Microparticles and method of production thereof

 

(57) Abstract:

The invention is used in medicine. Microparticles include biodegrading, biocompatible polymer matrix with encapsulated active substance and the residual organic solvent. The active substance has limited solubility in water. The organic solvent is free from halogenated hydrocarbons and selected from alcohol, linear or cyclic simple ester, ketone and ether complex. Microparticles in contact with the water system, through which the contents of the specified organic solvent in the microparticles is reduced to 2% or less by weight of the microparticles. The water system contains water and in contact with the microparticles is increased the temperature from 25 to 40oC. Water system may contain water and miscible with water, the solvent is an aliphatic alcohol WITH1-C4. Reducing the level of residual organic solvent reduces the decomposition rate is encapsulated in microparticles of biologically active substances and increase product stability during storage, as well as reducing the overall toxicity of the product and possible carcinogenic activity. 5 C. and 14 C.p. f-crystals, and and to a method for producing such particles. More specifically, the present invention relates to pharmaceutical compositions comprising the controlled release microparticles having improved stability during storage, and these microparticles include active substances encapsulated within the polymer matrix, and to a method for producing such particles.

The compounds may be encapsulated in the form of microparticles (e.g., particles having average size in the range from the nanometer to the millimeter, in particular in the range from 1 to 500 μm, especially from 25 to 180 μm) using various known methods. Especially advantageous to encapsulate biologically active or pharmaceutically active substance inside biocompatible, biodegradable, constituting the wall material (e.g. polymer) to provide prolonged or delayed release of drugs or other active agents. At these ways to be encapsulating material (drug or other active substance) as a whole is dissolved, dispersed or emulsified using well-known methods of mixing in a solvent containing forming stink the P CLASS="ptx2">

Very often, the solvents used in the known methods of microencapsulation, are halogenated hydrocarbons, in particular chloroform or methylene chloride, which act as solvents for the active substance and the encapsulated polymer. However, the presence of a small, but detectable residues of halogenated hydrocarbons in the final product is undesirable because of their General toxicity and possible carcinogenic activity.

In patent WO-95/13799 was disclosed a method of obtaining a biodegradable, biocompatible microparticles comprising a biodegradable, biocompatible linking the polymer and the biologically active substance, in which the dissolving and substance, and a polymer, a mixture of at least two essentially non-toxic solvents, free of halogenated hydrocarbons. This solvent mixture is dispersed in an aqueous solution for the formation of the emulsion, which is then added to the aqueous extraction medium, which preferably contains at least one of the solvent mixture, which is controlled by the rate of extraction of each solvent, and then formed biodegradable, bioso the risperidone, encapsulated in microparticles, obtained using a solvent system containing benzyl alcohol and ethyl acetate.

However, it was found that during storage of these products in the form of microparticles disintegrate. There is therefore a need in the substances with which it may be reduced decay rate, thus increasing the stability of the product during storage and increasing the possibility of its industrial production.

Suddenly, at the moment it was found that the decay rate of the product can be reduced by reducing the level of residual processing solvent. It is believed that one of the processes of disintegration occurred, at least partially, as a result of hydrolysis of the polymer matrix, and that the rate of hydrolysis is directly affected by the level of residual processing solvent (e.g., benzyl alcohol) in the product. By reducing the level of residual solvent in the microparticles decreases the decay rate, thus increasing the stability during storage.

Thus, in accordance with one aspect, the invention provides a method of obtaining a biodegradable, biocompatible the biocompatible polymeric matrix, containing the active (e.g., pharmaceutical or diagnostic) tool, and an organic solvent with an aqueous solvent system, whereby the contents of the specified organic solvent in said microparticles reduced to 2% or less of the mass of these particles, and the indicated solvent system such as to satisfy at least one of the following conditions: (a) that it is at least part of the time during which it is in contact with these particles, has a high temperature (for example, from 25 to 40o(C) and (b) that it contains water and miscible with water, the solvent for the specified organic solvent; and removing these particles from the specified water system solvent.

In the method of the invention, the initial content of organic solvent in the particles is usually over 3.5%, usually above 4.0%, by weight of the total particles. The advantage that the method reduced this content to less than 2%, preferably to less than 1.5% and most preferably to less than 1%. Consider organic solvent preferably contains a hydrophobic group containing at least 5 carbon, for example aryl group, concealed, is in the process of formation of particles, in which particles were obtained from the solution, forming a matrix of polymer material in an organic solvent or in the composition or mixture of solvents containing organic solvent. The organic solvent preferably is dehalogenation solvent and, particularly preferably, at least partially, is a mix with the water solvent, such as alcohol (e.g. benzyl alcohol), linear or cyclic simple ether, ketone or ester (e.g. ethyl acetate). When the organic solvent is a single solvent in such a combination composition or mixture of solvents, or any other solvent in the composition or mixture is preferably dehalogenation solvent and, particularly preferably, is at least partially represent mixed with water, the solvent, such as alcohol (for example, C1-C4alkanol, such as ethanol), linear or cyclic ester, ketone or ether.

If you use mixed with water, the solvent in the aqueous solvent system (i.e., the washing liquid is particularly preferably will at least partially be a mix with the water solvent, such as alcohol (for example, C1-C4alkanol, such as ethanol), linear or cyclic ester, ketone or ether.

The contacting with the aqueous solvent system may be implemented in one or more stages, for example a single contact or a series of washes, optional with different crafted systems solvent. Preferably the total contact time is the period from ten minutes to several hours, for example from 1 to 48 hours

Of course, the polymeric material forming the matrix must have a rather limited solubility in water system solvent, so that the particles are not completely dissolve in the solvent system during the period of contact.

Particularly preferably, the particles used in the method of the invention is prepared by obtaining a two-phase liquid system in which the first disperse liquid phase is present in the second continuous liquid phase. The first liquid phase comprises forming a matrix polymer dissolved in a first solvent system, in which are dissolved or dispersed active exemestane with one or more joint solvents, moreover, various solvents preferred are alcohols, ethers, esters or ketones and preferably do not include any halogenated solvents. Preferably one of the solvent in the first solvent system has a hydrophilic group such as aryl group such as phenyl group, particularly preferably it represents a benzyl alcohol. Preferably the second solvent having a higher solubility in water, such as ethyl acetate, is present in the first solvent system. The second liquid phase preferably includes one or more solvents such as water, and preferably is such that the polymer less soluble in it than in the first solvent system, but such that the solvent of the first solvent system is at least partially soluble, thus allowing the particles to be formed by diffusion of the solvent from the first liquid phase into a second liquid phase. The second liquid phase may predominantly contain hydrocolloid or surfactant.

The method of the present invention can be carried out using pre-formed particles or more predpochitaemaya or co-solvent is an organic solvent, specified above, and the polymer forming a matrix, and the active substance. Then the particle formation can be carried out, for example, by spray drying, or more preferably through education emulsion using a second liquid phase, for example the aqueous phase, the first phase is dispersed and the second phase is continuous, i.e., as described above.

In another aspect the invention also provides a material in the form of particles, including microparticles are biodegradable, biocompatible polymer matrix containing an active ingredient and an organic solvent, and a specified organic solvent is present in said particles in the amount of 2% or less of the total mass of these particles.

In an alternative aspect the invention provides a material in the form of particles, including microparticles are biodegradable, biocompatible polymer matrix containing the active substance, and these microparticles obtained by the method in accordance with the invention.

In another aspect, the invention provides a pharmaceutical composition comprising microparticles in accordance with the invention in conjunction with one aspect, the invention provides the use of the particles obtained by the method of the invention, for producing a medicinal product for use in a method of diagnosis or treatment.

From the point of view of another aspect, the invention provides a method of treatment of human or animal (e.g. a mammal), including the introduction of compositions in accordance with the invention.

The present invention provides an improved method of obtaining a pharmaceutical composition in the form of microparticles intended for controlled release of an effective amount of drug over an extended period of time, whereby the composition exhibits enhanced stability during storage. Possible duration of storage can be increased to approximately two or more years for microparticles produced in accordance with the method of the present invention. The invention also relates to a new composition itself, which includes at least one active substance, at least one biocompatible, biodegradative encapsulating binder and less than about 2 wt. % residual tx2">

In one preferred variant implementation of the method of the present invention includes:

A) obtaining a first phase, including:

(1) biodegradative, biocompatible polymer encapsulating binder and

(2) has limited solubility in water, the active substance is dissolved or dispersed in the first solvent;

B) obtaining a second water phase;

C) combining the specified first phase and the second phase under the influence of the mixing means for the formation of emulsions, in which the first phase is dispersed and the second phase is continuous;

(D) the Department specified the dispersed first phase of the specified continuous second phase and

E) washing the specified first dispersed phase

(1) water at a temperature in the range from approximately 25oWith up to approximately 40oWith or

(2) an aqueous solution comprising water and a second solvent to the residual first solvent specified in the first phase,

thus reducing the level of residual first solvent to less than about 2 wt.% these microparticles.

In a preferred aspect of the above method predstavljati an aqueous solution of hydrophilic colloid or surfactant. Water the second phase can represent water.

In another preferred variant implementation of the method of the present invention includes obtaining a first dispersed phase (also referred to here as the "oil phase" or "organic phase"), containing from about 5 to about 50 wt.% solids, of which from about 5 to about 95 wt.% represent the solution of the biodegradable, biocompatible polymer encapsulating binder, and including from about 5 to about 95 wt.% the active substance based on the polymeric binder in the mixture solvent, the mixture includes first and second mutually miscible joint solvents, and each has a solubility in water of from about 0.1 to about 25 wt.% at 20oS; emulsion containing 1 part by weight of the first phase in an amount of from 1 to 10 parts by weight of a processing environment of the emulsion, to form microdroplets of the composition of the dispersed first phase in the processing environment of continuous or "water" of the second phase; adding the combined first and second phases in water extraction coolant to terminate the reaction at UB is the measure of the active substance, moreover coolant to terminate the reaction, contains more soluble in water joint solvent mixture at a level from about 20% to about 70% of the saturation level of more soluble in water joint solvent in the cooling water to terminate the reaction when the temperature; removing the particles from the coolant to stop the reaction; the washing of the dispersed first phase of water at elevated temperature (i.e. above room temperature) or with an aqueous solution comprising water and a solvent for residual solvent in the first phase, thus reducing the level of residual solvent in the microparticles. The level of residual solvent in the microparticles is preferably reduced to about 2 wt.% microparticles.

In another preferred variant implementation of the method of the present invention includes:

(A) obtaining a first phase, including:

1) biodegradative, biocompatible polymer encapsulating binder selected from poly(glycolic acid), poly-D,L-lactic acid, poly-L-lactic acid and their copolymers, and

2) active substance selected from risperidone, 9-hydroxyrisperidone and zilavy alcohol, and the said mixture is free from halogenated hydrocarbons;

B) a second phase containing polyvinyl alcohol dissolved in water;

C) combining the specified first phase and the second phase in a static mixer to form an emulsion, in which the first phase is dispersed and the second phase is continuous;

D) immersing the above first and second phases in the coolant to terminate the reaction;

(E) the allocation of the specified first dispersed phase in the form of microparticles and

F) washing the specified dispersed first phase aqueous solution comprising water and ethanol, which reduces the level of benzyl alcohol to less than 2 wt.% these microparticles.

In another preferred variant implementation of the method of the invention includes:

A) obtaining a first phase, and the specified first phase comprises an active ingredient (for example, biologically active substance), a biodegradable, biocompatible polymer and a first solvent;

B) a second phase, in which the first phase is substantially not miscible;

C) passing a stream of the specified first phase through a static mixer at the first Saratoga so, that said the first phase of the second phase flowing simultaneously through the static mixer, thus forming microparticles that contain the specified active ingredient;

(E) the allocation of these microparticles and

F) washing these microparticles with water at elevated temperature or with an aqueous solution comprising water and a second solvent to the residual first solvent in said microparticles, which reduces the level of residual first solvent to less than about 2 wt.% these microparticles.

In other embodiments of the invention, the first phase can be obtained by dissolving the biologically active substance in a polymer solution dissolved in a solvent, free of halogenated hydrocarbons, and obtaining a dispersion comprising the active substance in the polymer solution, or emulsion comprising the active substance in the polymer solution.

In another aspect, the present invention relates to pharmaceutical compositions comprising biodegradable and biocompatible microparticles in a pharmaceutically acceptable carrier. The microparticles comprise a polymer encapsulating connecting the connection, and the second solvent, in which the residual solvent is the remainder of the solvent used for obtaining microparticles.

In another aspect, the present invention relates to pharmaceutical compositions comprising biodegradable and biocompatible microparticles whose size is in the range of from about 25 to 180 μm, in a pharmaceutically acceptable carrier. Microparticles include a copolymer of poly(glycolic acid) and poly(D,L-lactic acid) in which the molar ratio of lactide to glycolide is in the range from about 85:15 to about 50: 50, and having from about 35 to about 40% dispersed or dissolved active substances, including risperidone or 9-hydroxyrisperidone, and from about 0.5 to about 1.5 wt.% benzyl alcohol.

The advantage of the method of the present invention is that it can be used for production, along with others, biodegradable, biocompatible system that can inetservices patient. The method provides the possibility of mixing microparticles containing different drugs to obtain microparticles, free from residues of halogenated by ognisko speed of release of the drug (so that is, you can get a sample of the multiphase release). In addition, when the application of the method is improved stability when stored in the reduced content of residual solvent in the final product.

The advantage of the products obtained by the method of the present invention, is that you can get a duration in the range from 7 to more than 200 days, for example from 14 to 100 days, depending on the type selected microparticles. In preferred embodiments of the microparticles can have a structure that provides the possibility of treating patients for periods ranging from 14 to 60 days, from 20 to 60 days from 30 to 60 days from 60 to 100 days. Particularly advantageous is the duration of the period amounting to 90 days. The duration can be controlled through changes in the composition of the polymer, the ratio of polymer : drug, size of particles and the concentration of residual solvent remaining in the microparticle after processing.

Another important advantage of microparticles obtained by the method of the present invention is the fact that almost all the active substance is delivered to the patient, then the ohms all captured active substance to be released into the patient's body.

Another important advantage of microparticles obtained by the method of the present invention is that the content of residual solvent (solvents) in the final product in the form of microparticles can be reduced by approximately an order of magnitude, whereby it is possible to increase the useful product stability during storage from approximately six months to a product manufactured without stage washing (i.e., contact) of the present invention, up to about two years or more for particles made with the stage of washing.

Another advantage of the method of the present invention is that it may be favorable in controlling the release characteristics of the active substance in vivo or decrease unwanted or potentially harmful solvent.

To ensure clarity, the following descriptions are provided the following definitions. Under "microparticles" or "microspheres" refers to solid particles that contain an active substance dispersed or dissolved within the biodegradable, biocompatible polymer, which serves as the matrix particles. Under "limited soluble 25 wt.% at 20oC. Under "halogenosilanes hydrocarbons" refers to halogenated organic solvents, for example WITH1-C4halogenated alkanes, for example methylene chloride, chloroform, methyl chloride, carbon tetrachloride, ethylene dichloride, telengard, 2,2,2-trichloroethane and the like. Under "biodegradiruemym" refers to a material that will decompose under the influence of processes in the body for food that is easily separated by the body and does not accumulate in the body, causing a harmful impact. The biological breakdown products must also be biocompatible with the body. By "biocompatible" means that the referenced material is not toxic to the human body, is pharmaceutically acceptable, is not carcinogenic and does not cause significant inflammation in body tissues. Under the "wt.%" or "% by weight" refers to parts by weight on the total weight of the microparticles. For example, 10 wt.% substances would mean 10 parts of a substance by weight and 90 parts of polymer by weight. If no other specifications mentioned here the percentage represented by the mass, if it is not clear from the context that this is not so.

In the method of the present invention the solvent, predpochtitelnei PM comprising at least one biologically active substance. Especially preferred solvent is a solvent mixture comprising at least two solvents. The first solvent component of the solvent mixture preferably is a poor solvent for the active substance, but is a good solvent for the biodegradable, biocompatible polymer. The second solvent component of the solvent mixture is preferably a good solvent for the active substance. The active substance dissolved or dispersed in the solvent. In containing the substance medium was added to the polymer matrix material that produces a product having the desired loading of the active substance. Not necessarily all the ingredients of a product in the form of microparticles can be mixed together in a mixture of solvents.

The preferred solvent system is a mixture of at least two solvents. The solvents in the solvent mixture is preferably

(1) mutually miscible with each other,

(2) capable of mixing dissolving or dispersing the active ingredient,

(3) capable smesi the BR>
(5) a biocompatible,

(6) essentially do not mix with any applicable liquid to stop the reaction, for example having a solubility of from about 0.1 to 25%, and

(7) solvents, except halogenated hydrocarbons.

The perfect blend of solvents to encapsulate the active substance must have a high solubility for the polymer encapsulate substances in General, at least about 5 wt.% and preferably at least about 20 wt.% at 20oC. the Upper limit of solubility does not matter, but if it is higher than approximately 50 wt.% solution encapsulating polymer, the solution may become too viscous for efficient and convenient handling. This, of course, depends on the nature of the encapsulating polymer and its molecular weight.

The system solvent, though being not miscible with the continuous phase of the manufacturing environment and any coolant to terminate the reaction, which usually represent water or water-based, preferably has limited aqueous solubility. If the system solvent was infinitely soluble in the manufacturing environment, then MIC the solvent in the extractive medium to stop the reaction would be too low, it would require a large number of medium to stop the reaction. In General, for use in the manufacturing environment and any medium to stop the reaction acceptable solubility of the solvent is from about 0.1 to about 25%. To control the speed loss of the first solvent from the microparticles in the environment to stop the reaction in case of using the environment to stop the reaction advantageously so that it contains from about 70 to about 20 wt.% the saturation point of the first solvent, i.e. a solvent of higher solubility in the medium to stop the reaction.

Additional considerations when choosing the components of the mixture solvent of the present invention include the boiling point (i.e., the ease with which the solvent can evaporate for the formation of the final product) and specific gravity (trend dispersible or oil phase to swim during emulsification and stopping the reaction). Finally, the solvent system should have a low toxicity.

In General, the composition of the mixture solvent of two components will contain from about 25 to about 75 wt.% the first solvent and correspondingly from about 75 to about 25 wt.% storagedriver to control the size of the microparticles according to the definition by examining the contents of the tank to stop reaction by using optical microscopy. However, after drying in the result it was found generally low quality. Often the extraction was difficult due to adhesion. Also had the tendency to the rise of residual solvent. Using the solvent system of ethyl acetate and benzyl alcohol to disperse or oil phase has improved the quality of the microparticles and the characteristics of the release.

The mixture solvent of the present invention preferably is a mixture of at least two of the following substances: ester, alcohol and ketone. Preferred esters have the structure R1COOR2where R1and R2independently selected from the group consisting of alilovic parts having from 1 to 4 carbon atoms, i.e. methyl, ethyl, propyl, butyl and their isomers. The most preferred complex ether for use as a component used in the practice of the present invention the mixture solvent is ethyl acetate.

Preferred alcohols have the structure R3CH2HE, where R3selected from the group consisting of hydrogen, alkyl having from 1 to 3 carbon atoms, and aryl having from 6 to 10 carbon atoms. More preferably, R3predstaviteley, used in the practice of the present invention is benzyl alcohol.

Preferred ketones have the structure R4COR5where R4selected from the group consisting of alilovic parts having from 1 to 4 carbon atoms, i.e. methyl, ethyl, propyl, butyl and their isomers, a R5selected from the group consisting of alilovic parts, having 2 to 4 carbon atoms, i.e., ethyl, propyl, butyl and their isomers. The most preferred ketone for use as one component of the mixture of solvents used in the practice of the present invention is methyl.

The material of the polymer matrix microparticles obtained by the method of the present invention is biocompatible and biodegradiruemym. The matrix material should be biodegradiruemym in the sense that it must disintegrate under the influence of processes in the body for food that is easily separated by the body, and should not accumulate in the body. Products of biodegradation should also be biocompatible with the body, as any residual solvent that may remain in the microparticles.

Preferred examples of the material of the polymer matrix include poly(glycolic to the company code of the present invention may be used various commercially available poly(lactide-with-glycolide) materials (PLGA). For example, poly(D,L-lactic-co-picolina acid) commercially available from Medisorb Technologies International L. P., for example 50: 50 poly(D, L-lactic-co-picolina acid), known as MEDISORB50:50 DL. This product has the composition (in mol. %): 50% lactide and 50% of glycolide. Other suitable commercially available products are MEDISORB65: 35 DL, 75:25 DL, 85:15 DL and poly(D,L-lactic acid) (D,L-PLA). Poly(lactide-co-glycolide) are also available from Boehringer Ingelheim, for example PLGA 50:50 (ResomerRG 502), PLGA 75:25 (ResomerRG 752) and d,l-PLA (ResomerRG 206), and from Birmingham Polymers. These copolymers are available in a wide range of molecular weights and ratios of lactic acid and glycolic acid.

The most preferred polymer for use in the practice of this invention is the copolymer poly(D,L-lactide-co-glycolide). Preferably, the molar ratio of lactide and glycolide in this copolymer was in the range of from about 85:15 to about 35:65, more specifically from about 75:25 to about 50:50, for example 85:15, 75:25, 65: 35 or 50:50.

It should be understood that the problem addressed by the method of the present invention, is undesirable low stability during storage, EOI solvent-solvent mixture, used in the production of microparticles remains in sufficient concentration in the final product to enhance present and degrades the interaction between the active substance and the polymer. This problem, for example, is observed when the active substance, with the main part, such as risperidone, and a matrix polymer that has a group or Association, susceptible to base catalyzed hydrolysis. However, experts in this field will readily understand that the concept of the present invention is wider than described problem of stability during storage, and rather aim for a more General solution to the problem of washing products, with the remains of certain viscous solvent, detergent liquid comprising water and a water-soluble solvent for viscous solvent (solvents) in the product.

Of some importance is the molecular weight of the polymer matrix material. The molecular weight should be high enough to provide education of a satisfactory polymer coating, i.e., the polymer should be a good educational film. Usually a satisfactory molecular weight ranges from 5,000 to 500,000 daltons, preferably from 50,000 to 400,000, blocklike film properties also depend partly on the specific material of the polymer matrix of the particles, it is very difficult to determine the range of molecular weight, corresponding to all polymers. The molecular weight of the polymer is also important from the point of view of its influence on the rate of biodegradation of the polymer.

For the diffusion mechanism of release of the drug, the polymer must remain intact up until all the drug is released from the microparticles, and then disintegrate. The drug may also be released from the microparticles as the biological decomposition of the polymer filler. Using the appropriate selection of polymeric materials can be made composition in the form of microparticles, in which the resulting microparticles show how properties of diffusive release and biodegradation release. This can be used in achieving the types of multiphase release.

Specialists in this field will be clear that the removal of residual solvent by using a stage washing of the present invention can have an impact on the rate of release of the drug, and this influence can be either harmful or beneficial, depending on the circumstances. For example, when the residual solvent acts as plastifier, the rate of release of the active substance. If in this situation the desired higher speed release, this result will be favorable. However, if the speed is high enough to adversely affect the desired action of the active substance to the patient, the responsibility of the person making the composition, will use the funds to reduce the increased speed of release. If necessary, such modifications of the method are within the capabilities of ordinary experts in their respective fields and can be implemented without undue experimentation.

The composition obtained by the method of the present invention contains the active substance dispersed in a polymeric matrix material in the form of microparticles. The number of substances included in the microparticles is typically in the range from about 1 to about 90 wt.%, preferably from 30 to 50 wt.%, more preferably from 35 to 40 wt.%. Under Mac. % refers to the material mass% of total mass of microparticles. For example, 10 wt.% substances may mean 10 parts substance and 90 parts of polymer by weight.

When implementing the method of the present invention, when it comprises the solvent mixture during the emulsification solution. The active substance may be dispersed or dissolved in a solvent or mixture of solvents, at a time when it is added in the processing environment of continuous phase. The content is usually solid material (active ingredient plus the encapsulating polymer) in a solvent mixture during his first emulsification must be at least 5 wt.%, and preferably at least 20 wt.%. Minimizing the content of the solvent in the dispersion or oil phase provides microparticles best quality and requires a smaller amount of extraction medium.

Preferred active substances can be encapsulated using the method of the present invention are those which include at least one main part, for example a tertiary amino group. Particularly preferred active substances can be encapsulated using the method of the present invention are 1,2-benzazoles, more specifically 3-piperidinylidene 1,2-benzisoxazoles and 1,2-benzisothiazole. The most preferred active substances of this type for treatment using the method of the present invention are 3-[2-[4-(fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl] ethyl] -6,7,Tyl] -6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a] pyrimidine-4-one (9-hydroxyrisperidone) and their pharmaceutically acceptable salts. The most preferred risperidone (used here, the name of which is intended to include pharmaceutically acceptable salts).

Other biologically active substances that can be used with the method of the present invention include gastrointestinal therapeutic agents, such as aluminium hydroxide, calcium carbonate, magnesium carbonate, sodium carbonate and the like; non-steroidal contraceptives; parasympathomimetics means; psychotherapeutic agents such as haloperidol, bromperidol, fluphenazine, sulpirid, carpipramine, clomipramine, MOSPRIME, olanzapine and sertindole; large tranquilizers, such as chlorpromazine Hcl, clozapine, mesoridazine, mediabin, reserpine, thioridazine and the like; minor tranquilizers such as chlordiazepoxide, diazepam, meprobamate, temazepam and the like; sinologicheskoj anti money; sedative-hypnotics means, such as codeine, phenobarbital, phenobarbital sodium, secobarbital sodium and the like; steroids, such as testosterone and testosterone propionate; sulfonylamides; sympathomimetic means; vaccines; vitamins and nutrients such as nezamenitelny, pyrimethamine and the like; anti-migraines such as mazindol, phentermine, sumatriptan and the like; anti-parkinsonism, such as L-DOPA; antispasmodic agents such as atropine, methscopolamine bromide and the like; antispasmodic and anticholinergic agents such as bile therapy, remedies, digestive enzymes and the like; anti-cough, such as dextromethorphan, noscapine and the like; bronchodilators; cardiovascular agents such as anti-hypertensive compounds, rauwolfia alkaloids, coronary vasodilator, nitroglycerin, organic nitrates, pentaerythritoltetranitrate and the like; electrolyte replacements, such as potassium chloride; ergot alkaloids such as ergotamine with caffeine and without it, hydrogenated ergot alkaloids, dihydroergocristine metasulfite, dihydroergocristine methanesulfonate, dihydroergocryptine metasulfite and combinations thereof; alkaloids such as atropine sulfate, belladonna, hyoscine hydrobromide and the like; analgesic means; narcotics such as codeine, dihydrocodeinone, meperidine, morphine and the like; non-narcotic means, such is amphenicol, gentamicin, kanamycin A, kanamycin B, the penicillins, ampicillin, streptomycin A, antimycin A, chlorobutanol, metromidazole, oxytetracycline, penicillin G, tetracycline and the like; anti-cancer remedies; anti-convulsants such as mephenytoin, phenobarbital, trimethadione; anti-emetics such as tietilperazin; antihistamines, such as chlorphenesin, dimenhydrinate, diphenhydramine perphenazine, tripelennamine and the like; anti-inflammatory agents such as hormonal drugs, hydrocortisone, prednisone, non-hormonal means, allopurinol, aspirin, indomethacin, phenylbutazone and the like; prostaglandins; cytotoxic drugs, such as thiotepa, chlorambucil, cyclophosphamide, melphalan, nitrogen mustard, methotrexate and the like; antigens of microorganisms such as Neisseria gonorrhea, Mycobacterium tuberculosis, Herpes virus (Humonis, types 1 and 2), Candida albicans, Candida tropicalis, Trichomonas vaginalis, Haemophilus vaginalis, Streptococcus ecoli group, Micoplasma hominis, Hemophylus ducreyi, pyogenic granuloma inguinale, Lymphopathia venereum, Treponema pallidum, Brucella abortus, Brucella melitensis, Brucella suis, Brucella canis, Campylobacter fetus, Campylobacter fetus intestinalis, Leptospira of Roopa, Listeria monocytogenes, Brucella ovis virus 1 equine herpes virus equine arteritis diagnostics, virus IBR-IBP, the BVD virus-MB, Chlamydia psittaci, Trichomonas foetus, Toxoplasma plasma bovigenitalium, Aspergillus fumigatus, Absidia ramosa, Trypanosoma equiperdum, Babesia caballi, Clostridium tetani and the like; antibodies, counteracting the above-mentioned microorganisms, and enzymes such as ribonuclease, neuraminidase, trypsin, glycogen phosphorylase, lactic dehydrogenase sperm, sperm hyaluronidase, adenosinetriphosphatase, alkaline phosphatase, alkaline phosphatase a-esterase, aminopeptidase, trypsin, chymotrypsin, amylase, muramidase, acrosomal proteinase, diesterase, dehydrogenase glutamic acid, succinic acid dehydrogenase, beta-glycophosphate, lipase, ATPase, alpha patat-gamma glutamyltranspeptidase, the Sterol-3-beta-ol-dehydrogenase and DPN di prorata.

Other suitable active substances include estrogens, such as diethylstilbestrol, 17-beta-estradiol, estrone, ethinylestradiol, mestranol and the like; progestins, such as norethindrone, norgestrel, ethynodiol diacetate, lynestrenol, medroxyprogesterone acetate, dimethisterone, megestrol acetate, chlormadinone acetate, norgestimate, norethisterone, ethisterone, melengestrol, norethynodrel and the like, and spermicidal compounds such as nonylphenoxyacetic glycol, benzethonium chloride, lorendana and the like.

One of micromolecule blood, hematopoietic factors, cytokines, interleukins, colony stimulating factors, growth factors and their analogues and fragments, but are not limited to.

Microparticles can be mixed by size or by type in order to ensure the delivery of active substances to a patient multiphase manner and/or way to deliver to the patient the different active substances at different times, or a mixture of active substances in one and the same time. For example, secondary antibiotics, vaccines, or any desired active substance or in the form of microparticles, or in conventional unencapsulated public form can be mixed with the primary active agent and delivered to the patient.

The mixture of ingredients in the system solvent dispersion or oil phase emulsification in the manufacturing environment of continuous phase, and the environment continuous phase such that the dispersion of the microparticles containing the specified ingredients, formed in an environment of continuous phase.

While it is not absolutely necessary, it is preferable to saturate the manufacturing environment of continuous phase, at least one of the solvents, forming a system of continuous solvent or oil phase. It is a stable emulsion, before ente USA 4389330, can be applied vacuum. When system components of the solvent are ethyl acetate and benzyl alcohol, aqueous or continuous phase of the emulsion preferably contains from 1 to 8 wt.% ethyl acetate and from 1 to 4 wt.% benzyl alcohol.

Typically, to prevent agglomeration of the particles of the solvent and to control the size of microdroplets of solvent in the emulsion in a manufacturing environment add a surfactant or a hydrophilic colloid. Examples of compounds that can

be used as surfactants or hydrophilic colloids include, but are not limited to: poly(vinyl alcohol), carboxymethyl cellulose, gelatin, poly(vinyl pyrrolidone), Tween80, Tween20 and the like. The concentration of surfactant or hydrophilic colloid in the manufacturing environment should be sufficient to stabilize the emulsion and the effect on the final size of the microparticles. In General, the concentration of surfactant or hydrophilic colloid in the manufacturing environment will be from about 0.1 to about 10 wt. % based manufacturing environment, depending on the surfactant or hydrophilic colloid, solvent dispersible or oil phase and obrabativayu 0.5 to 2 wt.%, a solution of poly(vinyl alcohol) in water.

The emulsion can be formed by mechanical mixing of the mixed phase, or by adding small drops of the dispersed phase, which contains the active substance and forming a wall material in the manufacturing environment of continuous phase. The temperature during formation of the emulsion has no particular fundamental values, but may affect the size and quality of the microparticles and the solubility of the active substance into a continuous phase. Of course, it is desirable to have continuous phase as far as possible less active substances. Moreover, depending on the solvent mixture and the manufacturing environment of continuous phase, the temperature should not be too low, otherwise the solvent and the manufacturing environment can be solid or become too viscous for practical purposes. On the other hand, it should not be so high that the manufacturing environment is evaporated, or such that will not be supported liquid manufacturing environment. Moreover, the temperature of the emulsion may not be so high as to adversely affect the stability of the active substance in the form of particles included in the microparticles. Southwest work preferably from about 20oWith up to approximately 60oWith, depending on the selected active substances and fillers.

As stated above, the purpose of the microparticles containing the active substance are combined organic or oil (dispersed) phase and aqueous phase. Organic and aqueous phase are substantially or essentially not mixed, and the aqueous phase is the continuous phase of the emulsion. The organic phase comprises an active ingredient, and forming the walls of the polymer, i.e. the polymer matrix material. The organic phase obtained by dissolving or dispersing the active substance (s) in an organic solvent. The organic phase and the aqueous phase is preferably combined under the influence of the means for mixing, preferably a static mixer. Preferably the combined organic and aqueous phases are pumped through a static mixer to form an emulsion comprising microparticles containing the active substance encapsulated in the polymer matrix material, and then a large amount of coolant to terminate the reaction, with the aim of obtaining microparticles containing activate in the container, containing solution to stop the reaction in order to remove the greater part of the organic solvent from the microparticles, which leads to the formation of the hardened microparticles. Especially preferred method of blending static mixer disclosed Ramstack et al. in patent WO 95/13799.

One of the advantages of using a static mixer is that it can be made accurate and reliable scale sizes from laboratory to industrial parties, while achieving at the same time narrow and well-defined size distribution of microparticles containing a biologically or pharmaceutically active substances. Another advantage of this method is that the same equipment can be used to form microparticles containing the active substances are precisely defined size distribution for different size parties. In addition to improving technology method static mixers require a small amount of maintenance and repair and occupy less space than dynamic mixers, they have less energy need and they require relatively low investment costs.

After moving the microparticles of staticheskoy a large part of the solvent in the microparticles is removed by extraction. At this stage extractive stopping the reaction microparticles can suspendibility in the same manufacturing environment continuous phase used during emulsification, with hydrophilic colloid or surfactant or without them, or in another liquid. Extraction environment removes a significant portion of the solvent from the microparticles, but does not dissolve them. During the extraction, the extraction medium containing the dissolved solvent may optionally be removed and replaced with fresh extraction medium.

After completing the step of stopping the reaction of the microparticles can be allocated, as described above, and then, if desired, may be dried under the influence of air or by other conventional drying techniques, such as vacuum drying, drying over a desiccant or the like. This method is very effective for the encapsulation of active substances, as can be obtained from the main load, reaching about 80 wt.%, preferably up to about 50 wt.%.

When for the formation of droplets of the organic or oil phase in the emulsion is used a mixture of solvents, one of the solvents in the solvent mixture will be extracted at the stage stop the reactions is a mixture of ethyl acetate/benzyl alcohol. Thus, delayed large remnants of the second solvent (in this case, benzyl alcohol). Due to the high boiling point of benzyl alcohol it is not easily removed by exposure to particulate matter air or other conventional viparyayah funds. To increase the effectiveness of this procedure on Wednesday extractive stopping the reaction before the addition of the emulsion can be added any more quickly extracted solvents. Concentration more quickly extracted solvent in the environment extractive stopping the reaction is from about 20 to about 70% of the saturation point of the solvent medium at a temperature which is supposed to be used for extraction. Thus, when the coolant to terminate the reaction emulsion is added, extraction is more quickly extracted solvent slows down, and most of the second, slower extracted solvent is removed.

The exact maximum amount of this more quickly extracted solvent is added to the coolant to terminate the reaction, is important for the final quality of the microparticles. Too much R the spine of the active substance, causing what may be undesirable high rate of release. Too small amount of solvent in the medium to stop the reaction leads to high residual level more slowly extracted solvent and the poor quality of the microparticles. The temperature of the medium to stop the reaction also important because it affects the solubility and the rate of extraction solvent.

You can find and temperature, and the maximum amount of solvent for a favorable influence on the desired characteristics of the final product, i.e., highly porous microparticles with a quick release or microparticles with slow release, low porosity.

Coolant to terminate the reaction may be plain water, aqueous solution or other suitable liquid, volume, number and type of which depends on the solvent used in the emulsion phase. Preferably the coolant to terminate the reaction, represents water. In General, the amount of coolant to terminate the reaction, about 10 times higher than the saturated volume (i.e. 10 times more volume for stopping the reaction needed to complete my absorption is to terminate the reaction may vary, equivalent to from about 2 to about 20 times the saturated volume. It is advisable, moreover, to describe the need for coolant to terminate the reaction, relative to the size of the party (the product in the form of microparticles). This ratio is an indication of the efficiency of the extraction step and, in some cases, dictates the lot size for a given set of equipment. The larger the ratio, the greater the amount you want on the weight of the product. On the other hand, when a smaller value of the same amount of coolant to terminate the reaction, can be obtained more product. This ratio can vary from approximately 0.1 to approximately 10 liters of coolant to terminate the reaction, 1 g of the obtained microparticles. Preferred ways with a ratio of less than about 1 l 1,

When using the preferred combination of solvents, benzyl alcohol and ethyl acetate, it appears that the content of ethyl acetate in the cooling water to terminate the reaction, the effect on the residual level of the solvent in the microparticles of the product. At low concentrations of ethyl acetate in the coolant for PfP. At high content of ethyl acetate in the cooling water to terminate the reaction, the microparticles can hold more acetate than benzyl alcohol. When the coolant to terminate the reaction, approximately 1 l per 1 g of the active substance and subjected to cooling the polymer encapsulating material, the optimum content of ethyl acetate in the cooling water to terminate the reaction is about 2-4 wt.% at 0 to 10oC.

After the termination stage of the reaction microparticles are allocated from water cooling solution to terminate the reaction, using any convenient means of separating the liquid can be drained from the microparticles or suspension of microparticles can be filtered using, for example, column / tube sheet. Optionally, you can use various other combinations of separation techniques. The preferred filtering.

Then the filtered particles are subjected to a step of rinsing the present invention to further declines in the level of residual solvent (solvent), preferably up to a level in the range of from about 0.2 to 2.0%. In practice it was found that in the case of using asego of the invention, the levels of residual benzyl alcohol in General are still in the range of 4 to 8%. It appears that the level of residual solvent in the microparticles sufficient to accelerate the process of decay, which reduces thus the stability during storage. The decay of particles may, for example, occur by unwanted hydrolysis of hydrolyzable linkages matrix polymer main active substance. Thus, the stage (stages) rinsing the present invention are used to reduce the content of residual benzyl alcohol or other solvent in the microparticles to delay the process of decay.

As mentioned above, the solution for washing includes one or water or preferably water and mixed with the solvent, which is also a good solvent for residual solvent in the microparticles. In cases where as in the preferred method of the present invention, the residual solvent is benzyl alcohol, for use in the washing solution is preferred WITH1-C4aliphatic alcohols. These alcohols are methanol, ethanol, propanol, butanol and isomers. The most preferred alcohol is ethanol.

The alcohol concentration in the washing solution may vary is approximately 5%. Thus, the preferred range for the concentration of alcohol will usually be from about 5 to about 50 wt.%. More preferably the concentration will be in the range from approximately 15 to approximately 30%.

The temperature of the leaching solution is also important for the effectiveness of stage equipment. In General, higher temperatures will reduce the time required for washing to reduce the content of the remaining solvent to the desired level.

On the other hand, too high a temperature can have a damaging effect that it is possible to approach or exceed the softening temperature of the polymer matrix microparticles, thereby causing the formation of lumps or sticking. On the contrary, too low temperature may cause excessive hardening of the matrix material, thereby slowing the rate at which can be extracted residues, whereby the method can become unacceptably expensive. It was found that a convenient and effective is the temperature range from approximatelyoWith up to approximately 40oC. Preferably, the temperature will reach room temperature, i.e., from pribila water, it will be used at elevated temperatures, i.e. above room temperature, preferably in the range from approximately 25oWith up to approximately 40oS, most preferably approximately at 37oC.

It will usually be desirable to use more than one stage of washing, usually two or three. After each such step, the microparticles will be separated from the leaching solution by using well-known means of separation, such as filtration, decantation, centrifugation and the like. The preferred filtering.

After each step of separating the microparticles may optionally fully or partially dried using conventional means of drying at a temperature substantially similar to the temperature of the solution prior to washing. It was found that particularly applicable and easy it is to use dry compressed air at a temperature in the range of approximately 10oWith up to approximately 30oWith that and is preferred.

Product in the form of microparticles typically composed of spherical particles, although sometimes microparticles may have an uneven shape. Microparticles can vary in size is 0 μm, more preferably from 25 to 180 μm, resulting in the introduction of particles to the patient can be carried out by standard needle gauge.

Preferably the loaded drug microparticles are dispensed to patients in the form of a single injection, releasing the drug in the patient's body constant or pulsed manner and eliminating the need for repeated injections.

Microparticles containing the active substance are obtained and stored as a dry material. Before the introduction of the patient dry microparticles can suspendibility in pharmaceutical acceptable liquid carrier, such as 2.5 wt.% the solution of carboxymethyl cellulose, after which the suspension is injected into the body.

Microparticles can be mixed by size or by type in order to ensure the delivery of active substances to a patient multiphase manner and/or way that ensures the delivery of various active agents to the patient at different times or mixture of active substances in one and the same time. For example, secondary antibiotics, vaccines, or any desired active substance or in the form of microparticles, or normal, unencapsulated public form, can be mixed with the primary active substance and entered the efficiency of the polymer matrix, an additional stage (stages) rinsing the present invention can be favorable in aspects such as control of the release characteristics of the active substance in vivo or decrease unwanted or potentially harmful solvent.

Now the invention will be further illustrated by the following non-limiting examples with reference to the accompanying drawings, in which:

Fig.1 is a graph showing the reduction of benzyl alcohol in the final product as a function of the concentration of ethanol(5%, 15%, 20%, 25%) the solution for washing containing ethanol : water;

Fig. 2 is a graph showing the effect of concentration of microparticles on the level of residual benzyl alcohol (BS) in the final product;

Fig. 3 is a graph showing the temperatures of the stage washing on the level of residual benzyl alcohol (BS) in the final product, and

Fig.4 is a graph showing the influence of the level of residual solvent (benzyl alcohol) to reduce the molecular weight of the polymer matrix.

Example 1.

Under normal party 125 g 75 g lactide-glycolic acid copolymer (75 is onicescu phase. The aqueous phase includes 90.9 g of polyvinyl alcohol, 8910 g of water, 646,4 g of ethyl acetate and 298,3 g benzyl alcohol. The organic and aqueous phases are pumped through a static mixer to form an emulsion. The resulting emulsion is passed into the cooling liquid to stop the reaction, containing 17 kg of water, 4487,8 g of ethyl acetate, 371,0 g of sodium carbonate and 294,0 g of sodium bicarbonate. After 20 h at approximately 10oWith the resulting microspheres are then filtered and washed first washing solution containing at 11.25 kg of ethanol and 33,75 kg of water, for 2 h at 10oC. Then the beads filtered and washed with a solution containing at 11.25 kg of ethanol and 33,75 kg of water, for 6 h at 25oC. Then, 25oC for 1 h in filtered product serves the third solution for washing containing 756 g of citric acid, 482 g of sodium phosphate and 45.0 kg of water. The product is then rinsed with water, filtered and dried. Three parties made in accordance with this procedure, ensure that the content of risperidone 37,4, 37,0 and 36.6 wt.%. Levels of benzyl alcohol were 1,36, of 1.26 and 1.38 wt.%. The levels of ethyl acetate were of 0.09, 0.08 and 0.09 wt.%.

Example 2.

Influence of washing on the characteristics of the study to determine the impact on the characteristics of the final product and to identify favorable conditions for washing. The sample included risperidone, encapsulated in lactide-glycolic acid copolymer (75: 25) Medisorb. Before experiments with irrigation of the content of the drug was to 36.8 wt.%, and the level of benzyl alcohol was approximately 5.2 wt.%. Microspheres are implanted into the environment for rinsing, the samples are removed after selected periods of time and dried under vacuum.

In Fig.1 shows the decrease in levels of benzyl alcohol in the final product as a function of the concentration of ethanol (5%, 15%, 20% and 25%) solution for washing containing ethanol/water. Higher levels of ethanol gave a lower content of residual benzyl alcohol in the final product.

Fig.2 shows that in the range from 0.1 to 1.0 l of a solution of 1 g of the microspheres, the concentration of the microspheres at the stage of washing does not affect the level of residual benzyl alcohol (BS) in the final product.

In Fig. 3 shows the temperature effect of the stage of washing on the level of residual benzyl alcohol in the final product.

The table shows the increase in the glass transition temperature (Tg) of the final microspheres with increasing time washing and increasing concentrations of ethanol and reduce the corresponding concentration is of pirta were subjected to studies of stability at room temperature. In Fig. 4 shows that the process of disintegration, by measuring the rate of hydrolysis of the biodegradable, biocompatible polymer, strongly influenced by the level of residual solvent in the final product. Was built by the graph of the constant reduction of molecular weight from residual benzyl alcohol for ten different samples of the microspheres.

1. A method of obtaining a biodegradable, biocompatible microparticles, comprising the contacting of the microparticles, including biodegrading, biocompatible polymeric matrix containing the encapsulated active agent that has limited solubility in water, and at least one organic solvent selected from the group comprising alcohol, a linear or cyclic simple ether, ketone and ester, with a water system, through which the contents of the specified organic solvent in said microparticles is reduced to 2% or less by weight of these particles, and the specified water system is such that it contains water and at least part of the time during which it is in contact with these particles, has a high temperature in the range from approximately 25oWith up to approximately s specified organic solvent, which is free from halogenated hydrocarbons, and removing these particles from the specified water system.

2. The method according to p. 1, characterized in that it comprises A) a first phase comprising (1) biodegradative, biocompatible polymer encapsulating binder which is a polymer matrix, and (2) has limited solubility in water, the active substance is dissolved or dispersed in the first solvent, (C) obtaining a second aqueous phase, (C) combining the specified first phase and the second phase under the influence of the mixing means for the formation of emulsions, in which the first phase is dispersed and the second phase is continuous, D) the Department indicated the dispersed first phase of the specified continuous second phase, and (E) washing the specified first dispersed phase (1) water at a temperature in the range from approximately 25oWith up to approximately 40oWith or (2) an aqueous solution comprising water and a second solvent to the residual first solvent specified in the first phase, thus reducing the level of residual first solvent to less than about 2 wt. % from the specified Mick is between step C) and step D).

4. The method according to p. 1, characterized in that it includes A) obtaining a first phase, and the specified first phase comprises an active agent, a biodegradable, biocompatible polymer and a first solvent, B) a second phase, with which the first phase is, in essence, is not miscible With) the transmission of the specified first phase through a static mixer, (D) the deletion of the specified second phase through the static mixer, so that said first phase and second specified phase flow simultaneously through the static mixer, thus forming microparticles that contain the specified active ingredient, E) the selection of these microparticles, and (F) washing these microparticles with water at elevated temperature or with an aqueous solution comprising water and a second solvent to the residual first solvent in said microparticles, thereby reducing the level of residual first solvent to less than about 2 wt. % of these microparticles.

5. The method according to any of paragraphs. 2-4, wherein said first solvent is a mixture of at least two mutually miscible organic solvent and the second phase includes the wines of the above organic solvent is an ester, and the second represents benzyl alcohol.

7. The method according to any of paragraphs. 5 and 6, characterized in that the mixture of solvents include ethyl acetate and benzyl alcohol, the specified second phase includes polyvinyl alcohol, and said polymer encapsulating binder is selected from poly(glycolic acid), poly(D, L-lactic acid), poly(L-lactic acid) and their copolymers.

8. The method according to any of the preceding paragraphs, characterized in that the active substance includes at least one main part.

9. The method according to any of the preceding paragraphs, characterized in that the said active substance is selected from the group consisting of risperidone, 9-hydroxyrisperidone and their pharmaceutically acceptable salts.

10. The method according to any of the preceding paragraphs, characterized in that the specified water system includes water and1-C4the alcohol.

11. The method according to p. 10, wherein the specified1-C4alcohol is an ethanol.

12. The method according to p. 1, characterized in that it comprises (A) obtaining a first phase comprising 1) biodegradative, biocompatible polymer encapsulation svyazyvayuscyego, and 2) an active ingredient selected from risperidone, 9-hydroxyrisperidone and their pharmaceutically acceptable salts which are dissolved or dispersed in a mixture comprising ethyl acetate and benzyl alcohol, and the mixture is free from halogenated hydrocarbons, B) a second phase containing polyvinyl alcohol dissolved in water, (C) combining the specified first phase and the second phase in a static mixer to form an emulsion, in which the first phase is dispersed and the second phase is continuous, D) dive specified first and the second phases in the coolant to terminate the reaction, (E) the allocation of the specified first dispersed phase in the form of microparticles, and (F) washing the specified dispersed first phase aqueous solution comprising water and ethanol, thereby reducing the level of benzyl alcohol to less than 2 wt. % of these microparticles.

13. Microparticles are biodegradable, biocompatible polymer matrix containing the encapsulated active agent that has limited solubility in water and organic solvent which is free from halogenated hydrocarbons and selected from the group, the solvent is present in said particles in the amount of 2% or less of the total mass of these particles.

14. Microparticles are biodegradable, biocompatible polymer matrix containing the active substance obtained by the method according to any of paragraphs. 1-12.

15. Pharmaceutical composition comprising microparticles according to any one of paragraphs. 13 and 14, together with at least one pharmaceutically acceptable carrier or excipient.

16. The composition according to p. 15, characterized in that the polymeric binder is a copolymer of glycolic acid and D, L-lactic acid.

17. Composition according to any one of paragraphs. 15 and 16, characterized in that the contents of the specified residual solvent in said microparticles is in the range from 0.5 to 1.5 wt. %, and the residual solvent is a benzyl alcohol.

18. The composition according to p. 15, characterized in that it includes a biodegradable and biocompatible microparticles whose size is in the range from 25 to 180 μm, in a pharmaceutically acceptable carrier, and these microparticles include a copolymer of glycolic acid and D, L-lactic acid in which the molar ratio of lactide to glycolide is in the range from 85: 15 to 50: 50, and having from 35 to 40% dispersed or dissolved pour, and from 0.5 to 1.5 wt. % benzyl alcohol.

19. Microparticles obtained by the method according to any of paragraphs. 1-12 used to manufacture a medicinal product for use in a method of diagnosis or treatment.

 

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FIELD: pharmaceutical industry.

SUBSTANCE: invention relates to porous quick-breaking active ingredient-containing granules based on chitosan or basic derivative thereof prepared by drop-by-drop technique, wherein aqueous solution or dispersion of chitosan or basic derivative thereof, one or several active substances, optional secondary active substances, and acid are dropwise added to cooling fluid at maximum temperature -5°C. As a result, solution or dispersion is solidified in the form of drops, which are then separated and dried. Such procedure is used to prepare therapeutical or diagnostic agents.

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EFFECT: improved pharmaceutical properties of combinations.

23 cl, 3 dwg, 8 tbl, 19 ex

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16 cl, 2 ex

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44 cl, 1 tbl, 1 dwg, 7 ex

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EFFECT: improved preparing method.

57 cl, 14 tbl, 24 ex

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