JP7378929B2 - Method for producing liposomes - Google Patents
Method for producing liposomes Download PDFInfo
- Publication number
- JP7378929B2 JP7378929B2 JP2018244108A JP2018244108A JP7378929B2 JP 7378929 B2 JP7378929 B2 JP 7378929B2 JP 2018244108 A JP2018244108 A JP 2018244108A JP 2018244108 A JP2018244108 A JP 2018244108A JP 7378929 B2 JP7378929 B2 JP 7378929B2
- Authority
- JP
- Japan
- Prior art keywords
- drugs
- liposome
- poorly water
- soluble
- lipid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 239000002502 liposome Substances 0.000 title claims description 108
- 238000004519 manufacturing process Methods 0.000 title claims description 21
- 239000003814 drug Substances 0.000 claims description 107
- 229940079593 drug Drugs 0.000 claims description 106
- 150000002632 lipids Chemical class 0.000 claims description 81
- 238000010438 heat treatment Methods 0.000 claims description 47
- 239000000203 mixture Substances 0.000 claims description 47
- 238000000034 method Methods 0.000 claims description 37
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 33
- 239000003125 aqueous solvent Substances 0.000 claims description 32
- 239000012528 membrane Substances 0.000 claims description 31
- 239000000232 Lipid Bilayer Substances 0.000 claims description 29
- 238000001816 cooling Methods 0.000 claims description 24
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 20
- 239000002994 raw material Substances 0.000 claims description 20
- 238000002156 mixing Methods 0.000 claims description 16
- 239000003960 organic solvent Substances 0.000 claims description 14
- 238000002844 melting Methods 0.000 claims description 12
- 230000008018 melting Effects 0.000 claims description 12
- 238000000354 decomposition reaction Methods 0.000 claims description 11
- 230000009477 glass transition Effects 0.000 claims description 11
- 235000012000 cholesterol Nutrition 0.000 claims description 10
- 150000003904 phospholipids Chemical class 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 8
- 239000000155 melt Substances 0.000 claims description 5
- 229930013930 alkaloid Natural products 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 238000004513 sizing Methods 0.000 claims description 4
- 235000015961 tonic Nutrition 0.000 claims description 4
- 230000001256 tonic effect Effects 0.000 claims description 4
- 229960000716 tonics Drugs 0.000 claims description 4
- 206010028980 Neoplasm Diseases 0.000 claims description 3
- 150000003797 alkaloid derivatives Chemical class 0.000 claims description 3
- 230000003115 biocidal effect Effects 0.000 claims description 3
- 150000001720 carbohydrates Chemical class 0.000 claims description 3
- 206010020751 Hypersensitivity Diseases 0.000 claims description 2
- 208000026935 allergic disease Diseases 0.000 claims description 2
- 230000007815 allergy Effects 0.000 claims description 2
- 239000007844 bleaching agent Substances 0.000 claims description 2
- 210000004369 blood Anatomy 0.000 claims description 2
- 239000008280 blood Substances 0.000 claims description 2
- 210000001124 body fluid Anatomy 0.000 claims description 2
- 239000010839 body fluid Substances 0.000 claims description 2
- 210000003169 central nervous system Anatomy 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 210000002249 digestive system Anatomy 0.000 claims description 2
- 230000003779 hair growth Effects 0.000 claims description 2
- 229940088597 hormone Drugs 0.000 claims description 2
- 239000005556 hormone Substances 0.000 claims description 2
- 239000004081 narcotic agent Substances 0.000 claims description 2
- 210000000056 organ Anatomy 0.000 claims description 2
- 244000045947 parasite Species 0.000 claims description 2
- 210000001428 peripheral nervous system Anatomy 0.000 claims description 2
- 239000012217 radiopharmaceutical Substances 0.000 claims description 2
- 229940121896 radiopharmaceutical Drugs 0.000 claims description 2
- 230000002799 radiopharmaceutical effect Effects 0.000 claims description 2
- 210000002345 respiratory system Anatomy 0.000 claims description 2
- 210000000697 sensory organ Anatomy 0.000 claims description 2
- 229940088594 vitamin Drugs 0.000 claims description 2
- 229930003231 vitamin Natural products 0.000 claims description 2
- 239000011782 vitamin Substances 0.000 claims description 2
- 235000013343 vitamin Nutrition 0.000 claims description 2
- 230000003213 activating effect Effects 0.000 claims 1
- 239000002246 antineoplastic agent Substances 0.000 claims 1
- 210000000436 anus Anatomy 0.000 claims 1
- 210000004027 cell Anatomy 0.000 claims 1
- 229940127089 cytotoxic agent Drugs 0.000 claims 1
- 238000002483 medication Methods 0.000 claims 1
- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 description 32
- 239000006185 dispersion Substances 0.000 description 25
- APKFDSVGJQXUKY-KKGHZKTASA-N Amphotericin-B Natural products O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1C=CC=CC=CC=CC=CC=CC=C[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-KKGHZKTASA-N 0.000 description 24
- 229960003942 amphotericin b Drugs 0.000 description 24
- 238000005538 encapsulation Methods 0.000 description 22
- 239000000126 substance Substances 0.000 description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 10
- 230000000052 comparative effect Effects 0.000 description 9
- 235000014113 dietary fatty acids Nutrition 0.000 description 9
- 239000000194 fatty acid Substances 0.000 description 9
- 229930195729 fatty acid Natural products 0.000 description 9
- 229930183010 Amphotericin Natural products 0.000 description 8
- QGGFZZLFKABGNL-UHFFFAOYSA-N Amphotericin A Natural products OC1C(N)C(O)C(C)OC1OC1C=CC=CC=CC=CCCC=CC=CC(C)C(O)C(C)C(C)OC(=O)CC(O)CC(O)CCC(O)C(O)CC(O)CC(O)(CC(O)C2C(O)=O)OC2C1 QGGFZZLFKABGNL-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 229930006000 Sucrose Natural products 0.000 description 8
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 8
- 229940009444 amphotericin Drugs 0.000 description 8
- 239000005720 sucrose Substances 0.000 description 8
- 229930182558 Sterol Natural products 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 7
- 150000003432 sterols Chemical class 0.000 description 7
- 235000003702 sterols Nutrition 0.000 description 7
- 235000010384 tocopherol Nutrition 0.000 description 7
- 229960001295 tocopherol Drugs 0.000 description 7
- 229930003799 tocopherol Natural products 0.000 description 7
- 239000011732 tocopherol Substances 0.000 description 7
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 7
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 6
- FVJZSBGHRPJMMA-IOLBBIBUSA-N PG(18:0/18:0) Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@@H](O)CO)OC(=O)CCCCCCCCCCCCCCCCC FVJZSBGHRPJMMA-IOLBBIBUSA-N 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 150000004665 fatty acids Chemical class 0.000 description 6
- 239000011521 glass Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 229920000515 polycarbonate Polymers 0.000 description 6
- 239000004417 polycarbonate Substances 0.000 description 6
- -1 polyoxyethylene Polymers 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical class CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- NAQWICRLNQSPPW-UHFFFAOYSA-N 1,2,3,4-tetrachloronaphthalene Chemical compound C1=CC=CC2=C(Cl)C(Cl)=C(Cl)C(Cl)=C21 NAQWICRLNQSPPW-UHFFFAOYSA-N 0.000 description 4
- ATBOMIWRCZXYSZ-XZBBILGWSA-N [1-[2,3-dihydroxypropoxy(hydroxy)phosphoryl]oxy-3-hexadecanoyloxypropan-2-yl] (9e,12e)-octadeca-9,12-dienoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C\C\C=C\CCCCC ATBOMIWRCZXYSZ-XZBBILGWSA-N 0.000 description 4
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 4
- 239000003963 antioxidant agent Substances 0.000 description 4
- 235000006708 antioxidants Nutrition 0.000 description 4
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- OILXMJHPFNGGTO-UHFFFAOYSA-N (22E)-(24xi)-24-methylcholesta-5,22-dien-3beta-ol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)C=CC(C)C(C)C)C1(C)CC2 OILXMJHPFNGGTO-UHFFFAOYSA-N 0.000 description 3
- QYIXCDOBOSTCEI-QCYZZNICSA-N (5alpha)-cholestan-3beta-ol Chemical compound C([C@@H]1CC2)[C@@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@H](C)CCCC(C)C)[C@@]2(C)CC1 QYIXCDOBOSTCEI-QCYZZNICSA-N 0.000 description 3
- PZNPLUBHRSSFHT-RRHRGVEJSA-N 1-hexadecanoyl-2-octadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[C@@H](COP([O-])(=O)OCC[N+](C)(C)C)COC(=O)CCCCCCCCCCCCCCC PZNPLUBHRSSFHT-RRHRGVEJSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 description 3
- 229930186217 Glycolipid Natural products 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 3
- QYIXCDOBOSTCEI-UHFFFAOYSA-N alpha-cholestanol Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(C)CCCC(C)C)C1(C)CC2 QYIXCDOBOSTCEI-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 238000005342 ion exchange Methods 0.000 description 3
- 239000012768 molten material Substances 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 3
- 150000003905 phosphatidylinositols Chemical class 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000008347 soybean phospholipid Substances 0.000 description 3
- 230000007704 transition Effects 0.000 description 3
- JQWAHKMIYCERGA-UHFFFAOYSA-N (2-nonanoyloxy-3-octadeca-9,12-dienoyloxypropoxy)-[2-(trimethylazaniumyl)ethyl]phosphinate Chemical compound CCCCCCCCC(=O)OC(COP([O-])(=O)CC[N+](C)(C)C)COC(=O)CCCCCCCC=CCC=CCCCCC JQWAHKMIYCERGA-UHFFFAOYSA-N 0.000 description 2
- FROLUYNBHPUZQU-IIZJPUEISA-N (2R,3R,4S,5R)-2-(hydroxymethyl)-6-[3-[3-[(3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxypropoxy]propoxy]oxane-3,4,5-triol Chemical compound OC[C@H]1OC(OCCCOCCCOC2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@@H](O)[C@H]1O FROLUYNBHPUZQU-IIZJPUEISA-N 0.000 description 2
- OQMZNAMGEHIHNN-UHFFFAOYSA-N 7-Dehydrostigmasterol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CC(CC)C(C)C)CCC33)C)C3=CC=C21 OQMZNAMGEHIHNN-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- 108010052285 Membrane Proteins Proteins 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- LGJMUZUPVCAVPU-UHFFFAOYSA-N beta-Sitostanol Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(C)CCC(CC)C(C)C)C1(C)CC2 LGJMUZUPVCAVPU-UHFFFAOYSA-N 0.000 description 2
- 239000003012 bilayer membrane Substances 0.000 description 2
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- QBSJHOGDIUQWTH-UHFFFAOYSA-N dihydrolanosterol Natural products CC(C)CCCC(C)C1CCC2(C)C3=C(CCC12C)C4(C)CCC(C)(O)C(C)(C)C4CC3 QBSJHOGDIUQWTH-UHFFFAOYSA-N 0.000 description 2
- 150000002016 disaccharides Chemical class 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 150000002270 gangliosides Chemical class 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000004570 mortar (masonry) Substances 0.000 description 2
- SECPZKHBENQXJG-FPLPWBNLSA-N palmitoleic acid Chemical compound CCCCCC\C=C/CCCCCCCC(O)=O SECPZKHBENQXJG-FPLPWBNLSA-N 0.000 description 2
- 239000002459 polyene antibiotic agent Substances 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- 238000001507 sample dispersion Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 235000003441 saturated fatty acids Nutrition 0.000 description 2
- 150000004671 saturated fatty acids Chemical class 0.000 description 2
- NLQLSVXGSXCXFE-UHFFFAOYSA-N sitosterol Natural products CC=C(/CCC(C)C1CC2C3=CCC4C(C)C(O)CCC4(C)C3CCC2(C)C1)C(C)C NLQLSVXGSXCXFE-UHFFFAOYSA-N 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 150000005846 sugar alcohols Chemical class 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- KZJWDPNRJALLNS-VPUBHVLGSA-N (-)-beta-Sitosterol Natural products O[C@@H]1CC=2[C@@](C)([C@@H]3[C@H]([C@H]4[C@@](C)([C@H]([C@H](CC[C@@H](C(C)C)CC)C)CC4)CC3)CC=2)CC1 KZJWDPNRJALLNS-VPUBHVLGSA-N 0.000 description 1
- BQPPJGMMIYJVBR-UHFFFAOYSA-N (10S)-3c-Acetoxy-4.4.10r.13c.14t-pentamethyl-17c-((R)-1.5-dimethyl-hexen-(4)-yl)-(5tH)-Delta8-tetradecahydro-1H-cyclopenta[a]phenanthren Natural products CC12CCC(OC(C)=O)C(C)(C)C1CCC1=C2CCC2(C)C(C(CCC=C(C)C)C)CCC21C BQPPJGMMIYJVBR-UHFFFAOYSA-N 0.000 description 1
- MBZYKEVPFYHDOH-UHFFFAOYSA-N (10S)-3c-Hydroxy-4.4.10r.13t.14c-pentamethyl-17t-((R)-1.5-dimethyl-hexyl)-(5tH)-Delta8-tetradecahydro-1H-cyclopenta[a]phenanthren Natural products CC12CCC(O)C(C)(C)C1CCC1=C2CCC2(C)C(C(C)CCCC(C)C)CCC21C MBZYKEVPFYHDOH-UHFFFAOYSA-N 0.000 description 1
- CSVWWLUMXNHWSU-UHFFFAOYSA-N (22E)-(24xi)-24-ethyl-5alpha-cholest-22-en-3beta-ol Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(C)C=CC(CC)C(C)C)C1(C)CC2 CSVWWLUMXNHWSU-UHFFFAOYSA-N 0.000 description 1
- RQOCXCFLRBRBCS-UHFFFAOYSA-N (22E)-cholesta-5,7,22-trien-3beta-ol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CCC(C)C)CCC33)C)C3=CC=C21 RQOCXCFLRBRBCS-UHFFFAOYSA-N 0.000 description 1
- CHGIKSSZNBCNDW-UHFFFAOYSA-N (3beta,5alpha)-4,4-Dimethylcholesta-8,24-dien-3-ol Natural products CC12CCC(O)C(C)(C)C1CCC1=C2CCC2(C)C(C(CCC=C(C)C)C)CCC21 CHGIKSSZNBCNDW-UHFFFAOYSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- PORPENFLTBBHSG-MGBGTMOVSA-N 1,2-dihexadecanoyl-sn-glycerol-3-phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(O)=O)OC(=O)CCCCCCCCCCCCCCC PORPENFLTBBHSG-MGBGTMOVSA-N 0.000 description 1
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- XYTLYKGXLMKYMV-UHFFFAOYSA-N 14alpha-methylzymosterol Natural products CC12CCC(O)CC1CCC1=C2CCC2(C)C(C(CCC=C(C)C)C)CCC21C XYTLYKGXLMKYMV-UHFFFAOYSA-N 0.000 description 1
- SPSPIUSUWPLVKD-UHFFFAOYSA-N 2,3-dibutyl-6-methylphenol Chemical compound CCCCC1=CC=C(C)C(O)=C1CCCC SPSPIUSUWPLVKD-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- MBZYKEVPFYHDOH-BQNIITSRSA-N 24,25-dihydrolanosterol Chemical compound C([C@@]12C)C[C@H](O)C(C)(C)[C@@H]1CCC1=C2CC[C@]2(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@]21C MBZYKEVPFYHDOH-BQNIITSRSA-N 0.000 description 1
- KLEXDBGYSOIREE-UHFFFAOYSA-N 24xi-n-propylcholesterol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)CCC(CCC)C(C)C)C1(C)CC2 KLEXDBGYSOIREE-UHFFFAOYSA-N 0.000 description 1
- HVCOBJNICQPDBP-UHFFFAOYSA-N 3-[3-[3,5-dihydroxy-6-methyl-4-(3,4,5-trihydroxy-6-methyloxan-2-yl)oxyoxan-2-yl]oxydecanoyloxy]decanoic acid;hydrate Chemical compound O.OC1C(OC(CC(=O)OC(CCCCCCC)CC(O)=O)CCCCCCC)OC(C)C(O)C1OC1C(O)C(O)C(O)C(C)O1 HVCOBJNICQPDBP-UHFFFAOYSA-N 0.000 description 1
- FPTJELQXIUUCEY-UHFFFAOYSA-N 3beta-Hydroxy-lanostan Natural products C1CC2C(C)(C)C(O)CCC2(C)C2C1C1(C)CCC(C(C)CCCC(C)C)C1(C)CC2 FPTJELQXIUUCEY-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- OILXMJHPFNGGTO-NRHJOKMGSA-N Brassicasterol Natural products O[C@@H]1CC=2[C@@](C)([C@@H]3[C@H]([C@H]4[C@](C)([C@H]([C@@H](/C=C/[C@H](C(C)C)C)C)CC4)CC3)CC=2)CC1 OILXMJHPFNGGTO-NRHJOKMGSA-N 0.000 description 1
- YDNKGFDKKRUKPY-JHOUSYSJSA-N C16 ceramide Natural products CCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)C=CCCCCCCCCCCCCC YDNKGFDKKRUKPY-JHOUSYSJSA-N 0.000 description 1
- SGNBVLSWZMBQTH-FGAXOLDCSA-N Campesterol Natural products O[C@@H]1CC=2[C@@](C)([C@@H]3[C@H]([C@H]4[C@@](C)([C@H]([C@H](CC[C@H](C(C)C)C)C)CC4)CC3)CC=2)CC1 SGNBVLSWZMBQTH-FGAXOLDCSA-N 0.000 description 1
- LPZCCMIISIBREI-MTFRKTCUSA-N Citrostadienol Natural products CC=C(CC[C@@H](C)[C@H]1CC[C@H]2C3=CC[C@H]4[C@H](C)[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)C(C)C LPZCCMIISIBREI-MTFRKTCUSA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- ARVGMISWLZPBCH-UHFFFAOYSA-N Dehydro-beta-sitosterol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)CCC(CC)C(C)C)CCC33)C)C3=CC=C21 ARVGMISWLZPBCH-UHFFFAOYSA-N 0.000 description 1
- BDCFUHIWJODVNG-UHFFFAOYSA-N Desmosterol Natural products C1C=C2CC(O)C=CC2(C)C2C1C1CCC(C(C)CCC(CC)C(C)C)C1(C)CC2 BDCFUHIWJODVNG-UHFFFAOYSA-N 0.000 description 1
- DNVPQKQSNYMLRS-NXVQYWJNSA-N Ergosterol Natural products CC(C)[C@@H](C)C=C[C@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@@H]3CC[C@]12C DNVPQKQSNYMLRS-NXVQYWJNSA-N 0.000 description 1
- BKLIAINBCQPSOV-UHFFFAOYSA-N Gluanol Natural products CC(C)CC=CC(C)C1CCC2(C)C3=C(CCC12C)C4(C)CCC(O)C(C)(C)C4CC3 BKLIAINBCQPSOV-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 description 1
- BTEISVKTSQLKST-UHFFFAOYSA-N Haliclonasterol Natural products CC(C=CC(C)C(C)(C)C)C1CCC2C3=CC=C4CC(O)CCC4(C)C3CCC12C BTEISVKTSQLKST-UHFFFAOYSA-N 0.000 description 1
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 description 1
- 101001105486 Homo sapiens Proteasome subunit alpha type-7 Proteins 0.000 description 1
- 235000000072 L-ascorbyl-6-palmitate Nutrition 0.000 description 1
- QAQJMLQRFWZOBN-LAUBAEHRSA-N L-ascorbyl-6-palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-LAUBAEHRSA-N 0.000 description 1
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 description 1
- LOPKHWOTGJIQLC-UHFFFAOYSA-N Lanosterol Natural products CC(CCC=C(C)C)C1CCC2(C)C3=C(CCC12C)C4(C)CCC(C)(O)C(C)(C)C4CC3 LOPKHWOTGJIQLC-UHFFFAOYSA-N 0.000 description 1
- 239000005639 Lauric acid Substances 0.000 description 1
- OYHQOLUKZRVURQ-HZJYTTRNSA-N Linoleic acid Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(O)=O OYHQOLUKZRVURQ-HZJYTTRNSA-N 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- CRJGESKKUOMBCT-VQTJNVASSA-N N-acetylsphinganine Chemical compound CCCCCCCCCCCCCCC[C@@H](O)[C@H](CO)NC(C)=O CRJGESKKUOMBCT-VQTJNVASSA-N 0.000 description 1
- CAHGCLMLTWQZNJ-UHFFFAOYSA-N Nerifoliol Natural products CC12CCC(O)C(C)(C)C1CCC1=C2CCC2(C)C(C(CCC=C(C)C)C)CCC21C CAHGCLMLTWQZNJ-UHFFFAOYSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- 235000021319 Palmitoleic acid Nutrition 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- 102100021201 Proteasome subunit alpha type-7 Human genes 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- OILXMJHPFNGGTO-ZRUUVFCLSA-N UNPD197407 Natural products C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)C=C[C@H](C)C(C)C)[C@@]1(C)CC2 OILXMJHPFNGGTO-ZRUUVFCLSA-N 0.000 description 1
- HZYXFRGVBOPPNZ-UHFFFAOYSA-N UNPD88870 Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)=CCC(CC)C(C)C)C1(C)CC2 HZYXFRGVBOPPNZ-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 125000005211 alkyl trimethyl ammonium group Chemical group 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000003945 anionic surfactant Substances 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- WPIHMWBQRSAMDE-YCZTVTEBSA-N beta-D-galactosyl-(1->4)-beta-D-galactosyl-N-(pentacosanoyl)sphingosine Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCC(=O)N[C@@H](CO[C@@H]1O[C@H](CO)[C@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O)[C@H](O)\C=C\CCCCCCCCCCCCC WPIHMWBQRSAMDE-YCZTVTEBSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- MJVXAPPOFPTTCA-UHFFFAOYSA-N beta-Sistosterol Natural products CCC(CCC(C)C1CCC2C3CC=C4C(C)C(O)CCC4(C)C3CCC12C)C(C)C MJVXAPPOFPTTCA-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- NJKOMDUNNDKEAI-UHFFFAOYSA-N beta-sitosterol Natural products CCC(CCC(C)C1CCC2(C)C3CC=C4CC(O)CCC4C3CCC12C)C(C)C NJKOMDUNNDKEAI-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- OILXMJHPFNGGTO-ZAUYPBDWSA-N brassicasterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)/C=C/[C@H](C)C(C)C)[C@@]1(C)CC2 OILXMJHPFNGGTO-ZAUYPBDWSA-N 0.000 description 1
- 235000004420 brassicasterol Nutrition 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- SGNBVLSWZMBQTH-PODYLUTMSA-N campesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CC[C@@H](C)C(C)C)[C@@]1(C)CC2 SGNBVLSWZMBQTH-PODYLUTMSA-N 0.000 description 1
- 235000000431 campesterol Nutrition 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 239000003093 cationic surfactant Substances 0.000 description 1
- 230000020411 cell activation Effects 0.000 description 1
- 229940106189 ceramide Drugs 0.000 description 1
- ZVEQCJWYRWKARO-UHFFFAOYSA-N ceramide Natural products CCCCCCCCCCCCCCC(O)C(=O)NC(CO)C(O)C=CCCC=C(C)CCCCCCCCC ZVEQCJWYRWKARO-UHFFFAOYSA-N 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- SECPZKHBENQXJG-UHFFFAOYSA-N cis-palmitoleic acid Natural products CCCCCCC=CCCCCCCCC(O)=O SECPZKHBENQXJG-UHFFFAOYSA-N 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- AVSXSVCZWQODGV-DPAQBDIFSA-N desmosterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@@H](CCC=C(C)C)C)[C@@]1(C)CC2 AVSXSVCZWQODGV-DPAQBDIFSA-N 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- DNVPQKQSNYMLRS-SOWFXMKYSA-N ergosterol Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H](CC[C@]3([C@H]([C@H](C)/C=C/[C@@H](C)C(C)C)CC[C@H]33)C)C3=CC=C21 DNVPQKQSNYMLRS-SOWFXMKYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 229930182830 galactose Natural products 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 150000002327 glycerophospholipids Chemical class 0.000 description 1
- 150000002339 glycosphingolipids Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- JEGUKCSWCFPDGT-UHFFFAOYSA-N h2o hydrate Chemical compound O.O JEGUKCSWCFPDGT-UHFFFAOYSA-N 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000033444 hydroxylation Effects 0.000 description 1
- 238000005805 hydroxylation reaction Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229960000367 inositol Drugs 0.000 description 1
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- CAHGCLMLTWQZNJ-RGEKOYMOSA-N lanosterol Chemical compound C([C@]12C)C[C@@H](O)C(C)(C)[C@H]1CCC1=C2CC[C@]2(C)[C@H]([C@H](CCC=C(C)C)C)CC[C@@]21C CAHGCLMLTWQZNJ-RGEKOYMOSA-N 0.000 description 1
- 229940058690 lanosterol Drugs 0.000 description 1
- OYHQOLUKZRVURQ-IXWMQOLASA-N linoleic acid Natural products CCCCC\C=C/C\C=C\CCCCCCCC(O)=O OYHQOLUKZRVURQ-IXWMQOLASA-N 0.000 description 1
- 235000020778 linoleic acid Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000010297 mechanical methods and process Methods 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- DDOVBCWVTOHGCU-QMXMISKISA-N n-[(e,2s,3r)-3-hydroxy-1-[(2r,3r,4s,5r,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxynonadec-4-en-2-yl]octadecanamide Chemical compound CCCCCCCCCCCCCCCCCC(=O)N[C@H]([C@H](O)\C=C\CCCCCCCCCCCCCC)CO[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O DDOVBCWVTOHGCU-QMXMISKISA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- VVGIYYKRAMHVLU-UHFFFAOYSA-N newbouldiamide Natural products CCCCCCCCCCCCCCCCCCCC(O)C(O)C(O)C(CO)NC(=O)CCCCCCCCCCCCCCCCC VVGIYYKRAMHVLU-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 235000021313 oleic acid Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229920001281 polyalkylene Polymers 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 150000008442 polyphenolic compounds Chemical class 0.000 description 1
- 235000013824 polyphenols Nutrition 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- 238000010008 shearing Methods 0.000 description 1
- KZJWDPNRJALLNS-VJSFXXLFSA-N sitosterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CC[C@@H](CC)C(C)C)[C@@]1(C)CC2 KZJWDPNRJALLNS-VJSFXXLFSA-N 0.000 description 1
- 235000015500 sitosterol Nutrition 0.000 description 1
- 229950005143 sitosterol Drugs 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- ZDQYSKICYIVCPN-UHFFFAOYSA-L sodium succinate (anhydrous) Chemical compound [Na+].[Na+].[O-]C(=O)CCC([O-])=O ZDQYSKICYIVCPN-UHFFFAOYSA-L 0.000 description 1
- YNQYZBDRJZVSJE-QTOMIGAPSA-M sodium;2,3-dihydroxypropyl [(2r)-2,3-di(octadecanoyloxy)propyl] phosphate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC(O)CO)OC(=O)CCCCCCCCCCCCCCCCC YNQYZBDRJZVSJE-QTOMIGAPSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- HCXVJBMSMIARIN-PHZDYDNGSA-N stigmasterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)/C=C/[C@@H](CC)C(C)C)[C@@]1(C)CC2 HCXVJBMSMIARIN-PHZDYDNGSA-N 0.000 description 1
- 235000016831 stigmasterol Nutrition 0.000 description 1
- 229940032091 stigmasterol Drugs 0.000 description 1
- BFDNMXAIBMJLBB-UHFFFAOYSA-N stigmasterol Natural products CCC(C=CC(C)C1CCCC2C3CC=C4CC(O)CCC4(C)C3CCC12C)C(C)C BFDNMXAIBMJLBB-UHFFFAOYSA-N 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 description 1
- 238000009210 therapy by ultrasound Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Manufacturing Of Micro-Capsules (AREA)
- Medicinal Preparation (AREA)
- Cosmetics (AREA)
Description
本発明は、難水溶性薬物を内包するリポソームの製造方法に関する。 The present invention relates to a method for producing liposomes containing poorly water-soluble drugs.
リポソームは、両親媒性脂質分子の二分子膜からなる微小胞体である。リポソームは、その内部の水相に水溶性物質を、二分子膜内に脂溶性物質を封入することができ、また、高い生体親和性を有する。そのため、リポソームは、薬物送達システム(DDS)のキャリアとして開発研究が盛んに行われている。 Liposomes are microvesicles consisting of a bilayer membrane of amphiphilic lipid molecules. Liposomes can encapsulate water-soluble substances in their internal aqueous phase and lipid-soluble substances in their bilayer membranes, and also have high biocompatibility. Therefore, liposomes are being actively researched and developed as carriers for drug delivery systems (DDS).
難水溶性薬物を内包するリポソームの調製方法としては、有機溶媒法(バンガム法)が一般的である。例えば、特許文献1では、難水溶性のポリエン系抗生物質とホスファチジルグリセロールをクロロホルムとメタノールの等容量溶液に溶解した後、脱溶媒して乾燥し、次いで水和、剪断することでポリエン系抗生物質を封入したリポソームを調製する方法が報告されている。
一方、有機溶媒を使用しない無溶剤法として、リポソーム膜成分物質と水性溶液とを、粉末結晶としての膜成分の相転移温度以上でかつ低くても50℃にて撹拌する方法(特許文献2)、両親媒性物質と活性因子の水性溶媒分散液を高温加熱する方法(特許文献3)、超音波乳化機や高圧ホモジナイザー等による機械的な方法(非特許文献1)が報告されている。
As a method for preparing liposomes encapsulating poorly water-soluble drugs, an organic solvent method (Bangham method) is generally used. For example, in Patent Document 1, a poorly water-soluble polyene antibiotic and phosphatidylglycerol are dissolved in an equal volume solution of chloroform and methanol, and then the polyene antibiotic is dissolved by removing the solvent and drying, followed by hydration and shearing. A method for preparing liposomes encapsulating .
On the other hand, as a solvent-free method that does not use an organic solvent, a liposome membrane component substance and an aqueous solution are stirred at a temperature equal to or higher than the phase transition temperature of the membrane component as a powder crystal and at least 50°C (Patent Document 2). , a method of heating an aqueous solvent dispersion of an amphipathic substance and an active factor at high temperature (Patent Document 3), and a mechanical method using an ultrasonic emulsifier, a high-pressure homogenizer, etc. (Non-Patent Document 1) have been reported.
しかしながら、前述のリポソームの調製方法のうち、有機溶媒を使用する方法は、リポソームへの有機溶媒の残留が避けられず、また、工程が煩雑で相当の時間を要するため、安全性、工業的生産性の点で問題がある。これに対して、特許文献2、3等の方法は有機溶媒の使用を回避できる手法であるが、リポソームに難水溶性薬物は取り込まれ難く、得られるリポソームの薬物内包率は低いという問題があった。また、攪拌の際の高剪断力により、不安定な薬物を封入する場合は分解や変性の問題が生じ得る。
したがって、本発明は、難水溶性薬物を内包するリポソームの新たな製造方法を提供することに関する。
However, among the liposome preparation methods described above, the method using organic solvents inevitably leaves the organic solvent in the liposomes, and the process is complicated and takes a considerable amount of time, so it is difficult to ensure safety and industrial production. There is a problem with sexuality. On the other hand, methods such as Patent Documents 2 and 3 are methods that can avoid the use of organic solvents, but they have the problem that poorly water-soluble drugs are difficult to incorporate into liposomes, and the drug encapsulation rate of the resulting liposomes is low. Ta. Additionally, high shear forces during stirring can cause problems with decomposition and denaturation when unstable drugs are encapsulated.
Therefore, the present invention relates to providing a new method for producing liposomes containing poorly water-soluble drugs.
本発明者は、難水溶性薬物のリポソーム化技術について種々検討したところ、リポソームを構成する脂質と難水溶性薬物を加熱溶融させた後、冷却して脂質混合物を得、得られた脂質混合物を水性溶媒に分散することで、有機溶媒を用いなくとも高い内包率で難水溶性薬物を内包したリポソームが得られることを見出した。 The present inventor conducted various studies on liposome formation technology for poorly water-soluble drugs, and found that the lipids constituting liposomes and poorly water-soluble drugs were melted by heating, and then cooled to obtain a lipid mixture. It has been found that by dispersing the drug in an aqueous solvent, liposomes encapsulating a poorly water-soluble drug at a high encapsulation rate can be obtained without using an organic solvent.
すなわち、本発明は、水性溶媒への分散時に難水溶性薬物を内包するリポソームとなる脂質混合物の製造方法であって、水性溶媒が加熱混合原料の全質量に対して20質量%以下となる条件で、リポソームを構成する脂質及び難水溶性薬物を加熱混合して溶融させる工程と、溶融した溶融物を冷却する工程を含む、脂質混合物の製造方法を提供するものである。
また、本発明は、前記脂質混合物を水性溶媒へ分散する工程を含む、難水溶性薬物を内包するリポソームの製造方法を提供するものである。
That is, the present invention provides a method for producing a lipid mixture that becomes liposomes encapsulating poorly water-soluble drugs when dispersed in an aqueous solvent, the conditions being such that the aqueous solvent is 20% by mass or less based on the total mass of the heated mixed raw materials. The present invention provides a method for producing a lipid mixture, which includes a step of heating and mixing a lipid and a poorly water-soluble drug constituting a liposome to melt it, and a step of cooling the molten material.
The present invention also provides a method for producing a liposome encapsulating a poorly water-soluble drug, which includes the step of dispersing the lipid mixture in an aqueous solvent.
本発明によれば、簡便な工程により、高い内包率で難水溶性薬物をリポソームに内包させることができ、難水溶性薬物を内包するリポソームを工業的に有利に製造することができる。本発明の難水溶性薬物を内包するリポソームは、製造工程中に有機溶媒を用いずに製造可能なため、安全面からも好適である。 According to the present invention, a poorly water-soluble drug can be encapsulated in liposomes at a high encapsulation rate through a simple process, and liposomes encapsulating a poorly water-soluble drug can be advantageously produced industrially. The liposome encapsulating the poorly water-soluble drug of the present invention can be manufactured without using an organic solvent during the manufacturing process, and is therefore suitable from a safety standpoint.
本発明は、水性溶媒への分散時に難水溶性薬物を内包するリポソームとなる脂質混合物の製造方法であって、水性溶媒が加熱混合原料の全質量に対して20質量%以下となる条件で、リポソームを構成する脂質及び難水溶性薬物を加熱混合して溶融させる工程と、溶融した溶融物を冷却する工程を含む、脂質混合物の製造方法、及び、前記脂質混合物を水性溶媒へ分散する工程を含む、難水溶性薬物を内包するリポソームの製造方法である。 The present invention is a method for producing a lipid mixture that becomes a liposome containing a poorly water-soluble drug when dispersed in an aqueous solvent, under the condition that the aqueous solvent is 20% by mass or less based on the total mass of the heated mixed raw material, A method for producing a lipid mixture, comprising a step of heating and mixing a lipid and a poorly water-soluble drug constituting a liposome to melt it, and a step of cooling the molten mixture, and a step of dispersing the lipid mixture in an aqueous solvent. This is a method for producing liposomes encapsulating poorly water-soluble drugs.
本明細書において、脂質混合物とは、リポソームを構成する脂質と難水溶性薬物、及び必要に応じて含有されるその他の加熱混合原料を加熱混合して溶融させた後、冷却して得られる固体状もしくはペースト状の混合物を指す。当該脂質混合物は、水性溶媒への分散時に難水溶性薬物を内包するリポソームを形成する。 In this specification, a lipid mixture refers to a solid obtained by heating and mixing the lipids constituting the liposome, a poorly water-soluble drug, and other heat-mixed raw materials contained as necessary to melt the mixture, and then cooling the mixture. Refers to a paste-like mixture. The lipid mixture forms liposomes encapsulating poorly water-soluble drugs when dispersed in an aqueous solvent.
本明細書において、難水溶性薬物とは、25℃における水への溶解度が2.0g/L以下の薬物を意味する。本発明は、25℃における水への溶解度が1.5g/L以下の薬物、更には25℃における水への溶解度が1.0g/L以下の薬物を好ましく適用できる。ここで溶解度は、溶液1L中に溶解している溶質のグラム数を表し、単位は[g/L]ある。
難水溶性薬物の性質として、リポソームを構成する脂質二重膜への内包のしやすさの観点から、脂溶性又は両親媒性の薬物が好ましく適用できる。
As used herein, a poorly water-soluble drug means a drug having a solubility in water of 2.0 g/L or less at 25°C. The present invention is preferably applicable to drugs whose solubility in water at 25°C is 1.5 g/L or less, and further, to drugs whose solubility in water at 25°C is 1.0 g/L or less. Here, solubility represents the number of grams of solute dissolved in 1 L of solution, and its unit is [g/L].
Regarding the properties of poorly water-soluble drugs, fat-soluble or amphipathic drugs are preferably used from the viewpoint of ease of inclusion in the lipid bilayer membrane constituting liposomes.
難水溶性薬物としては、特に限定されず、医薬品や医薬部外品、化粧品、食品等に使用される化合物が挙げられる。例えば、中枢神経系用薬、末梢神経系用薬、感覚器官用薬、循環器官用薬、呼吸器官用薬、消化器官用薬、ホルモン剤、泌尿生殖器官及び肛門用薬、歯科口腔用薬、ビタミン剤、滋養強壮薬、血液・体液用薬、細胞賦活用薬、腫瘍用薬、放射性医薬品、アレルギー用薬、抗生物質製剤、化学療法剤、生物学的製剤、寄生動物に対する薬、アルカロイド系・非アルカロイド系麻薬、診断用薬、育毛剤、養毛剤、発毛剤、美白剤等が挙げられる。難水溶性薬物は、1種であっても、2種以上の混合物であってもよい。
なかでも、抗真菌薬等の抗生物質製剤、腫瘍用薬等はリポソーム製剤として実用化されており、本発明を適用することが好ましい。
The poorly water-soluble drug is not particularly limited, and includes compounds used in pharmaceuticals, quasi-drugs, cosmetics, foods, and the like. For example, drugs for the central nervous system, drugs for the peripheral nervous system, drugs for the sensory organs, drugs for the circulatory system, drugs for the respiratory system, drugs for the digestive system, hormones, drugs for the genitourinary and anal organs, drugs for the dental and oral cavity, Vitamin preparations, nutritional tonics, blood and body fluid drugs, cell activation drugs, tumor drugs, radiopharmaceuticals, allergy drugs, antibiotic preparations, chemotherapy drugs, biological preparations, drugs against parasites, alkaloids, Examples include non-alkaloid narcotics, diagnostic drugs, hair restorers, hair tonics, hair growth agents, and whitening agents. The poorly water-soluble drug may be used alone or in a mixture of two or more.
Among these, antibiotic preparations such as antifungal drugs, drugs for tumors, etc. have been put into practical use as liposome preparations, and it is preferable to apply the present invention thereto.
本発明で用いられるリポソームを構成する脂質は、脂質二重膜を形成する脂質として、リン脂質又は糖脂質の少なくとも1種を含む。これらの脂質は、アミノ基、第4級アンモニウム基等が導入されたカチオン性脂質や、ポリアルキレングリコールが導入されたポリアルキレングリコール修飾脂質であっても良い。 The lipid constituting the liposome used in the present invention contains at least one type of phospholipid or glycolipid as a lipid that forms a lipid bilayer membrane. These lipids may be cationic lipids into which an amino group, quaternary ammonium group, etc. are introduced, or polyalkylene glycol-modified lipids into which polyalkylene glycol is introduced.
リン脂質は、動植物から抽出、精製した天然物であっても、化学合成したものであってもよく、水素添加、水酸化処理等の加工を施したものであってもよい。
例えば、ホスファチジルコリン、ホスファチジン酸、ホスファチジルセリン、ホスファチジルエタノールアミン、ホスファチジルイノシトール、ホスファチジルグリセロール等のグリセロリン脂質;スフィンゴミエリン、セラミドシリアチン等のスフィンゴリン脂質;大豆レシチン、卵黄レシチン、大豆レシチン水素添加物、卵黄レシチン水素添加物等が挙げられ、リポソームの安定性の観点から、ホスファチジルコリン、ホスファチジルエタノールアミン、ホスファチジルイノシトール、ホスファチジルグリセロールが好ましい。
Phospholipids may be natural products extracted and purified from animals and plants, chemically synthesized, or processed through hydrogenation, hydroxylation, and the like.
For example, glycerophospholipids such as phosphatidylcholine, phosphatidic acid, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, and phosphatidylglycerol; sphingophospholipids such as sphingomyelin and ceramide syriatin; soy lecithin, egg yolk lecithin, soy lecithin hydrogenated product, egg yolk lecithin Examples include hydrogenated substances, and from the viewpoint of liposome stability, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, and phosphatidylglycerol are preferred.
糖脂質としては、例えば、スルホキシリボシルグリセリド、ジグリコシルジグリセリド、ジガラクトシルジグリセリド、ガラクトシルジグリセリド、グリコシルジグリセリド等のグリセロ糖脂質;ガラクトシルセラミド、ラクトシルセラミド、ガングリオシド等のスフィンゴ糖脂質が挙げられ、リポソームの安定性の観点から、スルホキシリボシルグリセリド、ジガラクトシルジグリセリド、ガングリオシドが好ましい。 Examples of glycolipids include glyceroglycolipids such as sulfoxyribosylglyceride, diglycosyldiglyceride, digalactosyldiglyceride, galactosyldiglyceride, and glycosyldiglyceride; glycosphingolipids such as galactosylceramide, lactosylceramide, and ganglioside; From the viewpoint of stability, sulfoxyribosylglyceride, digalactosyldiglyceride, and ganglioside are preferred.
これら脂質を構成する脂肪酸としては、飽和又は不飽和の直鎖炭化水素鎖が挙げられる。なかでも、リポソームの安定性の観点から、炭素数12~20の脂肪酸が好ましく、炭素数14~18の脂肪酸がより好ましく、飽和脂肪酸が更に好ましい。 The fatty acids constituting these lipids include saturated or unsaturated straight hydrocarbon chains. Among these, from the viewpoint of liposome stability, fatty acids having 12 to 20 carbon atoms are preferred, fatty acids having 14 to 18 carbon atoms are more preferred, and saturated fatty acids are even more preferred.
脂質二重膜を形成する脂質は、リポソームの安定性の観点から、リン脂質が好ましく、なかでも、ホスファチジルコリン、ホスファチジルエタノールアミン、ホスファチジルイノシトール、ホスファチジルグリセロールがより好ましく、ホスファチジルコリンが更に好ましい。 From the viewpoint of stability of the liposome, the lipid forming the lipid bilayer membrane is preferably a phospholipid, and among these, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, and phosphatidylglycerol are more preferable, and phosphatidylcholine is even more preferable.
リポソームを構成する脂質には、上述の脂質二重膜を形成するリン脂質又は糖脂質の他、当該形成された脂質二重膜に取り込まれる脂溶性成分(但し、本発明の「難水溶性薬物」を除く)を用いるのが、リポソームの脂質二重膜の安定性の観点から、好ましい。
脂質二重膜に取り込まれる脂溶性成分としては、例えば、ステロール類、脂肪酸類、脂溶性の抗酸化剤、界面活性剤等が挙げられる。
ステロール類としては、例えば、コレステロール、ジヒドロコレステロール、コレス
テロールコハク酸、コレスタノール、ラノステロール、ジヒドロラノステロール、デスモステロール等の動物由来ステロール;シトステロール、スチグマステロール、カンペステロール、ブラシカステロール等の植物由来ステロール;チモステロール、エルゴステロール等が挙げられる。なかでも、脂質二重膜の安定性の観点から、コレステロール、コレスタノールが好ましい。
ステロール類は、脂質二重膜の安定性の観点から、脂質二重膜を形成する脂質に対して、0.05~1.5モル用いることが好ましく、0.1~1.0モル用いることがより好ましく、0.2~0.8モル用いることが更に好ましい。
The lipids constituting the liposome include, in addition to the phospholipids or glycolipids that form the above-mentioned lipid bilayer membrane, fat-soluble components that are incorporated into the formed lipid bilayer membrane (however, the “poorly water-soluble drug” of the present invention ) is preferred from the viewpoint of stability of the lipid bilayer membrane of the liposome.
Examples of the fat-soluble components taken into the lipid bilayer membrane include sterols, fatty acids, fat-soluble antioxidants, and surfactants.
Examples of sterols include animal-derived sterols such as cholesterol, dihydrocholesterol, cholesterol succinate, cholestanol, lanosterol, dihydrolanosterol, and desmosterol; plant-derived sterols such as sitosterol, stigmasterol, campesterol, and brassicasterol; Examples include sterol and ergosterol. Among these, cholesterol and cholestanol are preferred from the viewpoint of stability of the lipid bilayer membrane.
From the viewpoint of stability of the lipid bilayer membrane, it is preferable to use sterols from 0.05 to 1.5 mol, and preferably from 0.1 to 1.0 mol, based on the lipid forming the lipid bilayer membrane. is more preferable, and it is still more preferable to use 0.2 to 0.8 mol.
脂肪酸類としては、ラウリン酸、ミリスチン酸、パルミチン酸、ステアリン酸等の飽和脂肪酸;パルミトレイン酸、オレイン酸、リノール酸等の不飽和脂肪酸が挙げられる。
脂肪酸類は、脂質二重膜の安定性の観点から、脂質二重膜を形成する脂質に対して、0.05~1.0モル用いることが好ましく、0.1~0.6モル用いることがより好ましく、0.1~0.4モル用いることが更に好ましい。
Examples of fatty acids include saturated fatty acids such as lauric acid, myristic acid, palmitic acid, and stearic acid; unsaturated fatty acids such as palmitoleic acid, oleic acid, and linoleic acid.
From the viewpoint of stability of the lipid bilayer membrane, fatty acids are preferably used in an amount of 0.05 to 1.0 mol, preferably 0.1 to 0.6 mol, based on the lipid forming the lipid bilayer membrane. is more preferable, and it is even more preferable to use 0.1 to 0.4 mol.
なお、脂質二重膜に取り込まれる脂溶性成分として、20℃で液状の油性成分(大豆油、オリーブ油等)を用いてもよいが、脂質混合物を水性溶媒へ分散した後にリポソーム構造を安定化させる観点からは、使用量を少なくすることが望ましい。後述する加熱混合原料中の液状の油性成分は、リポソームの脂質二重膜を形成する脂質に対して、25質量%以下が好ましく、10質量%以下がより好ましく、5質量%以下が更に好ましく、3質量%以下がより更に好ましく、1質量%以下がより更に好ましく、実質的に含まないことがより更に好ましい。 Note that as the lipophilic component incorporated into the lipid bilayer membrane, an oily component (soybean oil, olive oil, etc.) that is liquid at 20°C may be used, but the liposome structure may be stabilized after dispersing the lipid mixture in an aqueous solvent. From this point of view, it is desirable to use less. The liquid oil component in the heated mixed raw material described below is preferably 25% by mass or less, more preferably 10% by mass or less, even more preferably 5% by mass or less, based on the lipid forming the lipid bilayer membrane of the liposome. It is even more preferably 3% by mass or less, even more preferably 1% by mass or less, and even more preferably substantially free.
脂溶性の抗酸化剤としては、トコフェロール、アスコルビン酸パルミテート、ジブチルヒドロキシトルエン(BHT)等が挙げられる。
脂溶性の抗酸化剤は、脂質二重膜を形成する脂質及び難水溶性薬物の酸化安定性の観点から、脂質二重膜を形成する脂質に対して、0.001~0.1モル用いることが好ましく、0.002~0.05モル用いることがより好ましい。
Examples of fat-soluble antioxidants include tocopherol, ascorbic acid palmitate, dibutylhydroxytoluene (BHT), and the like.
The fat-soluble antioxidant is used in an amount of 0.001 to 0.1 mol based on the lipids forming the lipid bilayer membrane, from the viewpoint of oxidative stability of the lipids forming the lipid bilayer membrane and poorly water-soluble drugs. It is preferable to use 0.002 to 0.05 mol.
界面活性剤としては、ポリオキシエチレンアルキルエーテル、ソルビタン脂肪酸エステル、ポリオキシエチレンソルビタン脂肪酸エステル、ポリオキシエチレン付加ステロール、ポリオキシエチレン硬化ヒマシ油、グリセリン脂肪酸エステル等の非イオン性界面活性剤;ジアルキルリン酸及びそれらの塩等の陰イオン性界面活性剤;アルキルアミン、アルキルトリメチルアンモニウム、アルキルジメチルアンモニウム及びそれらの塩等の陽イオン性界面活性剤;膜タンパク質等が挙げられる。 Examples of surfactants include nonionic surfactants such as polyoxyethylene alkyl ether, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene added sterol, polyoxyethylene hydrogenated castor oil, and glycerin fatty acid ester; dialkyl phosphorus; Anionic surfactants such as acids and their salts; cationic surfactants such as alkylamines, alkyltrimethylammonium, alkyldimethylammonium and their salts; membrane proteins, and the like.
本発明では、リポソームを構成する脂質及び難水溶性薬物を加熱混合して溶融させる際、リポソームを構成する脂質及び難水溶性薬物を含有する加熱混合原料を調製し、加熱混合処理を行う。リポソームを構成する脂質と難水溶性薬物は、固体状や粉末状、又は少量の水性溶媒へ分散させたスラリーの状態で当該処理に供することができる。
加熱混合原料中のリポソームを構成する脂質の含有量は特に限定されないが、生産性の観点から、5質量%以上が好ましく、10質量%以上がより好ましく、15質量%以上が更に好ましく、脂質混合物の水分散性の観点から、95質量%以下が好ましく、90質量%以下がより好ましく、80質量%以下が更に好ましい。なお、本発明において、リポソームを構成する脂質の含有量とは、脂質二重膜を形成する脂質と、当該形成された脂質二重膜に取り込まれる脂溶性成分(但し、本発明の「難水溶性薬物」を除く)との総量である。
In the present invention, when heating and mixing the lipids and poorly water-soluble drug constituting the liposome to melt them, a heated mixed raw material containing the lipids constituting the liposome and the poorly water-soluble drug is prepared and subjected to a heat mixing treatment. The lipid and poorly water-soluble drug constituting the liposome can be subjected to the treatment in the form of a solid, a powder, or a slurry dispersed in a small amount of an aqueous solvent.
The content of lipids constituting liposomes in the heated mixed raw material is not particularly limited, but from the viewpoint of productivity, it is preferably 5% by mass or more, more preferably 10% by mass or more, even more preferably 15% by mass or more, and the lipid mixture From the viewpoint of water dispersibility, the content is preferably 95% by mass or less, more preferably 90% by mass or less, and even more preferably 80% by mass or less. In the present invention, the content of lipids constituting a liposome refers to the lipids forming the lipid bilayer membrane and the lipophilic components incorporated into the formed lipid bilayer membrane (however, the content of lipids constituting the liposome is defined as (excluding sex drugs).
加熱混合原料中、難水溶性薬物に対するリポソームを構成する脂質の質量比[リポソームを構成する脂質/難水溶性薬物]は、その種類によって異なるが、リポソームへの難水溶性薬物の内包率の観点から、2以上が好ましく、3以上がより好ましく、4以上が更に好ましく、5以上がより更に好ましく、6以上がより更に好ましい。また、生産性、薬効の観点から、50以下が好ましく、30以下がより好ましく、20以下が更に好ましい。 In the heated mixed raw material, the mass ratio of lipids constituting liposomes to poorly water-soluble drugs [lipids constituting liposomes/poorly water-soluble drugs] differs depending on the type, but it is important from the viewpoint of the encapsulation rate of poorly water-soluble drugs into liposomes. , preferably 2 or more, more preferably 3 or more, even more preferably 4 or more, even more preferably 5 or more, even more preferably 6 or more. Further, from the viewpoint of productivity and medicinal efficacy, the molecular weight is preferably 50 or less, more preferably 30 or less, and even more preferably 20 or less.
更に、加熱混合原料には、糖類を用いることが、加熱混合原料の混合性を高める観点、得られた脂質混合物の水分散性を高める観点から、好ましい。
糖類としては、例えば、グルコース、ガラクトース等の単糖類;トレハロース、スクロース、マルトース等の二糖類;ソルビトール、イノシトール等の糖アルコール類が挙げられる。なかでも、脂質混合物の水分散性の観点から、二糖類が好ましい。
なお、加熱混合原料を加熱混合して溶融させる際、リポソームを構成する脂質及び難水溶性薬物は溶融するが、糖類は溶融しても、していなくてもよい。
Furthermore, it is preferable to use saccharides in the heated mixed raw material from the viewpoint of improving the mixability of the heated mixed raw material and from the viewpoint of increasing the water dispersibility of the obtained lipid mixture.
Examples of sugars include monosaccharides such as glucose and galactose; disaccharides such as trehalose, sucrose and maltose; and sugar alcohols such as sorbitol and inositol. Among these, disaccharides are preferred from the viewpoint of water dispersibility of the lipid mixture.
Note that when heating and mixing raw materials to melt, the lipids and poorly water-soluble drugs constituting the liposomes are melted, but the saccharides may or may not be melted.
更に、加熱混合原料には、必要に応じて、クエン酸、乳酸、コハク酸及びそれらの塩等のpH調整剤、親水性の抗酸化剤(アスコルビン酸、ポリフェノール類)、水溶性膜タンパク質等を用いてもよい。 Furthermore, the heated mixed raw materials may contain pH adjusters such as citric acid, lactic acid, succinic acid and their salts, hydrophilic antioxidants (ascorbic acid, polyphenols), water-soluble membrane proteins, etc., as necessary. May be used.
本発明では、リポソームを構成する脂質及び難水溶性薬物を加熱混合して溶融させる工程を、水性溶媒が加熱混合原料の全質量に対して20質量%以下となる条件で行う。加熱溶融時の水性溶媒を少なくすることで難水溶性薬物の分解を回避でき、製造された脂質混合物を水性溶媒へ分散させた際に、難水溶性薬物を高効率でリポソームに内包できる。
本明細書において、水性溶媒とは、水、又は水溶性の溶質もしくは有機溶媒を含む水溶液をいう。水としては、水道水、蒸留水、イオン交換水、精製水が例示される。水溶性の溶質は、塩類、糖類、多価アルコール類、pH調整剤、浸透圧調整剤、増粘剤等が例示される。
有機溶媒は、水と均一に混合するものであれば特に限定されないが、リポソームの安全性の観点より、使用量を少なくすることが望ましい。有機溶媒を含む水溶液中の有機溶媒の濃度は、25質量%以下が好ましく、更に10質量%以下がより好ましく、5質量%以下が更に好ましく、1質量%以下がより更に好ましい。本発明では、実質的に有機溶媒の濃度が0質量%、すなわち有機溶媒を含まないのが好ましい。
In the present invention, the step of heat-mixing and melting the lipid and poorly water-soluble drug constituting the liposome is performed under conditions such that the amount of the aqueous solvent is 20% by mass or less based on the total mass of the heated and mixed raw materials. By reducing the amount of aqueous solvent used during heating and melting, decomposition of poorly water-soluble drugs can be avoided, and when the prepared lipid mixture is dispersed in an aqueous solvent, poorly water-soluble drugs can be encapsulated in liposomes with high efficiency.
As used herein, the aqueous solvent refers to water or an aqueous solution containing a water-soluble solute or an organic solvent. Examples of water include tap water, distilled water, ion exchange water, and purified water. Examples of water-soluble solutes include salts, sugars, polyhydric alcohols, pH adjusters, osmotic pressure adjusters, and thickeners.
The organic solvent is not particularly limited as long as it can be mixed uniformly with water, but from the viewpoint of the safety of the liposomes, it is desirable to reduce the amount used. The concentration of the organic solvent in the aqueous solution containing the organic solvent is preferably 25% by mass or less, more preferably 10% by mass or less, even more preferably 5% by mass or less, and even more preferably 1% by mass or less. In the present invention, it is preferable that the concentration of the organic solvent is substantially 0% by mass, that is, no organic solvent is contained.
水性溶媒は、難水溶性薬物の分解抑制の観点から、加熱混合原料の全質量に対して15質量%以下がより好ましく、10質量%以下が更に好ましく、5質量%以下がより更に好ましく、原料由来の水性媒体以外に含まないことが好ましい。 The aqueous solvent is more preferably 15% by mass or less, even more preferably 10% by mass or less, even more preferably 5% by mass or less based on the total mass of the heated mixed raw materials, from the viewpoint of suppressing the decomposition of poorly water-soluble drugs. It is preferable that it not be contained in anything other than the aqueous medium from which it is derived.
リポソームを構成する脂質及び難水溶性薬物を加熱混合して溶融させる方法は、特に制限されず、公知の方法を適用できる。
例えば、温調ジャケット着きのミキサー(ハイスピードミキサー、ヘンシェルミキサー、リボンミキサー、レディゲミキサー、プラネタリミキサー、スパイラルミキサー)、エクストルーダー(1軸エクストルーダー、2軸エクストルーダー、リングエクストルーダー)等の装置によって実施できる。
The method of heating and mixing and melting the lipid and poorly water-soluble drug constituting the liposome is not particularly limited, and any known method can be applied.
For example, equipment such as mixers with temperature-controlled jackets (high-speed mixers, Henschel mixers, ribbon mixers, Ledige mixers, planetary mixers, spiral mixers), extruders (single-shaft extruders, twin-shaft extruders, ring extruders), etc. It can be implemented by
加熱温度は、加熱混合原料のうち脂質二重膜を形成する脂質の少なくとも1種が溶融する温度以上である。加熱により脂質二重膜を形成する脂質のうちの少なくとも1種が溶融すると、リポソームを構成する脂質、難水溶性薬物が溶融する。
加熱温度は、難水溶性薬物の内包率の観点から、脂質二重膜を形成する脂質の少なくとも1種のガラス転移温度以上であることが好ましく、脂質二重膜を形成する脂質の少なくとも1種のガラス転移温度より4℃以上高い温度がより好ましく、脂質二重膜を形成する脂質の少なくとも1種のガラス転移温度より8℃以上高い温度が更に好ましい。また、ガラス転移点を有さない脂質二重膜を形成する脂質の場合、加熱温度は、脂質二重膜を形成する脂質の少なくとも1種の融点温度以上であることが好ましい。
脂質二重膜を形成する脂質のガラス転移温度、融点は、例えば、示唆操作熱分析計を用いて測定することができる。示差走査熱量計として、例えば、STAR System(メトラートレド製)を用いることができる。
具体例を挙げると、リン脂質の相転移温度は、下記の手順により測定できる。
試料をアルミニウム製の試料容器に秤量し、アルミニウム製のカバーをした後、シーラーを用い、密封する。密封した試料容器を、電気炉内のホルダーユニットに乗せる。また、空気を密封したブランク容器を、ホルダーユニットのブランク側に乗せる。電気炉に蓋をし、窒素雰囲気下で1℃、5分間保持する。次いで、1℃から180℃まで、昇温速度0.5℃/分で加熱する(昇温工程)。この、昇温工程において、示差走査熱量計を用いて、DSC曲線を計測する。この際、昇温工程で1つめの吸熱ピークが見られた際の温度を、リン脂質のガラス相転移温度又は融点とする。昇温工程で2つ目の吸熱ピークが見られたリン脂質については、1つ目の吸熱ピークが見られた温度をガラス転移温度、2つ目の吸熱ピークが見られた温度を融点とする。
The heating temperature is equal to or higher than the temperature at which at least one type of lipid forming a lipid bilayer membrane in the heated mixed raw materials melts. When at least one of the lipids forming the lipid bilayer membrane is melted by heating, the lipids and poorly water-soluble drug constituting the liposome are melted.
The heating temperature is preferably equal to or higher than the glass transition temperature of at least one of the lipids forming the lipid bilayer membrane, from the viewpoint of the encapsulation rate of the poorly water-soluble drug; The temperature is more preferably 4° C. or more higher than the glass transition temperature of , and even more preferably 8° C. or more higher than the glass transition temperature of at least one of the lipids forming the lipid bilayer membrane. Furthermore, in the case of a lipid that forms a lipid bilayer membrane that does not have a glass transition point, the heating temperature is preferably equal to or higher than the melting point temperature of at least one of the lipids that form the lipid bilayer membrane.
The glass transition temperature and melting point of a lipid that forms a lipid bilayer can be measured using, for example, an indicative operation thermal analyzer. As the differential scanning calorimeter, for example, STAR System (manufactured by Mettler Toledo) can be used.
To give a specific example, the phase transition temperature of phospholipids can be measured by the following procedure.
A sample is weighed into an aluminum sample container, covered with an aluminum cover, and then sealed using a sealer. Place the sealed sample container on the holder unit in the electric furnace. In addition, a blank container sealed with air is placed on the blank side of the holder unit. The electric furnace was covered with a lid and kept at 1° C. for 5 minutes under a nitrogen atmosphere. Next, it is heated from 1° C. to 180° C. at a heating rate of 0.5° C./min (temperature raising step). In this temperature raising step, a DSC curve is measured using a differential scanning calorimeter. At this time, the temperature at which the first endothermic peak is observed in the temperature raising step is defined as the glass phase transition temperature or melting point of the phospholipid. For phospholipids where a second endothermic peak was observed during the temperature raising process, the temperature at which the first endothermic peak was observed is the glass transition temperature, and the temperature at which the second endothermic peak was observed is the melting point. .
また、加熱温度は、難水溶性薬物の熱安定性の観点から、難水溶性薬物の分解温度以下であることが好ましく、難水溶性薬物の分解温度より20℃以上低い温度がより好ましく、難水溶性薬物の分解温度より10℃以上低い温度が更に好ましく、難水溶性薬物の分解温度より5℃以上低い温度がより更に好ましい。
難水溶性薬物の分解温度は、MERCK INDEX(メルク・アンド・カンパニー)等のデータベースに記載の化合物情報を参照することができ、記載されていない化合物については所定温度の恒温槽で静置した際の濃度変化を測定する手法や、示唆操作熱分析計等を用いた既知の手法により測定することができる。
In addition, from the viewpoint of thermal stability of the poorly water-soluble drug, the heating temperature is preferably below the decomposition temperature of the poorly water-soluble drug, more preferably a temperature that is 20°C or more lower than the decomposition temperature of the poorly water-soluble drug. The temperature is more preferably 10°C or more lower than the decomposition temperature of a water-soluble drug, and even more preferably 5°C or more lower than the decomposition temperature of a poorly water-soluble drug.
For the decomposition temperature of poorly water-soluble drugs, you can refer to compound information listed in databases such as MERCK INDEX (Merck & Company). It can be measured by a known method such as a method that measures changes in the concentration of , a suggestive operation thermal analyzer, or the like.
本発明において、加熱の温度は、先述のとおりであるが、難水溶性薬物の内包率の観点から、80℃以上が好ましく、90℃以上がより好ましく、100℃以上が更に好ましい。また、難水溶性薬物の分解抑制の観点から、200℃以下が好ましく、180℃以下がより好ましく、160℃以下が更に好ましく、140℃以下がより更に好ましく、130℃以下がより更に好ましい。 In the present invention, the heating temperature is as described above, but from the viewpoint of the encapsulation rate of the poorly water-soluble drug, it is preferably 80°C or higher, more preferably 90°C or higher, and even more preferably 100°C or higher. In addition, from the viewpoint of suppressing the decomposition of poorly water-soluble drugs, the temperature is preferably 200°C or lower, more preferably 180°C or lower, even more preferably 160°C or lower, even more preferably 140°C or lower, and even more preferably 130°C or lower.
加熱の手段は、例えば、水蒸気、電気が挙げられる。なお、本発明において、加熱温度とは、加熱混合原料の加熱部の温度をいう。 Examples of heating means include steam and electricity. In addition, in this invention, heating temperature refers to the temperature of the heating part of heated mixed raw materials.
加熱混合処理は、例えば、回分法、半回分法、流通法等いずれの方法によっても実施できる。なかでも、回分法、流通法は、加熱時間の制御が容易である点で好ましい。なお、本発明において、加熱時間とは、加熱混合原料を加熱部に接触開始した時点を起算点とし、加熱部よりも10℃以上低い冷却部に接触開始した時点を終点とする時間をいう。
加熱の時間は、適宜選択してよく、回分法の場合、難水溶性薬物の内包率の観点から、1.0分以上が好ましく、3.0分以上が更に好ましく、4.0分以上が更に好ましく、5.0分以上が更に好ましく、また、熱安定性の観点から、60分以下が好ましく、40分以下がより好ましく、20分以下が更に好ましい。
流通法で行う場合、加熱の時間は、反応器の高温高圧部の体積を加熱混合原料の供給速度で割ることにより算出される平均滞留時間を用いる。流通式の場合の加熱の時間は、難水溶性薬物の内包率の観点から、0.5分以上が好ましく、1分以上がより好ましく、3分以上が更に好ましい。また、難水溶性薬物の熱安定性の観点から、30分以下が好ましく、15分以下がより好ましく、10分以下が更に好ましい。
The heating and mixing treatment can be carried out by any method such as a batch method, a semi-batch method, or a distribution method. Among these, the batch method and the distribution method are preferable because the heating time can be easily controlled. In the present invention, the heating time refers to the time starting from the time when the heated mixed raw material starts contacting the heating part and ending when it starts contacting the cooling part which is 10° C. or more lower than the heating part.
The heating time may be selected as appropriate; in the case of a batch method, from the viewpoint of the inclusion rate of poorly water-soluble drugs, the heating time is preferably 1.0 minutes or more, more preferably 3.0 minutes or more, and 4.0 minutes or more. More preferably, it is 5.0 minutes or more, and from the viewpoint of thermal stability, it is preferably 60 minutes or less, more preferably 40 minutes or less, and even more preferably 20 minutes or less.
When using the flow method, the average residence time calculated by dividing the volume of the high-temperature, high-pressure section of the reactor by the supply rate of the heated mixed raw material is used as the heating time. In the case of the flow type, the heating time is preferably 0.5 minutes or more, more preferably 1 minute or more, and even more preferably 3 minutes or more, from the viewpoint of the encapsulation rate of the poorly water-soluble drug. In addition, from the viewpoint of thermal stability of poorly water-soluble drugs, the time is preferably 30 minutes or less, more preferably 15 minutes or less, and even more preferably 10 minutes or less.
加熱混合条件は使用する装置によって異なるが、例えば回分式2軸エクストルーダー(処理量7ml/回)の場合、混合性の観点から、スクリュー回転数は20r/min以上が好ましく、更に40r/min以上が好ましい。 Heating and mixing conditions vary depending on the equipment used, but for example, in the case of a batch-type twin-screw extruder (processing amount 7 ml/time), from the viewpoint of mixing properties, the screw rotation speed is preferably 20 r/min or more, and more preferably 40 r/min or more. is preferred.
次いで、溶融した溶融物を冷却する。溶融物の冷却は多段階的に行っても良い。例えば、加熱温度より10℃低い温度まで冷却後、いったん冷却を中断し、更に冷却しても良い。冷却の方法は、空冷式、熱交換機との接触等により実施できる。 The molten material is then cooled. Cooling of the melt may be performed in multiple stages. For example, after cooling to a temperature 10° C. lower than the heating temperature, cooling may be temporarily interrupted and further cooling may be performed. The cooling method can be carried out by air cooling, contact with a heat exchanger, or the like.
溶融物の冷却は、冷却速度が大きいほど難水溶性薬物への熱負荷が少なく好ましい。このため、冷却速度の上限は特に定めないが、製造設備の制約等の観点から、例えば10℃/分以上、更に20℃/分以上が好ましい。 For cooling of the melt, the faster the cooling rate, the lower the thermal load on the poorly water-soluble drug, which is preferable. Therefore, the upper limit of the cooling rate is not particularly determined, but from the viewpoint of constraints on manufacturing equipment, for example, it is preferably 10° C./min or more, and more preferably 20° C./min or more.
本発明では、溶融物を冷却した後、脂質混合物が得られる。脂質混合物は、必要に応じて粉砕処理等を行っても良い。 In the present invention, a lipid mixture is obtained after cooling the melt. The lipid mixture may be subjected to pulverization treatment, etc., if necessary.
得られた脂質混合物を水性溶媒へ分散させることで、難水溶性薬物を内包するリポソームが形成される。難水溶性薬物を内包するリポソームは、単層又は多層であり得る。
本発明では、例えば、脂質混合物を注射用バイアルへ充填し、難水溶性薬物の使用時に水性溶媒と混合することでリポソーム分散させてもよく、また、脂質混合物の製造の後に続けて水性溶媒との接触を行ってもよい。
By dispersing the obtained lipid mixture in an aqueous solvent, liposomes containing poorly water-soluble drugs are formed. Liposomes encapsulating poorly water-soluble drugs can be unilamellar or multilamellar.
In the present invention, for example, the lipid mixture may be filled into an injection vial and dispersed in liposomes by mixing with an aqueous solvent when using a poorly water-soluble drug. contact may be made.
脂質混合物を水性溶媒へ分散する方法は適宜選択することができる。例えば、水性溶媒を撹拌している所へ脂質混合物を投入してもよく、反対に脂質混合物へ水性溶媒を投入してもよい。分散性の観点からは、水性溶媒を撹拌している所へ脂質混合物を投入することが好ましい。撹拌の方法は特に限定されず、パドル翼撹拌、ホモミキサー、ホモジナイザー等を適宜選択できる。
脂質混合物と水性溶媒の混合比は利用目的によって適宜選定可能であるが、リポソーム分散性の観点から、脂質混合物に対する水性溶媒の質量比[水性溶媒/脂質混合物]が4g/g以上であることが好ましく、6g/g以上であることがより好ましく、8g/g以上であることが更に好ましい。また、有効性の観点から、400g/g以下であることが好ましく、300g/g以下であることがより好ましく、200g/g以下であることが更に好ましい。
The method of dispersing the lipid mixture into the aqueous solvent can be selected as appropriate. For example, the lipid mixture may be added to the aqueous solvent being stirred, or the aqueous solvent may be added to the lipid mixture. From the viewpoint of dispersibility, it is preferable to add the lipid mixture to a place where the aqueous solvent is being stirred. The stirring method is not particularly limited, and paddle blade stirring, homomixer, homogenizer, etc. can be selected as appropriate.
The mixing ratio of the lipid mixture and the aqueous solvent can be selected as appropriate depending on the purpose of use, but from the viewpoint of liposome dispersibility, the mass ratio of the aqueous solvent to the lipid mixture [aqueous solvent/lipid mixture] should be 4 g/g or more. It is preferably 6 g/g or more, more preferably 8 g/g or more. Moreover, from the viewpoint of effectiveness, it is preferably 400 g/g or less, more preferably 300 g/g or less, and even more preferably 200 g/g or less.
本発明では、水性溶媒へ分散したリポソームの粒子径を均一化にするためにリポソームをサイジングする工程を行ってもよい。リポソームのサイジングは、公知の方法を適用できる。例えば、超音波処理、高圧乳化処理、ポリカーボネートメンブレンフィルターを用いた処理等が挙げられ、水性溶媒との接触工程の後又は同時に実施できる。リポソームの平均粒子径は、適宜調節することができる。 In the present invention, a step of sizing the liposomes may be performed in order to make the particle size of the liposomes dispersed in an aqueous solvent uniform. For sizing of liposomes, known methods can be applied. Examples include ultrasonic treatment, high-pressure emulsification treatment, treatment using a polycarbonate membrane filter, etc., and can be carried out after or simultaneously with the contacting step with the aqueous solvent. The average particle size of liposomes can be adjusted as appropriate.
また、本発明では、保存性の観点から、リポソーム粒径を均一化した後、水分を除去して乾燥し、粉末状、顆粒状、固形状等の固体物の状態とすることもできる。水分を調整、除去する手段としては、凍結乾燥、蒸発乾固、噴霧乾燥等が挙げられる。乾燥方法は、特に制限されず、公知の方法を適用できる。 Further, in the present invention, from the viewpoint of storage stability, the liposomes can be made into a solid state such as a powder, granules, or solid by removing moisture and drying after making the liposome particle size uniform. Examples of means for adjusting and removing moisture include freeze drying, evaporation to dryness, and spray drying. The drying method is not particularly limited, and any known method can be applied.
かくして得られるリポソームは、高い内包率で難水溶性薬物を内包する。
リポソームの難水溶性薬物の内包率は、試料分散液中に存在する難水溶性薬物全量のうち、リポソームに内包された難水溶性薬物量の割合である。
本明細書において、難水溶性薬物のリポソーム内包率は、後述する実施例に記載の方法で算出できる。
The liposome thus obtained encapsulates a poorly water-soluble drug at a high encapsulation rate.
The encapsulation rate of the poorly water-soluble drug in the liposome is the ratio of the amount of the poorly water-soluble drug encapsulated in the liposome to the total amount of the poorly water-soluble drug present in the sample dispersion.
In this specification, the liposome encapsulation rate of a poorly water-soluble drug can be calculated by the method described in the Examples below.
本発明の難水溶性薬物を内包するリポソームは、治療や診断等の様々な分野に使用可能である。とりわけ、薬物送達システム(DDS)に好適に利用することができる。 The liposome containing the poorly water-soluble drug of the present invention can be used in various fields such as treatment and diagnosis. In particular, it can be suitably used for drug delivery systems (DDS).
[加熱混合原材]
水添大豆リン脂質(HSPC):商品名NC21、日油(株)製、ガラス転移温度 102℃
ジステアロイルホスファチジルグリセロールナトリウム(DSPG-Na):商品名MG8080LS、日油(株)製、ガラス転移温度 67℃、融点 125℃
コレステロール:富士フイルム和光純薬(株)製、融点 148℃
アムホテリシンB(AmpB):富士フイルム和光純薬(株)製、25℃での水溶解度 0.75g/L、融点 158℃、分解温度 170℃
スクロース:富士フイルム和光純薬(株)製
コハク酸二ナトリウム六水和物:関東化学(株)製
トコフェロール:富士フイルム和光純薬(株)製
塩酸:富士フイルム和光純薬(株)製
水酸化ナトリウム:富士フイルム和光純薬(株)製
[Heat-mixed raw materials]
Hydrogenated soybean phospholipid (HSPC): Product name NC21, manufactured by NOF Corporation, glass transition temperature 102°C
Distearoylphosphatidylglycerol sodium (DSPG-Na): Trade name MG8080LS, manufactured by NOF Corporation, glass transition temperature 67°C, melting point 125°C
Cholesterol: manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., melting point 148°C
Amphotericin B (AmpB): manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., water solubility at 25°C 0.75g/L, melting point 158°C, decomposition temperature 170°C
Sucrose: Fujifilm Wako Pure Chemical Industries, Ltd. Disodium succinate hexahydrate: Kanto Chemical Co., Ltd. Tocopherol: Fujifilm Wako Pure Chemical Industries, Ltd. Hydrochloric acid: Fujifilm Wako Pure Chemical Industries, Ltd. Hydroxide Sodium: Manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.
[アムホテリシン濃度の測定]
試料分散液を、0.15g/Lの酢酸/ジメチルスルホキシドで溶解し、分光光度計にて405nmの吸光度を測定した。
[Measurement of amphotericin concentration]
The sample dispersion liquid was dissolved in 0.15 g/L acetic acid/dimethyl sulfoxide, and the absorbance at 405 nm was measured using a spectrophotometer.
[アムホテリシンBのリポソーム内包率の算出]
リポソーム分散液中から下記の操作により未溶解のアムホテリシンBを除去した。
AVESTIN製 LF-STB リポソファストにポリカーボネート製フィルター(孔径1000nm)を設置し、65℃に加温したリポソーム分散液をリポソファストのシリンジに1mL仕込んだ。次いで、シリンジを押して分散液を孔径1000nmのポリカーボネートフィルターを透過させた。この操作を往復11回行い、リポソーム分散液を仕込んだシリンジと逆側のシリンジからリポソーム溶液を回収した。シリンジ操作の間、回収液が冷えないように、リポソファストをドライヤーで加温した。
ポリカーボネートフィルター透過前のアムホテリシンB濃度と、透過後のアムホテリシンB濃度(リポソーム内包アムホテリシンB濃度)をそれぞれ測定し、アムホテリシンBのリポソーム内包率を下記の式から算出した。
アムホテリシンBのリポソーム内包率(%)=[1000nmポリカーボネートフィルター透過後のアムホテリシンB濃度/1000nmポリカーボネートフィルター透過前のアムホテリシンB濃度]×100
[Calculation of liposome encapsulation rate of amphotericin B]
Undissolved amphotericin B was removed from the liposome dispersion by the following procedure.
A polycarbonate filter (pore size 1000 nm) was installed in LF-STB Liposophast manufactured by AVESTIN, and 1 mL of the liposome dispersion heated to 65° C. was charged into the syringe of Liposophast. Next, the syringe was pressed to pass the dispersion through a polycarbonate filter with a pore size of 1000 nm. This operation was repeated 11 times, and the liposome solution was collected from the syringe on the opposite side of the syringe containing the liposome dispersion. During syringe operation, the Liposophast was heated with a hairdryer to prevent the collected liquid from cooling.
The amphotericin B concentration before permeation through the polycarbonate filter and the amphotericin B concentration after permeation (liposome-encapsulated amphotericin B concentration) were measured, and the liposome encapsulation rate of amphotericin B was calculated from the following formula.
Liposome encapsulation rate of amphotericin B (%) = [Amphotericin B concentration after passing through a 1000 nm polycarbonate filter/Amphotericin B concentration before passing through a 1000 nm polycarbonate filter] x 100
実施例1
50mLのPP容器に、水添大豆リン脂質3.37g、ジステアロイルホスファチジルグリセロールナトリウム1.34g、コレステロール0.82g、トコフェロール0.011g、アムホテリシンB 0.79g、スクロース14.25g、コハク酸二ナトリウム六水和物0.43gを計量し、スパーテルで混合した。これら成分のうち、リポソームを構成する脂質は、水添大豆リン脂質、ジステアロイルホスファチジルグリセロールナトリウム、コレステロール、及びトコフェロールである。また、スクロースは事前に乳鉢で粉砕後に計量した。
Example 1
In a 50 mL PP container, 3.37 g of hydrogenated soybean phospholipids, 1.34 g of sodium distearoyl phosphatidylglycerol, 0.82 g of cholesterol, 0.011 g of tocopherol, 0.79 g of amphotericin B, 14.25 g of sucrose, and 6 g of disodium succinate. 0.43 g of hydrate was weighed and mixed with a spatula. Among these components, the lipids constituting the liposome are hydrogenated soybean phospholipid, sodium distearoyl phosphatidylglycerol, cholesterol, and tocopherol. In addition, sucrose was ground in a mortar and weighed in advance.
次いで、90℃に加熱した2軸エクストルーダー(HAAKE製、miniCTW)を50r/minで回転させ、計量、混合した原料を約7mL投入した。投入後、回転数を80r/minにし10分間処理した。10分間の加熱混合完了後、エクストルーダー排出口を開放して溶融物を排出し、直ちにファン(アイリスオーヤマ製)で送風し空冷を行って脂質混合物を得た。空冷は5分間行い、室温まで冷却したことを確認した。この時点で、脂質混合物はアムホテリシンB由来の黄色を有する棒状の固体であった。 Next, a twin-screw extruder (manufactured by HAAKE, miniCTW) heated to 90° C. was rotated at 50 r/min, and approximately 7 mL of the weighed and mixed raw materials were introduced. After charging, the rotation speed was set to 80 r/min and the treatment was carried out for 10 minutes. After heating and mixing for 10 minutes, the extruder outlet was opened to discharge the molten material, and immediately a fan (manufactured by Iris Ohyama) was used to blow air for air cooling to obtain a lipid mixture. Air cooling was performed for 5 minutes, and it was confirmed that it had cooled to room temperature. At this point, the lipid mixture was a rod-shaped solid with a yellow color derived from amphotericin B.
得られた脂質混合物を乳鉢で粉砕した。次いで、容量13.5mLのガラスビーカーに10.8gのイオン交換水を計量し、65℃に加温しつつ1.5cmのマグネチックスターラーで600r/minで撹拌している所へ、粉砕した脂質混合物を1.20g投入した。5分間撹拌した後、分散液を採取し、流水で室温に冷却してリポソーム分散液を得た。リポソーム分散液のアムホテリシン濃度の測定を行い、また、アムホテリシンBのリポソーム内包率を求めた。 The resulting lipid mixture was ground in a mortar. Next, 10.8 g of ion-exchanged water was weighed into a glass beaker with a capacity of 13.5 mL, and the crushed lipid was heated to 65°C and stirred at 600 r/min with a 1.5 cm magnetic stirrer. 1.20g of the mixture was added. After stirring for 5 minutes, the dispersion was collected and cooled to room temperature with running water to obtain a liposome dispersion. The amphotericin concentration of the liposome dispersion was measured, and the liposome encapsulation rate of amphotericin B was determined.
実施例2~4
2軸エクストルーダーの加熱温度を110℃、130℃又は150℃とした以外は実施例1と同様の処理を行い、脂質混合物を得た後、リポソーム分散液を得た。実施例1と同様にしてリポソーム分散液のアムホテリシン濃度の測定を行い、また、アムホテリシンBのリポソーム内包率を求めた。
Examples 2-4
The same treatment as in Example 1 was performed except that the heating temperature of the twin-screw extruder was set to 110°C, 130°C, or 150°C to obtain a lipid mixture and then a liposome dispersion. The amphotericin concentration of the liposome dispersion was measured in the same manner as in Example 1, and the liposome encapsulation rate of amphotericin B was determined.
比較例1
2軸エクストルーダーの加熱を行わず、室温(25℃)とした以外は実施例1と同様の処理を行い、混合物を得た後、リポソーム分散液を得た。実施例1と同様にしてリポソーム分散液のアムホテリシン濃度の測定を行い、また、アムホテリシンBのリポソーム内包率を求めた。
Comparative example 1
The same treatment as in Example 1 was performed except that the twin-screw extruder was not heated and the temperature was kept at room temperature (25°C) to obtain a mixture, and then a liposome dispersion was obtained. The amphotericin concentration of the liposome dispersion was measured in the same manner as in Example 1, and the liposome encapsulation rate of amphotericin B was determined.
比較例2(ホモミキサー法)
500mLビーカーに、イオン交換水300.00g、水添大豆リン脂質6.39g、ジステアロイルホスファチジルグリセロールナトリウム2.52g、コレステロール1.56g、トコフェロール0.02g、アムホテリシンB 1.50g、スクロース27.00g、コハク酸二ナトリウム六水和物0.81gを計量し、2.5モル/Lの塩酸水溶液を1.5g添加しpHを1.5に調整した。
この時点で、試薬分散水は懸濁状態であった。
次いで、90℃に温調したウォーターバス中に、容器を投入し加熱した。90℃への達温を確認後、ホモミキサー(IKA社製T25digital ULTRA-TURAX)にて17000r/minで2分間分散処理を行った。その後、容器を氷水中に移し2分間混合し、5℃まで冷却した。加熱から冷却工程までは、およそ10分で完了した。冷却後、流水で室温25℃にし、2.5モル/Lの水酸化ナトリウム水溶液を0.7g添加しpHを4.5に調整した。この時点で、容器内の試薬水は懸濁状態であった。1時間静置し、リポソーム分散液を回収した。実施例1と同様にしてリポソーム分散液のアムホテリシン濃度の測定を行い、また、アムホテリシンBのリポソーム内包率を求めた。
Comparative example 2 (homo mixer method)
In a 500 mL beaker, ion exchange water 300.00 g, hydrogenated soybean phospholipid 6.39 g, distearoyl phosphatidylglycerol sodium 2.52 g, cholesterol 1.56 g, tocopherol 0.02 g, amphotericin B 1.50 g, sucrose 27.00 g, 0.81 g of disodium succinate hexahydrate was weighed, and 1.5 g of a 2.5 mol/L hydrochloric acid aqueous solution was added to adjust the pH to 1.5.
At this point, the reagent dispersion water was in suspension.
Next, the container was placed in a water bath whose temperature was controlled to 90° C. and heated. After confirming that the temperature had reached 90°C, dispersion treatment was performed for 2 minutes at 17000 r/min using a homomixer (T25digital ULTRA-TURAX manufactured by IKA). Thereafter, the container was transferred to ice water, mixed for 2 minutes, and cooled to 5°C. The process from heating to cooling was completed in about 10 minutes. After cooling, the temperature was brought to 25° C. with running water, and 0.7 g of a 2.5 mol/L aqueous sodium hydroxide solution was added to adjust the pH to 4.5. At this point, the reagent water in the container was in suspension. The mixture was allowed to stand for 1 hour, and the liposome dispersion was collected. The amphotericin concentration of the liposome dispersion was measured in the same manner as in Example 1, and the liposome encapsulation rate of amphotericin B was determined.
比較例3(高圧ホモジナイザー法)
500mLビーカーに、イオン交換水300.00g、水添大豆リン脂質6.39g、ジステアロイルホスファチジルグリセロールナトリウム2.52g、コレステロール1.56g、トコフェロール0.02g、アムホテリシンB 1.50g、スクロース27.00g、コハク酸二ナトリウム六水和物0.81gを計量し、2.5モル/Lの塩酸水溶液を1.5g添加しpHを1.5に調整した。
この時点で、試薬分散水は懸濁状態であった。
次いで、90℃に温調したウォーターバス中に、容器を投入し加熱した。90℃への達温を確認後、高圧ホモジナイザー(SMT社製LAB2000)にて100MPa、5Passの分散処理を行った。その後、容器を氷水中に移し2分間混合し、5℃まで冷却した。加熱から冷却工程までは、およそ45分で完了した。冷却後、流水で室温25℃にし、2.5モル/Lの水酸化ナトリウム水溶液を0.7g添加しpHを4.5に調整した。この時点で、容器内の試薬水は懸濁状態であった。1時間静置し、リポソーム分散液を回収した。実施例1と同様にしてリポソーム分散液のアムホテリシン濃度の測定を行い、また、アムホテリシンBのリポソーム内包率を求めた。
Comparative example 3 (high pressure homogenizer method)
In a 500 mL beaker, ion exchange water 300.00 g, hydrogenated soybean phospholipid 6.39 g, distearoyl phosphatidylglycerol sodium 2.52 g, cholesterol 1.56 g, tocopherol 0.02 g, amphotericin B 1.50 g, sucrose 27.00 g, 0.81 g of disodium succinate hexahydrate was weighed, and 1.5 g of a 2.5 mol/L hydrochloric acid aqueous solution was added to adjust the pH to 1.5.
At this point, the reagent dispersion water was in suspension.
Next, the container was placed in a water bath whose temperature was controlled to 90° C. and heated. After confirming that the temperature reached 90°C, dispersion treatment was performed at 100 MPa and 5 passes using a high-pressure homogenizer (LAB2000 manufactured by SMT). Thereafter, the container was transferred to ice water, mixed for 2 minutes, and cooled to 5°C. The heating to cooling process was completed in approximately 45 minutes. After cooling, the temperature was brought to 25° C. with running water, and 0.7 g of a 2.5 mol/L aqueous sodium hydroxide solution was added to adjust the pH to 4.5. At this point, the reagent water in the container was in suspension. The mixture was allowed to stand for 1 hour, and the liposome dispersion was collected. The amphotericin concentration of the liposome dispersion was measured in the same manner as in Example 1, and the liposome encapsulation rate of amphotericin B was determined.
比較例4(水系加熱)
15mL容量のガラス製の耐熱圧容器に、イオン交換水10.590g、水添大豆リン脂質0.228g、ジステアロイルホスファチジルグリセロールナトリウム0.089g、コレステロール0.055g、トコフェロール0.001g、アムホテリシンB 0.053g、スクロース0.955g、コハク酸二ナトリウム六水和物0.029gを計量し、2.5モル/Lの塩酸水溶液を0.05g添加しpHを1.5に調整した。前記試薬を計量したガラス製耐熱圧容器に蓋をし、密閉した。
この時点で、試薬分散水は懸濁状態であった。
次いで、90℃に温調したオイルバス中に、密閉したガラス製耐熱圧容器を投入し、7分間加熱した。この時、容器内の温度が均一になるように、適時、耐熱圧容器を手で振った。密閉されていたことから、加熱時に系内は飽和蒸気圧であった。7分間の加熱完了後、ガラス製耐熱圧容器を氷水中に移し3分間混合し、5℃まで冷却した。加熱から冷却工程までは、およそ10分で完了した。冷却後、流水で室温25℃にし、2.5モル/Lの水酸化ナトリウム水溶液を0.7g添加しpHを4.5に調整した。この時点で、容器内の試薬水は懸濁状態であった。1時間静置し、耐熱圧容器の蓋をあけ、リポソーム分散液を回収した。実施例1と同様にしてリポソーム分散液のアムホテリシン濃度の測定を行い、また、アムホテリシンBのリポソーム内包率を求めた。
Comparative example 4 (water-based heating)
In a 15 mL glass heat-resistant and pressure-resistant container, add 10.590 g of ion-exchanged water, 0.228 g of hydrogenated soybean phospholipid, 0.089 g of sodium distearoylphosphatidylglycerol, 0.055 g of cholesterol, 0.001 g of tocopherol, and 0.0 g of amphotericin B. 0.053 g of sucrose, 0.955 g of sucrose, and 0.029 g of disodium succinate hexahydrate were weighed, and 0.05 g of a 2.5 mol/L hydrochloric acid aqueous solution was added to adjust the pH to 1.5. The glass heat-resistant and pressure-resistant container in which the reagent was measured was covered and sealed.
At this point, the reagent dispersion water was in suspension.
Next, the sealed glass heat-resistant and pressure-resistant container was placed in an oil bath whose temperature was controlled to 90° C., and heated for 7 minutes. At this time, the heat-resistant and pressure-resistant container was shaken by hand at appropriate times so that the temperature inside the container was uniform. Since it was sealed, the inside of the system was at saturated vapor pressure during heating. After heating for 7 minutes, the glass heat-resistant and pressure-resistant container was transferred to ice water, mixed for 3 minutes, and cooled to 5°C. The process from heating to cooling was completed in about 10 minutes. After cooling, the temperature was brought to 25° C. with running water, and 0.7 g of a 2.5 mol/L aqueous sodium hydroxide solution was added to adjust the pH to 4.5. At this point, the reagent water in the container was in suspension. After standing for 1 hour, the lid of the heat-resistant and pressure-resistant container was opened, and the liposome dispersion liquid was collected. The amphotericin concentration of the liposome dispersion was measured in the same manner as in Example 1, and the liposome encapsulation rate of amphotericin B was determined.
比較例5及び6(水系加熱)
オイルバスの加熱温度を130℃又は160℃とした以外は比較例4と同様の処理を行い、リポソーム分散液を回収した。実施例1と同様にしてリポソーム分散液のアムホテリシン濃度の測定を行い、また、アムホテリシンBのリポソーム内包率を求めた。
実施例1~4及び比較例1~6の配合組成、処理条件及び結果を表1に示す。
Comparative Examples 5 and 6 (water-based heating)
The same treatment as in Comparative Example 4 was performed except that the heating temperature of the oil bath was changed to 130° C. or 160° C., and a liposome dispersion liquid was collected. The amphotericin concentration of the liposome dispersion was measured in the same manner as in Example 1, and the liposome encapsulation rate of amphotericin B was determined.
Table 1 shows the formulations, processing conditions, and results of Examples 1 to 4 and Comparative Examples 1 to 6.
表1より明らかなように、実施例1~4のリポソームは、比較例1の加熱を行わずに混合処理のみを行ったリポソーム、及び比較例2~6の他の水を用いたリポソーム製造方法に比べてアムホテリシンBの内包率が高く、さらにリン脂質のガラス転移点温度以上に加熱することにより難水溶性薬物の内包率をさらに高められることが確認された。 As is clear from Table 1, the liposomes of Examples 1 to 4 are different from the liposomes in which only mixing treatment was performed without heating in Comparative Example 1, and the liposome manufacturing method using other water in Comparative Examples 2 to 6. It was confirmed that the encapsulation rate of amphotericin B was higher than that of phospholipids, and that the encapsulation rate of poorly water-soluble drugs could be further increased by heating the phospholipid to a temperature higher than the glass transition temperature.
Claims (7)
前記リポソームを構成する脂質が、リン脂質を含む脂質二重膜を形成する脂質と、脂質二重膜に取り込まれる脂溶性成分としてコレステロールを含有し、
前記加熱温度が、脂質二重膜を形成する脂質の少なくとも1種のガラス転移温度以上又は融点温度以上である、脂質混合物の製造方法。 A method for producing a lipid mixture that becomes a liposome encapsulating a poorly water-soluble drug when dispersed in an aqueous solvent, wherein the poorly water-soluble drug is a drug whose solubility in water at 25°C is 2.0 g/L or less. , a step of heating and mixing lipids, saccharides, and poorly water-soluble drugs constituting the liposome to melt them under conditions such that the aqueous solvent that does not contain an organic solvent is 20% by mass or less based on the total mass of the heated and mixed raw materials; cooling the melt,
The lipids constituting the liposome contain lipids forming a lipid bilayer membrane containing phospholipids and cholesterol as a fat -soluble component incorporated into the lipid bilayer membrane,
A method for producing a lipid mixture, wherein the heating temperature is higher than the glass transition temperature or melting point temperature of at least one of the lipids forming a lipid bilayer membrane.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2018244108A JP7378929B2 (en) | 2018-12-27 | 2018-12-27 | Method for producing liposomes |
JP2023154167A JP2023182631A (en) | 2018-12-27 | 2023-09-21 | Method for producing liposome |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2018244108A JP7378929B2 (en) | 2018-12-27 | 2018-12-27 | Method for producing liposomes |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2023154167A Division JP2023182631A (en) | 2018-12-27 | 2023-09-21 | Method for producing liposome |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2020105098A JP2020105098A (en) | 2020-07-09 |
JP7378929B2 true JP7378929B2 (en) | 2023-11-14 |
Family
ID=71448117
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2018244108A Active JP7378929B2 (en) | 2018-12-27 | 2018-12-27 | Method for producing liposomes |
JP2023154167A Pending JP2023182631A (en) | 2018-12-27 | 2023-09-21 | Method for producing liposome |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2023154167A Pending JP2023182631A (en) | 2018-12-27 | 2023-09-21 | Method for producing liposome |
Country Status (1)
Country | Link |
---|---|
JP (2) | JP7378929B2 (en) |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2008156322A (en) | 2006-12-26 | 2008-07-10 | Tama Seikagaku Kk | Composition of phytosterol and phosphatidylcholin and method for preparation of the same |
JP2008222653A (en) | 2007-03-14 | 2008-09-25 | Pola Chem Ind Inc | External preparation for skin with moisture retainability |
JP2014522816A (en) | 2011-06-22 | 2014-09-08 | ビョーメ バイオサイエンシズ ピーブイティー.リミテッド | Conjugate-based antifungal and antibacterial prodrugs |
JP2018035179A (en) | 2012-05-10 | 2018-03-08 | ペインレフォーム リミテッド | Depot formulations of hydrophobic active ingredient and methods for preparation thereof |
JP2018533628A (en) | 2015-11-10 | 2018-11-15 | チルドレンズ リサーチ インスティテュート、チルドレンズ ナショナル メディカル センター | Ekinomycin formulations, methods of making and using the same |
-
2018
- 2018-12-27 JP JP2018244108A patent/JP7378929B2/en active Active
-
2023
- 2023-09-21 JP JP2023154167A patent/JP2023182631A/en active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2008156322A (en) | 2006-12-26 | 2008-07-10 | Tama Seikagaku Kk | Composition of phytosterol and phosphatidylcholin and method for preparation of the same |
JP2008222653A (en) | 2007-03-14 | 2008-09-25 | Pola Chem Ind Inc | External preparation for skin with moisture retainability |
JP2014522816A (en) | 2011-06-22 | 2014-09-08 | ビョーメ バイオサイエンシズ ピーブイティー.リミテッド | Conjugate-based antifungal and antibacterial prodrugs |
JP2018035179A (en) | 2012-05-10 | 2018-03-08 | ペインレフォーム リミテッド | Depot formulations of hydrophobic active ingredient and methods for preparation thereof |
JP2018533628A (en) | 2015-11-10 | 2018-11-15 | チルドレンズ リサーチ インスティテュート、チルドレンズ ナショナル メディカル センター | Ekinomycin formulations, methods of making and using the same |
Also Published As
Publication number | Publication date |
---|---|
JP2023182631A (en) | 2023-12-26 |
JP2020105098A (en) | 2020-07-09 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Katouzian et al. | Formulation and application of a new generation of lipid nano-carriers for the food bioactive ingredients | |
Keller | Liposomes in nutrition | |
JP5368793B2 (en) | Compositions and methods for making and using nanoemulsions | |
JP4857392B2 (en) | Method for producing liposome and method for dissolving cholesterol | |
EP2263653A2 (en) | Preparation of lipid based nano-particles with a dual asymetric centrifuge | |
EP2298282B1 (en) | Combination of drugs having different physical properties into single dosage form | |
JPS607932A (en) | Preparation of liposome | |
WO2008101344A1 (en) | Soluble bioactive lipophilic compounds compositions | |
KR20070113711A (en) | Anti-wrinkle cosmetic composition encapsulating idebenone with nano sizes and its manufacturing method | |
TW201216968A (en) | Parenteral formulations of elacytarabine derivatives | |
KR102072439B1 (en) | Method for preparing liposome by environment-friendly solvent | |
JP7378929B2 (en) | Method for producing liposomes | |
US11154502B2 (en) | Lecithin vesicles for oral delivery | |
US8951450B2 (en) | Apparatus and method for production of liposomes | |
US20220023214A1 (en) | Lecithin Vesicles for Oral Delivery | |
KR20100024050A (en) | Multi-vesicular liposome, the method preparing thereof and the pharmaceutical or cosmetic composition containing the same | |
KR101507884B1 (en) | Nano-concentrated capsule composition with water-soluble active material using thermal sensitive lipid-conjugated pluronic, manufacturing method thereof and cosmetic composition using the same | |
JP3831958B2 (en) | Lipid mixed lipid and liposome dispersion | |
KR100831627B1 (en) | Reverse-Phase Multi-Lamella Vesicle Capturing Aqueous Physiologically Active Ingredients | |
KR102678046B1 (en) | A Stabilized Nano Liposome Delivery Carrier Comprising Nucleic Acid And A Method For Preparing The Same | |
EP2272488B1 (en) | Vesicle and cosmetic containing the same | |
JP2008120721A (en) | Method for producing liposome containing pharmaceutical agent having high specific gravity | |
Zhao | Preparation of liposomes and encapsulation of bioactives using supercritical carbon dioxide | |
Chaves et al. | Current Applications of Liposomes for the Delivery of Bioactives: A Review on the Encapsulation of Vitamins | |
JP4599849B2 (en) | Method for producing liposome-containing preparation, and liposome-containing preparation |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20211116 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20220912 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20220927 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20221128 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20230117 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20230320 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20230511 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20230704 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20230921 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20230928 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20231024 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20231101 |
|
R151 | Written notification of patent or utility model registration |
Ref document number: 7378929 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R151 |