NZ743307B2 - Efficient lipid delivery to human tear film using a salt-sensitive emulsion system - Google Patents
Efficient lipid delivery to human tear film using a salt-sensitive emulsion system Download PDFInfo
- Publication number
- NZ743307B2 NZ743307B2 NZ743307A NZ74330712A NZ743307B2 NZ 743307 B2 NZ743307 B2 NZ 743307B2 NZ 743307 A NZ743307 A NZ 743307A NZ 74330712 A NZ74330712 A NZ 74330712A NZ 743307 B2 NZ743307 B2 NZ 743307B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- concentration
- pharmaceutical composition
- low salt
- ophthalmic pharmaceutical
- composition according
- Prior art date
Links
- 239000000839 emulsion Substances 0.000 title claims abstract description 40
- 150000003839 salts Chemical class 0.000 title claims abstract description 40
- 150000002632 lipids Chemical class 0.000 title claims description 39
- 208000003556 Dry Eye Syndromes Diseases 0.000 claims abstract description 45
- 206010013774 Dry eye Diseases 0.000 claims abstract description 41
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims abstract description 22
- 235000019438 castor oil Nutrition 0.000 claims abstract description 17
- 239000004359 castor oil Substances 0.000 claims abstract description 17
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims abstract description 17
- 235000011187 glycerol Nutrition 0.000 claims abstract description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- NIXOWILDQLNWCW-UHFFFAOYSA-M acrylate group Chemical group C(C=C)(=O)[O-] NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 claims description 10
- 229920000642 polymer Polymers 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 239000004386 Erythritol Substances 0.000 claims description 8
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 claims description 8
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical group OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 claims description 8
- 229940009714 erythritol Drugs 0.000 claims description 8
- 235000019414 erythritol Nutrition 0.000 claims description 8
- 239000000314 lubricant Substances 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 7
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 7
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 7
- 229940068968 polysorbate 80 Drugs 0.000 claims description 7
- 229920000053 polysorbate 80 Polymers 0.000 claims description 7
- 239000003755 preservative agent Substances 0.000 claims description 7
- 230000002335 preservative effect Effects 0.000 claims description 7
- 230000001225 therapeutic effect Effects 0.000 claims description 7
- PHIQHXFUZVPYII-ZCFIWIBFSA-N (R)-carnitine Chemical compound C[N+](C)(C)C[C@H](O)CC([O-])=O PHIQHXFUZVPYII-ZCFIWIBFSA-N 0.000 claims description 6
- 229960001518 levocarnitine Drugs 0.000 claims description 6
- 239000004327 boric acid Substances 0.000 claims description 5
- 229920006037 cross link polymer Polymers 0.000 claims description 5
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000004094 surface-active agent Substances 0.000 claims description 4
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical group [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 3
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 claims description 3
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 claims description 3
- 125000005430 oxychloro group Chemical group 0.000 claims description 3
- 238000010979 pH adjustment Methods 0.000 claims 2
- -1 sorbitan ester Chemical class 0.000 claims 2
- 239000012929 tonicity agent Substances 0.000 claims 2
- 125000005619 boric acid group Chemical group 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 47
- 229920002134 Carboxymethyl cellulose Polymers 0.000 abstract description 8
- 239000001768 carboxy methyl cellulose Substances 0.000 abstract description 8
- 235000010948 carboxy methyl cellulose Nutrition 0.000 abstract description 8
- 239000008112 carboxymethyl-cellulose Substances 0.000 abstract description 8
- 239000000607 artificial tear Substances 0.000 abstract description 7
- 239000013543 active substance Substances 0.000 abstract description 5
- 239000004006 olive oil Substances 0.000 abstract description 4
- 235000008390 olive oil Nutrition 0.000 abstract description 4
- 229920000136 polysorbate Polymers 0.000 abstract description 3
- 229950008882 polysorbate Drugs 0.000 abstract description 3
- 238000011282 treatment Methods 0.000 description 37
- 208000024891 symptom Diseases 0.000 description 26
- 239000000047 product Substances 0.000 description 14
- 230000008859 change Effects 0.000 description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 13
- 238000009472 formulation Methods 0.000 description 13
- 201000010099 disease Diseases 0.000 description 10
- 230000000694 effects Effects 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 230000000699 topical effect Effects 0.000 description 9
- 230000002411 adverse Effects 0.000 description 8
- 238000010186 staining Methods 0.000 description 8
- 229940105329 carboxymethylcellulose Drugs 0.000 description 7
- 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 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 208000009319 Keratoconjunctivitis Sicca Diseases 0.000 description 5
- 230000007423 decrease Effects 0.000 description 5
- 239000006196 drop Substances 0.000 description 5
- 239000003889 eye drop Substances 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 238000000540 analysis of variance Methods 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 230000009286 beneficial effect Effects 0.000 description 4
- 210000004087 cornea Anatomy 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 229960005150 glycerol Drugs 0.000 description 4
- 210000004561 lacrimal apparatus Anatomy 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 238000001356 surgical procedure Methods 0.000 description 4
- 230000004304 visual acuity Effects 0.000 description 4
- 108010036949 Cyclosporine Proteins 0.000 description 3
- 230000005856 abnormality Effects 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 230000004397 blinking Effects 0.000 description 3
- 229960001265 ciclosporin Drugs 0.000 description 3
- 210000000795 conjunctiva Anatomy 0.000 description 3
- 229930182912 cyclosporin Natural products 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 230000007812 deficiency Effects 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 238000009826 distribution Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 229940012356 eye drops Drugs 0.000 description 3
- 210000000744 eyelid Anatomy 0.000 description 3
- 230000001965 increasing effect Effects 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 230000002035 prolonged effect Effects 0.000 description 3
- 238000011321 prophylaxis Methods 0.000 description 3
- 229940053174 restasis Drugs 0.000 description 3
- 206010002091 Anaesthesia Diseases 0.000 description 2
- 206010022459 Instillation site pain Diseases 0.000 description 2
- 238000001358 Pearson's chi-squared test Methods 0.000 description 2
- 208000021386 Sjogren Syndrome Diseases 0.000 description 2
- 206010047513 Vision blurred Diseases 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 229960001777 castor oil Drugs 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 230000007717 exclusion Effects 0.000 description 2
- 230000004438 eyesight Effects 0.000 description 2
- 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 2
- 230000006872 improvement Effects 0.000 description 2
- 206010023332 keratitis Diseases 0.000 description 2
- 201000010666 keratoconjunctivitis Diseases 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- 210000005036 nerve Anatomy 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 230000036407 pain Effects 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 230000035807 sensation Effects 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 238000013517 stratification Methods 0.000 description 2
- 230000035882 stress Effects 0.000 description 2
- 230000009469 supplementation Effects 0.000 description 2
- 230000004489 tear production Effects 0.000 description 2
- KZMRYBLIGYQPPP-UHFFFAOYSA-M 3-[[4-[(2-chlorophenyl)-[4-[ethyl-[(3-sulfonatophenyl)methyl]azaniumylidene]cyclohexa-2,5-dien-1-ylidene]methyl]-n-ethylanilino]methyl]benzenesulfonate Chemical compound C=1C=C(C(=C2C=CC(C=C2)=[N+](CC)CC=2C=C(C=CC=2)S([O-])(=O)=O)C=2C(=CC=CC=2)Cl)C=CC=1N(CC)CC1=CC=CC(S([O-])(=O)=O)=C1 KZMRYBLIGYQPPP-UHFFFAOYSA-M 0.000 description 1
- 208000027502 Ankle fracture Diseases 0.000 description 1
- 229930003347 Atropine Natural products 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 206010004637 Bile duct stone Diseases 0.000 description 1
- 201000004569 Blindness Diseases 0.000 description 1
- 208000002177 Cataract Diseases 0.000 description 1
- 208000009043 Chemical Burns Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 208000029147 Collagen-vascular disease Diseases 0.000 description 1
- 208000007775 Congenital alacrima Diseases 0.000 description 1
- 206010011013 Corneal erosion Diseases 0.000 description 1
- 206010055665 Corneal neovascularisation Diseases 0.000 description 1
- 206010011039 Corneal perforation Diseases 0.000 description 1
- 206010054760 Corneal thinning Diseases 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 206010015943 Eye inflammation Diseases 0.000 description 1
- 208000020564 Eye injury Diseases 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 206010072579 Granulomatosis with polyangiitis Diseases 0.000 description 1
- RKUNBYITZUJHSG-UHFFFAOYSA-N Hyosciamin-hydrochlorid Natural products CN1C(C2)CCC1CC2OC(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-UHFFFAOYSA-N 0.000 description 1
- 206010020852 Hypertonia Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 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 description 1
- 208000022120 Jeavons syndrome Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 206010065062 Meibomian gland dysfunction Diseases 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000023715 Ocular surface disease Diseases 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 241001303601 Rosacea Species 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 206010053615 Thermal burn Diseases 0.000 description 1
- 229940123445 Tricyclic antidepressant Drugs 0.000 description 1
- 206010064996 Ulcerative keratitis Diseases 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 206010047531 Visual acuity reduced Diseases 0.000 description 1
- 208000010011 Vitamin A Deficiency Diseases 0.000 description 1
- 238000002679 ablation Methods 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000005299 abrasion Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 208000003464 asthenopia Diseases 0.000 description 1
- RKUNBYITZUJHSG-SPUOUPEWSA-N atropine Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-SPUOUPEWSA-N 0.000 description 1
- 229960000396 atropine Drugs 0.000 description 1
- 238000003287 bathing Methods 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 208000010217 blepharitis Diseases 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000004581 coalescence Methods 0.000 description 1
- 208000036549 congenital autosomal dominant alacrima Diseases 0.000 description 1
- 201000000159 corneal neovascularization Diseases 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000002638 denervation Effects 0.000 description 1
- 230000001687 destabilization Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 239000003974 emollient agent Substances 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 230000003090 exacerbative effect Effects 0.000 description 1
- 208000001936 exophthalmos Diseases 0.000 description 1
- 231100000040 eye damage Toxicity 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 210000002175 goblet cell Anatomy 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 201000001371 inclusion conjunctivitis Diseases 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 229960005280 isotretinoin Drugs 0.000 description 1
- 206010023365 keratopathy Diseases 0.000 description 1
- 238000011005 laboratory method Methods 0.000 description 1
- 239000002960 lipid emulsion Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 208000018769 loss of vision Diseases 0.000 description 1
- 231100000864 loss of vision Toxicity 0.000 description 1
- 230000001050 lubricating effect Effects 0.000 description 1
- 238000005461 lubrication Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000005541 medical transmission Effects 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 210000004175 meibomian gland Anatomy 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 239000000133 nasal decongestant Substances 0.000 description 1
- 229940127240 opiate Drugs 0.000 description 1
- 229940127234 oral contraceptive Drugs 0.000 description 1
- 239000003539 oral contraceptive agent Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 150000002990 phenothiazines Chemical class 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 201000003004 ptosis Diseases 0.000 description 1
- 230000003362 replicative effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 201000004700 rosacea Diseases 0.000 description 1
- 231100000279 safety data Toxicity 0.000 description 1
- 201000000306 sarcoidosis Diseases 0.000 description 1
- 230000037390 scarring Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000000153 supplemental effect Effects 0.000 description 1
- 230000003319 supportive effect Effects 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 229940126703 systemic medication Drugs 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 229940126702 topical medication Drugs 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000723 toxicological property Toxicity 0.000 description 1
- 206010044325 trachoma Diseases 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 239000003029 tricyclic antidepressant agent Substances 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000004393 visual impairment Effects 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 208000005494 xerophthalmia Diseases 0.000 description 1
Abstract
The disclosure relates to composition useful as an artificial tear, which is a salt free emulsion comprising castor oil and specifically excludes olive oil and contains at least one active agent selected from the group consisting of polysorbate, carboxymethylcellulose and glycerine. The disclosure also relates to the use of the composition for treating dry eye. lso relates to the use of the composition for treating dry eye.
Description
EFFICIENT LIPID DELIVERY TO HUMAN TEAR FILM USING A SALT-SENSITIVE EMULSION SYSTEM By: Joseph G. Vehige and Peter A. Simmons CROSS-REFERENCES TO RELATED APPLICATIONS This application is a divisional of New Zealand patent application 725257, which itself is a divisional of New Zealand patent application number 626119 dated 7 December 2012, which is the national phase entry in New Zealand of PCT international application (published as WO2013/086449), and claims the benefit of U.S.
Provisional Application Serial Nos. 61/568,089, filed December 7, 2011 and 61/625,401 filed April 17, 2012, the disclosures of which are hereby incorporated in their entirety herein by reference.
FIELD OF INVENTION The present invention is directed to artificial tears suitable for treating dry eye syndrome and other ocular conditions in a human or other mammal.
BACKGROUND OF THE INVENTION Typical symptoms of keratoconjunctivitis or dry eye include feelings of dryness, burning, and a sandy-gritty eye sensation that can worsen during the day. Symptoms may also be described as itchy, scratchy, stingy or tired eyes. Other symptoms include pain, redness, a pulling sensation, and pressure behind the eye. The damage to the eye surface resulting from dry eye increases discomfort and sensitivity to bright light and both eyes usually are affected.
Because blinking coats the eye with tears, symptoms are worsened by activities in which the rate of blinking is reduced due to prolonged use of the eyes. These activities include prolonged reading, computer usage, driving or watching television. Symptoms increase in windy, dusty or smoky areas, in dry environments, high altitudes including airplanes, on days with low humidity, and in areas where an air conditioner, fan, or heater, is being used.
Symptoms are less severe during cool, rainy, or foggy weather, and in humid places. Most people who have dry eyes experience mild irritation with no long-term effects. However, if the condition is left untreated or becomes severe, it can produce complications that can cause eye damage, resulting in impaired vision or possibly in the loss of vision.
Having dry eyes for a prolonged period of time can lead to tiny abrasions on the surface of the eyes. In advanced cases, the epithelium undergoes pathologic changes, namely squamous metaplasia and loss of goblet cells sometimes due to activation of T cells acting against those cells.. Some severe cases result in thickening of the corneal surface, corneal erosion, punctate keratopathy, epithelial defects, corneal ulceration, corneal neovascularization, corneal scarring, corneal thinning, and even corneal perforation. An abnormality of any one of the three layers of tears which produces an unstable tear film, may result in symptoms of keratitis sicca.
Keratoconjunctivitis sicca is usually due to inadequate tear production. The aqueous tear layer is affected, resulting in aqueous tear deficiency or lacrimal hyposecretion. The lacrimal gland does not produce sufficient tears to keep the entire conjunctiva and cornea covered by a complete layer. This usually occurs in people who are otherwise healthy.
Increased age is associated with decreased tearing. This is the most common type found in postmenopausal women. Causes include idiopathic, congenital alacrima, xerophthalmia, lacrimal gland ablation, and sensory denervation. In rare cases, it may be a symptom of collagen vascular diseases, including rheumatoid arthritis, Wegener's granulomatosis, and systemic lupus erythematosus. Sjögren's syndrome and autoimmune diseases associated with Sjögren's syndrome are also conditions associated with aqueous tear deficiency. Drugs such as isotretinoin, sedatives, diuretics, tricyclic antidepressants, antihypertensives, oral contraceptives, antihistamines, nasal decongestants, beta-blockers, phenothiazines, atropine, and pain relieving opiates such as morphine can cause or worsen this condition. Infiltration of the lacrimal glands by sarcoidosis or tumors, or postradiation fibrosis of the lacrimal glands can also cause this condition.
Keratoconjunctivitis sicca can also be caused by abnormal tear composition resulting in rapid evaporation or premature destruction of the tears. When caused by rapid evaporation, it is termed evaporative dry eyes. In this condition, although the tear gland produces a sufficient amount of tears, the rate of evaporation of the tears is too rapid. There is a loss of water from the tears that results in tears that are too "salty" or hypertonic. As a result, the entire conjunctiva and cornea cannot be kept covered with a complete layer of tears during certain activities or in certain environments.
Aging is one of the most common causes of dry eyes. This is due to the fact that tear production decreases with age. It may be caused by thermal or chemical burns, or by adenoviruses. Diabetics are also at increased risk for dry eye.
An eye injury or other problem with the eyes or eyelids, such as bulging eyes or a drooping eyelid, can cause keratoconjunctivitis sicca. Disorders of the eyelid can impair the complex blinking motion required to spread tears.
About half of all people who wear contact lenses have dry eyes. This is because soft contact lenses, which float on the tear film that covers the cornea, absorb the tears in the eyes.
Dry eye also occurs or gets worse after refractive surgeries, in which the corneal nerves are cut during the creation of a corneal flap, because the corneal nerves stimulate tear secretion. Dry eyes caused by these procedures usually disappear after several months.
Abnormalities of the lipid tear layer caused by blepharitis and rosacea and abnormalities of the mucin tear layer caused by vitamin A deficiency, trachoma, diphtheric keratoconjunctivitis mucocutaneous disorders and certain topical medications may cause dry eye or keratoconjunctivitis sicca.
Dry eyes can usually be diagnosed by the symptoms alone. Tests can determine both the quantity and the quality of the tears. A slit lamp examination can be performed to diagnose dry eyes and to document any damage to the eye. A Schirmer's test can measure the amount of moisture bathing the eye. This test is useful for determining the severity of the condition.
A variety of approaches can be taken to treatment, such as: avoidance of exacerbating factors, tear stimulation and supplementation, increasing tear retention, and eyelid cleansing and treatment of eye inflammation. For mild and moderate cases, supplemental lubrication is the most important part of treatment. Application of artificial tears every few hours can provide temporary relief.
Lubricating tear ointments can be used during the day, but they generally are used at bedtime due to poor vision after application. They contain white petrolatum, mineral oil, and similar lubricants. They serve as a lubricant and an emollient. Depending on the severity of the condition, ointments may be applied from every hour to just at bedtime. Ointments should not be used with contact lenses. Inflammation occurring in response to tears film hypertonicity can be suppressed by mild topical steroids or with topical immunosuppressants such as cyclosporine.
SUMMARY OF THE INVENTION In a first aspect the present invention provides a low salt ophthalmic pharmaceutical composition comprising a sub-micron emulsion, a polymer lubricant, and a salt-sensitive viscosity modulating polymer, wherein said sub-micron emulsion comprises a surfactant and a therapeutic lipid consisting essentially of castor oil.
In a second aspect the present invention provides a low salt ophthalmic pharmaceutical composition comprising: a therapeutic lipid consisting essentially of castor oil at a concentration of about 0.25% (w/w); polysorbate 80 at a concentration of about 0.5% (w/w); acrylate/C -C acrylate crosspolymer at a concentration of about 0.1% (w/w), wherein 30 said acrylate/C -C acrylate crosspolymer has a standard emulsion viscosity between 1,700 30 and 4,500 cPs; carboxymethylcellulose sodium at a concentration of about 0.5% (w/w); glycerin at a concentration of about 1.0% (w/w); a stabilized oxychloro complex preservative at a concentration of about 0.01% (w/w); boric acid at a concentration of about 0.6% (w/w); erythritol at a concentration of about 0.25% (w/w); evocarnitine at a concentration of about 0.25% (w/w); NaOH; and water.
In a third aspect the present invention provides a use of a low salt ophthalmic pharmaceutical composition according to the first or second aspect, in the manufacture of a medicament for treating said dry eye syndrome in a patient in need thereof.
Also described is a composition useful as an artificial tear, which is a salt free sub- micron emulsion comprising castor oil and specifically excludes olive oil and contains at least one active agent selected from the group consisting of polysorbate, carboxymethylcellulose and glycerine.
Also described is a sub-micron emulsion for use in treating dry eye wherein the emulsion is salt-free and comprises castor oil, polysorbate 80, carboxymethylcellulose and glycerine, and specifically excludes olive oil.
Also described is an artificial tear emulsion comprising about 0.5% w/w Polysorbate 80, about 0.5% w/w carboxymethylcellulose, about 1.0% w/w glycerine, about 0.6% w/w boric acid, about 0.1% w/w pemulin, about 0.25% w/w castor oil, about 0.25% w/w erythritol, about 0.25% w/w levocarnitine, sodium hydroxide to adjust the pH to about 7.3 and water.
Also described is a use of a composition or sub-micron emulsion described herein in the manufacture of a medicament for treating dry eye in a patient in need thereof.
Also described is an artificial tear emulsion of the following formulation: Table I The Table I formulation includes the concentrations of actives and/or excipients as disclosed above which can be in concentrations which vary from what is stated above. The variation may be such that the amounts are "about" what is stated above so long as that amount would be found bioequivalent by a regulatory agency such as the FDA or the EMEA.
The formulation may be preserved or non-preserved (not containing Purite®), such as a unit dose version. This version would be the same as that in Table 1 except it would contain no Purite®.
Some embodiments described herein are included in the following paragraphs: 1) A composition useful as an artificial tear, which is a salt free emulsion comprising castor oil and specifically excludes olive oil and contains at least one active agent selected from the group consisting of polysorbate, carboxymethylcellulose and glycerine. 2) The composition of paragraph 1 wherein said mixture comprises from about 0.1% – 0.5% w/w, castor oil. 3) The composition of paragraphs 1 - 2 wherein castor oil is the only oil in the emulsion. 4) The composition of paragraphs 1 – 3 wherein the castor oil is emulsified in an aqueous phase.
) The composition of paragraph 4 wherein the castor oil is present in about 0.25% w/w . 6) The composition of paragraphs 4 - 5 further including a primary and a secondary emulsifier. 7) The composition of paragraphs 1 - 6 wherein the composition contains a preservative. 8) The composition of paragraph 7 wherein the preservative is selected from the group consisting of PURITE and benzalkoniuim chloride. 9) The composition of paragraph 8 wherein the preservative is PURITE is present in a concentration of about 0.01% w/w.
) An emulsion for use in treating dry eye wherein the emulsion is salt-free and comprises castor oil, polysorbate 80, carboxymethylcellulose and glycerine. 11) The emulsion of paragraph 10 wherein the emulsion also contains the emulsifier pemulin. 12) The emulsion of paragraphs 10 – 11 further comprising erythritol and levocarnitine. 13) An emulsion for treating dry eye as shown in Table 1. 14) A use of a composition or emulsion described herein in the manufacture of a medicament for treating dry eye in a patient in need thereof.
) A method of treating dry eye comprising administration of any one of the compositions or emulsions of paragraphs 1 – 13. 16) A composition for the treatment of dry eye or keratoconjunctivitis sicca wherein the composition comprises about 0.5% w/w Polysorbate 80, about 0.5% w/w carboxymethylcellulose, about 1.0% w/w glycerine, about 0.6% w/w boric acid, about 0.1% w/w pemulin, about 0.25% w/w castor oil, about 0.25% w/w erythritol, about 0.25% w/w levocarnitine, sodium hydroxide to adjust the pH to about 7.3 and water. 17) The composition of claim 16 further comprising 0.01% Purite®. 18) The composition of claim 16 wherein the composition is applied topically to an eye which is suffering from dry eye. 19) The composition of claim 16 wherein the composition is applied topically to an eye to alleviate the symptoms of dry eye.
) The composition of claim 16 wherein the composition is applied topically to an eye to prevent dry eye syndrome.
As used herein, the term "effective amount" or "effective dose" means an amount sufficient to achieve the desired result on the process or condition, and it accordingly will depend on the ingredient and the desired result. Nonetheless, once the desired effect is known, determining the effective amount is within the skill of a person skilled in the art.
"Formulation," "composition," and "preparation" as used herein are equivalent terms referring to a composition of matter suitable for pharmaceutical use (i.e., producing a therapeutic effect as well as possessing acceptable pharmacokinetic and toxicological properties).
The term "prevent" as used herein refers to a decrease in the occurrence of dermatological symptoms (e.g., urticardial wheals) in a patient. The prevention may be complete (i.e., no detectable symptoms) or partial, so that fewer symptoms are observed than would likely occur absent treatment.
As used herein, the terms "prevent" and "treat" are not intended to be absolute terms.
Treatment can refer to any delay in onset, e.g., reduction in the frequency or severity of symptoms, amelioration of symptoms, improvement in patient comfort, reduction in symptoms of dry eye, and the like. The effect of treatment can be compared to an individual or pool of individuals not receiving a given treatment, or to the same patient before, or after cessation of, treatment.
The term "therapeutically effective amount" as used herein refers to that amount of the composition or agent in a composition sufficient to ameliorate one or more aspects of the disorder.
Therapeutic efficacy can also be expressed as "-fold" increase or decrease. For example, a therapeutically effective amount can have at least a 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more effect over a control.
"Treatment" as used herein includes any cure, amelioration, or prevention of a disease. Treatment may prevent the disease from occurring; inhibit the disease’s spread; relieve the disease’s symptoms fully or partially remove the disease’s underlying cause, shorten a disease’s duration, or do a combination of the above. "Treating" or "treatment" as used herein (and as well-understood in the art) also broadly includes any approach for obtaining beneficial or desired results in a subject’s condition, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of the extent of a disease, stabilizing (i.e., not worsening) the state of disease, prevention of a disease’s transmission or spread, delay or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the reoccurrence of disease, and remission, whether partial or total and whether detectable or undetectable.
"Treating" and "treatment" as used herein may include prophylactic treatment.
Treatment methods include administering to a subject a therapeutically effective amount of an active agent. The administering step may consist of a single administration or may include a series of administrations. The length of the treatment period depends on a variety of factors, such as the severity of the condition, the age of the patient, the concentration of active agent, the activity of the compositions used in the treatment, or a combination thereof. It will also be appreciated that the effective dosage of an agent used for the treatment or prophylaxis may increase or decrease over the course of a particular treatment or prophylaxis regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration may be required. For example, the compositions are administered to the subject in an amount and for a duration sufficient to treat the patient.
The term "comprising" as used in this specification and claims means "consisting at least in part of". When interpreting statements in this specification, and claims which include the term "comprising", it is to be understood that other features that are additional to the features prefaced by this term in each statement or claim may also be present. Related terms such as "comprise" and "comprised" are to be interpreted in similar manner.
DETAILED DESCRIPTION OF THE INVENTION Delivering lipids to the human tear film to supplement and enhance the native lipid layer, often deficient due to dysfunction of meibomian glands and other causes, is a recognized strategy in treating signs and symptoms of dry eye. This is in theory especially beneficial in low humidity or when other internal/external factors increase tear film evaporation. Excessive loss of water from the tear film causes an increase in salt content and causes hyperosmotic stress to the cells of the ocular surface.
The native lipid layer is very thin and the total volume of lipid is a small fraction of the total tear film volume. To enhance the structure and function of the lipid layer by topical application of a lipid-containing drop requires only a small volume of oil to be delivered; excess lipid will displace and disrupt the total aqueous volume, by far the greatest component of tears. It is also necessary that the lipid be delivered quickly, during the brief contact time of a topical eye drop. Finally, the lipid delivered needs to become established as part of the native lipid layer, at the air interface.
The challenge of lipid release from an emulsion has been approached by using substantial amounts of lipid (1-5%) and/or building an emulsion system that readily separates.
The disadvantage of this approach includes: the product requires shaking, the clarity of the emulsion is greatly reduced, the total volume of lipid delivered to the eye is potentially large and variable and tolerability can be lower than an fully aqueous eye drop.
An alternate means of lipid release involves the use of a salt-sensitive emulsion system in a product intended for topical use that is largely free of salt. This system uses a surfactant and viscosity-increasing polymer to hold the lipid (eg. castor oil) in a stable sub-micron emulsion. When mixed with human tear, the natural salt content (often further elevated in dry eye) is sufficient to rapidly cause a drop in product viscosity due to action on the polymer structure. This loss of viscosity allows lipid release to occur to a significantly greater degree and much faster.
Efficiency of lipid delivery can be defined as the amount of lipid released from the emulsion, as a proportion of total lipid content, over time under standard test conditions.
Efficiency of lipid delivery in the presence of salt is supported, for example, using simple laboratory methods. Specifically, when diluted with water, this system shows a loss of viscosity proportional to water volume added. When exposed to salt (NaCl) by mixing 1:1 with even a weak saline solution (30 mOsm) a loss of viscosity of over 60 % occurs vs. 50% when mixed with water. Higher saline strength (up to about 600 mOsm) caused significantly greater loss of viscosity, confirming action of salt on polymer structure.
The release of lipid was demonstrated using a controlled centrifuge with real-time integrated optical detector (Lumisizer). During 2 minutes of 4000 RPM stress, uniformity of the emulsion was confirmed by equivalent optical transmission from bottom to top of the centrifuge sample holder for both full strength and water-diluted product. However, diluting the product with saline (volume and concentration replicating on-eye use) showed a clear and remarkable change in product uniformity consistent with lipid release and migration to the top of the sample holder, consistent with "floating" to the air interface. Surprisingly and beneficially, this may occur without coalescence (no increase in average lipid droplet size) allowing the lipid to mix into the native layer more effectively. Average particle (lipid droplet size) was unchanged when saline was added (Horiba) Clinical results have confirmed that the new lipid emulsion system works effectively in prolonging TBUT (tear break-up time) yet demonstrates tolerability and comfort improvements vs. an emulsion more optimized for drug delivery.
The benefits of using a salt-sensitive emulsion system as shown in Table I, that is largely free of salts, include but are not limited to: 1) No need to shake the product—excellent in bottle stability and uniformity; 2) Efficient delivery of lipid on eye due to the salt-induced decrease in viscosity and destabilization of emulsion structure enabling more efficient lipid release; 3) Improved tolerability by lowering total lipid content; 4) Effective stabilization and supplementation of the native lipid layer; and ) Possibly greater delivery of beneficial lipid in patients with higher tear salt content, a so-called "smart" vehicle.
The incorporation of osmoprotectants (l-carnitine and erythritol) and humectants/lubricants (glycerin and carboxymethylcellulose increases the clinical usefulness of this product to a broader range of dry eye patients than other emulsion systems targeting lipid deficiency or meibomian gland dysfunction.
Example 1 - A Multicenter, Investigator-masked, Randomized, 4-Arm, Parallel-group Study to Evaluate the Safety, Efficacy, and Acceptability of a Unit-dose Eye Drop Formulation in Subjects With Dry Eye Disease The objective of the study was to evaluate the safety, efficacy, and acceptability of the formulation of Table 1, but without containing Purite®, referred to as a Next Generation Emulsion Unit-dose or ("NGE UD") in subjects with signs and symptoms of dry eye disease.
Methodology This was a multicenter, investigator-masked, randomized, active-controlled, 4-arm, parallel group study designed to compare the safety, efficacy, and acceptability of NGE UD to commercially available OPTIVE™ Sensitive Preservative-free Lubricant Eye Drops Unit-dose ("OPTIVE UD"), NGE UD to Next Generation Emulsion Multidose ("NGE MD") (same formulation as Table 1 but with Purite®) , and NGE MD to OPTIVE™ Lubricant Eye Drops Multidose ("OPTIVE MD").
The planned study duration was 30 days for each subject and consisted of up to 3 scheduled visits (days 1 [baseline], 7, and 30 [exit]). On day 1, eligible subjects with signs and symptoms of dry eye disease were assigned according to a 2:2:1:1 treatment allocation ratio to use NGE UD, OPTIVE UD, NGE MD, or OPTIVE MD, respectively. The study randomization was stratified by baseline Ocular Surface Disease Index© (OSDI) score (mild/moderate symptoms = score of 18 to 32; severe symptoms = score of > 32 to 65). Approximately 300 subjects were to be enrolled at 13 to 14 sites within the USA in order to have 288 completed subjects assuming a dropout rate of approximately 5%. Subjects were instructed to instill 1 to 2 drops of their assigned study product in each eye, as needed, but at least 2 times daily for 30 days.
Number of Subjects (Planned and Enrolled) Approximately 300 subjects were planned to be enrolled in this study. A total of 315 subjects were enrolled.
Diagnosis and Main Criteria for Eligibility Diagnosis/Subjects with signs and symptoms of dry eye disease Key Inclusion Criteria: Male or female subjects, at least 18 years of age, with a baseline (day 1) OSDI score of ≥ 18 and ≤ 65 (based on a 0 to 100 scale) were eligible for enrollment. Subjects must have been using topical ophthalmic drops for dry eye at least twice daily, for at least 3 months prior to baseline, on average. If there was daily use of RESTASIS® Cyclosporine Ophthalmic Emulsion, it must have been in use for ≥ 6 months. Three consecutive tear break-up time (TBUT) tests ≤ 10 seconds in at least 1 eye at baseline were required. Using the modified National Eye Institute (NEI) Grid, all subjects had to have at least a Grade 1 staining in at least 1 of the 5 zones of the cornea or in at least 1 of the 6 zones of the conjunctiva that is related to dry eye in at least 1 eye at baseline.
Key Exclusion Criteria: Key exclusion criteria included a Schirmer test (with anesthesia) ≤ 2 mm in either eye at baseline; corneal or conjunctival staining score of 5 (modified NEI Grid) at baseline in any of the 5 corneal or 6 conjunctival zones of either eye; use of systemic medications that could have affected a dry eye condition or vision, unless that medication had been used at the same dose for at least 3 months prior to study enrollment and the dosage was not expected to change during the course of the study; history of anterior segment surgery or trauma that could have affected corneal sensitivity (eg, cataract surgery, laser-assisted in situ keratomileusis [LASIK], photorefractive keratectomy, or any surgery involving a limbal or corneal incision) within 12 months prior to baseline; and current use of, and/or use within 2 weeks prior to baseline, and/or likely use during the study period of any topical ophthalmic medications (eg, topical ophthalmic steroids, glaucoma drops, any topical cyclosporine product other than Restasis®.
Subjects who discontinued use of daily Restasis® less than 3 months prior to baseline were excluded from the study.
Duration of Treatment: The total duration of exposure to the study product (drops) for each subject was 30 days. The visit schedule consisted of a baseline visit (day 1) and 2 follow-up visits on days 7 (± 3 days) and 30/early exit (± 7 days).
Efficacy and Safety Measurements Efficacy: Primary – OSDI questionnaire score Secondary – TBUT (with fluorescein), corneal staining (modified NEI Grid, with fluorescein), conjunctival staining(modified NEI Grid, with lissamine green), and Schirmer test (with anesthesia) Other – Acceptability Questionnaire and Study Product Usage Questionnaire Safety: The safety measures were adverse events, biomicroscopy, and distance visual acuity.
Statistical Methods: The intent-to-treat (ITT) population consisted of all randomized subjects and was used for analyses of efficacy data based on the treatment randomized. The safety population consisted of all treated subjects and was used for analyses of all safety data based on the actual treatment received. The per-protocol (PP) population consisted of randomized subjects who had no major protocol violations, as determined prior to database lock.
The primary efficacy variable was the change from baseline in OSDI score at day 30 in the ITT population. The primary efficacy analysis was performed on the change from baseline in OSDI score at day 30 via a 2-way analysis of variance (ANOVA) model with treatment and baseline OSDI stratification as the main effects.
Last observation carried forward (LOCF) was used to impute missing data.
Noninferiority was tested using a 2-sided confidence interval (CI). The treatment difference and 95% CI in change from baseline in OSDI score at day 30 between NGE UD and OPTIVE UD (NGE UD minus OPTIVE UD) were calculated based on the ANOVA model. Non- inferiority was established if the upper limit of the 95% CI was less than the prespecified margin of 7.3.
The Secondary efficacy measures included TBUT, corneal staining, conjunctival staining, and Schirmer test. The raw values of these measures were summarized for the ITT population, with missing data imputation using LOCF at each scheduled follow-up visit. The treatment difference and 95% CI for between-treatment comparisons were calculated. The treatment differences and 95% CIs in change from baseline in OSDI score at day 30 between NGE UD and NGE MD, NGE MD and OPTIVE MD were also analyzed as secondary efficacy variables.
Acceptability was measured using the Acceptability Questionnaire, and product usage was measured using the Study Product Usage Questionnaire. Comparisons across groups were performed using ANOVA model with treatment and baseline OSDI stratification as the main effects.
The safety variables included adverse events, biomicroscopy, and distance visual acuity.
Since both eyes were treated, both eyes were included in the safety analyses. The Medical Dictionary for Regulatory Activities (MedDRA) nomenclature was used to code adverse events. The number and percent of subjects with clinically significant biomicroscopy findings at one or more visits in either eye were tabulated. The overall frequency distribution was analyzed using Pearson’s chi-square test. For a clinically significant biomicroscopic finding (more than 1 severity grade increase [worsening] from baseline) with an incidence rate of ≥ 5% in any treatment group, the mean severity grade and the frequency distribution of severity scores were summarized at each scheduled visit.
Data from the eye with the worst severity at the scheduled visit was tabulated. For distance visual acuity data, the total numbers of letters read correctly were summarized based on the eye with worse change from baseline at each scheduled visit. The frequency distribution was analyzed using Pearson’s chi-square test.
A total of 315 subjects were enrolled in the study and included in the ITT population; 105 subjects in the NGE UD group, 103 subjects in the OPTIVE UD group, 51 subjects in the NGE MD group, and 56 subjects in the OPTIVE MD group. Overall, 310 (98.4%) subjects in the ITT population completed the study. Of the subjects included in the per protocol population, 99.3% (303/305) completed the study whereas 98.4% (310/315) of the subjects in the safety population completed the study. A total of 384 subjects were screened of which 69 subjects were screen failures.
In the ITT population, the mean age of all subjects was 54.8 years (standard deviation 14.33) with 83.2% (262/315) of subjects in the > 40 years age group. In addition, 81.0% (255/315) of all subjects were female and 84.4% (266/315) were Caucasian.
Efficacy: The primary efficacy endpoint was met. At day 30, no statistically significant difference was observed between the NGE UD and the OPTIVE UD groups in the mean change from baseline in OSDI score (95% confidence interval [-5.42, 2.51]), in the ITT population. The NGE UD formulation was noninferior to the OPTIVE UD formulation in reducing the severity of symptoms of dryness as measured by the change from baseline in OSDI score.
Similar to the ITT population, there was no statistically significant difference between the NGE UD and OPTIVE UD groups of the PP population in the mean change from baseline in OSDI score at day 30. The 95% confidence interval at the day 30 visit was (-5.72, 2.37); with an upper limit that is lower than the clinically relevant margin of 7.3.
In all 4 treatment groups, there was a statistically significant difference (p < 0.001) in the mean change from baseline in OSDI score at the day 7 and day 30 visits for both the ITT and the PP population.
The NGE UD group was noninferior to the NGE MD group in the mean change from baseline in OSDI score at day 30.
The NGE UD group was noninferior to the OPTIVE UD and NGE MD groups in the secondary efficacy measures of TBUT, corneal staining, conjunctival staining, and Schirmer test.
Overall, there were no statistically significant differences between the NGE UD and OPTIVE UD groups, NGE UD and NGE MD groups, or NGE MD and OPTIVE MD groups, in the mean values for each question of the acceptability questionnaire at the day 7 and day 30 visits (except for question 5 in the NGE MD versus OPTIVE MD comparison at day 7 and NGE UD versus NGE MD comparison at day 30), and in the mean number of times per day that the study product was used during the week prior to the day 7 and day 30 visits.
Safety: At least 1 treatment-emergent adverse event (TEAE) of any causality was reported in 11.4%, .5%, 13.7%,and 10.7% of subjects in the NGE UD, OPTIVE UD, NGE MD and OPTIVE MD groups, respectively.
No deaths were reported in the study. Two serious adverse events were reported (bile duct stone [NGE UD group] and ankle fracture [OPTIVE MD group]), none of which were treatment related in the opinion of the investigator Overall 3 subjects discontinued from the study due to adverse events, 1 subject each in the NGE UD, NGE MD and OPTIVE MD groups.
Treatment-related TEAE were reported in 4.8%, 8.7%, 7.8%, and 5.4% of subjects in the NGE UD, OPTIVE UD, NGE MD, and OPTIVE MD groups, respectively. The most common treatment-related adverse events (preferred terms) across treatment groups were instillation site pain and vision blurred; NGE UD (3.8%, 2.9%), OPTIVE UD (3.9%, 2.9%), NGE MD (3.9%, 0.0%), and OPTIVE MD (3.6%, 1.8%).
In the majority of the subjects, no change was observed in the distance visual acuity at day 30 for all 4 treatment groups.
Conclusions Efficacy: The results of this study demonstrate that the NGE UD formulation is non- inferior to the OPTIVE UD formulation in reducing the severity of symptoms of dryness in subjects with mild to severe dry eye.
Safety: NGE UD appeared to be well tolerated during the study. The most commonly reported treatment-related adverse events were instillation site pain and vision blurred.
Throughout the study, there were no treatment-related serious adverse events. The safety profile was consistent with OPTIVE UD, OPTIVE MD, and NGE MD. This is supportive of the safety of the NGE UD formulation in clinical use, and confirms the safety of the NGE MD formulation.
In this specification where reference has been made to patent specifications, other external documents, or other sources of information, this is generally for the purpose of providing a context for discussing the features of the invention. Unless specifically stated otherwise, reference to such external documents is not to be construed as an admission that such documents, or such sources of information, in any jurisdiction, are prior art, or form part of the common general knowledge in the art.
In the description in this specification reference may be made to subject matter that is not within the scope of the claims of the current application. That subject matter should be readily identifiable by a person skilled in the art and may assist in putting into practice the invention as defined in the claims of this application.
Claims (20)
1. A low salt ophthalmic pharmaceutical composition comprising a sub-micron emulsion, a polymer lubricant, and a salt-sensitive viscosity modulating polymer, wherein said sub-micron emulsion comprises a surfactant and a therapeutic lipid consisting essentially of castor oil.
2. The low salt ophthalmic pharmaceutical composition according to claim 1, wherein said therapeutic lipid is castor oil present at a concentration of about 0.25% (w/w).
3. The low salt ophthalmic pharmaceutical composition according to claim 1, wherein said surfactant is a sorbitan ester, wherein said sorbitan ester is polysorbate 80 present at a concentration of about 0.5% (w/w).
4. The low salt ophthalmic pharmaceutical composition according to claim 1, wherein said salt-sensitive viscosity modulating polymer is an acrylate/C -C acrylate crosspolymer 10 30 having a standard emulsion viscosity between 1,700 and 4,500 cPs, wherein said salt- sensitive viscosity modulating polymer is present at a concentration of about 0.1% (w/w).
5. The low salt ophthalmic pharmaceutical composition according to claim 1, wherein said polymer lubricant is carboxymethylcellulose sodium present at a concentration of about 0.5% (w/w).
6. The low salt ophthalmic pharmaceutical composition according to claim 1, further comprising a compatible solute.
7. The low salt ophthalmic pharmaceutical composition according to claim 6, wherein said compatible solute is erythritol or levocarnitine.
8. The low salt ophthalmic pharmaceutical composition according to claim 7 comprising erythritol at a concentration of about 0.25% (w/w) and levocarnitine at a concentration of about 0.25% (w/w).
9. The low salt ophthalmic pharmaceutical composition according to claim 1, further comprising a tonicity agent, wherein said tonicity agent is glycerin present at a concentration of about 1.0% (w/w).
10. The low salt ophthalmic pharmaceutical composition according to claim 1, further comprising a preservative.
11. The low salt ophthalmic pharmaceutical composition according to claim 10, wherein said preservative is a stabilized oxychloro complex present at a concentration of about 0.01% (w/w).
12. The low salt ophthalmic pharmaceutical composition according to claim 1, further comprising a buffer.
13. The low salt ophthalmic pharmaceutical composition according to claim 12, wherein said buffer is boric acid present at a concentration of about 0.6% (w/w).
14. The low salt ophthalmic pharmaceutical composition according to claim 1, further comprising a pH adjustment agent.
15. The low salt ophthalmic pharmaceutical composition according to claim 14, wherein said pH adjustment agent is NaOH.
16. The low salt ophthalmic pharmaceutical composition according to claim 14 having pH about 7.3.
17. A low salt ophthalmic pharmaceutical composition comprising: a therapeutic lipid consisting essentially of castor oil at a concentration of about 0.25% (w/w); polysorbate 80 at a concentration of about 0.5% (w/w); acrylate/C -C acrylate crosspolymer at a concentration of about 0.1% (w/w), wherein 10 30 said acrylate/C -C acrylate crosspolymer has a standard emulsion viscosity between 10 30 1,700 and 4,500 cPs; carboxymethylcellulose sodium at a concentration of about 0.5% (w/w); glycerin at a concentration of about 1.0% (w/w); a stabilized oxychloro complex preservative at a concentration of about 0.01% (w/w); boric acid at a concentration of about 0.6% (w/w); erythritol at a concentration of about 0.25% (w/w); evocarnitine at a concentration of about 0.25% (w/w); NaOH; and water.
18. A use of a low salt ophthalmic pharmaceutical composition according to any one of claims 1-17, in the manufacture of a medicament for treating said dry eye syndrome in a patient in need thereof.
19. A low salt ophthalmic pharmaceutical composition as claimed in any one of claims 1- 17, substantially as herein described with reference to an example thereof.
20. A use as claimed in claim 18, substantially as herein described with reference to an example thereof.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161568089P | 2011-12-07 | 2011-12-07 | |
US61/568,089 | 2011-12-07 | ||
US201261625401P | 2012-04-17 | 2012-04-17 | |
US61/625,401 | 2012-04-17 | ||
NZ72525712 | 2012-12-07 |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ743307A NZ743307A (en) | 2020-01-31 |
NZ743307B2 true NZ743307B2 (en) | 2020-05-01 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2017265181B2 (en) | Efficient lipid delivery to human tear film using a salt-sensitive emulsion system | |
US20220008496A1 (en) | Artificial tears and therapeutic uses | |
US20210245512A1 (en) | Efficient lipid delivery to human tear film using a salt-sensitive emulsion system | |
JP6876079B2 (en) | Artificial tears containing sodium hyaluronate and carboxymethyl cellulose | |
US20220080048A1 (en) | Opthalmological compositions and methods of use thereof | |
ES2827426T3 (en) | Ophthalmic composition for corneal protection | |
JPWO2018074421A1 (en) | Ophthalmic agent and ophthalmic drug | |
NZ743307B2 (en) | Efficient lipid delivery to human tear film using a salt-sensitive emulsion system | |
NZ743307A (en) | Efficient lipid delivery to human tear film using a salt-sensitive emulsion system | |
WO2021087051A1 (en) | Topical compositions and methods of use thereof | |
RU2772357C2 (en) | Composition for effective lipid delivery to human tear film using salt-sensitive emulsion system | |
US20190224136A1 (en) | Artificial tear compositions and methods of use thereof | |
TWI632913B (en) | Compositions and treatment for eye diseases and disorders |