WO2004108115A1 - 微粒子の製造法 - Google Patents
微粒子の製造法 Download PDFInfo
- Publication number
- WO2004108115A1 WO2004108115A1 PCT/JP2004/008047 JP2004008047W WO2004108115A1 WO 2004108115 A1 WO2004108115 A1 WO 2004108115A1 JP 2004008047 W JP2004008047 W JP 2004008047W WO 2004108115 A1 WO2004108115 A1 WO 2004108115A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- drug
- solvent
- fine particles
- solubility
- biodegradable polymer
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 27
- 239000011859 microparticle Substances 0.000 title abstract description 23
- 229940079593 drug Drugs 0.000 claims abstract description 90
- 239000003814 drug Substances 0.000 claims abstract description 90
- 239000002904 solvent Substances 0.000 claims abstract description 49
- 150000008282 halocarbons Chemical class 0.000 claims abstract description 28
- 229920002988 biodegradable polymer Polymers 0.000 claims abstract description 16
- 239000004621 biodegradable polymer Substances 0.000 claims abstract description 16
- 239000003960 organic solvent Substances 0.000 claims abstract description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000001035 drying Methods 0.000 claims abstract description 8
- 239000012046 mixed solvent Substances 0.000 claims abstract description 8
- 239000010419 fine particle Substances 0.000 claims description 47
- 238000004519 manufacturing process Methods 0.000 claims description 47
- 229960002537 betamethasone Drugs 0.000 claims description 15
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 claims description 15
- 239000012071 phase Substances 0.000 claims description 10
- 239000008346 aqueous phase Substances 0.000 claims description 7
- 229920001577 copolymer Polymers 0.000 claims description 7
- 229920000747 poly(lactic acid) Polymers 0.000 claims description 7
- 239000004626 polylactic acid Substances 0.000 claims description 7
- 239000000839 emulsion Substances 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 4
- -1 phenylalkyl alcohol Chemical compound 0.000 claims description 4
- 150000003431 steroids Chemical class 0.000 claims description 3
- 229960003957 dexamethasone Drugs 0.000 claims description 2
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 claims description 2
- 229960005205 prednisolone Drugs 0.000 claims description 2
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 claims description 2
- XBBVURRQGJPTHH-UHFFFAOYSA-N 2-hydroxyacetic acid;2-hydroxypropanoic acid Chemical compound OCC(O)=O.CC(O)C(O)=O XBBVURRQGJPTHH-UHFFFAOYSA-N 0.000 claims 1
- 239000007788 liquid Substances 0.000 abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 24
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 9
- 235000019445 benzyl alcohol Nutrition 0.000 description 8
- 239000002245 particle Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 238000005259 measurement Methods 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 239000004372 Polyvinyl alcohol Substances 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 229920002451 polyvinyl alcohol Polymers 0.000 description 5
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 4
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 4
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 4
- 238000005538 encapsulation Methods 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 150000002430 hydrocarbons Chemical class 0.000 description 3
- 239000004310 lactic acid Substances 0.000 description 3
- 235000014655 lactic acid Nutrition 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- SYBYTAAJFKOIEJ-UHFFFAOYSA-N 3-Methylbutan-2-one Chemical compound CC(C)C(C)=O SYBYTAAJFKOIEJ-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 229940067107 phenylethyl alcohol Drugs 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 2
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 229940068968 polysorbate 80 Drugs 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- QQZOPKMRPOGIEB-UHFFFAOYSA-N 2-Oxohexane Chemical compound CCCCC(C)=O QQZOPKMRPOGIEB-UHFFFAOYSA-N 0.000 description 1
- KVZLHPXEUGJPAH-UHFFFAOYSA-N 2-oxidanylpropanoic acid Chemical compound CC(O)C(O)=O.CC(O)C(O)=O KVZLHPXEUGJPAH-UHFFFAOYSA-N 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 229920001651 Cyanoacrylate Polymers 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- MWCLLHOVUTZFKS-UHFFFAOYSA-N Methyl cyanoacrylate Chemical compound COC(=O)C(=C)C#N MWCLLHOVUTZFKS-UHFFFAOYSA-N 0.000 description 1
- 229920002732 Polyanhydride Polymers 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 229940061720 alpha hydroxy acid Drugs 0.000 description 1
- 150000001280 alpha hydroxy acids Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229920001222 biopolymer Polymers 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 239000002077 nanosphere Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 229920001308 poly(aminoacid) Polymers 0.000 description 1
- 239000005014 poly(hydroxyalkanoate) Substances 0.000 description 1
- 239000002745 poly(ortho ester) Substances 0.000 description 1
- 229920000903 polyhydroxyalkanoate Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- 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)
Definitions
- the present invention relates to a method for producing fine particles.
- microparticles such as microspheres and nanospheres made of biodegradable polymers have been studied as formulations useful for controlling the release of drugs.
- Various methods for producing such fine particles are known, and one of them is a submerged drying method.
- the submerged drying method is disclosed in Journal of Controlled Release, 2, 343-352, 1985.
- a method of dissolving a polymer serving as a material for a drug and fine particles in a volatile organic solvent adding this to an aqueous phase to form an oZw-type emulsion, and removing the organic solvent to obtain fine particles.
- the solvent used in the in-liquid drying method is preferably volatile and immiscible with water.
- Halogenated hydrocarbon solvents such as dichloromethane and chloroform are widely used.
- Japanese Patent Application Laid-Open No. 9-505308 discloses a method for producing fine particles using a mixed solvent of at least two of esters, alcohols and ketones. , Ethyl acetate, benzyl alcohol, methyl ethyl ketone, and the like. Further, the example describes a production example of fine particles using a mixed solvent of ethyl acetate and benzyl alcohol.
- halogenated hydrocarbon solvents are excellent solvents from the viewpoints of volatility, emulsification properties and the solubility of biopolymers.Halogenated hydrocarbon solvents should be used for the production of fine particles. Is desirable.
- the drug when the solubility of the drug in the halogenated hydrocarbon solvent is low, the drug is manufactured by dispersing the drug in the halogenated hydrocarbon solvent. On the other hand, the drug will be concentrated in the outer periphery of the microparticles, resulting in excessive release (early burst) and early release. Problem arises.
- the present inventors have conducted intensive studies on a solvent used in a method for producing fine particles containing a drug composed of a biodegradable polymer and having low solubility in halogenated hydrocarbons by a submerged drying method. , As a solvent for dissolving drugs and biodegradable polymers,
- Second solvent a water-immiscible organic solvent having a solubility of the above drug of 0.3% (W / V) or more,
- the present invention relates to a method for producing fine particles comprising a biodegradable polymer and containing a drug having low solubility in halogenated hydrocarbons by a submerged drying method, wherein the halogenated hydrocarbon (first solvent) is used. And dissolving the drug and the biodegradable molecule in a mixed solvent comprising a water-immiscible organic solvent (second solvent) in which the solubility of the drug is 0.3% (W / V) or more.
- This is a method for producing fine particles.
- the present invention relates to a method for producing fine particles applied to a drug having low solubility in octogenated hydrocarbons.
- the solubility of the drug in halogenated hydrocarbons is 0.1% (W / V). Is less than.
- examples of such drugs include vesamethasone, dexamethasone
- steroids such as prednisolone and derivatives thereof.
- the first solvent in the present invention is a halogenated hydrocarbon, that is, a halogenated alkyl having 1 to 4 carbon atoms.
- a halogenated hydrocarbon that is, a halogenated alkyl having 1 to 4 carbon atoms.
- dichloromethane and chloroform are used.
- the present invention is characterized by mixing a halogenated hydrocarbon as a first solvent with a water-immiscible second solvent having a drug solubility of 0.3% (W / V) or more. This allows a drug having low solubility in halogenated hydrocarbons to be dissolved in the oil phase.
- the solubility of the drug in the second solvent is preferably from 0.3 to 50% (W / V), particularly preferably from 0.5 to 30% (WZV).
- the second solvent is a water-immiscible organic solvent, so that leakage of the drug into the aqueous phase can be suppressed, and the drug can be uniformly dispersed in the fine particles.
- the solubility of the second solvent in water is preferably 1.0 to 30% (V / V).
- an appropriate water-immiscible organic solvent may be selected depending on the target drug.
- steroids having low solubility in halogenated hydrocarbons such as betamethasone
- phenylalkyl alcohols such as benzyl alcohol and phenylethyl alcohol
- ketones such as methylethyl ketone, methylbutyl ketone and methyl isopropyl ketone
- Aniline 1-butanol and the like.
- betamethasone benzyl alcohol is particularly preferred.
- the mixing ratio of the first solvent and the second solvent is not particularly limited, and may be appropriately changed depending on the kind of the drug, the effective therapeutic concentration of the drug, the release period, and the like, and is preferably 1:20 to 20: 1. 1: 1 to 1: 10 is preferred.
- biodegradable polymer examples include polylactic acid, a copolymer of lactic acid and glycolic acid (hereinafter abbreviated as PLGA), a lactic acid monoprolactone copolymer, a polyanhydride, a polyorthoester, a polyepsilone prolactone, Polyacryl cyanoacrylate, polyhydroxyalkanoate, polyphospho Examples include steles, polyamino acids, and poly ⁇ -hydroxy acids.
- PLGA a copolymer of lactic acid and glycolic acid
- a lactic acid monoprolactone copolymer examples include polyanhydride, a polyorthoester, a polyepsilone prolactone, Polyacryl cyanoacrylate, polyhydroxyalkanoate, polyphospho
- Polyacryl cyanoacrylate examples include steles, polyamino acids, and poly ⁇ -hydroxy acids.
- polylactic acid and PLG # are used.
- the weight average molecular weight of these biodegradable polymers is not particularly limited, and is appropriately selected depending on the type of drug contained in the microparticles, the effective therapeutic concentration of the drug, the drug release period, and the like.
- polylactic acid it is preferably 5000 to 70000.
- microparticles produced by the present invention are microparticles containing a drug and a biodegradable polymer, such as capsule-shaped microparticles containing one drug core in one particle, and one microparticle in one particle. And polynuclear capsule-shaped fine particles containing a large number of drug cores, or fine particles in which a drug is dissolved or dispersed in a biodegradable polymer.
- the particle diameter of the fine particles is preferably from 500 nm to 150 m.
- the drug and the biodegradable polymer are dissolved in a mixed solvent of the first solvent and the second solvent to form an oil phase.
- the concentration of the drug in this solution is, for example, 0.1 to 50% (W / V), preferably 0.3 to 10% (W / V).
- the concentration of the biodegradable polymer in the solution is, for example, 0.1 to 80% (W / V), preferably 2 to 50% (W / V).
- the weight ratio of the drug to the polymer varies depending on the type of the drug, the required drug content of the fine particles, and the like, but is preferably 1:20 to 1: 1. '
- the above oil phase is added to the external water phase at a constant rate, and dispersed and emulsified using a homomixer or the like to produce an oZw type emulsion.
- the amount of the outer aqueous phase used is usually 10 to 400 times, preferably 50 to 200 times the volume of the oil phase.
- An emulsifier can be added to the external aqueous phase. Examples of the emulsifier include polysorbate 80, polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose, lecithin and the like, with polyvinyl alcohol being particularly preferred.
- the concentration of the emulsifier in the external aqueous phase is, for example, preferably from 0.01 to 20% (W / V), particularly preferably from 0.02 to 2% (W / V).
- the removal of the solvent in the oil phase may be carried out by a commonly used method. For example, there are methods such as leaving the obtained oZw-type emulsion with stirring with a propeller-type stirrer, heating, or blowing nitrogen gas or the like. Also, remove the solvent by gradually reducing the pressure, or reduce the degree of vacuum using a tally evaporator. The solvent may be removed while adjusting.
- the microparticles thus obtained are collected by centrifugation or filtration, washed with purified water, and lyophilized to obtain the desired product.
- microparticles obtained by the process of the present invention can be formulated into various dosage forms.
- a dosage form include an injection, an implant, an oral administration, an eye drop, a preparation for nasal administration, and the like, with an injection being particularly preferred.
- injectables can be prepared using commonly used injection formulation techniques. For example, fine particles and commonly used additives may be added to distilled water for injection to prepare an injection.
- the additives include an osmotic pressure adjusting agent such as sodium chloride, a buffering agent such as sodium phosphate, a surfactant such as polysorbate 80, and a thickening agent such as methylcellulose.
- a drug having low solubility in octalogenated hydrocarbons is considered to have a solubility in halogenated hydrocarbons and drug of 0.
- Fine particles produced by dissolving in a mixed solvent consisting of a water-immiscible organic solvent of 3% or more have a high drug content in fine particles, have no initial burst, and can be used for a long time. The next release.
- FIG. 1 is a graph showing the time-dependent change in drug release from the fine particles produced in Production Example 4.
- Betamethasone (0.05 g) and a lactic acid-glycolic acid copolymer (0.25 g) having a weight average molecular weight of 20,000 were dissolved in dichloromethane (l mL) and benzyl alcohol (3 mL). .
- the resulting solution was dropped into 40 OmL of a 2% aqueous solution of polyvinyl alcohol, and mixed with a small homogenizer (Swiss, manufactured by Polytron Kinemachi Riki Co., Ltd.) for about 10 minutes to form an OZW emulsion.
- 0 / Fine particles were generated by removing dichloromethane and benzyl alcohol while stirring the W-type emulsion solution, and then collected by a centrifuge.
- the fine particles obtained by the above method had a particle diameter (median diameter) of 14 mm, a drug content of 11%, a fine particle recovery rate of 71%, and a drug encapsulation rate of 50%.
- microparticles had a particle diameter (median diameter) of 16 tm, a drug content of 8%, a microparticle recovery rate of 74%, and a drug encapsulation rate of 37%.
- Betamethasone (0.025 g) and polylactic acid (0.25 g) having a weight average molecular weight of 20,000 were dissolved in dichloromethane (1 mL) and benzyl alcohol (1.5 mL).
- the same operation as in Production Example 1 was performed, except that the solution was dropped into 20 mL of a 2% aqueous polyvinyl alcohol solution.
- the obtained fine particles had a drug content of 1.33%.
- Betamethasone (0.025 g) and polylactic acid (0.25 g) having a weight average molecular weight of 20,000 were dissolved in dichloromethane (4 OmL), and the resulting dispersion was dissolved in 20 OmL of a 2% aqueous polyvinyl alcohol solution. Fine particles were obtained by performing the same operation as in Production Example 1 except that the particles were dropped.
- Comparative Production Example 2 Except that betamethasone (0.05 g) and a copolymer of mono-lactic acid-lactic acid with a weight average molecular weight of 20,000 (0.25 g) were dissolved in ethyl acetate (lmL) and penzyl alcohol (3mL). The same operation as in Production Example 1 was performed. The resulting microparticles had a particle size (median diameter) of 15 / im, a drug content of 14%, a microparticle recovery of 66%, and a drug encapsulation rate of 54%.
- microparticles had a particle size (median diameter) of 14 ⁇ m, a drug content of 13%, a microparticle recovery of 57%, and a drug encapsulation rate of 43%.
- the drug content of the fine particles produced in Production Example 3 and Comparative Production Example 1 was measured by the following method.
- the betamethasone-containing fine particles (2 mg) were dissolved in acetonitrile (1 mL), and a 5 OmM methanolic potassium phosphate solution was added to make 1 OmL. The mixture was filtered through a filter (0.2 Aim), and the filtrate was collected. The collected filtrate was quantified using a high performance liquid chromatograph, and the content of betamethasone in the fine particles was calculated. ⁇ Result>
- Table 1 shows the results. As is evident from Table 1, when preparing betamethasone-containing microparticles, the drug content of microparticles obtained by the general method of dissolving the drug and polymer only in halogenated hydrocarbons (Comparative Production Example 1) was On the other hand, it was shown that the microparticles obtained by the method of the present invention (Production Example 3) had a significantly higher drug content.
- the initial release rates of the fine particles produced by Production Examples 1-2 and Comparative Production Examples 2-3 were measured ( ⁇ Method of measuring the initial release rate> -Shake the microparticles (4 mg) in 0.1 M phosphate buffer (PH7.4), and quantify betamethasone in 0.1 M phosphate buffer (PH7.4) one day later. The initial release was measured.
- Table 2 shows the results. Table 2 shows that the fine particles (Production Examples 1 and 2) obtained by the method of the present invention were obtained from the fine particles (Comparative Production Examples 2 and 3) obtained using a non-halogen solvent and phenylalkyl alcohol. Also showed low initial burst of drug.
- the values of the initial release rate in Production Example 1, Comparative Production Examples 2 and 3 are the average of three measurements, and the value of the initial release rate in Production Example 2 is one measurement value.
- the release amount of the fine particles produced in Production Example 4 was measured over time.
- the measuring method was the same as the method of the above-mentioned In Vitro release test (1), and the measurement was carried out for three months.
- FIG. 1 shows that the microparticles obtained by the method of the present invention did not have an initial burst and released a zero-order drug over 3 months.
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- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
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Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
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CA2527994A CA2527994C (en) | 2003-06-03 | 2004-06-03 | Process for producing microparticles |
US10/559,173 US7923034B2 (en) | 2003-06-03 | 2004-06-03 | Process for producing microparticles |
EP04735976A EP1629833A4 (en) | 2003-06-03 | 2004-06-03 | METHOD FOR PRODUCING A MICROPARTICLE |
KR1020057022972A KR101150044B1 (ko) | 2003-06-03 | 2004-06-03 | 미립자의 제조 방법 |
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JP2003158085 | 2003-06-03 | ||
JP2003-158085 | 2003-06-03 |
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WO2004108115A1 true WO2004108115A1 (ja) | 2004-12-16 |
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PCT/JP2004/008047 WO2004108115A1 (ja) | 2003-06-03 | 2004-06-03 | 微粒子の製造法 |
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US (1) | US7923034B2 (ja) |
EP (1) | EP1629833A4 (ja) |
JP (1) | JP4547995B2 (ja) |
KR (1) | KR101150044B1 (ja) |
CN (1) | CN100571682C (ja) |
CA (1) | CA2527994C (ja) |
WO (1) | WO2004108115A1 (ja) |
Families Citing this family (8)
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FR2916636B1 (fr) * | 2007-05-29 | 2009-09-04 | Octalia Technologies | Vehicule sous forme d'une emulsion huile-dans-eau notamment destine a une utilisation ophtalmique ou dermocosmetique |
CN103201319B (zh) * | 2011-01-31 | 2014-11-05 | 东丽株式会社 | 聚乳酸系树脂微粒的制造方法、聚乳酸系树脂微粒和使用该微粒的化妆品 |
KR101738127B1 (ko) * | 2014-08-08 | 2017-05-22 | (주)비씨월드제약 | 약물 함유 서방성 미립자의 제조 방법 |
KR102047983B1 (ko) | 2017-11-30 | 2019-11-22 | 주식회사 지투지바이오 | 안전성 및 저장 안정성이 향상된 생분해성 미립구의 제조방법 |
WO2020183718A1 (ja) | 2019-03-14 | 2020-09-17 | エム・テクニック株式会社 | Plga微粒子、その徐放性製剤及びその製造方法 |
CN116327735A (zh) | 2020-05-08 | 2023-06-27 | M技术株式会社 | 主剂均匀分散的微球和含有其的缓释制剂 |
EP4147720A4 (en) * | 2020-05-08 | 2023-04-26 | M. Technique Co., Ltd. | MICROPHONES WITH A UNIFORMLY DISPERSED BIOACTIVE SUBSTANCE AND PREPARATION WITH DELAYED RELEASE CONTAINING THEM |
CN115551485A (zh) | 2020-05-08 | 2022-12-30 | M技术株式会社 | 均匀分散有生理活性物质的微球及含有其的缓释制剂 |
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JPH0558882A (ja) * | 1991-09-04 | 1993-03-09 | Yoshiaki Kawashima | ナノカプセルの製造法 |
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- 2004-06-03 WO PCT/JP2004/008047 patent/WO2004108115A1/ja not_active Application Discontinuation
- 2004-06-03 US US10/559,173 patent/US7923034B2/en not_active Expired - Fee Related
- 2004-06-03 CA CA2527994A patent/CA2527994C/en not_active Expired - Fee Related
- 2004-06-03 JP JP2004165170A patent/JP4547995B2/ja not_active Expired - Fee Related
- 2004-06-03 CN CNB2004800153514A patent/CN100571682C/zh not_active Expired - Fee Related
- 2004-06-03 KR KR1020057022972A patent/KR101150044B1/ko not_active IP Right Cessation
- 2004-06-03 EP EP04735976A patent/EP1629833A4/en not_active Withdrawn
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JPS6067417A (ja) * | 1983-09-24 | 1985-04-17 | Tetsuo Kato | 生体内代謝性マイクロカプセルの製法 |
JPH0446115A (ja) * | 1990-06-13 | 1992-02-17 | Eisai Co Ltd | マイクロスフィアの製造法 |
JPH0558882A (ja) * | 1991-09-04 | 1993-03-09 | Yoshiaki Kawashima | ナノカプセルの製造法 |
JPH0687758A (ja) * | 1992-07-27 | 1994-03-29 | Rhone Merieux | Lhrhホルモンおよびその類似体を徐々に放出する微小球体の製造方法と、その微小球体と、それを含む製剤 |
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Also Published As
Publication number | Publication date |
---|---|
CN1798546A (zh) | 2006-07-05 |
US7923034B2 (en) | 2011-04-12 |
CA2527994C (en) | 2014-11-18 |
CA2527994A1 (en) | 2004-12-16 |
JP2005015476A (ja) | 2005-01-20 |
EP1629833A1 (en) | 2006-03-01 |
US20060134223A1 (en) | 2006-06-22 |
CN100571682C (zh) | 2009-12-23 |
JP4547995B2 (ja) | 2010-09-22 |
KR101150044B1 (ko) | 2012-05-30 |
EP1629833A4 (en) | 2010-04-21 |
KR20060025156A (ko) | 2006-03-20 |
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