JPH04253907A - Immunosuppressive agent for intravenous injection - Google Patents
Immunosuppressive agent for intravenous injectionInfo
- Publication number
- JPH04253907A JPH04253907A JP3147892A JP14789291A JPH04253907A JP H04253907 A JPH04253907 A JP H04253907A JP 3147892 A JP3147892 A JP 3147892A JP 14789291 A JP14789291 A JP 14789291A JP H04253907 A JPH04253907 A JP H04253907A
- Authority
- JP
- Japan
- Prior art keywords
- soybean oil
- cyclosporins
- intravenous injection
- immunosuppressive agent
- pts
- 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.)
- Pending
Links
- 239000003018 immunosuppressive agent Substances 0.000 title claims abstract description 11
- 238000010253 intravenous injection Methods 0.000 title claims abstract description 5
- 229940125721 immunosuppressive agent Drugs 0.000 title abstract 3
- 229930182912 cyclosporin Natural products 0.000 claims abstract description 17
- 108010036941 Cyclosporins Proteins 0.000 claims abstract description 13
- 239000004480 active ingredient Substances 0.000 claims abstract description 5
- 239000002960 lipid emulsion Substances 0.000 claims description 10
- 229960003444 immunosuppressant agent Drugs 0.000 claims description 8
- 230000001861 immunosuppressant effect Effects 0.000 claims description 7
- 239000003549 soybean oil Substances 0.000 abstract description 12
- 235000012424 soybean oil Nutrition 0.000 abstract description 12
- 230000000694 effects Effects 0.000 abstract description 10
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 abstract description 8
- 108010036949 Cyclosporine Proteins 0.000 abstract description 7
- 229960001265 ciclosporin Drugs 0.000 abstract description 7
- 150000003904 phospholipids Chemical class 0.000 abstract description 7
- 229930105110 Cyclosporin A Natural products 0.000 abstract description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 6
- 239000003995 emulsifying agent Substances 0.000 abstract description 5
- 239000000839 emulsion Substances 0.000 abstract description 5
- 239000002736 nonionic surfactant Substances 0.000 abstract description 5
- JTOKYIBTLUQVQV-QRVTZXGZSA-N (3s,6s,9s,12r,15s,18s,21s,24s,30s,33s)-30-[(1r)-1-hydroxyethyl]-33-[(e,1r,2r)-1-hydroxy-2-methylhex-4-enyl]-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontan Chemical compound C\C=C\C[C@@H](C)[C@@H](O)[C@@H]1N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C(=O)[C@H]([C@@H](C)O)NC1=O JTOKYIBTLUQVQV-QRVTZXGZSA-N 0.000 abstract description 2
- ZNVBEWJRWHNZMK-SYOLRUPNSA-N (3s,6s,9s,12r,15s,18s,21s,24s,30s,33s)-33-[(e,1r,2r)-1-hydroxy-2-methylhex-4-enyl]-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21,30-tri(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontane-2,5,8,11,14,17,20,2 Chemical compound C\C=C\C[C@@H](C)[C@@H](O)[C@@H]1N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C(=O)[C@H](C(C)C)NC1=O ZNVBEWJRWHNZMK-SYOLRUPNSA-N 0.000 abstract description 2
- JTOKYIBTLUQVQV-UHFFFAOYSA-N Cyclosporin C Natural products CC=CCC(C)C(O)C1N(C)C(=O)C(C(C)C)N(C)C(=O)C(CC(C)C)N(C)C(=O)C(CC(C)C)N(C)C(=O)C(C)NC(=O)C(C)NC(=O)C(CC(C)C)N(C)C(=O)C(C(C)C)NC(=O)C(CC(C)C)N(C)C(=O)CN(C)C(=O)C(C(C)O)NC1=O JTOKYIBTLUQVQV-UHFFFAOYSA-N 0.000 abstract description 2
- 108010019248 cyclosporin C Proteins 0.000 abstract description 2
- 108010019594 cyclosporin D Proteins 0.000 abstract description 2
- 230000002688 persistence Effects 0.000 abstract 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 229940090044 injection Drugs 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 238000001990 intravenous administration Methods 0.000 description 5
- 239000004359 castor oil Substances 0.000 description 4
- 235000019438 castor oil Nutrition 0.000 description 4
- 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 4
- 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 3
- 102000009027 Albumins Human genes 0.000 description 3
- 108010088751 Albumins Proteins 0.000 description 3
- -1 alkali metal salts Chemical class 0.000 description 3
- 235000014113 dietary fatty acids Nutrition 0.000 description 3
- 229930195729 fatty acid Natural products 0.000 description 3
- 239000000194 fatty acid Substances 0.000 description 3
- 150000004665 fatty acids Chemical class 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 229920001515 polyalkylene glycol Polymers 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- 229920002554 vinyl polymer Polymers 0.000 description 3
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 2
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 239000005642 Oleic acid Substances 0.000 description 2
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 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 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 2
- 239000007951 isotonicity adjuster Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000008215 water for injection Substances 0.000 description 2
- OYHQOLUKZRVURQ-NTGFUMLPSA-N (9Z,12Z)-9,10,12,13-tetratritiooctadeca-9,12-dienoic acid Chemical compound C(CCCCCCC\C(=C(/C\C(=C(/CCCCC)\[3H])\[3H])\[3H])\[3H])(=O)O OYHQOLUKZRVURQ-NTGFUMLPSA-N 0.000 description 1
- QGLWBTPVKHMVHM-KTKRTIGZSA-N (z)-octadec-9-en-1-amine Chemical compound CCCCCCCC\C=C/CCCCCCCCN QGLWBTPVKHMVHM-KTKRTIGZSA-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
- LDVVTQMJQSCDMK-UHFFFAOYSA-N 1,3-dihydroxypropan-2-yl formate Chemical compound OCC(CO)OC=O LDVVTQMJQSCDMK-UHFFFAOYSA-N 0.000 description 1
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound 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 1
- 208000009137 Behcet syndrome Diseases 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-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
- 208000009329 Graft vs Host Disease Diseases 0.000 description 1
- 229920001612 Hydroxyethyl starch Polymers 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- REYJJPSVUYRZGE-UHFFFAOYSA-N Octadecylamine Chemical compound CCCCCCCCCCCCCCCCCCN REYJJPSVUYRZGE-UHFFFAOYSA-N 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- BCKXLBQYZLBQEK-KVVVOXFISA-M Sodium oleate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC([O-])=O BCKXLBQYZLBQEK-KVVVOXFISA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- DTOSIQBPPRVQHS-PDBXOOCHSA-N alpha-linolenic acid Chemical compound CC\C=C/C\C=C/C\C=C/CCCCCCCC(O)=O DTOSIQBPPRVQHS-PDBXOOCHSA-N 0.000 description 1
- 235000020661 alpha-linolenic acid Nutrition 0.000 description 1
- 239000012752 auxiliary agent Substances 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
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 150000001841 cholesterols Chemical class 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000008344 egg yolk phospholipid Substances 0.000 description 1
- 229940068998 egg yolk phospholipid Drugs 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229940093181 glucose injection Drugs 0.000 description 1
- 208000024908 graft versus host disease Diseases 0.000 description 1
- KDCIHNCMPUBDKT-UHFFFAOYSA-N hexane;propan-2-one Chemical compound CC(C)=O.CCCCCC KDCIHNCMPUBDKT-UHFFFAOYSA-N 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 229940050526 hydroxyethylstarch Drugs 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 229960004488 linolenic acid Drugs 0.000 description 1
- KQQKGWQCNNTQJW-UHFFFAOYSA-N linolenic acid Natural products CC=CCCC=CCC=CCCCCCCCC(O)=O KQQKGWQCNNTQJW-UHFFFAOYSA-N 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- 239000007764 o/w emulsion Substances 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
- IOQPZZOEVPZRBK-UHFFFAOYSA-N octan-1-amine Chemical compound CCCCCCCCN IOQPZZOEVPZRBK-UHFFFAOYSA-N 0.000 description 1
- 235000021313 oleic acid Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 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 1
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 1
- 150000003905 phosphatidylinositols Chemical class 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000011076 safety test Methods 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229940083466 soybean lecithin Drugs 0.000 description 1
- 238000001256 steam distillation Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 description 1
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Abstract
Description
【０００１】0001
【産業上の利用分野】本発明は、副作用が軽減され、高
い持続性を有する静脈注射用免疫抑制剤に関する。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an intravenous immunosuppressant with reduced side effects and high durability.
【０００２】0002
【従来技術】サイクロスポリン類は、抗生物質由来の免
疫抑制剤であり、腎移植、骨髄移植における拒否反応の
抑制、移植片対宿主病の抑制、眼症状のある場合のベー
チェット病に適応される。[Prior Art] Cyclosporins are antibiotic-derived immunosuppressants, and are indicated for suppressing rejection reactions in kidney transplants and bone marrow transplants, suppressing graft-versus-host disease, and treating Behcet's disease in cases with ocular symptoms. Ru.
【０００３】サイクロスポリン類は、一般に経口、注射
投与により服用されているが、経口投与による場合、そ
の吸収量は個人差により一定しておらず、血中濃度が高
い場合の副作用および血中濃度が低い場合の拒否反応を
発現する恐れがあり、また注射投与による場合、過量投
与による副作用、稀にショックなどの過敏反応を示すこ
とがある。[0003] Cyclosporins are generally taken orally or by injection; however, when administered orally, the amount of absorption is not constant due to individual differences, and there are side effects and side effects when the blood concentration is high. If the concentration is low, there is a risk of rejection reactions, and if administered by injection, side effects may occur due to overdosage, and in rare cases, hypersensitivity reactions such as shock may occur.
【０００４】また、経口、注射投与の何れの場合も、持
続性は低く、経口投与の場合１日量を１〜２回に分服し
、注射投与の場合、１日量を生理食塩液またはブドウ糖
注射液で１００倍に希釈して点滴静注して、服用されて
いる。[0004] In addition, the sustainability of both oral and injection administration is low; in the case of oral administration, the daily dose is divided into 1 to 2 doses, and in the case of injection administration, the daily dose is administered in physiological saline or It is diluted 100 times with glucose injection and administered intravenously.
【０００５】[0005]
【発明が解決しようとする課題】従って、本発明の目的
は副作用が軽減され、持続性の高く、移植部位への分布
性に優れたサイクロスポリン類を有効成分とする免疫抑
制剤を提供することにある。[Problems to be Solved by the Invention] Therefore, an object of the present invention is to provide an immunosuppressant containing cyclosporins as an active ingredient, which has reduced side effects, is highly durable, and has excellent distribution to the transplant site. There is a particular thing.
【０００６】[0006]
【課題を解決するための手段】本発明者らは、鋭意研究
を重ねた結果、サイクロスポリン類を脂肪乳剤とし、こ
れを静脈注射用とすることにより、上記課題が悉く解決
されることを見出して本発明を完成するに至った。[Means for Solving the Problems] As a result of extensive research, the present inventors have found that all of the above problems can be solved by making cyclosporins into a fat emulsion and making it for intravenous injection. This discovery led to the completion of the present invention.
【０００７】すなわち、本発明の要旨は、サイクロスポ
リン類から選ばれる少なくとも一種を含有する脂肪乳剤
を有効成分とする静脈注射用免疫抑制剤である。本発明
に関して、サイクロスポリン類とは、真菌 Ｔｈｉｃｈ
ｏｄｅｒｍａｐｏｌｙｓｐｏｒｕｍ， Ｃｙｌｉｎｄｒ
ｏｃａｒｐｏｎ ｌｕｃｉｄｕｍ の代謝物であるサイ
クロスポリンＡ、ＣもしくはＤ、または他の免疫活性を
有するサイクロスポリン誘導体を意味し、その中でもサ
イクロスポリンＡが好適に用いられる。That is, the gist of the present invention is an intravenous immunosuppressant containing as an active ingredient a fat emulsion containing at least one selected from cyclosporins. In the context of the present invention, cyclosporins refer to fungi
odermapolysporum, Cylindr
It means cyclosporin A, C, or D, which is a metabolite of ocarpon lucidum, or other cyclosporin derivatives having immunological activity, and among them, cyclosporin A is preferably used.
【０００８】本発明において、脂肪乳剤は、好適には大
豆油５〜５０ｗ／ｖ％、大豆油１００部に対して乳化剤
１〜５０部（好ましくは５〜３０部）、および適量の水
から主としてなる。乳化剤としては、リン脂質または合
成非イオン性の界面活性剤、あるいはこれらを組み合わ
せたものが用いられる。In the present invention, the fat emulsion is preferably made mainly from 5 to 50 w/v% of soybean oil, 1 to 50 parts (preferably 5 to 30 parts) of an emulsifier per 100 parts of soybean oil, and an appropriate amount of water. Become. As the emulsifier, a phospholipid, a synthetic nonionic surfactant, or a combination thereof is used.
【０００９】この他、必要に応じて更に乳化補助剤〔た
とえば、０．３％（ｗ／ｖ）までの量の炭素数６〜２２
、好ましくは１２〜２０の脂肪酸または有機アミン類、
あるいはこれらの生理的に受け入れられる塩など〕、安
定化剤〔たとえば、０．５％（ｗ／ｖ）以下、好ましく
は０．１％（ｗ／ｖ）以下の量のコレステロール類また
は５％（ｗ／ｖ）以下、好ましくは１％（ｗ／ｖ）以下
の量のホスファチジン酸など〕、高分子物質〔たとえば
、サイクロスポリン１重量部に対して０．１〜５重量部
（好ましくは０．５〜１重量部）のアルブミン、デキス
トラン、ビニル重合体、非イオン性界面活性剤、ゼラチ
ン、ヒドロキシエチル澱粉など〕、等張化剤（たとえば
、グリセリン、ブドウ糖など）などを添加することもで
きる。サイクロスポリン類の脂肪乳剤中の含有量は、乳
剤の形態および用途によって適宜増減できるが、一般に
は当該乳剤中に極微量、たとえば５μｇ／ｍｌ〜１０ｍ
ｇ／ｍｌを含有させることで十分である。[0009] In addition, if necessary, an emulsifying auxiliary agent [for example, an amount of up to 0.3% (w/v) of carbon atoms 6 to 22
, preferably 12 to 20 fatty acids or organic amines,
or physiologically acceptable salts thereof], stabilizers [e.g., cholesterols in an amount of 0.5% (w/v) or less, preferably 0.1% (w/v) or less; (w/v) or less, preferably 1% (w/v) or less], polymeric substances [e.g., 0.1-5 parts by weight (preferably 0 .5 to 1 part by weight) of albumin, dextran, vinyl polymer, nonionic surfactant, gelatin, hydroxyethyl starch, etc.], isotonic agents (e.g., glycerin, glucose, etc.), etc. can also be added. . The content of cyclosporins in a fat emulsion can be increased or decreased as appropriate depending on the form of the emulsion and its intended use;
It is sufficient to contain g/ml.
【００１０】ここにおいて、大豆油は好ましくは高純度
の精製大豆油であり、好ましくは精製大豆油を、たとえ
ば水蒸気蒸留法により更に精製して得た高純度の精製大
豆油（純度：トリグリセリド、ジグリセリドおよびモノ
グリセリドとして９９．９％以上含有）である。[0010] Here, the soybean oil is preferably a highly purified refined soybean oil, preferably a highly purified refined soybean oil obtained by further refining the refined soybean oil, for example, by a steam distillation method (purity: triglyceride, diglyceride, etc.). and 99.9% or more monoglyceride content).
【００１１】リン脂質は卵黄レシチン、大豆レシチンな
どの精製リン脂質であり、常法の有機溶媒による分画法
によって調製することができる。すなわち、たとえば粗
卵黄リン脂質を冷ｎ−ヘキサン−アセトンに溶解し、攪
拌下、徐々にアセトンを添加し、不溶物を濾別回収し、
この操作を更にもう１回繰り返した後溶媒を留去するこ
とによって精製リン脂質を得ることができる。これは主
としてホスファチジルコリン、ホスファチジルエタノー
ルアミンからなり、これ以外のリン脂質として、ホスフ
ァチジルイノシトール、ホスファチジルセリン、スフィ
ンゴミエリンなどを含有していてもよい。Phospholipids are purified phospholipids such as egg yolk lecithin and soybean lecithin, and can be prepared by a conventional fractionation method using an organic solvent. That is, for example, crude egg yolk phospholipid is dissolved in cold n-hexane-acetone, acetone is gradually added while stirring, insoluble matter is separated and collected by filtration,
Purified phospholipids can be obtained by repeating this operation one more time and then distilling off the solvent. It mainly consists of phosphatidylcholine and phosphatidylethanolamine, and may also contain other phospholipids such as phosphatidylinositol, phosphatidylserine, and sphingomyelin.
【００１２】乳化補助剤としての炭素数６〜２２の脂肪
酸は、医薬品に添加可能なものであれば使用できる。こ
の脂肪酸は直鎖状、分枝状のいずれでもよく、直鎖状の
ステアリン酸、オレイン酸、リノール酸、パルミチン酸
、リノレン酸、ミリスチン酸などを用いるのが好ましい
。有機アミン類としてはエタノールアミン、トリエタノ
ールアミン、プロピルアミン、オクチルアミン、ステア
リルアミン、オレイルアミンなどを用いることができる
。これらの塩としては、生理的に受け入れられる塩、た
とえばアルカリ金属塩（ナトリウム塩、カリウム塩など
）、アルカリ土類金属（カルシウム塩など）などを用い
ることができる。[0012] Fatty acids having 6 to 22 carbon atoms as emulsification aids can be used as long as they can be added to pharmaceuticals. This fatty acid may be linear or branched, and it is preferable to use linear stearic acid, oleic acid, linoleic acid, palmitic acid, linolenic acid, myristic acid, or the like. As organic amines, ethanolamine, triethanolamine, propylamine, octylamine, stearylamine, oleylamine, etc. can be used. As these salts, physiologically acceptable salts such as alkali metal salts (sodium salts, potassium salts, etc.), alkaline earth metal salts (calcium salts, etc.), etc. can be used.
【００１３】安定化剤としてのコレステロールやホスフ
ァチジン酸は医薬用として使用が可能なものであればよ
い。高分子物質として用いられるアルブミン、ビニル重
合体、非イオン性界面活性剤としては次のものが好まし
い。すなわちアルブミンとしては、抗原性の問題からヒ
ト由来のものを用いることが好ましい。ビニル重合体と
しては、ポリビニルピロリドンなどを挙げることができ
る。Cholesterol and phosphatidic acid as stabilizers may be of any type as long as they can be used medicinally. As the albumin, vinyl polymer, and nonionic surfactant used as the polymeric substance, the following are preferable. That is, it is preferable to use human-derived albumin from the viewpoint of antigenicity. Examples of vinyl polymers include polyvinylpyrrolidone.
【００１４】また、非イオン性界面活性剤としては、ポ
リアルキレングリコール（たとえば、平均分子量１，０
００〜１０，０００、好ましくは４，０００〜６，００
０のポリエチレングリコール）、ポリオキシアルキレン
共重合体（たとえば、平均分子量１，０００〜２０，０
００、好ましくは６，０００〜１０，０００のポリオキ
シエチレン−ポリオキシプロピレン共重合体）、硬化ヒ
マシ油ポリオキシアルキレン誘導体〔たとえば、硬化ヒ
マシ油オキシポリエチレン−（４０）−エーテル、同−
（２０）−エーテル、同−（１００）−エーテルなど〕
、ヒマシ油ポリオキシアルキレン誘導体〔たとえば、ヒ
マシ油ポリオキシエチレン−（２０）−エーテル、同−
（４０）−エーテル、同−（１００）−エーテルなど〕
などを用いることができる。[0014] Also, as the nonionic surfactant, polyalkylene glycol (for example, polyalkylene glycol (for example, polyalkylene glycol with an average molecular weight of 1.0
00-10,000, preferably 4,000-6,000
0 polyethylene glycol), polyoxyalkylene copolymers (for example, average molecular weight 1,000 to 20,0
00, preferably 6,000 to 10,000 polyoxyethylene-polyoxypropylene copolymers), hydrogenated castor oil polyoxyalkylene derivatives [e.g., hydrogenated castor oil oxypolyethylene-(40)-ether,
(20)-ether, (100)-ether, etc.]
, castor oil polyoxyalkylene derivatives [e.g., castor oil polyoxyethylene-(20)-ether,
(40)-ether, (100)-ether, etc.]
etc. can be used.
【００１５】本発明に用いる脂肪乳剤の好ましい組成と
しては、
サイクロスポリン類 ５μｇ〜１０ｍｇ精製
大豆油 ５０〜５００ｍｇ
精製卵黄レシチン ５〜５０ｍｇオ
レイン酸 １〜１０ｍ
ｇ濃グリセリン ５〜５０
ｍｇ注射用水
適量合計
１ｍｌが例示される。[0015] The preferred composition of the fat emulsion used in the present invention is as follows: Cyclosporins 5 μg to 10 mg Refined soybean oil 50 to 500 mg
Purified egg yolk lecithin 5-50mg Oleic acid 1-10m
g concentrated glycerin 5-50
mg water for injection
Appropriate amount total
An example is 1 ml.
【００１６】本発明に関する脂肪乳剤は、たとえば次の
方法によって製造される。すなわち、所定量の大豆油、
リン脂質、サイクロスポリン類およびその他前記の添加
剤などを混合した後、必要量の注射用水を加え、ホモジ
ナイザーを用いて均質化処理を行い、水中油型乳剤を調
製することができる。ホモジナイザーとしては、加圧噴
射型ホモジナイザー、超音波ホモジナイザーなどが常用
される。製造上の都合によっては、脂肪乳剤の生成後に
安定化剤、等張剤などの添加剤を加えてもよい。The fat emulsion according to the present invention is produced, for example, by the following method. i.e. a predetermined amount of soybean oil,
After mixing phospholipids, cyclosporins, and the other additives mentioned above, a necessary amount of water for injection is added and homogenization is performed using a homogenizer to prepare an oil-in-water emulsion. As the homogenizer, a pressurized injection type homogenizer, an ultrasonic homogenizer, etc. are commonly used. Depending on manufacturing convenience, additives such as stabilizers and isotonic agents may be added after the production of the fat emulsion.
【００１７】本発明の静脈注射用免疫抑制剤は、その平
均粒子径が約０．１〜１．０μｍであり、保存安定性は
極めて良好である。その投与量は、病態、患部の大きさ
などにより異なるが、通常サイクロスポリン類として、
１日量０．１〜５ｍｇ（力価）／ｋｇ体重程度である。The intravenous immunosuppressant of the present invention has an average particle diameter of about 0.1 to 1.0 μm and has extremely good storage stability. The dosage varies depending on the pathological condition, the size of the affected area, etc., but it is usually used as a cyclosporin.
The daily dose is about 0.1 to 5 mg (potency)/kg body weight.
【００１８】[0018]
【発明の効果】本発明の静脈注射用免疫抑制剤によって
、サイクロスポリン類の薬理作用の持続時間が長く、従
って、投与量も比較的少量でよく、副作用を軽減させる
という効果がある。また、移植部位においては免疫系が
亢進しており、当該部位に脂肪乳剤が分布し易いという
効果も期待できる。EFFECTS OF THE INVENTION The intravenous immunosuppressant of the present invention has the effect that the pharmacological action of cyclosporins lasts for a long time, and therefore the dosage can be relatively small, reducing side effects. In addition, the immune system is activated at the transplant site, and the effect that the fat emulsion is easily distributed to the site can be expected.
【００１９】[0019]
【実施例】本発明をより詳細に説明するために実施例を
挙げるが本発明はこれらによって何ら限定されるもので
はない。
実施例１
精製大豆油１０ｇに精製卵黄レシチン１．２ｇ、オレイ
ン酸ナトリウム０．５ｇ、サイクロスポリン２００ｍｇ
を６０〜７５℃で加熱混合し、日本薬局方グリセリン２
．５ｇを加え、注射用蒸留水にて全量を１００ｍｌとし
、ホモミキサーで混合した後、粗乳化した。EXAMPLES Examples will be given to explain the present invention in more detail, but the present invention is not limited thereto. Example 1 10g of purified soybean oil, 1.2g of purified egg yolk lecithin, 0.5g of sodium oleate, 200mg of cyclosporin
Heat and mix at 60-75°C, and add glycerin 2 to the Japanese Pharmacopoeia.
．． 5 g was added, the total volume was made up to 100 ml with distilled water for injection, mixed with a homomixer, and then coarsely emulsified.
【００２０】これをマントン−ガウリン型ホモジナイザ
ーを用い、５００ｋｇ／ｃｍ２ の加圧下で乳化した。
これにより均質化された極めて微細なサイクロスポリン
を含有する脂肪乳剤を得た。この乳剤の平均粒子径は０
．２〜０．４μｍであり、１μｍ以上の粒子を含有しな
かった。[0020] This was emulsified using a Manton-Gaulin type homogenizer under a pressure of 500 kg/cm2. As a result, a homogenized extremely fine fat emulsion containing cyclosporine was obtained. The average grain size of this emulsion is 0
．． The particle size was 2 to 0.4 μm, and no particles larger than 1 μm were contained.
【００２１】試験例１（安全性試験）マウスにおいて、
本発明の静脈注射用免疫抑制剤を、サイクロスポリンと
して１００ｍｇ／ｋｇ体重を静注投与しても、死亡例は
なく、重篤な急性毒性は発現しなかった。Test Example 1 (Safety Test) In mice,
Even when the intravenous immunosuppressant of the present invention was administered as cyclosporin at 100 mg/kg body weight, there were no deaths and no serious acute toxicity occurred.
Claims (1)
くとも一種を含有する脂肪乳剤を有効成分とする静脈注
射用免疫抑制剤。1. An immunosuppressant for intravenous injection, the active ingredient being a fat emulsion containing at least one selected from cyclosporins.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3147892A JPH04253907A (en) | 1990-05-23 | 1991-05-22 | Immunosuppressive agent for intravenous injection |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP13489090 | 1990-05-23 | ||
| JP2-134890 | 1990-05-23 | ||
| JP3147892A JPH04253907A (en) | 1990-05-23 | 1991-05-22 | Immunosuppressive agent for intravenous injection |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH04253907A true JPH04253907A (en) | 1992-09-09 |
Family
ID=26468874
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP3147892A Pending JPH04253907A (en) | 1990-05-23 | 1991-05-22 | Immunosuppressive agent for intravenous injection |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH04253907A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997012626A1 (en) * | 1995-10-04 | 1997-04-10 | Hans Dietl | Pharmaceutical preparation containing cyclosporin(s) for oral administration and process for producing the said preparation |
| WO1997025977A1 (en) * | 1996-01-19 | 1997-07-24 | Novartis Ag | Pharmaceutical compositions |
| US5962019A (en) * | 1995-08-25 | 1999-10-05 | Sangstat Medical Corporation | Oral cyclosporin formulations |
| US6254885B1 (en) | 1995-08-25 | 2001-07-03 | Sangstat Medical Corporation | Oral cyclosphorin formulations |
| JP2003509453A (en) * | 1999-09-21 | 2003-03-11 | アールティーピー・ファーマ・インコーポレーテッド | Surface-modified granular compositions of biologically active substances |
-
1991
- 1991-05-22 JP JP3147892A patent/JPH04253907A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5962019A (en) * | 1995-08-25 | 1999-10-05 | Sangstat Medical Corporation | Oral cyclosporin formulations |
| US6254885B1 (en) | 1995-08-25 | 2001-07-03 | Sangstat Medical Corporation | Oral cyclosphorin formulations |
| WO1997012626A1 (en) * | 1995-10-04 | 1997-04-10 | Hans Dietl | Pharmaceutical preparation containing cyclosporin(s) for oral administration and process for producing the said preparation |
| US6136357A (en) * | 1995-10-04 | 2000-10-24 | Ciclomulsion Ag | Pharmaceutical preparation containing cyclosporin(S) for oral administration and process for producing the said preparation |
| WO1997025977A1 (en) * | 1996-01-19 | 1997-07-24 | Novartis Ag | Pharmaceutical compositions |
| EP1273289A1 (en) * | 1996-01-19 | 2003-01-08 | Novartis AG | Pharmaceutical compositions containing ascomycin derivatives |
| EP1273288A1 (en) * | 1996-01-19 | 2003-01-08 | Novartis AG | Pharmaceutical compositions containing rapamycin derivatives |
| JP2003509453A (en) * | 1999-09-21 | 2003-03-11 | アールティーピー・ファーマ・インコーポレーテッド | Surface-modified granular compositions of biologically active substances |
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