmotic devices according to the present invention provided a much more significant reduction in HbA1c (Fig.20).

[00296] moreover, Fig.21 shows a comparison of the mass loss obtained with the use of si�egyptina (Treatment F), pioglitazon (Treatment G) or injection èksenatida once a week (Treatment), treatment using the methods and osmotic delivery devices according to the present invention for continuous delivery of èksenatida (Treatment E). The data presented in the figure show that when comparing these types of treatment methods and osmotic delivery device according to the present invention provide the best weight loss.

[00297] Finally, all the subjects registered in the clinical trial of phase 2, were treated only with Metformin to treat diabetes type 2 diabetes before the study began. Metformin dose was not changed during the clinical research phase 2. Subjects were treated using a continuous delivery of 20 mcg/day 40 mcg/day èksenatida for 12 weeks or randomizable on the group that was treated independently entered by èksenatida twice a day (4 weeks at 5 mcg twice a day followed by 10 mcg twice a day for 8 weeks).

[00298] it is Known that Metformin causes certain undesirable effects gastro-intestinal tract, such as diarrhoea, nausea and vomiting. The subjects treated by continuous injection of 20 mcg/day èksenatida and dose èksenatida then increased to higher doses continuously enter�wow èksenatida, there were fewer unwanted side effects from the gastrointestinal tract than in those subjects that were administered injections of èksenatida 20 mcg/day and then increased to higher doses of continuously administered èksenatida.

[00299] Thus, the subjects who started treatment by continuous delivery èksenatida, it is better passed the adaptability on the effects of combinations of èksenatida entered with Metformin than in those who initially received injections èksenatida with Metformin. Accordingly, the use of continuous introduction èksenatida from the osmotic delivery device is the best option of treatment èksenatida for combination therapy with Metformin compared with injections èksenatida twice a day.

[00300] clinical studies phase 2 show that treatment with èksenatida by continuous delivery provided the following possible advantages: highly effective glucose control; reduction of side effects from the gastrointestinal tract compared with treatment by injection; eliminate the need to self-inject; significant weight loss; and 100% compliance with the prescribed regimen.

Example 4

Designs of clinical studies phase 3 for continuous delivery èksenatida

[00301] the Following�following research designs are presented solely for illustration, and, as will be clear to the specialist in the art, other designs of clinical studies in phase 3.

[00302] A. First, the research design

[00303] One of the designs of clinical studies phase 3 is the following. The study was a randomized, double-blind, placebo controlled study. The study group includes subjects with diabetes type 2 diabetes treated with Metformin, TZD, sulfonylurea, and any combination of Metformin, TZD or sulfonylation. Subjects demonstrate HbA1c greater than 7%. Subjects randomizer 1:2 between placebo and continuous delivery of unmodified synthetic èksenatida containing the amino acid sequence of Bloomington: Indiana-4, with the use of an implantable osmotic delivery devices, respectively. Only 300 subjects. Dose èksenatida used for continuous delivery, chosen on the basis of the results upon completion of the study phase 2, including the tolerability, activity in lowering glucose and activity in relation to weight loss. The dose for continuous delivery, obviously, includes 3 months of treatment 20 mg/day and 3 months of treatment with 60 mg/day. The randomization was performed with stratification based on the use of sulfonylation and HbA1c (less than 9% greater than or equal to about 9%).

[00304] Dan�s to obtain and estimates include the following data: HbA1c (primary endpoint), the concentration of glucose in the blood plasma on an empty stomach, weight, lipids, blood pressure, adiponectin, C-reactive protein (CRP), calcitonin, and amylase/lipase. In addition, it will be evaluated QOL.

[00305] Will be either open or blind 26-week extension phase for a long period of treatment using continuous delivery from implanted osmotic delivery devices.

[00306] V. Second, the research design

[00307] a Second design of the clinical study phase 3 is the following. The study was a randomized, double-blind, placebo controlled study of 3 phases, including a 26-week blinded study and mandatory 26-nedelyu extension. The research group includes subjects with diabetes type 2 diabetes receiving treatment with diet and exercise and/or oral treatment, selected from the following: TZD, sulfonylurea, TZD and Metformin, a sulfonylurea and Metformin, or TZD and a sulfonylurea; with the only exception of the treatment of Metformin. The only exception of the treatment of Metformin allows to evaluate the safety of a larger subgroup sulphonylurea. Inclusion criteria for subjects include stable background therapy maximum doses. No exceptions will be risk for cardiovascular disease.

[00308] the Subjects demonstrated an HbA1c greater than or R�wny of 7.5%. Subjects randomizer 1:2 between placebo and continuous delivery of unmodified synthetic èksenatida containing the amino acid sequence of Bloomington: Indiana-4, with the use of an implantable osmotic delivery devices, respectively. Just 375 of the subjects. The dose used for continuous delivery èksenatida include: group a (n=150), 13 weeks of treatment 20 mcg/day followed by 13 weeks of treatment with 60 μg/day; Group B (n=150), 13 weeks of treatment 20 mcg/day followed by 13 weeks of treatment with 40 μg/day; and Group C (n=75), the control and the placebo group, 13 weeks of treatment with placebo followed by 13 weeks of placebo treatment. The primary endpoint of the study is 26 week. There is a mandatory blind extended phase of treatment as follows: group a, 26 weeks of treatment with 60 μg/day; Group B, 26 weeks of treatment with 40 μg/day; and Group C, 26 weeks of treatment with 20 mg/day.

[00309] the Data for retrieval and evaluation include the following data: HbA1c (primary endpoint), the concentration of glucose in the blood plasma on an empty stomach, weight, lipids, blood pressure, adiponectin, C-reactive protein (CRP), calcitonin, and amylase/lipase. In addition, it will be evaluated QOL.

[00310] an Additional modification of this study may include the following. Adding randomized double-blind controls�creating placebo clinical studies 3 phase, in which group of the study includes subjects with diabetes mellitus type 2 treated with inhibitors of DPP-4 or TZDs as add-ons to Metformin treatment (i.e., subjects treated with an inhibitor of DPP-4 and Metformin or TZD and Metformin). This study is a 26-nedelyu-blind study with a mandatory 26-week extension. The study controlled by placebo with placebo for continuous delivery èksenatida and administered oral medications. The total number of subjects in this group is approximately 500. The dose of the treatment include: group a (n=170), 13 weeks of treatment by continuous delivery èksenatida 20 mcg/day followed by 13 weeks of treatment with 60 μg/day; Group B (n=170), 26 weeks of treatment with 45 mg/day of pioglitazone (TZD); and Group C (n=170), 26 weeks of treatment with 100 mg/day sitagliptin (an inhibitor of DPP-4). The primary endpoint of the study is 26 week. There is a mandatory blind extended phase of treatment as follows: group a, 26 weeks of treatment with continuous delivery èksenatida in the amount of 60 μg/day; Group B, 26 weeks of treatment with 45 mg/day of pioglitazone; and Group C, 26 weeks of treatment with 100 mg/day of sitagliptin.

[00311] the Aim of this study is to demonstrate the benefits of treatment with continuous delivery èksenatida with PR�the use of osmotic delivery devices for the treatment of inhibitors of DPP-4 and TZDs.

[00312] As obvious to the skilled in the art, various modifications and variations of the variants of the implementation described above, without going beyond the nature and scope of the present invention. Such modifications and variations fall within the scope of the present invention.

1. A method for the treatment of diabetes type 2 in humans, including:
consistent delivery èksenatida from the osmotic delivery device that includes
(a) an impermeable reservoir containing inner and outer surfaces, and first and second open ends,
(b) a semipermeable membrane that is installed with the seal relative to the first open end of the tank,
(c) osmotic mechanism within the tank and adjacent to the semipermeable membrane;
(d) a piston adjacent to the specified osmotic mechanism, and the said piston forms a movable seal with the inner surface of the reservoir, wherein the piston divides the reservoir for the first chamber and the second chamber where the first chamber contains an osmotic mechanism, and the second chamber contains a composition in the form of suspension, and
(e) diffusion controller, inserted in the second open end of the tank, and the specified controller is adjacent to the diffusion of the composition in the form of a suspension, wherein said composition is in the form of suspension contains a composition in the form of particles and composition for delivery, �ri this composition is in the form of particles contains particles èksenatida diameter from less than 10 to 30 micrometers, a composition for delivery comprises (i) a solvent selected from the group consisting of benzyl benzoate, laurolactam, and lauryl alcohol, and (ii) of the polymer constituting polyvinylpyrrolidone, wherein the composition is for delivery has a viscosity of from about 10,000 poises to about 20,000 poise at 37°C,
while essentially stable delivery èksenatida in therapeutic concentrations is achieved within a time period of 5 days or less after implantation of the specified osmotic device for the delivery person, and stated essentially stable delivery èksenatida from the osmotic delivery device is continuous for a period of at least 3 months at a dosage of èksenatida, expressed in μg/day selected from the group consisting of about 10 mcg/day; about 20 mcg/day, about 30 mcg/day; about 40 mcg/day, about 60 mg/day, and about 80 mcg/day.

2. A method according to claim 1, further comprising providing a significant reduction of glucose concentration in the blood plasma on an empty stomach the specified person after implantation of the osmotic delivery device to the person, compared with the glucose concentration in the blood plasma on an empty stomach with the designated person prior to implantation of the osmotic delivery device, for several days, selected from the group �ostoja of 7 days or less, 6 days or less 5 days or less 4 days or less 3 days or less 2 days or less 1 day or less after implantation of the osmotic delivery device to the specified person.

3. A method according to claim 1, characterized in that the osmotic delivery device can be removed from the patient with the termination of continuous delivery èksenatida.

4. A method according to claim 1, characterized in that therapeutic concentration is achieved within a time period selected from the group consisting of 4 days or less 3 days or less 2 days or less 1 day or less.

5. A method according to any one of claims.1-4, characterized in that exenatide exenatide is a with an amino acid sequence of Bloomington: Indiana-4.

6. A method according to any one of claims.1-4, characterized in that continuous delivery can be terminated, so that the concentration èksenatida becomes essentially netdetective in a sample of human blood using less than approximately 72 hours after the termination of the specified continuous delivery.

7. A method according to claim 6, characterized in that the end of the specified continuous delivery represents the removal of the indicated osmotic device of the specified person.

8. A method according to claim 6, characterized in that exenatide detects according to the radioimmunoassay analysis.

9. A method according to any one of claims.1-4, 7, 8, characterized in that the code�cated tank includes titanium or titanium alloy.

10. A method according to any one of claims.1-4, 7, 8, further comprising the first continuous period of introduction èksenatida at the first value of the dose, expressed in µg/day, with subsequent second continuous period of introduction, ensuring a higher dose èksenatida to the second value of the dose, expressed in µg/day, and second specified dose value more than a specified first value of the dose.

11. A method according to claim 10, characterized in that the first dose expressed in mg/day, administered using a first osmotic delivery device, and a second dose expressed in mg/day, administered with a second osmotic delivery device, and delivery èksenatida from at least first and second osmotic delivery device is continuous for a period of at least 3 months.

12. A method according to claim 10, characterized in that the second value of the dose, expressed in µg/day, at least two times greater than the first value of the dose, expressed in µg/day.

13. A method according to claim 10, characterized in that said method includes a third or more continuous period of delivery, resulting in an increased dose èksenatida to higher values of dose, expressed in µg/day, compared with the second value of the dose, expressed in µg/day.

14. A method according to claim 13, characterized in that the first value of the dose with p�following the second dose value, expressed in µg/day for continuous delivery selected from the group consisting of 10 µg/day with subsequent dose of 20 µg/day, 10 μg/day with subsequent dose of 40 µg/day, 10 μg/day with subsequent dose of 60 µg/day, 10 μg/day with subsequent dose of 80 µg/day, 20 μg/day with subsequent dose of 40 µg/day, 20 μg/day with subsequent dose of 60 µg/day, 20 μg/day with subsequent dose of 80 µg/day, 40 µg/day with subsequent dose of 60 µg/day, 40 µg/day with subsequent dose of 80 µg/day, 60 µg/day with subsequent dose of 80 µg/day.

15. A method according to claim 14, characterized in that the first dose of 20 µg/day, should the second dose, component 60 µg/day.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a citrate of a compound described by formula (II) below, and a pharmaceutical composition containing said citrate.

EFFECT: experimental results of the present inventions prove that said citrate can inhibit activity of phosphodiesterase type 5 and can be used for treating erectile dysfunction, for inhibiting thrombocyte aggregation and treating thrombosis, for reducing pulmonary hypertension and treating cardiovascular diseases, asthma and diabetic gastroparesis.

2 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to a compound of formula (I) or its pharmaceutically acceptable salts of formula (I), wherein X represents O, S; Y represents O, S; R1 independently represents H, alkyl; G1 represents ethyl; each G2 and G3 are independently specified in H, alkyl, trifluoromethyl, halogen, nitro, amido, cyano and tetrazolyl. The invention also refers to a pharmaceutical composition possessing activating action on peroxisome proliferator activated receptors subtype α, subtype δ and subtype γ and containing an effective amount of the compound of formula (I) or its pharmaceutically acceptable salts. The compounds of formula (I) are applicable for treating or producing a drug preparation for treating or preventing the diseases associated with peroxisome proliferator activated receptors subtype α, subtype δ and subtype γ. The compounds of formula (I) are produced by a reaction of the compound of formula (III) and the compound of formula (IV) when heated in acetonitrile under reflux in the presence of potassium carbonate to produce the compound of formula (II), to saponify the compound of formula (II) in alcoholic solution in the presence of alkali and to acidify the reaction mixture to produce the compound of formula (I). X, Y, R1, G1, G2 and G3 have the above values; R3 represents a leaving group specified in OH, Cl, Br, I, OTs, OMs.

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15 cl, 2 ex

FIELD: medicine.

SUBSTANCE: agent for treating diabetes mellitus involving dry aqueous extract of Geranium Dieisianium Knuth and dry aqueous extract of Uncaria tomentosa (Willd) D.C. bark enclosed into gelatine capsules. A method of treating diabetes mellitus provides prescribing the above agent in a daily dose of 180-360 mg after a meal. The above agent enables treating diabetes mellitus effectively by reducing dosages of blood glucose lowering drugs.

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2 cl, 5 tbl

FIELD: medicine, pharmaceutics.

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9 cl, 20 ex

FIELD: chemistry.

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24 cl, 5 dwg, 6 tbl, 16 ex

Oxyintomoduline // 2542362

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to peptide analogues of oxyintomoduline (OXM, glucagon-37), which can be modified for providing the stability of cleavage and inactivation with dipeptidyl peptidase IV (DPP-IV) for increasing a half-life time in vivo of the peptide analogue alongside with enabling the peptide analogue acting as a double agonist GLP-1/glucagon receptor (GCGR).

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16 cl, 16 dwg, 11 tbl, 12 ex

FIELD: medicine, pharmaceutics.

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15 cl, 1 tbl, 32 ex

FIELD: medicine.

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11 cl, 4 ex, 5 tbl, 3 dwg

FIELD: medicine, pharmaceutics.

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29 cl, 10 ex, 6 dwg

FIELD: chemistry.

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14 cl, 22 dwg, 10 tbl, 49 ex

FIELD: medicine, pharmaceutics.

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14 cl, 2 tbl, 8 dwg

FIELD: medicine.

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15 cl, 11 dwg

FIELD: medicine.

SUBSTANCE: group of inventions refers to medical equipment and characterises versions of an undersized disposable syringe with an automatic destruction function. According to the first version, the syringe comprises a syringe cylinder, a piston rod and a locking element. The syringe cylinder has an inner surface forming the cavity, an open end and a distal end. The piston rod has a lock portion, a flange for applying the user's force, an elongated body, a hollow along this elongated body and a group of first teeth. The group of first teeth is formed inside the hollow on the elongated body and forms a group of projections facing in the distal direction and equally distributed along the major portion of the elongated body. The locking element slides inside the cavity along the above major portion of the elongated body; this locking element interacts with the inside of the syringe cylinder so that the locking element cannot be movable towards an open end of the syringe cylinder, and can interact with the piston rod so that the piston rod and the locking element can be movable together in the distal direction to the distal end of the syringe cylinder. The above hollow extends from the locking element to the above flange. The locking element is buried into one hollow of the elongated body of the piston rod.

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42 cl, 19 dwg

FIELD: medicine.

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2 cl, 3 dwg, 2 ex

FIELD: medicine.

SUBSTANCE: testicular vein is catheterised to the level of the L-5 lower edge. That is followed by administering 3% Aethoxysklerol 1 ml to be distributed to an outer annulus of the inguinal canal. Then, Aethoxysklerol is sequentially administered at the level of the L-3 and L-1 lower edges. Each injection involves the spermatic cord cross-clamping at the outer annulus of the inguinal canal.

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1 ex, 1 dwg

Disposable syringe // 2523628

FIELD: medicine.

SUBSTANCE: what is presented is a syringe comprising a body, a rod piston and a needle. A body opening comprises a circular groove; the piston also comprises a rectangular circular groove which integrates an unclosed ring spring element. The width of the spring element correlates with that of the circular grooves in the body opening and on the piston. An external diameter of the spring element in a free condition correlates with the diameter of the circular groove in the body, while an internal diameter of the spring element in the free condition is less than the diameter of the body opening. The smaller body opening comprises a lightly tensed support with a working end face of the piston resting against when assembled and transported. The above circular groove in the body opening is rectangular or trapezium-shaped. The above unclosed ring spring element represents an irregular rectangle, square or trapeze in section with an upper side presented to a convex curve. The diameter of the circle formed by intersection of the above curve and a side of the irregular rectangle, square or trapeze is greater than the diameter of the body opening in the free condition of the unclosed ring spring element. The above rest comprises at least one through flattened surface.

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3 cl, 7 dwg

FIELD: chemistry.

SUBSTANCE: in a method of manufacturing a nanotube array for cell transfection a multi-layered film structure with mechanically strained layers is made on a crystal substrate. A contour of a film structure area released from the crystal substrate is formed with respect to a separately taken tube. A released area of the film structure is formed as one containing a portion, intended for the tube formation, and a portion, intended for formation of the curved film element, providing positioning of the tube relative to the crystal substrate. After that, the first of the said portion is released with its transformation into the tube due to mechanical strains, and the second portion, curving due to mechanical strains. The tube positioning relative to the crystal substrate is achieved in the following way: after release of the second portion, curving due to mechanical strains, from connection to the substrate, the Archimedes force is applied in addition to the action of mechanical strains, creating torque forces, trying to curve the film element.

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16 cl, 5 dwg, 11 ex

FIELD: medicine.

SUBSTANCE: group of inventions refers to medical equipment and describes versions of a sprayer for subcutaneous liquid injection and a needle unit. According to the first version, the sprayer comprises a body, a needle unit and a rubber element. The body comprises a drive, a cam turned by the drive, and a connection element reciprocated by the cam. The needle unit is detachably connected to the front end of the body. The rubber element is provided in the needle unit to block a leak-off of blood and liquid from a patient's skin flowing into the needle unit during a medical procedure. The needle unit comprises a needle holder, a liquid container, a movable rod and a lid. The needle unit of the sprayer for subcutaneous liquid injection, including a drug or a tattoo pigment applied on the skin, comprises a needle holder, a liquid container, a movable rod and a lid. The needle holder comprises needles and outlets for a liquid injection. The liquid container is connected to the needle holder via one hole and contains a liquid. One side of the movable rod is connected to the liquid container, and the other side thereof is detachably connected to one end of the drive in the above sprayer. The lid encloses the needle holder and the liquid container and comprises a support unit which the movable rod passes through. The group of inventions also involves a version of the sprayer and a version of the needle unit.

EFFECT: invention enables blocking a leak-off of the patient's blood and liquid flowing into the needle unit during a medical procedure.

16 cl, 9 dwg

FIELD: medicine.

SUBSTANCE: group of inventions refers to a system and a method for drug administration into a patient. The system comprises a movable drug container (5, 14); a device (3) for making the first identification element with the first patient, drug and/or treatment data to be attached to the drug container (5, 14); a reading device (6) for reading the first data from the first identification element (5a); a supply unit for supplying the drug to the patient from the container (5, 14) inserted into the supply unit (11). The reading device (6) is presented to read the second data included into the second patient's (9) identification element (10) and attached to the supply unit (11). A control unit (16) is provided in the supply unit (11) for supplying the first control signal (13) to activate a supply procedure to one of supply modules (12a-12e) of the supply unit (11), if the first and second data are matched. There are provided the second comparison unit (18) in the supply unit (11) for comparing the first drug data to the second drug data in a storage unit (19) of the supply unit (11), and a selection unit (21) for selecting the first and/or second drug data at least partially, if there is a mismatch of the first drug data, and the second drug data. What is disclosed is a method for drug supply.

EFFECT: inventions provide a safer drug supply to the greater number of patients.

7 cl, 3 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly to paediatrics and neonatology, and can be used for treating small premature infants at the hospital stage of developmental care. A therapeutic complex comprises administering a probiotic preparation into the newborns. The preparation is presented with a liquid probiotic containing E.faecium L3 109 CFU in 1 ml. If the enteral nutrition volume of the newborn is 5 ml or more, this preparation is orally administered in a dose of 0.5 ml 3 times a day for 14 days.

EFFECT: method is effective in children with a very low body weight, promotes normalising the intestinal microflora and reducing a rate of manifestations of infectious complications.

2 ex, 3 dwg, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical compositions containing (2-hydroxyethoxy)amide 6-(4-brom-2-chlorophenylamino)-7-fluor-3-methyl-3H-benzoimidazole-5-carboxylic acid hydrosulphate and solvates, crystalline forms and amorphous forms thereof, to using the above compositions as a drug; and to methods for preparing the above compositions.

EFFECT: preparing the new pharmaceutical compositions.

20 cl, 7 tbl, 7 ex, 5 dwg

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