GB2228198A - Orally administrable cyclosporin solutions - Google Patents
Orally administrable cyclosporin solutions Download PDFInfo
- Publication number
- GB2228198A GB2228198A GB9003616A GB9003616A GB2228198A GB 2228198 A GB2228198 A GB 2228198A GB 9003616 A GB9003616 A GB 9003616A GB 9003616 A GB9003616 A GB 9003616A GB 2228198 A GB2228198 A GB 2228198A
- Authority
- GB
- United Kingdom
- Prior art keywords
- components
- fatty acid
- composition according
- ciclosporin
- compositions
- 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.)
- Granted
Links
- 229960001265 ciclosporin Drugs 0.000 title claims description 98
- 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 title claims description 90
- 108010036949 Cyclosporine Proteins 0.000 title claims description 87
- 229930182912 cyclosporin Natural products 0.000 title claims description 65
- 229930105110 Cyclosporin A Natural products 0.000 title claims description 44
- 239000000203 mixture Substances 0.000 claims description 98
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 83
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 80
- 239000000194 fatty acid Substances 0.000 claims description 68
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 64
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 64
- 229930195729 fatty acid Natural products 0.000 claims description 64
- 239000004615 ingredient Substances 0.000 claims description 48
- 239000000047 product Substances 0.000 claims description 48
- -1 glycerol fatty acid Chemical class 0.000 claims description 47
- 150000004665 fatty acids Chemical class 0.000 claims description 40
- 238000005809 transesterification reaction Methods 0.000 claims description 23
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 20
- 239000000600 sorbitol Substances 0.000 claims description 20
- 235000015112 vegetable and seed oil Nutrition 0.000 claims description 20
- 239000008158 vegetable oil Substances 0.000 claims description 20
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 19
- 150000002148 esters Chemical class 0.000 claims description 18
- 239000008194 pharmaceutical composition Substances 0.000 claims description 14
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 claims description 12
- 239000004480 active ingredient Substances 0.000 claims description 8
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 7
- 239000004359 castor oil Substances 0.000 claims description 7
- 235000019438 castor oil Nutrition 0.000 claims description 6
- 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 6
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 claims description 4
- 239000007795 chemical reaction product Substances 0.000 claims description 3
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 2
- 150000003904 phospholipids Chemical class 0.000 claims description 2
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 claims description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 2
- 229920001400 block copolymer Polymers 0.000 claims 1
- KWABLUYIOFEZOY-UHFFFAOYSA-N dioctyl butanedioate Chemical compound CCCCCCCCOC(=O)CCC(=O)OCCCCCCCC KWABLUYIOFEZOY-UHFFFAOYSA-N 0.000 claims 1
- 239000002253 acid Substances 0.000 description 25
- 108010036941 Cyclosporins Proteins 0.000 description 24
- 210000004369 blood Anatomy 0.000 description 19
- 239000008280 blood Substances 0.000 description 19
- 238000007127 saponification reaction Methods 0.000 description 19
- 239000003921 oil Substances 0.000 description 18
- 235000019198 oils Nutrition 0.000 description 18
- 239000002904 solvent Substances 0.000 description 16
- 238000002560 therapeutic procedure Methods 0.000 description 16
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 14
- 239000011630 iodine Substances 0.000 description 14
- 229910052740 iodine Inorganic materials 0.000 description 14
- 235000005687 corn oil Nutrition 0.000 description 13
- 239000002285 corn oil Substances 0.000 description 12
- 239000002609 medium Substances 0.000 description 12
- 239000000470 constituent Substances 0.000 description 11
- 229920006395 saturated elastomer Polymers 0.000 description 11
- 150000003626 triacylglycerols Chemical class 0.000 description 11
- 235000021355 Stearic acid Nutrition 0.000 description 10
- IPCSVZSSVZVIGE-UHFFFAOYSA-N n-hexadecanoic acid Natural products CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 10
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid group Chemical group C(CCCCCCC\C=C/CCCCCCCC)(=O)O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 10
- 210000002966 serum Anatomy 0.000 description 10
- 238000000034 method Methods 0.000 description 9
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 239000008117 stearic acid Substances 0.000 description 9
- OGBUMNBNEWYMNJ-UHFFFAOYSA-N batilol Chemical class CCCCCCCCCCCCCCCCCCOCC(O)CO OGBUMNBNEWYMNJ-UHFFFAOYSA-N 0.000 description 8
- 239000004094 surface-active agent Substances 0.000 description 8
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 7
- 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 7
- 239000002552 dosage form Substances 0.000 description 7
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 7
- 230000004044 response Effects 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000003085 diluting agent Substances 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 229920000159 gelatin Polymers 0.000 description 6
- 235000019322 gelatine Nutrition 0.000 description 6
- 239000000787 lecithin Substances 0.000 description 6
- 235000010445 lecithin Nutrition 0.000 description 6
- 235000021313 oleic acid Nutrition 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 5
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 5
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 5
- 208000023275 Autoimmune disease Diseases 0.000 description 5
- 108010010803 Gelatin Proteins 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 239000005642 Oleic acid Substances 0.000 description 5
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 5
- 235000021314 Palmitic acid Nutrition 0.000 description 5
- 239000003240 coconut oil Substances 0.000 description 5
- 235000019864 coconut oil Nutrition 0.000 description 5
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Natural products CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 5
- 150000005690 diesters Chemical class 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 239000008273 gelatin Substances 0.000 description 5
- 235000011852 gelatine desserts Nutrition 0.000 description 5
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 5
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- LDVVTQMJQSCDMK-UHFFFAOYSA-N 1,3-dihydroxypropan-2-yl formate Chemical compound OCC(CO)OC=O LDVVTQMJQSCDMK-UHFFFAOYSA-N 0.000 description 4
- OYHQOLUKZRVURQ-HZJYTTRNSA-N Linoleic acid Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(O)=O OYHQOLUKZRVURQ-HZJYTTRNSA-N 0.000 description 4
- 235000020661 alpha-linolenic acid Nutrition 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical class CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 210000001035 gastrointestinal tract Anatomy 0.000 description 4
- 125000005456 glyceride group Chemical group 0.000 description 4
- 235000020778 linoleic acid Nutrition 0.000 description 4
- OYHQOLUKZRVURQ-IXWMQOLASA-N linoleic acid Natural products CCCCC\C=C/C\C=C\CCCCCCCC(O)=O OYHQOLUKZRVURQ-IXWMQOLASA-N 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 4
- 239000006186 oral dosage form Substances 0.000 description 4
- 238000007911 parenteral administration Methods 0.000 description 4
- 239000008389 polyethoxylated castor oil Substances 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 238000011282 treatment Methods 0.000 description 4
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 4
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 244000068988 Glycine max Species 0.000 description 3
- 235000010469 Glycine max Nutrition 0.000 description 3
- 206010020751 Hypersensitivity Diseases 0.000 description 3
- 240000006394 Sorghum bicolor Species 0.000 description 3
- NWGKJDSIEKMTRX-BFWOXRRGSA-N [(2r)-2-[(3r,4s)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)C1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-BFWOXRRGSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 208000026935 allergic disease Diseases 0.000 description 3
- 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 3
- 206010003246 arthritis Diseases 0.000 description 3
- 230000001363 autoimmune Effects 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000006184 cosolvent Substances 0.000 description 3
- 229940109239 creatinine Drugs 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 210000003743 erythrocyte Anatomy 0.000 description 3
- 229960004488 linolenic acid Drugs 0.000 description 3
- KQQKGWQCNNTQJW-UHFFFAOYSA-N linolenic acid Natural products CC=CCCC=CCC=CCCCCCCCC(O)=O KQQKGWQCNNTQJW-UHFFFAOYSA-N 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- FBUKVWPVBMHYJY-UHFFFAOYSA-N nonanoic acid Chemical compound CCCCCCCCC(O)=O FBUKVWPVBMHYJY-UHFFFAOYSA-N 0.000 description 3
- 239000004006 olive oil Substances 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 238000004806 packaging method and process Methods 0.000 description 3
- 229920001993 poloxamer 188 Polymers 0.000 description 3
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 3
- 229920000053 polysorbate 80 Polymers 0.000 description 3
- 239000008159 sesame oil Substances 0.000 description 3
- 235000011803 sesame oil Nutrition 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 239000002562 thickening agent Substances 0.000 description 3
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 3
- GEUKOOCPPICVTB-SMOCYEBVSA-N (3s,6s,9s,12r,15s,18s,21s,24s,30s)-33-[(1r,2r)-1-hydroxy-2-methylhexyl]-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-2,5,8,11,14,17,20,23,26,29,32- Chemical compound CCCC[C@@H](C)[C@@H](O)C1N(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 GEUKOOCPPICVTB-SMOCYEBVSA-N 0.000 description 2
- RZRNAYUHWVFMIP-KTKRTIGZSA-N 1-oleoylglycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-KTKRTIGZSA-N 0.000 description 2
- 235000019489 Almond oil Nutrition 0.000 description 2
- 101100248253 Arabidopsis thaliana RH40 gene Proteins 0.000 description 2
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 241001440269 Cutina Species 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 235000019483 Peanut oil Nutrition 0.000 description 2
- 201000004681 Psoriasis Diseases 0.000 description 2
- 206010052779 Transplant rejections Diseases 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 230000007815 allergy Effects 0.000 description 2
- 239000008168 almond oil Substances 0.000 description 2
- 208000007502 anemia Diseases 0.000 description 2
- 239000010775 animal oil Substances 0.000 description 2
- 230000002141 anti-parasite Effects 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
- 239000003613 bile acid Substances 0.000 description 2
- 238000004820 blood count 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
- 239000000824 cytostatic agent Substances 0.000 description 2
- 230000001085 cytostatic effect Effects 0.000 description 2
- 108010040781 dihydrocyclosporin D Proteins 0.000 description 2
- HQPMKSGTIOYHJT-UHFFFAOYSA-N ethane-1,2-diol;propane-1,2-diol Chemical compound OCCO.CC(O)CO HQPMKSGTIOYHJT-UHFFFAOYSA-N 0.000 description 2
- 230000007717 exclusion Effects 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- RZRNAYUHWVFMIP-HXUWFJFHSA-N glycerol monolinoleate Natural products CCCCCCCCC=CCCCCCCCC(=O)OC[C@H](O)CO RZRNAYUHWVFMIP-HXUWFJFHSA-N 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000002650 immunosuppressive therapy Methods 0.000 description 2
- 238000010348 incorporation Methods 0.000 description 2
- 230000004968 inflammatory condition Effects 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 201000006417 multiple sclerosis Diseases 0.000 description 2
- 230000003589 nefrotoxic effect Effects 0.000 description 2
- 231100000381 nephrotoxic Toxicity 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 235000008390 olive oil Nutrition 0.000 description 2
- 239000000312 peanut oil Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 229920001983 poloxamer Polymers 0.000 description 2
- 229920000136 polysorbate Polymers 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 235000003441 saturated fatty acids Nutrition 0.000 description 2
- 150000004671 saturated fatty acids Chemical class 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- GBIWPCXWDSDANU-JYFGSSRXSA-N (3s,6s,9s,12r,15s,18s,21s,24s,30s)-30-ethyl-33-[(e,1r,2r)-1-hydroxy-2-methylhex-4-enyl]-1,4,7,10,12,15,18,19,25,28-decamethyl-6,9,24-tris(2-methylpropyl)-3,21-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontane-2,5,8,11,14,17,20,23,2 Chemical compound CC[C@@H]1NC(=O)C([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](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 GBIWPCXWDSDANU-JYFGSSRXSA-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
- 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
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- OVYMWJFNQQOJBU-UHFFFAOYSA-N 1-octanoyloxypropan-2-yl octanoate Chemical compound CCCCCCCC(=O)OCC(C)OC(=O)CCCCCCC OVYMWJFNQQOJBU-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- OURWLMNRUGYRSC-UHFFFAOYSA-N 12-(1-hydroxypropan-2-yloxy)octadecanoic acid Chemical compound CCCCCCC(OC(C)CO)CCCCCCCCCCC(O)=O OURWLMNRUGYRSC-UHFFFAOYSA-N 0.000 description 1
- FKOKUHFZNIUSLW-UHFFFAOYSA-N 2-Hydroxypropyl stearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(C)O FKOKUHFZNIUSLW-UHFFFAOYSA-N 0.000 description 1
- KWVPFECTOKLOBL-KTKRTIGZSA-N 2-[(z)-octadec-9-enoxy]ethanol Chemical compound CCCCCCCC\C=C/CCCCCCCCOCCO KWVPFECTOKLOBL-KTKRTIGZSA-N 0.000 description 1
- WITKSCOBOCOGSC-UHFFFAOYSA-N 2-dodecanoyloxypropyl dodecanoate Chemical compound CCCCCCCCCCCC(=O)OCC(C)OC(=O)CCCCCCCCCCC WITKSCOBOCOGSC-UHFFFAOYSA-N 0.000 description 1
- JZSMZIOJUHECHW-GTJZZHROSA-N 2-hydroxypropyl (z,12r)-12-hydroxyoctadec-9-enoate Chemical compound CCCCCC[C@@H](O)C\C=C/CCCCCCCC(=O)OCC(C)O JZSMZIOJUHECHW-GTJZZHROSA-N 0.000 description 1
- BJRXGOFKVBOFCO-UHFFFAOYSA-N 2-hydroxypropyl 16-methylheptadecanoate Chemical compound CC(C)CCCCCCCCCCCCCCC(=O)OCC(C)O BJRXGOFKVBOFCO-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
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 206010061623 Adverse drug reaction Diseases 0.000 description 1
- 229910002012 Aerosil® Inorganic materials 0.000 description 1
- 108010082126 Alanine transaminase Proteins 0.000 description 1
- 208000007848 Alcoholism Diseases 0.000 description 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- 239000004382 Amylase Substances 0.000 description 1
- 102000013142 Amylases Human genes 0.000 description 1
- 108010065511 Amylases Proteins 0.000 description 1
- 241001550224 Apha Species 0.000 description 1
- 208000032467 Aplastic anaemia Diseases 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Natural products OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- 108010003415 Aspartate Aminotransferases Proteins 0.000 description 1
- 102000004625 Aspartate Aminotransferases Human genes 0.000 description 1
- 241000273930 Brevoortia tyrannus Species 0.000 description 1
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 description 1
- 239000005635 Caprylic acid (CAS 124-07-2) Substances 0.000 description 1
- 244000020518 Carthamus tinctorius Species 0.000 description 1
- 235000003255 Carthamus tinctorius Nutrition 0.000 description 1
- 241000251730 Chondrichthyes Species 0.000 description 1
- 206010008909 Chronic Hepatitis Diseases 0.000 description 1
- 208000015943 Coeliac disease Diseases 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010013654 Drug abuse Diseases 0.000 description 1
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 1
- 208000003556 Dry Eye Syndromes Diseases 0.000 description 1
- 206010013774 Dry eye Diseases 0.000 description 1
- 239000004150 EU approved colour Substances 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 208000003807 Graves Disease Diseases 0.000 description 1
- 208000015023 Graves' disease Diseases 0.000 description 1
- 206010019755 Hepatitis chronic active Diseases 0.000 description 1
- 241000384508 Hoplostethus atlanticus Species 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 208000029523 Interstitial Lung disease Diseases 0.000 description 1
- 208000009319 Keratoconjunctivitis Sicca Diseases 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- QAQJMLQRFWZOBN-LAUBAEHRSA-N L-ascorbyl-6-palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-LAUBAEHRSA-N 0.000 description 1
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- 240000004752 Laburnum anagyroides Species 0.000 description 1
- 208000004883 Lipoid Nephrosis Diseases 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- ZMKGDQSIRSGUDJ-UHFFFAOYSA-N NVa2 cyclosporine Natural products CCCC1NC(=O)C(C(O)C(C)CC=CC)N(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)C1=O ZMKGDQSIRSGUDJ-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 241000772415 Neovison vison Species 0.000 description 1
- 206010029164 Nephrotic syndrome Diseases 0.000 description 1
- 241000219925 Oenothera Species 0.000 description 1
- 235000004496 Oenothera biennis Nutrition 0.000 description 1
- 235000019482 Palm oil Nutrition 0.000 description 1
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 1
- 206010065159 Polychondritis Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920002685 Polyoxyl 35CastorOil Polymers 0.000 description 1
- 229920002690 Polyoxyl 40 HydrogenatedCastorOil Polymers 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 229920001219 Polysorbate 40 Polymers 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- 244000028344 Primula vulgaris Species 0.000 description 1
- 235000016311 Primula vulgaris Nutrition 0.000 description 1
- 244000018633 Prunus armeniaca Species 0.000 description 1
- 235000009827 Prunus armeniaca Nutrition 0.000 description 1
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 1
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 1
- 208000025747 Rheumatic disease Diseases 0.000 description 1
- 235000019485 Safflower oil Nutrition 0.000 description 1
- 244000000231 Sesamum indicum Species 0.000 description 1
- 235000003434 Sesamum indicum Nutrition 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000004147 Sorbitan trioleate Substances 0.000 description 1
- PRXRUNOAOLTIEF-ADSICKODSA-N Sorbitan trioleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC PRXRUNOAOLTIEF-ADSICKODSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 238000008050 Total Bilirubin Reagent Methods 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 1
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 1
- 206010046851 Uveitis Diseases 0.000 description 1
- 208000016807 X-linked intellectual disability-macrocephaly-macroorchidism syndrome Diseases 0.000 description 1
- IJCWFDPJFXGQBN-RYNSOKOISA-N [(2R)-2-[(2R,3R,4S)-4-hydroxy-3-octadecanoyloxyoxolan-2-yl]-2-octadecanoyloxyethyl] octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCCCCCCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCCCCCCCCCCCC IJCWFDPJFXGQBN-RYNSOKOISA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 206010001584 alcohol abuse Diseases 0.000 description 1
- 208000025746 alcohol use disease Diseases 0.000 description 1
- 208000002205 allergic conjunctivitis Diseases 0.000 description 1
- 239000005030 aluminium foil Substances 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 235000019418 amylase Nutrition 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000003096 antiparasitic agent Substances 0.000 description 1
- 239000003904 antiprotozoal agent Substances 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010385 ascorbyl palmitate Nutrition 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 239000008163 avocado oil Substances 0.000 description 1
- 239000010480 babassu oil Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 235000013361 beverage Nutrition 0.000 description 1
- 239000003833 bile salt Substances 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229940124301 concurrent medication Drugs 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 108010019249 cyclosporin G Proteins 0.000 description 1
- 108010019251 cyclosporin H Proteins 0.000 description 1
- PWEOPMBMTXREGV-UHFFFAOYSA-N decanoic acid;octanoic acid;propane-1,2-diol Chemical compound CC(O)CO.CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCCCC(O)=O.CCCCCCCCCC(O)=O PWEOPMBMTXREGV-UHFFFAOYSA-N 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 201000001981 dermatomyositis Diseases 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- 235000019797 dipotassium phosphate Nutrition 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- LLRANSBEYQZKFY-UHFFFAOYSA-N dodecanoic acid;propane-1,2-diol Chemical compound CC(O)CO.CCCCCCCCCCCC(O)=O LLRANSBEYQZKFY-UHFFFAOYSA-N 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229940035423 ethyl ether Drugs 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 229940013317 fish oils Drugs 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- UHUSDOQQWJGJQS-UHFFFAOYSA-N glycerol 1,2-dioctadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(CO)OC(=O)CCCCCCCCCCCCCCCCC UHUSDOQQWJGJQS-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- 230000034659 glycolysis Effects 0.000 description 1
- 239000003979 granulating agent Substances 0.000 description 1
- 229940087559 grape seed Drugs 0.000 description 1
- 239000008169 grapeseed oil Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000005534 hematocrit Methods 0.000 description 1
- 208000014951 hematologic disease Diseases 0.000 description 1
- 230000002949 hemolytic effect Effects 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- 208000016036 idiopathic nephrotic syndrome Diseases 0.000 description 1
- 238000003018 immunoassay Methods 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 229940125721 immunosuppressive agent Drugs 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- TYQCGQRIZGCHNB-JLAZNSOCSA-N l-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(O)=C(O)C1=O TYQCGQRIZGCHNB-JLAZNSOCSA-N 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 150000002889 oleic acids Chemical class 0.000 description 1
- 125000001117 oleyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 229940006093 opthalmologic coloring agent diagnostic Drugs 0.000 description 1
- 210000004789 organ system Anatomy 0.000 description 1
- 238000002103 osmometry Methods 0.000 description 1
- QUANRIQJNFHVEU-UHFFFAOYSA-N oxirane;propane-1,2,3-triol Chemical compound C1CO1.OCC(O)CO QUANRIQJNFHVEU-UHFFFAOYSA-N 0.000 description 1
- 239000002540 palm oil Substances 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000010773 plant oil Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 229940044519 poloxamer 188 Drugs 0.000 description 1
- 229920001281 polyalkylene Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 235000020777 polyunsaturated fatty acids Nutrition 0.000 description 1
- 231100000683 possible toxicity Toxicity 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229940063122 sandimmune Drugs 0.000 description 1
- 201000000306 sarcoidosis Diseases 0.000 description 1
- 201000004409 schistosomiasis Diseases 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 239000000779 smoke Substances 0.000 description 1
- 229940035044 sorbitan monolaurate Drugs 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 235000019337 sorbitan trioleate Nutrition 0.000 description 1
- 229960000391 sorbitan trioleate Drugs 0.000 description 1
- 239000001589 sorbitan tristearate Substances 0.000 description 1
- 235000011078 sorbitan tristearate Nutrition 0.000 description 1
- 229960004129 sorbitan tristearate Drugs 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 206010043554 thrombocytopenia Diseases 0.000 description 1
- 229940042585 tocopherol acetate Drugs 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 150000005691 triesters Chemical class 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229940045136 urea Drugs 0.000 description 1
- 229940116269 uric acid Drugs 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 208000018464 vernal keratoconjunctivitis Diseases 0.000 description 1
- 239000010497 wheat germ oil Substances 0.000 description 1
Classifications
-
- 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
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- 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
Description
4 1 1 c 100-7429 NOVEL CYCLOSPORIN GALENIC FORMS The present invention
relates to novel galenic formulations comprising a cyclosporin as active ingredient.
The cyclosporins comprise a class of structurally distinctive, cyclic, poly-N-methylated endecapeptides, commonly possessing pharmacological, in particular immunosuppressive, anti-inflammatory and/or anti-parasitic activity. The first of the cyclosporins to be isolated was the naturally occurring fungal metabolite Ciclosporin or Cyclosporine, also known as cyclosporin A and commercially available under the Registered Trade Mark SANDIMMUNR or SANDIMMUNEI. Ciclosporin is the cyclosporin of formula A.
-MeBmt-aAbu-Sar-MeLeu-Val-MeLeu-Ala-(D)Ala-HeLeu-MeLeu-MeVal 1 2 3 4 5 6 7 8 9 10 11 (A) wherein -MeBmt- represents the N-methyl-(4R)-4-but-2E-en-l-yl-4methyl- (Qthreonyl residue of formula B A 100-7429 c CH3 1 47 1 r X CH2 1 HO (R) CH CH (R) CH3 1 -N-CH-CO- 1 (S) CH3 (B) in which -x-y- is -CH=CH- (trans).
As the parent of the class Ciclosporin has so far received the most attention. The primary area of clinical investigation for Ciclosporin has been as an immunosuppressive agent, in particular in relation to its application to recipients of organ transplants, e.g. heart, lung, combined heart-lung, liver, kidney, pancreatic, bone-marrow, skin and corneal transplants and, in particular, allogenic organ transplants. In this field Ciclosporin has achieved a remarkable success and reputation.
At the same time, applicability of Ciclosporin to various autoiMmune diseases and to inflammatory conditions, in particular inflammatory conditions with an aetiology including an autoimmune component such as arthritis (for example rheumatoid arthritis, arthritis chronica progrediente and arthritis deformans) and rheumatic diseases, has been intensive and reports and results in vitro, in animal models and in clinical trials are vide-spread in the literature. Specific auto-immune diseases for which Ciclosporin therapy has been proposed or applied include, autoimmune hematological disorder (including e.g. hemolytic anaemia, aplastic anaemia, pure red cell anaemia and idiopathic thrombocytopaenia), systemic lupus erythematosus,
A C_ 100-7429 polychondritis, sclerodoma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, psoriasis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (including e.g. ulcerative colitis and CrohnIs disease) endocrine opthalmopathy, Graves disease, sarcoidosis, multiple sclerosis, primary billiary cirrhosis, juvenile diabetes (diabetes mellitus type I), uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or minimal change nephropathy).
Further areas of investigation have been potential applicability as an anti-parasitic, in particular anti-protozoal agent, with possible uses suggested including treatment of malaria, coccidiomycosis and schistosomiasis and, yet more recently, use in cancer therapy, e.g. as an agent for reversing or abrogating resistance to other anti-neoplastic or cytostatic therapy.
Since the original discovery of ciclosporin, a wide variety of naturally occurring cyclosporins have been isolated and identified and many further non-natural cyclosporins have been prepared by total- or semi-synthetic means or by the application of modified culture techniques. The class comprised by the cyclosporins is thus now substantial and includes, for example, the naturally occurring cyclosporins A through Z [e.f. Traber et al. 1, Helv. Chim. Acta. 60, 1247-1255 (1977); Traber et al. 2, Helv. Chim. Acta. 65 no. 162, 1655-1667 (1982); Kobel et al., Europ. J. Applied Microbiology and Biotechnology 14, 273-240 (1982); and von Wartburg et al. , Progress in Allergy, 38, 28-45 (1986)1, as well as various non-natural cyclosporin derivatives and artificial or synthetic cyclosporins Including the so called dihydro-cyclosporins [in which the moiety -x-y- of the -MeBmt- residue (Formula B above) is saturated to give -x-y- - CH2-CH2-1; derivatised cyclosporins (e.g. in which a further substituent is introduced at the a-carbon atom of the sarcosyl residue at the 3position of the cyclosporin molecule); cyclosporins in which the -MeBmtresidue is present in isomeric form (e.g. in which the configuration across positions 61 and 71 of the -MeBmt- residue is cis rather than trans); c 100-7429 and cyclosporins wherein variant amino acids are incorporated at specific positions within the peptide sequence, employing e.g. the total synthetic method for the production of cyclosporins developed by R. Venger - see e. g. Traber 1, Traber 2 and Kobel loc. cit.; U.S. Patents Nos. 4 108 985, 4 210 581 and 4 220 641; European Patent Publication Nos. 0 034 567, 0 056 782 and 0 296 122; International Patent Publication No. WO 86102080; Venger 1, Transp. Proc. 15, Suppl. 1:2230 (1983); Venger 2, Angew. Chem. Int. Ed., 24, 77 (1985); and Venger 3, Progress in the Chemistry of Organic Natural Products-50, 123 (1986).
The class comprised by the cyclosporins thus now includes, for example, [Thr12-, [Val]2-, [Nva]2- and [Nva]2[Nva]sCiclosporin (also known as cyclosporins C,D, G and M respectively), [31-0-acyl-MeBmt]l-Ciclosporin (also known as cyclosporin A acetate), [Dihydro-MeBmt]l-[Val]2Ciclosporin (also known as dihydro-cyclosporin D), [31-Desoxy-31-oxoMeBmt]l[Val]2- and -[Nva]2-Ciclosporin, [(D)Fluoromethyl-Sar]3Ciclosporin, [(D)Ser]8-Ciclosporin, [MeIleIll-Ciclosporin, [(D)MeVall"Cielosporin (also known as cyclosporin H), [MeAla]6-Ciclosporin, [(D)Pro]3-Ciclosporin and so on.
[In accordance with now conventional nomenclature for cyclosporins, these are defined by reference to the structure of Ciclosporin (i.e. Cyclosporin A). This is done by first indicating the amino acid residues present which differ from those present in Ciclosporin (e.g. 11[(D)Proj311 to indicate that the cyclosporin in question has a -(D)Prorather than -Sar- residue at the 3-position) and then applying the term 11Ciclosporinll to characterise remaining residues which are identical to those present in Ciclosporin. Individual residues are numbered starting with the residue -MeBmt-, -dihydro-MeBmt- or its equivalent in position 1. 1 Very many of these further cyclosporins exhibit comparable pharmaceutical utility to Ciclosporin or more specific utility, for example activity particularly in reversing tumor resistance to cytostatic therapy, and proposals for their application as therapeutic agents abound in the literature.
1 4 c 100-7429 Despite the very major contribution which Ciclosporin has made, in particular to the areas of organ transplant and the therapy of autoimmune diseases, difficulties encountered in providing more effective and convenient means of administration as well as the reported occurrence of undesirable side reactions, in particular nephrotoxic reaction, have been obvious serious impediments to its wider use or application.
The cyclosporins are characteristically highly hydrophobic. Proposed liquid formulations, e.g. for oral administration of cyclosporins, have hitherto been based on the use of oils in conjunction with solvent systems comprising, e.g. ethanol and Labrafils and equivalent excipients as carrier media. Thus the commercially available Ciclosporin drink- solution employs ethanol and olive oil as carrier medium in conjunction with Labrafil as co-solvent - see e.g. US patent no. 4,388,307. Use of the drink-solution and similar compositions as proposed in the art is however accompanied by a variety of difficulties.
First, adoption of oil based systems hitherto has required the use of high ethanol concentrations to maintain solubility. Use of ethanol is in itself inherently undesirable, in particular where administration to children is foreseen. In addition, evaporation of the ethanol, e.g. from encapsulated forms, or other forms (e.g. when opened) results in development of a precipitate. Where such compositions are presented in e. g. soft gelatin encapsulated form, this particular difficulty necessitates packaging of the encapsulated product in an air-tight compartment, for example an air-tight blister or aluminium-foil blister package or container. This in turn renders the product both bulky and more expensive to produce The storage characteristics of such formulations are not ideal.
Use of such dosage forms is also characterised by extreme variation in required patient dosaging. In order to achieve effective immunosuppressive therapy, cyclosporin blood or blood serum levels have to be maintained within in a specified range. This range in turn can vary, depending on the particular condition being treated, e.g. whether therapy is to prevent transplant rejection or for the control 6 - c 100-7429 of an autoimmune disease or condition, and on whether or not alternative immunosuppressive therapy is employed concomitantly with cyclosporin therapy. Experience shows however that, e.g. employing the available Ciclosporin drink solution, daily dosages needed to achieve required blood serum levels vary considerably from individual to individual and even for a single individual at different times. For this reason it is necessary to monitor blood/blood-serum levels of patients receiving Ciclosporin therapy at regular and frequent intervals in order that the daily dosage taken may be adjusted-to maintain blood/blood-serum levels within the required range. Monitoring of blood/blood-serum. levels, which is generally performed by RIA or equivalent immunoassay technique, e.g. employing monoclonal antibody based technology, has to be carried out for each patient receiving Ciclosporin therapy on a regular basis. This is inevitably time consuming and inconvenient and adds substantially to the overall cost of therapy.
It is also the case that blood/blood-serum cyclosporin levels achieved using available dosage systems exhibit extreme variation between peak and trough levels. That is, for each patient, effective cyclosporin levels in the blood vary widely between administration of individual dosages. This variation in patient response has been found to be attributable to a significant extent to variation in the availability of naturally occurring surfactant components, e.g. bile acids and salts, within the gastro-intestinal tract of the subject treated. For galenic formulations for cyclosporins hitherto known in the art, the presence of such natural surfactants in sufficient quantity is required if satisfactory resorption is to be achieved. However the availability of such surfactants in the gastro-intestinal tract inevitably varies from subject to subject and in individual subjects with time.
Apart from the unsatisfactory nature of such inconsistancy in therapy, this also means that individual patients must be monitored on each occasion within a relatively narrow time-window, to ensure, e.g. that a peak level is not inadvertantly recorded as a high response to dosage.
C' Beyond all these very evident practical difficulties lies the occurrence of undesirable side reactions already alluded to, observed employing available oral dosage forms.
Several proposals to meet these various problems have been suggested in the art, including both solid and liquid oral dosage forms. An overriding difficulty has however remained the inherent insolubility of the cyclosporins, e.g. Ciclosporin, in aqueous media and hence provision of a dosage from which can contain cyclosporins in sufficiently high concentration to permit convenient use and yet meet the required criteria in terms of bioavailability, e.g. enabling effective resorption from the stomach or gut lumen and achievement of consistent and appropriately high blood/blood-serum levels.
As already noted, current commercial oral dosage forms for Ciclosporin are disclosed and claimed, e.g. in US patent no. 4,388,307. The early phase of this development is reflected in Swiss patent application no. 8634/78-8 which serves as a priority document to this patent. This application is directed to galenic formulations comprising Ciclosporin as active ingredient together with a carrier medium comprising anyone or more of the following components:
sesame oil; ii) a non-ionic tenside, e.g. Tween 80, Cremophore EL, 40 or 60 or lecithins; iii) a trans-esterified non-ionic triglyceride, e.g. Labrafil; iv) mixtures of a lecithin (e.g. Epikuron), Ingredients (iii) and ethyloleate; v) neutral oils, e.g. saturated C&_12triglycerides such as Miglyol 812; and vi) mono- and/or di-glycerides such as glycerol monooleate, glycerol monostearate and glycerol distearate.
In the text and examples: (i) is described for use alone, for oral or parenteral administration; (ii) are described for use in combination with ethanol for oral or parenteral administration and in combination with components (v) for parenteral application; (iii) are described for use alone and in conjunction with a vegetable oil and, C' 100-7429 additionally, ethanol for oral or parenteral administration; (iv) is described in terms of the defined combination with possible further additives, for example conserving agents, for oral administration; (v) are described for use in combination with solvents such as ethanol, benzoic acid benzyl ester, 1,2-butyleneglycol-1-methyl ether and components (iii) (Labrafil) as well as in combination with components (ii) as set forth above, in particular for parenteral administration; and (vi) are described for use alone or in combination with thickening agents such as aerosil or cellulose for oral administration in encapsulated or pelleted form. No specific proposal is made for the combination of components (vi) [mono-/di-glycerides] with any other component (i) to (vi), or vice versa.
In the patent application which matured as US patent no. 4,388,307, the focus of development set out in the above Swiss application is concentrated on compositions comprising cyclosporins as active ingredient, together with a carrier medium comprising one or more of components (iii) [Labrafils etc.], (v) [neutral oils] and (vi) [mono-/di-glycerides, in particular stearic or oleic mono/di-glycerides, especially glycerol monooleate]. In relation to oral dosage forms, use of co-solvents, ethanol and vegetable oils such as olive oil and corn oil, is preferred. Components (v) are specifically indicated as preferred in relation to parenteral, dosage forms. Components (vi) are proposed for use with lecithins, optionally together with components (iii) in orally administered aqueous or aqueous/ethanolic emulsions.
Belgian Patent no. 895 724, which relates primarily to the use of [dihydro-MeBmtll-[Val]2-Ciclosporin (or dihydro-cyclosporin D) in the treatment of multiple sclerosis, also describes two oral formulations suitable for the administration of this particular compound. Both of these are based on the commercial Ciclosporin (Sandimmunll) drink- solution, with adaptation to suit the particular cyclosporin active ingredient. The first comprises 5-10% [Dihydro-MeBmt]'-[Val]2-Ciclosporin, 10-12% ethanol, 30-40% Maisine, ca. 4% Cremophore and 51-30% Labrafil (i. e. to 10OX). This corresponds to the composition of the SandimmunR drink- solution, but with the replacement of the natural vegetable oil component with 4 C 100-7429 Maisine and introduction of a minor pecentage of the tenside Cremophore. Maisine is a trans-esterification product of corn oil with glycerol, the more precise composition of which is described hereinafter. It comprises corn oil derived triglycerides and mono-/di-glycerides in the ratio ca. 1:8 p.p.w (tri-:mono-/di-glycerides). The ratio of cyclosporin: tenside in the disclosed composition is ca. 1:0.4-0.8, and the ratio of cyclosporin: triglycerides: mono-/di-glycerides is ca. 1:0.4-0.9:2.6-7.1. No proposal is made for possible increase in the tenside componentnor for any means of avoiding the use of Labrafil or ethanol components as cosolvents.
The second disclosed composition comprises: 15-25% [DihydroMOmtJ1-[Val]2Ciclosporin, 2-5% ethanol, 40-60% Maisine and 10-40% Imwitor 742, a coconut oil mono-glyceride product comprising >45% monoglycerides with additional di- and tri-glyceride components. Again, the use of ethanol is not avoided and no proposal is made for incorporation of any tenside component.
Australian patent application no. 87 335122 discloses the use of tensides belonging to the group comprising polyethoxylated castor oils, polyethoxylated hydrogenated castor oils and polyethoxylated fatty acids derived from castor oil or hydrogenated castor oil, such as Cremophores, Myrj, and Nikkol HCO-60 as solubilizers for the incorporation of difficultly soluble pharmaceutical agents into controlled release systems, such as hydrophilic gel systems. Difficultly soluble pharmaceuticals recited include Ciclosporine, though no example of the application of the system to cyclosporins is given. Nor is there any teaching for the use of the recited solubilizers/tensides in conjunction with simple fatty acid mono-, dior tri-glycerides.
In accordance with the present invention, it has now surprisingly been found that pharmaceutical compositions comprising cyclosporins, in particular Ciclosporin, an active ingredient, which meet or substantially reduce difficulties in dosaging hitherto encountered in the art, e.g. as discussed above, can be achieved by the use of carrier systems comprising fatty acid tri-glycerides and C 100-7429 mono-/di-glycerides in combination and in conjunction with a hydrophilic tenside. In particular, it has been found that, employing the defined carrier systems, it is possible to obtain oil-based compositions, which are not aqueous emulsions, and which do not require the presence of additional solvents, co-solvents or solubilizers, for example ethanol or Labrafils or the like, and which exhibit high stability as well as improved bioavailability characteristics as compared with known cyclosporin/fatty acid triglyceride/solvent/co-solvent systems, for example, the knownSandimmunR drink-solution. In a specific aspect the present invention provides for oil-based pharmaceutical compositions, in particular oil-based pharmaceutical compositions other than aqueous emulsions, which are free or substantially free of ethanol.
In particular, it has been found that compositions in accordance with the present invention enable effective cyclosporin dosaging with concomitant enhancement of resorption/bioavailability levels, and/or reduced variability in resorption/bioavailability levels, achieved both for individual patients receiving cyclosporin therapy as well as between individuals. In particular it has surprisingly been found that the compositions of the invention enable resorption of cyclosporins in a manner that is independent, or of substantially reduced dependency, upon the relative availability of natural surfactant materials, e.g. bile acids or salts, in the gastro-intestinal tract of the subject treated. By application of the teachings of the present invention, cyclosporin dosage forms are obtained providing reduced variability in achieved cyclosporin blood/blood serum levels between dosages as well as between individuals. The invention thus enables reduction of cyclosporin dosage levels required to achieve effective therapy. In addition, it permits closer standardisation as well as optimisation of on-going daily dosage requirements for individual subjects receiving cyclosporin therapy as well as for groups of patients undergoing equivalent therapy.
By closer standardisation of individual patient dosaging rate and blood/blood-serum level response, as well as dosaging and response parafor patient groups, monitoring requirements may be reduced, thus substantially reducing the cost of therapy.
C 100-7429 By reduction of required cyclosporin dosaging/standardisation of achieved bio-availability characteristics, the present invention also provides a means which may permit reduction in the occurrence of undesirable side- effects, in particular nephrotoxic reaction, in patients undergoing cyclosporin therapy.
In addition, the compositions of the invention exhibit improved stability on storage as compared with compositions based on the use of ethanol or equivalent alkanols and are, in particular, better adapted, e.g. for presentation in capsule, e.g. hard or soft gelatin capsule, form. Compositions in accordance with the findings of the present invention which are free or substantially free of ethanol have the particular advantage of eliminating or substantially reducing packaging difficulties, for example as hereinbefore discussed, e.g. in relation to the packaging of soft gelatin encapsulated forms.
In accordance with the present invention there is provided, in its broadest aspect:
A. A pharmaceutical composition comprising:
a) a cyclosporin as active ingredient in a carrier medium comprising b) a fatty acid triglyneride, c) a glycerol fatty acid partial ester or propylene glycol (e.g.
1,2-propylene glycol) or sorbitol complete or partial ester, and a tenside having a hydrophilic-lipophilic balance (M) of at least 10; with the proviso that, when components (b) and (c) consist or consist essentially of the individual components of a trans-esterification product of a vegetable oil with glycerol, said composition:
1 is free or substantially free of ethanol; or ii) comprises Ciclosporin or [Nva)2-Ciclosporin as component (a); or iii) comprises components (a) and (d) in a ratio of 1: at least 1 P.P.W.
c 100-7429 Provisos (i) to (M) above are not mutually exclusive. The present invention thus embraces compositions meeting the criteria of any one or more of said provisos.
The term "pharmaceutical composition" as used herein and in the accompanying claims is to be understood as defining compositions of which the individual components or ingredients are themselves pharmaceutically acceptable, e.g. where oral administration isforeseen, acceptable for oral use or, where topical administration is foreseen, topically acceptable.
Component (a) is suitably present in the compositions of the invention in an amount of from ca. 2-20%, more preferably ca. 5-15% based on the total weight of components (a) to (d) inclusive. Component (a) may be any therapeutically applicable cyclosporin, e.g. as hereinbefore indicated. The preferred component (a) in the compositions of the invention is Ciclosporin. A further preferred component (a) in the compositions of the invention is [Nva]2-Ciclosporin, also known as cyclosporin G.
Examples of suitable components (d) in the compositions of the invention are:
d. 1 Reaction products of a natural or hydrogenated castor oil and ethylene oxide. Such products may be obtained in known manner, e.g. by reaction of a natural or hydrogenated castor oil with ethylene oxide, e.g. in a molar ratio of from about 1:35 to about 1:60, with optional removal of the polyethyleneglycol component from the product, e.g. in accordance with the methods disclosed in German Auslegeschriften 1,182,388 and 1,518,819. Especially suitable are the various tensides available under the trade name Cremophor. Particularly suitable are the products Cremophor RH 40 having a saponification number of ca. 50-60, an acid number <l, an iodine number <l, a water content (Fischer) <2%, an nD60 of ca. 1,453 1,457 and an HLB of ca. 14 - 16; Cremophor RE 60 having a saponification number of ca. 40 - 50, an acid number <l, an iodine number <l, a water content (Fischer) 4.5-5.5%, and an nD 25 of ca.
c 100-7429 1.453-1.457 and an HLB of ca. 15-17; and Cremophor EL having a molecular weight (by steam osmometry) of ca. 1630, a saponification number of ca. 65-70, an acid number of ca. 2, an iodine number of ca. 28-32 and an nD 25 of ca. 1.471. Also suitable for use in this category are the various tensides available under the trade name Nikkol, e.g. Nikkol HCO-40 and HCO-60. The said product Nikkol HCO-60 is a reaction product of hydrogenated castor oil and ethylene oxide exhibiting the following characteristics: acid value ca. 0.3; saponification number of ca. 47.4; hydroxy value of ca. 42.5; pH (5%) of ca. 4.6; color APHA - ca. 40; m.p. = ca. 36.OOC; freezing point - ca. 32.4OC; H20 content (%, KF) - 0.03.
d.2 Polyoxyethylene-sorbitan-fatty acid esters, e.g. mono- and tri-lauryl, palmityl, stearyl and oleyl esters, e.g. of the type known and commercially available under the trade name Tween (c.f. Fiedler, I'Lexikon der Hilfstoffell, 2nd revised and expanded edition (1981), Vol. 2, p.p. 972-975) including the products Tween 20 [polyoxyethylene(20)sorbitanmonolauratel, 40 [polyoxyethylene(20)sorbitanmonopalmitate], 60 [polyoxyethylene(20)sorbitanmonostearate], 65 [polyoxyethylene(20)sorbitantristearate], L5 [polyoxyethylene(20)sorbitantrioleate], 21 [polyoxyethylene(4)sorbitanmonolaurate], Ll [polyoxyethylene(5)sorbitanmonooleate]. Especially preferred products of this class for use in the compositions of the invention are the above products Tween 40 and Tween 80.
d.3 Polyoxyethylene fatty acid esters, for example polyoxyethylene stearic acid esters of the type known and commercially available under the trade name Myrj (c.f. Fiedler, loc. cit., 1, p.228); an especially preferred product of this class for use in the compositions of the invention is the product Myrj 52 having a D25. ca. 1.l., m.p. - ca. 40- 44% an ELB value ca. 16.9., an acid value = ca. 0-1 and a saponification no. - ca. 25-35.
d.4 Polyoxyethylene-polyoxypropylene co-polymers and block C- 100-7429 co-polymers, e.g. of the type known and commercially available under the trade names Pluronic, Emkalyx and Poloxamer (c.f. Fiedler, loc. cit., 2, p.p. 720-723). An especially preferred product of this class for use in the compositions of the invention is the product Pluronic F68, having an m.p. = ca. 520C and a molecular weight of ca. 6800-8975. A further preferred product of this class for use in the compositions of the invention is the product Poloxamer 188.
d.5 Diotylsuccinate or di-[2-ethylhexyll-succinate (c.f. Fiedler, loc. cit., 1, p.p. 307).
d.6 Phospholipids, in particular lecithins (c.f. Fiedler, loc. cit., 1, p. p. 559-560). Lecithins suitable for use in the compositions of the invention include, in particular, soya bean lecithins.
d.7 Propylene glycol mono- and di-fatty acid esters such as propylene glycol dicaprylate (also known and commercially available under the trade name Miglyol 840), propylene glycol dilaurate, propylene glycol hydroxystearate, propylene glycol isostearate, propylene glycol laurate, propylene glycol ricinoleate, propylene glycol stearate and so forth (c.f. Fiedler, loc. cit., 2, p.p. 760 et seq.).
d.8 Sodium lauryl sulfate.
The ratio of components (a):(d) in the compositions of the invention is suitably of the order of 1:1 to 25 p.p.w., more preferably 1:1.25 to 20 p. p.w., yet more preferably 1:13 to 8 or 10 p.p.w, e.g. ca. 1:2 to 5 p.p.w.. Most preferably the ratio of components (a):(d) is 1: at least 2 p.p.w. Component (a) is thus suitably present in the compositions of the invention in an amount e.g. of from ca. 20-50%, more preferably 25-40%, by weight based on the total weight of components (a) and (d).
As will be apparent from definition (A) above components (b) and (c) in the compositions of the invention may comprise or consist or consist essentially of the individual components (b) and (c) of a - is - C 100-7429 single ingredient, e.g. single material or product. Examples of ingredients comprising both components (a) and (b) suitable for use in the present invention include for example known mixed fatty acid triglyceride and fatty acid mono-/di-glyceride products. Suitable products of this type include, in particular, transesterification products of vegetable oils [saturated, including hydrogenated, or non-saturated], for example almond oil, groundnut oil, palm oil or, preferably, corn oil, with glycerol, propylene glycol (e.g. 1,2-propylene glycol) or sorbitol.
Such trans-esterification products are generally obtained by heating of the vegetable oil, e.g. corn oil, with glycerol, propylene glycol orsorbitol, at high temperature under an inert atmosphere with continuous agitation, e.g. in a stainless steel reactor, to effect transesterification, e.g. glycerolysis, glycolysis or sorbitolysis.
Trans-esterification products suitable for use in accordance with the invention thus comprise mixtures of mono-, di- and tri-glycerides (i.e. glycerol mono-, di- and tri-esters) with generally minor amounts of free glycerol.
Where ingredients comprising both components (b) and (c) for use in the invention are obtained by trans-esterification of a vegetable oil with propylene glycol or sorbitol they will also contain minor amounts of free propylene glycol or sorbitol. They will also contain substantial amounts of esters thereof, e.g., in the case of trans-esterification products with propylene glycol, propylene glycol mono- and di-esters and, in the case of trans-esterification products with sorbitol, sorbitol mono-, di- and tetra-esters.
The amount of triglyceride present in ingredients comprising both components (b) and (c) for use in the invention will preferably be substantial, e.g. in excess of 5%, suitably from 7.5 to 12% or more by weight based on the total weight of 1(b)+(c)] in said ingredient.
The amount of free glycerol plus any free propylene glycol or sorbitol present in ingredients comprising both components (b) and (c) for use in the invention is preferably less than 10%, more preferably less c than 5%, most preferably 1 to 2X or less based on the total weight of said ingredient. The amount of mono-glyceride present in ingredients comprising both components (b) or (c) for use in the invention is preferably ca. 25 to 50%, more preferably ca. 30 to 45%, by weight based on the total weight of said ingredient.
When a trans-esterification product of a vegetable oil, e.g. corn oil, and glycerol is employed as ingredient providing [(b)+(c)] the amount of free glycerol present in said product is preferably less than 10%, more preferably less than 5%, most preferably less than ca. 4% by weight. The amount of mono-glyceride present is preferably about 30 or 35 to 50% by weight, more preferably about 35 or 40 to 45% by weight. The amount of diglyceride present is preferably less than about 60%, suitably less than 40%, by weight. The amount of tri-glyceride present is preferably about 10% by weight, e.g. ca. 7.5 to 14% (all percentages being based on the total weight of said product). The ratio of components (b):(c) in the defined trans-esterification products is thus suitably of the order of ca. 1:8 to ca. 1:9 p.p.w.
When a trans-esterification product of a vegetable oil, e.g. corn oil, and sorbitol is employed as ingredient providing [(b)+(c)l, the amount of free glycerol plus free sorbitol present in said product is preferably less than 5% by weight, more preferably ca. 1 to 2% by weight. The amount of mono-glyceride present is preferably ca. 30 to 40% by weight, more preferably ca. 35% by weight (all percentages being based on the total weight of said product).
Particularly suitable trans-esterification products set forth above suitable for use in accordance with the present invention are transesterification products of corn oil and glycerol, for example as commercially available under the trade name Maisine. Such products are comprised predominantly of linoleic and oleic acid mono-, di- and triglycerides together with minor amounts of palmitic and stearic acid mono-, di- and tri-glycerides (corn oil itself being comprised of ca. 56% by weight linoleic acid, 30% oleic acid, ca. 10% palmitic and ca. 3X stearic acid constituents). Physical characteristics for Maisine [available from the company Etablissements Gattefoss6, of 36, c 100-7429 Chemin de Genas, P.O.Box 603, 69804 Saint-Priest, Cedex (France)] are: approximate composition free glycerol monoglycerides diglycerides triglycerides free oleic acid content. - ca. 1% 10% max. (typically 3.9-4.9% or, in more recent batches, ca. 0.2%) ca. 40X (typically 41-44.1% or, in more recent batches, ca. 38%) ca. 40% (or, in more recentbatches, ca. 46%) ca. 10% (or, in more recent batches, ca. 12%) Further physical characteristics for Maisine are: acid value - max. ca. 2, iodine no. - ca. 85-105t saponification no. - ca. 150-175, mineral acid content = 0.
The fatty acid content for Maisine is typically: palmitic acid - ca. 11%; stearic acid - ca. 2.5%; oleic acid - ca. 29%; linoleic acid ca. 56%; others - ca. 1.5%.
Further trans-esterification products as set forth above suitable for use in accordance with the present invention are trans-esterification products of corn oil and sorbitol, for example as commercially available under the trade name Sorbito Glycerides from the company Etablissements Gattefossd, for example Sorbito Glycerides WL 713, which has the following approximate composition:
Product: trans-esterification product of ca. 2 Mol corn oil and ca. 1 Mol sorbitol:
Approximate composition - ca. 1 to 2% free glycerol free sorbitol monoglycerides - ca. 35% plus: di- and tri-glycerides and sorbitol mono-, di-, tri- and tetra- esters.
c 100-7429 Color (Echelle Garner) = <8. Highly soluble in ethanol and chloroform/slightly soluble in ethyl-ether/insoluble in H20. Acid no. = C; saponification no. = ca. 160-185; iodine no. = ca. 110-140.
In the case of compositions in accordance with the invention of which the components (b) and (c) consist or consist essentially of the individual components (b) and (c) of a single ingredient, e.g. of which the components (b) and (c) are comprised entirely or substantially entirely of trans-esterification products as described above, the ratio of (a):[(b)+(c)] is suitably of the order of " 1:035-35, preferably 1:1-25 p. p.w., more preferably the ratio is of the order of 1:3-10, especially ca. 1:6 p.p.w.. Where only ingredients comprising both (b) and (c) are employed, f(b)+(c)] are thus suitably present in the compositions of the invention in an amount of from ca. 15-70%, more preferably ca. 20-50% by weight, based on the total weight of components (a) to (d) inclusive.
In accordance with the foregoing the present invention also provides, in a specific embodiment:
B. A pharmaceutical composition comprising:
a) a cyclosporin as active ingredient in a carrier medium comprising:
b+c) a trans-esterification product of a vegetable oil and glycerol, propylene glycol or sorbitol, and d) a tenside having an HLB of at least 10; with the proviso that, when said composition comprises no other component (b) or (c) as defined under (A) above, said composition:
i) ii) is free or substantially free of ethanol; or comprises Ciclosporin or [Nva]2Ciclosporin as component (a); or iii) comprises components (a) and (d) in a ratio of 1: at least 1 P-P-W.
To enable combination of components (b) and (c) in the compositions of the invention in preferred proportion as hereinafter described, component (b) in the compositions of the invention will preferably z C. 1 100-7429 comprise at least one ingredient definable as a fatty acid triglyceride as such, e.g. material or product, which is, or which consists or consists essentially of components (b) as hereinbefore defined (i.e. fatty acid triglycerides), e.g. which comprises at least 75%, preferably at least 90%, more preferably at least 95% by weight of components (b). Component (c) in the compositions of the invention will also preferably comprise at least one ingredient which is definable as a glycerol fatty acid partial ester or propylene glycol or sorbitol complete or partial ester as such, e.g. which is or-which consists or consists essentially of components (c) as hereinbefore defined, e.g. which comprises at least 75%, preferably at least 90%, more preferably at least 95% by weight of said components (c).
More preferably components (b) and (c) in the compositions of the invention will comprise separate ingredients combinable in selected proportion (b):(c) as hereinafter described. With respect to the components (b) and (c), the compositions of the invention will thus most preferably comprise a bi-partite combination of ingredients complying with definition (b) and of ingredients complying with definition (c), e.g. a combination of a first ingredient or ingredients consisting or consisting essentially of components (b) and of a second ingredient or ingredients consisting or consisting essentially of components (c).
Suitable components (b) include both saturated (including hydrogenated) and unsaturated fatty acid tri-glycerides, in particular animal or vegetable oils. The fatty acid constituents of components (b) suitably include, saturated or mono-, di- or poly-unsaturated acids having e.g. chain lengths of from 6 to 22 carbon atoms. Especially suitable for use in accordance with the invention are fatty acid triglycerides having a high content of unsaturated fatty acid constituents in particular mono-, diand poly-unsaturated fatty acids having at least 16 carbon atoms, preferably 18 carbon atoms or more, in particular having a high oleic, linoleic or linolenic fatty acid constituent content. Of particular interest are fatty acid triglycerides having a linoleic and/or linolenic acid constituent content of at least 45%, preferably at least 60% and up to 65 or 80%, e.g. where super-refined oils are used.
100-7429 A first group of fatty acid triglycerides suitable for use in accordance with the invention includes saturated C6-12 fatty acid vegetable oil triglycerides, e.g. caprylic-capric acid triglycerides. Examples of ingredients suitable as components (b) thus include fractionated vegetable oils, e.g. fractionated coconut oils such as are known and commercially available under the trade name Miglyol (c.f. Fiedler, loc. cit., 2, 615 and 616), including Higlyol 810, a fractionated coconut oil, caprylic-capric acid triglyceride having a molecular weight of ca. 520 and a fatty acid constitution m C6 max. ca. 2X, Ca ca. 65-75%, CIO ca. 25- 35%, C12 max. ca. 2%. Miglyol 810 has the following further physical characteristics: aD20 = 1.4490-1.4510, acid no. - max. 0.1, saponification no. - ca. 340-360, iodine value - max. 1. Especially preferred is Miglyol 812, a fractionated coconut oil, caprylic-capric acid triglyceride having a molecular weight of ca. 5-0, and a fatty acid constitution = C6 max. ca. 3%, Ca ca. 50-65%, CIO ca. 35-40%, C12 max. ca. 5%. Miglyol 812 has the following further physical characteristics: aD20. 1.4480-1.4500, saponification no. - ca. 330-345, iodine value = max. 1.
Further ingredients of similar class suitable for use as components (b) include those known and commercially available under the trade name Estasan, for example Estasan GT 8-60 and GT 8-65. Estasan GT 8-60 is a vegetable oil fatty acid triglyceride in which the fatty acid components are comprised chiefly of saturated C$_10fatty acids, in particular caprylic and capric acids. Fatty acid constitution caproic (C6) max. ca. 3%, caprylic (C&) max. ca. 50-65%, capric (C10) max. ca. 35-45%, lauric (C12) max. ca. 3%. Estasan GT 8-60 exhibits the following additional physical characteristics: saponification no. ca. 325-345, iodine no. max. ca. 1, acid value - max. ca. 0.1, 20 - ca. 1.448-1.451. Estasan GT 8- 65 is also a vegetable oil fatty acid triglyceride, comprised chiefly of saturated Ca-10fatty acids, in particular caprylic and capric acids. Fatty acid constitution caproic max. ca. 1%, caprylic min. ca. 65%, capric ca. 25-35%, lauric max. ca. 1%.
Yet further ingredients of this class are those known and commercially C 100-7429 available under the trade name Myritol, for example Myritol 318 [c.f. Fiedler, loc. cit., 1, p.p. 635-636]. Myritol 318 is a caprylic/ capric acid triglyceride having a saponification no. = ca. 340-350, an iodine no. = ca. 0.5 and an nD 20 - ca. 1.448-1.450.
Further ingredients suitable for use as components (b) include, e.g. vegetable oils such as corn oils, almond oils, kernel oils (for example apricot kernel oils), avocado oils, babassu oils, higher fatty acid coconut oils, primrose oils, grapeseed oils, menhaden oils., olive oils, orange roughy oils, peanut oils, safflower oils, sesame oils, soybean oils and wheat-germ oils as well as animal oils such as fish oils, e.g. fish liver oils, for example shark oils, and mink oils. Refined oils of any of the above types are of particular interest for use in accordance with the present invention, in particular refined plant oils, e.g. having the following approximate oleic/linoleic/linolenic acid constituent content:
OLEIC ACID LINOLEIC LINOLENIC EXAMPLE ACID ACID ca. 9% ca. 68% ca. 15% evening primrose ca. 27% ca. 64% grapeseed ca. 4% ca. 13% ca. 76% safflower ca. 5% ca. 40% ca. 47% sesame ca. 25% ca. 54% ca. 6% soybean ca. 14% ca. 58% ca. 8% wheat-germ Component (c) suitably comprises a glycerol fatty acid partial ester, i.e. a fatty acid mono- or di-glyceride, or acetylated derivative thereof. Ingredients suitable for use as component (c) will preferably be free or substantially free of any fatty acid triglyceride componentt e.g. contain less than 25%, preferably less than 10%, more preferably less than 5Xt e. g. less than 1 or 2% fatty acid triglycerides.
Components (c) suitable for use in the compositions of the invention include both symmetric mono- and di-glycerides (i.e. 0-monoglycerides and a,al-diglycerides) as well as assymmetric mono- and di-glycerides (i.e. amonoglycerides and a,O-diglycerides) and acetylated C.
100-7429 derivatives thereof. They also include both uniform glycerides (i.e. in which the fatty acid constituent is composed primarily of a single fatty acid) as well as mixed glycerides (i.e. in which the fatty acid constituent is composed of various fatty acids) and acetylated derivatives thereof.
The fatty acid constituent of components (c) may include both saturated and unsaturated fatty acids having a chain length of from 6 to 22 carbon atoms. Preferably the fatty acid constituent will predominantly comprise saturated or unsaturated fatty acids having a chain length of from 8 to 18 carbon atoms, in particular 8, 10 or 14 to 18, e.g. 16 or 18 carbon atoms. Especially suitable are mono- and di-glycerides in which the fatty acid constituent is comprised predominantly of one or more members selected from the group consisting of caprylic, capric, linolenic, palmitic, stearic and oleic acids.
Particularly preferred for use as components (c) are ingredients comprising mono- and di-glycerides, wherein the mono-/di-glyceride content is at least 50%, preferably at least 60%, more preferably at least 75% by weight, and acetylated derivatives thereof. Examples of appropriate ingredients for use as components (c) are:
c. 1 Fatty acid mono- and di-glycerides as commercially available under the trade name Imwitor (c.f. Fiedler, loc. cit., 1, p. 491), in particular: caprylic and capric acid mono- and di-glycerides such as Imwitor 742, which comprises at least 45% mono-glycerides as aforesaid and exhibits the following, additional characterising data - acid value - max. ca. 2%, iodine value - max. ca. 1.0, saponification no. - ca. 250-280, free glycerol content - max. ca. 2%; and stearic acid mono-glycerides such as Imwitor 191, which comprises at least 90% mono-glycerides as aforesaid and exhibits the following, additional characterising data - m.p. - ca. 63-660C, acid value - max. ca. 3, saponification no. ca. 160-170, iodine value max. ca. 3, free glycerol content max. ca. 2%, and Imwitor 960K which comprises 30-40% monoglycerides as aforesaid and exhibits the following, additional characterising data - m.p.
C 100-7429 rising from ca. 56 to ca. 60% saponification no. = ca. 155-170, acid value - max. ca. 3, iodine value = max. ca. 3, free glycerol content - max. ca. 4%.
c.2 Fatty acid mono- and di-glycerides as commercially available under the trade name Cutina (c.f. Fiedler, loc. cit., 1, P.P. 263 and 264): in particular palmitic and stearic acid mono- and di-glycerides such as Cutina MD-A, which comprises mono- and di-glycerides as aforesaid and exhibits the following characterising data - acid value - max. ca. 8, saponification no. - ca. 160-170; and stearic acid mono-glycerides such as Cutina GMS which comprises mono-glycerides as aforesaid and exhibits the following characterising data m.p. - ca. 54-60% acid value - max. ca. 2, saponification no ca. 162-173, iodine value = max. ca. 2.
c.3 Fatty acid mono-glycerides as commercially available under the trade name Myverol (c.f. Fledler, loc. cit., 2, 637), in particular C18 fatty acid, e.g. linolenic acid, mono-glycerides such as Myverol 18-92, which comprises at least 90% mono-glycerides as aforesaid and exhibits the following additional characterising data: acid value - max. ca. 3.0, diglyceride content = max. ca. 5%, free glycerol content = max. ca. 1.2%.
c.4 Fatty acid mono-glycerides as commercially available under the trade name Myvaplex (c.f. Fiedler, loc. cit., 2, 637), in particular stearic acid mono-glycerides such as those of the Myvaplex 600 series, e.g. Myvaplex 600P which comprises ca. 94-90% mono-glycerides as aforesaid and exhibits the following additional characterising data - m.p. - ca. 730C, density - ca. 0.92 g/CM3 at 801C.
c.5 Fatty acid mono-glycerides as commercially available under the trade name Estagel, for example Estagel G-18 which is comprised primarily of C16-1s fatty acid mono-glycerides in particular palmitic and stearic acid mono-glycerides. The cc-monoglyceride C' 100-7429 content of Estagel G-18 is min. ca. 40%. Further characterising data: acid value = max. ca. 2, saponification no. = ca. 162-173, iodine no. = max. ca. 3, free glycerol content = max. ca. 6%.
c.6 Acetylated fatty acid mono- and di-glycerides such as commercially available under the trade name Myvacet (c.f. Fiedler, loc. cit.,2, p.p. 636-637), in particular mono- and di-acetylated fatty acid monoglycerides, for example mono- and di-acetylated stearic acid monoglycerides such as: Myvacet 9-40 which has the following characterising data - aDsO - ca. 1.4468-1.4476, m.p. ca. 5% acid value = max. ca. 1.5, saponification no. ca. 375-385; and Myvacet 9-45 which has the following characterising data - %S0. ca. 1.4465-1.4475, m.p. ca. 8-12.4% acid value = ca. 1.5, saponification no. = ca. 375-385.
Further components (c) which are of particular utility, are mixed glycerol fatty acid partial esters and propylene glycol complete and partial esters, e.g. products comprising fatty acid mono- and di- glycerides and propylene glycol fatty acid mono- and di-esters. Examples of such components (c) include:
c.7 Fatty acid mono- and di-glycerides/propylene glycol fatty acid monoand di-esters as commercially available under the trade name Atmos [c.f. Fiedler, loc. cit., 1, p. 156], in particular Atmos 300 in which the fatty acid moieties are comprised principally of oleic acid residues and Atmos 150 in which the fatty acid moieties are comprised principally of stearic acid residues.
c.8 Fatty acid mono- and di-glycerides/propylene glycol fatty acid monoand di-esters as commercially available under the trade name Arlacel [c.f. Fiedler, loc. cit., 1, p.p. 143-1441 in particular Arlacel 186 in which the fatty acid moieties are comprised principally of oleic acid residues.
Components (b) and (c) are preferably present in the compositions of the invention in a ratio of about 1:0.02 to 3.0 p.p.w. More preferably C the ratio of components (b):(c) is of the order of 1:0A to 2.5 p.p.w., most preferably 1:0.25-1.25 p.p.w. When components (b) and (c) in the compositions of the invention comprise separate ingredients, e.g. as described above, the said ingredients will thus suitably be employed in the same relative ratios. The amount of components (b) in the compositions of the invention is thus suitably of the order of from 10- 50%, preferably 20-40% by weight, based on the total weight of components (a) to (d) inclusive, and the amount of components (c) in the compositions of the invention is suitably of the order of from 1-30%, preferably 10-25% by weight, based on the total weight of components (a) to (d) inclusive.
The ratio of components (a):(b) plus (c) in the compositions of the invention is suitably of the order of 1:0.5 to 40 p.p.w. Preferably, the ratio of (a):(b) plus (c) is about 1:1 to 35, more preferably about 1:1.5 to 30 p.p.w., most preferably about 1:2 to 6.
In accordance with the foregoing the present invention also provides C) A pharmaceutical composition as defined under A above comprising at least one ingredient which consists or consists essentially of, a component or components as defined under (b) above; D) A pharmaceutical composition as defined under A above comprising at least one ingredient which consists or consists essentially of a component or components as defined under (c) above; E) A pharmaceutical composition as defined under A above in which components (a) and (b) comprise separate ingredients.
The compositions of the invention may include further components, for example thickening agents, granulating agents, dispersing agents, flavouring and/or colouring agents or anti-microbial agents etc... as required. They may also include polymeric thickening agents to permit processing into a solid or semi-solid mass suitable for tabletting or forming into granules.
The compositions of the invention will suitably include anti-oxidants C 1 100-7429 to improve shelf-life, for example butyl-hydroxy-toluene (or BHT), butyl- hydroxy-anisole (or BRA), ascorbyl palmitate, ascorbic acid, citric acid or cc-tocopherol-acetate.
In particular the compositions of the invention will suitably comprise one or more stabilizors or buffering agents, e.g. to prevent degradation of component (a) during processing or on storage. Such stabilizors may include acid stabilizors such as citric acid, acetic acid, tartaric acid or fumaric acid as well as basic stabilizors such as potassium hydrogen phosphate, glycine, lysine, arginine or tris(hydroxymethyl)aminomethane.
Such stabilizors or buffer agents will appropriately be added in an amount sufficient to achieve or maintain a pH within the range of from about 5 to 7, more preferably between 6 and 7.
When components (b) and (c) in the compositions of the invention are comprised of a single ingredient which is the trans-esterification product of a vegetable oil with glycerol, the compositions of the invention will preferably be subject to proviso (i) as set forth under (A) above, i.e. they will be free or substantially free of ethanol. More preferably they will be free or substantially free of any further component serving as diluent or as a solvent medium for component (a).
While proviso (i) is applied above in a specific instance, compositions in accordance with the invention which are free or substantially free of ethanol are in general preferred. Compositions in accordance with the invention which are free or substantially free of any further component serving as diluent or as solvent medium for (a), are also, in general, preferred. In a yet further series of embodiments the present invention thus also provides:
F. A pharmaceutical composition as defined under any one of (A) to (E) above which is free, or substantially free, of ethanol; and G. A pharmaceutical composition as defined under any one of (A) to (E) above which is free or substantially free of any further 1 - 27 - 100-7429 C, component serving as diluent or as solvent medium for component (a).
Compositions as aforesaid suitably comprise less than 2%, more suitably from 0 to 0.5 or 1% by weight ethanol, based on the total weight of the component ingredients. Compositions as aforesaid suitably comprise less than 20%, more preferably less than 10%, e.g. from 0 to 2.5 or 5.0% by weight further components serving as diluent or as solvent medium for component (a). Specific compositions in accordance with the present invention are pharmaceutical compositions as defined under any one of (A) to (G) above consisting, or consisting essentially, of components (b), (c) and (d) as carrier medium for (a), i.e. exclusive of any thickening, granulating, dispersing, flavouring, colouring, stabilizing agents or the like excipients that may also be present, and which are present as additives to the carrier medium.
1 V 14- - f- I.
J_ 1 ' By components serving as diluents are in particular to be understood, components serving to reduce the viscositylincrease the fluidity of the compositions of the invention. By components serving as solvent medium for (a) are in particular to be understood co-solvents or other materials which enhance the solubility of components (a) in the compositions of the invention. Examples of such components are, in particular, solvent or diluent components having an HLB of less than 10, for example, trans- esterification products of natural vegetable oil triglycerides and polyalkylene polyols such as known and commercially available under the trade name Labrafil (c.f. Fiedler, loc. cit., 2, 539) and ethanol.
Compositions in accordance with the invention may be applied in dosage form suitable for administration by any appropriate means, e.g. in the form of creams, gels or the like for topical or occular administration, or in the form of granules, tablets, capsules or the like for oral administration or in a form suitable for intra-lesional application, e.g. in the treatment of psoriasis. Preferably however the compositions of the invention will be administered orally. In a preferred embodiment the invention accordingly provides a composition as hereinbefore defined in a form appropriate or adapted for oral administration, in particular in oral unit dosage form. Especially C 100-7429 suitable unit dosage forms for oral administration include encapsulated forms, e.g. soft or hard gelatin encapsulated forms.
Oral unit dosage forms in accordance with the invention will suitably comprise from 5 to 200 mg, more preferably from 20 to 100 mg, e.g. ca. 25, 50 or 100 mg component (a), e.g. for administration 2-5 x daily.
In addition to the foregoing the present invention also provides a process for the production of pharmaceutical compositions as hereinabove defined and described which process comprises intimately admixing components (a), (b), (c) and (d) thereof.
In a preferred aspect the present invention provides a process as aforesaid, which process comprises intimately admixing a component (a) with a first ingredient (b) which consists or consists essentially of one or more fatty acid triglycerides and a second ingredient (c) which comprises a glycerol fatty acid partial ester or propylene glycol or sorbitol complete or partial ester, or with a first ingredient (b) which comprises a fatty acid triglyceride and a second ingredient (c) which consists or consists essentially of one or more glycerol fatty acid partial esters andlor propylene glycol and/or sorbitol complete or partial esters, and with (d) a tenside having a hydrophilic-lipophilic balance of at least 10.
In a more preferred aspect the present invention provides a process as aforesaid, which process comprises intimately admixing a component (a) with a first ingredient (b) which consists or consists essentially of one or more fatty acid triglycerides, a second ingredient (c) which consists or consists essentially of one or more glycerol fatty acid partial esters and/or propylene glycol andlor sorbitol complete or partial esters, and (d) a tenside having a hydrophilic-lipophilic balance of at least 10.
The following examples are illustrative of the manufacture of compositions in accordance with the present invention:
EXAMPLE 1
INGREDIENT a) Cyclosporin (e.g. Ciclosporin) b) Miglyol 812 c) Myverol 18-92 d) Cremophore RH 40 100-7429 QUANTITY (mg) 50.00 100.00 100.00 50.00 (a)-(d) are intimately admixed in the indicated proportions-in conventional manner and the obtained mixture filled into soft or hard gelatin capsules each containing 50 mg Cyclosporin.
EXAMPLE 2
Soft or hard gelatine capsules each comprising the following indicated ingredients in the indicated amounts, are prepared analogously to Example 1:
INGREDIENT 2a a) b) c) d) Cyclosporin (e.g. Ciclosporin) Miglyol 812Imwitor 742 Cremophore RH 40 2b a) Cyclosporin (e.g. Ciclosporin) b)+c) Maisine d) Cremophore RH 40 QUANTITY (mg) 50.00 100.00 100.00 100.00 50.00 300.00 100.00 2c a) Cyclosporin (e.g. Ciclosporin) 50.00 b) Soyabean oil 150.00 c) Myverol 18-92 50.00 d) Emulgin R040 250.00 C_ 2d a) b) c) d) 2e a) b) c) d) 2f a) b) c) d) Cyclosporin (e.g. Ciclosporin) Sesame oils Imwitor 900K Emulphor EL-719 Cyclosporin (e.g. Ciclosporin) Myritol 318 Estagel G-18 Pluronic F68 Cyclosporin (e.g. Ciclosporin) Estasan GT 8-60 Arlacel 186 Tween 80 2g a) Cyclosporin (e.g. Ciclosporin) b)+c)Maisine c) Myverol 18-92 d) Cremophore RH40 2h a) Cyclosporin (e.g. Ciclosporin) b) Miglyol 812 c) Myverol 18-92 d) Cremophore RH40 [ c.f. Fiedler, loc. cit. 1, p. 344] 100-7429 50.00 150.00 125.00 150.00 50.00 75.00 100.00 175.00 50.00 130.00 75.00 125.00 50.00 100.00 200.00 100.00 50.00 100.00 200.00 100.00 The compositions obtained in accordance with examples 1 and 2 are suitable for administration for the prevention of transplant rejection or in the treatment of autoimmune disease, e.g. on administration of from 1 to 5 capsules daily. Equivalent composition may be prepared substituting any other Cyclosporin, e.g. [Nva]2-Ciclosporin, for Ciclosporin as component (a) in the same or equivalent amount.
Utility of compositions in accordance with the invention may be shown in animal or clinical trials, for example performed as follows:
k 100-7429 BIOAVAILABILITY STUDY FOR COMPOSITIONS IN ACCORDANCE WITH THE INVENTION IN THE DOG Groups of 8 beagle dogs (male, ca. 11-13kg) are used. Animals receive no food within 18 hours of administration of test composition but are allowed free access to water until administration. Test composition is administered by gavage, followed by 20m1 NaCl 0.9% solution. The animals are allowed free access to food and water three hours after administration of test composition.
2m1 blood samples (or 5m1 for the blank) are taken from the vena saphena and collected in 5m1 plastic tubes containing EDTA at -15min. (blank), 30min., and 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post administration. Blood samples are stored at -180C pending assay.
Blood samples are analysed by RIA. Areas under the blood drug concentration versus time curves are calculated by the trapezoidal rule. Analysis of variance is performed with respect to AUC (area under curve), Cmax (maximum concentation) and Tmax (time of maximum).
Calculated average AUC (in ng hr./ml-l) and Cmax (in ng/ml-l) values from individual trial runs together with calculated variation in response between test animals receiving the same test composition (CV), demonstrate high bioavailability (AUC and Cmax.) coupled with relatively low variability in subject response both for AUC and Cmax for compositions in accordance with the invention, e.g. in accordance with example 1 above, as compared e.g. with results for the known Sandimmune drink solution administered at the same Ciclosporin dosage level.
CLINICAL TRIAL The advantageous properties of the compositions of the invention on oral administration may also be demonstrated in clinical trials, e.g. performed as follows:
C 100-7429 Trial subjects are adult volunteers, e.g. professionally educated males of from 30 to 55 years. Trial groups suitably comprise 12 subjects.
The following inclusion/exclusion criteria are applied: Inclusion: Normal screening ECG; normal blood-pressure and heart rate; body weight = 5095kg.
Exclusion: Clinically significant intercurrent medical condition which might interfere with drug absorption, distribution, metabolism, excretion or safety; symptoms of a significant clinical illness in the two-week pretrial period; clinically relevant abnormal laboratory values or electrocardiogram; need for concomitant medication during the entire course of the study; administration of any drug known to have a welldefined potential toxicity to a major organ system within the previous 3 months; administration of any investigational drug within 6 weeks prior to entry into the trial; history of drug or alcohol abuse; loss of 500m1 or more blood within the past 3 month period; adverse drug reaction or hypersensitivity; history of allergy requiring drug therapy; Hep.B/HIVpositive.
Complete physical examination and ECG is performed pre- and post-trial. The following parameters are evaluated within 1-month periods pre- and post-trial: Blood: - red blood cell count, haemoglobin, hematocrit, erythrocyte sedimentation, white blood cell count, smear, platelet count and fasting glucose; Serum/plasma - total protein and electrophoresis, cholesterol, triglycerides, W, K+, Fe++, Cal'+, Cl- creatinine, urea, uric acid, SGOT, SGPT, -GT, alkaline phosphatase, total bilirubin, a- amylase; Urine - pH, microalbumin, glucose, erythrocytes, ketone bodies, sediment. Creatinine clearance is also determined 1-month prior to trial entry.
Subjects each receive trial compositions in randomised sequence. Compositions are administered orally, once to a total dose of 150mg cyclosporin, e.g. Ciclosporin, and at least 14 days are allowed between each administration.
9 c 100-7429 Administration is performed in the morning after an overnight fast of 10hrs. with only water allowed. Only caffein-free beverages are permitted within the 24hr. period following administration. Subjects are not allowed to smoke within the 12hr. period following administration. Subjects receive a standardised lunch 4 hrs. following administration.
Blood samples (2ml) are taken 1 hr. prior to administration and, postadministration at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 9, 12, 14, 24, 28 and 32 hrs.. For determination of creatinine 2C blood samples are taken immediately prior to administration and at 12, 24 and 48 hrs. post-administration. Samples for cyclosporin determination are collected in two EDTA coated polystyrene tubes (lml each) at each time point and are deep frozen at -200C after gentle agitation. Cyclosporin is assayed in whole blood using RIA with specific and/or non-specific MAB assay detection limit in both cases = ca. lOng/ml.
In trials carried out in accordance with the above protocoll, e.g. comparing the composition of example 1 in hard gelatin encapsulated form with the current Ciclosporin drink solution (Ciclosporin = 50mg, Labrafil = 150mg, ethanol - 50mg, maize oil - 213mg, in soft gelatin encapsulated form: content end weight = 463mg/dosage) as standard, substantially increased bioavailability levels for the example 1 composition are recorded in comparison with the standard as reflected in both AUC (0-32 hrs) and Cmax values established. In addition, comparison of variation in whole blood Ciclosporin concentration (as determined by specific monoclonal RIA) with time following single administration of test compositions to a Ciclosporin dosage of 150mg, demonstrates marked reduction in variability of response between all subjects receiving composition in accordance with example 1 as compared with that for all subjects receiving the standard composition.
Similar or equivalent results may be obtained following oral administration of other compositions in accordance with the invention, e. g. as herein described in example 2.
- - 34 - 100-7429 C.
Claims (10)
1. A pharmaceutical composition comprising: a) a cyclosporin as active ingredient in a carrier medium comprising b) a fatty acid triglyceride c) a glycerol fatty acid partial ester or propylene glycol or sorbitol complete or partial ester, and d) a tenside having an HLB of at least 10; with the proviso that, when components (b) and (c) consist or consist essentially of the individual components of a trans-esterification product of a vegetable oil with glycerol, said composition:
i) is free or substantially free of ethanol; or ii) comprises Ciclosporin or [Nva]2-Ciclosporin as component (a); or iii) comprises components (a) and (d) in a ratio of 1: at least 1 P.P.W.
2. Composition according to claim 1, wherein (a) is present in an amount of from about 2 to about 20% by weight based on the total weight of components (a) to (d) inclusive.
Composition according to claim 1 or 2 wherein (d) comprises the reaction product of a natural or hydrogenated castor oil and ethylene oxide, a polyoxyethylene-sorbitan-fatty acid ester, a polyoxyethylene fatty acid ester, a polyoxyethylene-polyoxypropylene co-polymer or block co-polymer, dioctylsuccinate, di-[2-ethylhexyll-succinate, a phospholipid, a propylene glycol mono- or di-fatty acid ester or sodium lauryl sulfate.
4. Composition according to any one of claims 1 to 3 wherein (a) and (d) are present in a ratio of about 1:1 to 25 p.p.w. [(a):(d)].
5. Composition according to any one of claims 1 to 4 comprising a component (a) and a component (d) as defined in claim 1 and [(b)+(c)] a transesterification product of a vegetable oil and 1 100-7429 glycerol, propylene glycol or sorbitol.
6. Composition according to any one of claims 1 to 4 wherein (b) and (c) consist or consist essentially of the individual components (b) and (c) of a component [(b)+(c)] as defined in claim 6.
7. Composition according to claim 6 wherein (a) and [(b)+(c)] are present in a ratio of about 1:035 to 35 p.p.w. [(a):[(b)+(c)]].
8. Composition according to any one of claims 1 to 5 comprising at least one ingredient which consists or consists essentially of component or components (b) as defined in claim 1 or of a component or components (c) as defined in claim 1.
9. Composition according to any one of claims 1 to 6 or 8 wherein (c) comprises a glycerol fatty acid partial ester or acetylated derivative thereof.
10. Composition according to any one of claims 1 to 5, 8 or 9 wherein (b) and (c) are present in a ratio of about 1:0.02 to 3.0 p.p.w. [(b):(c)].
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB898903804A GB8903804D0 (en) | 1989-02-20 | 1989-02-20 | Improvements in or relating to organic compounds |
Publications (3)
Publication Number | Publication Date |
---|---|
GB9003616D0 GB9003616D0 (en) | 1990-04-11 |
GB2228198A true GB2228198A (en) | 1990-08-22 |
GB2228198B GB2228198B (en) | 1992-12-16 |
Family
ID=10651981
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB898903804A Pending GB8903804D0 (en) | 1984-07-24 | 1989-02-20 | Improvements in or relating to organic compounds |
GB9003616A Expired - Lifetime GB2228198B (en) | 1989-02-20 | 1990-02-16 | Novel cyclosporin galenic forms |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB898903804A Pending GB8903804D0 (en) | 1984-07-24 | 1989-02-20 | Improvements in or relating to organic compounds |
Country Status (9)
Country | Link |
---|---|
JP (1) | JPH0611703B2 (en) |
BE (1) | BE1005236A3 (en) |
CH (1) | CH680650A5 (en) |
CY (1) | CY1886A (en) |
DE (1) | DE4005190A1 (en) |
FR (1) | FR2643262B1 (en) |
GB (2) | GB8903804D0 (en) |
HK (1) | HK149595A (en) |
IT (1) | IT1240765B (en) |
Cited By (56)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2643263A1 (en) * | 1989-02-23 | 1990-08-24 | Glaxo Canada | PHARMACEUTICAL COMPOSITION BASED ON RANITIDINE |
WO1992009299A1 (en) * | 1990-11-27 | 1992-06-11 | BIOGAL Gyógyszergyár Rt. | Oral pharmaceutical composition containing cyclosporin and process for preparing same |
FR2678169A1 (en) * | 1991-06-27 | 1992-12-31 | Sandoz Sa | NOVEL PHARMACEUTICAL COMPOSITIONS COMPRISING CYCLOSPORINE FOR ORAL ADMINISTRATION. |
EP0547229A1 (en) * | 1991-06-27 | 1993-06-23 | Ltt Institute Co., Ltd. | External preparation containing cyclosporin |
GB2270842A (en) * | 1992-09-25 | 1994-03-30 | Sandoz Ltd | Emulsion preconcentrates containing cyclosporins |
WO1995001785A1 (en) * | 1993-07-08 | 1995-01-19 | Sandoz Ltd. | Pharmaceutical compositions for hardly soluble active substances |
WO1995024893A1 (en) * | 1994-03-16 | 1995-09-21 | R.P. Scherer Limited | Delivery systems for hydrophobic drugs |
WO1995031211A1 (en) * | 1994-05-17 | 1995-11-23 | Allergan | Lacrimal gland specific emulsions for topical application to ocular tissue |
US5589455A (en) * | 1994-12-28 | 1996-12-31 | Hanmi Pharm. Ind. Co., Ltd. | Cyclosporin-containing soft capsule compositions |
US5603951A (en) * | 1994-11-09 | 1997-02-18 | Hanmi Pharm. Ind. Co., Ltd. | Cyclosporin-containing soft capsule compositions |
US5614491A (en) * | 1993-11-30 | 1997-03-25 | Dr. Rentschler Arzneimittel Gmbh & Co. | Liquid preparations containing cyclosporin and process for preparing same |
WO1997026003A1 (en) * | 1996-01-18 | 1997-07-24 | Galena A S | Cyclosporin formulation |
AU688920B2 (en) * | 1991-06-27 | 1998-03-19 | Novartis Ag | Transesterified corn oil products |
US5759566A (en) * | 1992-07-28 | 1998-06-02 | Poli Industria Chimica Spa | Microemulsion pharmaceutical compositions for the delivery of pharmaceutically active agents |
US5766629A (en) * | 1995-08-25 | 1998-06-16 | Sangstat Medical Corporation | Oral cyclosporin formulations |
WO1998040051A1 (en) * | 1997-03-12 | 1998-09-17 | Abbott Laboratories | Lipophilic binary systems for the administration of lipophilic compounds |
US5827822A (en) * | 1996-03-25 | 1998-10-27 | Sangstat Medical Corporation | Cyclosporin a formulations as nanoparticles |
US5834017A (en) * | 1995-08-25 | 1998-11-10 | Sangstat Medical Corporation | Oral cyclopsporin formulations |
US5843891A (en) * | 1993-04-28 | 1998-12-01 | Sherman; Bernard C. | Pharmaceutical acceptable compositions containing an alcohol and a hydrophobic drug |
US5858401A (en) * | 1996-01-22 | 1999-01-12 | Sidmak Laboratories, Inc. | Pharmaceutical composition for cyclosporines |
US5962019A (en) * | 1995-08-25 | 1999-10-05 | Sangstat Medical Corporation | Oral cyclosporin formulations |
US5981607A (en) * | 1998-01-20 | 1999-11-09 | Allergan | Emulsion eye drop for alleviation of dry eye related symptoms in dry eye patients and/or contact lens wearers |
US6008191A (en) * | 1997-09-08 | 1999-12-28 | Panacea Biotec Limited | Pharmaceutical compositions containing cyclosporin |
WO2000038702A1 (en) * | 1998-12-23 | 2000-07-06 | Ratiopharm Gmbh | Cyclosporin solution |
US6121313A (en) * | 1997-07-29 | 2000-09-19 | Pharmacia & Upjohn Company | Pharmaceutical composition in a form of self-emulsifying formulation for lipophilic compounds |
US6187747B1 (en) | 1997-09-08 | 2001-02-13 | Panacea Biotech Limited | Pharmaceutical composition comprising cyclosporin |
WO2001032143A1 (en) * | 1999-11-02 | 2001-05-10 | Cipla Ltd. | A pharmaceutical composition for the administration of water-insoluble pharmaceutically active substances and a process for preparation thereof |
US6231887B1 (en) | 1997-07-29 | 2001-05-15 | Pharmacia & Upjohn Company | Pharmaceutical composition for acidic lipophilic compounds in a form of a self-emulsifying formulation |
US6258808B1 (en) | 1991-06-27 | 2001-07-10 | Novartis Ag | Pharmaceutical composition |
EP1151755A1 (en) * | 2000-05-04 | 2001-11-07 | Panacea Biotec Limited | Pharmaceutical compositions comprising cyclosporin as active ingredient |
GB2362573A (en) * | 2000-05-25 | 2001-11-28 | Cipla Ltd | Cyclosporin formulation |
WO2001097774A2 (en) * | 2000-06-21 | 2001-12-27 | Audit Institute For Medical Services And Quality Assurance Gmbh | Novel pharmaceutical composition for the topical application of water-insoluble and/or hardly water-soluble active agents |
US6346511B1 (en) | 1997-09-08 | 2002-02-12 | Panacea Biotec Limited | Pharmaceutical composition comprising cyclosporin |
US6432445B1 (en) | 1999-05-28 | 2002-08-13 | Novartis Ag | Pharmaceutical capsules comprising a cyclosporin |
US6475519B1 (en) | 1997-01-30 | 2002-11-05 | Novartis Ag | Oil-free pharmaceutical compositions containing cyclosporin A |
US6486124B2 (en) | 1994-11-03 | 2002-11-26 | Novartis Ag | Cyclosporin compositions and process therefor |
US6582718B2 (en) | 1992-05-13 | 2003-06-24 | Novartis Ag | Cyclosporin compositions |
US6951841B2 (en) | 1995-11-29 | 2005-10-04 | Novartis Ag | Pharmaceutical compositions of macrolides or cyclosporine with a polyethoxylated saturated hydroxy-fatty acid |
US6979672B2 (en) | 2002-12-20 | 2005-12-27 | Polichem, S.A. | Cyclosporin-based pharmaceutical compositions |
WO2006102157A1 (en) * | 2005-03-21 | 2006-09-28 | Ivax Pharmaceuticals S.R.O. | Crystallization inhibitor and its use in gelatin capsules |
US7494680B2 (en) | 2003-06-04 | 2009-02-24 | Kao Corporation | Fat or oil composition |
US7511014B2 (en) | 1989-02-20 | 2009-03-31 | Novartis Ag | Cyclosporin galenic forms |
EP0697881B2 (en) † | 1993-04-20 | 2009-05-06 | Novartis AG | New cyclosporine-containing pharmaceutical compositions for oral administration |
US8241664B2 (en) | 2005-04-15 | 2012-08-14 | Clarus Therapeutics, Inc | Pharmaceutical delivery systems for hydrophobic drugs and compositions comprising same |
US8778922B2 (en) | 2009-01-08 | 2014-07-15 | Lipocine Inc. | Steroidal compositions |
US9205057B2 (en) | 2010-11-30 | 2015-12-08 | Lipocine Inc. | High-strength testosterone undecanoate compositions |
US9278065B2 (en) | 2007-08-09 | 2016-03-08 | Ems S/A | Delivery systems for solubilising water-insoluble pharmaceutical active ingredients |
US9358241B2 (en) | 2010-11-30 | 2016-06-07 | Lipocine Inc. | High-strength testosterone undecanoate compositions |
US9757389B2 (en) | 2014-08-28 | 2017-09-12 | Lipocine Inc. | Bioavailable solid state (17-β)-hydroxy-4-androsten-3-one esters |
US10543219B2 (en) | 2010-04-12 | 2020-01-28 | Clarus Therapeutics, Inc. | Oral testosterone ester formulations and methods of treating testosterone deficiency comprising same |
US10561615B2 (en) | 2010-12-10 | 2020-02-18 | Lipocine Inc. | Testosterone undecanoate compositions |
WO2020210723A1 (en) * | 2019-04-11 | 2020-10-15 | R.P. Scherer Technologies, Llc | Formulation for oral delivery of proteins, peptides and small molecules with poor permeability |
US10894009B2 (en) | 2014-01-16 | 2021-01-19 | Maruho Co., Ltd. | Topical agent for transdermal administration |
US11433083B2 (en) | 2010-11-30 | 2022-09-06 | Lipocine Inc. | High-strength testosterone undecanoate compositions |
US11559530B2 (en) | 2016-11-28 | 2023-01-24 | Lipocine Inc. | Oral testosterone undecanoate therapy |
US11707467B2 (en) | 2014-08-28 | 2023-07-25 | Lipocine Inc. | (17-ß)-3-oxoandrost-4-en-17YL tridecanoate compositions and methods of their preparation and use |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE4412201A1 (en) * | 1993-04-20 | 1994-11-10 | Rentschler Arzneimittel | New pharmaceutical preparations for oral administration containing cyclosporin |
EP0694308A4 (en) * | 1994-02-17 | 1997-09-10 | Shiseido Co Ltd | Cyclosporin-containing emulsion composition |
US5891846A (en) * | 1994-02-17 | 1999-04-06 | Shiseido Company, Ltd. | Cyclosporin-containing emulsion composition |
IL131609A0 (en) * | 1997-03-12 | 2001-01-28 | Abbott Lab | Hydrophilic binary systems for the administration of cyclosporine |
ID25908A (en) * | 1998-03-06 | 2000-11-09 | Novartis Ag | EMULSION PRACTONCENTRATES CONTAINING CYCLOSPORINE OR MACROLIDES |
US6248363B1 (en) * | 1999-11-23 | 2001-06-19 | Lipocine, Inc. | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
FR2914188B1 (en) * | 2007-03-28 | 2012-06-22 | Trophos | NEW CHOLEST-4-EN-3-ONE OXIME COMPOSITION |
CA2690490C (en) * | 2010-01-19 | 2012-06-26 | Accucaps Industries Limited | Pharmaceutical formulations of loratadine for encapsulation and combinations thereof |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4388307A (en) * | 1978-03-07 | 1983-06-14 | Sandoz Ltd. | Galenical compositions |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CH641356A5 (en) * | 1979-02-27 | 1984-02-29 | Sandoz Ag | Pharmaceutical compositions containing cyclosporin |
PH19156A (en) * | 1982-02-01 | 1986-01-15 | Sandoz Ltd | Dihydrocyclosporin d in the treatment of multiple sclerosis |
-
1989
- 1989-02-20 GB GB898903804A patent/GB8903804D0/en active Pending
-
1990
- 1990-02-16 GB GB9003616A patent/GB2228198B/en not_active Expired - Lifetime
- 1990-02-16 CH CH504/90A patent/CH680650A5/de not_active IP Right Cessation
- 1990-02-19 FR FR9002086A patent/FR2643262B1/en not_active Expired - Lifetime
- 1990-02-19 DE DE4005190A patent/DE4005190A1/en not_active Ceased
- 1990-02-19 BE BE9000181A patent/BE1005236A3/en not_active IP Right Cessation
- 1990-02-19 JP JP2038168A patent/JPH0611703B2/en not_active Expired - Lifetime
- 1990-02-20 IT IT47650A patent/IT1240765B/en active IP Right Grant
-
1995
- 1995-09-21 HK HK149595A patent/HK149595A/en not_active IP Right Cessation
-
1996
- 1996-04-05 CY CY188696A patent/CY1886A/en unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4388307A (en) * | 1978-03-07 | 1983-06-14 | Sandoz Ltd. | Galenical compositions |
Cited By (117)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7511014B2 (en) | 1989-02-20 | 2009-03-31 | Novartis Ag | Cyclosporin galenic forms |
BE1003123A3 (en) * | 1989-02-23 | 1991-12-03 | Glaxo Canada | PHARMACEUTICAL COMPOSITIONS. |
FR2643263A1 (en) * | 1989-02-23 | 1990-08-24 | Glaxo Canada | PHARMACEUTICAL COMPOSITION BASED ON RANITIDINE |
AU651154B2 (en) * | 1990-11-27 | 1994-07-14 | Biogal Gyogyszergyar Rt | Oral pharmaceutical composition containing cyclosporin and process for preparing same |
WO1992009299A1 (en) * | 1990-11-27 | 1992-06-11 | BIOGAL Gyógyszergyár Rt. | Oral pharmaceutical composition containing cyclosporin and process for preparing same |
EP0539319A3 (en) * | 1991-06-27 | 1993-06-09 | Sandoz Ltd. | Pharmaceutical cyclosporin composition |
GB2257359B (en) * | 1991-06-27 | 1996-01-10 | Sandoz Ltd | Cyclosporin compositions for oral administration |
EP0547229A1 (en) * | 1991-06-27 | 1993-06-23 | Ltt Institute Co., Ltd. | External preparation containing cyclosporin |
FR2685706A1 (en) * | 1991-06-27 | 1993-07-02 | Sandoz Sa | PRODUCT FOR TRANSESTERIFYING OIL OF MAUIS WITH GLYCEROL AND ITS PREPARATION |
EP0547229A4 (en) * | 1991-06-27 | 1993-11-10 | Ltt Institute Co., Ltd. | External preparation containing cyclosporin |
AU688920B2 (en) * | 1991-06-27 | 1998-03-19 | Novartis Ag | Transesterified corn oil products |
EP0539319A2 (en) * | 1991-06-27 | 1993-04-28 | Sandoz Ltd. | Pharmaceutical cyclosporin composition |
AT403436B (en) * | 1991-06-27 | 1998-02-25 | Novartis Erfind Verwalt Gmbh | PHARMACEUTICAL COMPOSITION |
GB2257359A (en) * | 1991-06-27 | 1993-01-13 | Sandoz Ltd | Cyclosporin compositions for oral administration |
EP0953630A1 (en) * | 1991-06-27 | 1999-11-03 | Novartis AG | Transesterification products of corn oil and glycerol and their use in pharmaceutical compositions |
US6844459B2 (en) | 1991-06-27 | 2005-01-18 | Novartis Ag | Pharmaceutical Composition |
US6258808B1 (en) | 1991-06-27 | 2001-07-10 | Novartis Ag | Pharmaceutical composition |
US5504068A (en) * | 1991-06-27 | 1996-04-02 | Ltt Institute Co., Ltd. | Topical preparations containing cyclosporin |
FR2678169A1 (en) * | 1991-06-27 | 1992-12-31 | Sandoz Sa | NOVEL PHARMACEUTICAL COMPOSITIONS COMPRISING CYCLOSPORINE FOR ORAL ADMINISTRATION. |
CN1077798C (en) * | 1991-06-27 | 2002-01-16 | 诺瓦蒂斯有限公司 | Pharmaceutical composition |
US6582718B2 (en) | 1992-05-13 | 2003-06-24 | Novartis Ag | Cyclosporin compositions |
US6262022B1 (en) | 1992-06-25 | 2001-07-17 | Novartis Ag | Pharmaceutical compositions containing cyclosporin as the active agent |
US5759566A (en) * | 1992-07-28 | 1998-06-02 | Poli Industria Chimica Spa | Microemulsion pharmaceutical compositions for the delivery of pharmaceutically active agents |
GB2270842B (en) * | 1992-09-25 | 1997-04-02 | Sandoz Ltd | Pharmaceutical compositions containing cyclosporins |
US6420355B2 (en) | 1992-09-25 | 2002-07-16 | Novartis Ag | Pharmaceutical compositions containing cyclosporins |
DE4332436B4 (en) * | 1992-09-25 | 2007-04-26 | Novartis Ag | Cyclosporin-containing pharmaceutical compositions |
GB2270842A (en) * | 1992-09-25 | 1994-03-30 | Sandoz Ltd | Emulsion preconcentrates containing cyclosporins |
EP0697881B2 (en) † | 1993-04-20 | 2009-05-06 | Novartis AG | New cyclosporine-containing pharmaceutical compositions for oral administration |
US5843891A (en) * | 1993-04-28 | 1998-12-01 | Sherman; Bernard C. | Pharmaceutical acceptable compositions containing an alcohol and a hydrophobic drug |
WO1995001786A1 (en) * | 1993-07-08 | 1995-01-19 | Ciba-Geigy Ag | Pharmaceutical compositions for hardly soluble active substances |
CN1121853C (en) * | 1993-07-08 | 2003-09-24 | 诺瓦蒂斯有限公司 | Pharmaceutical compositions for hardly soluble active substances |
AU689486B2 (en) * | 1993-07-08 | 1998-04-02 | Novartis Ag | Pharmaceutical compositions for hardly soluble active substances |
CN1313154C (en) * | 1993-07-08 | 2007-05-02 | 诺瓦蒂斯有限公司 | Medicine composition of adding active component which undissolved in water in carrier composition and its preparing method |
EP1092429A1 (en) * | 1993-07-08 | 2001-04-18 | Novartis AG | Pharmaceutical preparations for drugs of low solubility |
WO1995001785A1 (en) * | 1993-07-08 | 1995-01-19 | Sandoz Ltd. | Pharmaceutical compositions for hardly soluble active substances |
US5614491A (en) * | 1993-11-30 | 1997-03-25 | Dr. Rentschler Arzneimittel Gmbh & Co. | Liquid preparations containing cyclosporin and process for preparing same |
US6096338A (en) * | 1994-03-16 | 2000-08-01 | R. P. Scherer Corporation | Delivery systems for hydrophobic drugs |
US5645856A (en) * | 1994-03-16 | 1997-07-08 | R. P. Scherer Corporation | Delivery systems for hydrophobic drugs |
EP1205180A3 (en) * | 1994-03-16 | 2002-11-27 | R.P. Scherer Technologies, Inc. | Delivery system for hydrophobic drugs |
EP1205180A2 (en) * | 1994-03-16 | 2002-05-15 | R.P. Scherer Technologies, Inc. | Delivery system for hydrophobic drugs |
WO1995024893A1 (en) * | 1994-03-16 | 1995-09-21 | R.P. Scherer Limited | Delivery systems for hydrophobic drugs |
AU693213B2 (en) * | 1994-05-17 | 1998-06-25 | Allergan, Inc. | Lacrimal gland specific emulsions for topical application to ocular tissue |
WO1995031211A1 (en) * | 1994-05-17 | 1995-11-23 | Allergan | Lacrimal gland specific emulsions for topical application to ocular tissue |
US6486124B2 (en) | 1994-11-03 | 2002-11-26 | Novartis Ag | Cyclosporin compositions and process therefor |
US5603951A (en) * | 1994-11-09 | 1997-02-18 | 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 |
US5834017A (en) * | 1995-08-25 | 1998-11-10 | Sangstat Medical Corporation | Oral cyclopsporin formulations |
US6254885B1 (en) | 1995-08-25 | 2001-07-03 | Sangstat Medical Corporation | Oral cyclosphorin formulations |
US5766629A (en) * | 1995-08-25 | 1998-06-16 | Sangstat Medical Corporation | Oral cyclosporin formulations |
US5962019A (en) * | 1995-08-25 | 1999-10-05 | Sangstat Medical Corporation | Oral cyclosporin formulations |
US6951841B2 (en) | 1995-11-29 | 2005-10-04 | Novartis Ag | Pharmaceutical compositions of macrolides or cyclosporine with a polyethoxylated saturated hydroxy-fatty acid |
WO1997026003A1 (en) * | 1996-01-18 | 1997-07-24 | Galena A S | Cyclosporin formulation |
US6046163A (en) * | 1996-01-18 | 2000-04-04 | Galena As | Cyclosporin formulation |
US7070802B1 (en) | 1996-01-22 | 2006-07-04 | Pliva, Inc. | Pharmaceutical compositions for lipophilic drugs |
US5858401A (en) * | 1996-01-22 | 1999-01-12 | Sidmak Laboratories, Inc. | Pharmaceutical composition for cyclosporines |
US5827822A (en) * | 1996-03-25 | 1998-10-27 | Sangstat Medical Corporation | Cyclosporin a formulations as nanoparticles |
US6475519B1 (en) | 1997-01-30 | 2002-11-05 | Novartis Ag | Oil-free pharmaceutical compositions containing cyclosporin A |
US6723339B2 (en) | 1997-01-30 | 2004-04-20 | Novartis Ag | Oil-free pharmaceutical compositions containing cyclosporin A |
WO1998040051A1 (en) * | 1997-03-12 | 1998-09-17 | Abbott Laboratories | Lipophilic binary systems for the administration of lipophilic compounds |
US6531139B1 (en) | 1997-07-29 | 2003-03-11 | Pharmacia & Upjohn Company | Self-emulsifying formulation for lipophilic compounds |
CZ296957B6 (en) * | 1997-07-29 | 2006-08-16 | Pharmacia & Upjohn Company | Pharmaceutical composition for acidic lipophilic compounds in a form of a self-emulsifying formulation |
US6231887B1 (en) | 1997-07-29 | 2001-05-15 | Pharmacia & Upjohn Company | Pharmaceutical composition for acidic lipophilic compounds in a form of a self-emulsifying formulation |
US6121313A (en) * | 1997-07-29 | 2000-09-19 | Pharmacia & Upjohn Company | Pharmaceutical composition in a form of self-emulsifying formulation for lipophilic compounds |
US6187747B1 (en) | 1997-09-08 | 2001-02-13 | Panacea Biotech Limited | Pharmaceutical composition comprising cyclosporin |
US6346511B1 (en) | 1997-09-08 | 2002-02-12 | Panacea Biotec Limited | Pharmaceutical composition comprising cyclosporin |
US6008191A (en) * | 1997-09-08 | 1999-12-28 | Panacea Biotec Limited | Pharmaceutical compositions containing cyclosporin |
US5981607A (en) * | 1998-01-20 | 1999-11-09 | Allergan | Emulsion eye drop for alleviation of dry eye related symptoms in dry eye patients and/or contact lens wearers |
WO2000038702A1 (en) * | 1998-12-23 | 2000-07-06 | Ratiopharm Gmbh | Cyclosporin solution |
US6432445B1 (en) | 1999-05-28 | 2002-08-13 | Novartis Ag | Pharmaceutical capsules comprising a cyclosporin |
US6767555B2 (en) | 1999-05-28 | 2004-07-27 | Novartis Ag | Pharmaceutical compositions |
WO2001032143A1 (en) * | 1999-11-02 | 2001-05-10 | Cipla Ltd. | A pharmaceutical composition for the administration of water-insoluble pharmaceutically active substances and a process for preparation thereof |
EP1151755A1 (en) * | 2000-05-04 | 2001-11-07 | Panacea Biotec Limited | Pharmaceutical compositions comprising cyclosporin as active ingredient |
GB2362573A (en) * | 2000-05-25 | 2001-11-28 | Cipla Ltd | Cyclosporin formulation |
WO2001097774A3 (en) * | 2000-06-21 | 2002-06-20 | Audit Inst For Medical Service | Novel pharmaceutical composition for the topical application of water-insoluble and/or hardly water-soluble active agents |
WO2001097774A2 (en) * | 2000-06-21 | 2001-12-27 | Audit Institute For Medical Services And Quality Assurance Gmbh | Novel pharmaceutical composition for the topical application of water-insoluble and/or hardly water-soluble active agents |
US6979672B2 (en) | 2002-12-20 | 2005-12-27 | Polichem, S.A. | Cyclosporin-based pharmaceutical compositions |
US7494680B2 (en) | 2003-06-04 | 2009-02-24 | Kao Corporation | Fat or oil composition |
WO2006102157A1 (en) * | 2005-03-21 | 2006-09-28 | Ivax Pharmaceuticals S.R.O. | Crystallization inhibitor and its use in gelatin capsules |
US8673351B2 (en) | 2005-03-21 | 2014-03-18 | Ivax Pharmaceuticals S.R.O. | Crystallization inhibitor and its use in gelatin capsules |
US8241664B2 (en) | 2005-04-15 | 2012-08-14 | Clarus Therapeutics, Inc | Pharmaceutical delivery systems for hydrophobic drugs and compositions comprising same |
US8778917B2 (en) | 2005-04-15 | 2014-07-15 | Clarus Therapeutics, Inc. | Pharmaceutical delivery systems for hydrophobic drugs and compositions comprising same |
US8828428B1 (en) | 2005-04-15 | 2014-09-09 | Clarus Therapeutics, Inc. | Pharmaceutical delivery systems for hydrophobic drugs and compositions comprising same |
US11179402B2 (en) | 2005-04-15 | 2021-11-23 | Clarus Therapeutics, Inc. | Pharmaceutical delivery systems for hydrophobic drugs and compositions comprising same |
US11331325B2 (en) | 2005-04-15 | 2022-05-17 | Clarus Therapeutics, Inc. | Pharmaceutical delivery systems for hydrophobic drugs and compositions comprising same |
US9278065B2 (en) | 2007-08-09 | 2016-03-08 | Ems S/A | Delivery systems for solubilising water-insoluble pharmaceutical active ingredients |
US11052096B2 (en) | 2009-01-08 | 2021-07-06 | Lipocine Inc. | Steroidal compositions |
US11304960B2 (en) | 2009-01-08 | 2022-04-19 | Chandrashekar Giliyar | Steroidal compositions |
US8865695B2 (en) | 2009-01-08 | 2014-10-21 | Lipocine Inc. | Steroidal compositions |
US8778922B2 (en) | 2009-01-08 | 2014-07-15 | Lipocine Inc. | Steroidal compositions |
US11179403B2 (en) | 2010-04-12 | 2021-11-23 | Clarus Therapeutics, Inc. | Oral testosterone ester formulations and methods of treating testosterone deficiency comprising same |
US10543219B2 (en) | 2010-04-12 | 2020-01-28 | Clarus Therapeutics, Inc. | Oral testosterone ester formulations and methods of treating testosterone deficiency comprising same |
US11426416B2 (en) | 2010-04-12 | 2022-08-30 | Clarus Therapeutics, Inc. | Oral testosterone ester formulations and methods of treating testosterone deficiency comprising same |
US10617696B2 (en) | 2010-04-12 | 2020-04-14 | Clarus Therapeutics, Inc. | Oral testosterone ester formulations and methods of treating testosterone deficiency comprising same |
US9757390B2 (en) | 2010-11-30 | 2017-09-12 | Lipocine Inc. | High-strength testosterone undecanoate compositions |
US9480690B2 (en) | 2010-11-30 | 2016-11-01 | Lipocine Inc. | High-strength testosterone undecanoate compositions |
US10226473B2 (en) | 2010-11-30 | 2019-03-12 | Lipocine Inc. | High-strength testosterone undecanoate compositions |
US10716794B2 (en) | 2010-11-30 | 2020-07-21 | Lipocine Inc. | High-strength testosterone undecanoate compositions |
US10799513B2 (en) | 2010-11-30 | 2020-10-13 | Lipocine Inc. | High-strength testosterone undecanoate compositions |
US11433083B2 (en) | 2010-11-30 | 2022-09-06 | Lipocine Inc. | High-strength testosterone undecanoate compositions |
US10881671B2 (en) | 2010-11-30 | 2021-01-05 | Lipocine Inc. | High-strength testosterone undecanoate compositions |
US9949985B2 (en) | 2010-11-30 | 2018-04-24 | Lipocine Inc. | High-strength testosterone undecanoate compositions |
US10973833B2 (en) | 2010-11-30 | 2021-04-13 | Lipocine Inc. | High-strength testosterone undecanoate compositions |
US9943527B2 (en) | 2010-11-30 | 2018-04-17 | Lipocine Inc. | High-strength testosterone undecanoate compositions |
US11364249B2 (en) | 2010-11-30 | 2022-06-21 | Lipocine Inc. | High-strength testosterone undecanoate compositions |
US11364250B2 (en) | 2010-11-30 | 2022-06-21 | Lipocine Inc. | High-strength testosterone undecanoate compositions |
US9205057B2 (en) | 2010-11-30 | 2015-12-08 | Lipocine Inc. | High-strength testosterone undecanoate compositions |
US11311555B2 (en) | 2010-11-30 | 2022-04-26 | Lipocine Inc. | High-strength testosterone undecanoate compositions |
US9358241B2 (en) | 2010-11-30 | 2016-06-07 | Lipocine Inc. | High-strength testosterone undecanoate compositions |
US10561615B2 (en) | 2010-12-10 | 2020-02-18 | Lipocine Inc. | Testosterone undecanoate compositions |
US10894009B2 (en) | 2014-01-16 | 2021-01-19 | Maruho Co., Ltd. | Topical agent for transdermal administration |
US11298365B2 (en) | 2014-08-28 | 2022-04-12 | Lipocine Inc. | Bioavailable solid state (17-β)-hydroxy-4-androsten-3-one esters |
US9757389B2 (en) | 2014-08-28 | 2017-09-12 | Lipocine Inc. | Bioavailable solid state (17-β)-hydroxy-4-androsten-3-one esters |
US11707467B2 (en) | 2014-08-28 | 2023-07-25 | Lipocine Inc. | (17-ß)-3-oxoandrost-4-en-17YL tridecanoate compositions and methods of their preparation and use |
US11872235B1 (en) | 2014-08-28 | 2024-01-16 | Lipocine Inc. | Bioavailable solid state (17-β)-Hydroxy-4-Androsten-3-one esters |
US11559530B2 (en) | 2016-11-28 | 2023-01-24 | Lipocine Inc. | Oral testosterone undecanoate therapy |
US11185589B2 (en) | 2019-04-11 | 2021-11-30 | R.P. Scherer Technologies, Llc | Formulation for oral delivery of proteins, peptides and small molecules with poor permeability |
WO2020210723A1 (en) * | 2019-04-11 | 2020-10-15 | R.P. Scherer Technologies, Llc | Formulation for oral delivery of proteins, peptides and small molecules with poor permeability |
Also Published As
Publication number | Publication date |
---|---|
DE4005190A1 (en) | 1990-08-23 |
HK149595A (en) | 1995-09-29 |
IT1240765B (en) | 1993-12-17 |
GB8903804D0 (en) | 1989-04-05 |
CY1886A (en) | 1996-04-05 |
JPH02255623A (en) | 1990-10-16 |
FR2643262B1 (en) | 1993-06-11 |
JPH0611703B2 (en) | 1994-02-16 |
FR2643262A1 (en) | 1990-08-24 |
IT9047650A1 (en) | 1990-08-21 |
IT9047650A0 (en) | 1990-02-20 |
CH680650A5 (en) | 1992-10-15 |
GB9003616D0 (en) | 1990-04-11 |
GB2228198B (en) | 1992-12-16 |
BE1005236A3 (en) | 1993-06-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6468968B2 (en) | Cyclosporin galenic forms | |
GB2228198A (en) | Orally administrable cyclosporin solutions | |
KR100894130B1 (en) | Pharmaceutical compositions comprising cyclosporins | |
US5342625A (en) | Pharmaceutical compositions comprising cyclosporins | |
US6007840A (en) | Pharmaceutical compositions comprising cyclosporins | |
EP0539319B1 (en) | Pharmaceutical cyclosporin composition | |
AU630413B2 (en) | Pharmaceutical compositions comprising cyclosporin and a fatty acid saccharide monoester | |
US6262022B1 (en) | Pharmaceutical compositions containing cyclosporin as the active agent | |
US7081445B2 (en) | Cyclosporin galenic forms | |
KR100267149B1 (en) | Pharmaceutical compositions comprising cyclosporins | |
KR100256007B1 (en) | Pharmaceutical compositions comprising cyclosporins |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
732E | Amendments to the register in respect of changes of name or changes affecting rights (sect. 32/1977) | ||
PE20 | Patent expired after termination of 20 years |
Expiry date: 20100215 |