Diketopiperazine microparticles with particular specific surface areas

FIELD: medicine.

SUBSTANCE: present invention refers to fumaryldiketopiperazine (FDKP) microparticles applicable for pulmonary delivery and having a specific surface area within the range of 15 m2/g to 67 m2/g and a diameter within the range of 0.5 mcm to 10 mcm. The invention also refers to a dry powder comprising said microparticles that is also applicable for pulmonary delivery, to an inhalation system comprising a powder inhalation apparatus and the above dry powder, as well as to a method for delivering an active agent being an ingredient of the dry powder by inhalation of the above dry powder. There are also disclosed methods for forming the FDKP microparticles, first of which comprises dissolving FDKP in aqueous ammonia, adding an acidic solution to aqueous ammonia at temperature up to 12°C to 26°C and collecting a precipitate containing the FDKP microparticles after rinsing with deionised water. A second method for forming the FDKP microparticles involves supplying equal portions of 10.5 wt % of an acetic acid solution and 2.5 wt % of a FDKP solution at temperature 14-18°C through a high-shear mixer.

EFFECT: invention aims at preparing the FDKP microparticles applicable for pulmonary delivery that have the good aerodynamic performance and provide the enhanced drug absorption.

18 cl, 4 tbl, 9 dwg, 2 ex

 

REFERENCE TO RELATED APPLICATIONS

[0001] Pursuant to 35 U.S.C. §119(e), this application claims the priority of provisional U.S. patent application 61/186773, filed June 12, 2009, the contents of which are incorporated in the present description in its entirety by reference.

The technical FIELD TO WHICH the INVENTION RELATES

[0002] Disclosed microparticles diketopiperazine with a specific surface area of less than about 67 m2/, Microparticles FDK can be used as delivery systems of drugs or active agents in the treatment of diseases or disorders, for example, endocrine origin, including diabetes and obesity.

The LEVEL of TECHNOLOGY

[0003] For many years the delivery of drugs was one of the main problems, in particular when you deliver the connection is unstable in the conditions, with which, before reaching its destination, it is faced in the gastrointestinal tract when administered orally to a subject. For example, in many cases it is preferable to oral administration of drugs, especially from the point of view of ease of administration, patient compliance to treatment and lower cost. However, many compounds are ineffective or have low or variable effectiveness of PR is oral administration. Apparently, this is due to instability of drugs in conditions of the digestive tract or because of their inefficient suction.

[0004] delivery of medicinal substance into the lungs was studied on the basis of the problems associated with the delivery of medicinal substance. For example, drugs delivered to the lungs, usually designed in such a way that they affected lung tissue, such as vasodilator, surfactants, chemotherapeutic agents or vaccines against influenza or other respiratory diseases. Other medicinal substances, including nucleotide drugs delivered to the lungs, since they are fabric which is particularly suitable for the treatment of, for example, in the case of genetic therapy of cystic fibrosis, in which light is injected retroviral vector expressing defective adelaideans.

[0005] In the light you can also carry out delivery of drugs, which are agents for systemic effects. Benefits delivery system agents into the lungs lie in their large surface area and the ease with which the absorption by the mucosal surface of the lung. One of the problems associated with all forms of drug delivery to the lungs, is the falsity of such delivery, associated with the passage of the drug through all natural barriers, such as cilia lining the trachea, as well as with the introduction of constant volume and weight of the medicinal substance.

[0006] Therefore, there is the potential to improve drug delivery to the lungs.

The INVENTION

[0007] the Present disclosure relates to systems, microparticles and ways to improve the delivery of drugs into the lungs. In disclosed embodiments, the implementation of improved delivery is achieved by providing microparticles of diketopiperazine (DCT) with specific surface area (SSA) in the range of about 35 m2/g to about 67 m2/, DKP Microparticles with a specific surface area in the range demonstrate characteristics that are favorable for delivery to the lungs, such as improved aerodynamic characteristics and improved absorption of drugs.

[0008] One disclosed in the present description of embodiments includes microparticles diketopiperazine with a specific surface area of less than about 67 m2/, Another variant implementation includes microparticles diketopiperazine with a specific surface area in the range of about 35 m2/g to about 67 m2/g is Another variant of implementation includes microparticles diketopiperazine, which in the absence of active agent specific surface area greater than about 35 m2/g but less than about 62 m2/g after adsorption of the particles of the active agent.

[0009] In another embodiment, microparticles fumarylacetoacetase (FDK) with a specific surface area ranging from about 35 m2/g to about 67 m2/g contains a medicinal substance or active agent, and the specified SSA determines to add a medicinal substance to the particle. Attaching the active agent to the particle usually leads to a reduction in SSA. In various embodiments, the implementation of microparticles fdcp medicinal substance may constitute, for example, the peptide or protein, including endocrine hormones, such as insulin, glucagon-like peptide-1 (GLP-1), glucagon, on the basis, parathyroid hormone, obestatin, calcitonin, oxyntomodulin etc. Another variant implementation of the microparticles fdcp with a specific surface area ranging from about 35 m2/g to about 67 m2/g may include the content of drug substance/peptide, which may vary depending on the conditions of the process of synthesis to obtain microparticles. In one of the specific examples can be obtained microparticles fdcp with the content of drug substance/peptide to the / establishment, which may vary depending on the target or delivered dose. For example, if the drug is insulin, insulin component may be from about 3 IU/mg to about 4 IU/mg containing microparticles powder dosage form. In some embodiments, the implementation of the medicinal substance is adsorbed on the surface of the microparticles. In other embodiments, the implementation of such loaded drug microparticles SSA of these microparticles is less than about 62 m2/year

[0010] Disclosed here options for implementation include dry powders containing microparticles. In one embodiment, the implementation of dry powders contain microparticles fdcp with a specific surface area of less than about 67 m2/, Another variant implementation includes microparticles diketopiperazine, whose specific surface area is in the range from about 35 m2/g to about 67 m2/, Another variant implementation includes containing the medicinal substance or active agent microparticles diketopiperazine with a specific surface area ranging from about 35 m2/g to about 62 m2/year

[0011] In embodiments, the implementation of the dry powder microparticles fdcp contain a medicinal substance. In another embodiment, the dry powder medicinal substance is own the th peptide, which the size of the molecule and the molecular weight can be different, including insulin, glucagon-like peptide-1, glucagon, on the basis, parathyroid hormone, calcitonin, oxyntomodulin, etc. In one of these embodiments of dry powders, in which the medicinal substance is insulin, the insulin content in the microparticles fdcp is from about 3 IU/mg to about 4 Units/mg.

[0012] Other embodiments of relate to the systems of drug delivery containing the inhaler, the container for a single dose of medicinal substance in the form of a dry powder, for example a cartridge, and powdered dosage form, containing disclosed in the present description microparticles and an active agent. In one embodiment, the implementation of the system of drug delivery for use with dry powders include inhalation system containing an inhaler with high resistance with air channels, which have a high resistance to air flow through these channels, to break up the agglomerates and dispensing powdered dosage forms. In one embodiment, the implementation of a resistance value in the inhalation system is, for example, from about 0,065 (√kPa)/liter per minute to about 0,200 (√kPa)/liter per minute In some variant of the x implementation of dry powders can be effectively served by inhalation through inhalation system in which the maximum differential pressure during inhalation may be from about 2 kPa to about 20 kPa, and can create in the peak flow rate from about 7 to 70 liters per minute In some embodiments, the implementation of the inhalation system is designed to provide a single dose by issuing powder inhaler in the form of a continuous stream or in the form of one or more pulses given to the patient powder. In some disclosed in the present description of embodiments, the implementation of the inhalation system for dry powders has given the balance of mass flow inside the inhaler. For example, the balance of flow, in which from about 10% to 70% of the total flow as it exits the inhaler to the patient is delivered through one or more metering holes that allow air flow to pass through the area containing the powdered dosage form, and from about 30% to 90% of the air flow is generated in the other channels of the inhaler. In addition, the bypass flow or flux that is not a member and does not extend from the staging area of the powder, such as a cartridge, can again be combined with the stream coming through the metering powder hole inside the inhaler in order to dilute, to accelerate and ultimately to destroy the agglomerates fluidizedpowder to the outlet of the mouthpiece of the inhaler. In one of the embodiments of the flow velocity in the system of the inhaler, in the range of about 7 to 70 l / min, provide the spraying of more than 75% of the powdered contents of the container or powdered contents of the cartridge, a portion of the weight from 1 to 30 mg In some embodiments, the implementation described above, the inhalation system can produce in one breath respirable fraction/portion constituting more than 40%, 50%, 60% or more than 70% of the dose of powder.

[0013] In specific embodiments, the implementation is available inhalation system containing inhaler for dry powders, dosage form in the form of a dry powder containing microparticles fumarylacetoacetase, and loaded microparticles fdcp have a specific surface area less than about 67 m2/g, and one or more active agents. In some aspects of this variant implementation of the inhalation system dosage form in the form of a dry powder is provided in the cartridge for a single dose. Alternatively, the dosage form in the form of a dry powder may be pre-loaded or filled in the inhaler. In this embodiment, the structural configuration of the inhalation system allows the mechanism of destruction of agglomerates in inhaler form respirable fraction greater than 50%; a more than half of the quantity of powder contained in the inhaler (cartridge), is emitted in the form of particles less than about 5.8 microns. In one of the embodiments inhalers can release during dispensing more than 85% powdered medicinal substance contained within the container. In some embodiments, the implementation inhalers can in one breath to release more than 85% of the contained powdered medicinal substance. In some embodiments, the implementation inhalers can release more than 90% of the content of the cartridge or container's content in less than 3 seconds with a pressure difference of from 2 kPa to 5 kPa in the form of a portion of up to 30 mg

[0014] Disclosed here options for implementation include the ways. In one of the embodiments provides a method of treating diseases or disorders associated with disorders of the endocrine system, containing an introduction to the needy in the person of the dosage form in the form of a dry powder containing microparticles fdcp with a specific surface area of less than about 67 m2/g and a medicinal substance suitable for the treatment of specified diseases or disorders. Another variant implementation includes microparticles diketopiperazine, whose specific surface area is in the range from about 35 m2/what to approximately 67 m 2/, Another variant implementation includes containing the active substance microparticles diketopiperazine with a specific surface area less than approximately 62 m2/, One of the embodiments includes a method of treating disorders associated with insulin containing introduction dry powder containing the above-described microparticles fdcp needs this man. The method includes the introduction of the subject of the dosage form in the form of a dry powder containing microparticles fumarylacetoacetase, SSA which is in the above ranges. In various embodiments, the implementation associated with insulin disorder can specifically include or exclude all or any of the following disorders: prediabetes, diabetes mellitus type 1 (phase “honeymoon” remission), the phase after the honeymoon, or both), diabetes mellitus type 2, gestational diabetes, hypoglycemia, hyperglycemia, insulin resistance, secretory dysfunction, impaired early-phase insulin secretion, loss of function of pancreatic β-cells, the loss of pancreatic β-cells and metabolism disorders. In one embodiment, the implementation of the dry powder contains insulin. In other embodiments, implementation of the dry powder contains glucagon, on the basis or GLP-1.

[0015] Other disclosed here options for implementation include the SPO is usually used for receiving suitable for introduction in light of the microparticles in the form of a dry powder. In one of the embodiments, the method comprises the formation of microparticles of diketopiperazine with a specific surface area of from about 35 m2/g to about 67 m2/g within the 95%confidence interval by selection of the conditions of manufacture for a target of obtaining particles with a specific surface area of about 52 m2/, In another embodiment, selection of the conditions of manufacture includes increasing or decreasing the temperature or the concentration of ammonia, acetic acid and/or diketopiperazine in the feed solution.

[0016] Another disclosed here is an implementation option includes a method of making microparticles suitable for introduction into the lungs in the form of a dry powder containing diketopiperazine, such as FDK. In one of the embodiments of the microparticles contain synthetic compounds fdcp or its composition, and microparticles have a specific surface area from about 35 m2/g to about 67 m2/g, and the determination of the surface area of the microparticles fdcp by estimating the surface area in m2/g standard analyzer for measuring surface area. In other embodiments, implementation of the specific surface area is determined after adsorption of the microparticle active agent instead of or in addition to the definition of the area of the surface is before the introduction of the active agent; SSA does not exceed approximately 62 m2/, In one embodiment, the implementation of the synthesis fdcp includes: (a) dissolving the composition fdkp in solution with cosaboutate pH, receiving the solution fdkp; (b) providing a solution of a volatile acid, and c) mixing the solution fdcp with a solution of volatile acids in the mixer with large shear forces to obtain microparticles.

[0017] In specific embodiments, the implementation of the method of producing microparticles fdcp with surface area ranging from about 35 m2/g to about 67 m2/g contains the saponification reaction and recrystallization. In one of the embodiments disclosed is a method of obtaining particles in the form of a dry powder suitable for administration to the lungs, including: a) the synthesis of the compounds or compositions fdcp, b) dissolving compounds fdcp obtained in stage a), in solution with cosaboutate pH with obtaining solution fdkp; (d) providing a solution of a volatile acid and (e) mixing the solution fdcp with a solution of volatile acids in the mixer with large shear forces to obtain microparticles. The method may also include the determination of the specific surface area of the particles after their formation.

[0018] In specific embodiments, the implementation of the method of synthesis of microparticles fdcp with a specific surface area of not more than about 67 m2/g, contains a supply equal to the ACC about 10.5 wt.% solution of acetic acid and about 2.5 wt.% solution fdcp at a temperature of from about 14°to about 18°C in a mixer with large shear effort such as Dual-feed SONOLATOR™, under the pressure of 2000 psi through a hole the size of 0.001 inch2to obtain a suspension. The method may further comprise the step of deposition of the microparticles from the solution and collecting the microparticles formed in the vessel with deionized water, about the same mass and temperature. In this embodiment, the slurry contains about 0.8% of solid microparticles. In some embodiments, the implementation of the method also includes the concentration of a suspension of microparticles by washing the microparticles, for example, in deionized water using filtration method with tangential flow. In this and other embodiments, implementation of sediment can be first concentrated to about 4% solids, and then washed with deionized water. In some embodiments, the implementation of the suspension usually can be concentrated to approximately 10% solids based on the original weight of the compositions used fdcp. A concentrated suspension can be estimated on the solids content by the method of drying in a drying Cabinet. In the disclosed here variants of implementation, the method further comprises determining the surface area of the particles after drying.

[0019] In specific embodiments, the implementation disclosed in the present description of the compositions and methods of the microparticles of diketopiperazine with the unit square the Yu surface of less than about 67 m 2/g is used diketopiperazine formula 2,5-diketo-3,6-bis(N-X-4-aminobutyl)piperazine, in which X is chosen from the group consisting of fumaryl, succinyl, malila and glutaryl. In the example embodiment, diketopiperazine has the formula (bis-3,6-(N-fumaryl-4-aminobutyl)-2,5-diketopiperazine or 2.5-diketo-3,6-bis(N-fumaryl-4-amino-butyl)piperazine.

[0020] Another disclosed here is an implementation option includes a method of making microparticles fdcp with a specific surface area of less than about 67 m2/g , containing the medicinal substance or active agent, and a specified specific surface area determined prior to the introduction part of the medicinal substance. In this embodiment, the method comprises adding to a suspension of microparticles of a solution containing an active agent, such as a peptide, including insulin, glucagon, glucagon-like peptide-1, oxyntomodulin, peptide YY, etc.; adding to the suspension an aqueous solution of ammonia, for example, to increase the pH of the slurry to 4.5; carrying out the reaction, the instantaneous freezing of the resulting suspension in liquid nitrogen and lyophilization of the formed pellets to obtain a dry powder containing microparticles fdcp with a specific surface area of less than about 67 m2/, aspect of this case for the specific surface area is rnost particles after adsorption of the microparticle active agent does not exceed about 62 m 2/year

[0021] In one embodiment, implementation of the disclosed method of insulin delivery to the needy in this patient, introducing a dry powder containing microparticles diketopiperazine with a specific surface area less than approximately 62 m2/g (67 m2/g based loaded microparticles), deep into the lungs by inhalation by the patient as a dry powder. In aspects of this variant implementation of the specific characteristics of the system of the inhaler.

[0022] Another disclosed here is an implementation option provides a method of drug delivery, such as insulin, to the needy in this patient, introducing a dry powder deep into the lungs by inhalation by the patient of the dry powder; and the dry powder contains microparticles of diketopiperazine containing insulin, where the microparticles are formed of diketopiperazine and have a surface area ranging from about 35 m2/g to about 67 m2/, In one aspect of this variant implementation of the specific surface area of the particles after adsorption on the particle of the active agent does not exceed 62 m2/, In aspects of this variant implementation of the specific characteristics of the system of the inhaler. Other options for implementation include methods of treatment associated with insulin disorders, containing introduction the dry powder, as described above, the needy in this man. In various embodiments, the implementation associated with insulin disorder can specifically include or exclude all or any of the following violations: prediabetes, diabetes mellitus type 1 (phase honeymoon phase after the honeymoon, or both phases), diabetes mellitus type 2, gestational diabetes, hypoglycemia, hyperglycemia, insulin resistance, secretory dysfunction, impaired early-phase insulin secretion, loss of function of pancreatic β-cells, the loss of pancreatic β-cells and metabolism disorders.

[0023] In one embodiment, the implementation is provided a method of treating diseases or disorders associated with disruption of the endocrine system, containing an introduction to the needy in the person of the dosage form in the form of a dry powder containing microparticles fdcp with a specific surface area of less than about 67 m2/g, and a medicinal substance suitable for the treatment of specified diseases or disorders. In one aspect of this variant implementation of the specific surface area of the particles after adsorption of the active agent on the microparticle does not exceed approximately 62 m2/, One of the embodiments includes a method of treatment associated with insulin disorders involving the introduction of a dry powder containing microparticles fdcp, as described above, the needy in this man. The method includes the introduction of the subject of the dosage form in the form of a dry powder containing microparticles fdcp with a specific surface area of not more than about 67 m2/g, and insulin. In the aspect of this variant implementation of the specific surface area of the particles after adsorption of the active agent on the microparticle does not exceed approximately 62 m2/, In various embodiments, the implementation associated with insulin disorder may, in particular, to include or exclude all or any of the following violations: prediabetes, diabetes mellitus type 1 (phase honeymoon phase after the honeymoon, or both phases), diabetes mellitus type 2, gestational diabetes, hypoglycemia, hyperglycemia, insulin resistance, secretory dysfunction, impaired early-phase insulin secretion, loss of function of pancreatic β-cells, the loss of pancreatic β-cells and metabolism disorders.

BRIEF DESCRIPTION of DRAWINGS

[0024] the following drawings form part of the present description and are included to further illustrate certain aspects of the disclosed examples here. The disclosure can be better understood with reference to one or more of these drawings in combination with the detailed description presented here are specific embodiments.

[0025] Nafiga and 1B shows microparticles with high and low specific surface area (SSA), respectively.

[0026] figure 2 shows a particle fumarylacetoacetase (FDK)with an overall view of the sphere.

[0027] figure 3 shows a block diagram of the process of obtaining fdcp.

[0028] On Figa and 4B show the estimated and actual SSA powders consisting of particles/insulin obtained according to the block diagram shown in Figure 3.

[0029] On Figa-C shows the relationship between RF/serving, SSA (microparticles fdcp) and the temperature of the solution.

[0030] On Figa shows the relationship between parameter RF/serving and SSA powders consisting of particles/insulin, and it is shown that powders with SSA> about 62 m2/g have a 5% chance for parameter values RF/serving <40%. On FIGU shows the target values for SSA in the production due to inaccurate forecasting of SSA on the basis of the feed concentration.

[0031] figure 7 shows the parameter RF/dose as a function of SSA powders consisting of particles/insulin. Each point represents a separate party powders consisting of particles/insulin.

[0032] On Figa shows the influence of the SSA powders consisting of particles/insulin, on the effective viscosity of a suspension of microparticles containing about 4% solids. On FIGU shows the relationship between the viscosity of the suspension and efficiency of the powder.

[0033] figure 9 shows the concentration of insulin in the sediment as a function of SSA particles is evaluated.

DETAILED DESCRIPTION

[0034] As indicated above, the delivery of medicinal substance into the lungs has many advantages. However, in light difficult to deliver a constant volume and weight of drug substance because of the problems associated with the transportation of drugs through natural physical barriers. In the present description of the disclosed microparticles diketopiperazine with a specific surface area of less than about 67 m2/g as agents of drug delivery, methods of making microparticles and methods of treatment using these microparticles.

[0035] when Used herein, the term “microparticle” refers to a particle diameter from about 0.5 μm to about 1000 μm, regardless of its precise external or internal structure. Microparticles having a diameter from about 0.5 μm to about 10 μm, can reach the lung, successfully passing through the most natural barriers. To pass through the bend in the throat requires a diameter of less than about 10 microns, and in order to prevent the exhalation of particles, the required diameter of approximately 0.5 μm or more. For deep penetration into the lung (or alveolar region), where, as expected, is the most effective absorption, it is preferable to maximize the fraction of particles contained in the “respirable fraction (RF), which according to the conventional view represents particles with an aerodynamic diameter of approximately 0.5 μm to approximately 5.7 μm, although, according to some references, there are several other ranges, measured by standard methods, such as a cascade impactor Andersen. To measure the aerodynamic particle size you can use other impactors, such as the new generation impactor NEXT GENERATION IMPACTOR™ (NGI™, MSP Corporation), defined in this way respirable fraction has similar aerodynamic sizes, for example <6.4 µm. In some embodiments, the implementation for determining the size of particles used device using diffraction of laser radiation, for example, a device using diffraction of laser radiation, disclosed in U.S. patent application 12/727179 (filed March 18, 2010, which is incorporated into this description in its entirety in parts relevant to the present description), where for evaluating the effectiveness of the inhalation system was measured volumetric average geometric diameter (VMGD) of particles. For example, in various embodiments, implementation cartridge is devastation on ≥80%, 85% or 90% and VMGD of emitted particles ≤12.5 μm, ≤7.0 µm or ≤4,8 μm may indicate improved aerodynamic characteristics. Disclosed here are the options exercise show that microparticles fdcp with a specific surface area of less than about 67 m2/g demonstrate characteristics that are favorable for drug delivery to the lungs, such as improved aerodynamic characteristics.

[0036] Respirable fraction per serving (RF/serving) represents the percentage of the flying particles from the full dose, the size of which is suitable for delivery into the lungs, which is a measure of the aerodynamic characteristics of the microparticles. As described herein, the RF-value/serving, equal to 40% or above 40%, reflects acceptable aerodynamic characteristics. In some disclosed here variants of implementation of the respirable fraction portion may exceed 50%. In the example embodiment, respirable fraction per serving can be up to about 80%, where about 80% of the portion of the flying of the particles have a size of <about 5.8 microns as measured using standard methods.

[0037] when Used herein, the term “dry powder” refers to fine composition, which is not suspended and is not dissolved in the propellant, the media or other liquid. This does not necessarily mean the complete absence of water molecules.

[0038] it Should be borne in mind that the specific parameter value RF/serving may depend on inhaler used to deliver the powder. Powders, as a rule, tend to form agglomerates, and crystalline microparticles DCT form a particularly cohesive powders. One of the functions of the inhaler for dry pores is SKOV is the destruction of agglomerates of the powder with the to the resulting particles contained respirable fraction suitable for dose delivered during inhalation. However, the destruction of agglomerates cohesive powders usually not full, so the grain size of particles observed when measuring respirable fraction delivered by the inhaler will not match the particle size distribution of the primary particles, i.e. the profile is shifted towards larger particles. Design inhalers vary in their efficiency of destruction of agglomerates, and thus the absolute value of RF/serving observed for different designs, also changes. However, the optimal value of the parameter RF/serving as the function of specific surface area can be similar for different inhalers.

[0039] when Used herein, the term “about” is used to indicate that a value includes the standard deviation of the measurement characteristic of the device or method used to determine this value.

[0040]Diketopiperazine

[0041] One class of agents for drug delivery, which was used to solve problems in the pharmaceutical field, such as the instability of the drug substance and/or poor absorption, is a 2.5-diketopiperazine. 2.5-diketopiperazine presents connected the eating of General formula 1, as shown below, where E1and E2are independently N or more precisely, NH. In other embodiments, the implementation of E1and/or E2represent independently oxygen or nitrogen, so that, when one of the substituents E1or E2is oxygen and the other is nitrogen, then according to the formula obtained similar to the substituents diatomologica, or when and E1and E2represent oxygen, according to the formula obtained similar to the substituents declomycin.

Formula 1

[0042] As shown, these 2.5-diketopiperazine can be used for drug delivery, particularly those which have acid groups, R1and R2as described , for example, in U.S. patent No. 5352461 “Self-Assembling Diketopiperazine Drug Delivery System”; 5503852 “Method for Making Self-Assembling Diketopiperazine Drug Delivery System”; 6071497 “Microparticles for Lung Delivery Comprising Diketopiperazine and 6331318 “Carbon-Substituted Diketopiperazine Delivery System”, each of which is incorporated into this description by reference in its entirety that part which relates to diketopiperazines and delivery of drugs using diketopiperazines. Diketopiperazine can be formed into microparticles, which include medicinal substance, or microparticles, which can be adsorbed drug. Combin the tion of drug substances and diketopiperazine may improve stability of the drug substance and/or absorption characteristics. These microparticles can be administered by various routes of administration. In the form of dry powders, these microparticles can be delivered via inhalation in certain areas of the respiratory system including the lungs.

[0043] Such particles are usually obtained by precipitation of the free acid (or base) in conditions of basic pH, which gives self-organizing micro-particles composed of aggregated crystalline plates. The stability of the particles can be increased by using a small amount of surfactant, such as Polysorbate-80, in solution DCT, which were precipitated particles (see, for example, the patent application U.S. 2007/0059373 “Method of drug formulation based on increasing the affinity of crystalline microparticle surfaces for active agents”, which is incorporated into this description in its entirety by reference in part, related to the formation and loading of microparticles DCT and dry powders). Ultimately, the solvent can be removed to obtain a dry powder. Appropriate removal of the solvent include lyophilization and spray drying (see, for example, the patent application U.S. 2007/0196503 “A method for improving the pharmaceutic properties of microparticles comprising diketopiperazine and an active agen” and U.S. patent 6444226 “Purification and stabilization of peptide and protein pharmaceutical agents”, each of which is included in the present description in its entirety by reference in part, related to the formation and loading of microca the TIC DCT and dry powders). These microparticles are different from microparticles prepared from salts of DCT. Such particles are usually formed (as opposed to dried) by spray drying, forming spheres and/or deformed spheres of amorphous salt (as opposed to the free acid or base) to the fact that they are chemically, physically and morphologically separate units. The present disclosure relates to FDK, which should be considered as a free acid or dissolved anion.

[0044] the Methods of synthesis of diketopiperazines described, for example, Katchalski and others, J. Amer. Chem. Soc. 68, 879-880 (1946) and Kopple, etc., J. Org. Chem. 33 (2), 862-864 (1968), the contents of which are fully incorporated into the present description by reference. 2.5 Diketo-3,6-di(aminobutyl)piperazine (Katchalski, etc. he's called lysine anhydride) can also be obtained through cyclodimerization N-ε-P-L-lysine in molten phenol similar to the way Kopple (Kopple) with subsequent removal of the blocking (P)-groups using appropriate reagents and conditions. For example, the CBz protective group can be removed using a 4.3 M HBr in acetic acid. This path may be preferred because it uses commercially available starting material, the reaction proceeds under conditions in which, according to saved the stereochemistry of the starting materials in the product, and all stages can be l the GKO increase in volume for use on an industrial scale. Methods of synthesis of diketopiperazines also described in U.S. patent 7709639 “Catalysis of Diketopiperazine Synthesis”, which is also included in the present description by reference.

[0045] Fumarylacetoacetase (bis-3,6-(N-fumaryl-4-aminobutyl)-2,5-diketo-diketopiperazine; FDK) is a preferred diketopiperazine for the introduction of light:

[0046] FDK provides a favorable matrix of microparticles due to its low solubility in acid, which dissolves in a neutral or basic pH. These properties allow to crystallize fdkp and contribute to the self-organization of crystals in the particles in acidic conditions. Particles are easily dissolved in physiological conditions with a neutral pH. As noted above, the microparticles having a diameter of from about 0.5 to about 10 microns, can reach the lung, successfully overcoming the most natural barriers. Particles of this size can be easily obtained from fdcp.

[0047] As noted above, the microparticles having a diameter of from about 0.5 to about 10 microns, can reach the lung, successfully overcoming the most natural barriers. Particles of this size can be easily obtained from diketopiperazines with acidic groups such as carboxylate groups in fdcp (and related molecules such as 2-diketo-3,6-di(4-X-aminobutyl)piperazine, where X represents succinyl, glutaryl or Maler). In the case of deposition in acidic medium are formed self-organizing particles composed of aggregates of crystalline wafers. The size of these plates is connected with a specific surface area of the particles, which in turn affects the structure, the loading and aerodynamic characteristics of the particles.

[0048] the Specific surface area of the microparticles DCT is a measure of the average size of the crystal and can be used to measure the relative contribution to the characteristics of the formation of crystal nuclei and growth of the microparticles. The specific surface area depends on the size of the crystal particles and the density (ρ) of matrix microparticles and inversely proportional to the characteristic dimension, L, of the crystals. Specific surface area is a distinctive feature of the population of particles and not necessarily characteristic of each particle in it. Disclosed here are the options implementation demonstrate that microparticles with a specific surface area of less than about 67 m2/g exhibit characteristics that are favorable for drug delivery to the lungs, such as improved aerodynamic characteristics when used moderately effective inhalers, such as the MEDTONE inhaler®, disclosed in U.S. patent 7464706 “Unit Dose Cartridge ad Dry Powder Inhaler”, which is included in the present description by reference in part the relevant subject matter. Another option is implementation specific surface area of not more than about 62 m2/g, provides greater assurance that the party of the particles will meet the minimum standard aerodynamic characteristics. Since the specific surface area also affects the rate of loading/content medicinal substances, in various embodiments, the implementation requires that the improved adsorption capacity medicinal substance specific surface area exceeded or was equal to about 35 m2/g, 40 m2/g or 45 m2/, in Addition, when the specific surface area falls below about 35 m2/g, there is an unstable emptying of the cartridge even when using highly effective inhalers, for example, disclosed in U.S. patent application 12/484125 A Dry Powder Inhaler and System for Drug Delivery”, filed June 12, 2009, and U.S. patent application 12/717884 “Improved Dry Powder Drug Delivery System”, filed on March 4, 2010, the contents of which are incorporated into this description by reference.

[0049]The upper limit of the range of the specific surface area

[0050] the Upper limit of the range of specific surface area, determined according to the present description, yet on the aerodynamic characteristics of the microparticles. These studies have shown that the existing trend to lower values of RF/serving, because the value of the specific surface area exceeds about 50 m2/, in Addition, when the specific surface area increases, so too is the distribution of RF/serving and increases the probability of violation of the criterion of choice RF/serving, for example, parameter RF/serving > 40%. Therefore, in some embodiments, the implementation of the upper limit can be selected equal to about 67 m2/year Based on the curve, approximated on the collected data for a large number of drugs predicted that this value provides the value of RF/serving, equal to 40%. In other embodiments, implementation of the upper limit can be selected equal to about 62 m2/, the Upper limit of 62 m2/g provides microparticles with reasonable parameter values RF/serving within the 95% confidence interval (see Figa).

[0051] Another reason for setting the upper limit of the specific surface area of the microparticles is that suspension of microparticles with high specific surface area is usually several orders of magnitude more viscous than the suspension of microparticles with a lower specific surface area. This phenomenon likely reflects the strengthening of the forces of attraction between particles associated with what Arsenium crystals. After lyophilization stronger attraction can generate aggregates, which are not destroyed efficiently, potentially reducing the value of the parameter RF/serving, because the viscosity of the suspension has a negative correlation with the parameter RF/serving.

[0052] the Specific surface area of the microparticles is determined for dried not put up powder and cannot be accurately predicted from the conditions of formation of microparticles. Therefore, it may be desirable to obtain specific surface area equal to approximately 52 m2/, When the specific surface area equal to approximately 52 m2/g, it is expected that only 5% of the particles exceed the more conservative upper limit 62 m2/g (Pigv). Within these 5% of the microparticles, which can exceed 62 m2/g, it is expected that other 5% (0,25%) will show the parameter RF/serving < 40%. Thus, these manufacturers provide microparticles having an argument RF/serving > 40% with over 99% confidence interval.

[0053]The lower limit of the specific surface area

[0054] the Lower limit defined here range specific surface area depends on the requirements of the load medicinal substance. The particles should have a specific surface area that is sufficient to load the required number l of the drug substances. If adsorbed insufficient quantity of medicinal substance (i.e. remains in solution), needsomeone medicinal substance can connect the bridge links formed microparticles, leading to formation of aggregates. Units can have a negative effect on the aerodynamic characteristics. In the case of insulin, in order to avoid the formation of insulin bridging ties in the appropriate therapeutic dose required lower limit of the specific surface area equal to approximately 35 m2/, the Formation of bridging ties is also a possible cause of the above poor emptying of the cartridge, which can be observed in the case of powders with a lower specific surface area. To provide greater assurance of the possibility to avoid these problems and opportunities to ensure that the maximum load can be used a higher lower limit of the specific surface area, for example 40 or 45 m2/, Alternative, other factors that affect the aerodynamic characteristics can be maintained in a more narrow range of tolerance. On Figa shows a cluster of particles with high specific surface area. On FIGU shows the connection of particles “bridging ties”educated insulin powder with low specific surface area the property.

[0055]The formation of microparticles fdcp.

[0056] the First stage in the process of obtaining microparticles fdcp represents formation of microparticles pH-induced crystallization fdkp and self-organization crystals fdkp in microparticles having a generally spherical shape (Figure 2). Therefore, obtaining microparticles, in essence, is the process of crystallization. The excess solvent can be removed by washing the suspension by repeated centrifugation, decantation and resuspending or diafiltrate.

[0057] To obtain the loaded insulin microparticles fdcp insulin can adsorb directly onto the microparticles as add (i.e. before lyophilization) initial solution of insulin in the suspension of microparticles fdcp. In one embodiment, the implementation after adding the initial solution of insulin can also be accomplished stage regulation of pH. This stage initiates the adsorption of insulin on the microparticles in suspension before further processing. The increase in the pH of the suspension to about 4.5 provides complete adsorption of insulin on microparticles in suspension without excessive leaching fdcp of the matrix particles and also improves the stability of insulin in bulk product medicinal substance. The suspension can be instantly frozen in the form of droplets (i.e. vergota kriogenoyi) in liquid nitrogen and freeze-dried to remove solvent and obtain a dry powder. In an alternative implementation options to obtain a dry powder suspension can be spray dried. Figure 3 shows the block diagram of the process of obtaining.

[0058] In one embodiment, the exercise provided a production process of obtaining the claimed microparticles fdcp containing insulin. In short, using a mixer with large shear efforts, such as Dual-feed SONOLATOR™, or, for example, a mixer with large shear effort, disclosed in application for U.S. patent 61/257311 (filed November 2, 2009, the contents of which are fully incorporated into the present description by reference), an equal mass of about 10.5 wt.% solution of acetic acid and about 2.5 wt.% solution fdcp at a temperature of about 16°C± about 2°C (tables 1 and 2) can be fed under pressure 2000 psi, using a Dual-feed SONOLATOR™, through a hole the size of 0.001 inch2. Sediment can collect in the tank with deionized water (DI) with approximately equal mass and temperature. The resulting suspension contains about 0.8% solids. Sludge can be concentrated by filtration and washed with tangential flow. The precipitate can be first concentrated to about 4% solids, then rinsed with deionized water. The final concentration of the suspension can be approximately 10% solids based on the original weight fdcp. The oxygen is arowana suspension may be assessed on the content of solid particles by the method of drying in a drying Cabinet.

[0059] In one embodiment, the implementation of the concentrated source solution of insulin can be prepared from 1 part of insulin and 9 parts to about 2 wt.% solution of acetic acid. The original solution of insulin can be added to the suspension using gravimetric dispensing boot about to 11.4 wt.% of insulin. A suspension of insulin-fdkp can be mixed for at least about 15 minutes. In some embodiments, the implementation of the mixing may take shorter or longer time. Then the suspension of insulin-fdkp you can chitravati using from about 14 to about 15 wt.% an aqueous solution of ammonia from the original pH of about 3.5 to a pH of about 4.5. The suspension can be instantly frozen in liquid nitrogen, forming pellets, and freeze-dried to obtain a bulk containing insulin microparticles fdcp. Blank microparticles FDK can be obtained the same way without stages boot insulin and pH adjustment. In one embodiment, the implementation of the bulk density of the powder fdkp-insulin containing these microparticles is from about 0.2 g/cm3to about 0.3 g/cm3.

Table 1
10.5% solution of acetic acid
ComponentWt.%
DI water89,00
Glacial acetic acid (GAA)10,50
10% Polysorbate 800,50

Filtered through filters with a pore size of 0.2 μm

Table 2
2.5% solution fdcp
ComponentWt.%
DI water95,40
FDKP2,50
NH4OH1,60
10% Polysorbate 800,50

Filtered through filters with a pore size of 0.2 μm

[0060]Regulation of specific surface area

[0061] On the distribution of size and shape of crystals fdcp affects the balance between the formation of the nucleus of new crystals and the growth of existing crystals. Both phenomena are strongly dependent upon concentration and supersaturation of the solution. The characteristic size of the crystal fdcp is a sign of the relative rate of formation of nuclei and growth. If demineralizowana kernel produces many crystals, but they are relatively small, since all competing for FDK in solution. If dominates growth, competing crystals smaller and the characteristic size of the crystals more.

[0062] the Crystallization is highly dependent on glut, which, in turn, strongly depends on the concentration of components in the feed streams. More strong oversaturation leads to the formation of a large number of small crystals; at lower supersaturation is a smaller crystals, but they are big. In terms of saturation: 1) increasing the concentration of fdkp increases the degree of saturation; 2) increasing the concentration of ammonia shifts the system to a higher pH, for example, at a pH of about 4.5, increases the equilibrium solubility and decreases the saturation; and 3) increasing the concentration of acetic acid increases the saturation by moving the end point towards lower pH values, at which the equilibrium solubility below. The decrease in the concentrations of these components cause the opposite effects.

[0063] the Temperature influences the formation of microparticles fdcp indirectly through influence on the solubility fdkp and kinetics of formation of nuclei of crystals fdkp and their growth. When low is emperature formed small crystals with high specific surface area. Suspensions of these particles show a high viscosity, pointing to the strong attraction between the particles. The temperature range from about 12°to about 26°C provides RF/serving > 40% within a 95% confidence interval. Given the relation between temperature and specific surface area, you can use a little more narrow, but internally consistent temperature range from about 13°to about 23°C.

[0064] Finally, it should be borne in mind that the adsorption of the active agent on the surface of the microparticles typically leads to a decrease in the specific surface area. Adsorption of active agent can fill, or otherwise clogging, some of the more narrow space between the crystal plates that make up the particle, thereby reducing the specific surface area. In addition, adsorption of the active agent adds the weight of the microparticle, substantially without affecting the diameter (size) of the microparticles. Since the specific surface area is inversely proportional to the mass of microparticles, there is a decrease in the specific surface area.

[0065]The selection and incorporation of active agents

[0066] While maintaining the described here microparticles required specific surface area less than about 67 m2/g, they can take other more the characteristics, favorable for delivery into the lungs and/or adsorption of the drug substance. In U.S. patent 6428771 “Method for Drug Delivery to the Pulmonary System”, included in the present description by reference, describes the delivery of DKP particles in the lungs. U.S. patent 6444226 “Purification and Stabilization of Peptide and Protein Pharmaceutical Agents, also included in the present description by reference, describe a favorable ways adsorption of drugs on the surface of the microparticles. The surface properties of the microparticles can be controlled to achieve the desired characteristics, as described in application for U.S. patent 11/532063 “Method of Drug Formulation based on Increasing the Affinity of Crystalline Microparticle Surfaces for Active Agents”, which is incorporated into this description by reference. In the application for U.S. patent 11/532065 “Method of Drug Formulation based on Increasing the Affinity of Active Agents for Crystalline Microparticle Surfaces for Active Agents”are also included in the present description by reference, describes a method of promoting adsorption of the active agent in the microparticles.

[0067] Described here microparticles can contain one or more active agents. The term “active agent”as used in this description is synonymous with the term “drug”refers to pharmaceutical agents, including low-molecular pharmaceutical means, biological agents and biologically active agents. The active agents may be naturally what about the origin, recombinant or synthetic origin, including proteins, polypeptides, peptides, nucleic acids, organic macromolecules, synthetic organic compounds, polysaccharides and other sugars, fatty acids and lipids, as well as antibodies and fragments thereof, including, without limitation, humanized or chimeric antibodies, F(ab), F(ab)2only single-chain antibody or fused with other polypeptides, or therapeutic or diagnostic monoclonal antibodies to cancer antigens. Active agents can include many kinds of biological activities and classes, such as vasoactive agents, neuroactive agents, hormones, anticoagulants, immunomodulating agents, cytotoxic agents, antibiotics, antiviral agents, antigens, infectious agents, inflammatory mediators, hormones and antigens on the cell surface. More specifically, the active agents may include, without limitation, cytokines, lipokine, enkephalins, alkynes, cyclosporine, anti-IL-8 antibodies, IL-8 antagonists, including ABX-IL-8; the prostaglandins, including PG-12, blockers LTB receptor, including LY29311, BML 284 and CP105696; triptan, such as sumatriptan and palmitoleate, insulin and its analogs, growth hormone and analogs, parathyroid hormone (PTH) and its analogues, parathyroid hormone-related peptide (PTHrP), ghrelin, obest the tin, enterostatin, factor, stimulating the formation of colonies of granulocytes (GM-CSF), Amylin, Amylin analogues, glucagon-like peptide-1 (GLP-1), clopidogrel, and PPACK (D-i.e. phenylalanyl-L-prolyl-L-arginine chloromethylketone), oxyntomodulin (OXM), peptide YY (3-36) (PYY), adiponectin, cholecystokinin (CCK), secretin, gastrin, glucagon, motilin, somatostatin, brain natriuretic peptide (BNP), trially natriuretic peptide (ANP), IGF-1, factor, stimulates growth hormone (GHRF), receptor antagonist predecessor beta-4 integrin (ITB4), nociceptin, nistatin, orphanin FQ2, calcitonin, CGRP, angiotensin, substance P, neurokinin A, pancreatic polypeptide, neuropeptide Y, Delta-sleep inducing peptide and vasoactive putting peptide. Microparticles can also be used to deliver other agents, such as contrast dyes such as Texas red.

[0068] the Content of drug substance delivered on the microparticles formed from fdcp with a specific surface area of less than about 67 m2/g is usually more than 0.01%. In one embodiment, the implementation of the content of drug substance delivered microparticles with the above-mentioned specific surface area may be in the range of from about 0.01% to about 20%, which is typical for peptides, such as insulin. For example,if the medicinal substance is insulin, declared microparticles typically include 3-4 Units/mg (approximately 10-15%) of insulin. In some embodiments, the implementation of the content of the medicinal substance in the particles may vary depending on the shape and size of the delivered drug.

[0069] When the condition described here microparticles required specific surface area, these particles can purchase other additional characteristics that are favorable for delivery into the lungs and/or adsorption of the drug substance. In U.S. patent 6428771 “Method for Drug Delivery to the Pulmonary System”, included in the present description by reference, describes the delivery of particles DCT in the lungs. In U.S. patent 6444226 “Purification and Stabilization of Peptide and Protein Pharmaceutical Agents, also included in the present description by reference, describes a favorable ways adsorption of drugs on the surface of the microparticles. Surface properties of the microparticles can be controlled to achieve the desired characteristics, as described in application for U.S. patent 11/532063 “Method of Drug Formulation based on Increasingg the Affinity of Crystalline Microparticles Surface for Active Agents”, which is incorporated into this description by reference. In the application for U.S. patent 11/532065 “Method of Drug Formulation based on Increasingg the Affinity of Active Agents for Crystalline Microparticles Surface for Active Agents ”, which is also included in the present description by reference, describes methods of stimulation adsorption Akti is different agents on microparticles.

EXAMPLES

[0070] the following examples are included to illustrate the embodiments disclosed microparticles. Specialists in the art should be obvious that disclosed in the examples below, the methods are described by the authors of the invention, methods are easily applicable for the practical implementation of the present disclosure, and thus are considered as the preferred methods for the practical implementation of the invention. However, from the point of view of the following disclosure, the experts in this field should understand that in particular disclosed embodiments, the implementation can be done numerous modifications, while providing the same or similar result.

EXAMPLE 1

[0071]I. The procedure of manufacturing

[0072]A. General procedures of manufacture to obtain microparticles fdkp/insulin

[0073] the Microparticles were obtained from fumarylacetoacetase (fdcp) and insulin. Fdkp was dissolved in water NH4OH, getting a solution. The feed stream of this solution was combined with the supplied stream of an aqueous solution of acetic acid (HOAc) in the mixer with large shear forces for the formation of a water suspension of microparticles.

[0074] the feed solution fdcp received, using about 2.5 wt.% the solution fdcp, NH4OH to concentrate the radio about 1.6 wt.% (from about 28 to about 30 wt.% NH 3and about 0.05 wt.% Polysorbate 80. The feed solution of acetic acid was obtained using about 10.5 wt.% glacial acetic acid and about 0.05 wt.% Polysorbate 80. Before using both the feed solution was filtered through a membrane with a pore size of about 0.2 μm.

[0075] figure 3 shows the block diagram of the process of obtaining the claimed microparticles fdcp containing insulin. In this embodiment, using a mixer with large shear effort, for example, Dual-Feed SONOLATOR™, or mixer disclosed in U.S. patent application 61/257311 (filed November 2, 2009, the disclosure of which is fully incorporated into this description by reference), an equal amount (by weight) of each feed solution was pumped through a Dual-Feed SONOLATOR™ hole size #5 (0,0011 square inch). The auxiliary pump was installed in such a way as to serve 50% of the equal flow rates for each feed stream, and the supply pressure was approximately 2000 psi. The receiving vessel contained DI water, the mass of which is equal to the mass of any of the submitted solutions (for example, through the SONOLATOR™ can be pumped 4 kg feed solution fdkp and 4 kg of feed solution of HOAc in the receiving vessel containing 4 kg of DI water).

[0076] the resulting suspension was concentrated and washed by filtration with tangential flow using 0,2 sup> 2PES (polyethersulfone) membrane. The first suspension was concentrated to about 4% solids, then spent diafiltration DI water, and finally concentrated to about 16% solids with a nominal characteristics. The actual percentage of solid particles of the suspension was washed defined “loss at drying”. For measuring the percentage of solid particles in suspension, you can use alternative methods, such as disclosed in application for U.S. patent 61/332292, filed may 7, 2010, “Determining Percent Solids in Suspension Using Raman Spectroscopy”, included in the present description by reference.

[0077] the Original solutions of insulin were prepared so that they contained about 10 wt.% insulin (in finished form) in a solvent containing about 2 wt.% HOAc in DI water, and sterilized by filtration. Based on the content of solid particles in suspension, the appropriate number of initial solution was added to the stirred suspension. Then the initial value of pH of about 3.6, the resulting suspension microparticle/insulin brought up to a pH value equal to about 4.5, using ammonia solution.

[0078] the Suspension containing microparticles fdcp containing insulin, endured in cryogenerator/tabletiruemuju machine, such as disclosed in application for U.S. patent 61/257385, filed November 2, 2009, the disclosure of which is fully included in the present is ASEE description in the form of links, and grained immediate freezing in liquid nitrogen. Ice pellets liofilizirovanny getting dry powder.

[0079]B. Production the procedure for obtaining microparticles fdkp/insulin used in studies with values of 5% and 10%

[0080] In studies with values of 5% and 10% studied the effect of feed concentration on specific surface area and the aerodynamic characteristics of the powder. In studies with values of 5% was performed experiments to determine the effect of three factors, i.e. the concentration fdcp, ammonia and acetic acid, which was studied using a 3×3 factorial experiment in which high and low levels of 5% from the reference conditions. In studies with values of 10% concentration fdcp, ammonia and acetic acid were also studied using a 3x3 factorial experiment, however, the high and low levels was 10% from the reference conditions.

Table 3
Evaluate the conditions for the formation of microparticles
levelFDKP (wt.% in the feed solution)A concentrated solution (wt.% in the feed solution)Acetic acid (SPLA) (wt.% in the feed solution)
+10%2,751,7611,55
+5%2,631,6811,03
Control2,501,6010,50
-5%2,381,529,98
-10%2,25the 1.449,45
Note: All submitted solutions contained approximately 0.05 wt.% Polysorbate 80 and maintained at a temperature of about 16°C, unless otherwise specified

[0081]C. Finite dimensions

[0082] Respirable fraction (RF/serving) no powders, which is a measure of aerodynamic characteristics and particle size distribution of the microparticles was determined by testing using a cascade impactor Andersen. To obtain a value for RF/serving cartridges filled bulk powder and blew through the MEDTONE inhaler® at a rate of approximately 30 l/min Powder collected in each stage of the inhaler, weighed, and the total amount is collected in powder normalized relative to the total quantity filled in the cartridge. Therefore, RF/serving is a powder collected at these stages of the impactor, and is respirable fraction divided by the amount of powder loaded in the cartridge.

[0083] Specific surface area (SSA) of the microparticles was determined by nitrogen adsorption and registered in terms of surface area by BET (Brunauer-Emmett-teller (Brunauer-Emmett-Teller)), using the analyzer, specific surface area (analyzer, surface area and porosity MICROMERITICS® TriStar 3000). The specific surface area depends on the crystal size and density (ρ) of the matrix particles and inversely proportional to the characteristic dimension, L, of FDKP crystals:

SSA=ydelbnandIplaboutyanddbpaboutinepxnaboutwith atandmandwith awith aand~L2ρL3~L-1

[0084]II.The impact of feed on specific surface area

[0085] the Specific surface area was measured by the all powders, from studies with values of 5% and 10%. Specific surface area predicted using linear regression equations (see figure 3). The standard deviation of the predictions were ±2 m2/g for studies with values of 5% and ±5.6 m2/g for studies with values of 10%. These results are consistent with theoretical expectations: higher concentrations fdcp, higher concentrations of HOAc or lower ammonia concentrations increased specific surface area were obtained smaller crystals), contributing to the formation of the nucleus crystals.

[0086]III. The influence of temperature

[0087] the Effect of temperature on the properties of the particles studied in a series of studies in which characteristics of the supplied solution, except for temperature, exhibited in accordance with the conditions in the control. The temperature of the solution was in the range from 4 to 32°C. was Defined as the specific surface area of powders of microparticles, and RF/serving powders obtained microparticles.

[0088] the relationship between RF/serving, specific surface area and temperature is shown in Figure 5 (RF/serving was determined with insulin-containing microparticles; specific surface area, given in the chart represents a specific surface area defined for particles on the adsorption of insulin). Parameter RF/serving powder of microparticles was maximum at temperatures close to about 18°C-19°C (Fig. 5A). The curve depicted by the dashed lines, represents the one-sided lower 95% confidence interval of the prediction (i.e. values above the curve are expected with 95% probability). Temperature in the range from about 12°to about 26°C provides RF/serving >40% with a 95% level of confidence. On the graph of dependence of the parameter RF/serving from the specific surface area net (without active ingredient powder of microparticles (Pigv) obtained curve similar to the curve for temperature. However, the order of the points back. (For example, sample “And” now appears on the right end of the axis, while the sample “B” is to the left). Microparticles with a specific surface area 26-67 m2/g provide RF/serving >40% with a 95% level of confidence. Given the relationship between temperature and specific surface area (Figs), for the formation of particles was determined a little bit more narrow, but internally consistent temperature range from about 13°to about 23°C.

[0089]IV. The effect of specific surface area on RF/portion

[0090] There is a tendency to shift towards smaller values of the parameter RF/serving when the values of the specific surface area above about 5 m 2/g (Figa). The upper limit equal to about 62 m2/g, can be used while still retaining the 95% confidence limit under appropriate parameter values RF/serving (i.e. >40%; Figv).

[0091] 7 shows that with the increase of specific surface area in the upper limit of the extension of the distribution parameter RF/serving, and there is a higher probability of discrepancy criterion RF/serving >40%. On Figa shown that suspension of microparticles with high specific surface area, for example, about 67 m2/g tend to increase viscosity on the order according to measurements carried out by using a Brookfield viscometer (Brookfield Engineering Laboratories, Inc., Middleboro, Massachusetts) compared to a suspension of microparticles with a lower specific surface area, for example, about <14 m2/, Figv shown that the suspension viscosity is inversely proportional to RF/serving.

[0092]V. Specific surface area and adsorption of insulin

[0093] Studied the relationship between specific surface area and adsorption of insulin.

[0094] a Suspension of microparticles was obtained in the manner described above for parties in studies with values of 5% and 10% and were loaded with insulin at about 11.4 percent. In addition, he also studied microparticles formed with a control filed concentrations, but temperature is dependent on the feed solution in the range from about 4°C to about 32°C. Titrated suspension had a pH value, rising from about 3.6 to about 4.5, using the serial add single drops of 14 wt.% of ammonia. Samples titrated suspension and sediment were evaluated in relation to the concentration of insulin. All suspensions (titrated and polirovannyj) liofilizirovanny to obtain dry powders. The powders were tested on specific surface area, using a MICROMERITICS® TriStar 3000.

[0095] When a low specific surface area, there is a linear relationship between the number of unbound insulin and specific surface area (Fig.9). Adsorption of at least 95% of insulin occurs when the specific surface area greater than about 35 m2/, the Degree of adsorption of insulin continues to increase with increasing specific surface area up to about 40 m2/year Above this specific surface area of the microparticles was adsorbing almost all of the insulin.

[0096] the Results of these studies determine favorable lower and upper limits of the specific surface area of particles in the range from about 35 m2/g to about 62 m2/, Providing microparticles, in which more than 80%, or more than 90%, or more than 95% of the particles have a specific surface area in this range, provides microparticles with favorable pairs the meters RF/serving and adsorption characteristics of medicinal substance in a 95% confidence limit.

EXAMPLE 2

[0097]The analysis of the geometric size of the particles blown out of the dosage form with the characteristics of the volumetric average geometric diameter (VMGD)

[0098] the Use of diffraction using laser scattering for dosage forms in the form of dry powders emitted from an inhaler for dry powders, is a common method used to characterize the level of destruction of agglomerates, resulting in a powder. The method applies to the measurement of the geometric size and not aerodynamic size, which is typical for the industry standard method of collision. Usually the geometric size of the emitted powder includes volumetric distribution characterized by an average particle size, VMGD. It is important that the geometrical size of emitted particles vary with a higher resolution compared to the aerodynamic sizes provided by means of a collision. Preferred are the smaller size, which leads to a higher probability of delivery of a single particle in the lung Airways. Thus, differences in the destruction of agglomerates in the inhaler and the ultimate effectiveness can be easier identified through diffraction. In these experiments inhalers tested using diffraction is the use of laser scattering at pressures similar to the real power of the breath of the patient, to determine the effectiveness of inhalation systems for the destruction of agglomerates of powdered dosage forms. In particular, the dosage form consisted of cohesive powders diketopiperazine loaded with the active ingredient insulin without it. These powdered dosage form had a specific surface area, the relationship isomers and indexes Carr. Table 4 shows the VMGD and efficiency of the container, already devastated during testing. Powders FDKP have index Carr, equal to about 50, and TI powder has an index of Carr, equal to about 40.

86,1
The system of the inhalerPowder% t TRANSSSAthe pressure drop (kPa)The size of the sample% CEVMGD (microns)
DPI2FDKP565541592,56,800
MEDTONE®FDKP56 55430to 89.521,200
DPI2FDKP+ act. agent564543098,04,020
DPI2FDKP+ act. agent564542097,03,700
DPI2FDKP+ act. agent564542098,43,935
DPI2FDKP+ act. agent5645420of 97.84,400
MEDTONE®FDKP+ act. agent56454109,280
MEDTONE®FDKP+ act. agent564541092,310,676
DPI2FDKP+ act. agent56452792,94,364
DPI2FDKP+ act. agent56452795,14,680
DPI2FDKP+ act. agent56454797,03,973
DPI2FDKP+ act. agent56454795,54,250
DPI2FDKP+ act. agent565641099,66,254
DPI2FDKP+ act. agent561441085,54,037
MEDTONE®FDKP+ act. agent565642089,712,045
MEDTONE®FDKP+ act. agent5614420of 37.910,776
DPI2FDKP+ act. agent5450410to 97.14,417
DPI2FDKP+ act. agent 544441096,04,189
DPI2FDKP+ act. agent563541092,03,235
DPI2FDKP+ act. agent503441093,25,611
DPI2FDKP+ act. agent663341079,04,678
DPI2FDKP+ act. agent454241093,25,610
DPI2FDKP+ act. agent5694 1078,95,860

[0099] the Data in table 4 show a higher degree of destruction of agglomerates of powder inhalers, identified as DPI2, compared with the MEDTONE inhaler®. Dosage forms diketopiperazine with surface area ranging from 14-56 m2/g demonstrated the effectiveness of desolation, greater than 85%, and VMGD less than 7 microns. Similarly, the dosage form having a ratio of TRANS-isomers in the range from 45-66%demonstrated superior efficacy compared with the unit-sample. However, it is worth noting that even if more efficient nebulizer at <15 m2/g has decreased emptying of the cartridge pointing to drop (decrease) in aerodynamic characteristics, since the content of the TRANS-isomer deviates from the desired range, unveiled here. Finally, it was shown that the system efficiency nebulizer drug forms, characterized by the index of Carr is 40-50, were also better in comparison with the device model. In all cases these values VMGD were below 7 microns.

[00100] Unless otherwise indicated, all numerical values expressing the number of components, properties such as molecular weight, reaction conditions, etc. used is in the description and the claims, it should be understood as characterized in all cases with the use of the term “about”. Therefore, unless otherwise specified, the numeric parameters specified in the description and the attached claims are approximate values that may vary depending on the desired properties that you want to get in the present invention. At least, not as attempts to limit application of the doctrine of equivalents in respect of the scope of the claims, each numerical parameter should be considered at least with regard to the number of significant digits and by applying ordinary rounding method. Notwithstanding that the numerical ranges and parameters that determine the scope of the invention, are approximate values, numeric values shown in the specific examples are listed as accurately as possible. However, any numeric value in a natural way contains certain errors resulting standard deviations inherent to their corresponding measurements during testing.

[00101] the terms specified in the grammatical forms of the singular used in the context of describing the invention (especially in the context of the following claims)should be considered as encompassing both the singular and plural is the divine number, if not specified, or it is clearly contrary to the context. Specifying ranges of values herein should be considered as a compact way of specifying each individual value is inside the specified range. Unless otherwise noted, each individual value is included in the description as if it would be listed separately. All methods described here can be performed in any suitable order unless otherwise stated or if it is not in obvious contradiction with the context. Use any of the examples or language implying an enumeration of examples (e.g., “such as”), is intended merely to better illuminate the invention and is not intended to limit the scope of the claimed invention. No wording used in the description should not be construed as indicating any undeclared element, essential for the practical implementation of the invention.

[00102] the term “or” in the claims is used to mean “and/or”unless expressly applies only to alternatives, or alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and “and/or”.

[00103] the Grouping of the alternative elements or options Khujand is the implementation of the disclosed here, the invention should not be construed as limitations. Each element of the group can be referred to and stated separately or in any combination with other group members or other elements listed in this document. It is assumed that one or more elements of the group can be included or removed from the group for reasons of convenience and/or patentability. In the exercise of any such inclusion or removal it is assumed that the description contains a group in a modified form, thus revealing all of the Markush group used in the attached claims.

[00104] In the present document describes the preferred embodiments of the present invention, including the best mode for carrying out the invention known to the inventors. Changes such preferred embodiments will be obvious to a person skilled in the art after reading the description above. The inventors assume that the experts in this field would be an appropriate way to use these changes, and the inventors suggest that the invention may be practiced otherwise than specifically described herein. Therefore, the present invention includes all modifications and equivalents of the subject matter disclosed in the accompanying claims, in part defined with testwuide legislation. In addition, any combination of the above-described elements in all possible variations covered by the invention, unless indicated otherwise or otherwise explicitly not inconsistent with the context.

[00105] the Disclosed specific embodiments of may be further limited to the use in the claims the expression “comprising” to “consisting essentially of”. If used in the claims, either in original form or in a revised form, the transition term “consisting of” excludes any element, stage or component that is not defined in the claims. The transition term “consisting essentially of” limits the amount of the claims specified materials or steps and those that are not materially affect the basic and the new feature(s). Embodiments of the invention described thus in the claims, explicitly described and confirmed in the present description.

[00106] in Addition, in the description were contained numerous references to patents and printed publications. Each of the above links and publications included in the present description separately in its entirety by reference.

[00107] in Addition, it should be borne in mind that embodiments of the disclosed here of the invention are illustrative the principles of the present invention. Other possible modifications are also within the scope of the invention. Thus, as an example and not of limitation, alternative configurations of the present invention can also be used in accordance with the above description. Thus, the present invention is not limited to exactly how it is shown and described.

1. Microparticles fumarylacetoacetase (FDK) with a specific surface area of between 15 m2/g and 67 m2/g and a diameter of between 0.5 μm and 10 μm, where the microparticles are suitable for delivery into the lungs.

2. Microparticles fumarylacetoacetase according to claim 1, in which the specified specific surface area is in the range from 40 m2/g to 67 m2/year

3. Microparticles fumarylacetoacetase according to claim 1, where the said microparticles contain a medicinal substance or active agent.

4. Microparticles fumarylacetoacetase according to claim 3, in which the specified specific surface area is less than 62 m2/year

5. Microparticles fumarylacetoacetase according to claim 4, in which the specified medicinal substance or active agent is a peptide or a protein.

6. Microparticles fumarylacetoacetase according to claim 5, in which a given peptide is an endocrine hormone.

7. Microparticles fumarylacetoacetase according to claim 6, in which said end is krinō hormone is an insulin parathyroid hormone, calcitonin, glucagon, glucagon-like peptide-1, oxyntomodulin, analog or active fragment specified endocrine hormone.

8. Dry powder containing microparticles fumarylacetoacetase according to claim 7, where the dry powder suitable for delivery into the lungs.

9. The method of forming microparticles fumarylacetoacetase with a specific surface area ranging from 35 m2/g to 67 m2/g and a diameter of between 0.5 μm and 10 μm, with a 95% confidence limit, containing:
a) dissolving fumarylacetoacetase supplied in an aqueous solution of ammonia;
b) adding an acidic solution to water supplied to the ammonia solution to obtain a mixture;
c) selection of the operating conditions for the target of obtaining particles with a specific surface area equal to 52 m2/g, where the selection of operating conditions includes the provision of specified feed solution at a temperature between 12°C and 26°C; and
d) collecting the precipitate after several rinses with deionized water, where the sediment contains microparticles fdcp with a specific surface area ranging from 35 m2/g to 67 m2/year

10. The method according to claim 9, further comprising providing a feed solution at a temperature from 14°C to 18°C.

11. The method of forming microparticles fumarylacetoacetase with the specific surface area is in the range from 35 m 2/g to 67 m2/g and a diameter of between 0.5 μm and 10 μm, within a 95% confidence interval containing the supply equal to the mass of 10.5 wt.% solution of acetic acid and 2.5 wt.% solution fumarylacetoacetase at a temperature from 14°C to 18°C in a mixer with a large shear forces.

12. The method according to claim 11, further containing increasing the pH of the reaction mixture containing a suspension of microparticles fumarylacetoacetase to pH 4.5 with aqueous ammonia.

13. The method according to item 12, in which the increase includes an increase in the concentration of ammonia in the slurry to obtain a pH of 4.5.

14. The method of delivery of the active agent to the needy in this patient, introducing a dry powder containing microparticles according to claim 5, through inhalation of the specified dry powder specified patient.

15. The method according to 14, in which the active agent is an endocrine hormone selected from the group consisting of insulin, parathyroid hormone, calcitonin, glucagon, glucagon-like peptide-1, oxyntomodulin, analog or active fragment specified endocrine hormone.

16. The method according to 14, in which the patient is diagnosed with diabetes.

17. Inhalation system containing an inhaler for inhaling powder and dry powder containing microparticles according to claim 5.

18. Microparticles fumarylacetoacetase is on according to claim 1, where these particles have a specific surface area of more than 35 m2/,



 

Same patents:

FIELD: medicine.

SUBSTANCE: invention refers to a pharmaceutical tablet for oral administration containing ulipristal acetate 3-18 wt %; a diluent 60 - 95 wt % specified in lactose monohydrate, microcrystalline cellulose, cellulose, mannitol and combinations thereof; a binding agent 0 - 10 wt % specified in hydroxypropyl methyl cellulose, povidone and combinations thereof; sodium croscarmellose 1 - 10 wt % and magnesium stearate 0.5 - 4 wt %.The invention also refers to a method for preparing the above tablet which involves mixing the ingredients and forming the tablet by wet granulation or direct compression.

EFFECT: invention provides the new formulation of the tablet with improved disintegration.

13 cl, 2 dwg, 5 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: microparticle contains an agglomerate of particles containing a hydrophilic active substance, wherein the particle contains an amphiphilic polymer composed of a hydrophobic segment of polyhydroxy acid and a hydrophilic segment of polysaccharide or polyethylene glycol, and a hydrophilic active substance. What is also disclosed is a method of producing the agglomerated microparticles, which involves (a) a stage of preparing a reverse phase emulsion, (b) a stage of preparing a solid residue containing the hydrophilic active substance, and (c) a stage of introducing the solid residue into a liquid phase containing a surface modifier.

EFFECT: agglomerated microparticles provide the effective encapsulation of the hydrophilic active substance and the release of the hydrophilic active substance at an appropriate speed.

14 cl, 22 dwg, 4 tbl, 31 ex

FIELD: biotechnologies.

SUBSTANCE: medicinal agent for inhibition of MASP-2-dependent complement is an agent containing an antibody or its fragment, bound with a full-size polypeptide MASP-2, but not bound with a MASP-2 N-terminal fragment containing CUBI-EGF-CUBII domains and not bound with a MASP-2 C-terminal fragment, containing of CCPII-SP domains.

EFFECT: invention makes it possible to selectively inhibit MASP-2-dependent activation of complement, at the same time leaving Clq-dependent classic path of complement activation as functionally unaffected.

9 cl, 39 dwg, 7 tbl, 31 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to combinations of peptides in each case with the same sequence length (SEQL) which can be prepared in a stable reproducible quality and quantity of a mixture (A) containing a number of x amino acid with protected acid groups or a number of z peptides with the acid groups protected by the protective groups and the activated amino groups, with the amino acids in the mixture (A) found in a specific molar ratio, and a mixture (B), containing a number of y amino acids with the amino groups protected by the protective groups, with a molar ratio of the amino acids of the mixture (B) being the same as the molar ratio of the amino acids of the mixture (A), and the number x=y, and x is a figure from 11 to 18.

EFFECT: new combinations of the peptides are presented.

13 cl, 2 dwg, 1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely gynaecology, and may be used for treating chronic inflammatory genital diseases in females. That is ensured by the use of Promed balm which is introduced into vagina once a day, as well as taken orally 3 times a day. Promed balm may be introduced into vagina taking into account biological rhythms from 19 to 21 o'clock, and taking into account biological rhythms 9 to 11 o'clock, from 13 to 15 o'clock and from 19 to 21 o'clock. The method provides the improved clinical effectiveness ensured by providing the local and systemic anti-inflammatory effect due to the delayed growth of pathogens and toxin purification of the female body as a result of a diuretic and choleretic effect, immunomodulatory action, as well as due to activation of biological centres and their rhythm functioning, and regulation of metabolism and genital glands. In addition, it has a regenerating effect on skin and mucous membranes and recovers the nervous system.

EFFECT: achieved diet fortification and prevented recurrence of the disease.

3 cl, 2 ex

FIELD: medicine.

SUBSTANCE: claimed invention relates to medicine, namely to therapy and can be used for treatment of patient with thermoregulation disorder, in particular suffering from high temperature attacks and hot flushes, night sweats and their combinations, as well as conditions, selected from female and male hormonal changes, connected with menopause, hormonal changes, caused by chemical way, disease states, causing hormonal irregularities and any combinations of said conditions. For this purpose paroxetine dosed in terms of paroxetine component, 7.5 mg/day is introduced to said patient.

EFFECT: method ensures efficient treatment of such conditions due to optimal dose.

9 cl, 2 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine and pharmacology. A method of treating of at least one vascular disease in a patient involving a stage of introduction into the patient suffering at least one vascular disease or manifesting its biomarkers of a therapeutically effective amount of a central dopamine agonist with said central dopamine agonist is effective for treating said at least one vascular disease in said patient; wherein said dopamine agonist is introduced so that the peak plasma concentration of the dopamine agonist is reached between 04:00 and 12:00 o'clock, while blood bioavailability of said dopamine agonist is reduced within approximately 50% of the peak plasma concentration approximately 2 to 6 hours after termination of a day peak or the steady-state plasma concentration of the dopamine agonist. According to one version of implementation, the central dopamine agonist represents bromocriptine optionally combined with a pharmaceutically acceptable carrier.

EFFECT: invention provides higher clinical effectiveness.

9 cl, 10 ex, 12 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine and represents a method of treating the patients with metabolic syndrome involving patient's staying in the low atmospheric pressure environment at heights of 1000, 1500 m above sea level with underlying basic therapy combined with the oral administration of a therapeutic beverage, differing by the fact that a hypoxia adaptation course is two-staged; the first stage involves staged climbing at height of 1000, 1500, 2000 and 2500 m above sea level; at the second stage, from the fifth session, a "working height" is 2500 metres with climbing up and down at speed 4-5 m/s at partial oxygen pressure 20-35 mm Hg, chamber pressure 75.5 kPa for 15-20 minutes within the therapeutic course of 12-14 daily procedures; the therapeutic beverage is mare's milk of weak or medium strength of permanent Turner acidity 71-100° in dose of 200-250 ml three times a day before meals of the length of 24 days.

EFFECT: invention provides improved clinical values, haemodynamics, carbohydrate and lipid metabolism, higher tolerance to physical activity.

2 cl, 2 ex, 5 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: stable fat emulsion contains prostaglandin as an active ingredient and phospholipids containing phosphatidylcholine and phosphatidyl glycerol in mass ratio 85:15 to 99.7:0.3. The fat emulsion under the invention and its active ingredient (prostaglandin) possess physical and chemical stability thereby increasing shelf life to approximately two years, and/or extended range of storage temperature to 10°C as compared with a commercially available fat prostaglandin emulsion.

EFFECT: fat emulsion under the invention enables satisfactory effectiveness even in the introduction of a low amount.

25 cl, 10 tbl, 12 ex

FIELD: medicine.

SUBSTANCE: to reduce tachycardia in such patients used is ivabradin (coraxan) in dose 5-7.5 mg for 7-14 days with further supporting course in dose 5 mg to the moment of when preoperative reparation is finished.

EFFECT: application of ivabradin in preoperative period in case of manifest thyrotoxicosis instead of traditional beta-adrenoblockers makes it possible to weaken sympathetic impact on sinus node and increase chronotropic myocardium reserve, avoiding at the same time undesirable cardioplegic effects, characteristic of beta-adrenoblockers.

2 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to medicine and pharmaceutical industry and describes an inhalation formulation in the form of aerosol for treating bronchial asthma and chronic obstructive pulmonary disease, containing beclomethasone dipropionate, a solvent an adjuvant and a propellant; the solvent is presented by absolute ethyl alcohol, while the adjuvant is an aerosol particle size control consisting of triethyl citrate and perfluorodecaline; the propellant is 1,1,1,4 tetrafluoroethane (HFA-134a) and/or 1,1,1,2,3,3,3-heptafluoropropane (HFA-227ea). The formulation has a higher efficacy.

EFFECT: developing the inhalation formulation in the form of aerosol for treating bronchial asthma and chronic obstructive pulmonary disease.

9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to medicine and pharmaceutical industry and describes an inhalation preparation for treating bronchial asthma and chronic obstructive pulmonary disease, containing micronized budesonide and micronised formoterol fumarate dehydrate as active ingredients, wherein the preparation contains a carrier presented by lactose of average particle diameter 1 to 10 mcm and sodium benzoate of bulk density 0.30-0.50 g/cm3, in the following proportions of the ingredients per a dose of the preparation: budesonide 50 mcg - 800 mcg, formoterol fumarate dehydrate 4.5 mcg - 18 mcg, lactose 5 mg - 50 mg, sodium benzoate 0.01 mg - 5 mg. What is also described is a method for producing the given preparation.

EFFECT: invention provides a higher percentage of a fraction of the active substances and respectively higher effectiveness.

4 cl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: powder composition for intrapulmonary administration contains particles of ciprofloxacin betaine 3,5-hydrate and an excipient. The particles have a mass median aerodynamic diameter making from approximately 1 to approximately 5 mcm; a pulmonary half-life of betaine 3,5-hydrate makes min. 1.5 h; while a roughness of the composition falls within the range of 3 to 10.

EFFECT: composition may be used to treat an endobronchial infection, such as an infection caused by Pseudomonas aeruginosa, and it is most applicable for treating mucoviscidosis.

6 cl, 8 dwg, 16 tbl, 12 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine, and concerns an inhalation pharmaceutical composition containing a therapeutic agent, a soluble excipient, a surfactant, and a hydrophobic substance for reducing moisture sensitivity, and representing leucine; a method for preparing the above composition; a kit for administering the therapeutic agent in the form of a water dispersion containing the premeasured amount of the above composition.

EFFECT: group of inventions provides a sudden increase of both of the active fraction and fine fraction.

39 cl, 1 ex, 10 dwg, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to medicine and pharmaceutical industry and concerns a solution of a high-efficacy pharmaceutical substance and excipients allowing to form a fine particle aerosol to penetrate into the bronchi and pulmonary alveoli. As an active ingredient, the solution for producing the preparation for inhalation contains ipratropium bromide monohydrate; and as excipients - sodium benzoate, edible organic acid, purified water in the following proportions provided pH is 3.2-3.5.

EFFECT: solution has high respirabile fractions.

5 cl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and pharmaceutical industry and concerns a dry powder preparation containing micronised: salmeterol xinafoate and fluticasone propionate. The preparation contains a carrier consisting of lactose of average particle size 100-120 mcm and sodium benzoate. What is also described is a method for producing the preparation.

EFFECT: formulation possesses higher percentage of a respirable fraction of the active substances.

4 cl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to dry powder-like pharmaceutical composition for inhalation and to method of its obtaining. Into composition of pharmaceutical composition included are two active ingredients, which represent salmeterol and fluticasone or their pharmaceutically acceptable salts, solvates or esters, two pharmaceutically acceptable excipients, which have value d50 respectively approximately 125-145 mcm and approximately 50-100 mcm and which represent mono- or disaccharides. Method of composition obtaining consists in formation of preliminary mixtures of each of active ingredients and each of pharmaceutically acceptable excipients and mixing two preliminary mixtures with obtaining with fraction of medication, with weight ratio of exipients in said two preliminary mixtures constituting from 1 to 5.

EFFECT: pharmaceutical composition is applied for treating asthma, COLD (chronic obstructive lung disease), allergies and infectious diseases.

6 cl, 7 dwg, 3 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: dry powder composition for pulmonary inhalation Parkinson's disease contains apomorphine and magnesium stearate with a nominal dose of apomorphine being 3 to 10 mg and providing a dose of fine particle fraction (FPF) making 2 to 6 mg when administered. A method for preparing the composition involves the stages of combining the apomorphine particles with the magnesium stearate particles by mixing and milling, milling including compression.

EFFECT: composition under the invention contains apomorphine in a stable dry powder form suitable for the direct administration of low doses of the drug with minimal adverse side effects.

15 cl, 12 dwg, 13 tbl, 12 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to medicine and describes a solution for producing an inhalation preparation containing fenoterol hydrobromide as an active agent, purified water and excipients with the excipients presented by sodium benzoate, an acidity regulator representing an organic acid in the following proportions, mg/ml: fenoterol hydrobromide 1.0-1.1; sodium benzoate 0.2-2.0; organic acid 1.4-1.7; purified water the rest provided pH makes 3.2-3.5.

EFFECT: solution has the high value of respirable fractions and high stability.

6 cl, 3 ex

FIELD: tobacco industry.

SUBSTANCE: imitative smoking device (1,51) contains an imitative cigarette having an essentially cylindrical cigarette-like shape and a charging unit (2, 50) having an essentially rectangular body shaped like a cigarette packet. The filling device (2, 50) contains charging gas (32, 59) for the imitative cigarette and a means for elective retention of the imitative cigarette. The imitative cigarette may be completely retained inside the body (3, 52). The cigarette may be retained at a place other than the charging place. A dose counter may be envisaged to give visual indication of doses in the charging device.

EFFECT: technical result achieved using the imitative cigarette device and the charging device for the imitative device according to the invention consists in smoking skill imitation, the imitative cigarette charging and its usage simplification.

7 cl, 15 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry, particularly to a method for preparing a powder. The method involves the stages of providing at least one first ingredient that has a consistence of viscous fluid and that has an initial melting point within the temperature range of 15°C to 40°C, providing at least one second ingredient that has a melting point, particularly within the range above an ambient temperature up to 120°C, preparing a homogenous liquid mixture containing one first ingredient and one second ingredient by mixing and heating the mixture to a temperature or maintaining a temperature of the mixture within the range above the melting point. Supplying the liquid mixture to an irrigation hardening unit and extracting the powder prepared by irrigation hardening. In addition, the present invention refers to the method for preparing the solid dosage form containing the powder prepared by the method described above.

EFFECT: improvement of the method.

17 cl, 6 ex, 2 tbl

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