The composition of cyclosporine for oral dosage forms (variants) and a way to achieve immunosuppression in the recipient organism

 

(57) Abstract:

The invention can be used in medicine, for example in organ transplantation. The composition comprises cyclosporin, at least one alcohol solvent having 2-3 carbon atoms, at least one nonionic polyoxyalkylene surface-active substance (surfactant) and at least one polyglycol. Surfactant selected from the group comprising polyoxyethylene alcohols and monetary fatty acids and ethoxylated polyols with 4-6 carbon atoms. Polyglycol has a molecular weight of 800 to 1,000 daltons. The alcohol solvent is preferably 5-75% vol. compositions and surfactant 5-80%. The composition may be in a solid capsule. Variant composition further comprises a physiologically acceptable carrier, and the composition is anhydrous. The way to achieve immunosuppression in the recipient's organism is orally administered to the recipient of the claimed composition. The invention allows introduces medication by mouth, which is more convenient for the patient, without any adverse effects. 3 S. and 13 C.p. f-crystals, 6 ill. , 1 table.

This application is a partial continuation of application serial the emergency N 08/519689, registered 25 August 1995, and these applications are incorporated in the present application as reference.

INTRODUCTION

THE TECHNICAL FIELD TO WHICH THE PRESENT INVENTION

The technical field to which the present invention is a pharmaceutical form of cyclosporine, intended for oral administration.

PRIOR ART

Despite attempts to avoid transplant rejection by cross-tissue typing of the recipient and the donor, in most methods of transplantation in which the donor organ is introduced to the recipient, to preserve the viability of the donor organ in the body of the recipient is crucial immunosuppressive therapy. In the methods of transplantation are a number of immunosuppressive drugs (immunosuppressive funds), including azathioprine, methotrexate, cyclophosphamide, FK-506, rapamycin and corticosteroids. The agents that are most commonly used in immunosuppressive therapy, due to their favorable effect on the reaction, mediated by T lymphocytes represent cyclosporine.

Cyclosporine is a class of cyclic polypeptides consisting of eleven amino acids, which are produced in ka is ntie lymphocytes, in particular T-lymphocytes during phase G0and G1the cell cycle. It is also shown that cyclosporine reversibly inhibit the production and secretion of lymphokine. Although there are a variety of cyclosporine, but the most widely used cyclosporine A.

It is reported that the use of cyclosporine A prolongs survival of allogeneic transplants, including the skin, heart, kidney, pancreas, bone marrow, small intestine and lung. For allogeneic transplants have shown that cyclosporin A suppresses humoral immunity and largely immune response mediated by cells, including allograft rejection, delayed hypersensitivity, experimental allergic encephalomyelitis, adjuvant arthritis Freund and graft-versus-host. Although cyclosporine achieved A success, but after transplant, it is necessary to continue the introduction of this tool, because the favorable effects of cyclosporine therapy are reversible, and if the introduction of cyclosporine to stop, it will graft rejection.

Although developed dosage forms cyclosporine for both intravenous and oral their Wedau and better tolerability his patient. In addition, intravenous administration of cyclosporine may cause anaphylactic reactions, and oral introduction this means no side effects were observed. Dosage forms cyclosporine intended for oral administration, which by now have been developed and are commercially available, include dosage forms as in the form of soft gelatin capsules, or in the form of solutions, both of which are sold under the trade names SANDIMMUNEand NEORALTM.

When used in immunosuppressive therapy dosage forms cyclosporine intended for oral administration, as individuals, health care providers, and manufacturers should be aware of the many associated problems. When using dosage forms cyclosporine intended for oral administration, the bioavailability of cyclosporine may be limited due to the fact that cyclosporine does not dissolve in water, and also due to the fact that cyclosporine has a tendency to precipitate in the aquatic environment. In addition, the concentration of cyclosporine in dosage forms intended for oral administration may be limited due to the hydrophobicity cyclosporineinduced for oral administration. For example, when using dosage forms cyclosporine soft gelatin capsules should be applied hermetic packaging, which is inconvenient because of its bulkiness and high cost. In addition, dosage forms cyclosporine can be unstable at low temperatures, as crystallization may occur cyclosporine.

Thus, the desirable dosage forms cyclosporine intended for oral administration, should solve at least some of the above problems. Ideally, the dosage form intended for oral administration, should contribute to the high biological availability, to include high concentrations of cyclosporine and to be suitable for the manufacture of both liquid and solid capsule form of the medication.

RELATED TO THIS APPLICATION LITERATURE

In the publication Physician''s Desk Reference (1994) pp 2071-2074 describes dosage forms cyclosporine intended for oral administration, which are commercially available under the trademark SANDIMMUNE.

Dosage forms cyclosporine intended for oral administration are described in the contribution of the S="ptx2">

Of interest to this application is the U.S. patents describing cyclosporine and their derivatives include NN 4220641, 4639434, 4289851 and 4384996. U.S. patent N 5047396 describes the drug cyclosporine, intended for intravenous administration. In the U.S. patents NN 4388307, 4970076 and 4990337 retrieves dosage forms cyclosporine intended for oral administration.

The manufacture of hard capsules intended for oral administration of pharmaceutical products described in the U.S. patents NN 4822618, 4576284, 5120710 and 4894235.

SUMMARY OF THE INVENTION

The present invention relates to dosage forms cyclosporine intended for oral administration, as well as their use in immunosuppressive therapy. In the dosage forms of the present invention, the cyclosporine is present in the oral suitable pharmaceutical carrier comprising at least one alcohol solvent containing from 2 to 3 carbon atoms, in combination with at least one non-ionic surface-active agent. In addition, dosage forms of the present invention may also include one or more co-solvents, and used the polyglycols. These dosage forms cyclosporine can be packaged in the form of hard capsules. The data of the dosage form is substantially anhydrous, which reduces the precipitation of cyclosporine from a pharmaceutical form and increases its bioavailability.

BRIEF DESCRIPTION OF FIGURES

In Fig. 1 shows the maximum concentration of cyclosporine (Kmax) obtained in rats, for multiple dosage forms intended for oral administration according to the present invention, where Kmaxpresented as relative values compared with the index Kmaxreceived for dosage forms for oral administration SANDIMMUNEORAL (SO).

In Fig. 2 shows the time (Tmax), which is achieved Kmaxfor each of the dosage forms shown in Fig. 1, where Tmaxpresented as relative values compared withmaxdosage forms SANDIMMUNEORAL (SO).

In Fig. 3 shows the relative value of the area under the curve (ACC) concentration in blood and time, for each of the dosage forms shown in Fig. 1, where CPD is given as a relative value compared with the value of CPD for Lekarstvo is by the person, for multiple dosage forms of the present invention, intended for oral administration, as well as for SANDIMMUNE solutionORAL (denoted in the figure as "Sand").

In Fig. 5 shows the time (Tmax), which is achieved Kmaxfor each of the dosage forms is shown in Fig. 4.

In Fig. 6 shows the area under the curve of concentration-time (CPD) for each of the dosage forms shown in Fig. 4.

DESCRIPTION OF SPECIFIC EMBODIMENTS OF THE INVENTION

This invention relates to dosage forms cyclosporine intended for oral administration, which contribute to increase the biological availability and can be made in the form of capsules, in particular solid capsules. In the dosage forms of the present invention cyclosporine is suitable oral carrier, comprising at least one alcohol solvent containing from 2 to 3 carbon atoms, in combination with at least one non-ionic surface-active agent. In addition, dosage forms of the present invention may include at least one co-solvent and a cosolvent, promenade of polyglycols. Each of the components of the dosage forms of the present invention is a pharmaceutically suitable. In addition to the fact that the dosage forms of the present invention contribute to the high biological availability, they also provide a reproducible amount of absorption of cyclosporine for various parties specific dosage forms. Dosage forms of the present invention are used in immunosuppressive therapy.

In the art known for a number of cyclosporine, which show immunosuppressive activity, and which can be introduced in the form of dosage forms of the present invention, intended for oral administration. Cyclosporine, which can be introduced in the form of dosage forms of the present invention include cyclosporin A, cyclosporin B, cyclosporin C, cyclosporin D, cyclosporin G, as well as their synthetic analogues. Cm. The Merck index (1989), 2759. Dosage forms for oral administration according to the present invention are particularly suitable for the introduction of cyclosporine A. When it is introduced in the form of dosage forms of the present invention, the cyclosporine is present in concentrations in the range from 50 to 150 mg/ml, tx2">

The media, which is a component of the dosage forms of the present invention, includes a component, which is the alcohol solvent and the alcohol solvent includes at least one alcohol, usually no more than three different alcohols, preferably no more than two different alcohols, and alcohols typically have from 2 to 3 carbon atoms and from 1 to 2 hydroxyl groups, thus, no more than 1 hydroxyl group accounts for 1.5 carbon atom. Suitable alcohols include ethanol and propylene glycol, preferably absolute ethanol. The total amount of alcohol solvent in the form of the drug is not less than about 1% (by volume), usually not less than 3% (volume), and can reach 95% (volume), but typically ranges from about 5 to 75% (volume), usually from about 5 to 60% (volume) and preferably from 10 to 60% of the volume of this dosage form. When in the form of the drug as an alcoholic solvent is ethanol, the amount of ethanol may be in the range of from 5 to 25% (volume), usually from about 5 to 20% (volume), preferably from about 10 to 25% of the volume of the dosage form, and if the alcohol rastvoryenii may be in the range of from 5 to 90% (volume), usually from about 5 to 85% (by volume), preferably from about 10 to 50% of the volume of the dosage form.

In suitable oral carrier is also present at least one non-ionic polyoxyalkylene surfactant, usually no more than two non-ionic polyoxyalkylene surfactants. These polyoxyalkylene surfactant should have a hydrophilic-lipophilic balance (products HLB) from about 5 to 20, usually from about 8 to 16. Preferably, the nonionic polyoxyalkylene surfactants used in pharmaceutical dosage forms of the present invention, are compounds of polyoxyethylene. The polyoxyethylene compounds applicable to the present invention include ethoxylated alcohols, i.e., polyoxyethylene alcohols or ethoxylated fatty alcohols in which the alcohol groups generally have from 10 to 18, usually from 10 to 14 carbon atoms, as well as their essential and difficult-ether substituents; and polyoxyethylene derivatives of partial esters of fatty acids, usually monoufia, and polyols having from 4 to 6 carbon atoms, usually 6 carbon atoms, and polyols may constitute anhydrides floor is the rule, have from 10 to 18 carbon atoms. The number ethyleneoxide groups typically is from 2 to 30, usually from about 2 to 25. Preferred surfactants include ether of laurinovoj acid and polyoxyethylene (4) (BRIDGE 30) and polyoxyethylene (20) monocarbide monooleate (TWEEN 80). The total number of non-ionic surfactants present in the dosage form according to this invention, is in the range from 5 to 80%, usually from 5 to 70%, preferably from 5 to 65%, more preferably from 5 to 60% (by volume), more preferably from 20 to 75% (volume) and often from 50 to 80% of the dosage form. If the dosage form is present TWEEN 80usually it is present in quantities of from 5 to 80%, preferably from 5 to 70%, more preferably from 5 to 60% and more preferably from 10 to 15% by weight of the dosage form. If the dosage form according to the present invention is present BRIDGE 30usually it is present in quantities of from 10 to 45%, preferably from 15 to 40% of the volume of the dosage form.

Dosage forms of the present invention may also include one or more co-solvents, usually not boratories include esters of fatty acids and diols, while the co-solvent can be a 100% ester fatty acids, 100% diol or a combination of both. In medicinal form, which includes 100% of ester of the fatty acid or 100% diol, various esters of fatty acids or diols can be used in combination. The total number of co-solvent present in the form of the drug may be in the range from about 20 to 80% (volume) and is usually in the range from 25 to 75% (volumetric). If the dosage form is a co-solvent, the ratio of co-solvent to the solvent in the dosage forms of the present invention may be in the range from 1:1 to 15: 1, but it usually is in the range from 1:1 to 13:1.

Esters of fatty acids, which can serve as co-solvents in the formulations of the present invention are esters of fatty acids in which the hydrocarbon chain of the fatty acid has a length of from 12 to 18, usually from 14 to 18 carbon atoms, and an ester of fatty acid is monoform lower alcohol. Suitable esters of fatty acids, as a rule, include the odd chain fatty acids, and hydrocarbon chain may who are to this invention, as a rule, animal or vegetable origin, and include palmitate, stearate, palmitoleate, linoleate, linolenate and the like, particularly monistat and oleate. Alcohol monoether fatty acid is a lower alcohol, having a length of from 2 to 4 carbon atoms, usually ranging in length from 2 to 3 carbon atoms, with or without branching. Esters of fatty acids, particularly preferred for the present invention is isopropylmyristate and etiloleat. Isopropylmyristate, if present, constitute from about 15 to 75% volume), and etiloleat, if present, is from 15 to 75% of the total dosage form. Usually an ester of fatty acid is present in an amount of not less than equal (by volume) and up to 8 times greater than the number of surfactants of this dosage form, usually no more than 5-fold amount relative to the amount of surfactant in the form of the drug (by volume). Ester of fatty acid is preferably anhydrous.

In the dosage forms of the present invention may also be present diols, and diols may be present in addition to the co-solvent, predstavleniya to the present invention as co-solvents, as a rule, at physiological temperatures are fluid and include diols, having from 8 to 28 carbon atoms, usually from 16 to 20 carbon atoms, and the diol can be polyoxyalkylene in which alkylen can have from 2 to 3 carbon atoms, however, diols having a greater number of carbon atoms, also find application. Diols suitable for use as co-solvents, can have a molecular weight in the range of from 200 to 10,000 daltons, typically from about 300 to 10,000 daltons, more typically from 400 to 10,000 daltons, preferably from 800 to 10,000 daltons. Diols, are preferred for the present invention include glycols, in particular polyethylene glycol 200 (PEG200), polyethylene glycol 300 (PEG300), polyethylene glycol 400 (PEG400), polyethylene glycol 600 (PEG600), polyethylene glycol 1000 (PEG1000), polyethylene glycol 3400 (PEG3400), polyethylene glycol 8000 (PEG8000) and the like. If diols are present as co-solvents in the formulations of the present invention, they typically range from 5 to 60%, typically from 5 to 55% by weight of the dosage form. Diols, especially glycols with vysokomotiviruet as substances, adsorbing water molecules that may be present in the dosage forms, thus greatly reducing the possibility of loss of cyclosporine in the sediment from the dosage form, which may occur due to the presence of free water molecules.

In the dosage forms of the present invention by themselves, the cosolvent can give the dosage form is desirable physical properties such as viscosity, stability, etc., When this is desirable, dosage form may also include additional agents, which may make dosage form desired physical properties, such as thickeners, suspendresume tools, hardeners, etc. and the list of such agents include acacia, carboxymethylcellulose, hydroxypropylcellulose, lecithin, methylcellulose, polyethylene glycols of high molecular weight, for example, glycols which have a molecular weight in the range of from 1,000 to 10,000, usually from 1000 to 8000 daltons, more typically from 1000 to 6000 daltons, povidone, sodium alginate, tragakant, etc. In the dosage forms of the present invention can also present a number of micro-components that perform various functions, such as the Total number of these thickeners and other additives, if they are present in the dosage form, is usually not more than 55 weight %, usually 45 weight %, more usually 25 weight % of the dosage form. In the dosage forms of the present invention may also be present a number of excipients, as is well known in the art. Such additional agents are preferably anhydrous.

The data of the dosage form substantially anhydrous, which means that they contain less than 1.0 volume % water, more preferably less than 0.1 % by volume of water.

Dosage forms of the present invention are stable in a wide temperature interval, which means that the physical integrity of the dosage form is not disturbed, for example, there is no crystallization of the active substance cyclosporine. The temperature interval in which the dosage form of the present invention remain stable, includes and low temperatures are such that are used when storing in the refrigerator, where such low temperatures are typically in the range from 0 to 15oC, as a rule, from 2 to 8oC.

Dosage forms of the present invention is suitable for introduced the Duc capsules, comprising a liquid dosage form known in the art and are described in U.S. patents NN 4822618 and 4576284 described in the present description as a reference. As a rule, hard capsules, which are used for the dosage forms of the present invention, include two parts: a component body and a component of the cap. The components of the body and cap together, the result is a closed cavity of a certain volume enclosed by the solid body of the capsule. Chassis components and the cap can be made of a hydrophilic polymer such as starch or gelatin. In the process of manufacturing hard capsules in the component housing pour liquid dosage form, and then the capsule is sealed using a cap that is worn over the body. The seal between these two components of the capsule can be made tight, thereby preventing leakage of the dosage form of capsules with sealant as described in Europatent 116744, the description of which is included in the present description by reference. In order to prevent decomposition of the capsules in the stomach, the capsule comprising a dosage form of the present invention, it is possible to cover ante the IKI known a number intersolubility coatings. See, for example, U.S. patent N 5206219, the description of which is included in this description by reference.

Dosage forms of the present invention can be entered actors who need them, together with one or more immunosuppressive agents, and immunosuppressants used for joint injections dosage forms cyclosporine according to the present invention, include, for example, rapamycin, FK-506, mycophenolate acid, their analogues and derivatives, azathioprine, methotrexate, cyclophosphamide, corticosteroids and any other immunodepressant compound or molecule or their analogues.

Dosage forms of the present invention are used in immunosuppressive therapy. Immunosuppressive therapy is indicated when a large number of different diseases, including idiopathic nephritic syndrome, insulin dependent diabetes type I syndrome Benita, the active phase of Crohn's disease, gipoplasticheskaya anemia, severe corticosteroidsayrshire asthma, psoriasis, rheumatoid arthritis and other diseases in which the immune system may play a pathogenic role. Of particular interest is the use of dosage forms of the present invention transplant, vkluchaya to preserve the viability of the transplanted organ, or tissue, or cells after their transplantation, i.e., to prevent transplant rejection or to prevent graft versus host, for example, after bone marrow transplantation.

When using the dosage forms of the present invention to apply to the recipient with immunosuppressive therapy orally administered an effective amount of cyclosporine in order to achieve the desired level of immunosuppression in the recipient, depending on the status that attracts the treatment. When changing the initial dose of cyclosporine is usually administered before surgery or after it. After transplantation of the donor organ to the recipient, cyclosporine, as a rule, appoint recipient re, i.e., chronically, for maintenance immunosuppression. The initial dosage is administered for 4-12 hours prior to transplantation, and its value may be in the range from 5 to 18 mg/kg body weight of the recipient, usually from 5 to 15 mg/kg of body weight of the recipient. After surgery, usually continue to enter medicine in the original dose daily for 1 to 3 weeks, usually from 1 to 2 weeks. Then, the dosage can be reduced gradually to a maintenance dose of 3 to 10 mg/kg / day, oksya in the range of from 3 to 8% per week and typically is about 5% per week. The dosage is usually adjusted on the basis of the lowest content of drug in the blood to maintain a concentration of from 100 to 350 ng/ml, on the basis of measurements carried out using HPLC, radioimmunoassay, ELISA or analysis with automatic TDx analyzer. Dosage forms of the present invention can be entered together with additional agents if additional remedial measures recommended or known in the art. For example, dosage forms of the present invention can be entered together with adrenal corticosteroids, azathioprine, and the like.

The introduction of the dosage forms of the present invention together with a transfer donor organ recipient will extend the viability of the donor organ in the body of the recipient, due to suppression of the immune response of the recipient to the presence of the donor organ. Under "extension viability" means that the donor organ remains viable in the body of the recipient over a longer period of time than in the case, if immunosuppressive therapy was not carried out along with a transfer of authority. Thus, extending the viability of the VC is to be viable during that period, when it retains its functionality in the body of the recipient.

Dosage forms of the present invention can also be prepared in the form of aqueous colloidal dispersions of nanoparticles of cyclosporine with good bioavailability. In such cases, the nanoparticles are substantially spherical, the cyclosporine is present in amorphous form, and the average particle size generally less than about 1000 nm, more than about 50 nm, typically in the range of about 200 to 800 nm, typically in the range of about 200 to 600 nm. Typically, at least about 50% of the total weight of the cyclosporin is present in the form of particles whose size is within the specified interval. May be present and larger particles, in particular, in the form of aggregates of nanoparticles, and their average diameter, typically less than 50 microns, more typically less than 25 μm, and the number of units does not exceed 40 weight % of the total number of cyclosporine.

The amount of amorphous particles of cyclosporine in such compositions should be sufficient for a therapeutic effect. Since this dosage form can be formed by introducing into the aquatic environment before taking medication or directly is elite impossible. When the preparation of an aqueous solution prior to orally administered cyclosporine is usually present in amounts of about 0.01 to 2.5 weight percent, usually about 0.01 to 0.5 weight percent. The temperature of mixing may be in the range of from 10 to 50oC, usually in the range from 20 to 40oC. Typically, the mixture includes mixing for a sufficient time to ensure the dissolution of cyclosporine.

Colloidal amorphous suspension of nanoparticles is stable enough to make grilled suspension could remain for some time before drug administration (without deposition), usually up to 6 hours, usually up to about 3 hours.

Additional details concerning the preparation and use of medicinal forms of nanoparticles of cyclosporine according to the present invention, can be found in the publication PCT/US97/04627.

The following examples are offered only to illustrate the invention, and the invention is not restricted by them.

DESCRIPTION OF EXPERIMENTS

Several dosage forms cyclosporine for oral administration was prepared according to the present invention. Biological dostupno. DOSAGE FORMS CYCLOSPORINE FOR ORAL ADMINISTRATION

Prepared following dosage forms cyclosporine A for oral administration. In each case, the specified number of cyclosporine A, surfactant and ethanol or propylene glycol were placed in a volumetric flask 1.0 ml, and in some cases brought up to a final volume of 1.0 ml by adding the desired amount of ester of fatty acid and/or diol (see table).

II. THE STUDY OF THE BIOAVAILABILITY OF DOSAGE FORMS 1-6 AND 7-16

Bioavailability of cyclosporine dosage forms 1-6 and 7-16 studied as follows. As an indicator of bioavailability was determined by the following pharmacokinetic parameters: (a) the maximum concentration of cyclosporine in the blood (Kmax); (b) time (Tmax) required to achieve Kmax; and the area under the curve (PPC), depicting the relationship of concentration and time. In addition to medications and 1-6 7-16 also studied the bioavailability for oral solution SANDIMMUNEOral (SO) under similar conditions for comparison. For each of the above dosage forms used not podvergalis wirawan food (Agway3000, Granvil mill, Greensboro, North Carolina) and water ad libitum (optional). One day before the experiment in the right jugular vein and right femoral vein was inserted silicone cannula under light ether anesthesia. After fasting throughout the night was administered cyclosporine through A gastric tube.

The next day after the introduction of cyclosporine were taken blood samples of 200 ál from the jugular vein in 0.5-ml polypropylene microcentrifuge tubes containing 0.3 mg of lyophilized Na EDTA and immediately shaken for 10 seconds. The time of sampling blood for animals that oral introduced the dosage form was 0, 0,5, 1, 2, 4, 8, 12, 24, 36, 48 and 72 hours after administration of the dosage form.

The content of cyclosporine A, including some of its metabolites, were determined in whole blood using polarization immunofluorescent assay (DFA) (using a Tdx analyzer, Abbott laboratory). Briefly, 150 μl sample of whole blood is quantitatively transferred into a 1.5-ml microcentrifuge tube. Cells were literally and was dissolved with 50 μl of contributing to the dissolution of the reagent containing a surfactant. Then proteins were besieged with 300 μl and the ora TDx according to the method recommended Abbot of diagnostics. Because the analysis using the TDx was developed for samples of human blood, some of the recommended procedures modified as follows. Prepared a series of standard solutions with known concentrations of cyclosporine A by adding a known quantity of cyclosporine A to rat blood treated with EDTA. If it was expected that the concentration of cyclosporin A in the sample is above 1.0 microgram/ml, the blood sample was diluted 10 times with 0.1 M phosphate buffer, pH 7.0. For diluted samples were building another calibration curve with a series of standard solutions containing known amounts of cyclosporine A, which consisted of 10% (by volume) of rat blood, and 90% of the phosphate buffer.

Descriptive pharmacokinetic parameters obtained using decompartmentalise analyses. The maximum concentration (Kmax) and the time at which this concentration is reached (Tmax), was identified by studying the profile of the dependence of concentration and time for each rat. The area under the curve (ACC) concentration time from time 0 to the last point of the data (CPD0--->>t) was calculated using the linear trapezoidal method. Residual prodemos concentration in the blood (K*) to the rate constant of first order associated with the final phase of excretion profile dependence of the concentration-time (z). Contact speed (z) were determined using log-linear regression of the data concentration-time apparent in the terminal log-linear phase of the curve of concentration-time (i.e., took the last 3 to 5 data points depending on the analyzed curve). Total CPD ( CPDt) was defined as the sum of ( ACCt) and ( ACCt).

The results for each dosage form was compared with the results obtained for the SO, and they are presented in Fig. 1-3. These results show that for most dosage forms higher bioavailability of cyclosporine was observed for formulations of the present invention, in comparison with indicators of oral solution SANDIMMUNEORAL (SO), which can be seen from the higher values of CPD for dosage forms of the present invention.

III BIOAVAILABILITY FOR HUMANS DOSAGE FORMS 9, 17-20 AND 21-25.

Subjects the subjects used 48 healthy men aged 19 to 55 years with deviations from E. starvation, double-blind method. 48 subjects were randomly divided into 6 groups of 8 subjects. Each group received a single dose of 300 mg of cyclosporine from the above dosage forms or SANDIMMUNE oral solutionORAL (SO) three times, with each infusion was separated from the other 7-day washout period.

Subjects were required to fast for 10 hours before and 4 hours after dose. Water during the test were allowed to drink at will, except for the period starting 1 hour before dose and ended 2 hours after a dose. Before the introduction of doses were taken blood samples of 15 ml For a dose of mixed 3 ml (300 mg) dosage forms with 200 ml of diluent and administered orally. Blood samples of 10 ml were taken at intervals of time t= 0, 0,5, 1, 1,5, 2, 3, 4, 6, 8, 10, 12, 16, 20 and 24 hours. At the end of the study also took a blood sample 15 ml.

The concentration of cyclosporine A in whole blood specimens were determined using an automatic analyzer TDx (Abbott diagnostics, N. Chicago, Illinois) according to the manufacturer's instructions this device.

Decompartmentalise pharmacokinetic parameters obtained using standard methods. Maksimalna the relationship of the concentration-time. The area under the curve (CPD) blood concentration-time calculated using the linear trapezoidal rule with respect to the last blood concentrations above the limit of sensitivity (25 ng/ml) and extrapolated to infinity.

Determined average values for the observed values of Kmax, Tmaxand CPD for each dosage form. Average values for each dosage form shown in figures 4-6. The results show that for each of the tested dosage forms Kmaxachieved at least twice as fast as for SANDIMMUNE solutionOral (SO), in the same conditions. Moreover, CPD observed for subjects dosage forms, was at least 2000 GCAS/ml greater than that observed for Oral solution (SO), in the same conditions. On the basis of these results it is concluded that the dosage form 9, 17-20 and 21-25 provide higher bioavailability than the Oral solution for oral administration (SO).

IV. RESISTANCE TO LOW TEMPERATURES OF LIQUID DOSAGE FORMS 9 AND 18

Liquid dosage forms 9 and 18 of cyclosporine a and solution for oral administration NEORALTMkept at various low temperatures and opredelennnogo introduction NEORALTMkept from evening until the next day or at a temperature of -10oC, or from 2 to 8oC. At a temperature of -10oC as a dosage form 18, as well as a solution for oral administration NEORALTMSummerdale, while the dosage form 9 has not hardened, although it became very viscous. It is interesting to note that stored in the cold solution dosage forms 9 there were no signs of falling crystalline precipitate of cyclosporine A. When all dosage forms moved in conditions of ambient temperature, then cured dosage form 18 thawed faster than setoguchi solution for oral administration NEORALTM.

When stored in conditions 2 to 8oC solution for oral administration NEORALTMzagustevat to a paste, while the dosage forms 9 and 18 remained viscous liquids. None of which were kept in the cold dosage forms 9 and 18 were observed precipitation cyclosporine A.

From the above results and discussion it is obvious that created new dosage forms cyclosporine with increased bioavailability. Dosage forms of the present invention can be included in the SEB is temperature, including low temperature, usually used when storing in the refrigerator. Dosage forms of the present invention suitable for use in the form of capsules, including hard capsules for ease of storage and handling.

All publications and patent applications cited in the present description of the invention, included as reference as if each individual publication or patent application was specifically and individually indicated as included in the present description by reference.

Although some details of the present invention are described with illustrations and examples to make it more clear, but experts in the art it is obvious, in the light of the recommendations arising from the present invention that it is possible to make certain changes and modifications that are within the essence and scope of the attached claims.

1. The composition of cyclosporine for oral administration, consisting mainly of cyclosporine; at least one alcohol solvent having from 2 to 3 carbon atoms; at least one non-ionic polyaxial and monoamino fatty acids and ethoxylated polyols, having from 4 to 6 carbon atoms; and at least one polyglycol, and at least one of polyglycols is saying. weight in the range from 800 to 10 000 daltons.

2. Composition under item 1, in which polyglycol is a polyethylene glycol.

3. The composition according to p. 2, in which the alcohol solvent is from about 5 to 75 vol.% song.

4. The composition according to p. 2, in which the alcohol solvent is from about 10 to 25 vol.% song.

5. The composition according to p. 4, in which the alcohol solvent is a absolute ethanol.

6. The composition according to p. 2, in which at least one non-ionic polyoxyalkylene surfactant is from about 5 to 80 wt.% song.

7. The composition according to p. 2, in which at least one non-ionic polyoxyalkylene surfactant is from about 10 to 50 wt.% song.

8. The composition according to p. 2, in which at least one non-ionic polyoxyalkylene surfactant is from about 20 to 75 vol.% song.

9. The composition according to p. 2, in which at least one non-ionic polyoxyalkylene surface-active substances is of siteline (4).

10. The composition according to p. 2, in which at least one polyethylene glycol is a polyethylene glycol (mol.weight of from 1000 to 8000 daltons.

11. The composition according to p. 2, in which at least one polyethylene glycol is a mixture of two different polyethylene glycols with different masses.

12. The composition according to p. 2, in which at least one polyethylene glycol is from 20 to 80 wt.% song.

13. Composition under item 1, in which the concentration of cyclosporine 100 mg/ml, the concentration of absolute alcohol is 12.5%, and the concentration of mono-oleate polyoxyethylene (20) monocarbide is 400 mg/ml.

14. Composition under item 1, which is a hard capsule.

15. The composition of cyclosporine for oral administration that includes cyclosporine and physiologically suitable carrier, and the composition is essentially anhydrous.

16. The way to achieve immunosuppression in the recipient's organism, comprising oral administration to a specified recipient compositions cyclosporine according to any one of paragraphs.1 - 15.

 

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The invention relates to a new derivative of 4-oxo-1,4-dihydropyrimidin, specifically: 2,6-diethyl-5-phenyl-1(5,6-dimethylbenzimidazolyl-1)-4-oxo-1,4-dihydropyrimidine (I) having immunosuppressive activity, which can find application in medicine

The invention relates to pharmaceutical industry and relates to pharmaceutical compositions for oral administration in the form of a solid dispersion

The invention relates to an external preparation for topical application, in particular to the outer local drug use, containing as activitiesthese substance 2-amino-2-(2-(4-octylphenyl)ethyl)propane-1,3-diol or its pharmaceutically acceptable acid salt additive

The invention relates to compositions intended for parenteral or oral administration

The invention relates to the field of pharmaceutical industry
The invention relates to medicine and concerns capsules (tablets) with radon
The invention relates to medicine, specifically to medicines antidiarrheal action
The invention relates to pharmacy and medicine and relates to dosage forms nootropic agents
The invention relates to containing cyclosporine A liquid dosage forms for oral administration

The invention relates to the field of pharmaceutical industry and relates to encapsulated forms of medicines and biologically active additives to food
The invention relates to containing cyclosporine A liquid dosage forms for oral administration

The invention relates to an anti-inflammatory drug for external use, comprising as active ingredient nimesulide
The invention relates to medicine, in particular to pharmaceutical compositions for intramuscular injection

The invention relates to the field of medicine and relates to transdermal compositions and tapes or dressings for transdermal delivery
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