MXPA96003560A - Compositions of stable prostaglandines enalmacenamie - Google Patents
Compositions of stable prostaglandines enalmacenamieInfo
- Publication number
- MXPA96003560A MXPA96003560A MXPA/A/1996/003560A MX9603560A MXPA96003560A MX PA96003560 A MXPA96003560 A MX PA96003560A MX 9603560 A MX9603560 A MX 9603560A MX PA96003560 A MXPA96003560 A MX PA96003560A
- Authority
- MX
- Mexico
- Prior art keywords
- oxa
- pentanor
- chloro
- acid
- prostenoic
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 55
- 125000003259 prostaglandin group Chemical group 0.000 title 1
- 150000003180 prostaglandins Chemical class 0.000 claims abstract description 53
- 239000008389 polyethoxylated castor oil Substances 0.000 claims abstract description 31
- 239000000126 substance Substances 0.000 claims abstract description 7
- 239000002253 acid Substances 0.000 claims description 66
- SKRDXYBATCVEMS-UHFFFAOYSA-N Isopropyl nitrite Chemical compound CC(C)ON=O SKRDXYBATCVEMS-UHFFFAOYSA-N 0.000 claims description 51
- -1 t-butyl ester Chemical class 0.000 claims description 28
- 239000004359 castor oil Substances 0.000 claims description 24
- 150000002148 esters Chemical class 0.000 claims description 23
- 235000019438 castor oil Nutrition 0.000 claims description 12
- 230000000087 stabilizing Effects 0.000 claims description 8
- 150000001408 amides Chemical class 0.000 claims description 7
- 229920000604 Polyethylene Glycol 200 Polymers 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- MTHSVFCYNBDYFN-UHFFFAOYSA-N Diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 claims description 4
- GGXICVAJURFBLW-CEYXHVGTSA-N Latanoprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CC[C@@H](O)CCC1=CC=CC=C1 GGXICVAJURFBLW-CEYXHVGTSA-N 0.000 claims description 4
- 229960001160 latanoprost Drugs 0.000 claims description 4
- VJGGHXVGBSZVMZ-QIZQQNKQSA-N (Z)-7-[(1R,2R,3R,5S)-2-[(E,3R)-4-(3-chlorophenoxy)-3-hydroxybut-1-enyl]-3,5-dihydroxycyclopentyl]hept-5-enoic acid Chemical compound C([C@H](O)\C=C\[C@@H]1[C@H]([C@@H](O)C[C@H]1O)C\C=C/CCCC(O)=O)OC1=CC=CC(Cl)=C1 VJGGHXVGBSZVMZ-QIZQQNKQSA-N 0.000 claims description 3
- 229960004409 Cloprostenol Drugs 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 239000003981 vehicle Substances 0.000 claims description 3
- GHXZTYHSJHQHIJ-UHFFFAOYSA-N Exidine Chemical compound C=1C=C(Cl)C=CC=1NC(N)=NC(N)=NCCCCCCN=C(N)N=C(N)NC1=CC=C(Cl)C=C1 GHXZTYHSJHQHIJ-UHFFFAOYSA-N 0.000 claims 15
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims 4
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims 2
- WWSWYXNVCBLWNZ-CHPNCWRZSA-N (Z)-7-[(1S,2S,3S,5R)-3,5-dihydroxy-2-[(E,3S)-3-hydroxy-4-[3-(trifluoromethyl)phenoxy]but-1-enyl]cyclopentyl]hept-5-enoic acid Chemical compound C([C@@H](O)\C=C\[C@H]1[C@@H]([C@H](O)C[C@@H]1O)C\C=C/CCCC(O)=O)OC1=CC=CC(C(F)(F)F)=C1 WWSWYXNVCBLWNZ-CHPNCWRZSA-N 0.000 claims 1
- 206010018307 Glaucoma and ocular hypertension Diseases 0.000 claims 1
- QKIUAMUSENSFQQ-UHFFFAOYSA-N dimethylazanide Chemical compound C[N-]C QKIUAMUSENSFQQ-UHFFFAOYSA-N 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 229950009951 fluprostenol Drugs 0.000 claims 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 229940082622 Prostaglandin cardiac therapy preparations Drugs 0.000 description 24
- 229940077717 Prostaglandin drugs for peptic ulcer and gastro-oesophageal reflux disease (GORD) Drugs 0.000 description 24
- 229940094443 oxytocics Prostaglandins Drugs 0.000 description 24
- 150000001875 compounds Chemical class 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000009472 formulation Methods 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 210000001508 Eye Anatomy 0.000 description 6
- 239000004094 surface-active agent Substances 0.000 description 6
- 239000000839 emulsion Substances 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 235000002639 sodium chloride Nutrition 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 230000000699 topical Effects 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- KGBXLFKZBHKPEV-UHFFFAOYSA-N Boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 3
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 239000004327 boric acid Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 230000035786 metabolism Effects 0.000 description 3
- 239000002736 nonionic surfactant Substances 0.000 description 3
- 230000002335 preservative Effects 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 230000001105 regulatory Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 230000002459 sustained Effects 0.000 description 3
- LENZDBCJOHFCAS-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- WRMNZCZEMHIOCP-UHFFFAOYSA-N Phenethyl alcohol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- 229920001214 Polysorbate 60 Polymers 0.000 description 2
- VDZOOKBUILJEDG-UHFFFAOYSA-M Tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 description 2
- 229940035504 Tromethamine Drugs 0.000 description 2
- 229940045997 Vitamin A Drugs 0.000 description 2
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 230000000845 anti-microbial Effects 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- ZGTMUACCHSMWAC-UHFFFAOYSA-L disodium;2-[2-[carboxylatomethyl(carboxymethyl)amino]ethyl-(carboxymethyl)amino]acetate Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 2
- 229940079593 drugs Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 2
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 2
- 229940113124 polysorbate 60 Drugs 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 229960003471 retinol Drugs 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229960000281 trometamol Drugs 0.000 description 2
- 235000019155 vitamin A Nutrition 0.000 description 2
- 239000011719 vitamin A Substances 0.000 description 2
- KFUDFIMHDRJVLV-MSKGSUGCSA-N (Z)-7-[(1S,2R,3R,5S)-2-[(2S)-3-(3-chlorophenoxy)-2-hydroxypropyl]sulfanyl-3,5-dihydroxycyclopentyl]hept-5-enoic acid Chemical compound C([C@H](O)CS[C@@H]1[C@H]([C@@H](O)C[C@H]1O)C\C=C/CCCC(O)=O)OC1=CC=CC(Cl)=C1 KFUDFIMHDRJVLV-MSKGSUGCSA-N 0.000 description 1
- PZGXJYSPQYRCBB-UHFFFAOYSA-N 2-chlorobutanal Chemical compound CCC(Cl)C=O PZGXJYSPQYRCBB-UHFFFAOYSA-N 0.000 description 1
- 229960000686 Benzalkonium Chloride Drugs 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N Carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 229940097362 Cyclodextrins Drugs 0.000 description 1
- 239000003109 Disodium ethylene diamine tetraacetate Substances 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 125000000393 L-methionino group Chemical group [H]OC(=O)[C@@]([H])(N([H])[*])C([H])([H])C(SC([H])([H])[H])([H])[H] 0.000 description 1
- 210000001331 Nose Anatomy 0.000 description 1
- 101710040930 PTGS2 Proteins 0.000 description 1
- 229940067107 Phenylethyl Alcohol Drugs 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920000954 Polyglycolide Polymers 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N Propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- KAQKFAOMNZTLHT-OZUDYXHBSA-N Prostacyclin Chemical compound O1\C(=C/CCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 KAQKFAOMNZTLHT-OZUDYXHBSA-N 0.000 description 1
- 235000004443 Ricinus communis Nutrition 0.000 description 1
- 210000003491 Skin Anatomy 0.000 description 1
- 229940075582 Sorbic Acid Drugs 0.000 description 1
- 229940088594 Vitamin Drugs 0.000 description 1
- 239000012445 acidic reagent Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 230000000875 corresponding Effects 0.000 description 1
- 230000001808 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 230000004059 degradation Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 125000003438 dodecyl group Chemical group [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])* 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 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 1
- 229960001123 epoprostenol Drugs 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 150000004676 glycans Polymers 0.000 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 239000001307 helium Substances 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium(0) Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
- 238000011141 high resolution liquid chromatography Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006011 modification reaction Methods 0.000 description 1
- 239000005445 natural product Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 235000010409 propane-1,2-diol alginate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000008299 semisolid dosage form Substances 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- WSWCOQWTEOXDQX-UHFFFAOYSA-N sorbic acid Chemical compound CC=CC=CC(O)=O WSWCOQWTEOXDQX-UHFFFAOYSA-N 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- 125000001874 trioxidanyl group Chemical group [*]OOO[H] 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 229930003231 vitamins Natural products 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
Abstract
The present invention relates to the use of polyethoxylated castor oils in prostaglandin compositions considerably increases the chemical stability of the prostaglandin.
Description
COMPOSITIONS OF STABLE PROSTAGLANDINS IN STORAGE
BACKGROUND OF THE INVENTION
The present invention relates generally to prostaglandin compositions. In particular, the present invention relates to storage stable pharmaceutical compositions containing prostaglandins and surfactants. As used herein, the term "prostaglandin" or "PG" refers to prostaglandins and derivatives and analogs thereof including pharmaceutically acceptable salts and esters, unless otherwise indicated in the context Prostaglandins have remarkably low solubility in water and are generally unstable, attempts have been made to solubilize and stabilize various prostaglandins by coupling them with different cyclodextrins, see for example: EP 330 511 A2 (Ueno et al.) and EP -35 6ft2 A2 ^ heeler). Variables: Surfactants, solubilizers, or both have been used with other types of drugs having low water solubility, however, the addition of surfactants, solubilizers, or both, may increase or adversely affect the chemical stability of the pharmaceutical compounds See Surfactant Systems, Their Chemistrv Pharmacv and Bioloav (eds. Att ood et al.), Chap an and Hall, New York, 1963, Chap. 11, particularly pp. 69 &-71.
* The use of nonionic surfactants such as polyethoxylated castor oils as solubilizing agents is known. See, for example, US 4,960, 99 (Nagy). It is also known to use nonionic surfactants such as polyethoxy castor oils in stable emulsions. US Pat. No. 4,075,333 (Josse) discloses stable formulations of intravenous vitamin emulsion. El Sayed et al., Int. 3. Pharma .. 13: 303-12 (19 & 3) describe stable oil-in-water emulsions of an ineplastic drug. US Pat. No. 5,155,372 (Ushio et al.) Discloses topically admissible formulations of vitamin A which are stable preparations in which a nonionic surfactant is used to form a vitamin A emulsion in an aqueous medium. What is needed is a commercially viable and stable prostaglandin composition in storage.
BRIEF DESCRIPTION OF THE INVENTION
The present invention is directed to the use of polyethoxy side castor oils in pharmaceutical compositions containing prostaglandins. It has now been unexpectedly discovered that the use of such polyethoxylated castor oils in such compositions increases the chemical stability of the prostaglandins in pharmaceutical compositions.
/, * 'S compositions of the present invention can be administered to the body in a variety of ways. When applied topically to the eye, the compositions of the present invention provide both initial and continuous comfort.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows the stabilizing effect at different concentrations of a polyethoxylated castor oil, in a prostaglandin formulation preserved at pH 5.0. Figure 2 compares the stabilizing effect of different surfactants in a prostaglandin formulation preserved at pH 5.0. Figure 3 compares the stabilizing effect of different surfactants in a preserved prostaglandin formulation at pH 7.4.
DETAILED DESCRIPTION OF THE INVENTION
Prostaglandin steres are difficult to formulate into stable storage solutions since they tend to be hydrolytically unstable. In some cases, the acids from which some prostaglandin esters are derived are also unstable. However, the pharmaceutical compositions of the present invention are storage stable. These compositions contain a p, '-ostaglandin and an amount of stability improvement of a polyethoxylated castor oil. The polyethoxylated castor oils useful in the compositions of the present invention are commercially available, and include those classified as PES-2 to PEG-200 castor oils, as well as those classified as PEG-5 to PEG-hydrogenated castor oils. 200. Such polyethoxy-side castor oils include those mono-invoiced by
Rhone-Poulenc (Cranbury, New Jersey) under the trademark Alkamuls "* *," those manufactured by BASF (Parsippany, New Jersey) under the brand name Cremophor < R *. It is preferred to use polyethoxylated castor oils classified as castor oil PEG-15 to PEG-50, and more preferred to use castor oils PEG-30 to PEG-35. It is more preferred to use those polyethoxylated castor oils known as Cremophor < R * EL &Alkamuls < R > EL-620 The terms "prastaglandin" and "PG" are generally used to describe a class of compounds which are prostagotoic acid derivatives and derivatives (1):
000H. * > . "'5 ^ ~ / 3 ^ / 1 1 10 13 15 ^ 17 ,, ~ 19. CH, 20 11 2 ^^ 14, - '16 ^ -' 18
(i)
PG's can be further classified, for example, according to their 5-member ring structure, using a letter designation:
Prostaglandins of the series A (PGA's)
Prostaglandins of the B series (PGB's)
Prostaglandins of the C series (PGC's)
/ r \
Prostaglandins of the D series (PGD's) Prostaglandins of the E series (PGE's)
- \
HO Prostaglandins of the F series (PGF's)
Prostaglandins of the J series (PGJ's)
'"PG's can also be classified based on the number of unsaturated bonds on the side chain:
PGi's (13,14-unsaturated): CCOH (chain at a) 8, ^ (chain flooded) CH PG -, - s (13, 14- and 5, 6- unsaturated)
W \ = - 2 OOOH (alpha chain) PG2 10. . 13 s ^ 17 ^ 19 CH- (chain flooded) 12 ^^ 16 18 20 CH
PG3 's (13, 14-5, 6- and 17, lft-unsaturated):
CH
The prostaglandins which can be used in the present invention include all pharmaceutically acceptable prostaglandins, their derivatives and analogs, and their pharmaceutically acceptable esters and salts. Such prostaglandins include the natural compounds: PGEa., R '^ a, PGFAß PGFjüß ,, PGFaß > , PGDa. and Pßl »(prostacyclin), as well as analogs and derivatives of these compounds having similar biological activities of greater or lesser potency. Analogs of the natural prostaglandins include, but are not limited to: alkyl substitutions (e.g., 15-methyl or 16,16-dimethyl), which confer increased or sustained potency by reducing the biological metabolism or selectively altering the action; saturation (eg, 13, 14-dihydro) or unsaturation (eg, 2,3-didehydro, &
? 2, 14-didehydro), which confers sustained potency by reducing the biological metabolism or selectively altering the action; deletions or replacements (eg, 11-deoxy, 9-deoxo-9-methylene), chlorine (or halogen) by oxygen (eg, 9 | 3-chloro), oxygen by carbon (e.g., 3-oxa), lower alkyl by oxygen (eg, 9-methyl), hydrogen by oxygen (e.g., l-CHaOH, l-CHaOAcil), which increases the chemical stability and / or selectivity of action, and modifications in the chain a > (for example, 16, 19,20-trinor-17 - "" '. nil, 17,16,19,20-tetranor-16-pheno? i), which increases the selectivity of action and reduces the biological metabolism The derivatives of these prostaglandins include all pharmaceutically acceptable salts and esters, which can be attached to the 1-carboxyl group or any of the hydroxy groups of the prostaglandin using the corresponding alcohol or organic acid reagent, as appropriate. the terms "analogues" and "derivatives" include compounds that exhibit functional and physical responses similar to those of prostaglandins per se Examples of prostaglandins that are useful in the present invention include the following compounds: Compound No. 1. (5Z) acid - (9R, 11R, 15R) ~ 9-chloro-15-cyclohexyl-11,15-dihydroxy-3-o? A-16, 17,16,19,20-pentanor-5-prostenoic acid;
2. isopropyl ester of the acid (5Z) - (9R, 11R, 15R> -9- cioro-15-cyclohexyl-ll, 15-dihydro-3-oxa-16, 17, 16, 19,20-pentanor-5- prostenoic; 3. (5Z) - (9R, 11R, 15R) -9- chloro-15-cyclohexyl-l, 15-dihydroxy-3-oxa-16, 1, 16, 19, t-butyl ester 20- pentanor-5-prostenoic; 4. (5Z) - (9S, 11R, 15R) -15- Cyclohexyl-3-oxa-9, 11, 15-tr ihydroxy-16, 17, 16, 19,20-pentanor-5-prostenoic acid isopropyl ester; "'5. (5Z) - (9R, 11R, 15S) -9- chloro-15-cyclohexyl-ll, 15-dihydro-i-3-oxa-16,17,16,19,20- isopropyl ester pentanor-5-prostenoic acid 6. (5Z) - (9R, 11R, 15R) -9-chloro-15-cyclohexyl-ll, 15-dihydro-i-3-oxa-16,17,16,19 amide , 20-pentanor-5-prostenoic acid; 7.- N, N-dimethylamide of (5Z) - (9R, 11R, 15R) -9- chloro-15-cyclohexyl, 15-dihydroxy-3-oxa- 16, 17, 16, 19, 20- ^ entanor-5-prostenoic acid, 6-methyl-1-methylhexyl ester of (5Z) - (9R, 11R, 15R> -9-chloro-15-cyclohexyl, 5-dihydroxy-3-o? A-16,17,16,19,20-pentanor-5-prostenoic acid; 9. (1-methylcyclopentyl ester of (5Z) - (9R, 11R, 15R) -9-chloro- 15-cyclohexyl-ll, 15-dihydro-3-o? A-16,17,16,19,20-pentanor-5-prostenoic acid;
. cyclopentyl ester of (5Z) - (9R, 11R, 15R> V-chloro-15-iclohexyl-ll, 15-dihydroxy-3-oxa-16,17,16,19,20-pentanor-5-prostenoi) or; 11. (2,2Z) - (9R, 11R, 15R> -9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16, 17, 16, 2,2-dimethylpropyl ester; 19,20-pentanor-5-prostenoic acid 12. ada antyl ester of (5Z) - (9R, 11R, 15R) -9-chloro-15-iclohexyl-ll, 15-dihydro-i-3-oxa-16 , 1, 16, 19, 20-pentanor-5-prostenoic; "13. (2,6-diisopropylphenyl) ester of (5Z) - (9R,
11, 15R) -9-chloro-15-cyclohexyl-ll, 15-dihydro-i-3-oxa-16,17,16,19, 20-pentanor-5-prostenoic acid; 14. 2,6-dimethylphenyl ester of acid < 5Z) - (9R, 11R, 15R) -9 ~ chloro-15-cyclohexyl-ll, 15-dihydroxy-3-o? A- 16,17,16,19,20-pentanor-5-prostenoic; 15. isopropyl ester of acid (SZ, 13E) - (9S, 11R, 15R) -3-oxa-9,11,15-trihydro-i-16- (3-chlorophenoxy) -17,16,19,20- . etranor-S, 13-prostadienoic; 16. (5Z) - (9Rt 11R, 15R) -9- chloro-15-cyclohexyl-l-hydroxy-15-methoxy-3-oxa-16,1, 16,19,20 t-butyl ester - pentanor-5-prostenoic; 17. (5Z) - (9R, 11R, 15R) -15- cyclohepyl-3-oxa-9, 11, 15-tr ihydroxy-16, 17, 16, 19,20-pentanor-5- isopropyl ester prostenoic;
16. isopropyl ester of the acid (5E) - (9R, 11R, 15R) -9 - «_ ioro-15-ci lohexil-ll, 15-di idroxi-3-o? a-16,17,16,19,20-pentanor -5-prostenoi or; 19. (5Z) - (9R, 11R) -9-Chloro-15-cyclohexyl-11-hydroxy-3-oxa-15-oxo-16,17,16,19,20-pentanor- 5- terbutil ester prostenoic; 20. (5Z) - (9S, 11R, 15R> -3-o? A-17-phenyl-9,11,15-trihydroxy-16, 19,20-trinor-5-prostenoic acid isopropyl ester; (5Z) - (9R, 11R, 15R) -9-chloro-15-c-iclohexyl-1- ~ iimet i -no) -3-oxa-16, 17,16,19,20-pentanor-5-prosteno -l1, 15-diol; 22. (5Z) - (9R, 11R, 15R) -9-chloro-15-cyclohexyl-1,1, 15-dihydro-i-3-o? A-16, 17, 16, 19,20-pentanor- 5-prostenol; 23. (9R, 11R, 15R) -9-chloro-15-cyclohexyl-11-hydro? I-3-thia-16,17,16, 19,20-pentanor-13-prost inoic acid; 24. Latanoprost (PhXA41); 25. isopropyl ester of cloprostenol; 26. (5Z) - (9S, 11R, 15R) -l-decarba? Il-pivaloyloxy) methyl-9,11,15-tr ihydroxy-16-C (3-chlorophenyl) oxy 1-17,16,19 acid , 20-tetranor-5-prostenoic; 27. (5Z) - (9S, 11R, 15R) -l-decarboxy? Il- (pivaloyl? I) et i 1-9, 11, 15-trihydro i-16C (3-chlorophenid I 117, 16, 19 , 20-tetranor-5, 13-prostadienoic acid, 26. (5Z) - (9R, 11R, 15R) -9-chloro-15-cyclohexyl, 15-dihydro i-16,17 isopropyl ester , 19,20-pentanor-5-prostenoic;
29. isopropyl ester of (5Z) - (9S, 11R, 15SJ 15- c.:clohexyl-9,ll, 15-trihydroxy-16,17,16,19,20-pentanor-5-prostenoic acid; acid (5Z, 13E) - (9S, 11R, 15R) -9,11,15-trihydro-i-16- (3-chlorophenoxy) -17,16,20,20-tetranor-5,13-prostadienoic acid; isopropyl ester of PGF-aβ, and 32. isopropyl ester of luprostenol All the above compounds are known The preferred "" ostaglandins to be used in the compositions of the present invention are compounds 2-6 above. Preferred are compounds 2 and 3. The structures of compounds 2 and 3 are shown below.
(3) (2) The prostaglandin compositions of the present invention contain one or more polyethoxylated castor oils in an amount effective to increase the stability of the prostaglandin. As illustrated in FIG. 1, the stabilizing effect of polyethoxylated castor oil increases with increasing concentration of polyethoxylated castor oil. However, other factors may limit the amount of polyethoxylated castor ceite to be used in the compositions of the present invention. For example, too much polyethoxylated castor oil should not be used to prevent it from adversely affecting the pharmacological activity of prostaglandins. In general, the compositions of the present invention include one or more polyethoxylated castor oils in an amount between about 0.02 and 20.0% by weight and one or more prostaglandins in an amount between 0.00001 and 0.2% by weight. It is preferred to use one or more polyexylated castor oils in an amount between about 0.1 and 5.0 wt%, and it is especially preferred to use an amount between 0.5 and 2.0% by weight approximately. It is preferred to use one or more prostaglandins in an amount between about 0.0001 and 0.1% by weight depending on the potency of the prostaglandin. The compositions of the present invention can be administered to the body in a variety of ways. Compositions can be administered by mouth, by intravenous injection, or by topical application to the skin, nose or eyes. More preferred are compositions prepared for topical administration to the eye. In addition to the main active ingredients described above, the compositions of the present invention may additionally comprise various formulation ingredients, such as antimicrobial preservatives, tonicity agents, and pH regulating agents. Examples of suitable antimicrobial preservatives include: benzalcanium chloride, thiol, chlorobutanal, met i lparaben, propylparaben, phenylethyl alcohol, disodium edetate, sorbic acid, Polyquad <; R > and other agents equally well known to those skilled in the art. Such preservatives, if used, will typically be employed in an amount between 0.001 and 0.001 and 1.0% by weight approximately. Examples of suitable agents that can be used to adjust the tonicity or molarity of the formulations include sodium chloride, potassium chloride, mannitol, dextrose, glycerin and polyethylene glycol. Such agents, if used, will be used in an amount between 0.1 and 10.0% by weight approximately. Examples of suitable pH regulating agents include acetic acid, citric acid, carbonic acid, phosphoric acid, boric acid and the pharmaceutically acceptable salts of the foregoing, and tromethamine. Such pH regulating agents, if used, will be employed in an amount between 0.001 and ... 0% by weight approximately. The compositions of the present invention may additionally include components to provide sustained release, comfort or both. Such components include mucomimetic anionic high molecular weight polymers and gelling polysaccharides, such as those described in US 4,661,760 (Mazuel et al.), US 4,911,920 (Jani et al.), And in Series No. 06 / 106,624 of the United States. United (Lang et al.) "Commonly condoned The content of these patents and the patent applications relating to the polymers cited above are hereby incorporated by reference, As will be appreciated by those skilled in the art, the compositions may be formulated in several. dosage forms suitable for topical ophthalmic release, including solutions, suspensions, emulsions, gels, and solid, erosible ocular inserts.The compositions are preferably aqueous, having a pH between 3.5 and 6.0 and an osmolality between -0.0 and 320 iliOsmoles per kilogram (mOsm). / kg) The present invention is also directed to methods for treating glaucoma and other diseases and ophthalmic abnormalities. The methods comprise the topical application to the eye or affected eyes of the patient of a therapeutically effective amount of a composition, in accordance with the present invention. The frequency and amount of dose will be determined by the clinician, based on several factors
'J. The methods will typically comprise topical application to the affected eye of one or two drops (approximately 30 microliters) of a liquid composition, or an equivalent amount of a solid or semisolid dosage form, either naively or twice daily.
^ - EXAMPLE
The following topically administrable ophthalmic formulations are representative of the compositions of the present invention.
Formulation (% p) INGREDIENT
Compound 2 0.01 0.01
Compound 3 0.01 Cremophor® EL 0.5 0.5 0.5
Sodium acetate 0.07 0.07 (Trihydrate) ^ ometa ina 0.12
Boric acid 0.3
Mannitol 4.6 4.6 4.6
Disodium EDTA 0.1 0.1 0.1
Benzal-conium chloride 0.01 0.01 0.01
NaOH and / or HCl c.s to c.s. for c.s. for pH5 pH5 pH5 Purified water q.s. for c.s. for c.s. for 100% 100% 100% Ü ^ JEPARACIQN OF FORMULATIONS A-C: Approximately 75% of the volume of the water batch was added to a clean glass container of appropriate size. To this was added sequentially sodium acetate, tromethamine, boric acid, mannitol, EDTA, benzalkonium chloride and Cremophor® EL so that there would be complete dissolution of one ingredient before the addition of the next. Then the pH of the solution was adjusted using NaOH and / or HCl, and the water was added to bring the volume to 100%. In a separate clean glass container, the appropriate amount of prostaglandin was added, followed by the appropriate amount of the vehicle whose preparation was described above. The container was then sealed and treated with sound in an ultrasonic bath for one hour or alternatively stirred with a magnetic stir bar overnight, until the prostaglandin completely dissolved. The resulting solution was then filtered on sterile (0.2 micron filter) sterile containers. These containers were then aseptically closed, capped and labeled. The stabilizing effect of the polyethoxylated castor oils in the compositions of the present invention was evaluated according to the following procedure. 1. Pipette the required amount of the methanolic supply solution of prostaglandin at 1% w / v 16
in 1.5 ml high resolution liquid chromatography (HPLC) sample bottles. 2. Dry the sample vials under a helium stream. 3. Add 1 ml of the appropriate vehicle (or the mobile phase of the HPLC for the standards). 4. Treat the bottles with sound for 1 hour to dissolve the prostaglandin. 5. Run the initial tests of CLAR. 6. Place the sample bottles of CLAR in 20-cm flasks with several ml of deionized water and cap tightly. (Note: this prevents loss due to evaporation). The patterns were stored with the mobile phase of CLAR in the titration flask. 7. Place the jars in the appropriate temperature controlled ovens and periodically reanalyze by CLAR. The patterns were stored in a refligerator. 6. CLAR data analysis: Divide the peak area of the sample between the peak area of the pattern and multiply by 100 to obtain the percent of pattern for each sample at each time point. 9. Graph the percent of pattern against time on a semi-logical graph. Make a monoe-equation for the data. Slope time 2.303 is the first order apparent degradation rate constant for each graph (Note: the factor of 2.303 converts the common logarithm to natural logarithm). Figure 1 demonstrates the effect of increasing the concentration of polyethoxylated castor oil in formulation A. The chemical stability of a given concentration of prostaglandin increases with increasing concentration of Cremophor.RTM. EL. Figure 2 demonstrates the superior stabilizing effect of the polyethoxylated castor oils Cremophor® EL and Alkamuls' * EL-620, on Polysorbate 60 in a type A formulation (pH = 5.0). Figure 3 demonstrates the superior stabilizing effect of polystyrene castor oils Cremophor,, EL and Alkamuls'!, EL-620, on Polysorbate 60 in a type C formulation (pH = 7.4). The data shown in Figures 1-3 were generated using a Phenomene CLAR column? 250 X 4.6 mm with packaging SpherisorbR 10 0DS (2). The mobile phase was acetonitrile / 0.1% phosphoric acid, 50/50, at pH 3 with NaOH, 5mM tetrabutylammonium hydroxide, and dodecyl 5mM sodium phosphate. The flow rate was 2mL / minute, the detection was at UV 190-192nm, and the injection amount was 25mcL. The invention has been described with reference to certain preferred embodiments; however, it should be understood that variations may be incorporated into other specific forms thereof, without departing from its spirit or essential characteristics. The embodiments described above are therefore considered illustrative and not restrictive in all considerations, the scope of the invention is indicated rather by the appended cl than by the foregoing description.
Claims (25)
1. - A pharmaceutical composition comprising a prostaglandin, a polyethoxylated castor oil in an amount effective to increase the chemical stability of the prostaglandin, and a pharmaceutically acceptable carrier.
2. The composition according to claim 1, further characterized in that the polyethoxylated castor oil is present in a concentration of between 0.02 and 20.0% by weight approximately.
3. The composition according to claim 2, further characterized in that the polyethoxylated castor oil is present in a concentration of between 0.1 and 5.0% by weight approximately.
4. The composition according to the pr indication 3, further characterized in that the polyethoxylated castor oil is present in a concentration of between 0.5 and 2.0% by weight approximately.
5. The composition according to claim 1, further characterized in that the polyethoxylated castor oil is selected from the group consisting of castor oils PEG-2 to PEG-200 and hydrogenated castor oils PEG-5 to PEG-200. 6.- The composition in accordance with the? "?
No. 5, characterized further because the polyethoxylated castor oil is selected from the group consisting of castor oil PEG-15 to PEG-50.
The composition according to claim 6, further characterized in that the polyethoxylated castor oil is selected from the group consisting of castor oil PEG-30 to PEG-35.
8. The composition according to claim 1, further characterized in that the aglandin pros is selected from the group consisting of: acid (5Z) - (9R, 11R, 15R) -9-chloro-15-c-clohex? 1-11, 15-d? h? drox? -3-oxa-16.17, 18.19, 20-pentanor-5-prostene? co; isopropyl ester of the acid (5Z3-Í9R, 11R, 15R) -9-chloro-15-c? clohex? l-ll, 15-d? h? drox? -3-oxa-16, 17,18.19, 20 -pentanor-5-prosteno? co; (5Z) - (9R, 11R, 15R) -9-chloro-15-c-clohexyl-1, 15-d? h? drox? -3-oxa-16,17,18 t-butyl ester , 19,20-pentanor-5-? Rostene? Co; isopropyl ester of acid (5Z) - (9S, 11R, 15R) -15-c? clohex? l-3-ox * 9,11, 15-tnh? drox? -16,17,18,19, 20-pentanor -5-prosteno? Co; isopropyl ester of (5Z) - (9R, 11R, 15S) -9-chloro-15- * c? clohex? l-ll, 15-d? h? drox? -3-oxa-16,17,18, 19,20-pentanor-5-prostenoic; amide of (5Z) - (9R, 11R, 15R) -9-chloro-15-c? clohex? l-ll, 15-d? h? drox? -3-oxa-16,17,18,19, 20-pentanor-5-prostenoic; N, Nd? Met? Lam? Of acid (5Z) - (9R, 11R, 15R) -9- chloro-15-c? Clohex? L-ll, 15-d? H? Drox? -3-oxa- 16,17,18,19 20-? En-tanor-5-prosteno? Co; l-met? Lc? Clohex? L ester (5Z) - (9R, 11R, 15R) -9-chloro-15- c? Clohex? l-ll, 5-d? h? drox? -3-oxa-L '"-17,18,19, 20-pentanor-5? rostene? co; 1-met? lc? clopent? the acid ester (5Z) - (9R, 11R, 15R) -9-chloro-15-c? clohex? l-ll, 15-d? h? droxi-3-oxa-16, 17, 18.19, 20-pentanor-5-prostene? Co; cyclopentyl ester of (5Z) - (9R, 11R, 15R) ~ 9-chloro-15-cyclohexyl-11, 15-d? Hydroxy-3-oxa-16, 17, 18, 19, 20-pentanor-5-prostenoic acid; 2,2-dimethylproicyl ester of (5Z) - (9R, 11R, 15R) -9-chloro-15-c-clohexyl-11, 15-dihydroxy- 3-oxa-IB, 17,18, 19,20-pentanor-5-prostenoic acid ada antyl ester (5Z) - (9R, 11R, 15R) -9-chloro-15-cyclohexyl-11, 15 -c,? idroxy-3-oxa-16, 17, 18,19, 20-? entanor-5-rostenoic, -6,6-diisopropylphenyl ester of (5Z) - (9R, 11R, 15R) -9 -cioro-15-cyclohexyl-ll, 15-dihydroxy-3-oxa-16, 17, 18,19, 2D-pentanor-5-prostenoic, - 2,5-d? meti (5Z) - (9R, 11R, 15R) -9-Chloro-15-cyclohexyl-11,15-ihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid lphenyl ester; isopropyl ester of acid (5Z, 13E) - (9S, 11R, 15R) -3-oxa-9, 11, 15-trihydroxy-16- (3-chlorophenoxy) -17, 18, 19, 20-tetranor-5, 13-prostadienoic; t-butyl éf'ar of (5Z) - (9R, 11R, 15R) -9-chloro-15-cyclohexyl-11-hydroxy-15-methoxy-3-oxa-16, 17,18,19 20-pentanor-5-prostene? Co; isopropyl ester of (5Z) - (9R, 11R, 15R) -15-cyclohexyl-3-oxa-9,11,15-trihydroxy-16,17,18,19,20-pentanor-5-prostene-co; isopropyl ester of (5E) - (9R, 11R, 15R) -9-chloro-15-cyclohexyl-11, 15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid; terbutilic acid ester (5Z) - (9R, HR) -9-chloro-15-cyclohexyl-l-hydroxy-3-oxa-15-oxo-16,17,18,19,20-pentanor-5-prostenoic acid; isopropyl ester of the acid (5Z) - (9S, 11R, 15R) -3-ov. ** "" 17-phenyl-9,11,15-trihydroxy-18,19,20-trinor-5-prostenoic acid; (5Z) - (9R, 11R, 15R) -9-chloro-15-cyclohexyl-1- (dimethylamino) -3-oxa-.16,17,18,19,20-pentanor-5-prostene-11, -diol; (5Z) - (9R, 11R, 15R) -9-chloro-15-cyclohexyl-ll, 15-dihydrox.i-3-oxa-16,17,18,19,20-pentanor-5-rostenol; (9R, 11R, 15R) -9-Chloro-15-cyclohexyl-11-hydroxy-3-thia-15,17, 18, 19, 20-pentanor-13-β-rostinoic acid; Latanoprost (PhXíHl); isopropyl ester of cloprostenol; (5Z) - (9S, 11R, 15R) -1-decarboxy-1- (p? valoyloxy) methyl-9,11,15-trihydroxy-16-C (3-chlorophenyl) oi ~ 1,8,19 20-tetranor-5-prostenoic; (5Z) - (9S, 11R, 15R) -l-decarboxy-l- (pivaloyloxy) methyl-9,11,15-trihydroxy-16C (3-chlorophenyl) oxy] 17, 18,19, 20-tetranor- 5, 13-prostenoic; isopropyl ester of (5Z) - (9R, 11R, 15R) -9-chloro-15-cyclohexyl-11, idioxy-16,1, 18,1, 20-pentanor-5-prostenoic acid; isopropyl ester of (5Z) - (9S, 11R, 15S) -15-cyclohexyl-9, 11,15-trihydro i-16, 17, 18, 19, 20-pentanor-5-prostenoic acid; amide of the acid (5Z, 13E) - (9S, 11R, 15R) -9,11,15-trihydroxy-16- (3-cir J "Ofenoxi) -17,18,19,20-tetranor-5,13-
9. The composition according to claim 8, further characterized in that the prostaglandin is selected from the group consisting of: isopropyl ester of < 5Z acid) (9R, 11R, 15R) -9-chloro-15-cyclohexyl-11, 15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic; t- util acid ester (5Z) ) - (9R, 11R, 15R) -9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid;
? 4 * ^ ropil acid ester (5Z) - (9S, 11R, 15R) -15-cyclohe3-oxa-9, 11, 15-trihydroxy-16, 17,18,19, 20-pentanor- 5-prostenoic; isopropyl ester of (5Z) - (9R, 11R, 15S) -9-chloro-15-c-clohe11, 15-dihydroxy-3-oxa-16,17,18,19,20-? entanor-5 -prostenoic; amide of (5Z) - (9R, 11R, 15R) -9-chloro-15-cyclohell, 15-dihydroxy-3-oxa-16,17,18,19,20-? entanor-5-prostenoic acid; N, N-dimethylamide of (5Z) - (9R, 11R, 15R1-9-chloro-15-cyclohe11,15-dihydroxy-3-oxa-16, 17, 18, 19,20-pentanor-5- rostenoic, and 1-methylcycloheester of the acid iy¿) - (9R, 11R, 15R) -9-chloro-15-cyclohell, 5-dihydroxy-3-oxa-16,17,18,19,20- pentanor-5-prostenoic.
10. The composition according to claim 9, further characterized in that the prostaglandin is selected from the group that you were connected to: (5Z) - (9R, 11R, 15R) -S-chloro-15-cycloheisopropyl ester , 15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid; and (5Z) - (9R, 11R, 15R) -9-chloro-15-CA * -he11,15-dihydroxy-3-oxa-16, 17, 18, 19, 20- t-butyl ester pentanor-5-prostenoic.
11. The composition according to claim 1, further characterized in that the prostaglandin is present in a concentration of between 0.0001 and 0.1% by weight approximately.
12. The composition according to claim 1, further characterized in that it is a topically adustable ophthalmic composition.
13. - A method for increasing the chemical stability of a pharmaceutical prostaglandin composition, comprising the addition of a polyethoted castor oil to the composition.
14. The method according to the claim
13, further characterized in that the polyethoted castor oil is present in a concentration of between 0.02 and 20.0% by weight approximately.
15. The method according to claim v, further characterized in that the polyethoted castor oil is present in a concentration of between 0.1 and 5.0% by weight approximately.
16. The method according to claim 15, further characterized in that the polyethoted castor oil is present in a concentration of between 0.5 and 2.0% by weight approximately.
17. The method according to claim 1, further characterized in that the polyethoted castor oil is selected from the group consisting of castor oil PEG-2 to PEG-200 and hydrogenated castor oil PEG-5 to PEG- 200.
18. The method according to claim 17, further characterized in that the polyethoted castor oil is selected from the group q? E consisting of PEG-15 to PEG-50 castor oils.
19. The method according to claim 1! further characterized in that the polye + oted castor oil is selected from the group consisting of PEG-30 to PEG-35 castor oils.
20. The method according to claim 13, further characterized in that the prostaglandin is selected from the group consisting of acid (5Z) - (9R, 11R, 15R) -9-chloro-15-c? Clohex? L-ll , 15-d? H? Drox? -3-oxa-16, 17, 18, 19,20-pentanor-5-prostene? Co; isopropyl ester of acid (5Z) - (9R, 11R, 15R) -9-chloro-15-c? clohex? l-ll, 15-ß. ,? idrox? -3-oxa-16,17,18,19,20-pentanor-5-prostene? co; acid t-butyl ester (5Z) - (9R, 11R, 15R) -9-chloro-15-c-clohe11, 15-d? h? drox? -3-oxa-16, 17, 18 , 19, 20-pentanor-5-prostene? Co; isopropyl ester of (5Z) - (9S, 11R, 15R) -15-c? clohex? -3-oxa-9,11, 15-tph? drox? -16,17,18,19,20-? entanor-5-prosteno? co; isopropyl ester of (5Z) - (9R, 11R, 15S) -9-chloro-15-cyclohe11, l5-d? h? drox? -3-oxa-16, 17, 18, 19,20 -pentanor-5-prostenoic; amide of (5Z) - (9R, 11R, 15R) -9-chloro-15-c, i.ohex? l-ll, 15-d? h? drox? -3-oxa-16,17,18, 19,20-pentanor-5-prostenoic; N, Nd? Met? Lam? Of the acid (5Z) - (9R, 11R, 15R) -9-chloro-15-c? Clohex? L-ll, 15-d? H? Drox? -3-oxa- 16,17,18,19,20-? Entanor-5-prostene? Co; l-met? Lc? Clohex? (5Z) ~ (9R, 11R, 15R) -9-chloro-15-c acid ester ? clohex? l-ll, 5-d? h? drox? -3-oxa-16, 17,18,1, 20-pentanor-5-prostene? co; 1-met? Lc? Clopenthe acid ester (5Z) - (9R, 11R, 15R) -9-chloro-15-c? Clohex? Ll-ll, 15-d? ? -3-oxa-16,1, 18, 19,20-pentane? -5-prostenoic acid; acid cyclopentyl ester (5Z) - (9R, 11R, 15R) -9-chloro-15-c • *? - 'ohex? l-ll, l5-dihydrox? -3-oxa-16, 17, 18.19 , 20-pentanor-5-prostenoic; 2, 2-dimethyl-ro-pyl ester of (5Z) - (9R, 11R, 15R) -9-chloro-15-cyclohexyl-11, 15-dihydro-3-oxa-16,17,18,19,20 -pentanor-5-prostenoic acid-adamantyl ester (5Z) - (9R, 11R, 15R) -9-chloro-15-cyclohexyl-ll, 15-dihydroxy-3-oxa-16, 17, 18, 19, 20-pentanor-5-prostenoic; 2,6-diisopropylphenyl ester of (5Z) - (9R, 11R, 15R) -9-chloro-15-cyclohexyl-11, 15-dihydroxy-3-oxa-16,17,18,19,20-pentanor- 5-prostenoic; 2, 6-dimethylphenyl ester of (5Z) - (9R, 11R, v -9-chloro-15-cyclohexy-11,15-dihydroxy-3-oxa-16,17,18, 19,20-? Entanor- 5-prostenoic acid isopropyl ester (5Z, 13E) - (9S, 11R, 15R) -3-oxa-9, 11, 15-trihydroxy-16- (3-chlorophenoxy) -17, 18, 19, 20- tet anor-5, 13-prostadienoico; t-butyl ester of (5Z) - (9R, 11R, 15R) -9-chloro-15-cyclohexyl-l-hydroxy-15-methoxy-3-oxa-16, 17 18,19,20-pentanor-5-prostenoic acid isopropyl ester (5Z) - (9R, 11R, 15R) -15-cyclohexyl-3-oxa-9,11,15-trihydroxy-16,17 18,19,20-pentanor-5-prostenoic; ij 'Oropyl ester of the acid I5E) - (9R, 11R, 15R) -9-chloro-15-cyclohexyl-ll, dihydroxy-3-oxa-16,17,18 , 19,20-pentanor-5-prostenoic; terbutilic acid ester (5Z) - (9R, HR) -9-chloro-15-cyclohexy-1, 1-hydroxy-3-oxa-15-oxo-16, 17, 18, 19, 20-pentanor-5-prostenoic acid; isopropyl ester of (5Z) - (9S, 11R, 15R) ~ 3-oxa-17-phenyl-9,11,15-trihydroxy-18,19,20-trinor-5-prostenoic acid ester; (5Z) - (9R, 11R, 15R) -9-chloro-15-cyclohexyl-1- (dimethylamino) -3-oxa-16,17,18,19,20-pentanor-5-rostene-ll, -diol; (5Z) - (9R, 11R, 15R) -9-chloro-15-cyclohexyl-ll, 15-dihydroxy-3-oxa-1. { ^ - .. 7? A? G ^ 20-pentanor-d-prostenol; acid (9R, 11R, 15R) ~ 9-chloro-15-cyclohexyl-ll-hydroxy-3-thia-16,17,18,19,20-pentanor-13-prostinoic acid; Latanoprost (PhXR41); isopropyl ester of cloprostenol; (5Z) - (9S, 11R, 15R) -l-decarboxy-l- (pivaloyloxy) methyl-9,11,15-trihydroxy-16-C (3-chlorophenyl) oxy-17,18,19, 20-tetranor-5-prostene? Co; (5Z) - (9R, 11R, 15R) -1-decarbon i-1- (pivaloyloxy) eti1-9, 11, 15-trihydroxy-16C (3-chlorophenyl) oxyl7,18,19,20-tetranor-5 , 13-prostadienoic; isopropyl ester of (5Z) - (9R, 11R, 15R) -9-chloro-15-ti ... clohexyl-11,15 ihydroxy-16, 17, 18, 19, 20-pentanor-5-proetenoic acid; isopropyl ester of (5Z) - (9S, 11R, 15SJ-15-cyclohexyl-9,11,15-trihydroxy-16,17,18,19,20-pentanor-5-prostenoic acid (5Z, 13E) amide ) - (9S, 11R, 15R) -9,11,15-trihydroxy-16- (3-chlorophenoxy) -17,18,19,20-tetranor-5,13-prostadienoic acid; isopropyl ester of PGFs? Ot; isopropyl ester of fluprostenol
21. The method according to claim 25 '~ further characterized in that the prostaglandin is selected from the group consisting of isopropyl ester of (5Z) - (9R, 11R, 15R) -9- chloro-15-cyclohexyl-ll, 15-dihydroxy-3-oxa-16,17,18,19,20-? entanor-5-prostenoic; t-butyl ester of (5Z) - (9R, 11R, 15R) -9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16, 17, 18, 19, 20-pentanor-5-prostenoic acid isopropyl ester (5Z) - (9S, 11R, 15R ) -15-cyclohexyl-l-3-oxa-9,11,15-trihydroxy-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester (5Z) - (9R, 11R, 15S ) -9-chloro-15-cie ohex? L-11, 15-dihydroxy-3-oxa-16, 17, 18, 19, 20-pentanor-5-prostene ico; (5Z) - (9R, 11R, 15R) -9-chloro-15-cyclohexyl-l, 15-dihydroxy-3-oxa-16, 17, 18, 19, 20-pentanor-5 amide -proetenoic; N, N-N-dimethylamide of (5Z) - (9R, 11R, 15R) -9-chloro-15-cyclohexyl-ll, 15-dihydroxy-3-oxa-16,17,18,19,20 ~ pentanor-5 -prostenoic; and (5Z) - (9R, 11R, 15R) -9-chloro-15-cyclohexyl-l, 5-dihydroxy-3-oxa-16,17,18, 19,20-pentanor-5-methylcyclohexyl ester -prostenoic.
22. The method according to claim 1, further characterized in that the prostaglandin is selected from the group consisting of (5Z) - (9R, 11R, 15R) -9-chloro-15-cyclohexyl-isopropyl ester, 15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid; and (5Z) - (9R, 11R, 15R) -9-chloro-15-cyclohexyl-11, 15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-t-butyl ester - Rostenoic?
23. The method according to claim 13, further characterized in that the prostaglandin is present in; a concentration between 0.0001% and 0.1% by weight, approximately.
24.- The method of compliance with the claim
13, further characterized in that the stabilizing composition is a topically adustable, ophthalmic composition.
25. The use of a composition comprising a prostaglandin, a polyethoxylated castor oil, in an amount effective to chemically stabilize the? 'taglandin, and an ophthalmically acceptable vehicle, in the preparation of a medicament for the treatment of glaucoma and ocular hypertension.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/362,677 US5631287A (en) | 1994-12-22 | 1994-12-22 | Storage-stable prostaglandin compositions |
| US08362677 | 1994-12-22 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| MXPA96003560A true MXPA96003560A (en) | 1998-01-01 |
| MX9603560A MX9603560A (en) | 1998-01-31 |
Family
ID=23427079
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| MX9603560A MX9603560A (en) | 1994-12-22 | 1996-08-21 | Storage-stable prostaglandin compositions. |
Country Status (12)
| Country | Link |
|---|---|
| US (2) | US5631287A (en) |
| EP (1) | EP0812198B1 (en) |
| JP (3) | JP3631255B2 (en) |
| AT (1) | ATE208621T1 (en) |
| AU (1) | AU700574B2 (en) |
| CA (1) | CA2181172C (en) |
| DE (1) | DE69523951T2 (en) |
| DK (1) | DK0812198T3 (en) |
| ES (1) | ES2162951T3 (en) |
| MX (1) | MX9603560A (en) |
| PT (1) | PT812198E (en) |
| WO (1) | WO1997029752A1 (en) |
Families Citing this family (50)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6011062A (en) * | 1994-12-22 | 2000-01-04 | Alcon Laboratories, Inc. | Storage-stable prostaglandin compositions |
| AR002194A1 (en) † | 1997-03-17 | 1998-01-07 | Sanchez Reynaldo Alemany | COMPUTERIZED INSTRUMENT FOR THE ANALYSIS OF MOVEMENT. |
| AU725677B2 (en) * | 1997-05-09 | 2000-10-19 | Mount Sinai School Of Medicine Of The City University Of New York, The | 8-iso-prostaglandins for glaucoma therapy |
| US6235781B1 (en) | 1998-07-14 | 2001-05-22 | Alcon Laboratories, Inc. | Prostaglandin product |
| ATE285795T1 (en) * | 1998-07-14 | 2005-01-15 | Alcon Mfg Ltd | POLYPROPYLENE BASED CONTAINERS FOR PROSTAGLANDIN CONTAINING PRODUCTS |
| AR020661A1 (en) | 1998-09-30 | 2002-05-22 | Alcon Lab Inc | A PHARMACEUTICAL COMPOSITION TOPICA OFTALMICA, OTICA OR NASAL AND THE USE OF THE SAME FOR THE MANUFACTURE OF A MEDICINAL PRODUCT |
| US7678836B2 (en) * | 1999-11-04 | 2010-03-16 | Fxs Ventures, Llc | Method for rendering a contact lens wettable |
| US7166730B2 (en) * | 2000-01-27 | 2007-01-23 | Fine Tech Laboratories, Ltd | Process for the preparation of prostaglandin derivatives |
| KR100854056B1 (en) * | 2000-09-13 | 2008-08-26 | 산텐 세이야꾸 가부시키가이샤 | Eye drops |
| EP1386611A4 (en) | 2001-04-19 | 2009-05-13 | Teika Pharmaceutical Co Ltd | Medicines and medicinal kits |
| DE60326226D1 (en) * | 2002-03-21 | 2009-04-02 | Cayman Chemical Co | PROSTAGLANDIN F2 ALPHA ANALOGUE IN COMBINATION WITH AN ANTIMICROBIAL AGENT FOR THE TREATMENT OF GLAUCOMA |
| US20040079671A1 (en) * | 2002-08-29 | 2004-04-29 | Paramita Bandyopadhyay | Medicinal product packaging |
| KR101253941B1 (en) * | 2002-09-09 | 2013-04-16 | 산텐 세이야꾸 가부시키가이샤 | Transparent eye drops containing latanoprost |
| ATE442146T1 (en) | 2003-11-07 | 2009-09-15 | Senju Pharma Co | PHARMACEUTICAL COMPOSITION CONTAINING PROSTAGLANDIN |
| GB0329620D0 (en) * | 2003-12-22 | 2004-01-28 | Pharmagene Lab Ltd | EP2 receptor agonists |
| PL1759702T3 (en) * | 2004-05-26 | 2009-06-30 | Bayardo Arturo Jimenez | Method of preparing a latanoprost ophthalmic solution and solution thus produced |
| ES2314354T3 (en) * | 2004-11-09 | 2009-03-16 | Novagali Pharma S.A. | EMULSION OF WATER OIL TYPE WITH LOW CONCENTRATION OF CATIONIC AGENT AND POTENTIAL POSITIVE ZETA. |
| GB0501192D0 (en) * | 2005-01-20 | 2005-03-02 | Resolution Chemicals Ltd | Stable prostaglandin-containing compositions |
| US8030349B2 (en) | 2005-08-02 | 2011-10-04 | Santen Pharmaceutical Co., Ltd. | Method for prevention of degradation of thermally unstable medicament |
| CN103768070A (en) * | 2006-03-13 | 2014-05-07 | 株式会社·R-技术上野 | Aqueous composition |
| WO2007111806A2 (en) | 2006-03-23 | 2007-10-04 | Massachusetts Eye And Ear Infirmary | Cyclopentane heptanoic acid compounds for reducing body fat |
| US20080095863A1 (en) * | 2006-10-24 | 2008-04-24 | Alcon Manufacturing Ltd. | 2-pyrrolidone derivatives for preservation of ophthalmic, otic and nasal compositions |
| US20100120908A1 (en) | 2007-02-07 | 2010-05-13 | Teika Pharmaceutical Co., Ltd | Eye drop preparation comprising latanoprost |
| EP1985298A1 (en) * | 2007-04-24 | 2008-10-29 | Azad Pharma AG | Ophtalmic oil-in-water emulsions containing prostaglandins |
| CA2702478C (en) * | 2007-10-16 | 2014-12-09 | Sun Pharma Advanced Research Company Limited | Ophthalmic composition |
| EP2077105A1 (en) | 2008-01-02 | 2009-07-08 | Novagali Pharma SA | Ophthalmic Micellar Compositions with Enhanced Stability |
| EP2077104A1 (en) | 2008-01-02 | 2009-07-08 | Novagali Pharma SA | Micellar compositions with ophtalmic applications |
| EP2254549B2 (en) | 2008-03-17 | 2019-05-29 | Alcon Research, Ltd. | Aqueous pharmaceutical compositions containing borate-polyol complexes |
| TWI544927B (en) | 2008-03-17 | 2016-08-11 | 愛爾康研究有限公司 | Pharmaceutical compositions having low concentration of surfactants for promoting bioavailability of therapeutic agents |
| JP2009256281A (en) * | 2008-04-21 | 2009-11-05 | Teika Seiyaku Kk | Isopropyl unoprostone containing ophthalmic preparation formulation |
| EP2127638A1 (en) | 2008-05-30 | 2009-12-02 | Santen Pharmaceutical Co., Ltd | Method and composition for treating ocular hypertension and glaucoma |
| US20110293549A1 (en) | 2009-02-03 | 2011-12-01 | Athena Cosmetics, Inc. | Composition, method and kit for enhancing hair |
| EP2228058A1 (en) | 2009-03-04 | 2010-09-15 | Novagali Pharma S.A. | Anionic oil-in-water emulsion containing prostaglandins and uses thereof |
| TWI489997B (en) | 2009-06-19 | 2015-07-01 | Alcon Res Ltd | Aqueous pharmaceutical compositions containing borate-polyol complexes |
| RU2012124216A (en) * | 2009-11-11 | 2013-12-20 | Микро Лабс Лимитед | PHARMACEUTICAL COMBINATION OF PROSTAGLANDINE AND NSAID COMPOUNDS FOR TREATMENT OF GLAUCOMA AND EYE HYPERTENSION |
| EP2389939A1 (en) * | 2010-05-28 | 2011-11-30 | Novagali Pharma S.A. | Use of prostaglandins F2alpha and analogues for the healing of corneal and conjunctival lesions |
| FR2961694B1 (en) | 2010-06-29 | 2013-01-25 | Thea Lab | POLYMERIC DELIVERY SYSTEM FOR NON-VISCOUS SOLUTION BASED ON PROSTAGLANDIN WITHOUT PRESERVATIVE |
| EP2452669A1 (en) | 2010-10-29 | 2012-05-16 | Omnivision GmbH | Ophthalmic composition |
| WO2012078649A1 (en) | 2010-12-06 | 2012-06-14 | Follica, Inc. | Methods for treating baldness and promoting hair growth |
| ES2687494T3 (en) | 2011-01-19 | 2018-10-25 | Topokine Therapeutics, Inc. | Methods and compositions to reduce body fat |
| US8426471B1 (en) | 2011-12-19 | 2013-04-23 | Topokine Therapeutics, Inc. | Methods and compositions for reducing body fat and adipocytes |
| ITRM20120036A1 (en) * | 2012-02-02 | 2013-08-03 | Robert Davis Steigerwalt Jr | TRANSDERMAL APPLICATION OF PROSTAGLANDINE E1 FOR THE TREATMENT OF OCULAR ISCHEMIA. |
| US20150313825A1 (en) | 2012-11-21 | 2015-11-05 | Topokine Therapeutics, Inc. | Methods and compositions for locally increasing body fat |
| NO2753788T3 (en) | 2013-05-10 | 2018-06-16 | ||
| WO2014186504A1 (en) | 2013-05-15 | 2014-11-20 | Topokine Therapeutics, Inc. | Methods and compositions for topical delivery of prostaglandins to subcutaneous fat |
| TWI612960B (en) * | 2014-01-10 | 2018-02-01 | Santen Pharmaceutical Co Ltd | Pyridylamino acetic acid compound and pharmaceutical composition containing polyoxyethylene castor oil |
| KR102281620B1 (en) | 2014-01-10 | 2021-07-23 | 산텐 세이야꾸 가부시키가이샤 | Pharmaceutical composition containing pyridylaminoacetic acid compound |
| US10188661B2 (en) | 2014-06-27 | 2019-01-29 | Topokine Therapeutics, Inc. | Topical dosage regimen |
| CA2999988C (en) | 2015-09-27 | 2024-06-11 | Follica, Inc. | Needling device and drug applicator |
| WO2020106522A1 (en) | 2018-11-21 | 2020-05-28 | Tremeau Pharmaceuticals, Inc. | Purified forms of rofecoxib, methods of manufacture and use |
Family Cites Families (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2526938C2 (en) * | 1975-02-14 | 1982-04-22 | F. Hoffmann-La Roche & Co. AG, 4002 Basel | Vitamin preparations |
| JPS6046094B2 (en) * | 1977-06-01 | 1985-10-14 | 科研製薬株式会社 | Stabilized prostaglandin E powder formulation |
| JPS59216820A (en) * | 1983-05-20 | 1984-12-06 | Taisho Pharmaceut Co Ltd | Fat emulsion of prostaglandin |
| DE3347128A1 (en) * | 1983-12-22 | 1985-07-11 | Schering AG, 1000 Berlin und 4709 Bergkamen | 9-HALOGEN- (DELTA) (ARROW HIGH) 2 (ARROW HIGH) -PROSTAGLAND IN DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS |
| DE3510978A1 (en) * | 1985-03-22 | 1986-09-25 | Schering AG, Berlin und Bergkamen, 1000 Berlin | NEW 9-HALOGEN PROSTAGLANDINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS |
| US5110493A (en) * | 1987-09-11 | 1992-05-05 | Syntex (U.S.A.) Inc. | Ophthalmic NSAID formulations containing a quaternary ammonium preservative and a nonionic surfactant |
| JP2597629B2 (en) * | 1988-02-26 | 1997-04-09 | 株式会社 上野製薬応用研究所 | Stabilization of 13,14-dihydro-15-ketoprostaglandins |
| US4960799A (en) * | 1988-09-13 | 1990-10-02 | Ciba-Geigy Corporation | Stabilized aqueous solutions of pharmaceutically acceptable salts of ortho-(2,6-dichlorophenyl)-aminophenylacetic acid for opthalmic use |
| JPH0669966B2 (en) * | 1989-07-05 | 1994-09-07 | 株式会社ミドリ十字 | Angiography aid |
| JPH03101622A (en) * | 1989-09-11 | 1991-04-26 | Green Cross Corp:The | Preventive and therapeutic agent of hepatitis |
| JP2785981B2 (en) * | 1989-11-20 | 1998-08-13 | 株式会社資生堂 | Emulsion composition |
| CA2031469A1 (en) * | 1989-12-28 | 1991-06-29 | Larry A. Wheeler | Use of inclusion complexes of prostaglandins with cyclodextrins in the treatment of ocular hypertension |
| JP3256997B2 (en) * | 1990-08-30 | 2002-02-18 | 千寿製薬株式会社 | Stable aqueous formulation |
| EP0664707B1 (en) * | 1992-10-13 | 1997-06-04 | Alcon Laboratories, Inc. | Combinations of prostaglandins and clonidine derivatives for the treatment of glaucoma |
| US5744155A (en) * | 1993-08-13 | 1998-04-28 | Friedman; Doron | Bioadhesive emulsion preparations for enhanced drug delivery |
| TW406020B (en) * | 1993-09-29 | 2000-09-21 | Bristol Myers Squibb Co | Stabilized pharmaceutical composition and its method for preparation and stabilizing solvent |
| AU687906B2 (en) * | 1993-12-15 | 1998-03-05 | Alcon Laboratories, Inc. | Use of certain prostaglandin analogues to treat glaucoma and ocular hypertension |
-
1994
- 1994-12-22 US US08/362,677 patent/US5631287A/en not_active Expired - Lifetime
-
1995
- 1995-12-19 AU AU46495/96A patent/AU700574B2/en not_active Expired
- 1995-12-19 DE DE69523951T patent/DE69523951T2/en not_active Expired - Lifetime
- 1995-12-19 ES ES95944447T patent/ES2162951T3/en not_active Expired - Lifetime
- 1995-12-19 PT PT95944447T patent/PT812198E/en unknown
- 1995-12-19 CA CA002181172A patent/CA2181172C/en not_active Expired - Lifetime
- 1995-12-19 EP EP95944447A patent/EP0812198B1/en not_active Expired - Lifetime
- 1995-12-19 WO PCT/US1995/017086 patent/WO1997029752A1/en active IP Right Grant
- 1995-12-19 AT AT95944447T patent/ATE208621T1/en active
- 1995-12-19 JP JP52494296A patent/JP3631255B2/en not_active Expired - Lifetime
- 1995-12-19 DK DK95944447T patent/DK0812198T3/en active
-
1996
- 1996-08-21 MX MX9603560A patent/MX9603560A/en unknown
- 1996-10-29 US US08/738,629 patent/US5849792A/en not_active Expired - Lifetime
-
2004
- 2004-10-15 JP JP2004302299A patent/JP2005015498A/en active Pending
-
2009
- 2009-11-24 JP JP2009266859A patent/JP2010043131A/en not_active Withdrawn
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