WO2021091333A1 - 지속 방출을 위한 마이크로스피어 및 이의 제조 방법 - Google Patents
지속 방출을 위한 마이크로스피어 및 이의 제조 방법 Download PDFInfo
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- WO2021091333A1 WO2021091333A1 PCT/KR2020/015565 KR2020015565W WO2021091333A1 WO 2021091333 A1 WO2021091333 A1 WO 2021091333A1 KR 2020015565 W KR2020015565 W KR 2020015565W WO 2021091333 A1 WO2021091333 A1 WO 2021091333A1
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- Prior art keywords
- microspheres
- drug
- continuous phase
- manufacturing
- microsphere
- Prior art date
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- 239000004005 microsphere Substances 0.000 title claims abstract description 142
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 25
- 238000000034 method Methods 0.000 title claims abstract description 21
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 56
- 239000011780 sodium chloride Substances 0.000 claims description 28
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 22
- 150000003839 salts Chemical class 0.000 claims description 18
- 238000002347 injection Methods 0.000 claims description 17
- 239000007924 injection Substances 0.000 claims description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- 239000003960 organic solvent Substances 0.000 claims description 13
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 11
- 229920002988 biodegradable polymer Polymers 0.000 claims description 11
- 239000004621 biodegradable polymer Substances 0.000 claims description 11
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 11
- 229920000747 poly(lactic acid) Polymers 0.000 claims description 10
- 239000001103 potassium chloride Substances 0.000 claims description 10
- 235000011164 potassium chloride Nutrition 0.000 claims description 10
- 238000013268 sustained release Methods 0.000 claims description 10
- 239000012730 sustained-release form Substances 0.000 claims description 10
- 230000000694 effects Effects 0.000 claims description 7
- 239000000839 emulsion Substances 0.000 claims description 7
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 6
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 238000011282 treatment Methods 0.000 claims description 6
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- 229920003169 water-soluble polymer Polymers 0.000 claims description 4
- 206010012289 Dementia Diseases 0.000 claims description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 claims description 3
- 235000019341 magnesium sulphate Nutrition 0.000 claims description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 3
- 235000011152 sodium sulphate Nutrition 0.000 claims description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 2
- 235000019797 dipotassium phosphate Nutrition 0.000 claims description 2
- 229910000396 dipotassium phosphate Inorganic materials 0.000 claims description 2
- 239000002526 disodium citrate Substances 0.000 claims description 2
- 235000019262 disodium citrate Nutrition 0.000 claims description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 2
- 229910000397 disodium phosphate Inorganic materials 0.000 claims description 2
- 235000019800 disodium phosphate Nutrition 0.000 claims description 2
- CEYULKASIQJZGP-UHFFFAOYSA-L disodium;2-(carboxymethyl)-2-hydroxybutanedioate Chemical compound [Na+].[Na+].[O-]C(=O)CC(O)(C(=O)O)CC([O-])=O CEYULKASIQJZGP-UHFFFAOYSA-L 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 229920001983 poloxamer Polymers 0.000 claims description 2
- 229960000502 poloxamer Drugs 0.000 claims description 2
- 229920002432 poly(vinyl methyl ether) polymer Polymers 0.000 claims description 2
- 229950008882 polysorbate Drugs 0.000 claims description 2
- 229940068984 polyvinyl alcohol Drugs 0.000 claims description 2
- 229920001289 polyvinyl ether Polymers 0.000 claims description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 2
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 claims description 2
- 229910052939 potassium sulfate Inorganic materials 0.000 claims description 2
- 235000011151 potassium sulphates Nutrition 0.000 claims description 2
- 239000001509 sodium citrate Substances 0.000 claims description 2
- 229940074404 sodium succinate Drugs 0.000 claims description 2
- ZDQYSKICYIVCPN-UHFFFAOYSA-L sodium succinate (anhydrous) Chemical compound [Na+].[Na+].[O-]C(=O)CCC([O-])=O ZDQYSKICYIVCPN-UHFFFAOYSA-L 0.000 claims description 2
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 claims description 2
- 229940038773 trisodium citrate Drugs 0.000 claims description 2
- 235000019263 trisodium citrate Nutrition 0.000 claims description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 2
- 229910000406 trisodium phosphate Inorganic materials 0.000 claims description 2
- 235000019801 trisodium phosphate Nutrition 0.000 claims description 2
- 239000007832 Na2SO4 Substances 0.000 claims 1
- -1 polyglycolactide Polymers 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 83
- 239000003814 drug Substances 0.000 abstract description 83
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 description 50
- 230000000052 comparative effect Effects 0.000 description 46
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 28
- 229960003530 donepezil Drugs 0.000 description 25
- 239000000243 solution Substances 0.000 description 24
- 239000013078 crystal Substances 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
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- 238000005406 washing Methods 0.000 description 13
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- 238000011068 loading method Methods 0.000 description 11
- 238000002360 preparation method Methods 0.000 description 11
- 238000005538 encapsulation Methods 0.000 description 10
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 8
- 239000004094 surface-active agent Substances 0.000 description 7
- 241000700159 Rattus Species 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- JJTUDXZGHPGLLC-IMJSIDKUSA-N 4511-42-6 Chemical compound C[C@@H]1OC(=O)[C@H](C)OC1=O JJTUDXZGHPGLLC-IMJSIDKUSA-N 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 238000004090 dissolution Methods 0.000 description 5
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000011148 porous material Substances 0.000 description 4
- 239000008215 water for injection Substances 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 230000002354 daily effect Effects 0.000 description 2
- 230000000857 drug effect Effects 0.000 description 2
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- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- 208000007848 Alcoholism Diseases 0.000 description 1
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- XVGOZDAJGBALKS-UHFFFAOYSA-N Blonanserin Chemical compound C1CN(CC)CCN1C1=CC(C=2C=CC(F)=CC=2)=C(CCCCCC2)C2=N1 XVGOZDAJGBALKS-UHFFFAOYSA-N 0.000 description 1
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- 101000610640 Homo sapiens U4/U6 small nuclear ribonucleoprotein Prp3 Proteins 0.000 description 1
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- 208000028017 Psychotic disease Diseases 0.000 description 1
- 101001110823 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-A Proteins 0.000 description 1
- 101000712176 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-B Proteins 0.000 description 1
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- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
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- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
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- GRWIABMEEKERFV-UHFFFAOYSA-N methanol;oxolane Chemical compound OC.C1CCOC1 GRWIABMEEKERFV-UHFFFAOYSA-N 0.000 description 1
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- DQCKKXVULJGBQN-XFWGSAIBSA-N naltrexone Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=O)O)CC1)O)CC1CC1 DQCKKXVULJGBQN-XFWGSAIBSA-N 0.000 description 1
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- 238000000746 purification Methods 0.000 description 1
- 229960001534 risperidone Drugs 0.000 description 1
- RAPZEAPATHNIPO-UHFFFAOYSA-N risperidone Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCCC4=NC=3C)=NOC2=C1 RAPZEAPATHNIPO-UHFFFAOYSA-N 0.000 description 1
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- KFQYTPMOWPVWEJ-INIZCTEOSA-N rotigotine Chemical compound CCCN([C@@H]1CC2=CC=CC(O)=C2CC1)CCC1=CC=CS1 KFQYTPMOWPVWEJ-INIZCTEOSA-N 0.000 description 1
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
- A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1611—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
- A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/20—Compounding polymers with additives, e.g. colouring
- C08J3/205—Compounding polymers with additives, e.g. colouring in the presence of a continuous liquid phase
- C08J3/21—Compounding polymers with additives, e.g. colouring in the presence of a continuous liquid phase the polymer being premixed with a liquid phase
- C08J3/215—Compounding polymers with additives, e.g. colouring in the presence of a continuous liquid phase the polymer being premixed with a liquid phase at least one additive being also premixed with a liquid phase
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2367/00—Characterised by the use of polyesters obtained by reactions forming a carboxylic ester link in the main chain; Derivatives of such polymers
- C08J2367/04—Polyesters derived from hydroxy carboxylic acids, e.g. lactones
Definitions
- the present invention relates to drug-containing microspheres used in sustained-release injections and a method of manufacturing the same.
- sustained-release injections are prepared by preparing microspheres encapsulated with a drug and containing them in an injection, wherein the microspheres are prepared so that the drug is encapsulated therein.
- the microsphere-containing injection agent When the microsphere-containing injection agent is injected into the body, the drug is slowly released in the microspheres injected into the body, so that the pharmacological effect can be continuously displayed.
- the drug when an injection solution containing microspheres for sustained release is injected into the body, the drug can be slowly released from the microspheres in the body, so that the pharmacological effect of the drug can be exhibited for a long period of time.
- sustained-release injections can reduce the number of invasions in the body and improve patient compliance. For example, if a drug that should be administered orally once or twice a day or injected once a day is prepared as a sustained-release injection containing microspheres as described above, the drug effect lasts for 30 days after administration of one injection. It can be formulated as possible.
- sustained-release formulations such as microsphere-containing injections If it can be formulated and administered once a month, for example, it can provide a very great advantage in terms of patient compliance.
- microspheres are generally manufactured by solvent evaporation.
- solvent evaporation method a polymer substance and a drug are dissolved in a volatile organic solvent, and then the organic solvent is evaporated to encapsulate the drug in the microspheres.
- the microspheres prepared in this way have a drug on the surface of the microspheres, there is a problem in that the drug is rapidly released initially when injected into the body. In this way, when the drug is rapidly released at the beginning of the injection, the blood concentration of the drug rises rapidly, which may cause side effects to the patient. In particular, when the blood concentration of drugs acting on the central nervous system rises rapidly, side effects such as tremors or movements may appear suddenly.
- a method of cleaning the surface is generally used. For example, by washing the drug deposited on the surface of the microspheres with an aqueous ethanol solution or washing with a Tween-based or Span-based surfactant, the drug deposited on the surface of the microspheres prepared by solvent evaporation or the like can be removed. .
- the present inventors studied a method for inhibiting the initial drug release of microspheres. As a result, when a salt is added to the continuous phase to prepare microspheres, the formation of drugs on the surface of the microspheres is prevented. It has been found that the formation of pores on the surface of the body can be prevented, thereby preventing the initial release of excessive amounts of the drug upon injection into the body.
- the present invention is to provide a method of manufacturing microspheres in which initial drug release is suppressed by simplifying the process and shortening the process time, while not affecting the microspheres or the drug encapsulated therein.
- the present invention relates to a method of manufacturing sustained release microspheres containing a drug.
- the method for producing microspheres according to the present invention comprises the steps of preparing a dispersed phase by dissolving an active ingredient and a biodegradable polymer in an organic solvent; Dissolving the salt in water to prepare a continuous phase; Mixing and stirring the dispersed phase and the continuous phase to form an emulsion; Removing the organic solvent; And a drying step.
- salts to be included in the continuous phase include, for example, sodium chloride (NaCl), potassium chloride (KCl), calcium chloride (CaCl 2 ), magnesium sulfate (MgSO 4 ), sodium sulfate (Na 2 SO 4 ), mannitol, ammonium , Potassium sulfate, disodium phosphate, dipotassium phosphate, trisodium phosphate, disodium citrate, trisodium citrate, and sodium succinate may be used, and the concentration in the continuous phase is 1 to 10% (w/v), preferably It is used so that it is 2 to 8% (w/v).
- microspheres according to the present invention are injected into the body with the drug encapsulated, for example, polylactide, poly(lactide-co-glycolide), polyglycolactide and poly(lactide-co-glycolide) )
- Biodegradable polymers such as glucose can be used.
- the continuous phase may be prepared and used to further include a water-soluble polymer.
- a water-soluble polymer for example, it can be used by selecting one or more from the group consisting of polyvinyl alcohol, polysorbate, poloxamer, polyvinylpyrrolidone, polyvinyl methyl ether, polyvinyl ether, and the like. Dispersibility of the emulsion may be maintained by the water-soluble polymer.
- an active ingredient that can be used in the present invention when a substance acting on the central nervous system is used, it is more effective in terms of patient compliance.
- a substance having dementia treatment activity such as donepezil, a treatment for Parkinson's disease such as pramipegsol, rotigotine, and ropinirol, antipsychotic drugs such as risperidone, blonanserin, and lusaridone , Alcoholism treatment drugs such as naltrexone may be used.
- the drug may be present in an amount of about 30-50%, preferably 40-50%, based on the total weight of the microspheres.
- the present invention relates to a microsphere manufactured by the manufacturing method as described above.
- the present invention relates to a sustained release injection containing microspheres as described above.
- the injection containing the sustained-release microspheres according to the present invention prevents the formation of drug crystals around or on the surface of the microspheres, and improves the drug encapsulation rate into the microspheres. Can be prevented. In addition, since the drug is continuously released, it is possible to increase patient compliance and reduce side effects caused by dose dumping.
- 1 to 12 are photographs showing SEM images for confirming the morphology of Donepezil microspheres according to each of the Examples and Comparative Examples.
- FIG. 13 and 14 are photographs showing an enlarged SEM image of the surfaces of the microspheres prepared in Comparative Example 1 and Example 1, respectively.
- Example 15 is a graph showing blood concentrations obtained for 24 hours after administration of microspheres prepared in Example 1, Comparative Example 1, Comparative Example 2, and Comparative Example 2-1 to SD rats.
- Example 1 Preparation of microspheres by adding polylactide polymer to NaCl 1% (w/v) continuous phase
- Donepezil (manufacturer: Neuland Laboratories, India) 2g (40% of drug loading in microspheres (hereinafter only referred to as “drug loading”)) and biodegradable polymer poly D,L-lactide (Resomer 3 g of R 203 H; manufacturer Evonik, Germany) was added to 9 g of dichloromethane (manufactured by Daejeong Hwa-Geum, Korea) and stirred to dissolve completely to prepare a polymer solution in a dispersed phase.
- dichloromethane manufactured by Daejeong Hwa-Geum, Korea
- 6.25 g of polyvinyl alcohol and 12.5 g of NaCl were dissolved in 1.25 L of water to prepare a continuous phase.
- the continuous phase in a double jacket beaker and maintain a temperature of 10°C or less using a constant temperature circulating water bath, and then put the dispersed phase (i.e., a polymer solution containing donepezil) into the continuous phase (i.e., aqueous solution of polyvinyl alcohol and NaCl) at high speed. Stirring to form an emulsion.
- a dispersed phase i.e., a polymer solution containing donepezil
- the continuous phase i.e., aqueous solution of polyvinyl alcohol and NaCl
- the organic solvent was volatilized at 47° C. for 2 hours, and slowly cooled to 10° C. for 1 hour.
- the cured microspheres were washed several times with water for injection, then wet-filtered using a sieve, and freeze-dried to obtain microspheres containing donepezil.
- Example 1-1 Preparation of microspheres by adding a polylactide polymer to NaCl 1% (w/v) continuous phase
- Donepezil (manufacturer: Neuland Laboratories, India) 2.25g (drug loading 45%) and biodegradable polymer poly D,L-lactide (Resomer R 203 H; manufacturer Evonik, Germany) 2.75g dichloromethane (manufacturer: Daejeonghwageum, Korea) was added to 8.25g and stirred to completely dissolve to prepare a dispersed polymer solution.
- 6.25 g of polyvinyl alcohol and 12.5 g of NaCl were dissolved in 1.25 L of water to prepare a continuous phase of NaCl 1% (w/v). The rest of the manufacturing method was carried out in the same manner as in Example 1 to prepare microspheres.
- Example 2 Preparation of microspheres by adding polylactide polymer to NaCl 5% (w/v) continuous phase
- Microspheres were prepared in the same manner as in Example 1, except that NaCl was added so as to be 5% (w/v) during continuous phase production.
- Example 2-1 Preparation of microspheres by adding polylactide polymer to 10% (w/v) NaCl in a continuous phase
- Microspheres were prepared in the same manner as in Example 1, except that NaCl was added to be 10% (w/v) during continuous phase production.
- Example 3 Preparation of microspheres by adding polylactide polymer to 1% (w/v) KCl in a continuous phase
- Microspheres were prepared in the same manner as in Example 1, except that KCl was added to 1% (w/v) instead of NaCl during continuous phase production.
- Example 3-1 Preparation of microspheres by adding a polylactide polymer to 5% (w/v) KCl in a continuous phase
- Microspheres were prepared in the same manner as in Example 1, except that KCl was added to 5% (w/v) instead of NaCl during continuous phase production.
- Example 4 Preparation of microspheres by adding poly(D,L-lactide-co-glycolide) polymer to NaCl 5% (w/v) continuous phase
- Donepezil (manufacturer: Neuland Laboratories, India) 2g (drug loading 40%) and biodegradable polymer PLGA (poly(D,L-lactide-co-glycolide); Resomer RG 753 H; manufacturer Evonik, Germany) 3g was added to 9g of dichloromethane (manufacturer: Daejeonghwa-geum, Korea), stirred and completely dissolved to prepare a dispersed polymer solution. The rest of the manufacturing method was carried out in the same manner as in Example 1, except that NaCl was added so as to be 5% by weight when preparing the continuous phase, thereby preparing microspheres.
- PLGA poly(D,L-lactide-co-glycolide); Resomer RG 753 H; manufacturer Evonik, Germany
- Comparative Example 1 Preparation of microspheres by adding a polylactide polymer to a continuous phase in which no salt is added
- the continuous phase in a double jacket beaker and keep it at a temperature of 10°C or less using a constant temperature circulating water bath, and then put the dispersed phase (i.e., a polymer solution containing donepezil) into the continuous phase (i.e., aqueous polyvinyl alcohol) while stirring at high speed. An emulsion was formed.
- a dispersed phase i.e., a polymer solution containing donepezil
- the continuous phase i.e., aqueous polyvinyl alcohol
- the organic solvent was volatilized at 47° C. for 2 hours, and slowly cooled to 10° C. for 1 hour.
- the cured microspheres were washed several times with water for injection, then wet-filtered using a sieve, and freeze-dried to obtain microspheres containing donepezil.
- Comparative Example 1-1 Preparation of microspheres without adding a polylactide polymer to a continuous phase in which no salt was added
- Donepezil (manufacturer: Neuland Laboratories, India) 2.25g (drug loading 45%) and biodegradable polymer poly D,L-lactide (Resomer R 203H; manufacturer Evonik, Germany) 2.75g dichloromethane (manufacturer: large Jeonghwageum, Korea) was added to 8.25 g and stirred to completely dissolve to prepare a dispersed polymer solution. The rest of the manufacturing method was carried out in the same manner as in Comparative Example 1 to prepare microspheres.
- Comparative Example 2 After preparing microspheres using a continuous phase to which no salt was added, washing with an aqueous EtOH solution
- the continuous phase in a double jacket and keep the temperature below 10°C using a constant temperature circulating water bath, and then put the dispersed phase (i.e., a polymer solution containing donepezil) into the continuous phase (i.e., polyvinyl alcohol aqueous solution) while stirring at high speed to create an emulsion. Formed.
- a polymer solution containing donepezil i.e., polyvinyl alcohol aqueous solution
- the organic solvent was volatilized at 47° C. for 2 hours, and slowly cooled to 10° C. for 1 hour.
- the cured microspheres were washed several times with water for injection and then first wet-filtered using a sieve to obtain microspheres.
- microspheres were washed with 20% EtOH aqueous solution at 10° C. for 1 hour, then wet-filtered again using a sieve, and freeze-dried to obtain microspheres containing donepezil.
- Comparative Example 2-1 Washing with aqueous Tween solution after preparing microspheres without salt added to the continuous phase
- microspheres containing donepezil were washed with 3% Tween 20 aqueous solution at 10° C. for 1 hour, then wet filtered again using a sieve, and then freeze-dried to finally obtain microspheres containing donepezil.
- Comparative Example 3 Preparation of microspheres by adding poly(D,L-lactide-co-glycolide) polymer to a continuous phase in which no salt was added
- Donepezil (manufacturer: Neuland Laboratories, India) 2g (theoretical drug loading 40%) and biodegradable polymer poly(D,L-lactide-co-glycolide) (Resomer RG 753 H: manufacturer Evonik, Germany) 3g was added to 9 g of dichloromethane (manufacturer: Daejeong Hwageum, Korea), stirred and completely dissolved to prepare a dispersed polymer solution. Further, 6.25 g of polyvinyl alcohol was dissolved in 1.25 L of water to prepare a continuous phase (a salt such as NaCl or KCl was not included).
- the dispersion phase i.e., the polymer solution containing donepezil
- the polyvinyl alcohol aqueous solution continuously stirring at high speed to create an emulsion. Formed.
- microspheres were volatilized at 47° C. for 2 hours and slowly cooled to 10° C. for 1 hour.
- the cured microspheres were washed several times with water for injection, then wet-filtered using a sieve, and freeze-dried to finally obtain microspheres containing donepezil.
- 1 to 14 show microspheres prepared in Examples 1, 1-1, 2, 2-1, 3, 3-1, 4, and Comparative Examples 1, 1-1, 2, 2-1, and 3, respectively. This is an SEM image.
- microspheres prepared in the examples did not show drug crystals in their peripheral areas.
- the microspheres prepared in Comparative Example 2 and Comparative Example 2-1 to which the existing drug crystal removal process (that is, the ethanol washing process or the surfactant washing process) was applied are also No decision was seen.
- the microspheres prepared in Comparative Example 1 can be observed to have pores formed on the surface, but as can be seen in Fig. 14, prepared by adding a salt to the continuous phase according to the present invention. In the microspheres of Example 1, no pores were formed on the surface.
- each Example and Comparative Example 1 The microspheres prepared in 1-1 and 3 were washed with 20% EtOH aqueous solution at 10° C. for 1 hour and then lyophilized to remove the drug crystals on the surface of the microspheres and the periphery.
- Table 1 shows the measured drug encapsulation rate (%) and the drug encapsulation rate in the microspheres after ethanol washing.
- Example 1 40% 91.89 90.76 1.13 Example 1-1 45% 96.78 95.54 1.24
- Example 2 40% 95.55 94.92 0.63
- Example 2-1 40% 95.42 92.61 2.81
- Example 3 40% 93.89 93.75 0.14
- Example 3-1 40% 90.94 90.82 0.12
- Example 4 40% 95.68 95.47 0.21 Comparative Example 1 40% 92.71 90.39 2.32 Comparative Example 1-1 45% 95.58 93.26 2.32 Comparative Example 2 40% 93.90 - - Comparative Example 2-1 40% 94.90 - - Comparative Example 3 40% 95.97 93.22 2.75
- Theoretical drug loading amount (%) amount of drug injected during microsphere manufacturing/(amount of drug injected for microsphere manufacturing + amount of polymer injected when manufacturing microsphere) X 100%
- Measured drug encapsulation rate (%) A measured amount of actual drug contained per 100 mg of microspheres immediately after preparation in Comparative Examples and Examples (mg) / (microspheres 100 mg X theoretical drug loading amount (%)) X 100%
- Drug encapsulation rate after ethanol washing B measured amount of actual drug contained per 100 mg of microspheres after washing in Example 2 (mg) / (microspheres 100 mg X theoretical drug loading amount (%)) X 100%
- microspheres prepared without additionally washing with ethanol or a surfactant exceeded 2% of the amount of drug crystals present outside the microspheres.
- microspheres are prepared by adding salts such as NaCl in the continuous phase, the amount of drug crystals that may exist outside the microspheres can be minimized, and accordingly, the actual encapsulation rate in the microspheres of the drug can be maximized. have.
- the initial daily elution amount of donepezil released from the microspheres was measured using HPLC.
- Table 2 below shows the dissolution rates of donepezil microspheres in one day according to each example and comparative example.
- Example 1 Dissolution rate per day (%) Example 1 3.25 Example 1-1 7.64 Example 2 6.06 Example 2-1 11.72 Example 3 5.25 Example 3-1 3.26 Example 4 10.25 Comparative Example 1 7.78 Comparative Example 1-1 10.87 Comparative Example 2 5.5 Comparative Example 2-1 4.9 Comparative Example 3 17.21
- Example 1 NaCl 1% added in the continuous phase
- Example 2 NaCl 5% added in the continuous phase
- Example 1 No NaCl added in the continuous phase
- Example 3 and Example 3-1 it was confirmed that when KCl was used, it exhibited the same effect as NaCl.
- the concentration of donepezil in the blood was measured after subcutaneous administration to the cervical part of the rat.
- Example 1 For the microspheres prepared in Example 1, Comparative Example 1, Comparative Example 2, and Comparative Example 2-1, the microspheres were weighed so that the dose of donepezil in the microspheres per rat was 25.2 mg/kg. Then, after dispersing in a 0.3 mL suspension, it was injected subcutaneously into SD rats.
- 0.3mL blood was collected from the jugular vein of the rat at regular time intervals, kept in ice-cooled state, and centrifuged to separate 100uL of plasma. The separated plasma was analyzed for the concentration of donepezil using LC/MS/MS.
- the microspheres of Comparative Example 1 to which the process of washing with ethanol or surfactant was not applied had the highest Cmax at 220.5 ng/mL, but the microspheres and surfactants of Comparative Example 2 washed with ethanol In the microspheres of Comparative Example 2-1 washed with, since the drug crystals were removed by washing, it was confirmed that Cmax was lowered to 141.03 ng/mL and 90.2 ng/mL, respectively.
- Example 1 prepared by adding 1% NaCl to the continuous phase had the lowest Cmax at 58.9 ng/mL because the drug crystals around the microspheres were removed and surface pores were also removed. In other words, it was possible to prevent the release of an excessive amount of drugs in the initial stage. This result was similar to the in vitro result.
- microspheres by adding NaCl to the continuous phase since the formation of drug crystals around the microspheres is suppressed, it is not necessary to additionally introduce a step of removing the drug crystals. It is possible to improve the drug encapsulation rate in the sphere. In addition, since no drug crystals are formed around the microspheres, when the microspheres are injected into the body, the initial release of the drug can be suppressed.
- the initial release of the drug can be suppressed.
- the drug since the drug is continuously released, the drug effect can be exhibited for a considerably long time with a single injection.
Abstract
Description
이론 약물 로딩량(%) | 측정된 약물 봉입률(%) A | EtOH 세척 후 약물 봉입률(%) B | 마이크로스피어 외부에 존재하는 약물 결정의 계산된 량(%) (A-B) |
|
실시예 1 | 40% | 91.89 | 90.76 | 1.13 |
실시예 1-1 | 45% | 96.78 | 95.54 | 1.24 |
실시예 2 | 40% | 95.55 | 94.92 | 0.63 |
실시예 2-1 | 40% | 95.42 | 92.61 | 2.81 |
실시예 3 | 40% | 93.89 | 93.75 | 0.14 |
실시예 3-1 | 40% | 90.94 | 90.82 | 0.12 |
실시예 4 | 40% | 95.68 | 95.47 | 0.21 |
비교예 1 | 40% | 92.71 | 90.39 | 2.32 |
비교예 1-1 | 45% | 95.58 | 93.26 | 2.32 |
비교예 2 | 40% | 93.90 | - | - |
비교예 2-1 | 40% | 94.90 | - | - |
비교예 3 | 40% | 95.97 | 93.22 | 2.75 |
1 일 용출률(%) | |
실시예 1 | 3.25 |
실시예 1-1 | 7.64 |
실시예 2 | 6.06 |
실시예 2-1 | 11.72 |
실시예 3 | 5.25 |
실시예 3-1 | 3.26 |
실시예 4 | 10.25 |
비교예 1 | 7.78 |
비교예 1-1 | 10.87 |
비교예 2 | 5.5 |
비교예 2-1 | 4.9 |
비교예 3 | 17.21 |
Claims (10)
- 활성성분 및 생분해성 고분자를 유기용매에 용해시켜 분산상을 제조하는 단계;염을 물에 용해시켜 연속상을 제조하는 단계;분산상과 연속상을 혼합 및 교반하여 에멀젼을 형성하는 단계;유기용매를 제거하는 단계; 및건조 단계를 포함하는 마이크로스피어 제조 방법.
- 제1항에 있어서, 상기 염은 염화나트륨(NaCl), 염화칼륨(KCl), 염화칼슘(CaCl2), 황산마그네슘(MgSO4), 황산나트륨(Na2SO4), 만니톨, 암모늄, 황산칼륨, 인산이나트륨, 인산이칼륨, 인산삼나트륨, 시트르산이나트륨, 시트르산삼나트륨 또는 숙신산나트륨으로 이루어진 군으로부터 1종 이상 선택되는 것을 특징으로 하는 마이크로스피어 제조 방법.
- 제2항에 있어서, 상기 염은 연속상에서의 농도가 1 내지 10%(w/v)인 것을 특징으로 하는 마이크로스피어 제조 방법.
- 제1항에 있어서, 생분해성 고분자는 폴리락티드, 폴리(락티드-코-글리콜라이드), 폴리글리코락티드 및 폴리(락티드-코-글리코라이드)글루코스로 이루어진 군으로부터 1종 이상 선택되는 것을 특징으로 하는 제조 방법.
- 제1항에 있어서, 상기 연속상은 추가로 수용성 고분자를 더 포함하는 것을 특징으로 하는 마이크로스피어 제조 방법.
- 제5항에 있어서, 상기 수용성 고분자는 폴리비닐알코올, 폴리소르베이트, 폴록사머, 폴리비닐피롤리돈, 폴리비닐메틸에테르, 폴리비닐에테르로 이루어진 군으로부터 1종 이상 선택되는 것을 특징으로 하는 마이크로스피어 제조 방법.
- 제1항에 있어서, 상기 활성성분은 중추신경계에 작용하는 물질인 것을 특징으로 하는 마이크로스피어 제조 방법.
- 제7항에 있어서, 상기 활성성분은 치매 치료 활성 또는 알츠하이머 치료 활성이 있는 물질인 것을 특징으로 하는 마이크로스피어 제조 방법.
- 제1항 내지 제8항 중 어느 한 항의 제조 방법에 따라 제조된 마이크로스피어.
- 제9항에 따른 마이크로스피어를 함유하는 지속 방출형 주사제.
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2020
- 2020-11-08 CA CA3157581A patent/CA3157581A1/en active Pending
- 2020-11-08 JP JP2022526486A patent/JP2023502014A/ja active Pending
- 2020-11-08 EP EP20883993.6A patent/EP4056170A4/en active Pending
- 2020-11-08 WO PCT/KR2020/015565 patent/WO2021091333A1/ko unknown
- 2020-11-08 US US17/775,082 patent/US20220387321A1/en active Pending
- 2020-11-08 CN CN202080077303.7A patent/CN114867470A/zh active Pending
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Also Published As
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EP4056170A4 (en) | 2023-11-22 |
KR102212717B1 (ko) | 2021-02-08 |
CN114867470A (zh) | 2022-08-05 |
JP2023502014A (ja) | 2023-01-20 |
US20220387321A1 (en) | 2022-12-08 |
EP4056170A1 (en) | 2022-09-14 |
CA3157581A1 (en) | 2021-05-14 |
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