Composition of biodegradable microspheres suitable for controlled release of glycose level-controlling peptide and its composition

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmacology and deals with method of obtaining microspheres from biodegradable polymer, including: addition of organic solvent to polymer, obtaining polymer solution (stage 1); dispersion of glucose level-regulating peptide in stage 1 polymer solution, obtaining medication dispersion and mixing alcohol or mixture of alcohol and organic acid with medication dispersion, obtaining solution with dispersed in it medication (stage 2); and obtaining microsphere from solution with dispersed in it stage 2 medication (stage 3), where glucose level-regulating peptide represents exedin-4 and where biodegradable polymer is selected from group, consisting of poly-L-lactic acid, D-lactic acid and glycolic acid copolymer, L-lactic acid and glycolic acid copolymer and D,L-lactic acid and glycolic acid copolymer.

EFFECT: invention ensures obtaining microsheres which demonstrate neither initial burst effect nor incomplete release, ensure release of medications of zero order and high efficiency of incapsulation and high stability.

13 cl, 15 ex, 7 tbl, 5 dwg

 

The technical field

The present invention relates to a biodegradable polymeric microsphere containing biodegradable polymer carrier with encapsulated therein regulating the level of glucose peptide that is capable of releasing regulating the level of glucose peptide in a controlled way, and to the way it was received.

The level of technology

After oral administration, the majority of protein and peptide drugs lose their active patterns in the acidic environment of the stomach or undergo enzymatic degradation. Also they are absorbed through the mucous membrane of the stomach or intestines at very low levels. For these reasons, protein or peptide drugs, as a rule, is not injected oral, that is, as a rule, administered by injection. Superonline introduction of protein or peptide drugs should be repeated, since most neironalna input protein or peptide drugs demonstrates a short half-life and low bioavailability in the body. In addition, in many cases, their introduction can last for a long period of time, such as months. To avoid these problems conducted active research compounds for dosage delayed release that has resulted to the use of biodegradable polymeric carriers with encapsulated them in protein or peptide drugs, who can unleash the protein or peptide drugs as biodegradation of polymeric carriers [Heller, J. et al., Controlled release of water-soluble macromolecules from bioerodible hydrogels, Biomaterials, 4, 262-266, 1983; Langer, R., New methods of drug delivery, Science, 249, 1527-1533, 1990; Langer, R., Chem. Eng. Commun., 6, 1-48, 1980; Langer, R. S. and Peppas, N. A., Biomaterials, 2, 201-214, 1981; Heller, J., CRC Crit. Rev. Ther. Drug Carrier Syst., 1(1), 39-90, 1984; Holland, S.J. Tighe, B. J. and Gould, P. L., J. Controlled Release, 155-180, 1986].

Aliphatic polyesters, currently used as polymeric carriers for protein or peptide drugs received FDA approval for their use, as was established by their biological compatibility. They are widely used as carriers for drug delivery or thread for sutures in operations.

Specific examples of aliphatic polyesters include poly-L-lactic acid, polyglycolic acid, copolymer of D-lactic acid and glycolic acid, copolymer of L-lactic acid and glycolic acid, copolymer of D,L-lactic acid and glycolic acid (hereafter in this document referred to as "PLGA"), polycaprolactone, polivalente, polyhydroxybutyrate and polyhydroxyvalerate [Peppas, L. B., Int. J. Pharm., 116, 1-9, 1995]. With the development in recent years of high molecular weight peptides or proteins as new drugs were taken according to CNAE attempts to release them from polymeric carriers in a controlled way. However, dosage forms containing polyester microspheres with encapsulated protein in them drugs have disadvantages, in that they demonstrate initial burst effect, uncontrolled rate of release over a period of time due to various factors or incomplete release of encapsulated drugs. For example, a model protein drug, such as bovine serum albumin, lysozyme, etc. are released in large quantities at the initial stage, however, show the final release of approximately 50% [Crotts, G. and Park, T. G., J. Control. Release, 44, 123-134, 1997; Leonard, N. B., Michael, L. H., Lee, M. M. J. Pharm. Sci., 84, 707-712]. As for microspheres using aliphatic polyester media with encapsulated them in recombinant human growth hormone, they initially release the drug in the amount of 30~50%, but 40~60% of the drug remains in the microspheres [Yan, C, et al., J. Control. Release, 32, 231-241, 1994; Kim, H. K. and Park, T. G., Biotechnol. Bioeng., 65, 659-667, 1999].

The initial burst release of drug due to the fact that protein drugs, aggregated or adsorbed on surfaces or in cavities of microspheres released by fast diffusion at the initial stud is I. In the process of making microspheres protein drugs can denaturing at the contact interface between water and an organic solvent, and thus they can form irreversible aggregates, which lead to unstable release. To prevent induced by the contact boundary between the denaturation of protein drugs described in the application upon receipt of the microspheres surface-active substances (for example, surface-active agents non-ionic type Tween, Pluronic F68, Brij 35, and so on) and stabilizers (for example, mannitol, gelatin, trehalose, carboxymethyl cellulose, etc. or an organic solvent containing no water [Gombotz, W. R., Healy, M., Brown, L., U.S. patent No. 5019400].

To solve uncontrolled speed of release of the medicinal product for some period of time and incomplete release of encapsulated drugs many recent studies associated with alternative methods of making microspheres for slow release of drugs, which include encapsulating the drug in a mixture of two or more polymers with different speeds decomposition in a predetermined ratio [Ravivarapu, H.B., Burton, K., Deluca, P.P., Eur J Pharm Biopharm 50(2) 263-270, 2000; patent application Korea No. 1998-0062142] or a mixture of two or more types of limernyh microspheres, having a different degradation rate with the corresponding encapsulated in them medicines in a predetermined ratio (U.S. patent No. 4897268), controlling through this as the initial release and continuous release of the drug or drugs from microspheres. However, in the microspheres obtained in a common manner, the decomposition products of the polymer with a high rate of decomposition, such as lactic acid and glycolic acid, lowers the pH, which provides the decomposition of the polymer having a low rate of decomposition, and this leads to the speed of release, quite different from the calculated values of the speed of release of the drug encapsulated in the respective polymers. In addition, the receipt of two or more types of microspheres for a single dosage form has disadvantages from the point of view of manufacturing processes and saving (patent application Korea No. 2000-0036178).

Methods for producing microspheres, phase separation (U.S. patent No. 4673595, patent application Korea No. 2007-0031304), spray drying (patent application Korea No. 2003-0023130) and evaporation of the organic solvent (U.S. patent No. 4389330) is mainly known. In the method of phase separation using solvent methylene chloride in combination with a silicone oil, heptanol etilovym alcohol, however, all of them must be eliminated, and thus they are economically disadvantageous. As for the spray drying method, it can lead to denaturation of the peptide or protein drugs, because it requires a spray drying the peptide or protein drugs at a high temperature such as 60°C. or more, together with an organic solvent. For these reasons, upon receipt of peptide or protein drugs most widely used method of evaporation of organic solvent. One of the most important factors in this way is the efficiency of encapsulating patent application Korea No. 2003-0081179).

Thus, there is a need for a method of producing microspheres that do not show any initial burst effect or incomplete release, allow the release of drugs zero order, are simple and cost-effective and provide a high encapsulation efficiency and high stability of the encapsulated drug.

Regulating glucose peptides belong to the group of peptides, which have therapeutic potential in the treatment of insulin-dependent diabetes, gestational diabetes or insulin-dependent Saha the aqueous diabetes, obesity and disorders of lipid metabolism (U.S. patent No. 6506724). Examples of regulating glucose peptides include the basis 3 basis 4 and their homologues and agonists, and glucagon, glucagon-like peptides (e.g., GLP-1, GLP-2) and their homologues and agonists (patent application Korea No. 2006-7015029).

On the basis of 4, selected from the secrets of the salivary glands of lizardsHeloderma horridumorHeloderma suspectumis a physiologically active peptide, consisting of 39 amino acid residues. On the basis 4 performs the function of stimulating the secretion of insulin from the beta cells of the pancreas, reducing the increased secretion of glucagon and induction increase appetite, thus being suitable for the treatment of diabetes and obesity [Eng. J. et al. 1990; Raufman, J. P. 1992; Goeke, R. 1993; Thorens, B. 1993].

For effective prevention and treatment of diabetes conducted research microspheres for slow release of basis 4 (patent application Korea No. 2006-7023921). However, conventional methods are difficult and inefficient, an example of which is the application and removal of many organic solvents in the method of phase separation, decomposition of peptides inherent in the use of high energy in the ultrasonic process, and the use of many of the excipients, including stabilizers, such as sugar, and amplifiers releases (for example, inorganic KIS is the notes and inorganic salts).

Description

Technical problem

Thus, the present invention is to provide microspheres that do not show any initial burst effect or incomplete release, allow the release of drugs zero order regardless of the period of time a stable release, are simple and economically advantageous from the point of view of their production and provide a high encapsulation efficiency and high stability of the encapsulated drug, and the method of their derivation, which is not a lot of organic solvents or high-energy treatment, such as irradiation by ultrasound or contribute to a release, and which is simple.

Technical solution

To solve the above task, the present invention relates to byroslawsky polymeric microspheres containing biodegradable polymer carrier with encapsulated therein regulating the level of glucose peptide that is capable of releasing regulating the level of glucose peptide in a controlled way. Also the present invention relates to a method for producing a biodegradable polymer microspheres.

The predominant effects

In addition to the fact that the microspheres are Rostami and economically advantageous from the point of view of their production and provide a high encapsulation efficiency and high stability of the encapsulated drug, microspheres in accordance with the present invention demonstrate the release of drugs zero order, for example of the basis 4, and thus allow medicines continuously releasedin vitroandin vivoof them within three to four weeks without an initial burst effect, and without incomplete release.

Description of the drawings

In FIG. 1 presents a graph which shows the curve of the release ofin vitrofor microspheres obtained by the process of dispersion of the medicinal product of example 1 in accordance with the present invention.

In FIG. 2 presents a graph which shows the curves of the release ofin vitrofor microspheres obtained according to examples 4 through 8 in accordance with the present invention.

In FIG. 3 presents a graph which shows the curves of the release ofin vitrofor microspheres obtained in comparative examples 1 and 2.

In FIG. 4 shows a curve of the release ofin vivofor microspheres obtained in example 1-1.

In FIG. 5 shows a chromatogram of basis 4 obtained for microspheres obtained in example 1-1, was analyzed by reversed-phase high-performance liquid chromatography (RP-HPLC).

The best way to implement

Below is a detailed description of the infusion is of his own invention.

The present invention relates to a biodegradable polymeric microsphere for controlled release regulating the level of glucose peptide containing the biodegradable polymer carrier with encapsulated therein regulating the level of glucose peptide.

Examples of regulating the level of glucose peptide suitable for use in the present invention include natural, recombinant or synthetic basis 3 basis 4 and their homologues and agonists, glucagon, glucagon-like peptides (e.g., GLP-1, GLP-2) and their homologues and agonists, and preferred are synthetic basis 3 basis 4 and their homologues and agonists. Most preferred is a synthetic basis 4.

The content of regulating the glucose levels of the peptide in the microspheres can vary depending on the method of administration, dosage and properties of the protein.

Suitable for use as biorazlagaemykh polymer carrier are biorazlagaemykh polyester polymers. As a framework for microspheres and contained regulating the level of glucose peptide, biorazlagaemykh polyester polymers gradually degrade, releasing thereby regulating glucose peptide. Examples of the biodegradable polyester polymers include, but are not limited to, poly-L-lactic acid is one polyglycolic acid, copolymer of D-lactic and glycolic acid, copolymer of L-lactic acid and glycolic acid, copolymer of D,L-lactic acid and glycolic acid, polycaprolactone, polivalente, polyhydroxybutyrate and polyhydroxyvalerate. Because in this area typically use biodegradable polyester polymer is not imposed specific limitations on its use in the present invention. The polymer is preferably selected from the group consisting of poly-L-lactic acid, copolymer of D-lactic acid and glycolic acid, copolymer of L-lactic acid and glycolic acid, copolymer of D,L-lactic acid and glycolic acid (PLGA) and their combinations. More preferred is a copolymer of D,L-lactic acid and glycolic acid (PLGA), alone or in combination with poly-L-lactic acid.

Also the present invention relates to a method for producing a biodegradable polymer microspheres for controlled release regulating the level of glucose peptide.

A method of obtaining a biodegradable polymeric microspheres include:

adding organic solvent to the polymer to obtain a polymer solution (stage 1);

the dispersion regulating the glucose levels of the peptide in the polymer solution phase 1 to obtain a dispersion, and then adding alcohol and a mixture of alcohol and organic acid to the dispersion to obtain a solution with the dispersed drug (stage 2); and

the formation of microspheres from the solution with the dispersed drug phase 2 (stage 3).

Detailed description of the method is given in stages.

First, in stage 1 obtain a polymer solution.

In stage 1, the polymer is dissolved in an organic solvent. The polymer is byroslawsky, and it can be used as a carrier. Preferred is a biodegradable polyester polymer.

As the biodegradable polymer carrier has a high solubility therein and can be removed by evaporation, you can use any volatile organic solvent without particular limitations. In the present invention the organic solvent acts not only as a solubilizer for the dissolution of the polymer, but also as a dispersing agent for uniform dispersion regulating the glucose levels of the peptide in the polymer solution. Examples of the organic solvent suitable for use in the present invention include methylene chloride, ethyl acetate, chloroform, acetone, dimethylsulfoxide, dimethylformamide, N-organic, dioxane, tetrahydrofuran, ethyl acetate, methyl ethyl ketone, acetonitrile, and combinations thereof, and the preferred is methylene chloride, ethyl acetate and chloroform, and the most preferred is methylene chloride.

The dal is, stage 2 yields a solution with the dispersed drug. In stage 2 of regulating the level of glucose peptide is dispersed in the polymer solution. Regulating the level of glucose peptide is the same as described above. It is preferable to obtain a dispersion medicines add synthetic basis 4. In dispersion medicines ratio regulating the level of glucose peptide and polymer (wt./wt.) choose from a range sufficient for the dissolution of regulating the level of glucose peptide.

Then the alcohol alone or in combination with an organic acid dissolved in a dispersion of the drug. Alcohol and organic acid acting as solubilization, capable of dissolving both the polymer and regulating the level of glucose peptide. In addition, you can add a stabilizer or surfactant.

In the method in accordance with the present invention it is very important to obtain a dispersion of the drug in order to add an organic solvent to the polymer, adding regulate the glucose level of the peptide and the addition of alcohol or mixture of alcohol and organic acids. When the insertion order change, that is, when the polymer is added with an organic solvent and an alcohol or mixture of alcohol and organic the tion of the acid with the subsequent dissolution of regulating the level of glucose peptide, or when the solution is regulating the level of glucose peptide in alcohol or mixture of alcohol and organic acids are added to the polymer solution obtained microsphere demonstrates incomplete curve release.

Suitable in this invention are methyl alcohol, ethyl alcohol, isopropyl alcohol and butyl alcohol, and methyl alcohol is preferred due to its high solubility for biorazlagaemykh polymer carrier and regulating the level of glucose peptide. Alcohol, which is intended to dissolve the dispersion of the medicinal product, preferably used in the smallest possible number, but it should be enough to dissolve the dispersion of the drug. The number can be defined depending on the type of alcohol. In the case of methyl alcohol, the ratio of drugs and alcohol (about./about.) preferably is in the range from 1:1 to 6:1, more preferably from 3:1 to 4:1, for the complete dissolution dispersion of the drug. You can also use any organic acid without restriction, provided that it can dissolve the polymer carrier and regulating the level of glucose peptide. Examples of organic solvents suitable for the present invention include oxalic acid, okalossa acid, FUM the world acid, malic acid, succinic acid, acetic acid, butyric acid, palmitic acid, tartaric acid, ascorbic acid, uric acid, sulfonic acid, sulinowo acid, formic acid, citric acid, solomonow acid, alpha-ketoglutaric acid, succinic acid and nucleic acid, and preferred are acetic acid, formic acid, and a combination thereof. Like alcohol, the amount of organic acid is determined depending on its type.

Based supplements are not imposed specific restrictions provided that they can dissolve the dispersion of the drug and are soluble in the solvent for dispersion of the drug. For example, you can use the glycols (Solutol HS-15TM, TPGSTM, GelucireTM), oil (LabrafilTM, LabrasolTM, Medium Chain TriglycerideTM), proteins (lectin), surfactants (N-organic, polyvinylpyrrolidone, TweenTM, SpanTM, CremophorTM, PoloxamerTM, BrijTM, Sunsoft 818HTMand gidropropilmetilzelluloza. Their concentration in the solubilizer is in the range from 0.01 to 15% (wt./about.) and preferably from 0.1 to 12.5% (wt./vol.).

Finally, stage 3 is designed for the formation of microspheres from the solution with the dispersed drug phase 2.

Obrazovanneishei can be achieved by dispersion solution with the dispersed drug in aqueous solution, containing emulsifier, or using spray dryers.

When the solution with the dispersed drug is dispersed in an aqueous solution containing an emulsifier, use a stirrer and a homogenizer to form microspheres, which are then dried. Emulsifier suitable in the present invention, may be a lipophilic emulsifier, dispersible in organic solvents or hydrophilic emulsifier, dispersible in aqueous solvents. Examples of hydrophilic emulsifier include Tween, Triton, Brij, polyvinylpyrrolidone and polyvinyl alcohol, and preferred is polyvinyl alcohol. The organic solvent may be saturated emulsifier or unsaturated them. As the organic solvent preferably you can use methylene chloride, ethyl acetate or chloroform, and the most preferred is methylene chloride. The concentration of emulsifier in the aqueous solution is in the range from 0.01 to 5.0% (wt./about.) and preferably from 0.5 to 2% (wt./vol.).

At this stage, the drying can be performed using freeze-drying or vacuum drying. The obtained microspheres can be collected by centrifugation at freeze-drying or using a vacuum filter system during vacuum drying before final drying.

Mick is ospery, obtained according to this method, are microspheres of the type oil-in-water, and their average size is in the range from 5 to 70 μm and preferably from 10 to 30 μm, which is suitable for injection. Can be fitted with various values of the particle size by controlling the volume ratio of oil phase, i.e. the solution with the dispersed drug, and the aqueous phase in which is dissolved emulsifier.

In the case of spray drying, the microspheres can be obtained simply by spraying the solution with the dispersed drug from spray dryers. In the interests of efficiency for spray drying set at 115~125°C at the inlet and at 80~90°C at the outlet. Then dried by spray drying the microspheres can be subjected to additional drying process such as freeze drying or vacuum drying to remove residual solvent.

In addition, bioresource polymeric microsphere in accordance with the present invention can be obtained by a method including:

adding organic solvent to the polymer to obtain a polymer solution (stage 1);

emulsification of the polymer solution stage 1 with an aqueous solution regulating the level of glucose peptide containing surfactant, to obtain the primary Amul the FIC (stage 2'); and

the formation of microspheres from the primary emulsion phase 2' (stage 3').

In stage 1, the polymer is dissolved in an organic solvent. The polymer is byroslawsky, and it can be used as a carrier. Preferred is a polyester polymer. You can use any volatile organic solvent without particular limitation, provided that it has a high solubility for biorazlagaemykh polymer carrier and it can be easily removed by evaporation. In the present invention the organic solvent acts not only as a solubilizer for the dissolution of the polymer, but also as a dispersant substances for uniform dispersion regulating the glucose levels of the peptide in the polymer solution.

Examples of the organic solvent suitable for use in the present invention include methylene chloride, ethyl acetate, chloroform, acetone, dimethylsulfoxide, dimethylformamide, N-organic, dioxane, tetrahydrofuran, ethyl acetate, methyl ethyl ketone, acetonitrile, and combinations thereof, and the preferred is methylene chloride, ethyl acetate and chloroform, and the most preferred is methylene chloride.

In stage 2 of the' aqueous solution of regulating the level of glucose peptide-containing surfactant that is added to a solution of the polymer is followed by emulsification using a stirrer or homogenizer to obtain a primary emulsion. As regulating the level of glucose peptide preferably you can use synthetic basis 4.

The addition of an aqueous solution regulating the level of glucose peptide containing surfactant to the polymer solution leads to the formation of microspheres double emulsion of the type water-in-oil-in-water.

In stage 2' in aqueous solution regulating the level of glucose peptide can contain any surfactant, provided that it can dissolve regulating the level of glucose peptide in aqueous solution. Examples of surfactants that are available in the present invention include Tween, Triton, Brij, polyvinylpyrrolidone and polyvinyl alcohol.

The formation of microspheres can be achieved by dispersing the primary emulsion stage 2' in an aqueous solution containing an emulsifier, mixing agitator and the homogenizer and drying. Emulsifier suitable in the present invention, may be a lipophilic emulsifier, dispersible in organic solvents or hydrophilic emulsifier, dispersible in aqueous solvents. Examples of hydrophilic emulsifier include Tween, Triton, Brij, polyvinylpyrrolidone and polyvinyl alcohol, and preferred is polyvinyl alcohol. You can use emulsifier, saturated or unsaturated the organic solvent. Preferred as the organic solvent can be used methylene chloride, ethyl acetate or chloroform, and the most preferred is methylene chloride. The concentration of emulsifier in the aqueous solution is in the range from 0.01 to 5.0% (wt./about.) and preferably from 0.5 to 2% (wt./vol.).

At this stage, you can resort to freeze-drying or vacuum drying. The obtained microspheres can be collected by centrifugation at freeze-drying or by using a system of vacuum filter vacuum drying, before final drying.

Having the advantage that they do not show any initial burst effect or incomplete release, support the release of basis 4 zero order, provide high efficiency of encapsulation due to the simple way of obtaining them and the high stability of encapsulated basis 4 and continuously release from them on the basis of 4in vitroandin vivowithin three weeks or more microspheres obtained in accordance with the present invention is suitable as a means for release of the basis 4 in a controlled manner.

Ways of carrying out the invention

A better understanding of the present invention can be obtained using the following examples, which are listed below to illustrate, but which shall not be construed as limiting the present invention.

EXAMPLE 1: Obtaining microspheres based on the types of polymers and ratios in the mixture (emulsion of the type oil-in-water)

300 mg of the polymer (Boehringer Ingelheim) was completely dissolved in methylene chloride. This polymer solution was dispersively 9 mg of basis 4 (American Peptide) to obtain the variance of the basis 4. The polymer used, as shown in table 1, consisted of a single polymer product or a mixture of two different polymer products in different ratios in the mixture. For each of the dispersions of drugs, which are distinguished by the type of polymer and its proportion in the mixture, was added methyl alcohol in a specified number (dispersion alcohol:drug 1:4.about.) obtaining solutions with dispersed them in medicine. 10 ml of each solution with dispersed therein drug was emulsiable with 250 ml of 1% aqueous solution saturated with methylene chloride polyvinyl alcohol (wt./about.) using a mixer or homogenizer to form microspheres. As the methylene chloride was allowed to slowly evaporate in the air by stirring at room temperature for several hours under atmospheric pressure, hardened microspheres. After centrifugation thus collected microspheres were washed with distilled water, zamorajivanie -70°C and subjected to freeze-drying at room temperature under 50 mtorr within 3 days of using the device for freeze-drying Advantage (VirTis, NY, U.S.A.) to produce microspheres of the type oil-in-water, which can unleash on the basis of 4 in a controlled manner.

TABLE 1
ExamplesOn the basis of 4 (mg)The polymer (mg)The type of polymerThe ratio for mixing
1-1RG502H1
1-2RG502H:R2029010
1-3RG502H:R2028020
1-49300RG502H:RG5029010
1-5RG502H:RG50280 20
1-6RG502H:RG5039010
1-7RG502H:RG5038020

EXAMPLE 2: Obtain microspheres with regard to the relationship of alcohol and dispersion of the medicinal product (emulsion of the type oil-in-water)

300 mg of the polymer (RG502H, Boehringer Ingelheim) was completely dissolved in methylene chloride. This polymer solution was dispersively 9 mg of basis 4 (American Peptide) to obtain the variance of the basis 4. To the dispersion of medicines has added the specified amount of methyl alcohol (variance alcohol:drug: 1:1-1:7.vol.), as shown in table 2, to obtain solutions with dispersed them in medicine. They were emulsiable and dried as in example 1 to obtain microspheres.

TABLE 2
ExamplesMeOH (vol.)The variance of the basis 4 (vol.)The state of the solution with dispersed therein medication
2-111Solution
2-22Solution
2-33Solution
1-14Solution
2-45Solution
2-56Solution
2-67Variance

As shown in table 2, the solution is not formed, when the volume ratio of the variance of the medicinal product and methyl alcohol was 7 or more.

EXAMPLE 3: Obtaining microspheres from a solution with dispersed therein medicinal product containing the additive (emulsion of the type oil-in-water)

Microspheres were obtained analogously to example 1-1, except that a solution of dispersed therein medicines mixed various additives in an amount of 0.1 or 12,5% vol. the solvent. Table 3 summarises the additive and about.%, mixed with RA is tworoom.

TABLE 3
ExamplesOn the basis of 4 (mg)The polymer (mg)SupplementsMixing
93000,1%12,5%
3-1Solutol HS-15oo
3-2TPGSoo
3-3Gelucireaboutabout
3-4Labrafiloo
3-5Labrasoloo
3-6The medium-chain triglycerideoo
3-7 Lecithinoo
3-8N-organicoo
3-9Polyvinylpyrrolidoneoo
3-10Hydroxypropylmethyl-celluloseoo
3-11Tweenoo
3-12Spanoo
3-13Cremophoroo
3-14Poloxameroo
3-15Brijoo
3-16Sunsoft 818H oo

As shown in FIG. 3, with a solution dispersed therein drugs can mix various additives in a wide range of concentrations.

EXAMPLE 4: Obtaining microspheres from aqueous solution of the emulsifier, unsaturated organic solvent (emulsion of the type oil-in-water)

Microspheres were obtained analogously to example 1-1, except that a solution with dispersed therein drug was added to 250 ml of 1% aqueous solution of polyvinyl alcohol 1% (wt./vol.), unsaturated methylene chloride and emulsified using a stirrer or homogenizer.

EXAMPLE 5: Obtain microspheres with different sizes of particles (emulsion of the type oil-in-water)

Microspheres were obtained analogously to example 1-1, except that the volume ratio of saturated 1% aqueous solution of methylene chloride polyvinyl alcohol (wt./about.) and the solution dispersed therein medicinal product, i.e. the volume ratio of aqueous phase and oil phase were as shown in table 4.

TABLE 4
ExamplesOn the basis of 4 (mg)The polymer (mg)Water f is for:oil phase (about./about.)
5-193001:15
5-21:30
5-31:60

EXAMPLE 6: Obtaining microspheres based on the drying of emulsion oil-in-water)

Microspheres, hardened after the gradual evaporation of the methylene chloride by stirring at room temperature under atmospheric pressure for several hours, as in example 1-1, was filtered through a vacuum filter, washed with distilled water and obezvozhivani before final drying at room temperature under a pressure of 50 mtorr within 3 days of using the device for drying Advantage (VirTis, NY, U.S.A.).

EXAMPLE 7: Obtain microspheres using spray drying the emulsion of the type oil-in-water)

A solution with dispersed therein medicinal product obtained in example 1-1, was mixed with an aqueous solution of emulsifier, and were injected with speed of 2.5 ml / min in a device for spray drying (spray drying Buchi Mini B-290) when sprayed at the rate of 400 nl/h through a nozzle size of 0.7 mm thus Obtained microspheres were dried in vacuum to obtain micro dosing is fer, of which can continuously be released on the basis of 4. The temperature of the device for spray drying was set at 120+2°C at the inlet and 85+2°C at the exit.

EXAMPLE 8: Obtaining microspheres using an aqueous solution of a medicinal product (emulsion of the type water-in-oil-in-water)

300 mg of the polymer (RG502H, Boehringer Ingelheim) was completely dissolved in methylene chloride. To this polymer solution was added an aqueous solution of the basis 4 obtained by dissolving 9 mg of basis 4 (American Peptide) in 0.3 ml of 0.5% aqueous solution of polyvinyl alcohol (wt./vol.), and then stirred using a homogenizer to obtain a primary emulsion. 10 ml of the primary emulsion was emulsiable with 250 ml saturated with methylene chloride 1% aqueous solution of polyvinyl alcohol 1% (wt./about.) using a mixer or homogenizer to form microspheres. As the methylene chloride was allowed to slowly evaporate in the air by stirring at room temperature for several hours under atmospheric pressure, hardened microspheres. After centrifugation thus collected microspheres were washed with distilled water, frozen at -70°C and subjected to freeze-drying at room temperature under 50 mtorr within 3 days of using the device for freeze-drying Advantage (VirTis, NY, U.S.A.) with what rucenim microspheres of the type water-in-oil-in-water, who can unleash the basis of 4 in a controlled manner.

COMPARATIVE EXAMPLE 1:

Obtain microspheres of the type oil-in-water process dispersion of the medicinal product (1)

To a solution of 300 mg of the polymer (RG502H, Boehringer Ingelheim) in methylene chloride was added methyl alcohol in an amount corresponding to one-fourth volume of methylene chloride, to obtain the polymer solution/methylene chloride/methyl alcohol. On the basis of 4 were mixed in the ratio of 9:300 basis 4:polymer (wt./wt.) with a solution of the polymer/methylene chloride/methyl alcohol to obtain a solution with dispersed therein medicinal product without the process of dispersion of the drug. Microspheres were obtained from a solution with dispersed therein drug analogously to example 1.

COMPARATIVE EXAMPLE 2: Obtain microspheres of the type oil-in-water process dispersion of the medicinal product (2)

Microspheres were obtained analogously to example 1, except that a solution of 9 mg of basis 4 in 0.2 ml of methyl alcohol was added to a solution of 300 mg of the polymer (RG502H, Boehringer Ingelheim) in 0.8 ml of methylene chloride to obtain a solution with dispersed therein medicinal product without the process of dispersion of the drug.

EXPERIMENTAL EXAMPLE 1: the Efficiency of encapsulation of the basis 4 in which crosfire

30 mg all of microspheres with basis 4 encapsulated in them, obtained according to examples 1 and 4-8, sufficiently dissolved in 0.5 ml DMSO in containers made of polystyrene and added to 1.5 ml of distilled water, and then was stirred for 12 hours or more for the extraction of basis 4 as the aqueous phase. Extracted on the basis of 4 quantitatively analyzed to calculate the efficiency of encapsulation, which is expressed as a percentage of the true value of the encapsulation to theoretical value of the encapsulate.

The calculations are summarized in table 5.

TABLE 5
ExamplesThe efficiency of encapsulation (%)
1-185
1-286
1-388
1-481
1-583
1-684
1-780
484
5-185
5-285
5-384
685
793
883

As shown in table 5, the calculated encapsulation efficiency of the microspheres obtained in accordance with the present invention, was 80% or more.

EXPERIMENTAL EXAMPLE 2: Measurement of average particle size of the microspheres

30 mg of microspheres with encapsulated them in a basis-4 obtained in examples 1 and 4-8, dispersible in 1 l of distilled water containing Tween 20 in the amount of 0.02% (vol./vol.), and then measured the average particle size using the device for analysis of particle size. The measurement results are presented in table 6.

TABLE 6
ExamplesThe average particle size (µm)
1-122
1-216
1-318
1-416
1-519
1-622
1-721
426
5-18
5-225
5-365
621
759
816

As shown in table 6, the size of the microspheres obtained in accordance with the present invention, is in the range, the average particle size of from 8 to 65 μm, which is small enough to use needles of small size.

EXPERIMENTAL EXAMPLE 3: the Release of drug from microspheresin vitro

The microspheres obtained according to examples and comparative examples were evaluated in relation to the release of basis 4in vitroin the following conditions.

30 mg of microspheres placed in a container made of polystyrene, was dispersible in 1.5 ml PBS (phosphate-saline buffer, pH 7,4)containing Tween 20 in number is the amount of 0.02% (vol./vol.). During incubation at 37°C. the dispersion was centrifuged in accordance with the incubation time for the deposition of microspheres. To determine the number of basis 4 released from the microspheres, the supernatant was analyzed on the level of basis 4. Precipitated microspheres was again dispersible in fresh PBS for subsequent experiments on the analysis. In FIG. 1 through 3 release (%) of the basis 4 of microspheres plotted on a graph against time of incubation.

In FIG. 1 and 2 presents the number of basis 4 released over timein vitrofrom the microspheres obtained by the process of dispersion of basis in accordance with the present invention of examples 1 and 4-8, and FIG. 3 shows the number of basis 4 releasedin vitroover time of the microspheres obtained in comparative examples 1 and 2, when the dispersion of the basis was excluded.

As is evident from the graphs of FIG. 1 and 2, the microspheres obtained by a process of dispersion of basis in accordance with the present invention, does not show any initial burst release (3% of the basis 4 is released during the first day)or incomplete release with maintenance release zero order within 21 days. In contrast, as seen in FIG. 3, the microspheres obtained without the process, the dispersion of the basis, showed incomplete release, and 21 days was released only 83% (comparative example 1) and 49% (comparative example 2).

Thus, containing the basis 4 of the microspheres obtained in accordance with the present invention, showed no initial burst release or partial release, but retained the release of basis 4 zero order within three weeks, and thus they can be used effectively as a means for sustained release of basis 4.

EXPERIMENTAL EXAMPLE 4: Pharmacokinetic evaluation of microspheres

The following conditions microspheres obtained in examples and comparative examples were evaluated in relation to the release of basis 4in vivoand pharmacokinetic properties.

A specified number of microspheres obtained according to examples 1 and 4 to 8 and comparative examples 1 and 2 (corresponding to 140 µg basis 4), suspended in an aqueous solution, containing 1.5% CMC, 0.5% of Tween 20 and 0.9% NaCl, followed by subcutaneous injection of a suspension at a dose of 0.2 ml each of the five rats Sprague-Dawley. Then samples were collected the blood of rats with predetermined intervals and quantitatively analyzed on the level of basis-4 using ELISA to determine the release from microspheres of basis 4. In FIG. 4 shows a curve of the release ofin vivo of the basis 4 of the microspheres, obtained in example 1-1.

As is evident from the release curve of FIG. 4, the microspheres obtained in accordance with the present invention, does not show any initial burst release or partial release, but keep in experimental animals release zero order within 20 days, as in experimentin vitro.

Also from the results of measurement of the release of the basis 4 was calculated pharmacokinetic parameters, the maximum blood concentration (Cmax) and AUCAbout-14dusing WinNonlin, and they are summarized in table 7.

TABLE 7
ExamplesCmax(ng/ml)AUC0-14d(day*ng/ml/mg/kg)
1-11,92±0,3011,85±0,30
1-22,78±0,699,29±C,57
1-31,33±0,209,24±0,76
1-41,18±0,129,63±1,08
1-51,04±0,13 8,98±0,62
1-6of 2.26±0,379,92±0,81
1-7was 4.02±0,159,31±0,67
41,91±0,11a 12.05±0,78
5-13,13±0,319,74±1,08
5-21,31±0,1112,01±0,11
5-31,29±0,1011,07±0,91
62,05+0,3310,84±0,78
71,67±0,278,31±0,27
83,28±0,429,40±0,58
C. 10,94±0,17of 5.34±0,61
C. 20,85±0,245,07±0,20

As shown in table 7, it was calculated that the values of Cmaxand AUC for all microspheres of examples 1-1 through 1-7, 4, 5-1 through 5-3 and 6 through 8 were higher than the values for comparative examples 1 and 2, stokesay, the microspheres obtained in accordance with the present invention, are excellent means for a controlled release of basis 4.

Therefore, based on the data of FIG. 4 and table 7, the present invention relates to byroslawsky polymeric microspheres, which are excellent not only from the point of view of efficiency of encapsulation, but also can continuously release on the basis of 4 within 2 to 4 weeks to complete without a lag-phase.

EXPERIMENTAL EXAMPLE 5: analysis of the stability of the basis 4 the microspheres

10 mg contains the basis 4 of the microspheres obtained in example 1-1 was placed in a container made of polystyrene and sufficiently dissolved in 1 ml DMSO. The resulting solution was diluted five times with ammonium bicarbonate, and then carried out by reversed-phase high-performance liquid chromatography (RP-HPLC) to identify the peaks and retention time of basis 4. The results are presented in FIG. 5.

In FIG. 5 shows a chromatogram of basis-4, obtained from the microspheres produced in example 1-1. As can be seen in the chromatogram, observed one peak, and the retention time was the same as for the control.

1. A method of producing microspheres biorazlagaemykh polymer, including:
adding organic solvent to the polymer to obtain a solution of polim the RA (stage 1);
the dispersion regulating the glucose levels of the peptide in the polymer solution phase 1 to obtain a dispersion of a drug and mixing of alcohol or mixture of alcohol and organic acids with dispersion medicines with obtaining a solution with dispersed therein medicinal product (stage 2); and obtaining microspheres from a solution with dispersed therein drug stage 2 (stage 3), which regulates the level of glucose peptide represents the basis 4 and where the biodegradable polymer is selected from the group consisting of poly-L-lactic acid, copolymer of D-lactic acid and glycolic acid, copolymer of L-lactic acid and glycolic acid copolymer,L-lactic acid and glycolic acid.

2. The method according to claim 1, where the organic solvent is selected from the group consisting of methylene chloride, ethyl acetate and chloroform.

3. The method according to claim 1 where the alcohol stage 2 represents methyl alcohol.

4. The method according to claim 1 where the alcohol stage 2 is used in a ratio of alcohol: a solution of the polymer is 1:1-1:6.

5. The method according to claim 1, further comprising an additive to the solution dispersed therein drugs stage 2.

6. The method according to claim 5, where the additive is selected from the group consisting of polyethylene glycol, Labrafll, Labrasol, medium-chain triglyceride, lecithin, N-methylpyrrolidone, the floor is vinylpyrrolidone, hydroxypropylmethylcellulose, Tween, Span, Cremophor, Poloxamer, Brij and Sunsoft 818H.

7. The method according to claim 5, where the additive is used in amounts of from 0.01 to 15% (wt./about.) from the volume of the solution.

8. The method according to claim 1, where the stage 3 is carried out by dispersing solution with dispersed therein drug stage 2 in an aqueous solution containing an emulsifier, the formation of microspheres using a stirrer or homogenizer, and drying the microspheres by freeze drying or vacuum drying.

9. The method of claim 8, where the emulsifier is selected from the group consisting of Triton, Brij, polyvinylpyrrolidone and polyvinyl alcohol

10. The method of claim 8, where the emulsifier is saturated in an organic solvent selected from the group consisting of methylene chloride, ethyl acetate and chloroform.

11. The method according to claim 1, where the stage 3 is carried out by spraying a solution with dispersed therein drug stage 2 using the device for spray drying.

12. The method according to claim 11, where the device for spray drying is set to the temperature of 115-125°C to inbound it flow and temperature of 80-90°C for coming out of the stream.

13. The method according to claim 11, where spray drying is carried out after an additional freeze-drying or vacuum drying.



 

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13 cl, 65 tbl, 712 ex

FIELD: chemistry.

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4 cl, 4 dwg, 1 tbl, 29 ex

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23 cl, 6 ex, 7 dwg

FIELD: medicine.

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19 cl, 1 ex, 3 dwg, 3 tbl

FIELD: medicine.

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1 ex, 3 tbl

FIELD: medicine.

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68 cl, 34 dwg, 38 tbl

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6 cl, 3 tbl, 23 ex

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17 cl, 1 dwg, 2 tbl, 3 ex

FIELD: medicine, pharmaceutics.

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31 cl, 4 ex

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34 cl, 9 tbl, 2 dwg, 6 ex

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22 cl, 3 tbl, 1 ex

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6 cl, 4 dwg, 3 tbl, 6 ex

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30 cl, 7 dwg, 17ex

FIELD: medicine, pharmaceutics.

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29 cl, 19 ex, 8 tbl

FIELD: medicine, veterinary science.

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8 cl, 2 tbl, 38 ex

FIELD: medicine, pharmaceutics.

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EFFECT: rasagiline tablets under the invention are characterised by low fragility, sufficient hardness and quickly degrade in mouth cavity, eg for 50-90 seconds.

58 cl, 2 tbl, 7 ex

FIELD: medicine.

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6 cl, 2 dwg, 2 tbl

FIELD: medicine.

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32 cl, 9 ex

FIELD: medicine.

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EFFECT: according to the invention the composition is characterised by prolonged release of gindarine from oral dosage capsular form.

10 cl, 18 ex

FIELD: medicine, pharmaceutics.

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EFFECT: reduced contamination of the injection devices during injection.

23 cl, 6 ex, 7 dwg

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