EP0969857A1 - Pharmaceutical compositions - Google Patents
Pharmaceutical compositionsInfo
- Publication number
- EP0969857A1 EP0969857A1 EP98912470A EP98912470A EP0969857A1 EP 0969857 A1 EP0969857 A1 EP 0969857A1 EP 98912470 A EP98912470 A EP 98912470A EP 98912470 A EP98912470 A EP 98912470A EP 0969857 A1 EP0969857 A1 EP 0969857A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- cyclosporin
- preparation
- fatty acid
- composition
- present
- 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.)
- Withdrawn
Links
- 239000008194 pharmaceutical composition Substances 0.000 title 1
- 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 claims abstract description 97
- 108010036949 Cyclosporine Proteins 0.000 claims abstract description 97
- 229930105110 Cyclosporin A Natural products 0.000 claims abstract description 90
- 229960001265 ciclosporin Drugs 0.000 claims abstract description 88
- 238000002360 preparation method Methods 0.000 claims abstract description 88
- 229930182912 cyclosporin Natural products 0.000 claims abstract description 85
- 239000000203 mixture Substances 0.000 claims abstract description 80
- 239000007901 soft capsule Substances 0.000 claims abstract description 46
- 239000004094 surface-active agent Substances 0.000 claims abstract description 31
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 26
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 26
- 239000000194 fatty acid Substances 0.000 claims abstract description 23
- 235000014113 dietary fatty acids Nutrition 0.000 claims abstract description 21
- 229930195729 fatty acid Natural products 0.000 claims abstract description 21
- RUOJZAUFBMNUDX-UHFFFAOYSA-N propylene carbonate Chemical compound CC1COC(=O)O1 RUOJZAUFBMNUDX-UHFFFAOYSA-N 0.000 claims abstract description 20
- 150000004665 fatty acids Chemical class 0.000 claims abstract description 19
- LDVVTQMJQSCDMK-UHFFFAOYSA-N 1,3-dihydroxypropan-2-yl formate Chemical compound OCC(CO)OC=O LDVVTQMJQSCDMK-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000004480 active ingredient Substances 0.000 claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 12
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 claims abstract description 11
- 150000003138 primary alcohols Chemical class 0.000 claims abstract description 9
- 150000004667 medium chain fatty acids Chemical class 0.000 claims abstract description 8
- 239000003921 oil Substances 0.000 claims description 20
- 235000019198 oils Nutrition 0.000 claims description 20
- -1 polyoxyethylene Polymers 0.000 claims description 15
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 10
- 229920001213 Polysorbate 20 Polymers 0.000 claims description 9
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 claims description 9
- 239000004359 castor oil Substances 0.000 claims description 8
- 235000019438 castor oil Nutrition 0.000 claims description 8
- 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 claims description 8
- FBUKVWPVBMHYJY-UHFFFAOYSA-N nonanoic acid Chemical group CCCCCCCCC(O)=O FBUKVWPVBMHYJY-UHFFFAOYSA-N 0.000 claims description 6
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 3
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims description 2
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims description 2
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims description 2
- 239000005642 Oleic acid Substances 0.000 claims description 2
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000008172 hydrogenated vegetable oil Substances 0.000 claims description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 32
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 30
- 238000001816 cooling Methods 0.000 description 30
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 26
- 239000002775 capsule Substances 0.000 description 25
- 238000012360 testing method Methods 0.000 description 25
- 229920000159 gelatin Polymers 0.000 description 16
- 235000019322 gelatine Nutrition 0.000 description 16
- 108010010803 Gelatin Proteins 0.000 description 15
- 239000008273 gelatin Substances 0.000 description 15
- 235000011852 gelatine desserts Nutrition 0.000 description 15
- 239000004014 plasticizer Substances 0.000 description 14
- 235000011187 glycerol Nutrition 0.000 description 13
- 239000000126 substance Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000000839 emulsion Substances 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 238000003860 storage Methods 0.000 description 8
- 241000283973 Oryctolagus cuniculus Species 0.000 description 7
- 239000012141 concentrate Substances 0.000 description 7
- 239000008280 blood Substances 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 239000013065 commercial product Substances 0.000 description 6
- FMMOOAYVCKXGMF-MURFETPASA-N ethyl linoleate Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(=O)OCC FMMOOAYVCKXGMF-MURFETPASA-N 0.000 description 6
- 229940031016 ethyl linoleate Drugs 0.000 description 6
- FMMOOAYVCKXGMF-UHFFFAOYSA-N linoleic acid ethyl ester Natural products CCCCCC=CCC=CCCCCCCCC(=O)OCC FMMOOAYVCKXGMF-UHFFFAOYSA-N 0.000 description 6
- 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 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- 229940113115 polyethylene glycol 200 Drugs 0.000 description 5
- 238000001556 precipitation Methods 0.000 description 5
- RZRNAYUHWVFMIP-KTKRTIGZSA-N 1-oleoylglycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-KTKRTIGZSA-N 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 239000007903 gelatin capsule Substances 0.000 description 4
- 230000006872 improvement Effects 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 239000000654 additive Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000005538 encapsulation Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000012669 liquid formulation Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 3
- 229920000136 polysorbate Polymers 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000002054 transplantation Methods 0.000 description 3
- 235000015112 vegetable and seed oil Nutrition 0.000 description 3
- 239000008158 vegetable oil Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 229930003427 Vitamin E Natural products 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- 230000001506 immunosuppresive effect Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 239000004530 micro-emulsion Substances 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 239000012466 permeate Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 150000004671 saturated fatty acids Chemical class 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 235000019165 vitamin E Nutrition 0.000 description 2
- 239000011709 vitamin E Substances 0.000 description 2
- 229940046009 vitamin E Drugs 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- MEJYDZQQVZJMPP-ULAWRXDQSA-N (3s,3ar,6r,6ar)-3,6-dimethoxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan Chemical compound CO[C@H]1CO[C@@H]2[C@H](OC)CO[C@@H]21 MEJYDZQQVZJMPP-ULAWRXDQSA-N 0.000 description 1
- 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 description 1
- UCOQITKXMNKTKF-MXGZYYNMSA-N (3s,6s,9s,12r,15s,18s,21s,24s,30s,33s)-33-[(e,1r,2r)-1-hydroxy-2-methylhex-4-enyl]-1,4,7,10,12,15,19,25,28,30-decamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontane-2,5,8,11,14,17,20,23 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)NC1=O UCOQITKXMNKTKF-MXGZYYNMSA-N 0.000 description 1
- 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 description 1
- ZMKGDQSIRSGUDJ-VSROPUKISA-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-di(propan-2-yl)-30-propyl-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontane-2,5,8,11,14,1 Chemical compound CCC[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 ZMKGDQSIRSGUDJ-VSROPUKISA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- OIQOAYVCKAHSEJ-UHFFFAOYSA-N 2-[2,3-bis(2-hydroxyethoxy)propoxy]ethanol;hexadecanoic acid;octadecanoic acid Chemical compound OCCOCC(OCCO)COCCO.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O OIQOAYVCKAHSEJ-UHFFFAOYSA-N 0.000 description 1
- JNODDICFTDYODH-UHFFFAOYSA-N 2-hydroxytetrahydrofuran Chemical compound OC1CCCO1 JNODDICFTDYODH-UHFFFAOYSA-N 0.000 description 1
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 1
- XZIIFPSPUDAGJM-UHFFFAOYSA-N 6-chloro-2-n,2-n-diethylpyrimidine-2,4-diamine Chemical compound CCN(CC)C1=NC(N)=CC(Cl)=N1 XZIIFPSPUDAGJM-UHFFFAOYSA-N 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
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- 108010069514 Cyclic Peptides Proteins 0.000 description 1
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- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
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- OYHQOLUKZRVURQ-HZJYTTRNSA-N Linoleic acid Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(O)=O OYHQOLUKZRVURQ-HZJYTTRNSA-N 0.000 description 1
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical class O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
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- RZRNAYUHWVFMIP-UHFFFAOYSA-N monoelaidin Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-UHFFFAOYSA-N 0.000 description 1
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- 150000003077 polyols Chemical class 0.000 description 1
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- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 229940063122 sandimmune Drugs 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 201000004409 schistosomiasis Diseases 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 229940035044 sorbitan monolaurate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 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 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
- A61K38/13—Cyclosporins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
Definitions
- This invention relates to an, e.g. soft capsule, preparation containing cyclosporin as an active ingredient. More specifically, the present invention relates to a soft capsule preparation containing cyclosporin as an active ingredient; propylene carbonate or polyethylene glycol or their mixture; one or a mixture of two or more selected from the group consisting of an esterifled compound of fatty acid and primary alcohol, medium chain fatty acid triglyceride and fatty acid monoglyceride as an oil component; and a surfactant having HLB (hydrophilic - lipophilic balance) value of 8 to 17.
- HLB hydrophilic - lipophilic balance
- Cyclosporin is a specific macromolecular (molecular weight 1202.64) cyclic peptide compound consisting of 11 amino acids, which has broad spectrum of useful pharmacological activities, particularly immuno-suppressive activity and anti-inflammatory activity. Therefore, cyclosporin has been used for suppression of inherent immunological responses of the living body, which are caused by tissue and organ transplantation, for example, transplantation of the heart, lung, liver, kidney, pancreas, bone marrow, skin and cornea, and especially the transplantation of foreign tissues and organs.
- cyclosporin is useful for the suppression of hematological disorders such as anemia, various autoimmune diseases such as systemic lupus erythematosus, idiopathic malabsorption syndrome, etc., and inflammatory diseases such as arthritis, rheumatoid disorders, etc.
- Cyclosporin is useful in treatment of protozoal diseases such as malaria, schistosomiasis, etc. , and furthermore, recently it is also used in chemotherapy. Cyclosporin is highly lipophilic and hydrophobic. Therefore, cyclosporin is sparingly soluble in water, and as well dissolved in an organic solvent such as methanol, ethanol, acetone, ether, chloroform and the like.
- cyclosporin Due to low water- solubility of cyclosporin having above-mentioned properties, when cyclosporin is administered orally, its bioavailability is extremely low and may be greatly influenced by the conditions of each individual patient. Accordingly, it is very difficult to retain an effective therapeutic concentration. Moreover, cyclosporin may show considerable side effects such as nephrotoxicity. Thus, cyclosporin is very difficult to formulate into a preparation for oral administration due to its low water solubility. Accordingly, numerous studies have been extensively conducted to discover a preparation suitable for the effective oral administration of cyclosporin, which can provide a suitable uniform dosage and appropriate bioavailability.
- the preparations suitable for oral administration of sparingly water-soluble cyclosporin have been usually formulated in the form of a emulsion pre-concentrate.
- a liquid composition in the form of an emulsion pre-concentrate has been formulated into a soft capsule preparation, which is now commercially available as Sandimmune (registered trademark).
- the cyclosporin soft capsule contains ethanol due to the solubility requirements of cyclosporin.
- the soft capsule preparations may be wrapped in a special packing material, such as an aluminium-aluminum blister package.
- a certain cyclosporin composition consisting of the components as defined below can satisfy the above-mentioned requirements, and then completed the present invention. Therefore, it is an aspect of the present invention to provide a composition suitable for formulation into soft capsules, which comprises cyclosporin as an active ingredient; a hydrophilic substance polyethylene glycol or a non- hydrophilic substance propylene carbonate or their mixture; an oil component as defined below, and a surfactant.
- a soft capsule preparation comprising a composition which contains cyclosporin as an active ingredient; a hydrophilic substance polyethylene glycol or a non-hydrophilic substance propylene carbonate or their mixture; one or a mixture of two or more selected from the group consisting of an esterified compound of fatty acid and primary alcohol, medium chain fatty acid triglyceride (if desired) and fatty acid monoglyceride as an oil component; and a surfactant having an HLB
- the present invention provides a process for preparing the soft gelatin capsule preparation as defined above.
- the present invention is described herein particularly with respect to soft gelatine capsules, it is to be appreciated that the invention covers the composition itself which may be used as such e.g. as a drink solution, e.g. as Sandimmun Neoral, or be in other unit dosage forms.
- the present invention relates to a cyclosporin-containing capsule which has a high storage stability such that there is little variation of the composition over time, and has an increased bioavailability, and which contains a composition comprising cyclosporin as an active ingredient; a hydrophilic substance polyethylene glycol or a non-hydrophilic substance propylene carbonate or their mixture as a second component; an oil component as defined below; and a surfactant.
- a gelatin shell must be used.
- the soft capsule preparation has some disadvantages in that the emulsified state of the emulsion pre-concentrate may be changed due to the inflow of glycerine into the emulsion and, therefore, the solubility of cyclosporin is significantly lower to result in the precipitation of cyclosporin from the emulsion.
- a gelatin shell using a mixture of propylene glycol and polyethylene glycol, not glycerine, as a plasticizer is selected for the soft capsule shell, which can solve the problem related with inflow of glycerine.
- the capsule shell band containing propylene glycol and polyethylene glycol according to the present invention is prepared by means of a water-cooling method which is conventionally used for a cooling drum, it is not easily removed from the drum.
- Such removability of the capsule shell band from the cooling drum may be improved by over-cooling the cooling drum by continuously circulating a cooling water to reduce temperature of the band to about 17°C.
- the capsule shell band which is cooled to lower temperature may provide a low extent of seal during the encapsulation process and may cause lowering of productivity.
- the process for preparing the gelatin shell band not containing glycerine plasticizer according to the present invention adopts an air-cooling method, instead of the prior water-cooling method, in which the capsule shell band can be cooled down to the optimum temperature by providing an air flow from a fan and therefore, can be readily removed from the cooling drum and further, it is maintained at the optimum temperature of about 21°C to increase the extent of seal in the encapsulation process and ensure a high productivity.
- the present products can be produced by using the glycerine-free gelatin capsule shell and applying the air-cooling method to the composition which does not contain ethanol as a low boiling volatile solvent and therefore, has a high storage stability such that there is little variation of the composition over time, and has an increase bioavailability.
- the present invention relates to a cyclosporin preparation, which comprises a composition containing 1 ) cyclosporin as an active ingredient;
- HLB Hydrophilic Lipophilic Balance
- the present invention provides a cyclosporin preparation, which comprises a composition containing
- this composition is free from polyethylene glycol.
- composition which is also a composition of the invention, may optionally additionally comprise any other component as described herein, if desired in the amounts described herein.
- Cyclosporin which is used as the pharmaceutically active ingredient in the composition according to the present invention, is acyclic peptide compound having useful immuno-suppressive activity and anti-inflammatory activity as described above. Although cyclosporin A, B, C, D, G and the like can be used as the cyclosporin component in the present invention. Cyclosporin A is mostly preferred since its clinical effectiveness and pharmacological properties are well established in the art.
- the second component in the composition according to the present invention and which may act as a co-surfactant propylene carbonate or polyethylene glycol or their mixture can be used.
- Propylene carbonate which has a high boiling point (about 242°C), is nonvolatile, shows low hygroscopic property and shell permeability, and has a high solubility for cyclosporin, may be used as the non-hydrophilic substance.
- polyethylene glycol which has a high boiling point, is non-volatile, does not permeate the gelatin shell of the soft capsule, and has a high solubility for cyclosporin can also be used as the hydrophilic substance.
- polyethylene glycol (PEG) having molecular weight of 200 to 600, particularly PEG 200 can be preferably used.
- the mixture of non-hydrophilic substance and hydrophilic substance as defined above can also be used.
- the mixture of polyethylene glycol and propylene carbonate can be generally combined in the ratio of 1:0.1-5, preferably 1:0.1-3, most preferably 1:0.2-2, on the basis of weight.
- the use of polyethylene glycol and propylene carbonate provides certain advantages. That is, the stability of the cyclosporin-containing composition during storage is improved and therefore the contents of the components contained therein are substantially uniformly maintained.
- the use of propylene carbonate can even increase the solubility of the active ingredient cyclosporin and inhibit the inflow of water from the gelatin capsule shell into the composition to provide a more stable composition.
- the second component is used preferably in the ratio of 0.1 to 10 parts by weight, more preferably 0.5 to 8 parts by weight, and most preferably 1 to 5 parts by weight, per 1 part by weight of cyclosporin.
- the third component used in the emulsion pre-concentrate according to the present invention is an oil component.
- esterified compounds of fatty acid and primary alcohol As the oil component in the present invention, one or a mixture of two or more selected from the group consisting of esterified compounds of fatty acid and primary alcohol, medium chain fatty acid triglycerides (when present) and fatty acid monoglycerides can be used.
- the esterified compound of fatty acid and primary alcohol which can be used in the present invention may include an esterified compound of fatty acid having 8 to
- the medium chain fatty acid triglyceride when present, a triglyceride of saturated fatty acid having 8 to 10 carbon atoms can be used with caprylic/capric acid triglyceride as a vegetable oil triglyceride of saturated fatty acid being most preferably used.
- the fatty acid monoglyceride which can also be used as the oil component in the present invention includes a monoglyceride of fatty acid having 18 to 20 carbon atoms, particularly monoglyceride of oleic acid.
- the oil component may be used in the ratio of 1 to 10 parts by weight, preferably 2 to 6 parts by weight, per 1 part by weight of cyclosporin.
- fatty acid monoglyceride and fatty acid ester are present as oil component, e.g. in the ratio 1:1 to 1:2, e.g. 1:1 to 1:1.2.
- caprylic/capric acid triglyceride is also present e.g. in a ratio to ethyl linoleate of from 1:0.1 to 0.2.
- the mixing ratio of fatty acid monoglyceride: an esterified compound of fatty acid and primary alcohol: medium chain fatty acid triglyceride may be generally in the range of 1:0.1-5; 0.1-10 preferably in the range of 1:0.1- 3.0:0.1-3.0, on the basis of weight.
- the fourth component used in the composition according to the present invention is a surfactant.
- the suitable surfactants for use in the present invention include any of pharmaceutically acceptable surfactants having an HLB
- Hydrophilic Lipophilic Balance 8 to 17, which are capable of stably emulsifying the lipophilic portion of the composition comprising the cyclosporin-containing oil component and the hydrophilic portion comprising the co-surfactant in water to form a stable microemulsion.
- the preferred surfactant according to the present invention include polyoxyethylene products of hydrogenated vegetable oils, polyoxyethylene-sorbitan-fatty acid esters, and the like, for example, NIKKOL HCO-50, NIKKOL HCO_40, NIKKOL HCO-60, TWEEN 20, TWEEN 21, TWEEN 40, TWEEN 60, TWEEN 80, TWEEN 81, etc.
- a polyoxyethylene (50) hydrogenated castor oil which is commercialised under the trade mark NIKKOL HCO-50
- the surfactant can include any one of the above-mentioned surfactants alone or, preferably, in a combination of two or more surfactants selected from the above surfactants.
- the surfactants can be used in the ratio of 1 to 10 parts by weight, preferably in the ratio of 2 to 8 parts by weight, per 1 part by weight of cyclosporin.
- the constitutional ratio of polyoxyethylene (50) hydrogenated castor oil; polyoxyethylene (20) sorbitan monolaurate is preferably in the range of 1:0.1-5, more preferably in the range of 1:0.5-4, on the basis of weight.
- compositions illustrated in the following examples can be mentioned as further preferred compositions according to the present invention.
- the composition of the present invention containing the above-mentioned components can be formulated into the form of a soft capsule. Since the soft capsule preparation according to the present invention does not use ethanol as the low-boiling volatile solvent, it is pharmaceutically stable and can establish the desired improvements including improvement of bioavailability.
- the soft capsule may have some disadvantages in that the emulsified state of the emulsion pre-concentrate may be changed due to the inflow of glycerine into the emulsion and therefore, the solubility of cyclosporin is significantly lowered which may result in the precipitation of cyclosporin from the emulsion.
- the present invention it is found that when the capsule shell is formulated by using a mixture of polyethylene glycol and propylene glycol, not glycerine, as a plasticizer, the soft capsule preparation which is stable for a long period can be obtained.
- a plasticizer any polyethylene glycol which can be liquified may be used as a plasticizer, it is preferable to use polyethylene glycol having molecular weight of 200 to 600. Particularly, polyethylene glycol 200 is preferably used.
- the mixture of polyethyene glycol and propylene glycol is preferably used in the ratio of 0.1 to 0.5 parts by weight, more preferably 0.1 to 0.4 parts by weight and most preferably 0.2 to 0.3 parts by weight, with respect to one part by weight of gelatin used for preparing the capsule shell.
- propylene glycol is combined preferably in the ratio of 1 to 10 parts by weight, more preferably 3 to 8 parts by weight and most preferably 3 to 6 parts by weight, with respect to one part by weight of polyethylene glycol.
- the process for preparing the gelatin capsule shell band according to the present invention adopts the air-cooling method, instead of the water- cooling method.
- the air-cooling method since the capsule shell band is not overheated and can be readily removed from the cooling drum while maintaining the optimum temperature of about 21°C, the extent of seal in the encapsulation process is high to ensure a high productivity and therefore, the process can be efficiently conducted.
- a suitable air volume flow for the cooling drum to cool the capsule shell is preferably 5 to 15mVmin., most preferably about lOm min.
- propylene carbonate may be used alone or as a main component thereof, cyclosporin-containing soft capsule preparations which are stable for long time can be formulated without using a certain plasticizer in a gelatin shell, considering a solubility of cyclosporin and a stability of soft capsule.
- the plasticizer one or more selcted from the group consisting of glycerine, sorbitol, hexanetriol, propylene carbonate, hexane glycol, sorbitans, tetrahydrofuryl alcohol ether, diethylene glycol monoethyl ether, l,3-dimethyl-2-imidazolidone, dimethylisosorbide, etc.
- the plasticizer which can be used in the present invention is not restricted to those as mentioned above.
- the capsule preparation can further contain, if necessary, pharmaceutically acceptable additives which are conventionally utilized in the preparation of soft capsules.
- additives include, for example, lecithin, viscosity regulator, perfume (e.g. peppermint oil, etc.), anti-oxidant (e.g. tocopherol, Vitamin E etc.), preservative (e.g. parabene, etc.), coloring agent, amino acids, etc.
- the soft capsule preparation according to the present invention can be prepared by uniformly mixing the co-surfactant, the oil component and the surfactant, dissolving cyclosporin therein while stirring and gently warming to the temperature of approximately 60°C, and then formulating the resulting concentrate, with or without the above-mentioned pharmaceutically acceptable additives conventionally utilized in preparation of soft capsules, with the gelatin shell containing polyethylene glycol and propylene glycol as the plasticizer in a machine for preparing soft capsules by means of the air-cooled method into the desired suitable cyclosporin soft capsule.
- compositions and preparations of the present invention are useful for the same indications and may be administered in the same way and dosage range as known cyclosporin compositions, if necessary adjusting the dose on the basis of standard bioavailability trials in animals, e.g. dogs, or humans, e.g. as described hereinafter.
- animals e.g. dogs
- humans e.g. as described hereinafter.
- details of the compositions of any excipients or components are not specifically described herein, these are described in the literature, e.g. H.P.
- Cyclosporin 25 25 25 25 25 25 25 polyethylene glycol 200 45 70 100 45 45 propylene carbonate 25 - 50 25 25 polyoxyethylene (50) hydrogenated castor oil 35 35 35 50 35 polyoxyethylene (20) sorbitan monolaurate 85 85 85 100 85 ethyl linoleate 40 40 40 40 80 caprylic/capric acid triglyceride 5 5 5 5 10 oleic acid monoglyceride 35 35 35 35 35 70 total 295mg 295mg 375mg 325mg 375mg
- the soft capsule preparation was prepared from the composition of Example 1 using the following composition for capsule shell and then the change in the property and condition of the content due to the inflow of glycerine was visually observed.
- Table 1 Stability of the content of the capsule preparation according to the capsule shell
- the capsule preparation prepared using the composition of 6.1 control group containing glycerine as the plasticizer causes some problems including the formation of precipitation due to the inflow of glycerine, whereas the capsule preparation prepared using the composition of 6.2 test group containing polyethylene glycol and propylene glycol as the plasticizer maintains the stable condition.
- the soft capsule preparation having the composition of Example 1 was prepared using the composition of the capsule shell of 6.2 test group used in the above Example 6 by means of the water-cooling method (water temperature about 12°C) and the air-cooling method (air volume flow about 10 mVmin), respectively.
- Table 2 Removability of the gelatin shell band from the cooling drum depending on the cooling method
- Example 6.2 > 100 degree ⁇ 50 degree (poor removability) (good removability)
- the soft capsule preparation prepared by the air-cooling method according to the present invention shows a far better removability from the cooling drum in comparisoin with that prepared by the water-cooling method. Specifically, it is generally considered that if the degree of angle for removing the gelatin shell band from the cooling drum is about 70 or more, the removability is poor, and if the degree of angle for removing the shell band is below about 70, the removability is good.
- the soft capsule preparation prepared by the water-cooling method is not satisfactorily removed from the cooling drum even when the preparation is removed at the angle of 100 degrees or more.
- the soft capsule preparation prepared by the air-cooling ethod according to the present invention can be easily removed from the cooling drum at the angle of 50 degree and below and therefore, can provide a good sealing strength and productivity.
- Example 6.2 as the test preparation was compared with the bioavailability of the commercial product containing ethanol, SANDIMMUN Capsule, as the control preparation to estimate the influence of the cyclosporin preparation according to the present invention on the bioavailability of cyclosporin and its difference between respective subjects.
- both of the test preparation and the control preparation were administered in an amount of 300 mg as cyclosporin per kg of rabbit.
- Rabbits were uniformly fed with the conventional rabbit solid feed composition for 4 days or more under the same condition in wire cages.
- rabbits were fasted for 48 hours in a restraint cage made of steel, during which rabbits were allowed to freely take water.
- Levin's tube having a diameter of 5 mm was interposed by the depth of 30 cm through the esophagus after the surface of the Levin's tube was coated with vaseline in order to reduce friction.
- test preparations and the control preparation were emulsified with 50 ml of water and then introduced into a syringe which is attached to the Levin's tube.
- Ear veins of rabbit were dilated using xylene and then blood was taken from each rabbit's ear vein before the test and after 0.5, 1, 1.5, 2, 3, 4, 6, 10 and 24 hours by means of heparin- treated disposable syringe.
- To 1 ml of blood thus obtained were added 0.5 ml of aqueous saturated sodium chloride solution and 2 ml of ether, and then the mixture was shaken for 5 minutes and centrifuged with 5000 rpm for 10 minutes to separate the supernatant (ether layer).
- the results obtained from the test preparation and the control preparation are i l l u s t r a t e d i n t h e f o l l o w i n g T a b l e 3 :
- AUC Area under the blood concentration curve
- P(B/A) Ratio of mean value of the test preparation to mean value of the control preparation
- the test preparation shows the increased AUC and C ⁇ values which are about 4 times or more and about 7 times or more, respectively, as high as those of the control preparation. Accordingly, it can be identified that the bioavailability of the test preparation is significantly increased in comparison with that of the control preparation.
- the test preparation of the present invention exhibits an effect of decreasing the difference between respective test subjects (CV %) by about 2 times or more in
- the soft capsule preparation according to the present invention when administered per oral, it shows the increased bioavailability of cyclosporin about 4 times as high as that of the prior commercial product containing ethanol, SANDIMMUN* Capsule and also a decrease of the difference between cyclosporin bioavailabilities in respective subjects, and at the same time, remains stable without any change during the long term storage.
- the soft capsule preparation according to the present invention provides a significant improvement in the field of preparation of cyclosporin soft capsules.
- Soft gels are made up containing:
- Polyethylene glycol 200 45 mg 180 mg
- Cyclosporin 25 25 100 25 25 25 propylene carbonate 50 100 200 50 100 polyoxyethylene (50) hydrogenated castor oil 90 80 300 90 90 polyoxyethylene (20) sorbitan monolaurate 80 80 280 80 80 ethyl linoleate 40 30 150 - 40 caprylic /capric acid triglyceride 5 10 20 5 5 oleic acid monoglyceride 35 50 120 35 35 35
- Cyclosporin 25 25 25 25 25 25 polyethylene glycol 200 35 50 25 20 propylene carbonate 45 100 45 80 polyoxyethylene (50) hydrogenated castor oil 30 35 50 35 polyoxyethylene (20) sorbitan monolaurate 80 90 75 85 ethyl linoleate 35 40 40 80 caprylic /capric acid triglyceride 5 5 5 10 oleic acid monoglyceride 35 30 35 85 total 290mg 375mg 300mg 420mg
- the bioavailability of the soft capsule preparation prepared from the composition of Example 10 according to a conventional manner as the test preparation was compared with the bioavailability of the commercial product containing ethanol, SANDIMMUN Capsule, as the control preparation to estimate the influence of the cyclosporin preparation according to the present invention on the bioavailability of cyclosporin and its difference between respective subjects.
- AUC Area under the blood concentration curve
- test preparation shows the increased AUC and C mix values which are about 4 times or more and about 7 times or more, respectively, as high as those of the control preparation. Accordingly, it can be identified that the bioavailability of the test preparation is significantly increased in comparison with that of the control preparation.
- the test preparation of the present invention exhibits an effect of decreasing the difference between respective test subjects (CV %) by about 2 times or more in AUC value and by about 1.5 times in C ⁇ value, in comparison with the control preparation.
- the soft capsule preparation according to the present invention when administered per oral, it shows the increased bioavailability of cyclosporin about 4 times as high as that of the prior commercial product containing ethanol, SANDIMMUN" Capsule and also a decrease of the difference between cyclosporin bioavailabilities in respective subjects, and at the same time, remains stable without any change during the long term storage.
- the soft capsule preparation according to the present invention provides a significant improvement in the field of preparation of cyclosporin soft capsules.
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Abstract
The present invention relates to a cyclosporin-containing soft capsule preparation which comprises a composition containing cyclosporin as an active ingredient; a hydrophilic component polyethylene glycol or a non-hydrophilic component propylene carbonate or their mixture, one or a mixture of two or more selected from the group consisting of an esterified compound of fatty acid and primary alcohol, medium chain fatty acid triglyceride and fatty acid monoglyceride as an oil component; and a surfactant having an HLB (Hydrophilic Lipophilic Balance) value of 8 to 17.
Description
PHARMACEUπCAL COMPOSFTIONS
This invention relates to an, e.g. soft capsule, preparation containing cyclosporin as an active ingredient. More specifically, the present invention relates to a soft capsule preparation containing cyclosporin as an active ingredient; propylene carbonate or polyethylene glycol or their mixture; one or a mixture of two or more selected from the group consisting of an esterifled compound of fatty acid and primary alcohol, medium chain fatty acid triglyceride and fatty acid monoglyceride as an oil component; and a surfactant having HLB (hydrophilic - lipophilic balance) value of 8 to 17.
Cyclosporin is a specific macromolecular (molecular weight 1202.64) cyclic peptide compound consisting of 11 amino acids, which has broad spectrum of useful pharmacological activities, particularly immuno-suppressive activity and anti-inflammatory activity. Therefore, cyclosporin has been used for suppression of inherent immunological responses of the living body, which are caused by tissue and organ transplantation, for example, transplantation of the heart, lung, liver, kidney, pancreas, bone marrow, skin and cornea, and especially the transplantation of foreign tissues and organs. In addition, cyclosporin is useful for the suppression of hematological disorders such as anemia, various autoimmune diseases such as systemic lupus erythematosus, idiopathic malabsorption syndrome, etc., and inflammatory diseases such as arthritis, rheumatoid disorders, etc. Cyclosporin is useful in treatment of protozoal diseases such as malaria, schistosomiasis, etc. , and furthermore, recently it is also used in chemotherapy. Cyclosporin is highly lipophilic and hydrophobic. Therefore, cyclosporin is sparingly soluble in water, and as well dissolved in an organic solvent such as methanol, ethanol, acetone, ether, chloroform and the like. Due to low water- solubility of cyclosporin having above-mentioned properties, when cyclosporin is administered orally, its bioavailability is extremely low and may be greatly influenced by the conditions of each individual patient. Accordingly, it is very difficult to retain an effective therapeutic concentration. Moreover, cyclosporin may show considerable side effects such as nephrotoxicity. Thus, cyclosporin is very difficult to formulate into a preparation for oral administration due to its low water solubility. Accordingly, numerous studies have been extensively conducted to discover a preparation suitable for the effective oral administration
of cyclosporin, which can provide a suitable uniform dosage and appropriate bioavailability.
In the prior art, the preparations suitable for oral administration of sparingly water-soluble cyclosporin have been usually formulated in the form of a emulsion pre-concentrate.
One typical method using this combination is taught in U.S. Patent No. 4,388,307 which issued on June 14, 1983. This patent discloses a liquid formulation of cyclosporin using ethanol. According to the method disclosed in this US Patent Specification, cyclosporin is combined with a carrier consisting of ethanol as a co-surfactant; olive oil as a vegetable oil, and a transesterification product of a natural vegetable oil triglyceride and a polyalkylene polyol as a surfactant to form the liquid formulation. However, the resulting liquid formulation is administered as an aqueous dilution which makes it very difficult to adapt the subject to its administration and to provide a uniform dosage for oral administration.
In order to mitigate the inconvenience of diluting the cyclosporin liquid composition in water prior to oral administration, a liquid composition in the form of an emulsion pre-concentrate has been formulated into a soft capsule preparation, which is now commercially available as Sandimmune (registered trademark). In this case the cyclosporin soft capsule contains ethanol due to the solubility requirements of cyclosporin. However, since ethanol may permeate the gelatin shell of the capsule as it is volatile even at normal temperature, to prevent the volatilization of ethanol from the soft capsule preparations during storage and distribution, the soft capsule preparations may be wrapped in a special packing material, such as an aluminium-aluminum blister package. Recently it has been possible to develop a cyclosporin preparation which has a stability during the storage period and further provides substantially no change in biological availability and its difference between individual subjects, so that the biological effect of cyclosporin can be uniformly maintained. One of the preparations developed for this purpose is disclosed in Korean Laid-open Patent Publication No. 93-113. This preparation is commercialized under the registered trademark Sandimmun Neoral. However, since this preparation also uses ethanol, it may have some disadvantages as in the prior ethanol-containing preparations, in storage stability, and changes in the ethanol content.
Accordingly, the present inventors have studied numerous combinations of various surfactants, oil components, co-surfactants etc. to find a cyclosporin composition which is stable, and provides higher bioavailability and lower difference in blood levels between individual subjects than those of the prior cyclosporin preparations in view of their pharmacokinetic properties. As a result, we have identified that a certain cyclosporin composition consisting of the components as defined below can satisfy the above-mentioned requirements, and then completed the present invention. Therefore, it is an aspect of the present invention to provide a composition suitable for formulation into soft capsules, which comprises cyclosporin as an active ingredient; a hydrophilic substance polyethylene glycol or a non- hydrophilic substance propylene carbonate or their mixture; an oil component as defined below, and a surfactant. It is a further aspect of the present invention to provide a soft capsule preparation comprising a composition which contains cyclosporin as an active ingredient; a hydrophilic substance polyethylene glycol or a non-hydrophilic substance propylene carbonate or their mixture; one or a mixture of two or more selected from the group consisting of an esterified compound of fatty acid and primary alcohol, medium chain fatty acid triglyceride (if desired) and fatty acid monoglyceride as an oil component; and a surfactant having an HLB
(Hydrophilic Lipophilic Balance) value of 8 to 17.
Further it is another aspect of the present invention to provide a process for preparing the soft gelatin capsule preparation as defined above. Even though the present invention is described herein particularly with respect to soft gelatine capsules, it is to be appreciated that the invention covers the composition itself which may be used as such e.g. as a drink solution, e.g. as Sandimmun Neoral, or be in other unit dosage forms.
In one aspect, the present invention relates to a cyclosporin-containing capsule which has a high storage stability such that there is little variation of the composition over time, and has an increased bioavailability, and which contains a composition comprising cyclosporin as an active ingredient; a hydrophilic substance polyethylene glycol or a non-hydrophilic substance propylene carbonate or their mixture as a second component; an oil component as defined below; and a surfactant.
To formulate such cyclosporin-containing composition into the soft capsule preparation, a gelatin shell must be used. However, when the soft capsule is formulated with the general capsule shell containing glycerine as plasticizer, the soft capsule preparation has some disadvantages in that the emulsified state of the emulsion pre-concentrate may be changed due to the inflow of glycerine into the emulsion and, therefore, the solubility of cyclosporin is significantly lower to result in the precipitation of cyclosporin from the emulsion. Accordingly, in the present invention preferably a gelatin shell using a mixture of propylene glycol and polyethylene glycol, not glycerine, as a plasticizer is selected for the soft capsule shell, which can solve the problem related with inflow of glycerine.
However, when the capsule shell band containing propylene glycol and polyethylene glycol according to the present invention is prepared by means of a water-cooling method which is conventionally used for a cooling drum, it is not easily removed from the drum. Such removability of the capsule shell band from the cooling drum may be improved by over-cooling the cooling drum by continuously circulating a cooling water to reduce temperature of the band to about 17°C. However, the capsule shell band which is cooled to lower temperature may provide a low extent of seal during the encapsulation process and may cause lowering of productivity.
Therefore, the process for preparing the gelatin shell band not containing glycerine plasticizer according to the present invention adopts an air-cooling method, instead of the prior water-cooling method, in which the capsule shell band can be cooled down to the optimum temperature by providing an air flow from a fan and therefore, can be readily removed from the cooling drum and further, it is maintained at the optimum temperature of about 21°C to increase the extent of seal in the encapsulation process and ensure a high productivity. As mentioned above, the present products can be produced by using the glycerine-free gelatin capsule shell and applying the air-cooling method to the composition which does not contain ethanol as a low boiling volatile solvent and therefore, has a high storage stability such that there is little variation of the composition over time, and has an increase bioavailability. More specifically, the present invention relates to a cyclosporin preparation, which comprises a composition containing
1 ) cyclosporin as an active ingredient;
2) polyethylene glycol or propylene carbonate or their mixture;
3) one or a mixture of two or more selected from the group consisting of an esterified compound of fatty acid and primary alcohol, medium chain fatty acid triglyceride and fatty acid monoglyceride as an oil component, and
4) a surfactant having an HLB (Hydrophilic Lipophilic Balance) value of 8 to 17, e.g. in a gelatin shell containing polyethylene glycol and propylene glycol as a plasticizer. In another aspect the present invention provides a cyclosporin preparation, which comprises a composition containing
1 ) cyclosporin as an active ingredient; and
2) propylene carbonate. In yet a further aspect of the present invention this composition is free from polyethylene glycol.
Such a composition, which is also a composition of the invention, may optionally additionally comprise any other component as described herein, if desired in the amounts described herein.
Cyclosporin, which is used as the pharmaceutically active ingredient in the composition according to the present invention, is acyclic peptide compound having useful immuno-suppressive activity and anti-inflammatory activity as described above. Although cyclosporin A, B, C, D, G and the like can be used as the cyclosporin component in the present invention. Cyclosporin A is mostly preferred since its clinical effectiveness and pharmacological properties are well established in the art. As the second component in the composition according to the present invention, and which may act as a co-surfactant propylene carbonate or polyethylene glycol or their mixture can be used.
Propylene carbonate which has a high boiling point (about 242°C), is nonvolatile, shows low hygroscopic property and shell permeability, and has a high solubility for cyclosporin, may be used as the non-hydrophilic substance.
Alternatively, polyethylene glycol which has a high boiling point, is non-volatile, does not permeate the gelatin shell of the soft capsule, and has a high solubility for cyclosporin, can also be used as the hydrophilic substance. In the composition according to the present invention, although any polyethylene
glycol which can be liquified can be used, polyethylene glycol (PEG) having molecular weight of 200 to 600, particularly PEG 200, can be preferably used.
In the present invention, the mixture of non-hydrophilic substance and hydrophilic substance as defined above can also be used. When the mixture of polyethylene glycol and propylene carbonate is used as the component in the present invention, they can be generally combined in the ratio of 1:0.1-5, preferably 1:0.1-3, most preferably 1:0.2-2, on the basis of weight. In the present invention, the use of polyethylene glycol and propylene carbonate provides certain advantages. That is, the stability of the cyclosporin-containing composition during storage is improved and therefore the contents of the components contained therein are substantially uniformly maintained. Furthermore, the use of propylene carbonate can even increase the solubility of the active ingredient cyclosporin and inhibit the inflow of water from the gelatin capsule shell into the composition to provide a more stable composition. In the composition of the present invention, the second component is used preferably in the ratio of 0.1 to 10 parts by weight, more preferably 0.5 to 8 parts by weight, and most preferably 1 to 5 parts by weight, per 1 part by weight of cyclosporin. The third component used in the emulsion pre-concentrate according to the present invention is an oil component. As the oil component in the present invention, one or a mixture of two or more selected from the group consisting of esterified compounds of fatty acid and primary alcohol, medium chain fatty acid triglycerides (when present) and fatty acid monoglycerides can be used. The esterified compound of fatty acid and primary alcohol which can be used in the present invention may include an esterified compound of fatty acid having 8 to
20 carbon atoms and primary alcohol having 2 to 3 carbon atoms, for example, isopropyl myristate, isopropyl palmitate, ethyl linoleate, ethyl oleate, etc., with an esterified compound of linoleic acid and ethanol being particularly preferably. In addition, as the medium chain fatty acid triglyceride (when present) a triglyceride of saturated fatty acid having 8 to 10 carbon atoms can be used with caprylic/capric acid triglyceride as a vegetable oil triglyceride of saturated fatty acid being most preferably used. The fatty acid monoglyceride which can also be used as the oil component in the present invention includes a monoglyceride of fatty acid having 18 to 20 carbon atoms, particularly monoglyceride of oleic acid.
In a microemulsion pre-concentrate according to the present invention, the oil component may be used in the ratio of 1 to 10 parts by weight, preferably 2 to 6 parts by weight, per 1 part by weight of cyclosporin. Preferably fatty acid monoglyceride and fatty acid ester are present as oil component, e.g. in the ratio 1:1 to 1:2, e.g. 1:1 to 1:1.2.
Optionally caprylic/capric acid triglyceride is also present e.g. in a ratio to ethyl linoleate of from 1:0.1 to 0.2.
In the oil mixture used as the oil component according to the present invention, the mixing ratio of fatty acid monoglyceride: an esterified compound of fatty acid and primary alcohol: medium chain fatty acid triglyceride (when present) may be generally in the range of 1:0.1-5; 0.1-10 preferably in the range of 1:0.1- 3.0:0.1-3.0, on the basis of weight.
The fourth component used in the composition according to the present invention is a surfactant. The suitable surfactants for use in the present invention include any of pharmaceutically acceptable surfactants having an HLB
(Hydrophilic Lipophilic Balance) value of 8 to 17, which are capable of stably emulsifying the lipophilic portion of the composition comprising the cyclosporin-containing oil component and the hydrophilic portion comprising the co-surfactant in water to form a stable microemulsion. Examples of the preferred surfactant according to the present invention include polyoxyethylene products of hydrogenated vegetable oils, polyoxyethylene-sorbitan-fatty acid esters, and the like, for example, NIKKOL HCO-50, NIKKOL HCO_40, NIKKOL HCO-60, TWEEN 20, TWEEN 21, TWEEN 40, TWEEN 60, TWEEN 80, TWEEN 81, etc. Particularly, a polyoxyethylene (50) hydrogenated castor oil which is commercialised under the trade mark NIKKOL HCO-50
(NIKKO Chemical Co., Ltd.) and a polyoxyethlyene (20) sorbitan monolaurate which is commercialised under the trade mark TWEEN 20 (ICI Chemicals), having an acid value below 1, a saponification value of about 48-56, a hydroxyl value of about 45-55 and pH value (5%) of 4.5-7.0, can be preferably used. The surfactant can include any one of the above-mentioned surfactants alone or, preferably, in a combination of two or more surfactants selected from the above surfactants. In the composition according to the present invention, the surfactants can be used in the ratio of 1 to 10 parts by weight, preferably in the ratio of 2 to 8 parts by weight, per 1 part by weight of cyclosporin.
In addition, when the mixture of two surfactants, i.e. polyoxyethylene (50) hydrogenated castor oil and polyoxyethylene (20) sorbitan monolaurate is used in the composition of the present invention, the constitutional ratio of polyoxyethylene (50) hydrogenated castor oil; polyoxyethylene (20) sorbitan monolaurate is preferably in the range of 1:0.1-5, more preferably in the range of 1:0.5-4, on the basis of weight.
In the composition according to the present invention, the four components are present preferably in the ratio of cyclosporin: second component; oil component; surfactant = 1 : 0.1- 10 : 1-10 : 1-10, and more preferably in the ratio of cyclosporin: second component: oil component : surfactant = 1 : 0.5-8: 2-6 : 2-8, by weight.
In addition to this composition, the composition illustrated in the following examples can be mentioned as further preferred compositions according to the present invention. For oral administration, the composition of the present invention containing the above-mentioned components can be formulated into the form of a soft capsule. Since the soft capsule preparation according to the present invention does not use ethanol as the low-boiling volatile solvent, it is pharmaceutically stable and can establish the desired improvements including improvement of bioavailability.
However, it may be difficult to reproductively prepare as a conventional soft capsule shell by means of a conventional method for preparation of soft capsules. When the soft capsule is formulated with the conventional capsule shell containing glycerine as plasticizer, the soft capsule thus prepared may have some disadvantages in that the emulsified state of the emulsion pre-concentrate may be changed due to the inflow of glycerine into the emulsion and therefore, the solubility of cyclosporin is significantly lowered which may result in the precipitation of cyclosporin from the emulsion. Accordingly, in another aspect the present invention it is found that when the capsule shell is formulated by using a mixture of polyethylene glycol and propylene glycol, not glycerine, as a plasticizer, the soft capsule preparation which is stable for a long period can be obtained. Although any polyethylene glycol which can be liquified may be used as a plasticizer, it is preferable to use polyethylene glycol having molecular weight of 200 to 600.
Particularly, polyethylene glycol 200 is preferably used. In the soft capsule shell according to the present invention, the mixture of polyethyene glycol and propylene glycol is preferably used in the ratio of 0.1 to 0.5 parts by weight, more preferably 0.1 to 0.4 parts by weight and most preferably 0.2 to 0.3 parts by weight, with respect to one part by weight of gelatin used for preparing the capsule shell. In the mixture of polyethylene glycol and propylene glycol as the plasticizer, propylene glycol is combined preferably in the ratio of 1 to 10 parts by weight, more preferably 3 to 8 parts by weight and most preferably 3 to 6 parts by weight, with respect to one part by weight of polyethylene glycol. In order to increase the removability of the soft capsule shell band from the cooling drum, the process for preparing the gelatin capsule shell band according to the present invention adopts the air-cooling method, instead of the water- cooling method. According to this air-cooling method, since the capsule shell band is not overheated and can be readily removed from the cooling drum while maintaining the optimum temperature of about 21°C, the extent of seal in the encapsulation process is high to ensure a high productivity and therefore, the process can be efficiently conducted.
In preparing the soft capsule according to the present invention, a suitable air volume flow for the cooling drum to cool the capsule shell is preferably 5 to 15mVmin., most preferably about lOm min.
Since as the second component in the present invention propylene carbonate may be used alone or as a main component thereof, cyclosporin-containing soft capsule preparations which are stable for long time can be formulated without using a certain plasticizer in a gelatin shell, considering a solubility of cyclosporin and a stability of soft capsule.
In such a gelatin shell, the plasticizer, one or more selcted from the group consisting of glycerine, sorbitol, hexanetriol, propylene carbonate, hexane glycol, sorbitans, tetrahydrofuryl alcohol ether, diethylene glycol monoethyl ether, l,3-dimethyl-2-imidazolidone, dimethylisosorbide, etc. can be used without any limitation. However, it should be understood that the plasticizer which can be used in the present invention is not restricted to those as mentioned above.
In formulating the composition according to the present invention into soft capsules, the capsule preparation can further contain, if necessary, pharmaceutically acceptable additives which are conventionally utilized in the
preparation of soft capsules. Such additives include, for example, lecithin, viscosity regulator, perfume (e.g. peppermint oil, etc.), anti-oxidant (e.g. tocopherol, Vitamin E etc.), preservative (e.g. parabene, etc.), coloring agent, amino acids, etc. The soft capsule preparation according to the present invention can be prepared by uniformly mixing the co-surfactant, the oil component and the surfactant, dissolving cyclosporin therein while stirring and gently warming to the temperature of approximately 60°C, and then formulating the resulting concentrate, with or without the above-mentioned pharmaceutically acceptable additives conventionally utilized in preparation of soft capsules, with the gelatin shell containing polyethylene glycol and propylene glycol as the plasticizer in a machine for preparing soft capsules by means of the air-cooled method into the desired suitable cyclosporin soft capsule. The compositions and preparations of the present invention are useful for the same indications and may be administered in the same way and dosage range as known cyclosporin compositions, if necessary adjusting the dose on the basis of standard bioavailability trials in animals, e.g. dogs, or humans, e.g. as described hereinafter. Insofar as details of the compositions of any excipients or components are not specifically described herein, these are described in the literature, e.g. H.P.
Fiedler, Lexikon der Hilfsstoffe, Edito Cantor Verlag, Aulendorf, Germany, 4th Edition 1996, Handbook of Pharmaceutical Excipients, American Pharmaceutical Association, Washington, and The Pharmaceutical Society, London, 2nd Edition, 1994 and Korean Patent Application 94-29208 filed 9.11.94.
The present invention will be more specifically illustrated by the following examples. However, it should be understood that the present invention is not limited by these examples in any manner.
EXAMPLES: 1 2 3 4 5
Component Content (me / CaD.)
Cyclosporin 25 25 25 25 25 polyethylene glycol 200 45 70 100 45 45 propylene carbonate 25 - 50 25 25 polyoxyethylene (50) hydrogenated castor oil 35 35 35 50 35 polyoxyethylene (20) sorbitan monolaurate 85 85 85 100 85 ethyl linoleate 40 40 40 40 80 caprylic/capric acid triglyceride 5 5 5 5 10 oleic acid monoglyceride 35 35 35 35 70 total 295mg 295mg 375mg 325mg 375mg
EXAMPLE 6:
The soft capsule preparation was prepared from the composition of Example 1 using the following composition for capsule shell and then the change in the property and condition of the content due to the inflow of glycerine was visually observed.
6.1 (control group)
Component Weight ratio gelatin 20 purified water 16 glycerine 9
6.2 (test group)
Component Weight ratio gelatin 20 purified water 16 propylene glycol 4 polyethylene glycol 200 1
The results as observed are described in the following Table 1.
Table 1: Stability of the content of the capsule preparation according to the capsule shell
Composition Just after After After After After After of Capsule formulation 1 day 2 days 5 days 10 days 30 days
Control group 0 + + ++ +++ +++
Test group 0 0 0 0 0 0
Note: 0 = the content is stable
+ = poor emulsification
++ = slight precipitation
+++ = precipitation
As can be seen from the result described in table 1, the capsule preparation prepared using the composition of 6.1 control group containing glycerine as the plasticizer causes some problems including the formation of precipitation due to the inflow of glycerine, whereas the capsule preparation prepared using the composition of 6.2 test group containing polyethylene glycol and propylene glycol as the plasticizer maintains the stable condition.
EXAMPLE 7:
The soft capsule preparation having the composition of Example 1 was prepared using the composition of the capsule shell of 6.2 test group used in the above Example 6 by means of the water-cooling method (water temperature about 12°C) and the air-cooling method (air volume flow about 10 mVmin), respectively.
In each case, the removability of the capsule shell band from the cooling drum was observed and compared. The result as observed is described in the following
Table 2.
Table 2: Removability of the gelatin shell band from the cooling drum depending on the cooling method
(Unit: degree of angle)
Shell Water-cooling Air-cooling
Composition Method Method
Example 6.2 > 100 degree < 50 degree (poor removability) (good removability)
As can be seen from the result described in the Table 2 above, the soft capsule preparation prepared by the air-cooling method according to the present invention shows a far better removability from the cooling drum in comparisoin with that prepared by the water-cooling method. Specifically, it is generally considered that if the degree of angle for removing the gelatin shell band from the cooling drum is about 70 or more, the removability is poor, and if the degree of angle for removing the shell band is below about 70, the removability is good. The soft capsule preparation prepared by the water-cooling method is not satisfactorily removed from the cooling drum even when the preparation is removed at the angle of 100 degrees or more.
Contrary to this, the soft capsule preparation prepared by the air-cooling ethod according to the present invention can be easily removed from the cooling drum at the angle of 50 degree and below and therefore, can provide a good sealing strength and productivity.
EXAMPLE 8:
The bioavailability of the preparation prepared by encapsulating the composition of Example 1 with the gelatin shell having the composition of
Example 6.2 as the test preparation was compared with the bioavailability of the commercial product containing ethanol, SANDIMMUN Capsule, as the control preparation to estimate the influence of the cyclosporin preparation according to the present invention on the bioavailability of cyclosporin and its difference between respective subjects.
In this experiment, both of the test preparation and the control preparation were administered in an amount of 300 mg as cyclosporin per kg of rabbit.
Rabbits were uniformly fed with the conventional rabbit solid feed composition for 4 days or more under the same condition in wire cages. When the oral preparation were administered, rabbits were fasted for 48 hours in a restraint cage made of steel, during which rabbits were allowed to freely take water. Levin's tube having a diameter of 5 mm was interposed by the depth of 30 cm through the esophagus after the surface of the Levin's tube was coated with vaseline in order to reduce friction. Each of the test preparations and the control preparation was emulsified with 50 ml of water and then introduced into a syringe which is attached to the Levin's tube. Ear veins of rabbit were dilated using xylene and then blood was taken from each rabbit's ear vein before the test and after 0.5, 1, 1.5, 2, 3, 4, 6, 10 and 24 hours by means of heparin- treated disposable syringe. To 1 ml of blood thus obtained were added 0.5 ml of aqueous saturated sodium chloride solution and 2 ml of ether, and then the mixture was shaken for 5 minutes and centrifuged with 5000 rpm for 10 minutes to separate the supernatant (ether layer). 1 ml of the supernatant was collected and then developed in an activated silica sep-pakR (Waters). The developed sep-pak was washed with 5 ml of n-hexane and eluated with 2 ml of methanol. The eluate was evaporated to dryness in nitrogen gas under reduced pressure. The residue was analysed by means of HPLC (High Performance Liquid Chromatography) [HPLC condition: column μ-BondapakR C18 (Waters), mobile phase CH,CN: MeOH; H2O - 55: 15 : 30, detection 210 nm, flow rate
1.0 ml /min., column temperature 70°C, sensitivity 0.01 Aufs. injection volume
100 μl].
The results obtained from the test preparation and the control preparation are i l l u s t r a t e d i n t h e f o l l o w i n g T a b l e 3 :
Table 3: Bioavailability of the test preparation of the present invention and the commercial product (SANDIMMUNR)
Control Prep. (A) Test Prep. (B)
Parameter
(B/A)
M ± S.D. CV % M ± S.D. CV % (n=6) (S.DJM) (n=6) (S.D./M)
AUC 13.5±10.0 74.0 % 57.0117.0 29.8 % 4.1 (μg.hr/ml)
max 0.8 ±0.3 37.5 % 6.011.5 25.0 % 7.5 (μg.hr/ml)
Note: AUC = Area under the blood concentration curve
C^ = Maximum blood concentration of cyclosporin
Ml S.D. = Mean value 1 Standard deviation CV = Ratio of standard deviation to mean value
P(B/A) = Ratio of mean value of the test preparation to mean value of the control preparation
As can be seen from the above table, the test preparation shows the increased AUC and C^ values which are about 4 times or more and about 7 times or more, respectively, as high as those of the control preparation. Accordingly, it can be identified that the bioavailability of the test preparation is significantly increased in comparison with that of the control preparation. In addition, the test preparation of the present invention exhibits an effect of decreasing the difference between respective test subjects (CV %) by about 2 times or more in
AUC value and by about 1.5 times in C^ value, in comparison with the control preparation.
Accordingly, it could be determined that when the soft capsule preparation according to the present invention is administered per oral, it shows the increased bioavailability of cyclosporin about 4 times as high as that of the prior commercial product containing ethanol, SANDIMMUN* Capsule and also a decrease of the difference between cyclosporin bioavailabilities in respective subjects, and at the same time, remains stable without any change during the long term storage. Thus, it is apparent that the soft capsule preparation
according to the present invention provides a significant improvement in the field of preparation of cyclosporin soft capsules.
EXAMPLE 9:
Soft gels are made up containing:
I II
Cyclosporin A 25 mg 100 mg
Polyethylene glycol 200 45 mg 180 mg
Propylene carbonate 25 mg 100 mg
Polyoxyethylene 50-hydrogenated castor oil 40 mg 160 mg
Polysorbate 20 85 mg 340 mg
Ethyl linoleate 40 mg 160 mg
Glyceryl mono-oleate 40 mg 160 mg
Vitamin E 1 mg 4 mg
Total 301 mg 1204 mg
EXAMPLES: 10 11 12 13 14
Component Content (mε/CaD.)
Cyclosporin 25 25 100 25 25 propylene carbonate 50 100 200 50 100 polyoxyethylene (50) hydrogenated castor oil 90 80 300 90 90 polyoxyethylene (20) sorbitan monolaurate 80 80 280 80 80 ethyl linoleate 40 30 150 - 40 caprylic /capric acid triglyceride 5 10 20 5 5 oleic acid monoglyceride 35 50 120 35 35
Labrafil - - 50 - - total 325mg 375mg 1220mg 285mg 375mg
EXAMPLES: 15 16 17 18
Component Content (mε/CaD.)
Cyclosporin 25 25 25 25 polyethylene glycol 200 35 50 25 20 propylene carbonate 45 100 45 80 polyoxyethylene (50) hydrogenated castor oil 30 35 50 35 polyoxyethylene (20) sorbitan monolaurate 80 90 75 85 ethyl linoleate 35 40 40 80 caprylic /capric acid triglyceride 5 5 5 10 oleic acid monoglyceride 35 30 35 85 total 290mg 375mg 300mg 420mg
EXAMPLE 19:
The bioavailability of the soft capsule preparation prepared from the composition of Example 10 according to a conventional manner as the test preparation was compared with the bioavailability of the commercial product containing ethanol, SANDIMMUN Capsule, as the control preparation to estimate the influence of the cyclosporin preparation according to the present invention on the bioavailability of cyclosporin and its difference between respective subjects.
The experimental protocol was the same as under Example 8 described.
The results obtained from the test preparation and the control preparation are i l l u s t r a t e d i n t h e f o l l o w i n g T a b l e 4 :
Table 4: Bioavailability of the test preparation of the present invention and the commercial product (SANDIMMUN*)
Control Prep. (A) Test Prep. (B)
Parameter P (B/A)
M i S.D. CV % M i S.D. CV %
(n=6) (S.DJM) (n=6) (S.D./M) AUC 13.5110.0 74.0 % 60.1118.0 30.8 %
4.4 (μg.hr/ml)
0.810.3 37.5 % 6.211.5 24.2 % 7.7 (μg.hr/ml)
Note: AUC = Area under the blood concentration curve
C^ = Maximum blood concentration of cyclosporin
Mi S.D.= Mean value i Standard deviation CV = Ratio of standard deviation to mean value
P(B/A) = Ratio of mean value of the test preparation to mean value of the control preparation As can be seen from the above table, the test preparation shows the increased AUC and C mix values which are about 4 times or more and about 7 times or more, respectively, as high as those of the control preparation. Accordingly, it can be identified that the bioavailability of the test preparation is significantly increased in comparison with that of the control preparation. In addition, the test preparation of the present invention exhibits an effect of decreasing the difference between respective test subjects (CV %) by about 2 times or more in AUC value and by about 1.5 times in C^ value, in comparison with the control preparation.
Accordingly, it could be determined that when the soft capsule preparation according to the present invention is administered per oral, it shows the increased bioavailability of cyclosporin about 4 times as high as that of the prior commercial product containing ethanol, SANDIMMUN" Capsule and also a decrease of the difference between cyclosporin bioavailabilities in respective subjects, and at the same time, remains stable without any change during the long term storage. Thus, it is apparent that the soft capsule preparation according to the present invention provides a significant improvement in the field of preparation of cyclosporin soft capsules.
Claims
1. A cyclosporin-containing preparation which comprises a composition containing:
(1) cyclosporin as an active ingredient,
(2) polyethylene glycol or propylene carbonate or their mixture,
(3) one or a mixture of two or more selected from the group consisting of an esterified compound of fatty acid and primary alcohol, medium chain fatty acid triglyceride and fatty acid monoglyceride as an oil component, and
(4) a surfactant having HLB (Hydrophilic-lipophilic balance) value of 8 to 17.
2. The cyclosporin-containing composition of claim 1, wherein said medium chain fatty acid triglyceride is caprylic/capric acid triglyceride.
3. The cyclosporin-containing preparation of claim 1 or 2 wherein said fatty acid monoglyceride is a monoglyceride of oleic acid.
4. The cyclosporin-containing preparation of any preceding claim wherein said surfactant is a polyoxyethylene product of hydrogenated vegetable oil or a polyoxethylene-sorbitan-fatty acid ester.
5. The cyclosporin-containing soft capsule preparation of claim 4 wherein said surfactant is a mixed surfactant consisting of a polyoxyethylene(50) hydrogenated castor oil : a polyoxyethylene(20) sorbitan monolaurate in the mixing ratio of 1:0.1-5.
6. The cyclosporin-containing soft capsule preparation of any preceding claim wherein said cyclosporin, said component (2), said oil component and said surfactant are present in the ratio of 1:0.1-10 : 1-10 : 1-10 on the basis of weight.
7. The cyclosporin-containing preparation of claim 6 wherein said cyclosporin, said component (2), said oil component and said surfactant are present in the ratio of 1:0.5-8 : 2-6 : 2-8 on the basis of weight.
8. A cyclosporin-containing preparation, which comprises a composition containing
1 ) cyclosporin as an active ingredient; and
2) propylene carbonate
9. A composition according to claim 8 containing one or more further components as defined in any one of claims 1 to 7.
10. A cyclosporin-containing preparation according to claim 8 wherein said composition is free from polyethylene glycol.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1019970008750A KR19980073479A (en) | 1997-03-14 | 1997-03-14 | Cyclosporine-containing soft capsules |
| KR9708750 | 1997-03-14 | ||
| PCT/EP1998/001432 WO1998041225A1 (en) | 1997-03-14 | 1998-03-12 | Pharmaceutical compositions |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP0969857A1 true EP0969857A1 (en) | 2000-01-12 |
Family
ID=19499792
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP98912470A Withdrawn EP0969857A1 (en) | 1997-03-14 | 1998-03-12 | Pharmaceutical compositions |
Country Status (24)
| Country | Link |
|---|---|
| EP (1) | EP0969857A1 (en) |
| JP (1) | JP3748573B2 (en) |
| KR (2) | KR19980073479A (en) |
| CN (1) | CN1161150C (en) |
| AR (1) | AR012054A1 (en) |
| AU (1) | AU741923B2 (en) |
| BR (1) | BR9808324A (en) |
| CA (1) | CA2283901A1 (en) |
| CO (1) | CO4940404A1 (en) |
| CZ (1) | CZ324399A3 (en) |
| DE (1) | DE19882184T1 (en) |
| GB (1) | GB2337703A (en) |
| HU (1) | HUP0001515A3 (en) |
| ID (1) | ID23531A (en) |
| IL (1) | IL131703A0 (en) |
| MY (1) | MY118614A (en) |
| NO (1) | NO994436L (en) |
| PE (1) | PE59499A1 (en) |
| PL (1) | PL335729A1 (en) |
| RU (1) | RU2185188C2 (en) |
| SK (1) | SK123299A3 (en) |
| TR (1) | TR199902229T2 (en) |
| WO (1) | WO1998041225A1 (en) |
| ZA (1) | ZA982117B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2380673B (en) * | 1998-03-06 | 2003-05-28 | Novartis Ag | Emulsion preconcentrates containing cyclosporin or a macrolide |
| US7203158B2 (en) * | 2000-12-06 | 2007-04-10 | Matsushita Electric Industrial Co., Ltd. | OFDM signal transmission system, portable terminal, and e-commerce system |
| GB0526419D0 (en) * | 2005-12-23 | 2006-02-08 | Cyclacel Ltd | Formulation |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0711550A1 (en) * | 1994-11-09 | 1996-05-15 | Hanmi Pharm. Ind. Co., Ltd. | Cyclosporin-containing soft capsule compositions |
| US5589455A (en) * | 1994-12-28 | 1996-12-31 | Hanmi Pharm. Ind. Co., Ltd. | Cyclosporin-containing soft capsule compositions |
| WO1997004810A1 (en) * | 1995-07-28 | 1997-02-13 | The Regents Of The University Of California | Dax-1 protein, methods for production and use thereof |
| WO1997022358A1 (en) * | 1995-12-15 | 1997-06-26 | Bernard Charles Sherman | Microemulsion preconcentrates comprising cyclosporins |
| EP0813876A1 (en) * | 1996-06-19 | 1997-12-29 | Hanmi Pharm. Ind. Co., Ltd. | Cyclosporin-containing soft capsule preparations |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU215966B (en) * | 1994-11-21 | 1999-07-28 | BIOGAL Gyógyszergyár Rt. | Oral multiple emulsion-preconcentrate containing cyclosporin |
| KR20000016761A (en) * | 1996-06-19 | 2000-03-25 | 멘레 코르넬리아, 발데그 베르너 | Cyclosporin-containing soft capsule preparations |
-
1997
- 1997-03-14 KR KR1019970008750A patent/KR19980073479A/en not_active Ceased
-
1998
- 1998-03-12 MY MYPI98001086A patent/MY118614A/en unknown
- 1998-03-12 SK SK1232-99A patent/SK123299A3/en unknown
- 1998-03-12 ID IDW990997A patent/ID23531A/en unknown
- 1998-03-12 AU AU67293/98A patent/AU741923B2/en not_active Ceased
- 1998-03-12 JP JP54011298A patent/JP3748573B2/en not_active Expired - Fee Related
- 1998-03-12 CN CNB988033569A patent/CN1161150C/en not_active Expired - Fee Related
- 1998-03-12 IL IL13170398A patent/IL131703A0/en unknown
- 1998-03-12 PE PE1998000174A patent/PE59499A1/en not_active Application Discontinuation
- 1998-03-12 GB GB9921495A patent/GB2337703A/en not_active Withdrawn
- 1998-03-12 CZ CZ993243A patent/CZ324399A3/en unknown
- 1998-03-12 PL PL98335729A patent/PL335729A1/en unknown
- 1998-03-12 DE DE19882184T patent/DE19882184T1/en not_active Withdrawn
- 1998-03-12 WO PCT/EP1998/001432 patent/WO1998041225A1/en not_active Application Discontinuation
- 1998-03-12 BR BR9808324-4A patent/BR9808324A/en not_active Application Discontinuation
- 1998-03-12 TR TR1999/02229T patent/TR199902229T2/en unknown
- 1998-03-12 RU RU99121398/14A patent/RU2185188C2/en not_active IP Right Cessation
- 1998-03-12 EP EP98912470A patent/EP0969857A1/en not_active Withdrawn
- 1998-03-12 CA CA002283901A patent/CA2283901A1/en not_active Abandoned
- 1998-03-12 KR KR1019997008022A patent/KR20000075940A/en not_active Ceased
- 1998-03-12 ZA ZA982117A patent/ZA982117B/en unknown
- 1998-03-12 HU HU0001515A patent/HUP0001515A3/en unknown
- 1998-03-13 AR ARP980101125A patent/AR012054A1/en not_active Application Discontinuation
- 1998-03-13 CO CO98014254A patent/CO4940404A1/en unknown
-
1999
- 1999-09-13 NO NO994436A patent/NO994436L/en not_active Application Discontinuation
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0711550A1 (en) * | 1994-11-09 | 1996-05-15 | Hanmi Pharm. Ind. Co., Ltd. | Cyclosporin-containing soft capsule compositions |
| US5589455A (en) * | 1994-12-28 | 1996-12-31 | Hanmi Pharm. Ind. Co., Ltd. | Cyclosporin-containing soft capsule compositions |
| WO1997004810A1 (en) * | 1995-07-28 | 1997-02-13 | The Regents Of The University Of California | Dax-1 protein, methods for production and use thereof |
| WO1997022358A1 (en) * | 1995-12-15 | 1997-06-26 | Bernard Charles Sherman | Microemulsion preconcentrates comprising cyclosporins |
| EP0813876A1 (en) * | 1996-06-19 | 1997-12-29 | Hanmi Pharm. Ind. Co., Ltd. | Cyclosporin-containing soft capsule preparations |
Non-Patent Citations (1)
| Title |
|---|
| See also references of WO9841225A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| HUP0001515A2 (en) | 2000-09-28 |
| HUP0001515A3 (en) | 2000-10-30 |
| SK123299A3 (en) | 2000-02-14 |
| JP2000514831A (en) | 2000-11-07 |
| IL131703A0 (en) | 2001-03-19 |
| DE19882184T1 (en) | 2000-02-10 |
| BR9808324A (en) | 2000-05-16 |
| AR012054A1 (en) | 2000-09-27 |
| WO1998041225A1 (en) | 1998-09-24 |
| KR20000075940A (en) | 2000-12-26 |
| CN1250378A (en) | 2000-04-12 |
| CN1161150C (en) | 2004-08-11 |
| MY118614A (en) | 2004-12-31 |
| AU741923B2 (en) | 2001-12-13 |
| TR199902229T2 (en) | 1999-12-21 |
| AU6729398A (en) | 1998-10-12 |
| GB9921495D0 (en) | 1999-11-17 |
| PL335729A1 (en) | 2000-05-08 |
| NO994436D0 (en) | 1999-09-13 |
| CO4940404A1 (en) | 2000-07-24 |
| ZA982117B (en) | 1998-09-14 |
| PE59499A1 (en) | 1999-07-05 |
| NO994436L (en) | 1999-09-13 |
| RU2185188C2 (en) | 2002-07-20 |
| JP3748573B2 (en) | 2006-02-22 |
| CA2283901A1 (en) | 1998-09-24 |
| ID23531A (en) | 2000-04-27 |
| CZ324399A3 (en) | 1999-12-15 |
| KR19980073479A (en) | 1998-11-05 |
| GB2337703A (en) | 1999-12-01 |
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