JP6974670B2 - 弱酸性薬物を含むリポソーム組成物およびその使用 - Google Patents
弱酸性薬物を含むリポソーム組成物およびその使用 Download PDFInfo
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- JP6974670B2 JP6974670B2 JP2020503870A JP2020503870A JP6974670B2 JP 6974670 B2 JP6974670 B2 JP 6974670B2 JP 2020503870 A JP2020503870 A JP 2020503870A JP 2020503870 A JP2020503870 A JP 2020503870A JP 6974670 B2 JP6974670 B2 JP 6974670B2
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- bicarbonate
- pharmaceutical composition
- drug
- aqueous medium
- phospholipid
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- 239000003814 drug Substances 0.000 title claims description 118
- 229940079593 drug Drugs 0.000 title claims description 114
- 230000002378 acidificating effect Effects 0.000 title claims description 41
- 239000000203 mixture Substances 0.000 title claims description 15
- 239000002502 liposome Substances 0.000 claims description 133
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 51
- 150000002632 lipids Chemical class 0.000 claims description 45
- 239000012736 aqueous medium Substances 0.000 claims description 42
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol 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)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 41
- 239000008194 pharmaceutical composition Substances 0.000 claims description 40
- 150000003904 phospholipids Chemical class 0.000 claims description 29
- 239000000232 Lipid Bilayer Substances 0.000 claims description 27
- 235000012000 cholesterol Nutrition 0.000 claims description 21
- 238000005538 encapsulation Methods 0.000 claims description 16
- -1 ethyl PC Chemical compound 0.000 claims description 12
- 208000023504 respiratory system disease Diseases 0.000 claims description 12
- KAQKFAOMNZTLHT-VVUHWYTRSA-N epoprostenol Chemical compound O1C(=CCCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 KAQKFAOMNZTLHT-VVUHWYTRSA-N 0.000 claims description 8
- 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 claims description 8
- 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 claims description 4
- GZDFHIJNHHMENY-UHFFFAOYSA-N Dimethyl dicarbonate Chemical compound COC(=O)OC(=O)OC GZDFHIJNHHMENY-UHFFFAOYSA-N 0.000 claims description 4
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 claims description 4
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 claims 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 claims description 4
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 claims description 4
- 150000008104 phosphatidylethanolamines Chemical class 0.000 claims description 4
- 150000003905 phosphatidylinositols Chemical class 0.000 claims description 4
- REYJJPSVUYRZGE-UHFFFAOYSA-N Octadecylamine Chemical compound CCCCCCCCCCCCCCCCCCN REYJJPSVUYRZGE-UHFFFAOYSA-N 0.000 claims description 3
- 229930182558 Sterol Natural products 0.000 claims description 3
- 239000001294 propane Substances 0.000 claims description 3
- 150000003180 prostaglandins Chemical class 0.000 claims description 3
- 150000003431 steroids Chemical class 0.000 claims description 3
- 150000003432 sterols Chemical class 0.000 claims description 3
- 235000003702 sterols Nutrition 0.000 claims description 3
- 229940124597 therapeutic agent Drugs 0.000 claims description 3
- 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 claims description 2
- 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 claims description 2
- 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 claims description 2
- 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 claims description 2
- 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 claims description 2
- LDGWQMRUWMSZIU-LQDDAWAPSA-M 2,3-bis[(z)-octadec-9-enoxy]propyl-trimethylazanium;chloride Chemical compound [Cl-].CCCCCCCC\C=C/CCCCCCCCOCC(C[N+](C)(C)C)OCCCCCCCC\C=C/CCCCCCCC LDGWQMRUWMSZIU-LQDDAWAPSA-M 0.000 claims description 2
- KSXTUUUQYQYKCR-LQDDAWAPSA-M 2,3-bis[[(z)-octadec-9-enoyl]oxy]propyl-trimethylazanium;chloride Chemical compound [Cl-].CCCCCCCC\C=C/CCCCCCCC(=O)OCC(C[N+](C)(C)C)OC(=O)CCCCCCC\C=C/CCCCCCCC KSXTUUUQYQYKCR-LQDDAWAPSA-M 0.000 claims description 2
- 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 claims 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 claims description 2
- 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 claims description 2
- 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 claims description 2
- 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 claims description 2
- 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 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- PFNFFQXMRSDOHW-UHFFFAOYSA-N Spermine Natural products NCCCNCCCCNCCCN PFNFFQXMRSDOHW-UHFFFAOYSA-N 0.000 claims description 2
- HIHOWBSBBDRPDW-PTHRTHQKSA-N [(3s,8s,9s,10r,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-yl] n-[2-(dimethylamino)ethyl]carbamate Chemical compound C1C=C2C[C@@H](OC(=O)NCCN(C)C)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 HIHOWBSBBDRPDW-PTHRTHQKSA-N 0.000 claims description 2
- ISXSJGHXHUZXNF-LXZPIJOJSA-N [(3s,8s,9s,10r,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-yl] n-[2-(dimethylamino)ethyl]carbamate;hydrochloride Chemical compound Cl.C1C=C2C[C@@H](OC(=O)NCCN(C)C)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 ISXSJGHXHUZXNF-LXZPIJOJSA-N 0.000 claims description 2
- ZMCUDHNSHCRDBT-UHFFFAOYSA-M caesium bicarbonate Chemical compound [Cs+].OC([O-])=O ZMCUDHNSHCRDBT-UHFFFAOYSA-M 0.000 claims description 2
- NKWPZUCBCARRDP-UHFFFAOYSA-L calcium bicarbonate Chemical compound [Ca+2].OC([O-])=O.OC([O-])=O NKWPZUCBCARRDP-UHFFFAOYSA-L 0.000 claims description 2
- 229910000020 calcium bicarbonate Inorganic materials 0.000 claims description 2
- DKIDFDYBDZCAAU-UHFFFAOYSA-L carbonic acid;iron(2+);carbonate Chemical compound [Fe+2].OC([O-])=O.OC([O-])=O DKIDFDYBDZCAAU-UHFFFAOYSA-L 0.000 claims description 2
- UMGXUWVIJIQANV-UHFFFAOYSA-M didecyl(dimethyl)azanium;bromide Chemical compound [Br-].CCCCCCCCCC[N+](C)(C)CCCCCCCCCC UMGXUWVIJIQANV-UHFFFAOYSA-M 0.000 claims 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 claims description 2
- OGQYPPBGSLZBEG-UHFFFAOYSA-N dimethyl(dioctadecyl)azanium Chemical compound CCCCCCCCCCCCCCCCCC[N+](C)(C)CCCCCCCCCCCCCCCCCC OGQYPPBGSLZBEG-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- JGENYNHRIOHZOP-UHFFFAOYSA-N ethyl 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CCOP([O-])(=O)OCC[N+](C)(C)C JGENYNHRIOHZOP-UHFFFAOYSA-N 0.000 claims description 2
- IYFXESRMJKRSNZ-UHFFFAOYSA-L hydrogen carbonate;nickel(2+) Chemical compound [Ni+2].OC([O-])=O.OC([O-])=O IYFXESRMJKRSNZ-UHFFFAOYSA-L 0.000 claims description 2
- 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 claims description 2
- 229940058690 lanosterol Drugs 0.000 claims description 2
- HQRPHMAXFVUBJX-UHFFFAOYSA-M lithium;hydrogen carbonate Chemical compound [Li+].OC([O-])=O HQRPHMAXFVUBJX-UHFFFAOYSA-M 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- KILNVBDSWZSGLL-KXQOOQHDSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCC KILNVBDSWZSGLL-KXQOOQHDSA-N 0.000 claims 2
- 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 claims 2
- NRJAVPSFFCBXDT-HUESYALOSA-N 1,2-distearoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCCCC NRJAVPSFFCBXDT-HUESYALOSA-N 0.000 claims 2
- 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 claims 2
- 101001105486 Homo sapiens Proteasome subunit alpha type-7 Proteins 0.000 claims 2
- 102100021201 Proteasome subunit alpha type-7 Human genes 0.000 claims 2
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 claims 2
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- 239000003146 anticoagulant agent Substances 0.000 claims 1
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- BPHQZTVXXXJVHI-UHFFFAOYSA-N dimyristoyl phosphatidylglycerol Chemical compound CCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCCCCCCCC BPHQZTVXXXJVHI-UHFFFAOYSA-N 0.000 claims 1
- BIABMEZBCHDPBV-UHFFFAOYSA-N dipalmitoyl phosphatidylglycerol Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCCCCCCCCCC BIABMEZBCHDPBV-UHFFFAOYSA-N 0.000 claims 1
- FVJZSBGHRPJMMA-UHFFFAOYSA-N distearoyl phosphatidylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCCCCCCCCCCCC FVJZSBGHRPJMMA-UHFFFAOYSA-N 0.000 claims 1
- QWDJLDTYWNBUKE-UHFFFAOYSA-L magnesium bicarbonate Chemical compound [Mg+2].OC([O-])=O.OC([O-])=O QWDJLDTYWNBUKE-UHFFFAOYSA-L 0.000 claims 1
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- 235000014824 magnesium bicarbonate Nutrition 0.000 claims 1
- 239000002370 magnesium bicarbonate Substances 0.000 claims 1
- DDBRXOJCLVGHLX-UHFFFAOYSA-N n,n-dimethylmethanamine;propane Chemical compound CCC.CN(C)C DDBRXOJCLVGHLX-UHFFFAOYSA-N 0.000 claims 1
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Classifications
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- A61K9/10—Dispersions; Emulsions
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
- A61K31/558—Eicosanoids, e.g. leukotrienes or prostaglandins having heterocyclic rings containing oxygen as the only ring hetero atom, e.g. thromboxanes
- A61K31/5585—Eicosanoids, e.g. leukotrienes or prostaglandins having heterocyclic rings containing oxygen as the only ring hetero atom, e.g. thromboxanes having five-membered rings containing oxygen as the only ring hetero atom, e.g. prostacyclin
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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- A—HUMAN NECESSITIES
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- A61P11/06—Antiasthmatics
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
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- Organic Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
この出願は、2017年7月24日に出願された米国出願第62/536,034号及び2017年12月6日に出願された米国出願第62/595,207号の利益を主張しており、その開示全体は参照により本明細書に組み込まれる。
リポソームは、内部水性媒体を含む脂質二重層によって形成される小胞である。リポソームはさまざまな治療薬のキャリアとして使用され、血液循環時間の延長、細胞毒性の低減、持続的な薬物放出、特定の組織への特定の薬物送達などの改善された送達特性を提供する。治療薬の送達にリポソームを使用する場合、より高い薬物カプセル化効率が望ましい。
一実施形態では、本発明は、(a)少なくとも1つの小胞形成脂質を含む脂質二重層と(b)重炭酸塩と弱酸性薬物を含む脂質二重層内部の内部水性媒体を含む、1つ以上のリポソームを含む医薬組成物を開示し、リポソームは外部媒体に懸濁され、薬物と重炭酸塩のモル比は約0.1:1〜1:1である。
(i)少なくとも1つの小胞形成脂質を使用して脂質溶液を調製する;
(ii)ステップ(i)の脂質溶液を重炭酸塩と混合して、脂質二重層と内部水性媒体を含む少なくとも1つのリポソームを形成し、リポソームは外部媒体に懸濁している;
(iii)外部媒体中の重炭酸塩の濃度を調整して、リポソームの外部媒体のpHを低くし、リポソームの内部水性媒体のpHを高くし、外部媒体のpHは弱酸性薬のpKaを超える;そして
(i∨)弱酸性薬物を外部媒体に加える。
特に定義されない限り、本明細書で使用されるすべての技術用語および科学用語は、本発明が属する技術分野の当業者によって一般に理解されるのと同じ意味を有する。
(i)少なくとも1つの小胞形成脂質を使用して脂質溶液を調製する;
(ii)ステップ(i)の脂質溶液を重炭酸塩と混合して、脂質二重層と内部水性媒体を含む少なくとも1つのリポソームを形成し、ここでリポソームは外部媒体に懸濁している;
(iii)外部媒体中の重炭酸塩の濃度を調整して、リポソームの外部媒体のpHを低くし、リポソームの内部水性媒体のpHを高くし、ここで外部媒体のpHは弱酸性薬のpKaを超える;そして
(iv)弱酸性薬物を外部媒体に加える。
1.材料および方法
1.1 酢酸ナトリウム(NaC2H2O2)を使用したPGE1リポソーム調製
リポソームコロイド懸濁液は、エタノール注入技術により調製された。簡単に言うと、496.8mgの水素化大豆ホスファチジルコリン(HSPC)、154.65mgのコレステロール、および42.15mgの1,2−ジステアロリ−sn−グリセロ−3−ホスホエタノールアミン−N−[メトキシ(ポリエチレングリコール)−2000](DSPE−PEG2000)をエタノール2.86mlに溶解した。エタノール中の脂質溶液を、17.4mlの酢酸ナトリウム(200mMまたは400mM)に注入し、60℃で激しく攪拌した。脂質溶液が酢酸ナトリウムと接触するとすぐにリポソームが形成された。これに続いて、リポソーム懸濁液を200nmおよび100nmのポリカーボネート膜を通して押し出した(それぞれ6回)。約100nmのリポソームが得られ、クエン酸緩衝液(pH5.5)に対してダイアフィルトレーションして、リポソームの外部媒体と内部水性媒体の間に高い内側/低い外側pH勾配を形成した。空のリポソーム懸濁液は、薬物充填プロセスの前に4℃で保存された。
リポソーム懸濁液は、酢酸ナトリウム(200mMまたは400mM)を重炭酸ナトリウム(たとえば200mM、400mMまたは他の濃度)に置き換えたことを除いて、セクション1.1に記載の方法に従って調製した。
リポソームにカプセル化された薬物の量は、フォトダイオードアレイ(PDA)検出器を備えたWaters Alliance(登録商標)HPLCシステムを使用して定量化された。簡単に説明すると、100μLの各サンプル溶液のアリコートを、流速1.0 μmL/分の移動相として、体積比80:20のメタノールとリン酸緩衝液(6.7 mM濃度、pH 3.0)の混合物と共にHPLCシステムに直接注入した。C18カラム(Phenomenex Prodigy 5U ODS−3 150×4.6mm)で分離を行い、その後、65℃でKOHの1Nと混合して後反応を行った。薬物のピーク、例えば、PGE1は280nmで検出された。保持時間は約4.6分だった。
カプセル化効率(EE)、すなわち、リポソーム懸濁液に存在する薬物の総量(すなわち、外部媒体中の薬物およびリポソームの内部水性媒体に充填された薬物)に対するリポソームの内部水性媒体にカプセル化(または充填)された薬物の割合を以下のように定量化した。簡単に言えば、リポソーム懸濁液をカラムクロマトグラフィーにかけた。遊離または非関連薬物(すなわち、外部媒体中の薬物)および内部水性媒体中にカプセル化された薬物を含むリポソームは、G−25カラムを通してリポソーム懸濁液を溶出することによりそれぞれに分離された。遊離薬物の量は、PDA検出を備えたWaters HPLCを使用して決定され、リポソームをメタノール(90%メタノール及び10%リポソーム懸濁液)で破壊した後、リポソームの内部水性媒体中のカプセル化された薬物の量も同じ方法を使用して決定された。カプセル化効率は、次の式を使用して計算された。
リポソームの平均粒子サイズは、動的光散乱により値が求められた。リポソームのサイズ分布を示す値である多分散性指数(PdI)は、平均粒子に対するものと同じ評価手法を使用して、粒子サイズ分析器(Beckman Coulter DelsaTM Nano C粒子分析器)で決定された。
2.1 重炭酸ナトリウムは、より高い薬物カプセル化効率を提供する
表2は、薬物のカプセル化効率(E.E.)および充填塩として重炭酸ナトリウムおよび酢酸ナトリウムを使用したリポソーム懸濁液の薬物と塩のモル比を示す。
実施例1のセクション1.1に従って、PGE1充填のために様々な濃度の重炭酸ナトリウムを使用するリポソーム懸濁液を調製した。リポソーム懸濁液を、オスモル濃度280〜300mOsm/Kgの外部緩衝液中で25℃および37℃で20分間インキュベートし、人間の生理学的状態をシミュレートした。
実施例1のセクション1.1の方法に従ってリポソーム懸濁液を調製し、PGE1に異なる濃度の重炭酸ナトリウム(50mM、150mM、200mM、250mM、300mM、400mM、500mM、600mM、および800mM)を充填した。
実施例1の方法に従って、3:2:0.075のモル比でHSPC、コレステロールおよびDSPE−mPEG2000を含む最初の(4−1)リポソーム懸濁液を調製した。
HSPC、コレステロールおよびmPEG2000−DSPEを3:2:0.075のモル比で含む第1(5−1)リポソーム懸濁液、ならびにHSPC、コレステロール、およびmPEG2000−DSPEを3:2:0.28のモル比で含む第2(5−2)および第3(5−3)リポソーム懸濁液を調製した。トレプロスチニルを、200mMの重炭酸塩でリポソーム懸濁液に充填した。
実施例4の医薬組成物(400mM重炭酸塩を使用して約1.5mgのトレプロスチニルをカプセル化した4−2リポソーム懸濁液)の肺高血圧症に対する治療効果のインビボ評価を、それぞれ約300〜350gの重さの18匹のオスのスプラーグドーリーラットを使用して実施した。
Claims (14)
- 1つ以上のリポソームを含む医薬組成物であって、
前記リポソームは、
(a)少なくとも1つの小胞形成脂質を含む脂質二重層と
(b)約50mMから約800mMの濃度である重炭酸塩および約1から約6のpKaを有する弱酸性薬物を含む脂質二重層内部の内部水性媒体を含み、
前記リポソームは外部水性媒体に懸濁され、前記外部水性媒体のpHは前記弱酸性薬物のpKaと約7との間であり、前記内部水性媒体のpHは、前記外部水性媒体のpHよりも少なくとも1単位高い、医薬組成物。 - 前記弱酸性薬物と前記重炭酸塩のモル比は約0.1:1〜約1:1である、請求項1に記載の医薬組成物。
- 前記重炭酸塩の濃度は約250mMから約800mMである、請求項1に記載の医薬組成物。
- 前記弱酸性薬物のカプセル化効率は少なくとも80%である、請求項1に記載の医薬組成物。
- 前記小胞形成脂質は、第1のリン脂質および第2のリン脂質の混合物、または第1のリン脂質と荷電脂質の混合物である、請求項1に記載の医薬組成物。
- 前記第1のリン脂質は、ホスファチジルコリン(PC)、ホスファチジルグリセロール(PG)、ホスファチジルイノシトール(PI)、ホスファチジン酸(PA)、ホスファチジルエタノールアミン(PE)、ホスファチジルセリン(PS)、およびその任意の組み合わせからなる群から選択され、前記第2のリン脂質はPEG修飾リン脂質、正に帯電したまたは負に帯電したリン脂質であり、前記荷電脂質は正に帯電したまたは負に帯電した脂質である、請求項5に記載の医薬組成物。
- 前記第1のリン脂質はHSPC、DSPC、DPPC、DMPCまたはそれらの組み合わせから選択され、前記第2のリン脂質はDSPG、DPPG、DMPG、PEG−DSPEまたはそれらの組み合わせから選択される、請求項5に記載の医薬組成物。
- 前記第1のリン脂質はHSPC、DSPC、DPPC、DMPCまたはそれらの組み合わせから選択され、前記荷電脂質はステアリルアミン、1,2−ジオレオイル−3−トリメチルアンモニウム−プロパン(DOTAP)、3β−[N−(N’,N’−ジメチルアミノエタン)−カルバモイル]コレステロール(DC−コレステロール)、N4−コレステロール−スペルミン(GL67)、ジメチルジオクタデシルアンモニウム(DDAB)、1,2−ジ−0−オクタデセニル−3−トリメチルアンモニウムプロパン(DOTMA)、エチルホスホコリン(エチルPC)またはそれらの組み合わせから選択される、請求項5に記載の医薬組成物。
- コレステロール、ヘキサスクシネートコレステロール、エルゴステロール、ラノステロール、およびそれらの組み合わせからなる群から選択されるステロールをさらに含む、請求項5に記載の医薬組成物。
- 前記第1のリン脂質:コレステロール:前記第2のリン脂質または前記荷電脂質のモル比は50〜70:20〜45:0.1〜10である、請求項9に記載の医薬組成物。
- 前記重炭酸塩は、重炭酸カリウム、重炭酸ナトリウム、重炭酸カルシウム、重炭酸マグネシウム、重炭酸セシウム、重炭酸リチウム、重炭酸ニッケル、重炭酸第一鉄またはそれらの組み合わせからなる群から選択される、請求項1に記載の医薬組成物。
- 前記弱酸性薬物は、プロスタグランジン、ステロイド、非ステロイド性抗炎症薬(NSAID)、または抗凝固剤である、請求項1記載の医薬組成物。
- 治療有効量の請求項1〜12のいずれか1項に記載の医薬組成物を含む、呼吸器疾患を治療するための治療剤。
- 1つ以上のリポソームを含む医薬組成物であって、
前記リポソームは、
(a)少なくとも1つの小胞形成脂質を含む脂質二重層;および
(b)約50mMから約800mMの濃度である重炭酸塩およびプロスタサイクリンを含む脂質二重層内部の内部水性媒体を含み、前記リポソームは外部水性媒体に懸濁され、前記外部水性媒体のpHは前記弱酸性薬物のpKaと約7との間であり、前記内部水性媒体のpHは、前記外部水性媒体のpHよりも少なくとも1単位高い、医薬組成物。
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RU2020102279A3 (ja) | 2021-09-23 |
RU2020102279A (ru) | 2021-08-24 |
IL272187B (en) | 2022-08-01 |
EP3658134A4 (en) | 2021-05-05 |
US11964050B2 (en) | 2024-04-23 |
KR20200016976A (ko) | 2020-02-17 |
KR102337566B1 (ko) | 2021-12-14 |
CN111372580A (zh) | 2020-07-03 |
CA3070951A1 (en) | 2019-01-31 |
ZA202000439B (en) | 2022-07-27 |
BR112020001411A2 (pt) | 2020-07-28 |
JP2020528432A (ja) | 2020-09-24 |
AU2018307509A1 (en) | 2020-02-13 |
WO2019023092A1 (en) | 2019-01-31 |
US20190022004A1 (en) | 2019-01-24 |
SG11202000593TA (en) | 2020-02-27 |
TW201907908A (zh) | 2019-03-01 |
SA520411119B1 (ar) | 2024-02-12 |
CA3070951C (en) | 2023-03-21 |
IL272187A (en) | 2020-03-31 |
AU2018307509B2 (en) | 2021-04-29 |
TWI728255B (zh) | 2021-05-21 |
EP3658134A1 (en) | 2020-06-03 |
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