WO2012092375A1 - Method for treating dry eye - Google Patents
Method for treating dry eye Download PDFInfo
- Publication number
- WO2012092375A1 WO2012092375A1 PCT/US2011/067594 US2011067594W WO2012092375A1 WO 2012092375 A1 WO2012092375 A1 WO 2012092375A1 US 2011067594 W US2011067594 W US 2011067594W WO 2012092375 A1 WO2012092375 A1 WO 2012092375A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- azithromycin
- retinoid
- dry eye
- effective amount
- retinyl palmitate
- Prior art date
Links
- 208000003556 Dry Eye Syndromes Diseases 0.000 title claims abstract description 64
- 238000000034 method Methods 0.000 title claims abstract description 40
- 206010013774 Dry eye Diseases 0.000 title claims description 22
- MQTOSJVFKKJCRP-BICOPXKESA-N azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 claims abstract description 75
- 229960004099 azithromycin Drugs 0.000 claims abstract description 67
- VYGQUTWHTHXGQB-FFHKNEKCSA-N Retinol Palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C VYGQUTWHTHXGQB-FFHKNEKCSA-N 0.000 claims abstract description 64
- 150000004492 retinoid derivatives Chemical class 0.000 claims abstract description 46
- 229940108325 retinyl palmitate Drugs 0.000 claims abstract description 32
- 235000019172 retinyl palmitate Nutrition 0.000 claims abstract description 32
- 239000011769 retinyl palmitate Substances 0.000 claims abstract description 32
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 15
- 239000000203 mixture Substances 0.000 claims description 28
- 239000004480 active ingredient Substances 0.000 claims description 18
- 230000000694 effects Effects 0.000 claims description 13
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 claims description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 8
- 206010010804 Contact lens intolerance Diseases 0.000 claims description 7
- 208000035475 disorder Diseases 0.000 claims description 7
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 claims description 5
- 229960001727 tretinoin Drugs 0.000 claims description 5
- 208000009319 Keratoconjunctivitis Sicca Diseases 0.000 claims description 4
- 206010042033 Stevens-Johnson syndrome Diseases 0.000 claims description 4
- 231100000168 Stevens-Johnson syndrome Toxicity 0.000 claims description 4
- 230000006378 damage Effects 0.000 claims description 4
- 230000007812 deficiency Effects 0.000 claims description 4
- 229960003471 retinol Drugs 0.000 claims description 4
- 235000020944 retinol Nutrition 0.000 claims description 4
- 239000011607 retinol Substances 0.000 claims description 4
- HQUPLSLYZHKKQT-WVVFQGGUSA-N (2r,3s,4r,5r,8r,10r,11r,12s,13s,14r)-11-[(2s,3r,4s,6r)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2r,4r,5s,6s)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-o Chemical compound O.O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 HQUPLSLYZHKKQT-WVVFQGGUSA-N 0.000 claims description 3
- 206010010071 Coma Diseases 0.000 claims description 3
- 208000028006 Corneal injury Diseases 0.000 claims description 3
- 208000001730 Familial dysautonomia Diseases 0.000 claims description 3
- 208000002720 Malnutrition Diseases 0.000 claims description 3
- 206010034277 Pemphigoid Diseases 0.000 claims description 3
- 201000001638 Riley-Day syndrome Diseases 0.000 claims description 3
- 208000021386 Sjogren Syndrome Diseases 0.000 claims description 3
- 229960003256 azithromycin monohydrate Drugs 0.000 claims description 3
- 230000002950 deficient Effects 0.000 claims description 3
- 230000000762 glandular Effects 0.000 claims description 3
- 208000015181 infectious disease Diseases 0.000 claims description 3
- 208000030212 nutrition disease Diseases 0.000 claims description 3
- 230000000144 pharmacologic effect Effects 0.000 claims description 3
- 239000000779 smoke Substances 0.000 claims description 3
- 208000023275 Autoimmune disease Diseases 0.000 claims description 2
- SHGAZHPCJJPHSC-NUEINMDLSA-N Isotretinoin Chemical compound OC(=O)C=C(C)/C=C/C=C(C)C=CC1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-NUEINMDLSA-N 0.000 claims description 2
- NAVMQTYZDKMPEU-UHFFFAOYSA-N Targretin Chemical compound CC1=CC(C(CCC2(C)C)(C)C)=C2C=C1C(=C)C1=CC=C(C(O)=O)C=C1 NAVMQTYZDKMPEU-UHFFFAOYSA-N 0.000 claims description 2
- OGQICQVSFDPSEI-UHFFFAOYSA-N Zorac Chemical compound N1=CC(C(=O)OCC)=CC=C1C#CC1=CC=C(SCCC2(C)C)C2=C1 OGQICQVSFDPSEI-UHFFFAOYSA-N 0.000 claims description 2
- 229960005339 acitretin Drugs 0.000 claims description 2
- 229960002916 adapalene Drugs 0.000 claims description 2
- LZCDAPDGXCYOEH-UHFFFAOYSA-N adapalene Chemical compound C1=C(C(O)=O)C=CC2=CC(C3=CC=C(C(=C3)C34CC5CC(CC(C5)C3)C4)OC)=CC=C21 LZCDAPDGXCYOEH-UHFFFAOYSA-N 0.000 claims description 2
- IHUNBGSDBOWDMA-AQFIFDHZSA-N all-trans-acitretin Chemical compound COC1=CC(C)=C(\C=C\C(\C)=C\C=C\C(\C)=C\C(O)=O)C(C)=C1C IHUNBGSDBOWDMA-AQFIFDHZSA-N 0.000 claims description 2
- 229960002938 bexarotene Drugs 0.000 claims description 2
- 229960002199 etretinate Drugs 0.000 claims description 2
- HQMNCQVAMBCHCO-DJRRULDNSA-N etretinate Chemical compound CCOC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)C=C(OC)C(C)=C1C HQMNCQVAMBCHCO-DJRRULDNSA-N 0.000 claims description 2
- 229960005280 isotretinoin Drugs 0.000 claims description 2
- 229960000565 tazarotene Drugs 0.000 claims description 2
- 206010010356 Congenital anomaly Diseases 0.000 claims 1
- 208000024891 symptom Diseases 0.000 abstract description 20
- 238000009472 formulation Methods 0.000 description 25
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- 229940079593 drug Drugs 0.000 description 14
- 239000003814 drug Substances 0.000 description 14
- 238000011282 treatment Methods 0.000 description 14
- 230000000699 topical effect Effects 0.000 description 11
- 210000000744 eyelid Anatomy 0.000 description 9
- 210000000981 epithelium Anatomy 0.000 description 7
- 210000004175 meibomian gland Anatomy 0.000 description 7
- 230000028327 secretion Effects 0.000 description 7
- 208000003251 Pruritus Diseases 0.000 description 6
- 229940006387 azasite Drugs 0.000 description 6
- 230000008859 change Effects 0.000 description 6
- 230000007794 irritation Effects 0.000 description 6
- 229940054534 ophthalmic solution Drugs 0.000 description 6
- 239000002997 ophthalmic solution Substances 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 230000035807 sensation Effects 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 230000003780 keratinization Effects 0.000 description 5
- 238000002560 therapeutic procedure Methods 0.000 description 5
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 4
- 210000004907 gland Anatomy 0.000 description 4
- 239000003755 preservative agent Substances 0.000 description 4
- 238000010186 staining Methods 0.000 description 4
- 150000003431 steroids Chemical class 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 235000019155 vitamin A Nutrition 0.000 description 4
- 239000011719 vitamin A Substances 0.000 description 4
- 229940045997 vitamin a Drugs 0.000 description 4
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- 102000011782 Keratins Human genes 0.000 description 3
- 108010076876 Keratins Proteins 0.000 description 3
- 206010037508 Punctate keratitis Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 239000000607 artificial tear Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 229960000686 benzalkonium chloride Drugs 0.000 description 3
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 210000004087 cornea Anatomy 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 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 3
- 210000002175 goblet cell Anatomy 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 229930002330 retinoic acid Natural products 0.000 description 3
- 239000000375 suspending agent Substances 0.000 description 3
- 230000009885 systemic effect Effects 0.000 description 3
- 238000011200 topical administration Methods 0.000 description 3
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 3
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- 208000007775 Congenital alacrima Diseases 0.000 description 2
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 2
- 206010015150 Erythema Diseases 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 206010065062 Meibomian gland dysfunction Diseases 0.000 description 2
- 206010034960 Photophobia Diseases 0.000 description 2
- 229920000148 Polycarbophil calcium Polymers 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
- 229940006385 azithromycin ophthalmic solution Drugs 0.000 description 2
- 201000007032 bacterial conjunctivitis Diseases 0.000 description 2
- 208000010217 blepharitis Diseases 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 229940082638 cardiac stimulant phosphodiesterase inhibitors Drugs 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 208000036549 congenital autosomal dominant alacrima Diseases 0.000 description 2
- 210000000795 conjunctiva Anatomy 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- -1 dextrans Chemical class 0.000 description 2
- 239000008121 dextrose Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 229940124274 edetate disodium Drugs 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 230000007803 itching Effects 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 210000004379 membrane Anatomy 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 102000006255 nuclear receptors Human genes 0.000 description 2
- 108020004017 nuclear receptors Proteins 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 229940100654 ophthalmic suspension Drugs 0.000 description 2
- 230000003204 osmotic effect Effects 0.000 description 2
- 239000005022 packaging material Substances 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 2
- 229950005134 polycarbophil Drugs 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 229960002668 sodium chloride Drugs 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- BJORNXNYWNIWEY-UHFFFAOYSA-N tetrahydrozoline hydrochloride Chemical compound Cl.N1CCN=C1C1C2=CC=CC=C2CCC1 BJORNXNYWNIWEY-UHFFFAOYSA-N 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- 229940028445 visine Drugs 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- JSFATNQSLKRBCI-VAEKSGALSA-N 15-HETE Natural products CCCCC[C@H](O)\C=C\C=C/C\C=C/C\C=C/CCCC(O)=O JSFATNQSLKRBCI-VAEKSGALSA-N 0.000 description 1
- JSFATNQSLKRBCI-UHFFFAOYSA-N 15-Hydroxyeicosatetraenoic acid Chemical compound CCCCCC(O)C=CC=CCC=CCC=CCCCC(O)=O JSFATNQSLKRBCI-UHFFFAOYSA-N 0.000 description 1
- APIXJSLKIYYUKG-UHFFFAOYSA-N 3 Isobutyl 1 methylxanthine Chemical compound O=C1N(C)C(=O)N(CC(C)C)C2=C1N=CN2 APIXJSLKIYYUKG-UHFFFAOYSA-N 0.000 description 1
- CYDQOEWLBCCFJZ-UHFFFAOYSA-N 4-(4-fluorophenyl)oxane-4-carboxylic acid Chemical compound C=1C=C(F)C=CC=1C1(C(=O)O)CCOCC1 CYDQOEWLBCCFJZ-UHFFFAOYSA-N 0.000 description 1
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 102000019034 Chemokines Human genes 0.000 description 1
- 108010012236 Chemokines Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 108010036949 Cyclosporine Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 206010052140 Eye pruritus Diseases 0.000 description 1
- 229920002683 Glycosaminoglycan Polymers 0.000 description 1
- 241000606768 Haemophilus influenzae Species 0.000 description 1
- 239000004166 Lanolin Substances 0.000 description 1
- 206010064912 Malignant transformation Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 102000002274 Matrix Metalloproteinases Human genes 0.000 description 1
- 108010000684 Matrix Metalloproteinases Proteins 0.000 description 1
- 239000000637 Melanocyte-Stimulating Hormone Substances 0.000 description 1
- 108010007013 Melanocyte-Stimulating Hormones Proteins 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 108020005497 Nuclear hormone receptor Proteins 0.000 description 1
- 208000022873 Ocular disease Diseases 0.000 description 1
- 208000023715 Ocular surface disease Diseases 0.000 description 1
- NMLMACJWHPHKGR-NCOIDOBVSA-N P(1),P(4)-bis(uridin-5'-yl) tetraphosphate Chemical compound N1([C@@H]2O[C@@H]([C@H]([C@H]2O)O)COP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@H]([C@@H](O2)N2C(NC(=O)C=C2)=O)O)O)C=CC(=O)NC1=O NMLMACJWHPHKGR-NCOIDOBVSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- ALLWOAVDORUJLA-UHFFFAOYSA-N Rebamipida Chemical compound C=1C(=O)NC2=CC=CC=C2C=1CC(C(=O)O)NC(=O)C1=CC=C(Cl)C=C1 ALLWOAVDORUJLA-UHFFFAOYSA-N 0.000 description 1
- 102000034527 Retinoid X Receptors Human genes 0.000 description 1
- 108010038912 Retinoid X Receptors Proteins 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 229920002385 Sodium hyaluronate Polymers 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 241001134658 Streptococcus mitis Species 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 229910021538 borax Inorganic materials 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 229940096529 carboxypolymethylene Drugs 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- 238000003759 clinical diagnosis Methods 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 229940124301 concurrent medication Drugs 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 239000003431 cross linking reagent Substances 0.000 description 1
- 229930182912 cyclosporin Natural products 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 229950003529 diquafosol Drugs 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 210000003560 epithelium corneal Anatomy 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 102000034240 fibrous proteins Human genes 0.000 description 1
- 108091005899 fibrous proteins Proteins 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 230000002650 habitual effect Effects 0.000 description 1
- 229940047650 haemophilus influenzae Drugs 0.000 description 1
- 238000002657 hormone replacement therapy Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 239000005414 inactive ingredient Substances 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 230000004941 influx Effects 0.000 description 1
- 230000005722 itchiness Effects 0.000 description 1
- 210000005128 keratinized epithelium Anatomy 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000036212 malign transformation Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 230000001254 nonsecretory effect Effects 0.000 description 1
- 230000000414 obstructive effect Effects 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 239000003209 petroleum derivative Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229920000570 polyether Polymers 0.000 description 1
- 229920001223 polyethylene glycol 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
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 229950004535 rebamipide Drugs 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000002207 retinal effect Effects 0.000 description 1
- NCYCYZXNIZJOKI-OVSJKPMPSA-N retinal group Chemical group C\C(=C/C=O)\C=C\C=C(\C=C\C1=C(CCCC1(C)C)C)/C NCYCYZXNIZJOKI-OVSJKPMPSA-N 0.000 description 1
- 102000003702 retinoic acid receptors Human genes 0.000 description 1
- 108090000064 retinoic acid receptors Proteins 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000000580 secretagogue effect Effects 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- 229940010747 sodium hyaluronate Drugs 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 239000001540 sodium lactate Substances 0.000 description 1
- 235000011088 sodium lactate Nutrition 0.000 description 1
- 229940005581 sodium lactate Drugs 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 210000004085 squamous epithelial cell Anatomy 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000003270 steroid hormone Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 230000004489 tear production Effects 0.000 description 1
- 150000003505 terpenes Chemical group 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- DHCDFWKWKRSZHF-UHFFFAOYSA-L thiosulfate(2-) Chemical compound [O-]S([S-])(=O)=O DHCDFWKWKRSZHF-UHFFFAOYSA-L 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 239000005495 thyroid hormone Substances 0.000 description 1
- 229940036555 thyroid hormone Drugs 0.000 description 1
- 230000003867 tiredness Effects 0.000 description 1
- 208000016255 tiredness Diseases 0.000 description 1
- 230000007838 tissue remodeling Effects 0.000 description 1
- 229940100613 topical solution Drugs 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/203—Retinoic acids ; Salts thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
- A61K31/232—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having three or more double bonds, e.g. etretinate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
Definitions
- This invention relates to methods of treating dry eye by administering
- This invention also relates to a pharmaceutical composition comprising azithromycin and a retinoid such as retinyl palmitate.
- Dry eye disease is a disorder due to an insufficient quantity of tears.
- the signs and symptoms of dry eye disease include ocular surface staining, eyelid swelling and redness, ocular irritation and foreign body sensation (gritty or sandy eyes).
- the quantity of tears can be reduced by either a failure to produce a sufficient amount of tears or by rapid evaporation of the tear film.
- Bron et al. disclose that the tear film lipid layer is the major barrier to evaporation from the ocular surface. A decrease in the thickness or functional integrity of the tear film may cause evaporative dry eye. Obstructive meibomian gland dysfunction is the most common cause of evaporative dry eye.
- Dry eye disease is the general term for indications produced by abnormalities of the precorneal tear film characterized by a decrease in tear production or an increase in tear film evaporation, together with the ocular surface disease and symptoms that result.
- dry eye disease Among the indications that are referred to by the general term “dry eye disease” are:
- keratoconjunctivitis sicca KCS
- age-related dry eye Stevens-Johnson syndrome
- Sjogren's syndrome ocular cicatrical pemphigoid
- corneal injury infection
- Riley-Day syndrome congenital alacrima
- nutritional disorders or deficiencies including vitamins
- pharmacologic side effects contact lens intolerance, eye stress and glandular and tissue destruction, environmental exposure to smog, smoke, excessively dry air, airborne particulates, autoimmune and other immunodeficient disorders, and comatose patients rendered unable to blink.
- Dry eye disease although seen pathologically during ophthalmic exams as superficial punctate keratopathy (SPK) of the ocular surface epithelium, is largely a symptomatic disease. Chronic dryness leads to pain and irritation that is often debilitating to the subject, preventing the performance of normal daily activities such as reading, driving, etc. Dry eye is most common in postmenopausal women; however, hormone replacement therapy has not been proven to help dry eye signs and symptoms.
- SPK superficial punctate keratopathy
- Contact lens wear is commonly associated with symptoms of ocular irritation including symptoms such as dryness, discomfort, soreness, tiredness, and irritation, among other symptoms. Reports have shown that between 25-50% of contact lens wearers have these symptoms, albeit of differing frequencies and severities. Further, these symptoms have been shown to increase in their intensity or severity over the course of a day's wear of lenses, with an average increase of approximately 25% as demonstrated in at least one study.
- IBMX 3-isobutyl-l -methylxanthine
- Dry eye disease is different from blepharitis; the two diseases have different patient populations. Dry eye symptoms are dryness, burning, photophobia, foreign body sensation and grittiness in the eyes. Dry eye disease is characterized by an insufficient or defective tear film.
- the primary end points for studying dry eye diseases are corneal and conjunctival staining, measuring tear volume (Schirmer tests), Tear break-up time, dryness, burning, photophobia, foreign body sensation and grittiness.
- Keratin is a tough, fibrous protein that is not water-soluble and is the main component of hair, nails and the epidermis (Ong, et al., Current Eye Research, 10, 1 1 13-1 1 19 (1991)).
- Keratinization is a process which involves the conversion of epithelial or other cell types in to cells that are largely comprised of keratin (Tseng, et ah, Ophthalmology, 91 , 545-552 (1984), and Jester, et al., Inv. Ophthal. Vis. Sci. 30, 927-935 (1989). Keratinization of cells in ocular surface tissues such as the conjunctiva, goblet cells and the meibomian glands may play a role in the development of dry eye (Nicholaides, et al., Inv, Ophthal Vis. Sci. 30, 946-951 (1989).
- the secretions from the squamous epithelial cells and goblet cells in the conjunctiva contribute to the tear film mucin and aqueous components.
- Overexpression of keratin, or hyperkeratinization, of these cell types may impact both the quality and quantity of the tear film. Keratinization of the meibomian glands may occur on the lid margin, obstructing the orifice of the glands, or inside the glands to the epithelial lining of the glands.
- Hyperkeratinization either in the glands or of the surface epithelium may alter the lipid secretions which comprise the outer layer of the tear film.
- Retinoids include Vitamin A (retinol), retinoic acid, and retinyl palmitate as well as related compounds that are synthetic or naturally occurring cellular components or metabolites.
- the effects of RA and synthetic derivatives are mediated by two classes of nuclear receptors, the retinoic acid receptors which belong to the erbA-related steroid/thyroid nuclear receptor superfamily and the retinoid X receptors which also belong to the same super family of steroid/thyroid hormones (Gorodeski, et al., Am. J. Physiol. Cell. Physiol. 275, 758-765 (1998).
- Vitamin A and related retinoids are involved in the maintenance of mucosal membranes via control of the proliferation and differentiation of epithelial cells.
- a deficiency of retinoids results in a gradual change of the ocular mucosa to a non-secretory keratinized epithelium.
- Retinoic acid plays a fundamental role in cell proliferation, and cell differentiation and it may also prevent malignant transformation (Darmon, 1991 , Sem. Dev. Biol. 2:219).
- Retinoids have been utilized to treat a number of conditions involving keratinization of epithelial tissue, including: acne vulgaris, psoriasis, wound healing and premalignant lesions (Kligman, A., Cutis, 39, 486-488 (1987).
- Formulations containing retinoids have also been utilized to treat ocular disorders involving the epithelium, such as dry eye, Stevens- Johnson syndrome (Kobayashi, et al., Ophthalmologica, 21 1 , 358-361 (1997); Selek, et al., Eur. J. Ophthalmol, 10, 121-127 (2000) and Kim, et al, Amer. J. Oph, 147, 206-213.e3 (2009)).
- Topical retinoid formulations include ointments and liquid formulations that may be applied 2-4 times per day for one or more months. Increases in goblet cell density in ocular mucosal tissue, tear break up time and Schirmer score measurements have been noted following topical retinoid therapy.
- Topical preparations allow for sufficient efficacy at the site of the disorder, yet avoid systemic side effects, Side effects of topical retinoid formulations include irritation and redness during the initial period of therapy.
- Practices to reduce the side effects of topical retinoid formulations include a reduction in the concentration of the active ingredient, a reduction in frequency of administration or discontinuation of therapy, which make the retinoid treatment less effective.
- Azithromycin is a macrolide antibiotic.
- AZASITE ® (azithromycin ophthalmic solution) is a 1 % sterile aqueous topical ophthalmic solution of azithromycin formulated in DURASITE ® (polycarbophil, edetate disodium, sodium chloride).
- DURASITE ® polycarbophil, edetate disodium, sodium chloride.
- AZASITE ® is approved by the U.S. Food and Drug Administration (FDA) for treatment of bacterial conjunctivitis, caused by susceptible isolates of CDC coryneform group G, Haemophilus influenzae, Staphylococcus aureus, Streptococcus mitis group, and Streptococcus pneumoniae
- the recommended dosage regimen for the treatment of bacterial conjunctivitis is as follows: instill 1 drop in the affected eye(s) twice daily, 8 to 12 hours apart for the first 2 days and then instill 1 drop in the affected eye(s) once daily for the next 5 days (AZASITE ® Package Insert, 2007).
- Azithromycin has immunomodulatory and anti-inflammatory effects that are separate from the antimicrobial effects. Studies have been conducted that demonstrate a reduction in inflammatory cell influx, pro-inflammatory mediator release (e.g. cytokines and
- Topical application of azithromycin to the ocular surface has been shown to improve the quality of the meibomian gland secretions.
- Daily administration of topical azithromycin in subjects with meibomian gland dysfunction improved the physicochemical properties of the meibum towards that of normal subjects (Foulks, G.N., Cornea, 29(7), 781 -8 (2010)).
- the present invention is directed to a method for treating dry eye disease.
- the method comprises the steps of: identifying a patient suffering from dry eye disease, and topically administering to the patient an effective amount of azithromycin or a
- Azithromycin and the retinoid can be administered either sequentially or by co-administration.
- Preferred azithromycin is azithromycin monohydrate and preferred retinoid is retinyl palmitate.
- An effective concentration of azithromycin is about 0.5%-2% (w/v), and an effective
- concentration of retinyl palmitate is about 0.01 -0.1 % (w/v).
- An effect dosing regimen would consist of topical administration of 1-2 drops (approximately 50 microliters) in each eye once or twice a day.
- the present invention is also directed to a pharmaceutical composition
- a pharmaceutical composition comprising active ingredients and a pharmaceutically acceptable carrier, wherein the active ingredients consisting essentially of 0.5-2% (w/v) of azithromycin and 0.01-1%) (w/v) retinyl palmitate.
- the pharmaceutical composition preferably is an ophthalmic solution or suspension.
- the inventor has discovered an effective method for treating dry eye disease by administering azithromycin and a retinoid to a patient suffering from dry eye disease.
- the inventor has discovered that combined administration of azithromycin and a retinoid is more effective in treating dry eye disease than the single administration of either azithromycin or a retinoid.
- the present invention is directed to a method for treating dry eye.
- the method comprises the steps of: identifying a patient suffering from dry eye disease, and topically administering to the patient an effective amount of azithromycin or a pharmaceutically acceptable salt thereof and an effective amount of a retinoid.
- Azithromycin and the retinoid can be administered to the patient separately or co-administered in one single formulation.
- the method comprises the steps of: identifying a patient suffering from dry eye, and administering to the patient a pharmaceutical composition comprising active ingredients and a pharmaceutically acceptable carrier, wherein the active ingredients consisting essentially of an effective amount of azithromycin and an effective amount of a retinoid.
- the active ingredients only include azithromycin and a retinoid and those that do not materially affect the basic and novel characteristics of the claimed invention.
- the present invention is suitable for treating dry eye diseases caused by one or more of keratoconjunctivitis sicca, age-related dry eye, Stevens-Johnson syndrome, Sjogren's syndrome, ocular cicatrical pemphigoid, corneal injury, infection, Riley-Day syndrome, congenital alacrima, nutritional disorders or deficiencies, pharmacologic side effects, contact lens intolerance, eye stress resulting in glandular and tissue destruction, autoimmune disorders, immuno-deficient disorders, comatose patients who are unable to blink, or environmental exposure to smog, smoke, excessively dry air, or airborne
- the present invention is also suitable to treat patients suffering from dry eye disease, but not suffering from blepharitis.
- the present invention is also directed to a method for reducing contact lens intolerance in a subject.
- the method comprises the steps of: identifying a subject suffering from contact lens intolerance due to dry eye disease; and topically administering to the patient a pharmaceutical composition comprising active ingredients and a pharmaceutically acceptable carrier, wherein the active ingredients consisting essentially of an effective amount of azithromycin and an effective amount of a retinoid.
- the active ingredients only include azithromycin and a retinoid and those that do not materially affect the basic and novel characteristics of the claimed invention.
- the present method increases comfortable contact lens wearing time and/or total duration of contact lens wearing time per day in the subject.
- Retinoids refer to a class of compounds consisting of four isoprenoid units joined in a head-to-tail manner. All retinoids may be formally derived from a monocyclic parent compound containing five carbon-carbon double bonds and a functional group at the terminus of the acyclic portion. Retinoids are a class of chemical compounds that are chemically related to vitamin A (retinol). Examples of retinoids useful in the present invention include: vitamin A (retinol), retinyl palmitate, retinal, tretinoin (retinoic acid), isotretinoin, etretinate, acitretin, tazarotene, bexarotene, and adapalene. Retinyl palmitate is a preferred compound for this invention.
- an effective amount is meant an amount that has a therapeutic effect, which reduces the signs and/or symptoms of dry eye disease.
- the effective concentration of azithromycin is about 0.5%-2% (w/v), e.g., about 1%
- an effective concentration of retinyl palmitate is about 0.01 -0.1 % (w/v), e.g., about 0.05%.
- An effect dosing regimen would consist of topical administration of 1-2 drops (approximately 50 microliters) in each eye once or twice a day.
- the effective concentration of azithromycin is 1% (w/v), and an effective amount of retinyl palmitate is 0.05% (w/v).
- the present invention is directed to a pharmaceutical composition
- a pharmaceutical composition comprising azithromycin or a pharmaceutically acceptable salt thereof, a retinoid, and a pharmaceutically acceptable carrier.
- Preferred azithromycin is azithromycin monohydrate and preferred retinoid is retinyl palmitate.
- the pharmaceutical composition preferably is an ophthalmic solution or suspension.
- a preferred pharmaceutical composition comprises active ingredients and a pharmaceutically acceptable carrier, wherein the active ingredients consisting essentially of 0,5-2% of azithromycin and 0.01 -1 % retinyl palmitate.
- the topical solution containing azithromycin and a retinoid can contain a
- the ophthalmic vehicles include, but are not limited to, saline solution, water polyethers such as polyethylene glycol, polyvinyls such as polyvinyl alcohol and povidone, cellulose derivatives such as methylcellulose and hydroxypropyl methylcellulose, petroleum derivatives such as mineral oil and white petrolatum, animal fats such as lanolin, polymers of acrylic acid such as carboxypolymethylene gel, vegetable fats such as peanut oil and polysaccharides such as dextrans, and glycosaminoglycans such as sodium hyaluronate and salts such as sodium chloride and potassium chloride.
- water polyethers such as polyethylene glycol
- polyvinyls such as polyvinyl alcohol and povidone
- cellulose derivatives such as methylcellulose and hydroxypropyl methylcellulose
- petroleum derivatives such as mineral oil and white petrolatum
- animal fats such as lanolin
- polymers of acrylic acid such as carboxypolymethylene gel
- vegetable fats such as peanut
- Preferred ophthalmic formulations of azithromycin and retinoids suitable for the present method are those disclosed in U.S. Patent Nos. 6,239,1 13, 6,569,443 and 7,056,893; the formulations of which are incorporated herein by reference.
- the formulation is an aqueous polymeric suspension comprising water, azithromycin, retinyl palmitate, and 0.1 to 10% of a polymeric suspending agent.
- the polymeric suspending agent comprises a water-swellable water-insoluble crosslinked carboxy-vinyl polymer.
- the polymeric suspending agent comprises least 90% (w/v) acrylic acid monomers and 0.1 % to 5% (w/v) crosslinking agent.
- the formulations may further comprise polyvinyl alcohols and providone.
- AZASITE ® (azithromycin ophthalmic solution), which is a 1% (w/v) sterile aqueous topical ophthalmic solution of azithromycin formulated in DURASITE ® (polycarbophil, edetate disodium, sodium chloride), is a preferred ophthalmic formulation.
- Retinyl palmitate can be added to AZASITE ® to form a combination formulation.
- the preferred ophthalmic formulations are able to keep prolonged high azithromycin and retinyl palmitate
- the formulation optionally includes a preservative, such as benzalkonium chloride and other inactive ingredients such as EDTA.
- a preservative such as benzalkonium chloride and other inactive ingredients such as EDTA.
- benzalkonium chloride has the benefit of increasing the penetration of azithromycin into eye tissues.
- preferred formulations are those without any preservatives due to the potential for damage to the corneal epithelium that may result from long term, frequent exposure to preservatives such as benzalkonium chloride.
- the formulations without preservatives are prepared in a unit dose and stored in a single-use container.
- the pH of the formulation is typically adjusted by adding any physiologically and ophthamologically acceptable pH adjusting acids, bases or buffers to within the range of about 5 to 7.5; preferably 6 to 7.
- acids include acetic, boric, citric, lactic, phosphoric, hydrochloric, and the like
- bases include sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate,
- salts and buffers include citrate/dextrose, sodium bicarbonate, ammonium chloride and mixtures of the aforementioned acids and bases.
- the osmotic pressure of the aqueous ophthalmic composition is generally from about 200 to about 400 milliosmolar (mOsM), more preferably from 260 to 340 mOsM.
- the osmotic pressure can be adjusted by using appropriate amounts of physiologically and ophthamologically acceptable ionic or non-ionic agents.
- Sodium chloride is a preferred ionic agent, and the amount of sodium chloride ranges from about 0.01 % to about 1 % (w/v), and preferably from about 0.05% to about 0.45% (w/v).
- Equivalent amounts of one or more salts made up of cations such as potassium, ammonium and the like and anions such as chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, bisulfate, sodium bisulfate, ammonium sulfate, and the like can be used in addition to or instead of sodium chloride to achieve osmolality within the above-stated range.
- non-ionic agents such as mannitol, dextrose, sorbitol, glucose and the like can also be used to adjust the osmolality.
- topical administration is an effective method for delivering azithromycin and the retinoid.
- Instillation to the ocular surface is a localized administration method and can therefore be more effective in reaching the target area, i.e., the eye, and providing a high and localized concentration of azithromycin and the retinoid.
- Formulations described by the present invention can be administered to the eyes of a patient by any suitable means, but are preferably administered as a liquid or gel suspension in the form of drops, spray or gel.
- the formulation is in the form of drops, and is dropped onto the ocular surface.
- the formulation is contained within a swab or sponge which can be applied to the ocular surface.
- the formulation is contained within a liquid spray or ointment which can be applied to the ocular surface.
- the formulation is injected directly into the lacrimal tissues or onto the eye surface.
- the formulation (e.g., in the form of drops) is first applied on a finger tip or other applicator, then applied or rubbed directly onto the lid margin.
- azithromycin and a retinoid can be applied to the eye via liposomes.
- azithromycin and a retinoid can be infused into the tear film via a pump-catheter system.
- Another embodiment of the present invention involves azithromycin and a retinoid contained within a continuous or selective-release device, for example, membranes such as, but not limited to, those employed in the OCUSERTTM System
- azithromycin and a retinoid can be contained within, carried by, or attached to contact lenses or other compatible controlled release materials, which are placed on the eye.
- the azithromycin and retinoid are administered 1 , 2, 3 or 4 times a day sequentially (i.e. one after the other), or co-administered together.
- azithromycin and retinyl palmitate are admixed as one pharmaceutical composition and administered to patients by instillation on to the ocular surface.
- One single pharmaceutical composition and one single treatment provide ease of use and result in better compliance of patients.
- azithromycin and retinyl palmitate are each in a separate formulation and administered separately to patients.
- the daily dose to treat dry eye disease can be divided among one or several unit dose administrations.
- the daily dose for example, can range from one drop (about 50 ⁇ ), one to four times a day, depending upon the age and condition of the subject.
- a preferred regimen is one drop of a 1 % azithromycin (w/v) and 0.05% (w/v) retinyl palmitate solution, about 1 to 2 times a day.
- a preferred dosage is one drop in each eye twice a day for two days and then once a day thereafter.
- the present method can be combined with mechanical therapy such as warm compress or lid hygiene (lid cleansing).
- mechanical therapy such as warm compress or lid hygiene (lid cleansing).
- the inventor has discovered that the combined administration of azithromycin and a retinoid to a dry eye disease patient has several advantages that cannot be achieved by a single administration of either azithromycin or a retinoid.
- Dry eye disease is a chronic disease, and subjects with dry eye disease often have physical alterations to the meibomian glands and the epithelium surrounding the orifices of the meibomian glands, as well as the corneal and conjunctival epithelium.
- the inventor has discovered that the combined treatment of a retinoid and azithromycin allows for a normal meibomian gland function which improves the quality of the meibomian gland secretions, and allows for the improved secretions to be secreted and reach the ocular surface.
- the combined treatment also provides enhanced mucosal secretions from the ocular surface epithelium. Additionally, the anti-inflammatory properties of azithromycin reduce the side effects of irritation and inflammation during the early phase of a retinoid treatment, which enhance the tolerability of topically applied retinoid without having to reduce the amount or frequency of the retinoid application.
- Example 1 Use of azithromycin and a retinoid for reducing symptoms in patients with dry eye disease
- the objective of this study is to compare the efficacy of an ophthalmic formulation of azithromycin 1% and retinyl palmitate 0.05% combined, versus the ophthalmic formulations of the respective active ingredients alone over a four week treatment period on the symptoms of subjects with dry eye disease.
- Subjects are 18 years of age or older, and have a clinical diagnosis of mild to moderate dry eye disease. A total of 120 subjects are enrolled in the study. Methods
- Visit 2 Patients return for Visit 2 (Day 14), and Visit 3 (Day 30) and are asked to rate their symptoms including: ocular itching, ocular burning/pain, and foreign body sensation.
- the mean scores for individual symptoms for each group are compared for Visits 2-3 to baseline (Visit 1). A statistically significant difference (p ⁇ 0.05) is observed in favor of the azithromycin and retinyl palmitate treatment group for at least one of the Visits.
- Example 2 Use of Azithromycin and a retinoid for treating patients with contact lens related dry eye disease
- the objective of this study is to compare the efficacy of the study drugs (1 %
- CLDEQ Contact Lens Dry Eye Questionnaire
- Visit 1 (Day 1 )
- Subjects are asked to rate their level of ocular dryness on a 0-4 scale. Tear osmolarity is then assessed for each eye using the TearLab Osmolarity System®. Subjects are then instructed to remove their contact lenses and slit-lamp biomicroscopy and external eye exams are performed. Fluorescein corneal staining is then performed on each eye (5 ⁇ of 2 % fluorescein applied to the ocular surface) and graded according to National Eye Institute (NEI) criteria.
- NAI National Eye Institute
- Subjects randomized to azithromcyin and retinyl palmitate are instructed to administer one drop to each eye BID for both drugs the first two days and then one drop QID for both drugs for days 3-29.
- Subjects randomized to rewetting drops are instructed to administer one to two drops QID throughout the 29 day treatment period.
- the first dose of study medication is self-administered at the clinic once dosing instructions are provided.
- Subjects are instructed to apply a new pair of contact lenses to their eyes 10 minutes after the instillation of study medication.
- Subjects are queried for adverse events (AEs) and scheduled to return for Visit 2 in approximately two weeks.
- AEs adverse events
- Subjects are instructed to record the AM ocular dryness assessment prior to instilling study medication (and lens application), and record PM dryness levels prior to lens removal each day. Further, subjects are required to record the time that contacts are inserted, the time lenses became uncomfortable and the time lenses are removed.
- the primary efficacy endpoint for this study is the change from baseline in the duration of subject-reported comfortable contact lens daily wear time (hours/day) at the Week 4 Endpoint.
- the Week 4 Endpoint is defined as the average of the change from baseline values for comfortable contact lens daily wear time from days 23 to 29.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Molecular Biology (AREA)
- Emergency Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
This invention relates to methods of treating dry eye disease. The methods comprise identifying a patient suffering from dry eye disease, and topically administering to the eyes of the patient an effective amount of azithromycin and an effective amount of a retinoid. The method is useful in relieving the signs and symptoms of dry eye disease. This invention also relates to a pharmaceutical composition comprising azithromycin and a retinoid such as retinyl palmitate.
Description
METHOD FOR TREATING DRY EYE
TECHNICAL FIELD
This invention relates to methods of treating dry eye by administering
azithromycin and a retinoid to a subject. The method is useful in relieving dry eye signs and symptoms. This invention also relates to a pharmaceutical composition comprising azithromycin and a retinoid such as retinyl palmitate.
BACKGROUND OF THE INVENTION
Dry eye disease is a disorder due to an insufficient quantity of tears. The signs and symptoms of dry eye disease include ocular surface staining, eyelid swelling and redness, ocular irritation and foreign body sensation (gritty or sandy eyes). The quantity of tears can be reduced by either a failure to produce a sufficient amount of tears or by rapid evaporation of the tear film. Bron et al. (The Ocular Surface, 2: 149 - 164) disclose that the tear film lipid layer is the major barrier to evaporation from the ocular surface. A decrease in the thickness or functional integrity of the tear film may cause evaporative dry eye. Obstructive meibomian gland dysfunction is the most common cause of evaporative dry eye.
Dry eye disease is the general term for indications produced by abnormalities of the precorneal tear film characterized by a decrease in tear production or an increase in tear film evaporation, together with the ocular surface disease and symptoms that result.
Approximately 38 million Americans are affected with some type of dry eye disorder.
Among the indications that are referred to by the general term "dry eye disease" are:
keratoconjunctivitis sicca (KCS), age-related dry eye, Stevens-Johnson syndrome, Sjogren's syndrome, ocular cicatrical pemphigoid, corneal injury, infection, Riley-Day syndrome, congenital alacrima, nutritional disorders or deficiencies (including vitamins), pharmacologic side effects, contact lens intolerance, eye stress and glandular and tissue destruction, environmental exposure to smog, smoke, excessively dry air, airborne particulates, autoimmune and other immunodeficient disorders, and comatose patients rendered unable to blink.
Dry eye disease, although seen pathologically during ophthalmic exams as superficial punctate keratopathy (SPK) of the ocular surface epithelium, is largely a symptomatic disease. Chronic dryness leads to pain and irritation that is often debilitating to the subject, preventing the performance of normal daily activities such as reading, driving, etc. Dry eye
is most common in postmenopausal women; however, hormone replacement therapy has not been proven to help dry eye signs and symptoms.
Contact lens wear is commonly associated with symptoms of ocular irritation including symptoms such as dryness, discomfort, soreness, tiredness, and irritation, among other symptoms. Reports have shown that between 25-50% of contact lens wearers have these symptoms, albeit of differing frequencies and severities. Further, these symptoms have been shown to increase in their intensity or severity over the course of a day's wear of lenses, with an average increase of approximately 25% as demonstrated in at least one study.
(Dougherty et al. Br. J. Ophthalmol. 1984;68:524-8)
Currently, the pharmaceutical treatment of dry eye disease is mostly limited to administration of artificial tears (saline solution) or anti-inflammatory agents (cyclosporine, steroids). Secretagogues (diquafosol, 15-HETE, rebamipide) to increase the production of tears are currently under development. In addition, artificial tears often have
contraindications and incompatibility with soft contact lenses (M. Lemp, Cornea 9(1), S48-550 (1990)). The use of phosphodiesterase inhibitors, such as
3-isobutyl-l -methylxanthine (IBMX) to stimulate tear secretion is disclosed in U.S. Pat. No. 4,753,945. The effectiveness of these phosphodiesterase inhibitors has been investigated (J. Gilbard, et al., Arch. Ophthal, 1 12, 1614-16 (1994) and 109, 672-76 (1991); idem, Inv.
Ophthal. Vis. Sci. 31 , 1381-88 (1990)). Stimulation of tear secretion by topical application of melanocyte stimulating hormones is described in U.S. Pat. No. 4,868,154. Although these interventions can reduce inflammation and/or reduce SPK associated with dry eye, they have not been proven to significantly reduce the symptoms of dry eye.
Dry eye disease is different from blepharitis; the two diseases have different patient populations. Dry eye symptoms are dryness, burning, photophobia, foreign body sensation and grittiness in the eyes. Dry eye disease is characterized by an insufficient or defective tear film. The primary end points for studying dry eye diseases are corneal and conjunctival staining, measuring tear volume (Schirmer tests), Tear break-up time, dryness, burning, photophobia, foreign body sensation and grittiness.
Keratin is a tough, fibrous protein that is not water-soluble and is the main component of hair, nails and the epidermis (Ong, et al., Current Eye Research, 10, 1 1 13-1 1 19 (1991)).
Keratinization is a process which involves the conversion of epithelial or other cell types in to cells that are largely comprised of keratin (Tseng, et ah, Ophthalmology, 91 , 545-552 (1984), and Jester, et al., Inv. Ophthal. Vis. Sci. 30, 927-935 (1989). Keratinization of cells in ocular surface tissues such as the conjunctiva, goblet cells and the meibomian glands may play a
role in the development of dry eye (Nicholaides, et al., Inv, Ophthal Vis. Sci. 30, 946-951 (1989). The secretions from the squamous epithelial cells and goblet cells in the conjunctiva contribute to the tear film mucin and aqueous components. Overexpression of keratin, or hyperkeratinization, of these cell types may impact both the quality and quantity of the tear film. Keratinization of the meibomian glands may occur on the lid margin, obstructing the orifice of the glands, or inside the glands to the epithelial lining of the glands.
Hyperkeratinization either in the glands or of the surface epithelium may alter the lipid secretions which comprise the outer layer of the tear film.
Retinoids include Vitamin A (retinol), retinoic acid, and retinyl palmitate as well as related compounds that are synthetic or naturally occurring cellular components or metabolites. The effects of RA and synthetic derivatives are mediated by two classes of nuclear receptors, the retinoic acid receptors which belong to the erbA-related steroid/thyroid nuclear receptor superfamily and the retinoid X receptors which also belong to the same super family of steroid/thyroid hormones (Gorodeski, et al., Am. J. Physiol. Cell. Physiol. 275, 758-765 (1998).
Vitamin A and related retinoids are involved in the maintenance of mucosal membranes via control of the proliferation and differentiation of epithelial cells. A deficiency of retinoids results in a gradual change of the ocular mucosa to a non-secretory keratinized epithelium. (Kobayashi, et al., Ophthalmologica, 21 1 , 358-361 (1997)). Retinoic acid plays a fundamental role in cell proliferation, and cell differentiation and it may also prevent malignant transformation (Darmon, 1991 , Sem. Dev. Biol. 2:219).
Retinoids have been utilized to treat a number of conditions involving keratinization of epithelial tissue, including: acne vulgaris, psoriasis, wound healing and premalignant lesions (Kligman, A., Cutis, 39, 486-488 (1987). Formulations containing retinoids have also been utilized to treat ocular disorders involving the epithelium, such as dry eye, Stevens- Johnson syndrome (Kobayashi, et al., Ophthalmologica, 21 1 , 358-361 (1997); Selek, et al., Eur. J. Ophthalmol, 10, 121-127 (2000) and Kim, et al, Amer. J. Oph, 147, 206-213.e3 (2009)). Topical retinoid formulations include ointments and liquid formulations that may be applied 2-4 times per day for one or more months. Increases in goblet cell density in ocular mucosal tissue, tear break up time and Schirmer score measurements have been noted following topical retinoid therapy.
Systemic treatment with retinoids for epithelial keratinization disorders may be effective, but side effects due to toxicity are common (Kligman, A., Cutis, 39, 486-488 (1987). Topical preparations allow for sufficient efficacy at the site of the disorder, yet avoid
systemic side effects, Side effects of topical retinoid formulations include irritation and redness during the initial period of therapy. Practices to reduce the side effects of topical retinoid formulations include a reduction in the concentration of the active ingredient, a reduction in frequency of administration or discontinuation of therapy, which make the retinoid treatment less effective.
Azithromycin is a macrolide antibiotic. AZASITE® (azithromycin ophthalmic solution) is a 1 % sterile aqueous topical ophthalmic solution of azithromycin formulated in DURASITE® (polycarbophil, edetate disodium, sodium chloride). AZASITE® is approved by the U.S. Food and Drug Administration (FDA) for treatment of bacterial conjunctivitis, caused by susceptible isolates of CDC coryneform group G, Haemophilus influenzae, Staphylococcus aureus, Streptococcus mitis group, and Streptococcus pneumoniae
(AZASITE® Package Insert, 2007). The recommended dosage regimen for the treatment of bacterial conjunctivitis is as follows: instill 1 drop in the affected eye(s) twice daily, 8 to 12 hours apart for the first 2 days and then instill 1 drop in the affected eye(s) once daily for the next 5 days (AZASITE® Package Insert, 2007).
Azithromycin has immunomodulatory and anti-inflammatory effects that are separate from the antimicrobial effects. Studies have been conducted that demonstrate a reduction in inflammatory cell influx, pro-inflammatory mediator release (e.g. cytokines and
chemokines), and tissue remodeling mediators such as matrix metalloproteinases (Amsden, G.W., Journal of Antimicrobial Chemotherapy, 55, 10-21 (2005), Li, D.Q., Invest
Ophthalmol Vis Sci, 51 (1 1), 5623-9 (2010)).
Topical application of azithromycin to the ocular surface has been shown to improve the quality of the meibomian gland secretions. Daily administration of topical azithromycin in subjects with meibomian gland dysfunction improved the physicochemical properties of the meibum towards that of normal subjects (Foulks, G.N., Cornea, 29(7), 781 -8 (2010)).
Despite the high prevalence of dry eye disease, present therapies often result in poor patient compliance and disappointing results. Therefore, there is a need for an effective and safe method to treat dry eye disease.
SUMMARY OF THE INVENTION
The present invention is directed to a method for treating dry eye disease. The method comprises the steps of: identifying a patient suffering from dry eye disease, and topically administering to the patient an effective amount of azithromycin or a
pharmaceutically acceptable salt thereof and an effective amount of a retinoid. Azithromycin
and the retinoid can be administered either sequentially or by co-administration. Preferred azithromycin is azithromycin monohydrate and preferred retinoid is retinyl palmitate. An effective concentration of azithromycin is about 0.5%-2% (w/v), and an effective
concentration of retinyl palmitate is about 0.01 -0.1 % (w/v). An effect dosing regimen would consist of topical administration of 1-2 drops (approximately 50 microliters) in each eye once or twice a day.
The present invention is also directed to a pharmaceutical composition comprising active ingredients and a pharmaceutically acceptable carrier, wherein the active ingredients consisting essentially of 0.5-2% (w/v) of azithromycin and 0.01-1%) (w/v) retinyl palmitate. The pharmaceutical composition preferably is an ophthalmic solution or suspension.
DETAILED DESCRIPTION OF THE INVENTION
The inventor has discovered an effective method for treating dry eye disease by administering azithromycin and a retinoid to a patient suffering from dry eye disease.
The inventor has discovered that combined administration of azithromycin and a retinoid is more effective in treating dry eye disease than the single administration of either azithromycin or a retinoid.
The present invention is directed to a method for treating dry eye. The method comprises the steps of: identifying a patient suffering from dry eye disease, and topically administering to the patient an effective amount of azithromycin or a pharmaceutically acceptable salt thereof and an effective amount of a retinoid. Azithromycin and the retinoid can be administered to the patient separately or co-administered in one single formulation.
In another embodiment, the method comprises the steps of: identifying a patient suffering from dry eye, and administering to the patient a pharmaceutical composition comprising active ingredients and a pharmaceutically acceptable carrier, wherein the active ingredients consisting essentially of an effective amount of azithromycin and an effective amount of a retinoid. The active ingredients only include azithromycin and a retinoid and those that do not materially affect the basic and novel characteristics of the claimed invention.
Particularly, the present invention is suitable for treating dry eye diseases caused by one or more of keratoconjunctivitis sicca, age-related dry eye, Stevens-Johnson syndrome, Sjogren's syndrome, ocular cicatrical pemphigoid, corneal injury, infection, Riley-Day syndrome, congenital alacrima, nutritional disorders or deficiencies, pharmacologic side effects, contact lens intolerance, eye stress resulting in glandular and tissue destruction,
autoimmune disorders, immuno-deficient disorders, comatose patients who are unable to blink, or environmental exposure to smog, smoke, excessively dry air, or airborne
particulates. The present invention is also suitable to treat patients suffering from dry eye disease, but not suffering from blepharitis.
The present invention is also directed to a method for reducing contact lens intolerance in a subject. The method comprises the steps of: identifying a subject suffering from contact lens intolerance due to dry eye disease; and topically administering to the patient a pharmaceutical composition comprising active ingredients and a pharmaceutically acceptable carrier, wherein the active ingredients consisting essentially of an effective amount of azithromycin and an effective amount of a retinoid. The active ingredients only include azithromycin and a retinoid and those that do not materially affect the basic and novel characteristics of the claimed invention. The present method increases comfortable contact lens wearing time and/or total duration of contact lens wearing time per day in the subject.
"Retinoids" as used in this application, refer to a class of compounds consisting of four isoprenoid units joined in a head-to-tail manner. All retinoids may be formally derived from a monocyclic parent compound containing five carbon-carbon double bonds and a functional group at the terminus of the acyclic portion. Retinoids are a class of chemical compounds that are chemically related to vitamin A (retinol). Examples of retinoids useful in the present invention include: vitamin A (retinol), retinyl palmitate, retinal, tretinoin (retinoic acid), isotretinoin, etretinate, acitretin, tazarotene, bexarotene, and adapalene. Retinyl palmitate is a preferred compound for this invention.
"An effective amount" as used herein, is meant an amount that has a therapeutic effect, which reduces the signs and/or symptoms of dry eye disease. In the present method, the effective concentration of azithromycin is about 0.5%-2% (w/v), e.g., about 1%, and an effective concentration of retinyl palmitate is about 0.01 -0.1 % (w/v), e.g., about 0.05%. An effect dosing regimen would consist of topical administration of 1-2 drops (approximately 50 microliters) in each eye once or twice a day. In one embodiment, the effective concentration of azithromycin is 1% (w/v), and an effective amount of retinyl palmitate is 0.05% (w/v).
"About" as used in this application, refers to ± 10% of the recited value.
Pharmaceutical Composition
The present invention is directed to a pharmaceutical composition comprising azithromycin or a pharmaceutically acceptable salt thereof, a retinoid, and a pharmaceutically acceptable carrier. Preferred azithromycin is azithromycin monohydrate and preferred
retinoid is retinyl palmitate. The pharmaceutical composition preferably is an ophthalmic solution or suspension. A preferred pharmaceutical composition comprises active ingredients and a pharmaceutically acceptable carrier, wherein the active ingredients consisting essentially of 0,5-2% of azithromycin and 0.01 -1 % retinyl palmitate.
The topical solution containing azithromycin and a retinoid can contain a
physiologically compatible vehicle, as those skilled in the ophthalmic art can select using conventional criteria. The ophthalmic vehicles include, but are not limited to, saline solution, water polyethers such as polyethylene glycol, polyvinyls such as polyvinyl alcohol and povidone, cellulose derivatives such as methylcellulose and hydroxypropyl methylcellulose, petroleum derivatives such as mineral oil and white petrolatum, animal fats such as lanolin, polymers of acrylic acid such as carboxypolymethylene gel, vegetable fats such as peanut oil and polysaccharides such as dextrans, and glycosaminoglycans such as sodium hyaluronate and salts such as sodium chloride and potassium chloride.
Preferred ophthalmic formulations of azithromycin and retinoids suitable for the present method are those disclosed in U.S. Patent Nos. 6,239,1 13, 6,569,443 and 7,056,893; the formulations of which are incorporated herein by reference. For example, the formulation is an aqueous polymeric suspension comprising water, azithromycin, retinyl palmitate, and 0.1 to 10% of a polymeric suspending agent. The polymeric suspending agent comprises a water-swellable water-insoluble crosslinked carboxy-vinyl polymer. For example, the polymeric suspending agent comprises least 90% (w/v) acrylic acid monomers and 0.1 % to 5% (w/v) crosslinking agent. The formulations may further comprise polyvinyl alcohols and providone.
AZASITE® (azithromycin ophthalmic solution), which is a 1% (w/v) sterile aqueous topical ophthalmic solution of azithromycin formulated in DURASITE® (polycarbophil, edetate disodium, sodium chloride), is a preferred ophthalmic formulation. Retinyl palmitate can be added to AZASITE® to form a combination formulation. The preferred ophthalmic formulations are able to keep prolonged high azithromycin and retinyl palmitate
concentrations on the ocular surface, thus facilitating its penetration into the eye tissues.
The formulation optionally includes a preservative, such as benzalkonium chloride and other inactive ingredients such as EDTA. For a short term use of less than two weeks, preferably less than one week, benzalkonium chloride has the benefit of increasing the penetration of azithromycin into eye tissues. However, for chronic (over two weeks) use, preferred formulations are those without any preservatives due to the potential for damage to the corneal epithelium that may result from long term, frequent exposure to preservatives
such as benzalkonium chloride. The formulations without preservatives are prepared in a unit dose and stored in a single-use container.
The pH of the formulation is typically adjusted by adding any physiologically and ophthamologically acceptable pH adjusting acids, bases or buffers to within the range of about 5 to 7.5; preferably 6 to 7. Examples of acids include acetic, boric, citric, lactic, phosphoric, hydrochloric, and the like, and examples of bases include sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate,
tromethamine, THAM (trishydroxymethylamino-methane), and the like. Salts and buffers include citrate/dextrose, sodium bicarbonate, ammonium chloride and mixtures of the aforementioned acids and bases.
The osmotic pressure of the aqueous ophthalmic composition is generally from about 200 to about 400 milliosmolar (mOsM), more preferably from 260 to 340 mOsM. The osmotic pressure can be adjusted by using appropriate amounts of physiologically and ophthamologically acceptable ionic or non-ionic agents. Sodium chloride is a preferred ionic agent, and the amount of sodium chloride ranges from about 0.01 % to about 1 % (w/v), and preferably from about 0.05% to about 0.45% (w/v). Equivalent amounts of one or more salts made up of cations such as potassium, ammonium and the like and anions such as chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, bisulfate, sodium bisulfate, ammonium sulfate, and the like can be used in addition to or instead of sodium chloride to achieve osmolality within the above-stated range. Further, non-ionic agents such as mannitol, dextrose, sorbitol, glucose and the like can also be used to adjust the osmolality.
Administration
The inventor has also discovered that topical administration is an effective method for delivering azithromycin and the retinoid. Instillation to the ocular surface is a localized administration method and can therefore be more effective in reaching the target area, i.e., the eye, and providing a high and localized concentration of azithromycin and the retinoid.
Topical instillation avoids undesired side effects due to systemic exposure of the
azithromycin and the retinoid and reduces the risk of patients from developing antibiotic resistance.
Formulations described by the present invention can be administered to the eyes of a patient by any suitable means, but are preferably administered as a liquid or gel suspension in the form of drops, spray or gel. In one embodiment, the formulation is in the form of drops, and is dropped onto the ocular surface. In another embodiment, the formulation is contained
within a swab or sponge which can be applied to the ocular surface. In another embodiment, the formulation is contained within a liquid spray or ointment which can be applied to the ocular surface. In another embodiment, the formulation is injected directly into the lacrimal tissues or onto the eye surface. In a further embodiment, the formulation (e.g., in the form of drops) is first applied on a finger tip or other applicator, then applied or rubbed directly onto the lid margin. Alternatively, azithromycin and a retinoid can be applied to the eye via liposomes. Further, azithromycin and a retinoid can be infused into the tear film via a pump-catheter system. Another embodiment of the present invention involves azithromycin and a retinoid contained within a continuous or selective-release device, for example, membranes such as, but not limited to, those employed in the OCUSERT™ System
(polymeric ocular inserts for the administration of drugs, Alza Corp., Palo Alto, CA). As an additional embodiment, azithromycin and a retinoid can be contained within, carried by, or attached to contact lenses or other compatible controlled release materials, which are placed on the eye.
In one embodiment, the azithromycin and retinoid are administered 1 , 2, 3 or 4 times a day sequentially (i.e. one after the other), or co-administered together. In one embodiment, azithromycin and retinyl palmitate are admixed as one pharmaceutical composition and administered to patients by instillation on to the ocular surface. One single pharmaceutical composition and one single treatment provide ease of use and result in better compliance of patients. In another embodiment, azithromycin and retinyl palmitate are each in a separate formulation and administered separately to patients.
The daily dose to treat dry eye disease can be divided among one or several unit dose administrations. The daily dose, for example, can range from one drop (about 50 μΐ), one to four times a day, depending upon the age and condition of the subject. A preferred regimen is one drop of a 1 % azithromycin (w/v) and 0.05% (w/v) retinyl palmitate solution, about 1 to 2 times a day. For example, a preferred dosage is one drop in each eye twice a day for two days and then once a day thereafter.
When treating dry eye disease, the present method can be combined with mechanical therapy such as warm compress or lid hygiene (lid cleansing).
Unexpected Advantages of the Present Invention
The inventor has discovered that the combined administration of azithromycin and a retinoid to a dry eye disease patient has several advantages that cannot be achieved by a single administration of either azithromycin or a retinoid.
Dry eye disease is a chronic disease, and subjects with dry eye disease often have physical alterations to the meibomian glands and the epithelium surrounding the orifices of the meibomian glands, as well as the corneal and conjunctival epithelium. The inventor has discovered that the combined treatment of a retinoid and azithromycin allows for a normal meibomian gland function which improves the quality of the meibomian gland secretions, and allows for the improved secretions to be secreted and reach the ocular surface. The combined treatment also provides enhanced mucosal secretions from the ocular surface epithelium. Additionally, the anti-inflammatory properties of azithromycin reduce the side effects of irritation and inflammation during the early phase of a retinoid treatment, which enhance the tolerability of topically applied retinoid without having to reduce the amount or frequency of the retinoid application.
The invention is illustrated further by the following examples which are not to be construed as limiting the invention in scope or spirit to the specific procedures described in it. EXAMPLES
Example 1. Use of azithromycin and a retinoid for reducing symptoms in patients with dry eye disease
Objectives
The objective of this study is to compare the efficacy of an ophthalmic formulation of azithromycin 1% and retinyl palmitate 0.05% combined, versus the ophthalmic formulations of the respective active ingredients alone over a four week treatment period on the symptoms of subjects with dry eye disease.
Subjects
Subjects are 18 years of age or older, and have a clinical diagnosis of mild to moderate dry eye disease. A total of 120 subjects are enrolled in the study.
Methods
This is a double-masked study. At Visit 1 (Day 1), all subjects are randomized in 1 : 1 : 1 ratio to receive either (a) combination of azithromycin and retinyl palmitate or (b) azithromycin alone or (c) retinyl palmitate alone, for 30 days. Study drug is administered as one drop in each eye BID for the first 2 days and then QD for the remainder of the study. Study drugs are self-administered by the subjects. The subjects are prohibited from using any ocular or other medications that could confound the results of the assessments during study participation, such as antihistamines, steroids, antibiotics or preserved artificial tears.
Patients return for Visit 2 (Day 14), and Visit 3 (Day 30) and are asked to rate their symptoms including: ocular itching, ocular burning/pain, and foreign body sensation.
Scores on the Symptoms of Dry Eye Disease
Patients rate the severity of their dry eye symptoms at Visits 1 , 2, and 3 according to the following three classifications.
Eyelid itching
Do your eyelids feel itchy?
(0) None: My eyelids do not feel itchy.
(1) Mild: Once in a while, my eyelids feel slightly itchy, but I do not have a desire to rub them.
(2) Moderate: Occasionally, my eyelids feel itchy, and I need to rub them.
(3) Severe: It is difficult to relieve the sensation of itchiness even when I rub my eyelids.
(4) Very severe: I have unbearable eyelid itching with an irresistible urge to rub my eyelids.
Foreign body sensation/sandiness, grittiness
Do you feel like there's something sandy or gritty in your eye?
(0) None: My eyes do not feel sandy or gritty.
(1) Mild: I am aware of the surface of my eyes once in a while.
(2) Moderate My eyes feel like there is something small in them
occasionally.
(3) Severe: My eyes feel like there is something large or gritty in them.
(4) Very severe: I am unable to open my eyes due to feeling of a foreign body in my eyes.
Ocular burning or pain
Are your eyes burning or painful?
(0) None: My eyes do not burn or ache.
(1) Mild: I am aware of the surface of my eyes; they mildly burn or ache.
I feel my eyes are burning, but still tolerable
My eyes feel throbbing or fiery due to burning/pain.
I am unable to open my eyes due to burning/pain
Results
The mean scores for individual symptoms for each group are compared for Visits 2-3 to baseline (Visit 1). A statistically significant difference (p<0.05) is observed in favor of the azithromycin and retinyl palmitate treatment group for at least one of the Visits.
Conclusions
The above results indicate that combination of azithromycin and retinyl palmitate reduces the symptoms of dry eye disease significantly greater than either azithromycin or retinyl palmitate alone.
Example 2. Use of Azithromycin and a retinoid for treating patients with contact lens related dry eye disease
Objectives
The objective of this study is to compare the efficacy of the study drugs (1 %
Azithromycin in an ophthalmic solution and 0.05% retinyl palmitate in an ophthalmic solution), versus rewetting drops (Visine for Contacts1 M) over a four week treatment period in patients with contact lens-realted dry eye disease (CLDE).
Subjects
Subjects are 18 years of age or older. Subjects have a positive diagnosis of CLDE based on their responses to the Contact Lens Dry Eye Questionnaire (CLDEQ, Nichols et al, Cornea 21 :469-75 (2002)) and a score of > 2, (i.e., moderate severity on a 0-4 scale, where
O^no ocular dryness and 4=very severe ocular dryness) on a self-reported assessment of ocular dryness at the screening Visit. Over 30 subjects are enrolled in the study.
Methods
Visit 1 (Day 1 )
Subjects are asked to rate their level of ocular dryness on a 0-4 scale. Tear osmolarity is then assessed for each eye using the TearLab Osmolarity System®. Subjects are then instructed to remove their contact lenses and slit-lamp biomicroscopy and external eye exams are performed. Fluorescein corneal staining is then performed on each eye (5 μΐ of 2 % fluorescein applied to the ocular surface) and graded according to National Eye Institute (NEI) criteria.
Eligible subjects are then randomized to receive either the study drugs (1 %
Azithromycin and 0.05% retinyl palmitate), or rewetting drops (Visine for Contacts™) in a 1 : 1 ratio and they are not masked as to the treatment assignment. Subjects randomized to azithromcyin and retinyl palmitate are instructed to administer one drop to each eye BID for both drugs the first two days and then one drop QID for both drugs for days 3-29. Subjects randomized to rewetting drops are instructed to administer one to two drops QID throughout the 29 day treatment period. The first dose of study medication is self-administered at the clinic once dosing instructions are provided. Subjects are instructed to apply a new pair of contact lenses to their eyes 10 minutes after the instillation of study medication. Subjects are queried for adverse events (AEs) and scheduled to return for Visit 2 in approximately two weeks.
Subjects are instructed to record the AM ocular dryness assessment prior to instilling study medication (and lens application), and record PM dryness levels prior to lens removal each day. Further, subjects are required to record the time that contacts are inserted, the time lenses became uncomfortable and the time lenses are removed.
Visit 2 (Day 14 ± 2)
Concomitant medication usage is recorded, an AE query performed, study medication and diary cards are collected. Subjects undergo habitual HCVA and LCVA assessment, complete the CLDEQ, and have tear osmolarity readings measured prior to removing their contact lenses. Biomicroscopy, external eye exam, and fluorescein corneal staining are subsequently performed. The subjects then re-apply their lenses and additional study medication and diary cards are provided.
Visit 3 (Day 29± 1 )
All assessments and procedures are performed the same manner as at Visit 2. Statistical Analyses
The primary efficacy endpoint for this study is the change from baseline in the duration of subject-reported comfortable contact lens daily wear time (hours/day) at the Week 4 Endpoint. The Week 4 Endpoint is defined as the average of the change from baseline values for comfortable contact lens daily wear time from days 23 to 29.
Secondary efficacy endpoints from the data captured from the diaries included:
change from baseline in comfortable contact lens wear time at Week 1 (days 2-8), Week 2 (days 9- 15), Week 3 (days 16-22), change from baseline in total contact lens wear time (Week 1 -4 time intervals as defined for comfortable contact lens wear), and change from baseline in subject-reported levels of ocular dryness both at the morning (AM) assessment and evening (PM) assessment.
The invention, and the manner and process of making and using it, are now described in such full, clear, concise and exact terms as to enable any person skilled in the art to which it pertains, to make and use the same. It is to be understood that the foregoing describes preferred embodiments of the present invention and that modifications may be made therein without departing from the scope of the present invention as set forth in the claims. To particularly point out and distinctly claim the subject matter regarded as invention, the following claims conclude this specification.
Claims
1. A method for treating dry eye disease, comprising the steps of:
identifying a patient suffering from dry eye disease, and
topically administering to the patient a pharmaceutical composition comprising active ingredients and a pharmaceutically acceptable carrier, wherein the active ingredients consisting essentially of an effective amount of azithromycin and an effective amount of a retinoid.
2. The method according to Claim 1 , wherein said azithromycin and said retinoid are administered separately.
3. The method according to Claim 1 , wherein said azithromycin and said retinoid are coadministered in one composition.
4. The method according to any one of Claims 1 -3, wherein said retinoid is retinol, retinyl palmitate, tretinoin, isotretinoin, etretinate, acitretin, tazarotene, bexarotene, or adapalene.
5. The method according to any one of Claims 4, wherein said retinoid is retinyl palmitate.
6. The method according to any one of Claims 1-3, wherein said azithromycin is azithromycin monohydrate.
7. The method according to any one of Claims 1 -3, wherein the effective amount of azithromycin is about 0.5-2% (w/v),
8. The method according to any one of Claims 7, wherein the effective amount of azithromycin is about 1 % (w/v).
9. The method according to Claim 5, wherein the effective amount of retinyl palmitate is about 0.01 -1% (w/v).
10. The method according to Claim 9, wherein the effective amount of retinyl palmitate is about 0.05% (w/v).
1 1. The method according to Claim 1 , wherein said dry eye disease is caused by one or more of keratoconjunctivitis sicca, age-related dry eye, Stevens-Johnson syndrome, Sjogren's syndrome, ocular cicatrical pemphigoid, corneal injury, infection, Riley-Day syndrome, congenital aiacrima, nutritional disorders or deficiencies, pharmacologic side effects, contact lens intolerance, eye stress resulting in glandular and tissue destruction, autoimmune disorders, immuno-deficient disorders, comatose patients who are unable to blink, or environmental exposure to smog, smoke, excessively dry air, or airborne particulates.
12. A method for reducing contact lens intolerance in a subject, comprising the steps of: identifying a subject suffering from contact lens intolerance due to dry eye disease; and
topically administering to the patient a pharmaceutical composition comprising active ingredients and a pharmaceutically acceptable carrier, wherein the active ingredients consisting essentially of an effective amount of azithromycin and an effective amount of a retinoid.
13. A pharmaceutical composition comprising active ingredients and a pharmaceutically acceptable carrier, wherein the active ingredients consisting essentially of 0.5-2% (w/v) of azithromycin and 0.01-1 % (w/v) retinyl palmitate.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US13/976,714 US20130281390A1 (en) | 2010-12-29 | 2011-12-28 | Method for treating dry eye |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201061427959P | 2010-12-29 | 2010-12-29 | |
US61/427,959 | 2010-12-29 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2012092375A1 true WO2012092375A1 (en) | 2012-07-05 |
Family
ID=46383516
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2011/067594 WO2012092375A1 (en) | 2010-12-29 | 2011-12-28 | Method for treating dry eye |
Country Status (2)
Country | Link |
---|---|
US (1) | US20130281390A1 (en) |
WO (1) | WO2012092375A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016162795A1 (en) * | 2015-04-09 | 2016-10-13 | Laboratori Baldacci S.P.A. | Pyrrolidone carboxylic acid (pca) for ophthalmic use |
US11419886B2 (en) | 2020-11-23 | 2022-08-23 | Sight Sciences, Inc. | Formulations and methods for treating conditions of the eye |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9463201B2 (en) | 2014-10-19 | 2016-10-11 | M.G. Therapeutics Ltd | Compositions and methods for the treatment of meibomian gland dysfunction |
CN113144203A (en) | 2015-09-28 | 2021-07-23 | 阿祖拉眼科有限公司 | Thiol and disulfide-containing agents for increasing meibomian gland lipid secretion |
WO2017178892A2 (en) | 2016-04-14 | 2017-10-19 | M.G. Therapeutics Ltd. | Selenium disulfide compositions for use in treating meibomian gland dysfunction |
CN109381707B (en) * | 2017-08-03 | 2022-02-15 | 沈阳药科大学 | Azithromycin ion pair liposome eye drops and preparation method thereof |
CN115279458A (en) | 2020-01-10 | 2022-11-01 | 阿祖拉眼科有限公司 | Compositions and sensitivity profiles |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5185372A (en) * | 1990-08-30 | 1993-02-09 | Senju Pharmaceutical Company, Limited | Stable aqueous preparation |
US20070003585A1 (en) * | 2005-06-29 | 2007-01-04 | Stiefel Laboratories, Inc. | Topical skin treating compositions |
US20070087980A1 (en) * | 2004-07-02 | 2007-04-19 | Wakamoto Pharmaceutical Co., Ltd. | azithromycin-containing aqueous pharmaceutical composition and a method for the preparation of the same |
US20080038317A1 (en) * | 2004-09-10 | 2008-02-14 | Chin-Ming Chang | Therapeutic Lacrimal Canalicular Inserts And Related Methods |
US20100190734A1 (en) * | 2009-01-23 | 2010-07-29 | Romulus Kimbro Brazzell | Method of treating dry eye disease with azithromycin |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8349806B2 (en) * | 2008-07-10 | 2013-01-08 | Inspire Pharmaceuticals, Inc. | Method of treating blepharitis |
-
2011
- 2011-12-28 WO PCT/US2011/067594 patent/WO2012092375A1/en active Application Filing
- 2011-12-28 US US13/976,714 patent/US20130281390A1/en not_active Abandoned
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5185372A (en) * | 1990-08-30 | 1993-02-09 | Senju Pharmaceutical Company, Limited | Stable aqueous preparation |
US20070087980A1 (en) * | 2004-07-02 | 2007-04-19 | Wakamoto Pharmaceutical Co., Ltd. | azithromycin-containing aqueous pharmaceutical composition and a method for the preparation of the same |
US20080038317A1 (en) * | 2004-09-10 | 2008-02-14 | Chin-Ming Chang | Therapeutic Lacrimal Canalicular Inserts And Related Methods |
US20070003585A1 (en) * | 2005-06-29 | 2007-01-04 | Stiefel Laboratories, Inc. | Topical skin treating compositions |
US20100190734A1 (en) * | 2009-01-23 | 2010-07-29 | Romulus Kimbro Brazzell | Method of treating dry eye disease with azithromycin |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016162795A1 (en) * | 2015-04-09 | 2016-10-13 | Laboratori Baldacci S.P.A. | Pyrrolidone carboxylic acid (pca) for ophthalmic use |
US10272067B2 (en) | 2015-04-09 | 2019-04-30 | Laboratori Baldacci S.P.A. | Pyrrolidone carboxylic acid (PCA) for ophthalmic use |
US10456374B2 (en) | 2015-04-09 | 2019-10-29 | Laboratori Baldacci S.P.A. | Pyrrolidone carboxylic acid (PCA) for ophthalmic use |
RU2720993C2 (en) * | 2015-04-09 | 2020-05-15 | Лаборатори Бальдаччи С.П.А. | Pyrrolidone-carboxylic acid (pca) for ophthalmic use |
US11419886B2 (en) | 2020-11-23 | 2022-08-23 | Sight Sciences, Inc. | Formulations and methods for treating conditions of the eye |
US11554134B2 (en) | 2020-11-23 | 2023-01-17 | Sight Sciences, Inc. | Formulations and methods for treating conditions of the eye |
US11925657B2 (en) | 2020-11-23 | 2024-03-12 | Sight Sciences, Inc. | Formulations and methods for treating conditions of the eye |
Also Published As
Publication number | Publication date |
---|---|
US20130281390A1 (en) | 2013-10-24 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP2313103B1 (en) | Method of treating blepharitis | |
Calonge | The treatment of dry eye | |
Luchs | Efficacy of topical azithromycin ophthalmic solution 1% in the treatment of posterior blepharitis | |
TWI335819B (en) | Use of oculosurface selective glucocorticoid in the treatment of dry eye | |
Jackson | Management of dysfunctional tear syndrome: a Canadian consensus | |
WO2012092375A1 (en) | Method for treating dry eye | |
JP7012075B2 (en) | Pharmaceutical composition for use in the treatment of blepharitis | |
US20100190734A1 (en) | Method of treating dry eye disease with azithromycin | |
US7247623B2 (en) | Method of treating dry eye disease with non-drying antihistamines | |
JP2011515494A (en) | Methods for improving lid and tear film function and treating lid margin disease using tetracycline family antibiotics | |
EP0630254A1 (en) | Method of ophthalmic drug delivery | |
CZ200136A3 (en) | Vitamin E and esters thereof intended for use when local treating mucous membrane disease | |
Satitpitakul et al. | Efficacy of azithromycin 1.5% eyedrops vs oral doxycycline in meibomian gland dysfunction: a randomized trial | |
WO2012092378A1 (en) | Method for treating blepharitis | |
JP2022525254A (en) | Use of notoginsenoside extract in the preparation of ophthalmic pharmaceutical formulations | |
WO2024078515A1 (en) | Ophthalmic pharmaceutical composition containing levamisole, preparation method therefor, and use thereof | |
US20170239307A1 (en) | Composition of doxycycline in liposomes for the prevention, improvement and/or treatment of ocular pathologies | |
CN116867496A (en) | Treatment of neurological sensitization disorders | |
Wagh et al. | Drug delivery and pharmacotherapy for dry eye disease | |
JP2022545419A (en) | Compositions and methods for the treatment of anterior and posterior blepharitis | |
US20110245190A1 (en) | Method for improving post surgery visual acuity outcome with azithromycin | |
Rocha et al. | EYELID MARGIN DISEASE (BLEPHARITIS AND MEIBOMIAN GLAND DYSFUNCTION): CLINICAL REVIEW OF EVIDENCE-BASED AND EMERGING TREATMENTS | |
WO2024100454A2 (en) | Composition and methods for improving signs and symptoms of ocular disorders | |
JP2021517139A (en) | Usage of Selective SYK Inhibitors and Pharmaceutical Compositions | |
Albietz et al. | Ocular therapeutics |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 11854255 Country of ref document: EP Kind code of ref document: A1 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 13976714 Country of ref document: US |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 11854255 Country of ref document: EP Kind code of ref document: A1 |