KR101583351B1 - Sustained-release microspheres enhancing removal rate of residual solvent and method of manufacturing thereof - Google Patents

Abstract

The present invention relates to a manufacturing method of sustained-release microspheres capable of continuously controlling a release of a drug and, more particularly, to a manufacturing method of sustained-release microspheres capable of suppressing initial excessive release of a bioactive substance and remarkably enhancing the removal of a residual solvent by additionally employing an initial recovery process to a solvent exchange evaporation method using a cosolvent for manufacturing microspheres, wherein a drug is encapsulated in a carrier made of a biocompatible polymer. The manufacturing method of the sustained-release microspheres comprises: a step of separately dissolving a bioactive drug or a biocompatible polymer in an organic solvent; a step of mixing the dissolved bioactive drug solution and the biocompatible polymer solution; a step of agitating the mixture of the solutions of the bioactive drug and the biocompatible polymer after putting the mixture into an aqueous medium; and a step of cleansing microspheres after performing the initial recovery process of the microspheres within 0 to 60 minutes after the agitation.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a sustained-release microparticle having improved initial release inhibition and residual solvent removal rate,

The present invention relates to a method for producing sustained-release microparticles capable of continuously controlling drug release, and more particularly, to a method for preparing microparticles containing a drug in a carrier made of a biodegradable polymer by solvent evaporation using a co- To a method for producing a sustained-release microparticle in which not only an initial excessive release of a physiologically active substance is inhibited but also a residual solvent removal rate is remarkably increased.

Conventionally, common production methods of sustained release injectable preparations are known, such as a coacervation method, a melt extrusion method, a spray drying method, and a solvent evaporation method. Among these methods, the solvent evaporation method, which is classified into the dual oil evaporation method (W / O / W; water / oil / water) and the single oil evaporation method (o / w; oil / water)

Many of these sustained-release injectable preparations have been attempted to produce microparticles with increased drug encapsulation, easy manufacturing processes and relatively low initial over-release. According to Korean Patent No. 0566573, biodegradable polymers And a method of preparing microparticles by dissolving a drug in a solvent, spraying the solution at a constant flow rate using a spray drying method, and drying under reduced pressure. However, this manufacturing method has disadvantages of not only an initial excessive discharge shortage of the physiologically active substance but also the cost of installing the expensive spray dryer and the aseptic treatment of the facilities.

Korean Patent Registration No. 0994658 discloses a manufacturing method for improving the dispersibility of the microspheres by injecting more drugs into the microspheres using the osmotic pressure regulator in the step of preparing the microspheres using the solvent evaporation method. However, the inclusion of more drug increases the amount of drug distributed on the surface, leaving the disadvantages of initial overdose still.

Korean Patent No. 0409413 discloses a method for producing microspheres by an underwater drying method and then heating and drying the biodegradable polymer at a temperature higher than the glass transition temperature (Tg) of the biodegradable polymer to significantly suppress the initial overdischarge and minimize the organic solvent. The method has the disadvantage that the physiologically active substance can be denatured by heat.

U.S. Pat. No. 5,366,734 discloses a method for preparing an agent that mixes drugs in a biodegradable polymer, solidifies it into an implant form, and coating the exterior to lower initial overdischarge. However, since such an implant is too large in size, The size of the needle of the syringe must be enlarged in order to make the patient feel panic, and local anesthesia must be performed due to the pain.

Disclosure of Invention Technical Problem [8] Accordingly, the present invention has been made keeping in mind the above problems occurring in the prior art, and an object of the present invention is to provide a sustained-release microparticle having excellent characteristics, which suppresses initial excessive release of physiologically active substance, And a method for producing the same.

Hereinafter, various embodiments described herein will be described with reference to the drawings. In the following description, for purposes of complete understanding of the present invention, various specific details are set forth, such as specific forms, compositions and processes, and the like. However, certain embodiments may be practiced without one or more of these specific details, or with other known methods and forms. In other instances, well-known processes and techniques of manufacture are not described in any detail, in order not to unnecessarily obscure the present invention. Reference throughout this specification to "one embodiment" or "embodiment" means that a particular feature, form, composition, or characteristic described in connection with the embodiment is included in at least one embodiment of the invention. Accordingly, the appearances of the phrase " in one embodiment "or" an embodiment "in various places throughout this specification are not necessarily indicative of the same embodiment of the present invention. In addition, a particular feature, form, composition, or characteristic may be combined in any suitable manner in one or more embodiments.

Unless defined otherwise in the specification, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

In one embodiment of the present invention, a "physiologically active drug" is a biologically effective drug including, but not limited to, drugs for the treatment of hepatitis B virus infection such as lamivudine, adefovir, entecavir . In addition, risperidone, paliperidone, aripiprazole, olanzapine and neuroleptic; A gastrointestinal therapeutic agent such as aluminum hydroxide, calcium carbonate, magnesium carbonate, sodium carbonate and the like; Nonsteroidal contraceptive pill: Parasympathetic stimulant; Antipsychotic drugs such as haloperidol, bromperidol, fluphenazine, sulpiride, caripipramine, clocapramine, mosapramine, olanzapine, and sertindole; Chiropragmine HCL, clozapine, mezzanine, methiapine, leisure pin, thioridazine and the like; A psychostabilizer such as chlorodiaxanthide, diazepam, meflobamate, and themejem; Non-scientific (nasal) decongestants; Hypnotic sedatives such as codeine, phenobarbital, sodium pentobarbital, and sodium secobarbital; Steroids such as testosterone and testosterone propionate; Sulfonamide; Sympathetic excitement drug: vaccine; Vitamins and nutrients such as essential amino acids and essential fatty acids; Antimalaria agents such as 4-aminoquinoline, 8-aminoquinoline, and pyrimethamine; Anti-migraine agents such as marginal stone, penttermin, and sumatriptan; A therapeutic agent for Parkinson's disease such as L-dopa; Antipyretics such as atropine, metscopolamine bromide and the like; Anticholinergic drugs such as anti-inflammatory drugs, digestive drugs and enzymes; Jinhae medicines such as dextromethorphan and noscapine; Bronchodilators; Cardiovascular agents such as hypertension therapeutic compounds, Rauwolfia alkaloids, coronary vasodilators, nitroglycerin, organic compounds, pentaerythritol tetranitrate; Electrolyte replacement therapy such as potassium chloride; Ergot alkaloids such as caffeine-free or ergotamine, hydrated ergot alkaloids, dihydroergocristine methanesulfate, dihydroergone cornine methanesulfonate, dihydroergarko-tripeptide methanesulfate, and combinations thereof; Alkaloids such as atropine sulfate, belladonas, and hyosine hydrobromide; Analgesic medicine; Anesthetics such as codeine, dihydrocodeineone, mepiridine, morpholine and the like; Non-narcotic such as salicylate, aspirin, acetaminophen, d-proxiphen, etc .; Antibiotics such as cephalosporin, chloramphenicol, gentamicin, kanamycin A, kanamycin B, penicillin, ampicillin, streptomycin A, antimycin A, chlorophenthanol, metromidazole, oxytetracycline penicillin G, tetracycline ; Anticancer agents; Antipyretics such as mefenitone, phenobarbital and trimetadione; Anti-histamines such as chlorpinazine, dimehydrinate, diphenhydramine, perphenazine, and tripelenamine; Anti-inflammatory agents such as hormone preparations, hydrocortisone prednisolone, prednisone, non-hormone preparations, allopurinol, aspirin, indomethacin, phenylbutazone and the like; Cytotoxic agents such as prostaglandins, thiotepa, chlorambucil, cyclophosphamide, melaran, nitrogen mustard, methotrexate and the like; Nessseria gonarrhea, Micobacterium tuberculosis, Herpes virus (Humonis, types 1 and 2), Candida albicans, Candida albicans (Candida albicans), Candida albicans Candida tropicalis, Trichomonas vaginalis, Haemophilus vaginalis, Streptococcus ecoli, Micoplasma hominis, Hemophilus doublecray, Hemophilus ducreyi, Granuloma inguinale, Lymphopathia venereum, Trepone mapallidum, Brucella abortus, Brucella melitensis, Brucella melitensis, Brucella suis, Brucella canis, Campylobacter pterus, Campylobacter pterus testinis, Leptospira pomona, Listeria Brucella ovis, Equine Herpes virus, horse arthritis virus, IBR-IBP virus, BVD-MB virus, Clamydia psittaci, Tricomonas spp., Tricomonas spp. for example, yeast extract, Foetus, Toxoplasma gondii, Escherichia coli, Actinobacillus equuli, Salmonella abortusovis, Salmonella abortus equi, Pseudomonas aeruginosa, But are not limited to, Corynebacterium equi, Corynebacterium pyogenes, Actinobaccilus seminis, Mycoplasma bovigentium, Aspergillus fumigatus, Absidia ramosa, Trypanosoma equiperdum, Barbesia cavalli, Clostridium tetani, etc. Water antigen; An antibody that neutralizes the microorganisms, a ribonuclease, a neuraminidase, a trypsin, a glucocogenphosphorylase, a sperm lactdehydegenase, a sperm hyaluronidase, an adenosine triphosphatase, an alkaline phosphatase, But are not limited to, an enzyme, an enzyme, an enzyme, an enzyme, an enzyme, an alkaline phosphatase, an aminopeptidase, trypsin, chymotrypsin, amylase, muramadinease, acrosomal proteinase, diesterase, glutamate dehydrogenase, Enzymes such as glycosphosphatase, lipase, ATP-aza alpha peptate gamma glutamyl transpeptidase, sterol-3-beta-all-dehydrogenase and DPN-di-aflorease, diethylstilbestrol, Estrogen such as 17-beta-estradiol, estrone, ethidyl estradiol, mestanol; But are not limited to, norepinephrine, norethindrone, norgestrel, ethynodiol diacetate, linestrenol, medroxyprogesterone acetate, dimestysterone, megestroate, acetate, chlormadinone acetate, nogeustimate, , Progesterone such as melengesterol, norethynol; And sanitizer compounds such as nonylphenoxy polyoxyethylene glycol, benzethonium chloride, chlorindanol, and the like.

In one embodiment of the invention, "microparticles" or "microparticles" are solid particles dispersed or dissolved in biodegradable, biocompatible polymers that act as matrix particles and include solid particles comprising the active agent. As the sustained-release preparation, the size of the microspheres is preferably 10 nm-1 mm, more preferably 10-200 m.

In one embodiment of the present invention, "biocompatibility" means that the related substance is not toxic to the body, is pharmaceutically acceptable, is not carcinogenic, and does not significantly cause inflammation in body tissues. Thus, a "biocompatible polymer" refers to, for example but not limited to, polylactide, polyglycolide, poly (lactide-co-glycolide) and poly (lactide-co-glycolide) glucose. In the present invention, the proportion of the poly (lactide glycolide) copolymer of the biocompatible polymer may be 50:50 to 95: 5. For example, Resomer RG502H, RG503H, RG504H, RG752H, RG752S, RG753S, RG755S, RG756S, RG757S, RG858S, R202H, R203H, R207H or 5050 DLG, 6535 DLG, 7525 DLG, 8515 DLG from Lakeshare Co., , 955 LDG, and the like.

In one embodiment of the invention, "Entecavir" refers to 2-amino-1,9-dihydro-9 - [(1S, 3R, 4S) -4- hydroxy- 4-hydroxy-3- (hydroxymethyl) -2-methylenecyclopentyl] -6H-pyrrolo [ -purin-6-one, which is known as a therapeutic agent for chronic hepatitis B virus having selective activity against type B herpes virus. Entecavir is a known substance disclosed in US Pat. No. 5,206,244, its preparation method and medicinal use, and has obtained permission from the US FDA for tablets and liquid preparations. Patients with chronic hepatitis B should take entecavir every day for a lifetime, although the bioavailability at oral administration is close to 100%, but the absorption rate is lowered by diet, so it is inconvenient to take oral 2 hours before meals. Prescription patterns of currently available entecavir oral formulations prescribe about 1-3 months for the first 1-2 years, and after 6 months stabilization of HBV, it is common to prescribe 6 months. In the first patient treated in this manner, approximately 70% of patients are undetectable after 1 year of treatment and undetectable at 90% of patients after 3 years. Thus, long-term use of entecavir is necessary for the treatment of HBV infection, and there is a disadvantage that adherence to daily administration of the entecavir is lowered, necessitating a slow release preparation.

In one embodiment of the present invention, "alkyl halide" refers to a compound in which one or more halogen atoms are bonded to an alkyl group. The most representative example is methylene chloride.

In one embodiment of the present invention, "sulfoxide" refers to a chemical form of the R ₂ SO form wherein the number of bonds of sulfur is three. The most typical examples are dimethyl sulfoxide (DMSO) and the like.

In one embodiment of the present invention, there is provided a method for producing a biocompatible polymer, comprising dissolving a physiologically active agent or a biocompatible polymer in an organic solvent, respectively; Mixing the physiologically active agent solution and the biocompatible polymer solution and stirring the mixture; Introducing the mixture into an aqueous medium to form an emulsion; The present invention also provides a method for producing sustained-release microparticles comprising the steps of: (a) preparing a sustained-release microparticle, which is dissolved in an alkyl halide and is dissolved in a sulfoxide, Wherein the alkyl halide is methylene chloride, wherein the sulfoxide is dimethylsulfoxide, and after the washing step, the aqueous solution of 15-20 mu m Wherein the microparticles have a particle size in the range of 10 m to 200 m, wherein the microparticles are washed with water for injection or with a surfactant. Wherein the surfactant is a solution containing the surfactant Wherein the physiologically active agent is at least one selected from the group consisting of polysorbate, polysorbate, sponge, poloxamer, polyethylene glycol and tocopherol, wherein the physiologically active agent is selected from the group consisting of growth hormone, erythropoietin, An insulin-like growth factor, an epithelial growth factor, a platelet-derived growth factor, a fibroblast growth factor, a metastatic growth factor, an interferon, an interleukin, an interferon, and an interleukin , Tumor necrosis factor, streptokinase, eukaryotic agent, staphylokinase, diene AIDS, glucocerebrosidase, alpha galactosidase, exenatide, octreotide, insulin, glucagon, luteinizing hormone secretion hormone, Goserelin, leuprorelin, follicle stimulating hormone, thyroid stimulating hormone Corticotropin Releasing Factor, Brain Natriuretic Peptide, Thymopentin, Corticotropin, Elcato, Fertilene, Calcitonin, Corticotropin Releasing Factor, The compounds of the present invention may be selected from the group consisting of Elcatonin, Beta Amyloid, Triptorelin, Buserelin, Thymosin, Somatostatin, Alarelin, Angiotensin, Such as Argipressin, Atosiban, Bivalirudin, Cetrorelix, Deslorelin, Desmopressin, Elcatonin, Enfuviride, (S) selected from the group consisting of Enfuvirtide, Eptifibatide, GLP-1, Gonandorelin, Lyspressin, Nafarelin, Nesiritide, Oxytocin, Pramlintide, Secretin, Teriparatide, Wherein the sustained release microparticle is at least one selected from the group consisting of Terlipressin, Tetracosactide, Vapreotide, paclitaxel, and sirolimus, wherein the physiological activity Wherein the drug is any one selected from the group consisting of entecavir, donepezil, lamivudine, risperidone and paliperidone, wherein the biocompatible polymer is selected from the group consisting of polylactide, polyglycolide, poly (lactide-co (Lactide-co-glycolide) and poly (lactide-co-glycolide) glucose. The present invention also provides a method for producing sustained-release microparticles.

In another embodiment of the present invention, there is provided a sustained-release microparticle comprising a physiologically active agent and a biocompatible polymer, wherein the physiologically active agent and the biocompatible polymer mixture are washed and then volatilized, wherein the physiologically active agent is not dissolved in the alkyl halide Wherein said sulfide provides a sustained release micropart that is soluble in sulfoxide and wherein said alkyl halide provides a sustained release microsphere that is methylene chloride and wherein said sulfoxide provides a sustained release microsphere that is dimethylsulfoxide, Wherein the surfactant is at least one selected from the group consisting of polysorbate, sponge, poloxamer, polyethylene glycol and tocopherol, wherein the surfactant is a solution containing water for injection or a surfactant. And the particle size of the microspheres is within 10 [mu] m Wherein the physiologically active agent is selected from the group consisting of growth hormone, erythropoietin, monoclonal antibody, granulocyte colony stimulating factor, macrophage colony stimulating factor, granulocyte macrophage colony stimulating factor, strombopoietin, insulin A proliferative growth factor, an interferon, an interferon, a tumor necrosis factor, a streptokinase, an europinicin, a staphylokinase, a diene AIDS, glucocerebrosidase, Gonadotropins, alpha glutamate, alpha glutamate, alpha glutamate, alpha glutamate, alpha glutamate, alpha glutathione, alpha glutocytase, exenatide, octreotide, insulin, glucagon, luteinizing hormone secretion hormone, goserelin, leuprorelin, follicle stimulating hormone, , Calcitonin, Corticotropin Releasing Factor, Brain Natriureti Peptide (Brain Natriureti c peptide, thymopentin, corticotropin, elcatonin, beta amyloid, tryptorelin, buserelin, thymosin, Somatostatin, Alarelin, Angiotensin, Argipressin, Atosiban, Bivalirudin, Cetrorelix, Deslorelin, , Desmopressin, Elcatonin, Enfuvirtide, Eptifibatide, GLP-1, Gonandorelin, Lyspressin, Nafirelin, Nesiritide, Oxytocin, Pramlintide, Secretin, Teriparatide, Terlipressin, Tetracosaccharide, Tetracycline, One selected from the group consisting of Vapreotide, paclitaxel, and sirolimus Wherein the physiologically active agent is a sustained-release microparticle selected from the group consisting of entecavir, donepezil, lamivudine, risperidone, and paliperidone, wherein the content of the physiologically active agent is Wherein the biocompatible polymer is selected from the group consisting of polylactide, polyglycolide, poly (lactide-co-glycolide) and poly (lactide-co-glycolide) Wherein the biocompatible polymer provides a sustained release microparticle having a ratio of polylactide and polyglycolide of 50:50 to 95: 5. The present invention also provides a sustained release microparticle comprising the biodegradable polymer.

In another embodiment of the present invention, there is provided a pharmaceutical composition comprising one or more sustained release microspheres.

In another embodiment of the present invention, there is provided an injection comprising one or more of the sustained-release microparticles.

Hereinafter, the present invention will be described in detail.

In the production of microparticles containing physiologically active agents, the technique of controlling the release of the drug and the technique of removing the residual solution are important factors. The sustained-release microparticles of the present invention are expected to greatly utilize the microparticles containing various physiologically active agents since they effectively remove the residual solvent by controlling the initial release of the physiologically active drug and applying the initial recovery and washing method during the manufacturing process .

1 is a simplified schematic diagram of an initial post-recovery cleaning process, in accordance with one embodiment of the present invention.

Hereinafter, the present invention will be described in more detail with reference to Examples. It will be apparent to those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .

Example 1: Preparation of microspheres

A biodegradable polymer having a ratio of lactide to glycolides of 75:25 was prepared by dissolving the polymer in a solvent of methylene chloride (Merck) to have a polymer concentration of 13 to 15% (w / w). In addition, entecavir (Estech pharma, Korea) was prepared by dissolving in DMSO (solvent: 3,000) solvent so that 25 to 30% (w / w) was contained in the total solids. Then, to make a mixed solution of biodegradable polymer and entecavir, the solution in which the biodegradable polymer was melted and the solution in which the entecavir dissolved was mixed with each other and then sufficiently stirred.

The mixed solution was added with an aqueous solution of 0.5% polyvinyl alcohol (Mn = 30,000 to 70,000; Sigma) at 20 캜 using an L4R mixer (Silverson, UK) as a water phase to form an emulsion.

The prepared emulsion was initially collected at 0 minute, 15 minutes, 30 minutes, or 60 minutes, washed thoroughly with an injection water, and then subjected to wet filtration with a membrane having a size of 25 mu m and 180 mu m. The collected microspheres were then heated in injection water or 0.5% polyvinyl alcohol solution to 47 ° C, volatilized for 3 hours, cooled to 20 ° C for 1 hour, washed again and filtered. Thereafter, it was freeze-dried and refrigerated (see Fig. 1).

Table 1 shows the preparation conditions of various microparticle preparation examples and comparative examples.

Example 2: Observation of morphology of microspheres

Approximately 10 mg of microspheres were fixed on an aluminum stub and platinum coated for 3 minutes under a vacuum of 0.1 torr and a high voltage (10 kV), and then mounted on a SEM (equipment name: SEC-SNE 3200M mini-SEM) And the surface of the microspheres was observed using an image analysis program (mini-SEM).

Example 3: Particle size measurement

Particle sizes of microspheres were observed by wet method. The particle size was measured using HELOS / KFS (SYMPATEC) equipment, and the SUCELL dispenser was used for the R5 lens. The results of the particle size measurement are shown in Table 2.

Example 4: Residual solvent test of microspheres

About 100 mg of the microspheres were placed in a 10-mL volumetric flask, and dimethylformamide was added thereto. Then, the solution was transferred to a 2 mL vial to prepare a sample solution, and the residual solvent in the microspheres was measured by gas chromatography. The column used was filled with capillary series, and the inner diameter was 30 m × 0.53 mm, the film thickness was 1.0 μm, the injection amount was 1 μl, and the temperature was 250 ° C. using a flame ionization detector. The results are shown in Table 3.

As shown in Table 3, the residual amount of methylene chloride organic solvent in all the microspheres except Comparative Example 3 was found to be similar. However, in the case of the microspheres prepared using the DMSO organic solvent, there was a large difference in the residual amounts of the organic solvents between the preparation microparticles to which the initial recovery process was applied and the comparative microparticles to which the initial recovery process was not applied. The comparative example showed that 5 to 14 times more DMSO remained than in the preparation example. This is due to the surface of the microspheres that have not yet been fully cured during the initial wash, because methylene chloride, which is hydrophobic by the injection water, does not escape externally, but amphibious DMSO exits to the outside.

Also, as shown in Production Examples 3, 4 and 9, the residual amount of DMSO according to the initial recovery solution (injection water or 0.5% polyvinyl alcohol solution) and washing solution (distilled water or 0.5% polyvinyl alcohol) I did. Likewise, as in Production Examples 5, 6 and 7, it was found that the amount of DMSO can be sufficiently removed up to 1 hour depending on the delay time until the initial recovery after stirring.

Finally, when the type of drug was changed (Entecavir -> Donepezil), the application of the initial recovery process had a significant effect on the residual amount of DMSO. These results indicate that applying the initial recovery process to other drugs can significantly reduce the amount of residual solvent.

Example 5: Measurement of entecavir content of microspheres

Approximately 50 mg of the microspheres were placed in a 100 mL flask and dissolved in 20 mL of dimethylsulfoxide (DMSO) to completely dissolve the solution, and the solution was titrated with hydrochloric acid solution (0.01 mol / L). Filtered through a 0.45 mu m syringe filter, used as a sample solution, and the content of entecavir contained in the microspheres was measured using liquid chromatography. At this time, the column used was YMC C18 ODS 5 탆, 4.6 × 150 mm, the injection amount was 10 μl, and the detection wavelength was 254 nm. The mobile phase was measured using water: acetonitrile (92: 8). The measurement results are shown in Table 4.

As shown in Table 4, in each of the same conditions, there was not a large difference in the inclusion rate between the preparation microparticle to which the initial cleaning process was applied and the comparative microparticle to which the initial cleaning process was not applied (Production Example 1 and Comparative Example 1, Production Example 2 and Comparative Example 2, Production Examples 3 to 7 and Comparative Example 3). In addition, the inclusion rate of entecavir was similar even after the initial recovery and the delayed time until the initial recovery after the agitation even when the agitation solution or the 0.5% polyvinyl alcohol solution was used. appear.

Example 6: In vitro dissolution test of microspheres

Approximately 20 mg of each of the microparticles prepared in Production Examples 1 to 4 and Comparative Examples 1 to 3 was placed in a 250 ml aliquot and 200 ml of 0.01% Cetrimonium Bromide eluate was added and incubated at 37 ° C for 3 The supernatant was taken for a certain period of time during the week, and the elution amount of entecavir was measured by liquid chromatography. The measurement results and the graph are shown in Table 5.

As shown in Table 5, in each of the same conditions, the preparation microparticles to which the initial cleaning process was applied showed lower initial release and lower release rates than the comparative microparticles without the initial cleaning process (Production Example 1 And Comparative Example 1, Production Example 2 and Comparative Example 2, Production Examples 3 to 4 and Comparative Example 3). In addition, in the case of using 0.5% polyvinyl alcohol solution as the agitation solution after the initial recovery, as compared with the case of using 0.5% polyvinyl alcohol solution in the case of using the injection water for the initial time, the release rate The difference is small.

Example 7: SD rat pharmacokinetic test of the microparticles

Eight-week old rats (SD rats, male) were used in the post-purification experiment for one week in an animal laboratory. As an entecavir, 7 mg / head / 28 day microspheres were suspended in the injection solution, injected into the right hindlimb muscle of the rat, and then blood was taken from the jugular vein of the rat for a certain period of one month. The amount of entecavir in the blood was measured by separating plasma from the collected blood, and the results are shown in Table 6.

As shown in Table 6, the initial (day 1) drug blood concentrations in the same conditions were significantly lower in the preparative microparticles after the initial recovery than in the comparison without microparticles appear. It is expected that the initial recovery process will lower the initial release of the drug and reduce the side effects.

Claims (25)

Dissolving the physiologically active agent or biocompatible polymer in an organic solvent, respectively;
Mixing a physiologically active drug solution and a biocompatible polymer solution;
Adding a mixture of the physiologically active drug solution and the biocompatible polymer solution to an aqueous medium and stirring the mixture; And
And a step of washing and washing the microparticles after an elapse of 0 to 60 minutes after the agitation.
The method according to claim 1,
Wherein the physiologically active agent is not dissolved in the alkyl halide but dissolved in the sulfoxide.
3. The method of claim 2,
Wherein the alkyl halide is methylene chloride.
3. The method of claim 2,
Wherein the sulfoxide is dimethylsulfoxide.
The method according to claim 1,
Further comprising the step of wet filtration with a sawtooth having a size of 15 [mu] m to 200 [mu] m after the washing step.
The method according to claim 1,
Wherein the particle size of the microspheres is 10 to 200 m.
The method according to claim 1,
Wherein the microparticles are washed with a solution containing water for injection or a surfactant.
8. The method of claim 7,
Wherein the surfactant is at least one selected from the group consisting of polysorbate, span, poloxamer, polyethylene glycol, and tocopherol.
The method according to claim 1,
Biologically active agents include growth hormone, erythropoietin, monoclonal antibody, granulocyte colony stimulating factor, macrophage colony stimulating factor, granulocyte macrophage colony stimulating factor, strombopoietin, insulin like growth factor, epithelial growth factor, platelet derived growth A prodrug, an agent, a fibroblast growth factor, a metastatic growth factor, an interferon, an interleukin, a tumor necrosis factor, a streptokinase, an europinic agent, a staphylokinase, a diene AIDS, a glucocerebrosidase, an alpha galactosidase, (Goserelin), Leuprorelin, follicle stimulating hormone, thyroid stimulating hormone, Fertirelin, Calcitonin, corticotropin releasing factor (FGF), insulin, glucagon, luteinizing hormone releasing hormone, Goserelin, Corticotropin Releasing Factor, Brain Natriuretic Peptide, Thymopentin, Corticotropin, Corticotropin, Elcatonin, Beta Amyloid, Triptorelin, Buserelin, Thymosin, somatostatin, Alarelin, angiotensin Angiotensin, Argipressin, Atosiban, Bivalirudin, Cetrorelix, Deslorelin, Desmopressin, Elcatonin, Elcatonin, Enfuvirtide, Eptifibatide, GLP-1, Gonandorelin, Lyspressin, Nafarelin, Nesiritide, Oxytocin The compounds of the present invention may be used in combination with other therapeutic agents such as oxytocin, Pramlintide, Secretin, Teriparatide, Terlipressin, Tetracosactide, Vapreotide, paclitaxel, Wherein the sustained-release microparticles are at least one selected from the group consisting of mucus, mucus, and mucus.
The method according to claim 1,
Wherein the physiologically active agent is any one selected from the group consisting of entecavir, donepezil, lamivudine, risperidone, and paliperidone.
The method according to claim 1,
Wherein the biocompatible polymer is at least one selected from the group consisting of polylactide, polyglycolide, poly (lactide-co-glycolide) and poly (lactide-co-glycolide) glucose.
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