MXPA96000140A - Use of tocyferyl derivatives of vitamin e in oftalmi compositions - Google Patents
Use of tocyferyl derivatives of vitamin e in oftalmi compositionsInfo
- Publication number
- MXPA96000140A MXPA96000140A MXPA/A/1996/000140A MX9600140A MXPA96000140A MX PA96000140 A MXPA96000140 A MX PA96000140A MX 9600140 A MX9600140 A MX 9600140A MX PA96000140 A MXPA96000140 A MX PA96000140A
- Authority
- MX
- Mexico
- Prior art keywords
- vitamin
- agents
- ophthalmic
- tocopheryl
- agent
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 54
- 235000013343 vitamin Nutrition 0.000 title claims description 9
- 239000011782 vitamin Substances 0.000 title claims description 9
- 229930003231 vitamins Natural products 0.000 title claims description 9
- 229940088594 Vitamin Drugs 0.000 title claims description 8
- 150000003722 vitamin derivatives Chemical class 0.000 title claims description 8
- 150000003712 vitamin E derivatives Chemical class 0.000 claims abstract description 38
- 235000019165 vitamin E Nutrition 0.000 claims abstract description 32
- 239000011709 vitamin E Substances 0.000 claims abstract description 32
- 229930003427 Vitamin E Natural products 0.000 claims abstract description 31
- 229940046009 Vitamin E Drugs 0.000 claims abstract description 31
- 239000003732 agents acting on the eye Substances 0.000 claims abstract description 25
- 238000002360 preparation method Methods 0.000 claims abstract description 8
- 230000000699 topical Effects 0.000 claims abstract description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 23
- 150000002148 esters Chemical class 0.000 claims description 22
- -1 anti-allergens Substances 0.000 claims description 14
- 239000011780 sodium chloride Substances 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 8
- 229960001259 diclofenac Drugs 0.000 claims description 7
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 claims description 7
- 229960004492 Suprofen Drugs 0.000 claims description 4
- MDKGKXOCJGEUJW-UHFFFAOYSA-N Suprofen Chemical compound C1=CC(C(C(O)=O)C)=CC=C1C(=O)C1=CC=CS1 MDKGKXOCJGEUJW-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 claims description 4
- 230000001437 anti-cataract Effects 0.000 claims description 3
- 239000003443 antiviral agent Substances 0.000 claims description 3
- 201000009910 diseases by infectious agent Diseases 0.000 claims description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 3
- 231100000344 non-irritating Toxicity 0.000 claims description 3
- 229960003444 IMMUNOSUPPRESSANTS Drugs 0.000 claims description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 2
- 230000000840 anti-viral Effects 0.000 claims description 2
- 239000003102 growth factor Substances 0.000 claims description 2
- 230000001861 immunosuppresant Effects 0.000 claims description 2
- 239000003018 immunosuppressive agent Substances 0.000 claims description 2
- 230000003637 steroidlike Effects 0.000 claims 7
- 150000001408 amides Chemical class 0.000 claims 6
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims 4
- 239000002260 anti-inflammatory agent Substances 0.000 claims 4
- 229940116904 ANTIINFLAMMATORY THERAPEUTIC RADIOPHARMACEUTICALS Drugs 0.000 claims 3
- 229940074726 OPHTHALMOLOGIC ANTIINFLAMMATORY AGENTS Drugs 0.000 claims 3
- 229940100197 ANTIMETABOLITES Drugs 0.000 claims 2
- 230000000340 anti-metabolite Effects 0.000 claims 2
- 230000000111 anti-oxidant Effects 0.000 claims 2
- 239000002256 antimetabolite Substances 0.000 claims 2
- 239000003963 antioxidant agent Substances 0.000 claims 2
- 235000006708 antioxidants Nutrition 0.000 claims 2
- 239000000651 prodrug Substances 0.000 claims 2
- 229940002612 prodrugs Drugs 0.000 claims 2
- 239000001384 succinic acid Substances 0.000 claims 2
- 150000003611 tocopherol derivatives Chemical class 0.000 claims 2
- 241001093575 Alma Species 0.000 claims 1
- 206010013023 Diphtheria Diseases 0.000 claims 1
- 241000233866 Fungi Species 0.000 claims 1
- DKYWVDODHFEZIM-UHFFFAOYSA-N Ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 claims 1
- OZWKMVRBQXNZKK-UHFFFAOYSA-N Ketorolac Chemical compound OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 OZWKMVRBQXNZKK-UHFFFAOYSA-N 0.000 claims 1
- 239000002202 Polyethylene glycol Substances 0.000 claims 1
- 239000000654 additive Substances 0.000 claims 1
- 230000000996 additive Effects 0.000 claims 1
- 239000003242 anti bacterial agent Substances 0.000 claims 1
- 230000003110 anti-inflammatory Effects 0.000 claims 1
- 229940121363 anti-inflammatory agents Drugs 0.000 claims 1
- 239000002220 antihypertensive agent Substances 0.000 claims 1
- 239000004599 antimicrobial Substances 0.000 claims 1
- 230000002538 fungal Effects 0.000 claims 1
- 150000002334 glycols Chemical class 0.000 claims 1
- 229960000991 ketoprofen Drugs 0.000 claims 1
- 229920001223 polyethylene glycol Polymers 0.000 claims 1
- 230000003522 irritant Effects 0.000 abstract 1
- 239000002085 irritant Substances 0.000 abstract 1
- 231100000021 irritant Toxicity 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- AOBORMOPSGHCAX-UHFFFAOYSA-N Tocophersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-UHFFFAOYSA-N 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- KGBXLFKZBHKPEV-UHFFFAOYSA-N Boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 6
- 239000004327 boric acid Substances 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 5
- 239000004615 ingredient Substances 0.000 description 5
- 150000003180 prostaglandins Chemical class 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 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 4
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 229960000686 Benzalkonium Chloride Drugs 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
- 238000010521 absorption reaction Methods 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 239000011347 resin Substances 0.000 description 3
- 229920005989 resin Polymers 0.000 description 3
- 229940086735 succinate Drugs 0.000 description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 3
- 230000002459 sustained Effects 0.000 description 3
- PUSNGFYSTWMJSK-GSZQVNRLSA-N (2R,3R,4S,5R,6R)-2,3,4-trimethoxy-6-(methoxymethyl)-5-[(2S,3R,4S,5R,6R)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxyoxane;1-[[(2R,3R,4S,5R,6S)-3,4,5-tris(2-hydroxypropoxy)-6-[(2R,3R,4S,5R,6R)-4,5,6-tris(2-hydroxypropoxy)-2-(2-hydroxypropoxymethyl)oxan- Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](OC)O[C@@H]1COC.CC(O)CO[C@@H]1[C@@H](OCC(C)O)[C@H](OCC(C)O)[C@@H](COCC(O)C)O[C@H]1O[C@H]1[C@H](OCC(C)O)[C@@H](OCC(C)O)[C@H](OCC(C)O)O[C@@H]1COCC(C)O PUSNGFYSTWMJSK-GSZQVNRLSA-N 0.000 description 2
- PMATZTZNYRCHOR-CGLBZJNRSA-N (3S,6S,9S,12R,15S,18S,21S,24S,30S,33S)-30-ethyl-33-[(E,1R,2R)-1-hydroxy-2-methylhex-4-enyl]-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontane-2,5,8,11,14,17 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 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 229960004484 CARBACHOL Drugs 0.000 description 2
- AIXAANGOTKPUOY-UHFFFAOYSA-N Carbachol Chemical compound [Cl-].C[N+](C)(C)CCOC(N)=O AIXAANGOTKPUOY-UHFFFAOYSA-N 0.000 description 2
- 108010036949 Cyclosporine Proteins 0.000 description 2
- 229960003957 Dexamethasone Drugs 0.000 description 2
- UREBDLICKHMUKA-CXSFZGCWSA-N Dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 2
- 206010052143 Ocular discomfort Diseases 0.000 description 2
- 208000003251 Pruritus Diseases 0.000 description 2
- 229940035504 Tromethamine Drugs 0.000 description 2
- 229960001948 caffeine Drugs 0.000 description 2
- 229960001265 ciclosporin Drugs 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- KPHWPUGNDIVLNH-UHFFFAOYSA-M diclofenac sodium Chemical compound [Na+].[O-]C(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl KPHWPUGNDIVLNH-UHFFFAOYSA-M 0.000 description 2
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drugs Drugs 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 239000011859 microparticle Substances 0.000 description 2
- 229920001888 polyacrylic acid Polymers 0.000 description 2
- 229940037001 sodium edetate Drugs 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 2
- 229960000281 trometamol Drugs 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 235000019166 vitamin D Nutrition 0.000 description 2
- 239000011710 vitamin D Substances 0.000 description 2
- GJSURZIOUXUGAL-UHFFFAOYSA-N 2-((2,6-Dichlorophenyl)imino)imidazolidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K 2qpq Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 239000005541 ACE inhibitor Substances 0.000 description 1
- 229920000936 Agarose Polymers 0.000 description 1
- 229940088710 Antibiotic Drugs 0.000 description 1
- IEJXVRYNEISIKR-UHFFFAOYSA-N Apraclonidine Chemical compound ClC1=CC(N)=CC(Cl)=C1NC1=NCCN1 IEJXVRYNEISIKR-UHFFFAOYSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 229940030609 CALCIUM CHANNEL BLOCKERS Drugs 0.000 description 1
- LWAFSWPYPHEXKX-UHFFFAOYSA-N Carteolol Chemical compound N1C(=O)CCC2=C1C=CC=C2OCC(O)CNC(C)(C)C LWAFSWPYPHEXKX-UHFFFAOYSA-N 0.000 description 1
- 229960001222 Carteolol Drugs 0.000 description 1
- 235000013912 Ceratonia siliqua Nutrition 0.000 description 1
- 240000008886 Ceratonia siliqua Species 0.000 description 1
- 240000005497 Cyamopsis tetragonoloba Species 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 229960001193 Diclofenac Sodium Drugs 0.000 description 1
- SZXQTJUDPRGNJN-UHFFFAOYSA-N Dipropylene glycol Chemical compound OCCCOCCCO SZXQTJUDPRGNJN-UHFFFAOYSA-N 0.000 description 1
- 206010013082 Discomfort Diseases 0.000 description 1
- 229940052760 Dopamine agonists Drugs 0.000 description 1
- 206010013774 Dry eye Diseases 0.000 description 1
- UCTWMZQNUQWSLP-VIFPVBQESA-N Epinephrine Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 1
- 102100001490 FAM168B Human genes 0.000 description 1
- 101710039387 FAM168B Proteins 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 229940034031 Ipol Drugs 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 1
- 210000004185 Liver Anatomy 0.000 description 1
- NCXMLFZGDNKEPB-FFPOYIOWSA-N Natamycin Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C[C@@H](C)OC(=O)/C=C/[C@H]2O[C@@H]2C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 NCXMLFZGDNKEPB-FFPOYIOWSA-N 0.000 description 1
- 229960003255 Natamycin Drugs 0.000 description 1
- XAPRFLSJBSXESP-UHFFFAOYSA-N Oxycinchophen Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=C(O)C=1C1=CC=CC=C1 XAPRFLSJBSXESP-UHFFFAOYSA-N 0.000 description 1
- QCHFTSOMWOSFHM-WPRPVWTQSA-N Pilopine HS Chemical compound C1OC(=O)[C@@H](CC)[C@H]1CC1=CN=CN1C QCHFTSOMWOSFHM-WPRPVWTQSA-N 0.000 description 1
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 1
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 1
- 241000025483 Symphonia globulifera Species 0.000 description 1
- 210000001138 Tears Anatomy 0.000 description 1
- MGSRCZKZVOBKFT-UHFFFAOYSA-N Thymol Chemical compound CC(C)C1=CC=C(C)C=C1O MGSRCZKZVOBKFT-UHFFFAOYSA-N 0.000 description 1
- 239000005844 Thymol Substances 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 229940116362 Tragacanth Drugs 0.000 description 1
- 229940029983 VITAMINS Drugs 0.000 description 1
- 229940046008 Vitamin D Drugs 0.000 description 1
- 229930003316 Vitamin D Natural products 0.000 description 1
- 229940021016 Vitamin IV solution additives Drugs 0.000 description 1
- LRFVTYWOQMYALW-UHFFFAOYSA-N Xanthine Chemical class O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229940053550 agents used for ADHD and nootropics psychostimulants Xanthine derivatives Drugs 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 230000000964 angiostatic Effects 0.000 description 1
- 230000000844 anti-bacterial Effects 0.000 description 1
- 230000003064 anti-oxidating Effects 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940006133 antiglaucoma drugs and miotics Carbonic anhydrase inhibitors Drugs 0.000 description 1
- 229940121357 antivirals Drugs 0.000 description 1
- 229960002610 apraclonidine Drugs 0.000 description 1
- 239000008135 aqueous vehicle Substances 0.000 description 1
- 229960001716 benzalkonium Drugs 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- CYDRXTMLKJDRQH-UHFFFAOYSA-N benzyl-dodecyl-dimethylazanium Chemical compound CCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 CYDRXTMLKJDRQH-UHFFFAOYSA-N 0.000 description 1
- 230000000903 blocking Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 239000003489 carbonate dehydratase inhibitor Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229920003086 cellulose ether Polymers 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 229960002896 clonidine Drugs 0.000 description 1
- 150000001990 dicarboxylic acid derivatives Chemical class 0.000 description 1
- 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 1
- 239000003210 dopamine receptor blocking agent Substances 0.000 description 1
- 239000003136 dopamine receptor stimulating agent Substances 0.000 description 1
- 239000012154 double-distilled water Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 229910000267 dualite Inorganic materials 0.000 description 1
- 230000002708 enhancing Effects 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 150000004676 glycans Polymers 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000001145 hydrido group Chemical group *[H] 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 201000009673 liver disease Diseases 0.000 description 1
- 229940083747 low-ceiling diuretics Xanthine derivatives Drugs 0.000 description 1
- 230000003547 miosis Effects 0.000 description 1
- 230000003551 muscarinic Effects 0.000 description 1
- 239000004311 natamycin Substances 0.000 description 1
- 235000010298 natamycin Nutrition 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drugs Drugs 0.000 description 1
- 229940005943 ophthalmologic Antivirals Drugs 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229960001416 pilocarpine Drugs 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920000642 polymer 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
- 230000002335 preservative Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 150000007660 quinolones Chemical class 0.000 description 1
- 150000003873 salicylate salts Chemical class 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000002294 steroidal antiinflammatory agent Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229960000790 thymol Drugs 0.000 description 1
- 229930007823 thymol Natural products 0.000 description 1
- 229940026754 topical Antivirals Drugs 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000004034 viscosity adjusting agent Substances 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
Abstract
Ophthalmic compositions containing vitamin E tocopheryl derivatives that are comfortable and non-irritant are described, and the new use of ophthalmic agents together with vitamin E tocopheryl derivatives in the preparation of compositions to significantly reduce the discomfort and irritation associated with administration topical ophthalmic of ophthalmic agents alone, in addition, these tocopheryl derivatives of vitamin E significantly increase the aqueous solubility of certain poorly soluble ophthalmic agents
Description
USE OF VITAMIN E TOCOPHERYL DERIVATIVES IN OPHTHALMIC COMPOSITIONS
BACKGROUND OF THE INVENTION
The present invention relates generally to ophthalmic compositions. In particular, the present invention relates to the use of certain vitamin E tocopheryl derivatives to provide non-irritating and comfortable ophthalmic compositions. In addition, the present invention relates to the use of those tocopheryl derivatives of vitamin E for incrementai * the solubility of poorly soluble ophthalmic agents in aqueous compositions. For purposes of the present specification, the vitamin E tocopheryl derivatives useful in the present invention should be referred to as tocopheryl derivatives of vitamin E or vitamin E derivatives or "TPGS". The sensations of itching and burning, as well as general discomfort, are usually associated with the topical ophthalmic application of certain types of ophthalmic agents. It is considered that such ocular discomfort is due to the presence of certain functional groups in these agents. Examples of such ocular discomfort agents include, but are not limited to: blockers such as betapolol; prostanglandins and prostaglandin derivatives; muscarinics such as pilocarpjna; < x-aclr nérgi os such as epinephrine, clonidine and apraclon id ina; col ers such as carbachol; and nonsteroidal anti-inflammatory drugs ("NSAIDs") such as diclofenac and suprofen. Several attempts have been made to formulate topical ophthalmic compositions to reduce the inherent discomfort associated with those ophthalmic agents. Such attempts include those described in US 4, 559, 433 (Han et al.), US 14,911,920 (Jan. and others), US 5, 093, J 26 (Jan. and others, and (JS 5,212,162 (Missel et al.). Han et al. describes the addition of xanthine derivatives, such as to caffeine, to diminish the itching associated with topical ocular application of NSAJDs The two references of 3ani and others teach about the addition of certain ion exchange resins to blocking compositions to increase comfort and provide sustained release Missel et al. teaches combinations of gelling polysaccharides and finely divided drug carrier substrates ("DCS") that provide sustained and comfortable sustained release ophthalmic compositions In addition, US, 4,960,799 (Nagy) describes water-stable ophthalmic compositions containing diclofenac and / or pharmaceutically acceptable salts thereof Nagy compositions include EOTA and a solubilizer such as or ethoxylated castor oil.
BRIEF DESCRIPTION OF THE INVENTION
It has been unexpectedly discovered that the addition of certain vitamin E tocopheryl derivatives to the ophthalmic compositions provides such comfortable and non-irritating compositions. It has also been discovered that these vitamin E derivatives greatly improve the aqueous solubility of many compounds that are only sparingly soluble in aqueous compositions.
DETAILED DESCRIPTION OF THE INVENTION
Tocopheryl derivatives of vitamin E are water-soluble biologically active vitamin E analogues. These vitamin E derivatives have been used as alternatives to vitamin E, especially when water solubility is desired. In addition, the Patent of E.U.A. No. 3,102,076 describes the use of these derivatives to solubilize vitamins intimate in water of natural occurrence, such as vitamins A, D and E. The use of these vitamin E derivatives has also been reported to improve the absorption of the vitamin. A and the c? > by i.na. See, for example, Sol ', al, RJ et al., "I provement of Cyclosporin Absorption in Ohildren after Liver Tran plantat ion by Means of Water-soluble Vita in E", The lancet 336: 212-215 (1991), and Argao, EA et al., "< x-Toco? Hecyl Polyethylen Glycol-1000 succinate Enhances the Absorption of Vitamin D in" hronic Dhslestatic Liver disease of Jnfancy And Chiluhod ", Pediatpc Res. 31 (2): 146-150 <; 1992). Tocopheryl derivatives of vitamin E useful in the compositions of the present invention are polyoxyalkyl glycosides highly soluble in water of tocopheryl esters of vitamin E of a dicycloproteic acid. Representative characters of this type include the isocyclic polioether esters of vitamin E tocopheryl esters of a dicarboxylic acid wherein the polyoleic ester portion of the ester (sometimes referred to only as the polyoxyethylene glycol portion of the ester) has a molecular weight in the scale of approximately 600 to approximately 6,000, preferably in the range of approximately 600 to approximately 1,500. Such methods and methods for the preparation are described in US Patent No. 2,660,749 (Cawley et al.). The most preferred ester is the succinate of -tocof i Ipol io leti lenglical (1000), a polyexyl ester and glycol ester of succinate of < x-tocopheron in Junde the polyae and lengl icol portion of the molecule has an average molecular weight of about 1000. In general, one or more vitamin E derivatives are used in the compositions of the present invention in an amount T nor a about 30% by weight (p%). If the vitamin E derivatives are used as solubilization agents, it is preferred to use an amount between about 0.1 and about 20 in pee, very preferably between "" approximately 0.1 and about 5"? When the vitamin E derivatives are used to improve comfort, it is preferred to use an amount between approximately 0.1 and approximately 20% by weight, more preferable between approximately 0.5 and approximately 10% by weight. Suitable ophthalmic agents that can be included in the compositions of the present invention and administered by the method of the present invention include, but are not limited to, the racemic and enantiomeric forms and ophthalmically acceptable salts and esters of the following types of compounds : Agents for glauca, such as blockers (for example betaxalolol, thymol, and carteolol); «-agonists, (for example apraclonidine, and 2-substituted amino imidazolines) related); carbonic anhydrase inhibitors; dopamine agonists and antagonists; miotic mycotic cells (for example pilocarpine and carbachol); prostaglandin and postaglandin derivatives; ACE inhibitors; stabilizers (eg, glucarticaids and angiostatic steroids); and calcium channel blockers; Ant i-h ipei-tensors; non-steroidal anti-inflammatory agents; which include but are not limited to those classified as aryl- or heteroaryl-alkanoic acids such as diclofenac, flurbiprafe, suprofen, cetacolac, indametacin and cetoprsfen; Steroidal anti-inflammatory agents such as "'uorometoluna, dexamethasone, predncoluna, terahydritector 1 1 sol and tt i ame molona; antibacterials and agents against infections, such as anoglycosides (for example trcibamycin), quinolones (for example ciprofloxa ina and oflola apna), beta lactams (for example cef aos-pop ñas such as cef amlando); Anti fungal agents, such as natamycin; Antivirals, such as acicluvir and gane ícluvir; Anti-cataract and antioxidizing agents; Apti -allergic; Anti-metallites, such as 5-f lua? -ourac? 1 (5-FU) and metatrexate; Immunosuppressants, such as ciclosporin, Fr'-506 and leflummide; Growth factors such as EGF, FGF, PDGF, and Frofarmacos of the drug classes noted above.
Ophthalmic agent ions may also be used in the compositions of the present invention. Furthermore, in formulations without ophthalmic agents, the present invention can also be used to supply tears in the prevention or treatment of dry eye. Possibly Monday of the present invention may include other ophthalmically acceptable components, for example, pH regulators; (for example, phosphate, borate and citrate), chelating agents (for example • v ~ DTA), preservatives (for example benzalkonium urea,
Polyquide, i and Ovpied1"-) and tonicity agents (sodium chloride and mannitol) The compositions of the present invention may also include viscosity modifying agents such as cellulose ethers, such as hydroxypropyl ether cellulose.
(JPMC), hicirox iet ilcelulosa (HFC), et i 1 h idrox iet icelcellulose, hydroxypropylcellulose, methycellulose, and carboxy and ilcellulose; carbomers (Car-b pol); alcohol pol i v iní 1 ico, polivini lpirrolidona; alginates; carrageenans; and guar, caray, agarose, carob, tragacanth and xanthan gums. The concentration of the viscosity modifiers will vary from about 0.1 to about 5% by weight, although such formulations will generally have a viscosity between approximately 10 and approximately 1000 centipaise. Ophthalmic compositions containing TFGS may additionally contain polymers that can withstand the sol-a-gel transition by exposure to physical or chemical stimuli, such as changes in pH, ionic concentration, and / or temperature. The ophthalmic agents contained in the compositions of the present invention can optionally be encapsulated in microparticles. These charged microparticles can be dispersed in aqueous vehicles having TPGS to improve comfort. In addition, the water-soluble or water-insoluble complexes of the ophthalmic agent can be incorporated into a vehicle containing TPGS. Example of the 6
Water soluble complexes include traditional complexes formed between the ophthalmic agent and caffeine, cyclodexamins, salicylates, benzoates. Examples of water-insoluble complexes include ophthalmic-drug-resin complexes. The following examples are presented to illustrate various aspects of the present invention, although it is not intended to limit the scope of the invention in any aspect.
EXAMPLE 1
The following formulations are representative of the preferred compositions of the present invention.
FORMULATION (% IN WEIGHT) JNGRFDJENTFS A B C D E F G Diclofenac sodium 0.1 0.1 0.1 0.1 0.1 0.1
Dexamethasone - 0.1 Vitamin E TPGS (1000) 3.0 3.0 3.0 3.0 3.0 3.0 3.0
Trometamine 0.23 0.23 0. 3 1.2 1.2 - 0.23
Boric acid 1.0 1.0 1.0 1.5 1.5 - 1.0
Manitol 4.0 - - 3.0 4.0 - 4.0
Benzalkonium Chloride 0.01 0.01 0.01 0.100.01 0.01
NaCl 0.7 0. Disodium FDTA 0.1 0.1 .1 0.1 0.1 HPMC 0.1 0.3 0.1 0.3 Argin ina - 0.5 - HCl and / or NaOH pH at 7.4 Purified water 100 *
Preparation: Formulation D was prepared as follows, and formulations A-C and E-G were prepared in a similar manner. A 10 * base solution of vitamin E TPGS was prepared as follows. Approximately 150 g of vitamin E TPGS were melted in a beaker by heating on a hot plate with stirring to ensure homogeneity. Approximately 100 g (g) of melted TPGS was added to 600 ml of double distilled water near boiling. This mixture was stirred and allowed to cool to room temperature to ensure complete dissolution. Sufficient water was then added to the solution to make one liter of the bd'fe solution. Sodium diclofenac was added to (0.3 g) of the base solution to 90 ml of the TPGS solution after the complete dissolution of diclofenac, each of the following ingredients was added sequentially to the solution with stirring until that each ingredient was completely dissolved before adding the following ingredient: 1.5 g of arginine; 9.0 g of mannitol, 4. g of boric acid, 3.6 g of trameta ina and 0.3 g of sodium edetate. To the previous solution, 6.0 ml of a 0.5% solution of benzalcomo chloride was added, followed by the addition of 15 ml of a 2 * HPMC solution. An additional 150 ml of water was added and the pH of the formulation was adjusted to 7.4 HCl and / or NaOH. To the resulting solution, enough water was added to bring the total volume of the solution to 300 ml. The collapse of the final solution was approximately 300mOs / 1"g.
EXAMPLE 2
The following formulation is another representative composition of the present invention, wherein a prostaglandin was formed in complex with cyclodextrin and is formulated in accordance with the teachings of the present invention.
13
INGREDIENT CONCENTRATION (* by weight)
Prosta landina 0.25 Hydro i ro i 1-ß-c i lodextr ina 3.0 Trometain ina 1.2 Boric acid 1.5 Mannitol 1.0 Benzalkonium Chloride 0.0.1. EDTA Disodium 0.1 Vitamin E TPGS (1000) 3.0 HCl / NaOH pH to 74. Purified Water q.s. 100 *
Prepare ion: Appropriate amounts of tromethamine, boric acid, mapitol, BAC and EDT were added to 90 ml of a base solution at .10 * of TPGS. In a separate vessel, 9 g of hydroxypropyl 1-β-iclodextrin were dissolved in 150 ml of water. To these were added 0.75 g of a prostaglandin. The two solutions were mixed together later, adjusting the pH to 7.4 and water was added to bring the volume up to 300 ml.
EXAMPLE 3
The following formulation is another representative composition of the present invention, wherein a prostaglandin linked to Dualite® > (resins of 7 lolest iramin, available from Rohm &Haas, Philadelphia, Fennsylvania), is formulated in accordance with 1.1 > n the teachings of the present invention.
INGREDIENT CONCENTRATION (* by weight)
Pros ag land ina 0.25 I) uol? Te '"> 0.25 Vitamin E TPGS 3.0 Tro e a ina 1.2 Boric acid 1.5 Mani ol 4.0 Benzalkonium chloride 0.01 FDTA Disodium 0.3 HCl / NaOH pH to 7.4 Purified water q.s. 100 *
Preparation: A prostagland was dissolved (.75 g) in 200 ml of water. Finely divided Duolite (0.75 g) was added, and the solution allowed to equilibrate for 2 hours, during which time about 95 * of the drug was bound to the resin. In a repaired vessel, prudent amounts of tromethamine, boric acid, BAC, sodium edetate and amthol were added to 90 ml of the 10 * TPGS base solution. The two parts were then mixed and the pH was adjusted to 7.4 with HCl and / or NaOH. A sufficient amount of water was added to the formulation to bring the final volume to 300 ml.
The invention has been described by reference to certain preferred embodiments; however, it must be understood that it can be modalized in other specific ways or variations thereof without departing from the spirit or essential characteristics. The embodiments described above are therefore considered as illustrative in all respects and not co-or restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description.
Claims (7)
1. - An ophthalmic composition comprising: a therapeutically effective amount of one or more ophthalmic agents selected from the group consisting of: anti glaucous agents, belt tensioning agents, anti-inflammatory agents, non-sterile aggregates, steroidal antimicrobial agents, antibacterial agents, agents against infections, agents with fungi, anti-viral agents, anti-cataract agents, anti-oxidants, anti-allergens, anti-metabolites, immunosuppressants, anti-viral factors , and prodrugs thereof; an amount of a vitamin E tocopheryl derivative effective to significantly reduce the discomfort and irritation associated with topical ophthalmic administration of said ophthalmic agent; and a vehicle of chemically acceptable.
2. The composition of unfority with claim 1, characterized further park the ophthalmic agent is a non-steroidal anti-inf lamate agent.
3. The confrmity composition L in claim 2, further characterized in that the anti-inflammatory or steroidal agent comprises an aryl- or heteroaryl-alkanoic acid, to an ophthalmically acceptable salt, ester or amide thereof. 4.- L *? composition according to claim 3, face also raised because the non-steroidal anti-inflammatory agent is selected from the group consisting of: diclofenac, f lurbiprof in, suprofen, ketoralac, intimetacin, ketoprofen and salts, ophthalmically acceptable esters or amides thereof. 5. The composition according to claim 4, further characterized in that the non-steroidal anti-inflammatory agent is selected from the group consisting of diclofenac and its ophthalmically acceptable salts, esters or amides. 6. The composition according to claim 4, further characterized in that the anti-inflammatory agent na steraidal is selected from the group consisting of suprofen and its ophthalmically acceptable salts, esters or amides. 7. The composition according to claim 1, further characterized in that the tocopheryl derivatives of vitamin E are selected from one or more polyoxyethylene glycol esters of vitamin E of a succinic acid tocopheryl ester wherein the polyoxiet portion is selected. Illeglycol of the ester has a molecular weight on a scale between about 600 and about 60000. 6. The composition according to claim 7, further characterized in that the polyoxie and glycol portion of the ester has an average molecular weight of about 1000. The composition of the composition and claim 1, bristling face further, because the concentration of the tocopherol derivative of vitamin E or approximately 30% by weight. 10. The composition according to claim 9, further characterized in that the concentration of the tocopheryl derivative of vitamin E is between 0.1 and approximately 20 * by weight. 11. The composition according to claim 10, further characterized in that the concentration of the vitamin E tocopheryl derivative is between * approximately 0.5 and approximately 10 * by weight. 12. The use of an ophthalmic agent selected from the group consisting of anti-glaucous agents, anti-hypertensive agents, anti-infants, anti-steroidal agents, anti-inflammatory agents, steroidal anti-vaccines, anti-inflammatory agents infections, fungal agents, antiviral agents, anti-cataract agents, anti-oxidants, anti-allergens, anti-metabolites, suppressants, growth factors, and prodrugs thereof, in the preparation of a composition of a derivative of Tocopherol of vitamin E, for the preparation of compositions to significantly reduce the discomfort and irritation associated with the ophthalmic administration of the ophthalmic agent alone. 13. The use of an ophthalmic agent according to claim 1, further characterized in that the "ophthalmic agent" is a non-steroidal anti- non-steroidal agent and is for topical ophthalmic application 1
4. The use of an ophthalmic agent in accordance with claim 13, characterized in addition, because the nonsteroidal anti-inf lamatous agent comprises an aryl- or beteroaryl-alkanoic acid, or an ophthalmically acceptable salt, ester or amide thereof. 1
5. The use of an ophthalmic agent in accordance with claim 14, further characterized in that the non-steroidal additive anti-inf agent is selected from the group consisting of diclofenac and its ophthalmically acceptable salts, esters or amides 16.- New use of a derivative of vitamin E tocaferyl in the preparation of fields Cycres with one or more ophthalmic agents that are irritating to the eye, effective in significantly reducing the discomfort and irritation associated with topical ophthalmic administration of said agent of alma. Use of a vitamin E diplexel derivative according to claim 16, further characterized in that the tocopheryl derivative of vitamin E is selected from one or more polyethylene glycol ester of vitamin E of a succinic acid tocopheryl ester wherein the polyoleethylene glycol portion of the ester has a molecular weight on a scale between about 600 and about 6000. 1
6. The use of a vitamin 16 tocopheryl derivative. according to claim 17, further characterized in that the polyoxie i lengl icol portion of the ester has an average molecular weight of approximately 1000. 19. The use of a vitamin E tocopheryl derivative according to claim 16, further characterized in that the concentration of the tocopheryl derivative of vitamin E is less than approximately 30 * by weight. 20.- Fl use of a vitamin tocopheryl derivative E in accordance with claim 19, further characterized in that the concentration of the vitamin tocopheryl derivative E is approximately 0.1 and approximately 20 * in weight. 21.- The use of a vitamin diphtheria derivative E according to claim 20, further characterized in that the concentration of the tocafecillin derivative of vitamin E is about 10 * by weight. USE OF VITAMIN E TOCOPHERYL DERIVATIVES IN OPHTHALMIC COMPOSITIONS SUMMARY OF THE INVENTION Ophthalmic compositions containing vitamin E tocopheryl derivatives that are comfortable and non-irritating are described, and the new use of ophthalmic agents together with tocopheryl derivatives of vitamin E in the preparation of compositions to significantly reduce the discomfort and irritation associated with the topical ophthalmic administration of ophthalmic agents alone; moreover, those derivatives of vitamin E tocopheryl significantly increase the aqueous solubility of certain poorly soluble ophthalmic agents. RM / mvs * crm #
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US24005794A | 1994-05-06 | 1994-05-06 | |
US240057 | 1994-05-06 |
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MX9600140A MX9600140A (en) | 1998-11-29 |
MXPA96000140A true MXPA96000140A (en) | 1999-01-15 |
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