EP1058560A1 - Topical ophthalmic preparations containing immunosuppressive agents - Google Patents
Topical ophthalmic preparations containing immunosuppressive agentsInfo
- Publication number
- EP1058560A1 EP1058560A1 EP98958793A EP98958793A EP1058560A1 EP 1058560 A1 EP1058560 A1 EP 1058560A1 EP 98958793 A EP98958793 A EP 98958793A EP 98958793 A EP98958793 A EP 98958793A EP 1058560 A1 EP1058560 A1 EP 1058560A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- preparations
- weight
- immunosuppressive agents
- ciclosporin
- cornea
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 42
- 229940125721 immunosuppressive agent Drugs 0.000 title claims abstract description 14
- 239000003018 immunosuppressive agent Substances 0.000 title claims abstract description 14
- 230000000699 topical effect Effects 0.000 title claims abstract description 12
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 9
- 229920002635 polyurethane Polymers 0.000 claims abstract description 8
- 239000004814 polyurethane Substances 0.000 claims abstract description 8
- 239000003246 corticosteroid Substances 0.000 claims abstract description 7
- 229960001334 corticosteroids Drugs 0.000 claims abstract description 7
- 239000003120 macrolide antibiotic agent Substances 0.000 claims abstract description 7
- 230000001225 therapeutic effect Effects 0.000 claims abstract description 6
- 238000011200 topical administration Methods 0.000 claims abstract description 6
- 150000002596 lactones Chemical class 0.000 claims abstract description 4
- 125000002950 monocyclic group Chemical group 0.000 claims abstract description 4
- 229960001265 ciclosporin Drugs 0.000 claims description 23
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 claims description 16
- 108010036949 Cyclosporine Proteins 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 11
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 claims description 4
- 229960005205 prednisolone Drugs 0.000 claims description 4
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 claims description 4
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 claims description 4
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 claims description 4
- 229960002930 sirolimus Drugs 0.000 claims description 4
- 229960001967 tacrolimus Drugs 0.000 claims description 4
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 claims description 4
- 229960003957 dexamethasone Drugs 0.000 claims description 3
- 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 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 27
- 229940124597 therapeutic agent Drugs 0.000 abstract description 26
- 229920001577 copolymer Polymers 0.000 abstract description 18
- -1 poly(oxy-1,2-ethanediyl) Polymers 0.000 abstract description 9
- KORSJDCBLAPZEQ-UHFFFAOYSA-N dicyclohexylmethane-4,4'-diisocyanate Chemical compound C1CC(N=C=O)CCC1CC1CCC(N=C=O)CC1 KORSJDCBLAPZEQ-UHFFFAOYSA-N 0.000 abstract 2
- 210000004087 cornea Anatomy 0.000 description 26
- 210000001508 eye Anatomy 0.000 description 21
- 241000282472 Canis lupus familiaris Species 0.000 description 17
- 210000001519 tissue Anatomy 0.000 description 15
- 239000003981 vehicle Substances 0.000 description 12
- 229930182912 cyclosporin Natural products 0.000 description 11
- 108010036941 Cyclosporins Proteins 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- 239000003889 eye drop Substances 0.000 description 9
- 229940012356 eye drops Drugs 0.000 description 9
- 210000000554 iris Anatomy 0.000 description 9
- 230000035515 penetration Effects 0.000 description 9
- 230000000694 effects Effects 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 206010022998 Irritability Diseases 0.000 description 6
- 241000283973 Oryctolagus cuniculus Species 0.000 description 6
- 210000000795 conjunctiva Anatomy 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 238000010586 diagram Methods 0.000 description 4
- 210000004907 gland Anatomy 0.000 description 4
- 230000000622 irritating effect Effects 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 239000000902 placebo Substances 0.000 description 4
- 210000001138 tear Anatomy 0.000 description 4
- 210000001745 uvea Anatomy 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 208000022873 Ocular disease Diseases 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 210000005252 bulbus oculi Anatomy 0.000 description 3
- 239000004359 castor oil Substances 0.000 description 3
- 235000019438 castor oil Nutrition 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 235000005687 corn oil Nutrition 0.000 description 3
- 210000000695 crystalline len Anatomy 0.000 description 3
- 239000006196 drop Substances 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 3
- 230000001965 increasing effect Effects 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 231100000344 non-irritating Toxicity 0.000 description 3
- 229940068196 placebo Drugs 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 230000032258 transport Effects 0.000 description 3
- AXTGDCSMTYGJND-UHFFFAOYSA-N 1-dodecylazepan-2-one Chemical compound CCCCCCCCCCCCN1CCCCCC1=O AXTGDCSMTYGJND-UHFFFAOYSA-N 0.000 description 2
- 208000023275 Autoimmune disease Diseases 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- IUJDSEJGGMCXSG-UHFFFAOYSA-N Thiopental Chemical compound CCCC(C)C1(CC)C(=O)NC(=S)NC1=O IUJDSEJGGMCXSG-UHFFFAOYSA-N 0.000 description 2
- 206010046851 Uveitis Diseases 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 230000000740 bleeding effect Effects 0.000 description 2
- KBPLFHHGFOOTCA-UHFFFAOYSA-N caprylic alcohol Natural products CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N dodecahydrosqualene Natural products CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 description 2
- 235000020188 drinking water Nutrition 0.000 description 2
- 239000003651 drinking water Substances 0.000 description 2
- 230000002500 effect on skin Effects 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 210000000744 eyelid Anatomy 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 230000003118 histopathologic effect Effects 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 230000001506 immunosuppresive effect Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000003883 ointment base Substances 0.000 description 2
- 210000001328 optic nerve Anatomy 0.000 description 2
- 238000012856 packing Methods 0.000 description 2
- 238000005192 partition Methods 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 229920001515 polyalkylene glycol Polymers 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- 229920001451 polypropylene glycol Polymers 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 210000001525 retina Anatomy 0.000 description 2
- 210000003786 sclera Anatomy 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000007910 systemic administration Methods 0.000 description 2
- 230000004489 tear production Effects 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 229960003279 thiopental Drugs 0.000 description 2
- 150000003626 triacylglycerols Chemical class 0.000 description 2
- 229940099259 vaseline Drugs 0.000 description 2
- 235000013311 vegetables Nutrition 0.000 description 2
- YYGNTYWPHWGJRM-UHFFFAOYSA-N (6E,10E,14E,18E)-2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaene Chemical compound CC(C)=CCCC(C)=CCCC(C)=CCCC=C(C)CCC=C(C)CCC=C(C)C YYGNTYWPHWGJRM-UHFFFAOYSA-N 0.000 description 1
- JIABEENURMZTTI-UHFFFAOYSA-N 1-isocyanato-2-[(2-isocyanatophenyl)methyl]benzene Chemical class O=C=NC1=CC=CC=C1CC1=CC=CC=C1N=C=O JIABEENURMZTTI-UHFFFAOYSA-N 0.000 description 1
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 1
- VHRSUDSXCMQTMA-PJHHCJLFSA-N 6alpha-methylprednisolone Chemical compound C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)CO)CC[C@H]21 VHRSUDSXCMQTMA-PJHHCJLFSA-N 0.000 description 1
- 208000027496 Behcet disease Diseases 0.000 description 1
- 208000009137 Behcet syndrome Diseases 0.000 description 1
- FMLMMQFORWCANB-UHFFFAOYSA-N CCCCCCCCCCCCCCCCCCCCC(C)C(C)(C)C(C)=C(C)C Chemical compound CCCCCCCCCCCCCCCCCCCCC(C)C(C)(C)C(C)=C(C)C FMLMMQFORWCANB-UHFFFAOYSA-N 0.000 description 1
- 241000238097 Callinectes sapidus Species 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 1
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 1
- 229930105110 Cyclosporin A Natural products 0.000 description 1
- 208000003556 Dry Eye Syndromes Diseases 0.000 description 1
- 206010013774 Dry eye Diseases 0.000 description 1
- 229920005682 EO-PO block copolymer Polymers 0.000 description 1
- 206010015150 Erythema Diseases 0.000 description 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 229920002683 Glycosaminoglycan Polymers 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000009319 Keratoconjunctivitis Sicca Diseases 0.000 description 1
- 206010023644 Lacrimation increased Diseases 0.000 description 1
- 241000446313 Lamella Species 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- BHEOSNUKNHRBNM-UHFFFAOYSA-N Tetramethylsqualene Natural products CC(=C)C(C)CCC(=C)C(C)CCC(C)=CCCC=C(C)CCC(C)C(=C)CCC(C)C(C)=C BHEOSNUKNHRBNM-UHFFFAOYSA-N 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- OFUHPGMOWVHNPN-QWZFGMNQSA-N [(2r)-2,5,7,8-tetramethyl-2-[(4r,8r)-4,8,12-trimethyltridecyl]-3,4-dihydrochromen-6-yl] (9z,12z)-octadeca-9,12-dienoate Chemical compound O1[C@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)CCC2=C(C)C(OC(=O)CCCCCCC\C=C/C\C=C/CCCCC)=C(C)C(C)=C21 OFUHPGMOWVHNPN-QWZFGMNQSA-N 0.000 description 1
- BKZCZANSHGDPSH-KTKRTIGZSA-N [3-(2,3-dihydroxypropoxy)-2-hydroxypropyl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(O)COCC(O)CO BKZCZANSHGDPSH-KTKRTIGZSA-N 0.000 description 1
- ZHAFUINZIZIXFC-UHFFFAOYSA-N [9-(dimethylamino)-10-methylbenzo[a]phenoxazin-5-ylidene]azanium;chloride Chemical compound [Cl-].O1C2=CC(=[NH2+])C3=CC=CC=C3C2=NC2=C1C=C(N(C)C)C(C)=C2 ZHAFUINZIZIXFC-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 125000005037 alkyl phenyl group Polymers 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000947 anti-immunosuppressive effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000004397 blinking Effects 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 210000004240 ciliary body Anatomy 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 210000000736 corneocyte Anatomy 0.000 description 1
- 229960004544 cortisone Drugs 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 1
- 125000005442 diisocyanate group Chemical group 0.000 description 1
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical class C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 206010014801 endophthalmitis Diseases 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 210000003560 epithelium corneal Anatomy 0.000 description 1
- 231100000321 erythema Toxicity 0.000 description 1
- 208000030533 eye disease Diseases 0.000 description 1
- 239000003885 eye ointment Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 235000021323 fish oil Nutrition 0.000 description 1
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 1
- FAOZLTXFLGPHNG-KNAQIMQKSA-N fluorometholone Chemical compound C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@]2(F)[C@@H](O)C[C@]2(C)[C@@](O)(C(C)=O)CC[C@H]21 FAOZLTXFLGPHNG-KNAQIMQKSA-N 0.000 description 1
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 description 1
- 235000019256 formaldehyde Nutrition 0.000 description 1
- 229960004279 formaldehyde Drugs 0.000 description 1
- 238000005227 gel permeation chromatography Methods 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 238000010562 histological examination Methods 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 239000012052 hydrophilic carrier Substances 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000008105 immune reaction Effects 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000000749 insecticidal effect Effects 0.000 description 1
- 206010023332 keratitis Diseases 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 230000004317 lacrimation Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 229940041033 macrolides Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229960004584 methylprednisolone Drugs 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N n-Octanol Natural products CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- JXTPJDDICSTXJX-UHFFFAOYSA-N n-Triacontane Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCC JXTPJDDICSTXJX-UHFFFAOYSA-N 0.000 description 1
- 239000007908 nanoemulsion Substances 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000011587 new zealand white rabbit Methods 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 210000001747 pupil Anatomy 0.000 description 1
- 230000036647 reaction Effects 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 239000011492 sheep wool Substances 0.000 description 1
- 229920002545 silicone oil Polymers 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 229940032094 squalane Drugs 0.000 description 1
- 229940031439 squalene Drugs 0.000 description 1
- TUHBEKDERLKLEC-UHFFFAOYSA-N squalene Natural products CC(=CCCC(=CCCC(=CCCC=C(/C)CCC=C(/C)CC=C(C)C)C)C)C TUHBEKDERLKLEC-UHFFFAOYSA-N 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 210000004127 vitreous body Anatomy 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 210000002268 wool Anatomy 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
Definitions
- the invention relates to therapeutic preparations destined for topical ophthalmic application of lipophilic immunosuppressive agents, dissolved or dispersed in physiologically acceptable vehicles comprising excipients which enhance penetration of therapeutic agents into ocular tissues.
- Topical ophthalmic application includes both external administration of therapeutic preparations into the conjunctival sac under the lid and onto the cornea and subconjunctival and retrobulbar administration by injection.
- the efficiency of topically administered pharmaceuticals for the treatment of ocular diseases is influenced, besides of anatomical and physiological characteristics of the eye, especially by physical and chemical characteristics of the therapeutic agent and by the character of the administration form and its composition. It is well known that the transport of therapeutic agents into ocular tissues is hampered by defensive mechanisms of the eye such as increased lacrimation and blinking, which decrease the concentration of the therapeutic agent in the precorneal area. Absorption of the therapeutic agent is enabled by prolonged contact with the cornea and by the penetrating capacity of the therapeutic agent. The bioavailability of the therapeutic agents following topical administration onto the eye is usually as low as 1 to 10 % of the agent administered.
- Typical lipophilic immunosuppressive agents which can be used for the treatment of ocular diseases include for example agents having anti-inflammatory and immunosuppressive activity belonging to the groups of monocyclic poly-N-methylated undecapeptides. of lactonic macrolides or of corticosteroids.
- Undecapeptides suitable for ophthalmic treatment comprise the group of cyclosporins. particularly ciclosporin, [Nva] " -ciclosporin. [Val] " -ciclosporin and dihydrofVal] -ciclosporin.
- Macrolide antibiotics suitable for the treatment of ocular diseases, include especially tacrolimus and sirolimus. Tacrolimus and structurally similar derivatives are generally designated as ascomycins; sirolimus and structurally similar derivatives are generally designated as rapamycins.
- corticosteroids useful in topical ophthalmic application includes substances like, for example, cortisone and hydrocortisone, prednisolone and methyl prednisolone, dexamethasone and fluoromethalone.
- Therapeutic effects of the above cyclosporins in topical administration are demonstrated especially in risky transplantations of the cornea and in autoimmune diseases such as keratoconjunctivitis sicca, chronic keratitis, Behcet's syndrome, Sj ⁇ gren's syndrome, endogenous uveitis. but also in ulcerative diseases of the cornea such as Moren's ulcus.
- the macrolide antibiotics have proved their high immunosuppressive effects in organ and tissue grafting and are promising in keratoplasty.
- the corticosteroids are useful in therapy of inflammations following ocular surgery and they also suppress immune reactions following cornea grafting.
- All the tree groups of the active agents described in this invention have also been administered in a systemic way for the treatment of inflammatory and autoimmune diseases of the eye.
- systemic administration can only be used to a reduced extent because of serious side effects of such therapy.
- the side effects associated with systemic administration can be reduced or eliminated in rational topical administration by concentrating the activity of the preparation only to the site treated and its nearest neighbourhood.
- the therapeutic agents from the groups of N-methylated cyclic undecapeptides, macrolide lactones and corticosteroids in their non-ionised form have only a low solubility in water or in hydrophilic carriers which are physiologically acceptable for ophthalmic administration. That, in fact, makes preparation of classical hydrophilic eye drops very difficult.
- water solubilities of the cyclosporins range between 16 and 30 ⁇ g/ml at 25 °C, the more polar molecule of [Thr] 2 -ciclosporin being more water soluble than the less polar [NVa] 2 -ciclosporin.
- the values of partition coefficient P between the aqueous phase and the lipophilic phase represented by n-octanol can be used.
- the value of log P ranges from 1.2 (prednisolone) to 4.3 (flurbiprofene).
- log P for agents having immunosuppressive activity ranges from 1.1 to 3.1.
- the first patents disclosing ophthalmic topical administration of agents from the group of cyclosporins as a method of treatment of phaco-anaphylactic endophthalmitis and uveitis in the anterior and posterior ocular segments or of eye diseases manifested by reduced lacrimal production include US patents 4,649,047 and 4,839,342. Both these patents do not closely specify the administration form and both envisage use of solutions, suspensions and ointments with a pharmaceutically acceptable vehicles comprising vegetable, animal, mineral and silicone oils; liposomes and, further, alcohols, dimethyl sulfoxide and polyoxyethylated castor oil. Said patents disclose no weight ratios of suitable excipients in the examples or in the claims.
- US patent 4,865,846 relates to the group of corticosteroids, cyclosporins and antibiotics for ophthalmic administration and it claims transport systems in which solutions of therapeutic agents in a liquid or ointment base are present together with particles of biodegradable materials containing the same or even different therapeutic agents as well as a method of preparing such transport systems. It concludes from the examples of said patent that preparing of three-dimensional particles having a size of from 0.4 to 1.0 mm from bioerodible materials such as collagen, gelatine, polyvinylalcohol and methylcellulose derivatives, suspending said particles in a liquid or ointment base as well as incorporating therapeutic agents into said bioerodible particles is very laborious and not very suitable for a validable production process.
- bioerodible materials such as collagen, gelatine, polyvinylalcohol and methylcellulose derivatives
- Topical preparations for administration to the eye and surrounding tissues containing cyclosporins in a vehicle composed of a mixture of vegetable oils and vaseline are disclosed in UK patent 2,224,205.
- the therapeutic agents obtained by the methods described in this patent contain, as emulsifiers, substances based on steroidal materials from sheep wool. A departure from using such materials has been reported recently for possible allergenetic and irritative effects of possible insecticidal residues included in the wool fat.
- Ophthalmic preparations having low concentrations of cyclosporin in an aqueous medium containing surfactants from the group of polyethoxylated fatty acid esters, polyethoxylated alkyl ethers and polyethoxylated alkyl phenyl ethers are described in the international patent application WO 93/23010.
- Emulsified ophthalmic formulations having specific affinity to tear glands, containing cyclosporins, are described in the international patent application WO 95/3121 1.
- Euacidic and isotonic nanoemulsions useful for application containing from 0.01 to 5 % of therapeutic agents including corticoids and cyclosporins, are described in the European patent application EP 0 696 452 Al . None of the above mentioned patent documents solves the specific problem of increasing penetration of the therapeutic agent through the cornea into the internal ocular structures such as the aqueous humour, iris or uvea.
- the object of the present invention is to increase penetration through the cornea of topically administered therapeutic agents, thus obtaining therapeutically active levels of the therapeutic agents in the internal tissues of the eye, by means of use of especially suitable adjuvants in the therapeutic agents.
- This task is extremely difficult in the case of therapeutic agents which are very poorly soluble in body fluids and tissues.
- therapeutic agents which arc very poorly soluble in water are those substances which require 1000 to 10000 volume parts of water to dissolve 1 weight part of the substance.
- Such agents include especially immunosuppressive agents from the group of monocyclic undecapeptides represented by ciclosporin or [Nva] -ciclosporin, from the group of lactones having macrolide structures represented by sirolimus or tacrolimus, and from the group of corticoids represented for example by prednisolone or dexamethasone.
- the present invention describes therapeutic preparations for topical ophthalmic application, which are characterised by the presence of from 0.02 to 5.0 weight % of immunosuppressive agents, dissolved or dispersed in physiologically acceptable vehicles comprising up to 10 weight % of polyalkyleneglycol-polyurethane copolymers of general formula I
- PEG and PPG correspond to polyethyleneglycol and polypropyleneglycol. resp., and SMDI corresponds to saturated methylene diphenyl isocyanate.
- Said compounds are marketed, for example, under trade designations Polyolprepolymer-2 (PPG-12/SMDI copolymer), Polyolprepolymer-14 (PPG-51/SMDI copolymer) and Polyolprepolymer-15 (PEG-8/SMDI copolymer) and are produced by PENEDERM Incorporated.
- Polyolprepolymer-2 PPG-12/SMDI copolymer
- Polyolprepolymer-14 PPG-51/SMDI copolymer
- Polyolprepolymer-15 PEG-8/SMDI copolymer
- these copolymers have been known. They have a strong activity to the skin and easily form deposits in the stratum comeum. Thus, long-persistent liquid reservoirs of therapeutic agents are formed among the corneocytes, which enable prolonged action of the therapeutic agents in the skin.
- the therapeutic agents of the invention having a content of polyalkyleneglycol-polyurethane copolymer excipients in the applicable concentration range up to 10 weight % do not produce any increase of ocular irritability, although demonstrably increased penetration of therapeutically active immunosuppressive agents into internal ocular structures occurs.
- histological examination following repeated administration of the preparations according of the invention does not indicate any possibility of damage thereof.
- manifestations of ocular irritability and toxicity have been described for the administration azone in concentrations which are as low as 0.1 % and higher; azone being a known substance used for enhancing permeability of therapeutic agents through the cornea (Ismail I.M. et al., Pharm. Res., 9(6), 817-821, 1992).
- the polyalkylene-polyurethane copolymers comprise mixtures of oligomers the proportion of which is expressed by the indexticianm" in the general formula, amounting predominantly to from 1 to 4.
- Various types of the copolymers produced have typical molecular weight distributions as determined by gel permeation chromatography. For example, for the PPG- 12/SMDI copolymer, the proportions of the molecular weights are: from 22 to 23 % (for the molecular weight 1500-2000 peak) from 16 to 25 % (for the molecular weight 2400-3300 peak) from 28 to 45 % (for the molecular weight > 3700 peak)
- Lipophilic ophthalmic vehicles consist of, on one hand, vegetable or animal triacyl glycerols (e.g., castor oil, maize oil, sesame oil or fish oil) and hydrogenated forms thereof. Hydrocarbon mixtures such as saturated hydrocarbons hexamethyl tetracosaene known as vaseline ⁇ r unsaturated branched hydrocarbons known as squalene, or the hydrogenated form thereof - squalane - can also be inco ⁇ orated among triacyl glycerols in limited amounts.
- Lipophilic vehicles also include structured lipids consisting of triglyceryl esters having medium long C 8 to C ⁇ 2 acyl residues in combinations with long C ⁇ 4 to C 2 acyl residues.
- polyglyceryl esters of C] 4 to C 2 fatty acids having a value of hydrophilic-lipophilic balance (HLB) lower than 6 and having an oily character are useful as non-irritating lipophilic ophthalmic vehicles.
- C ⁇ 2 to C 23 fatty alcohols can be used for this pu ⁇ ose.
- Hydrophilic ophthalmic vehicles for the preparations of the invention generally consist of water or alkylene glycols such as, particularly, glycerol or polyethylene glycols. Also useful are ethyleneoxide-propyleneoxide block copolymers, known as poloxamers or meroxapols.
- Both types of ophthalmic vehicles are also characteristic in having a liquid or semi- solid consistency at temperatures of from 15 to 37 °C.
- excipients may be present in the vehicles of the topical ophthalmic preparations according to this invention in technologically necessary amounts and the choice thereof is dependent on the specific administration form selected.
- excipients include solvents and solubilising materials, physiologically acceptable for the eye, having a liquid or semi-solid consistency.
- excipients additionally include stabilisers of the present phases.
- anti-microbial agents are usually added.
- the molecular weight of the PEG-8/SMDI copolymer does not exceed 3000, it will be advisable to take its contribution to the osmotic pressure in the preparations with a hydrophilic vehicle into account and, if needed, to adjust the tonicity in a usual way with additional excipients having a ionic or non-ionic character.
- the appended drawings are graphic illustrations of the effects of the addition of 1 % of the PPG-51/SMDI copolymer to topical ophthalmic preparations of Example 3 on abso ⁇ tion of ciclosporin into the cornea (diagram 1) and its penetration into the iris (diagram 2), into the aqueous humour (diagram 3) and into the uvea (diagram 4).
- a significant increase in abso ⁇ tion occurred in the groups of pigmented male and female rabbits.
- the average increase of the ciclosporin concentration following 12 administrations of 1 drop each was as follows: cornea, 3.30 x; iris, 5.24 x; aqueous humour, 5.08 x; and uvea, 5.2 x.
- Example 1 Eye drops 1% 2%
- Example 1 Eye drops of Example 1 containing 1 % and 2 % ciclosporin and the corresponding placebos without the copolymer were evaluated for ocular irritability by the method recommended by the ETAD committee for toxicology.
- Eye drops were tested each on 6 New Zealand white rabbits.
- the animals were of a conventional quality having weights of from 2.19 to 4.62 kg, corresponding to their ages.
- the rabbits were housed individually in metal cages and acclimatised to the vivarium conditions (temperature of 22 ⁇ 2 ° C, relative humidity of 50 to 70 %).
- the rabbits were fed with standard KKK/L diet and drinking water ad libitum.
- Eye drops were administered in a single dose of 50 ⁇ l into each eye, divided into two sequential portions of 25 ⁇ l each.
- the condition of the eye (conjunctiva, cornea, iris and tear production) was monitored before administering and 24, 48 and 72 hours after administering.
- the cornea was examined using commercially available fluorescein solution at a blue point light.
- the physiological solution was applied to the eyes in the same manner and the same amount after 24 hours. Changes in the conjunctiva, cornea, iris and tear production were evaluated according to the scheme given in Table I. Cumulative values of the changes detected after 24. 48 and 72 hours in all the 6 rabbits are the following:
- Maize oil up to 100.000 ml up to 100.000 ml
- the preparations were evaluated for tolerance in administration in dogs for 19 days according to the method described with histopathologic examination and penetration of ciclosporin into ocular tissues was evaluated. 10 male Beagle dogs aged 12 to 16 months were used for the test. The dogs were treated in periodic intervals. In the appropriate period they were treated with Canvac, Dohyvac-Parvo and Lyscelin vaccines.
- the animals were housed individually in cots having dimensions 0.9 x 1.0 m under conventional conditions. They were fed with standard pelletised Ro XIII diet at a ration of 300 g for each dog. Drinking water was available to the dogs ad libitum.
- the tested preparations according to Example 2 were administered four times daily to 5 dogs (test group) in two-hours intervals one drop onto the cornea of each eye by means of a dropper from the standard packing. After dropping, spreading of the preparation on the cornea was achieved by slight clamping of the eyelids.
- a control group (5 dogs) was administered placebo in the same manner. Both preparations were administered for 19 sequential days. Ophthalmologic examinations were made before the start of the administration and at the end of the administration period. Ocular tolerance was again evaluated according to the scheme in Table I. daily before the first administration.
- histological preparations were made by standard paraffin method, cut in a thickness of about 6 ⁇ m and stained with hematoxylline-eosine, by the PAS method for mucopolysaccharides, with cresyl violet, with Alcian blue, by the method of Van Gieson and by the Halle-Miiller technique.
- the measured values of ciclosporin in the vitreous body, lens, sclera and retina were at the background level.
- Both formulations were labelled with tritiated ciclosporin in the amount of 1 mBq/mg of the active substance. Both preparations were administered to a group of 6 rabbits weighing 3 to 3.5 kg each, consisting of 3 males (M) and 3 females (F). Preparation A was instilled into the left eye, always onto the cornea (not into the conjunctival sac).
- Administrations were made at 15 minute intervals for 3 hours (a total of 12 administrations) at an amount of 15 ⁇ l of the preparation by means of a micropipette (a total of 3.6 mg ciclosporin). 15 minutes following the last administration the animals were killed, aqueous humours were taken from all eyes and the cornea, iris and uvea were prepared.
- the tissue samples were weighed and treated for radioactivity measurements at a Wallac Rackbeta liquid scintillation spectrohoptometer.
- the measured activity values (dpm) were calculated as concentration of ng ciclosporin/g tissue.
- Tocopherol the copolymer and the active substance are dissolved in the sterilised mixture of castor oil and hydrogenated oil at 60 °C, hot filtered under aseptic conditions and filled into tubes fitted with ocular applicators.
- the prepared solution is filtered through a membrane having the separation limit of 0.2 ⁇ m and is filled into glass vials fitted with ocular applicators.
- the prepared solution is filtered through a membrane having the separation limit of 0.2 ⁇ m and is filled into polyethylene vials fitted with ocular applicators.
- the invention can find application in pharmaceutical industry in producing topical ophthalmic preparations.
- the preparations of the invention are characterised in high penetration of immunosuppressive agents into ocular tissues and in a very good tolerability. Table I
Abstract
Therapeutic preparations for topical ophthalmic application, containing from 0.02 to 5.0 weight % of immunosuppressive agents belonging to the groups of monocyclic undecapeptides, macrolide lactones or corticosteroids, in a vehicle comprising up to 10 weight % of polyalkyleneglycol-polyurethane copolymers. Said copolymers consist preferably of poly(oxy-1,2-ethanediyl)-α-hydro-φ-hydroxypolymers with 1,1'-methylene-bis-(4-isocyanatocyclohexane) having an average molecular weight of from 1000 to 3000 in a hydrophilic vehicle and preferably of poly[oxy(methyl-1,2-ethanediyl)]-α-hydro-φ-hydroxypolymers with 1,1'-methylene-bis-(4-isocyanatocyclohexane) having an average molecular weight of from 1600 to 18000 in a lipophilic vehicle. Said therapeutic agents can further contain additional excipients common in topical administration forms.
Description
TOPICAL OPHTHALMIC PREPARATIONS CONTAINING IMMUNOSUPPRESSIVE AGENTS
Technical Field
The invention relates to therapeutic preparations destined for topical ophthalmic application of lipophilic immunosuppressive agents, dissolved or dispersed in physiologically acceptable vehicles comprising excipients which enhance penetration of therapeutic agents into ocular tissues.
Background Art
Topical ophthalmic application includes both external administration of therapeutic preparations into the conjunctival sac under the lid and onto the cornea and subconjunctival and retrobulbar administration by injection.
The efficiency of topically administered pharmaceuticals for the treatment of ocular diseases is influenced, besides of anatomical and physiological characteristics of the eye, especially by physical and chemical characteristics of the therapeutic agent and by the character of the administration form and its composition. It is well known that the transport of therapeutic agents into ocular tissues is hampered by defensive mechanisms of the eye such as increased lacrimation and blinking, which decrease the concentration of the therapeutic agent in the precorneal area. Absorption of the therapeutic agent is enabled by prolonged contact with the cornea and by the penetrating capacity of the therapeutic agent. The bioavailability of the therapeutic agents following topical administration onto the eye is usually as low as 1 to 10 % of the agent administered.
Typical lipophilic immunosuppressive agents which can be used for the treatment of ocular diseases include for example agents having anti-inflammatory and immunosuppressive activity belonging to the groups of monocyclic poly-N-methylated undecapeptides. of lactonic macrolides or of corticosteroids. Undecapeptides suitable for ophthalmic treatment comprise the group of cyclosporins. particularly ciclosporin, [Nva]"-ciclosporin. [Val]"-ciclosporin and dihydrofVal] -ciclosporin.
Macrolide antibiotics, suitable for the treatment of ocular diseases, include especially tacrolimus and sirolimus. Tacrolimus and structurally similar derivatives are generally designated as ascomycins; sirolimus and structurally similar derivatives are generally designated as rapamycins.
The group of corticosteroids useful in topical ophthalmic application includes substances like, for example, cortisone and hydrocortisone, prednisolone and methyl prednisolone, dexamethasone and fluoromethalone.
Therapeutic effects of the above cyclosporins in topical administration are demonstrated especially in risky transplantations of the cornea and in autoimmune diseases such as keratoconjunctivitis sicca, chronic keratitis, Behcet's syndrome, Sjδgren's syndrome, endogenous uveitis. but also in ulcerative diseases of the cornea such as Moren's ulcus.
The macrolide antibiotics have proved their high immunosuppressive effects in organ and tissue grafting and are promising in keratoplasty. The corticosteroids are useful in therapy of inflammations following ocular surgery and they also suppress immune reactions following cornea grafting.
All the tree groups of the active agents described in this invention have also been administered in a systemic way for the treatment of inflammatory and autoimmune diseases of the eye. However, systemic administration can only be used to a reduced extent because of serious side effects of such therapy. The side effects associated with systemic administration can be reduced or eliminated in rational topical administration by concentrating the activity of the preparation only to the site treated and its nearest neighbourhood.
The therapeutic agents from the groups of N-methylated cyclic undecapeptides, macrolide lactones and corticosteroids in their non-ionised form have only a low solubility in water or in hydrophilic carriers which are physiologically acceptable for ophthalmic administration. That, in fact, makes preparation of classical hydrophilic eye drops very difficult. For example, water solubilities of the cyclosporins range between 16 and 30 μg/ml at 25 °C, the more polar molecule of [Thr]2-ciclosporin being more water soluble than the less polar [NVa]2-ciclosporin. For relative evaluation of lipophilicity of the agents from said groups, the values of partition coefficient P between the aqueous phase and the lipophilic phase represented by n-octanol can be used. For corticosteroidal agents, for example, the value of log P ranges from 1.2 (prednisolone) to 4.3 (flurbiprofene). In the group of
cyclosporins, log P for agents having immunosuppressive activity ranges from 1.1 to 3.1. No values of partitions coefficients for ascomycins and rapamycins have been published, but it can be assumed based on water solubilities that they will be comparable to those for cyclosporins.
The first patents disclosing ophthalmic topical administration of agents from the group of cyclosporins as a method of treatment of phaco-anaphylactic endophthalmitis and uveitis in the anterior and posterior ocular segments or of eye diseases manifested by reduced lacrimal production include US patents 4,649,047 and 4,839,342. Both these patents do not closely specify the administration form and both envisage use of solutions, suspensions and ointments with a pharmaceutically acceptable vehicles comprising vegetable, animal, mineral and silicone oils; liposomes and, further, alcohols, dimethyl sulfoxide and polyoxyethylated castor oil. Said patents disclose no weight ratios of suitable excipients in the examples or in the claims.
US patent 4,865,846 relates to the group of corticosteroids, cyclosporins and antibiotics for ophthalmic administration and it claims transport systems in which solutions of therapeutic agents in a liquid or ointment base are present together with particles of biodegradable materials containing the same or even different therapeutic agents as well as a method of preparing such transport systems. It concludes from the examples of said patent that preparing of three-dimensional particles having a size of from 0.4 to 1.0 mm from bioerodible materials such as collagen, gelatine, polyvinylalcohol and methylcellulose derivatives, suspending said particles in a liquid or ointment base as well as incorporating therapeutic agents into said bioerodible particles is very laborious and not very suitable for a validable production process.
Topical preparations for administration to the eye and surrounding tissues containing cyclosporins in a vehicle composed of a mixture of vegetable oils and vaseline are disclosed in UK patent 2,224,205. The therapeutic agents obtained by the methods described in this patent, however, contain, as emulsifiers, substances based on steroidal materials from sheep wool. A departure from using such materials has been reported recently for possible allergenetic and irritative effects of possible insecticidal residues included in the wool fat.
Ophthalmic preparations having low concentrations of cyclosporin in an aqueous medium containing surfactants from the group of polyethoxylated fatty acid esters, polyethoxylated alkyl ethers and polyethoxylated alkyl phenyl ethers are described in the
international patent application WO 93/23010. Emulsified ophthalmic formulations having specific affinity to tear glands, containing cyclosporins, are described in the international patent application WO 95/3121 1.
Euacidic and isotonic nanoemulsions useful for application, containing from 0.01 to 5 % of therapeutic agents including corticoids and cyclosporins, are described in the European patent application EP 0 696 452 Al . None of the above mentioned patent documents solves the specific problem of increasing penetration of the therapeutic agent through the cornea into the internal ocular structures such as the aqueous humour, iris or uvea.
Disclosure of the Invention
The object of the present invention is to increase penetration through the cornea of topically administered therapeutic agents, thus obtaining therapeutically active levels of the therapeutic agents in the internal tissues of the eye, by means of use of especially suitable adjuvants in the therapeutic agents. This task is extremely difficult in the case of therapeutic agents which are very poorly soluble in body fluids and tissues. Generally, therapeutic agents which arc very poorly soluble in water are those substances which require 1000 to 10000 volume parts of water to dissolve 1 weight part of the substance. Such agents include especially immunosuppressive agents from the group of monocyclic undecapeptides represented by ciclosporin or [Nva] -ciclosporin, from the group of lactones having macrolide structures represented by sirolimus or tacrolimus, and from the group of corticoids represented for example by prednisolone or dexamethasone.
The present invention describes therapeutic preparations for topical ophthalmic application, which are characterised by the presence of from 0.02 to 5.0 weight % of immunosuppressive agents, dissolved or dispersed in physiologically acceptable vehicles comprising up to 10 weight % of polyalkyleneglycol-polyurethane copolymers of general formula I
R R
0 O R
HO-(-CH-CH O-) Π.- C-N V CH2/ VN-C-(-0-CH 2-CH-) n -θ]-H
H 1-1
(I),
wherein n is between 8 and 51, m is predominantly between 1 and 4 and R means CH3 or H.
The chemically correct CAS names of these compounds are given in the shortened CTFA nomenclature throughout the description below:
In the CTFA nomenclature, PEG and PPG correspond to polyethyleneglycol and polypropyleneglycol. resp., and SMDI corresponds to saturated methylene diphenyl isocyanate.
Said compounds are marketed, for example, under trade designations Polyolprepolymer-2 (PPG-12/SMDI copolymer), Polyolprepolymer-14 (PPG-51/SMDI copolymer) and Polyolprepolymer-15 (PEG-8/SMDI copolymer) and are produced by PENEDERM Incorporated.
In dermal use, these copolymers have been known. They have a strong activity to the skin and easily form deposits in the stratum comeum. Thus, long-persistent liquid reservoirs of therapeutic agents are formed among the corneocytes, which enable prolonged action of the therapeutic agents in the skin.
Use of polyol prepolymers in dermal and cosmetic preparation is claimed, for example, in US patents 4,971 ,800, 5,045,317 and 5,051,260.
In spite of considerable differences in the anatomic structure of the skin from that of the ocular cornea, it has been suφrisingly found that polyalkyleneglycol-polyurethane copolymers markedly increase penetration of very poorly soluble immunosuppressive agents through the cornea. Said phenomena has been demonstrated in ophthalmic preparations
wherein the above described therapeutic agents were incoφorated in the presence of said copolymers into both hydrophilic and hydrophobic, physiologically harmless vehicles.
It has also been suφrisingly found that the therapeutic agents of the invention having a content of polyalkyleneglycol-polyurethane copolymer excipients in the applicable concentration range up to 10 weight % do not produce any increase of ocular irritability, although demonstrably increased penetration of therapeutically active immunosuppressive agents into internal ocular structures occurs. Moreover, histological examination following repeated administration of the preparations according of the invention does not indicate any possibility of damage thereof. On the contrary, manifestations of ocular irritability and toxicity have been described for the administration azone in concentrations which are as low as 0.1 % and higher; azone being a known substance used for enhancing permeability of therapeutic agents through the cornea (Ismail I.M. et al., Pharm. Res., 9(6), 817-821, 1992).
Obtaining good biological characteristics is dependent on qualitative parameters of the copolymers of this invention, especially on residual concentrations of the unreacted diisocyanate component and the respective polyalkylene glycols. Typical parameters of the copolymers are summarised as follows:
The polyalkylene-polyurethane copolymers comprise mixtures of oligomers the proportion of which is expressed by the index „m" in the general formula, amounting predominantly to from 1 to 4.
Various types of the copolymers produced have typical molecular weight distributions as determined by gel permeation chromatography. For example, for the PPG- 12/SMDI copolymer, the proportions of the molecular weights are: from 22 to 23 % (for the molecular weight 1500-2000 peak) from 16 to 25 % (for the molecular weight 2400-3300 peak) from 28 to 45 % (for the molecular weight > 3700 peak)
Both types of copolymers having terminal hydroxyl groups in their polyalkyleneglycol parts markedly increase deposit of the mentioned therapeutic agent into the middle part of the cornea (stroma), which has a high content of water. Due to stepwise lipophilicity of the copolymer fractions having different molecular weight a concentration gradient forms in the cornea, which is the cause why the very poorly water-soluble immunosuppressive agents are not fixed only in the strongly lipophilic layer of the corneal epithelium formed by only approximately 5 upper layers of living cells.
Lipophilic ophthalmic vehicles consist of, on one hand, vegetable or animal triacyl glycerols (e.g., castor oil, maize oil, sesame oil or fish oil) and hydrogenated forms thereof. Hydrocarbon mixtures such as saturated hydrocarbons hexamethyl tetracosaene known as vaseline υr unsaturated branched hydrocarbons known as squalene, or the hydrogenated form thereof - squalane - can also be incoφorated among triacyl glycerols in limited amounts. Lipophilic vehicles also include structured lipids consisting of triglyceryl esters having medium long C8 to Cι2 acyl residues in combinations with long Cι4 to C 2 acyl residues. Also polyglyceryl esters of C]4 to C2 fatty acids having a value of hydrophilic-lipophilic balance (HLB) lower than 6 and having an oily character are useful as non-irritating lipophilic ophthalmic vehicles. Also the Cι2 to C23 fatty alcohols can be used for this puφose.
Hydrophilic ophthalmic vehicles for the preparations of the invention generally consist of water or alkylene glycols such as, particularly, glycerol or polyethylene glycols. Also useful are ethyleneoxide-propyleneoxide block copolymers, known as poloxamers or meroxapols.
Both types of ophthalmic vehicles are also characteristic in having a liquid or semi- solid consistency at temperatures of from 15 to 37 °C.
Additional excipients may be present in the vehicles of the topical ophthalmic preparations according to this invention in technologically necessary amounts and the choice thereof is dependent on the specific administration form selected. For solutions, such
excipients include solvents and solubilising materials, physiologically acceptable for the eye, having a liquid or semi-solid consistency. In emulsifiable and suspendable dispersion preparations, such excipients additionally include stabilisers of the present phases. In multi- dose packings of the ophthalmic preparations, anti-microbial agents are usually added.
As the molecular weight of the PEG-8/SMDI copolymer does not exceed 3000, it will be advisable to take its contribution to the osmotic pressure in the preparations with a hydrophilic vehicle into account and, if needed, to adjust the tonicity in a usual way with additional excipients having a ionic or non-ionic character.
Brief description of the drawings
The appended drawings are graphic illustrations of the effects of the addition of 1 % of the PPG-51/SMDI copolymer to topical ophthalmic preparations of Example 3 on absoφtion of ciclosporin into the cornea (diagram 1) and its penetration into the iris (diagram 2), into the aqueous humour (diagram 3) and into the uvea (diagram 4). A significant increase in absoφtion occurred in the groups of pigmented male and female rabbits. The average increase of the ciclosporin concentration following 12 administrations of 1 drop each was as follows: cornea, 3.30 x; iris, 5.24 x; aqueous humour, 5.08 x; and uvea, 5.2 x.
Table I depicting the scheme of the evaluation of the ocular reaction is also appended.
Examples
The following examples describe various compositions of the preparation of this invention without being limiting in any way.
Example 1 Eye drops 1% 2%
In a kettle of 100 1 volume equipped with a Steridose Systems AB magnetic stirrer PPG-12/SMDI copolymer and diglyceryl monooleate are mixed with maize oil. Freshly sublimed chlorobutanol and ciclosporin are dissolved in the resulting mixture at ambient temperature. The solution is aseptically filtered into a sterilised reservoir through a membrane filter having the separation limit of 0.2 μm. The product is filled into polyethylene vials having the volume of 5 ml on a BFS system apparatus.
Both concentration variants of the preparation were evaluated for ocular irritability in rabbits according to the method described below.
Eye drops of Example 1 containing 1 % and 2 % ciclosporin and the corresponding placebos without the copolymer were evaluated for ocular irritability by the method recommended by the ETAD committee for toxicology.
Eye drops were tested each on 6 New Zealand white rabbits. The animals were of a conventional quality having weights of from 2.19 to 4.62 kg, corresponding to their ages. The rabbits were housed individually in metal cages and acclimatised to the vivarium conditions (temperature of 22 ± 2 °C, relative humidity of 50 to 70 %). The rabbits were fed with standard KKK/L diet and drinking water ad libitum.
Eye drops were administered in a single dose of 50 μl into each eye, divided into two sequential portions of 25 μl each. The condition of the eye (conjunctiva, cornea, iris and tear production) was monitored before administering and 24, 48 and 72 hours after administering. The cornea was examined using commercially available fluorescein solution at a blue point light. The physiological solution was applied to the eyes in the same manner and the same amount after 24 hours. Changes in the conjunctiva, cornea, iris and tear production were evaluated according to the scheme given in Table I. Cumulative values of the changes detected after 24. 48 and 72 hours in all the 6 rabbits are the following:
∑ changes in cornea, iris and conjunctiva
Resulting degree of irritability [ 3 x 6 ]
Classification of irritability: resulting degree 0 to 10 non-irritating 11 to 25 slightly irritating 26 to 56 moderately irritating 57 to 110 strongly irritating
Example 2 Eye drops B (placebo)
Ciclosporin 2.000 g 2.000 g
PPG-51/SMDI copolymer 2.000 g -
Decaglyceryl pentaoleate 5.000 g 5.000 g
Tocopheryl linoleate 0.700 g 0.700 g
Maize oil up to 100.000 ml up to 100.000 ml
The preparations were evaluated for tolerance in administration in dogs for 19 days according to the method described with histopathologic examination and penetration of ciclosporin into ocular tissues was evaluated.
10 male Beagle dogs aged 12 to 16 months were used for the test. The dogs were treated in periodic intervals. In the appropriate period they were treated with Canvac, Dohyvac-Parvo and Lyscelin vaccines.
The animals were housed individually in cots having dimensions 0.9 x 1.0 m under conventional conditions. They were fed with standard pelletised Ro XIII diet at a ration of 300 g for each dog. Drinking water was available to the dogs ad libitum.
The tested preparations according to Example 2 were administered four times daily to 5 dogs (test group) in two-hours intervals one drop onto the cornea of each eye by means of a dropper from the standard packing. After dropping, spreading of the preparation on the cornea was achieved by slight clamping of the eyelids. A control group (5 dogs) was administered placebo in the same manner. Both preparations were administered for 19 sequential days. Ophthalmologic examinations were made before the start of the administration and at the end of the administration period. Ocular tolerance was again evaluated according to the scheme in Table I. daily before the first administration. Presence and extent of possible cloudiness of the cornea (degrees from 0 to 4), condition and reaction of the iris (degrees from 0 to 2), presence of erythema or oedema of the conjunctivas (degrees 0 to 4) and presence of secretion (degrees 0 to 3) were evaluated. Both variants A and B were classified as non-irritating.
Two dogs were use for histopathologic examination, which were administered 1 drop of the preparation of Example 2 into each conjunctival sac four times daily. A control dog was also tested, which was administered placebo in the same manner. The duration of the test was 19 days.
1 hour after the last administration the dogs were killed by bleeding in thiopental anaesthetisation. Eyeballs were carefully removed from the orbits and fixed in 10% neutral formol. Using a shaφ razor blade, an incision was made through each eye, extending from the entry of the ocular nerve to the edge of the cornea. The larger ocular segment was then used to make a lamella of a width of about 8 mm, which contained the cornea, pupil, lens and optic nerve. The respective tear glands were removed from the outer part of each orbit close to the eyeball.
The histological preparations were made by standard paraffin method, cut in a thickness of about 6 μm and stained with hematoxylline-eosine, by the PAS method for
mucopolysaccharides, with cresyl violet, with Alcian blue, by the method of Van Gieson and by the Halle-Miiller technique.
Both the histotopographs of the eyeballs of the control dog and those of both dogs which were administered the preparation of Example 2 did not show any anomalies in any of the recorded ocular structures (cornea, sclera, conjunctiva, chorioid, retina, ciliary body, iris, lens, anterior and posterior chambers, optic nerve, sections of eye muscles and peribulbar tissue). Neither the conjunctiva lining the posterior area of the upper eyelid, neither the tear gland were changed.
Penetration into eye tissues
Groups of 4 Beagle dogs aged 12 to 16 moths each were used in the study. Three of them were administered, to both eyes, preparation A or B according to Example 2, specifically labelled with tritiated ciclosporin having an activity of 2 mCi/ml in an amount of 0.03 ml. Administrations were made 4x daily in two-hour intervals for two days; on the third day the preparation was administered three times. A total of 1 1 administrations were made. The fourth dog received the preparation of Example 2 without specific labelling in the same amount and frequency.
One hour following the last administration the dogs were killed by bleeding from carotids in thiopental anaesthetisation. Both eyes were then removed from each dog, including conjunctivae and tear glands. Right eyes from all the four dogs were embedded in 2% carboxymethylcellulose gel and frozen in a n-hexane/dry ice mixture for autoradiographic assay. Samples of 25 % of the individual tissues were taken from left eyes, weighed and then dissolved in 1 ml 25% KOH in 20% ethanol. Radioactivity was measured using a Wallac Rackbeta liquid scintillation spectrophotometer. The activity values measured (dpm) were calculated as ng of the substance administered/g tissue.
The measured values of ciclosporin in the vitreous body, lens, sclera and retina were at the background level.
Example 3 Eye drops B
Both formulations were labelled with tritiated ciclosporin in the amount of 1 mBq/mg of the active substance. Both preparations were administered to a group of 6 rabbits weighing 3 to 3.5 kg each, consisting of 3 males (M) and 3 females (F). Preparation A was instilled into the left eye, always onto the cornea (not into the conjunctival sac).
Administrations were made at 15 minute intervals for 3 hours (a total of 12 administrations) at an amount of 15 μl of the preparation by means of a micropipette (a total of 3.6 mg ciclosporin). 15 minutes following the last administration the animals were killed, aqueous humours were taken from all eyes and the cornea, iris and uvea were prepared.
The tissue samples were weighed and treated for radioactivity measurements at a Wallac Rackbeta liquid scintillation spectrohoptometer. The measured activity values (dpm) were calculated as concentration of ng ciclosporin/g tissue.
The average values of tissue concentrations of ciclosporin (n = 6) in both preparations are the following:
Example 4 Eye ointment
Tocopherol. the copolymer and the active substance are dissolved in the sterilised mixture of castor oil and hydrogenated oil at 60 °C, hot filtered under aseptic conditions and filled into tubes fitted with ocular applicators.
Example 5 Eye drops
The prepared solution is filtered through a membrane having the separation limit of 0.2 μm and is filled into glass vials fitted with ocular applicators.
Example 6 Eye drops
The prepared solution is filtered through a membrane having the separation limit of 0.2 μm and is filled into polyethylene vials fitted with ocular applicators.
Industrial applicability
The invention can find application in pharmaceutical industry in producing topical ophthalmic preparations. The preparations of the invention are characterised in high penetration of immunosuppressive agents into ocular tissues and in a very good tolerability.
Table I
Evaluation scheme of eye reaction
Claims
1. Therapeutic preparations for topical ophthalmic application, characterised by the presence of from 0.02 to 5.0 weight % of immunosuppressive agents, dissolved or dispersed in a physiologically acceptable vehicle comprising up to 10 weight % of polyalkyleneglycol- polyurethane copolymers of general formula I
R ' O ┬░ R
HO-(-CH-CH O-) Π.-[C-N VCH2 VN-C-(-O-CH 2-CH-) n -θ]-W
H W m
(I), wherein n is between 8 and 51, m is predominantly between 1 and 4 and R means the group
CH or hydrogen, optionally together with additional excipients common for topical administration forms.
2. Preparations of claim 1 characterised in that in case of a hydrophilic vehicle the polyalkyleneglycol-polyurethane copolymers are poly(oxy-l,2-ethanediyl)-α-hydro-ω- hydroxypolymers with l,l '-methylene-bis-(4-isocyanatocyclohexane) having an average molecular weight of from 1000 to 3000.
3. Preparations of claim 1 characterised in that in case of a lipophilic vehicle the polyalkyleneglycol-polyurethane copolymers are poly[oxy(methyl-l,2-ethanediyl)]-α-hydro- ω -hydroxypolymers with l,l'-methylene-bis-(4-isocyanatocyclohexane) having an average molecular weight of from 1600 to 18000.
4. Preparations of claim 1 to 3 characterised in that the immunosuppressive agents are selected from the groups of monocyclic undecapeptides or macrolide lactones or corticosteroids and are used either individually or in any mutual mixtures.
5. Preparations of claim 1 to 4 characterised in that the immunosuppressive agents are ciclosporin and or [Nva]2-ciclosporin in an amount of from 0.1 to 3.0 weight % and/or tacrolimus and/or sirolimus in an amount of from 0.05 to 2.0 weight % and/or dexamethasone and/or prednisolone in an amount of from 0.02 to 1.0 weight %.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CZ19974237A CZ287497B6 (en) | 1997-12-30 | 1997-12-30 | Topic eye preparations containing immunosuppressive substances |
CZ423797 | 1997-12-30 | ||
PCT/CZ1998/000054 WO1999034830A1 (en) | 1997-12-30 | 1998-12-17 | Topical ophthalmic preparations containing immunosuppressive agents |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1058560A1 true EP1058560A1 (en) | 2000-12-13 |
Family
ID=5467853
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP98958793A Withdrawn EP1058560A1 (en) | 1997-12-30 | 1998-12-17 | Topical ophthalmic preparations containing immunosuppressive agents |
Country Status (12)
Country | Link |
---|---|
EP (1) | EP1058560A1 (en) |
JP (1) | JP2002500200A (en) |
AU (1) | AU1481399A (en) |
BG (1) | BG104558A (en) |
CA (1) | CA2317010A1 (en) |
CZ (1) | CZ287497B6 (en) |
HR (1) | HRP20000258A2 (en) |
HU (1) | HUP0004173A2 (en) |
NO (1) | NO20003344L (en) |
PL (1) | PL341604A1 (en) |
SK (1) | SK284246B6 (en) |
WO (1) | WO1999034830A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10842729B2 (en) | 2017-09-13 | 2020-11-24 | Living Proof, Inc. | Color protectant compositions |
US10987300B2 (en) | 2017-09-13 | 2021-04-27 | Living Proof, Inc. | Long lasting cosmetic compositions |
US11622929B2 (en) | 2016-03-08 | 2023-04-11 | Living Proof, Inc. | Long lasting cosmetic compositions |
Families Citing this family (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU781049B2 (en) * | 1998-12-24 | 2005-05-05 | Sucampo Ag | Agent for treating visual cell function disorder |
US6864232B1 (en) | 1998-12-24 | 2005-03-08 | Sucampo Ag | Agent for treating visual cell function disorder |
TWI324925B (en) * | 2001-08-23 | 2010-05-21 | Novartis Ag | Ophthalmic composition |
ES2428354T3 (en) | 2002-09-18 | 2013-11-07 | Trustees Of The University Of Pennsylvania | Rapamycin for use in the inhibition or prevention of choroidal neovascularization |
US7354574B2 (en) | 2002-11-07 | 2008-04-08 | Advanced Ocular Systems Limited | Treatment of ocular disease |
US7083802B2 (en) * | 2003-07-31 | 2006-08-01 | Advanced Ocular Systems Limited | Treatment of ocular disease |
US7087237B2 (en) | 2003-09-19 | 2006-08-08 | Advanced Ocular Systems Limited | Ocular solutions |
US7083803B2 (en) | 2003-09-19 | 2006-08-01 | Advanced Ocular Systems Limited | Ocular solutions |
WO2006086750A1 (en) | 2005-02-09 | 2006-08-17 | Macusight, Inc. | Liquid formulations for treatment of diseases or conditions |
WO2007011880A2 (en) | 2005-07-18 | 2007-01-25 | Minu, L.L.C. | Enhanced ocular neuroprotection/neurostimulation |
JP5528708B2 (en) | 2006-02-09 | 2014-06-25 | 参天製薬株式会社 | Stable formulations and methods for preparing and using them |
US8222271B2 (en) | 2006-03-23 | 2012-07-17 | Santen Pharmaceutical Co., Ltd. | Formulations and methods for vascular permeability-related diseases or conditions |
DK2948134T3 (en) | 2013-01-24 | 2020-06-02 | Palvella Therapeutics Inc | COMPOSITIONS FOR TRANSDERMAL ADMINISTRATION OF MTOR INHIBITORS |
CN105431138B (en) * | 2013-03-27 | 2019-01-11 | 全球药物科技有限公司 | Eye medicine combination, preparation method and the usage |
CA3049402A1 (en) | 2017-01-06 | 2018-07-12 | Palvella Therapeutics Llc | Anhydrous compositions of mtor inhibitors and methods of use |
EP3817743A4 (en) | 2018-07-02 | 2022-07-06 | Palvella Therapeutics, Inc. | Anhydrous compositions of mtor inhibitors and methods of use |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5045317A (en) * | 1987-07-16 | 1991-09-03 | The Regents Of The University Of California | Enhancing the cutaneous penetration of pharmacologically active agents |
US4971800A (en) * | 1988-07-08 | 1990-11-20 | The Regents Of The University Of California | Method and compositions for enhancing the cutaneous penetration of pharmacologically active agents |
US5051260A (en) * | 1987-07-16 | 1991-09-24 | The Regents Of The University Of California | Method and composition for enhancing the cutaneous penetration of pharmacologically active agents |
-
1997
- 1997-12-30 CZ CZ19974237A patent/CZ287497B6/en not_active IP Right Cessation
-
1998
- 1998-12-14 SK SK1717-98A patent/SK284246B6/en not_active IP Right Cessation
- 1998-12-17 HU HU0004173A patent/HUP0004173A2/en unknown
- 1998-12-17 CA CA002317010A patent/CA2317010A1/en not_active Abandoned
- 1998-12-17 PL PL98341604A patent/PL341604A1/en unknown
- 1998-12-17 JP JP2000527277A patent/JP2002500200A/en not_active Withdrawn
- 1998-12-17 AU AU14813/99A patent/AU1481399A/en not_active Abandoned
- 1998-12-17 WO PCT/CZ1998/000054 patent/WO1999034830A1/en not_active Application Discontinuation
- 1998-12-17 EP EP98958793A patent/EP1058560A1/en not_active Withdrawn
-
2000
- 2000-05-03 HR HR20000258A patent/HRP20000258A2/en not_active Application Discontinuation
- 2000-06-27 BG BG104558A patent/BG104558A/en unknown
- 2000-06-27 NO NO20003344A patent/NO20003344L/en not_active Application Discontinuation
Non-Patent Citations (1)
Title |
---|
See references of WO9934830A1 * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11622929B2 (en) | 2016-03-08 | 2023-04-11 | Living Proof, Inc. | Long lasting cosmetic compositions |
US10842729B2 (en) | 2017-09-13 | 2020-11-24 | Living Proof, Inc. | Color protectant compositions |
US10987300B2 (en) | 2017-09-13 | 2021-04-27 | Living Proof, Inc. | Long lasting cosmetic compositions |
US11707426B2 (en) | 2017-09-13 | 2023-07-25 | Living Proof, Inc. | Color protectant compositions |
Also Published As
Publication number | Publication date |
---|---|
CA2317010A1 (en) | 1999-07-15 |
SK171798A3 (en) | 1999-10-08 |
NO20003344D0 (en) | 2000-06-27 |
HUP0004173A2 (en) | 2001-08-28 |
PL341604A1 (en) | 2001-04-23 |
BG104558A (en) | 2001-02-28 |
CZ423797A3 (en) | 1999-07-14 |
NO20003344L (en) | 2000-06-27 |
JP2002500200A (en) | 2002-01-08 |
CZ287497B6 (en) | 2000-12-13 |
AU1481399A (en) | 1999-07-26 |
SK284246B6 (en) | 2004-12-01 |
WO1999034830A1 (en) | 1999-07-15 |
HRP20000258A2 (en) | 2001-04-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11324757B2 (en) | Pharmaceutical composition for treatment of increased intraocular pressure | |
EP1058560A1 (en) | Topical ophthalmic preparations containing immunosuppressive agents | |
Shen et al. | Preparation and ocular pharmacokinetics of ganciclovir liposomes | |
EP3000474B1 (en) | Nanoemulsion eyedrop composition containing cyclosporine and method for preparing same | |
US5951971A (en) | Ophthalmic compositions | |
Pleyer et al. | Ocular absorption of topically applied FK506 from liposomal and oil formulations in the rabbit eye. | |
SK285220B6 (en) | Ophthalmic formulations | |
JP6824270B2 (en) | PEGylated lipid nanoparticles with bioactive lipophilic compounds | |
WO2021124301A1 (en) | Formulations and method for treatment of inflammatory diseases | |
EP2575854B1 (en) | Cyclosporin emulsions | |
CN112516084A (en) | In situ gel containing cyclosporine micelles as sustained release ophthalmic drug delivery system | |
KR20150000405A (en) | Oil-in-Water Emulsion Composition of Water-Insoluble Pharmaceutical Compounds and Method for Preparing the Same | |
MXPA00006508A (en) | Topical ophthalmic preparations containing immunosuppressive agents | |
RU2634267C2 (en) | Aqueous ophthalmic solution based on cyclosporin a | |
US20030206929A1 (en) | Amphotercin b structured emulsion | |
US20230093908A1 (en) | In-situ Gel Containing Cyclosporine Micelles as Sustained Ophthalmic Drug Delivery System |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 20000427 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU NL PT SE |
|
AX | Request for extension of the european patent |
Free format text: RO PAYMENT 20000427;SI PAYMENT 20000427 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
18D | Application deemed to be withdrawn |
Effective date: 20030701 |