Method and Device for Ophthalmic Administration of Active Pharmaceutical Ingredients

• US 20080233053A1
• Filed: 02/06/2006
• Published: 09/25/2008
• Est. Priority Date: 02/07/2005
• Status: Abandoned Application

• Current Assignee: PharmaLight Inc.
• Original Assignee: PharmaLight Inc.
• Inventors: Gross, Yossi, Koevary, Steven B., Herzog, Rafi
• Application Number:
  US11/883,774
• Publication Number:
  US 20080233053A1
• Time in Patent Office: Days
• US Class Current: 424/45
• CPC Class Codes: A61K 31/138 Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine atenolol A61K31/165; pindolol A61K31/404; timolol A61K31/5377
• CPC Class Codes: A61K 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 31/222 with compounds having aromatic groups, e.g. dipivefrine, ibopamine
• CPC Class Codes: A61K 31/382 having six-membered rings, e.g. thioxanthenes thiothixene A61K31/496
• CPC Class Codes: A61K 31/4168 having a nitrogen attached in position 2, e.g. clonidine
• CPC Class Codes: A61K 31/4178 not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
• CPC Class Codes: A61K 31/433 Thidiazoles
• CPC Class Codes: A61K 31/4704 2-Quinolinones, e.g. carbostyril
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/498 Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/542 ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/5575 having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 31/575 substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
• CPC Class Codes: A61K 31/661 Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/46 Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts
• CPC Class Codes: A61K 9/0048 : Eye, e.g. artificial tears
• CPC Class Codes: A61K 9/12 : Aerosols; Foams A61K9/0043, A61K9/0056, A61K9/006, A61K9/0073 take precedence; spray-films A61K9/7015

Abstract

Disclosed is the use of a mist of a pharmaceutical composition for ophthalmic delivery of a protein or peptide active pharmaceutical ingredient, a related method of treatment and a device useful in implementing the use and method. Disclosed is also the use of a mist for ophthalmic delivery of a pharmaceutical composition including a highly irritating penetration enhancer and an ophthalmically acceptable carrier, a related method of treatment and a device useful in implementing the use and method. Disclosed is also a device for ophthalmic administration configured to direct a mist of a pharmaceutical composition to the eye only when the eye is open. Disclosed is also a self-sterilizing device for ophthalmic administration. Disclosed is also a device and a method for increasing the bioavailability of an ophthalmically administered API in a pharmaceutical composition.

Claims

1-161. -161. (canceled)

162. A method of treatment, comprising:

a) providing a pharmaceutical composition including an active pharmaceutical ingredient and an ophthalmically acceptable carrier;

b) generating a mist of said composition; and

c) contacting said mist with a posterior surface of an eye of a subject in need thereof

thereby depositing an effective amount of said API on said posterior surface

wherein said active ingredient is selected from the group consisting of peptides and proteins.

163. The method of claim 162, wherein said need is selected from the group consisting of curing a condition, treating a condition, preventing a condition, treating symptoms of a condition, curing symptoms of a condition, ameliorating symptoms of a condition, treating effects of a condition, ameliorating effects of a condition, and preventing results of a condition.

164. The method of claim 163, wherein said condition is selected from the group consisting of behavioral conditions, brain disorders, cancer, eye cancers, brain cancers, cerebral cancers, nerve cancers, central nervous system disorders, choroidal neovascularization, corneal neovascularization, glaucoma, infections, inflammatory diseases, inflammations, inflammatory diseases of the retina, intravitreal neovascularization, iris neovascularization, macular edema, mental illnesses, neural conditions, neurological disorders, ocular diseases, ocular inflammation, optic disc neovascularization, optical nerve disorders, pannus posterior segment edema, postoperative ocular pain, proliferative vitreoretinopathy, prostaglandin formation, psychological conditions, psychoses and psychiatric disorders, pterygium, retinoblastoma, retinal edema, retinal degeneration, retinal revascularization, uveitis and vascular retinopathy.

165. The method of claim 164, wherein said condition is a condition susceptible to an interaction of an active pharmaceutical ingredient with a part of an eye.

166. The method of claim 164, wherein said condition is a condition susceptible to an interaction of an active pharmaceutical ingredient with a nerve.

167. The method of claim 163, wherein said need requires delivery of an active ingredient to the blood stream of said subject.

168. The method of claim 163, wherein said need requires delivery of an active ingredient to a part of an eye of said subject.

169. The method of claim 163, wherein said need requires delivery of an active ingredient to a part of the nervous system of said subject.

170. The method of claim 162, said composition further comprising a penetration enhancer.

171. The method or device of claim 170, wherein said penetration enhancer comprises at least 0.05% by weight of said pharmaceutical composition.

172. The method of claim 162, said active ingredient selected from the group consisting of ACTH, angiotensin converting enzyme, bertilimumab, bevacizumab, calcitonin, concanavalin, dynorphin A, dynorphin B, enkephalins, endorphins, endothelin-1, enzyme, glial cell-line derived neurotrophic factor (GDNF), glucagon, gonadotropin releasing hormone, growth hormone releasing hormone, hyaluronidase, ierdelimumab, IgG1, insulin, leptin, lerdelimumab, leucine-enkephalin, luteinizing hormone releasing hormone, lypressin, lysozyme, metelimumab, methionine-enkephalin, monoclonal antibodies, alpha-neoendorphin, beta-neoendorphin, neurotrophic factors, obestatin, oxytocin, peptide hormones, protein hormones, ranibizumab, ribonuclease, secretin, somatostatin, somatotropin, thyrotrophin releasing hormone, vasopressin, viral vectors and homologues thereof.

173. The method of claim 162, said active ingredient selected from the group consisting of leptin and homologues thereof.

174. The method of claim 162, said active ingredient selected from the group consisting of antibodies or antibody homologues.

175. The method or device of claim 174, said antibody comprising IgG1.

176. The method of claim 162, wherein said active ingredient is a denaturizable active ingredient.

177. The method of claim 162, wherein said active ingredient has a molecular weight of greater than 1 kDa.

178. A device for ophthalmic administration of a pharmaceutical composition, comprising:

a) a nebulizer;

b) a composition reservoir functionally associated with said nebulizer; and

c) a pharmaceutical composition including an active pharmaceutical ingredient and an ophthalmically acceptable carrier contained within said reservoir

wherein said active ingredient is selected from the group consisting of peptides and proteins.

179. The device of claim 178, said composition further comprising a penetration enhancer.

180. The device of claim 179, wherein said penetration enhancer comprises at least 0.05% by weight of said pharmaceutical composition.

181. The device of claims 178, said active ingredient selected from the group consisting of ACTH, angiotensin converting enzyme, bertilimumab, bevacizumab, calcitonin, concanavalin, dynorphin A, dynorphin B, enkephalins, endorphins, endothelin-1, enzyme, glial cell-line derived neurotrophic factor (GDNF), glucagon, gonadotropin releasing hormone, growth hormone releasing hormone, hyaluronidase, ierdelimumab, IgG1, insulin, leptin, lerdelimumab, leucine-enkephalin, luteinizing hormone releasing hormone, lypressin, lysozyme, metelimumab, methionine-enkephalin, monoclonal antibodies, alpha-neoendorphin, beta-neoendorphin, neurotrophic factors, obestatin, oxytocin, peptide hormones, protein hormones, ranibizumab, ribonuclease, secretin, somatostatin, somatotropin, thyrotrophin releasing hormone, vasopressin, viral vectors and homologues thereof.

182. The device of claim 178, said active ingredient selected from the group consisting of leptin and homologues thereof.

183. The device of claims 178, said active ingredient selected from the group consisting of antibodies or antibody homologues.

184. The device of claim 183, said antibody comprising IgG1.

185. The device of claim 178, wherein said active ingredient is a denaturizable active ingredient.

186. The device of claim 178, wherein said active ingredient has a molecular weight of greater than 1 kDa.

187. A method of delivering a composition, comprising:

a) providing a pharmaceutical composition including a highly irritating penetration enhancer and an ophthalmically acceptable carrier;

b) generating a mist of said composition; and

c) contacting said mist with a posterior surface of an eye of a subject in need thereof.

188. The method of claim 187, wherein said penetration enhancer comprises at least 0.05% by weight of said pharmaceutical composition.

189. The method of claim 187, wherein said need is selected from the group consisting of curing a condition, treating a condition, preventing a condition, treating symptoms of a condition, curing symptoms of a condition, ameliorating symptoms of a condition, treating effects of a condition, ameliorating effects of a condition, and preventing results of a condition.

190. The method of claim 189, wherein said condition is a condition susceptible to an interaction of an active pharmaceutical ingredient with a part of an eye.

191. The method of claim 189, wherein said condition is a condition susceptible to an interaction of an active pharmaceutical ingredient with a nerve.

192. The method of claim 189, wherein said need requires delivery of an active ingredient to the blood stream of said subject.

193. The method of claim 189, wherein said need requires delivery of an active ingredient to a part of an eye of said subject.

194. The method of claim 189, wherein said need requires delivery of an active ingredient to a part of the nervous system of said subject.

195. The method of claim 187, said penetration enhancer being a penetration enhancer that is inherently highly irritating.

196. The method of claim 195, wherein said highly irritating penetration enhancer is selected from the group consisting of benzalkonium chloride, BL-9, deoxycholic acid, digitonin, escin, fusidic acid, fusidate, fusidic acid derivatives, saponin, saponins, sodium deoxycholate, acetone, acyl lactylates, acyl peptides, acylsarcosinates, alcohols, alkanolamine salts of fatty acids, alkyl benzene sulphonates, alkyl ether sulphates, alkyl sulphates, allantoin, anionic surface-active agents, 1-substituted azacycloheptan-2-ones, benzyl benzoate, benzyl salicylate, butan-1,4-diol, butyl benzoate, butyl laurate, butyl myristate, butyl stearate, cationic surface-active agents, citric acid, cocoamidopropylbetaine, decyl methyl sulfoxide, decyl oleate, dibutyl azelate, dibutyl phthalate, dibenzyl sebacate, dibutyl sebacate, dibutyl suberate, dibutyl succinate, dicapryl adipate, didecyl phthalate, diethylene glycol, diethyl sebacate, diethyl-m-toluamide, di(2-hydroxypropyl)ether, diisopropyl adipate, diisopropyl sebacate, N,N-dimethyl acetamide, dimethyl azelate, N,N-dimethyl formamide, 1,5-dimethyl-2-pyrrolidone, dimethyl sebacate, dioctyl adipate, dioctyl azelate, dioctyl sebacate, 1,4 dioxane, 1-dodecylazacycloheptan-2-one, dodecyl dimethyl amine oxides, ethyl caprate, ethyl caproate, ethyl caprylate, 2-ethyl-hexyl pelargonate, ethyl-2-hydroxypropanoate, ethyl laurate, ethyl myristate, 1-ethyl-2-pyrrolidone, ethyl salicylate, glycerol monolaurate, hexyl laurate, 2-hydroxyoctanoic acid, 2-hydroxypropanoic acid, 2-hydroxypropionic acid, isethionates, isopropyl isostearate, isopropyl palmitate, guar hydroxypropyltrimonium chloride, hexan-2,5-diol, khellin, lamepons, lauryl alcohol, lecithin, maypons, metal salts of fatty acids, methyl nicotinate, 2-methyl propan-2-ol, 1-methyl-2-pyrrolidone, 5-methyl-2-pyrrolidone, methyl taurides, miranol, nonionic surface-active agents, octyl alcohol, octylphenoxy polyethoxyethanol, oleic ethanolamide, pleyl alcohol, pentan-2,4-diol, phenoxyethanol, phosphatidyl choline, phosphine oxides, polyalkoxylated ether glycollates, poly(dialkylpiperidinium chloride), poly(dipropyldiallylammonium chloride), polyethylene glycol monolaurate, polyglycerol esters, poly(vinyl pyridinium chloride), propan-1-ol, propan-2-ol, propylene glycol, propylene glycol dipelargonate, propylene glycol monolaurate, pyroglutamic acids, 2-pyrrolidone, pyruvic acids, Quaternium 5, Quaternium 18, Quaternium 19, Quaternium 23, Quaternium 31, Quaternium 40, Quaternium 57, quartenary amine salts, quaternised poly(dimethylaminoethylmethacrylate), quaternised poly(vinyl alcohol), sapamin hydrochloride, sodium cocaminopropionate, sodium dioctyl sulphosuccinate, sodium laurate, sodium lauryl ether sulphate, sodium lauryl sulphate, sorbitan monooleate, sorbitan monolaurate, sugar esters, sulphosuccinate, tetrahydrofuran, tetrahydrofurfuryl alcohol, transcutol, triethanolamine dodecyl benzene sulphonate, triethanolamine oleate, urazole, urea, and derivatives, esters, salts and mixtures thereof.

197. The method of claim 187, said penetration enhancer being a penetration enhancer that is highly irritating at high concentrations.

198. The method of claim 197, wherein said highly irritating penetration enhancer is selected from the group consisting of ammonium glycyrrhizide, Brij 35, Brij 78, Brij-98, cetylpyridium chloride, chenodeoxycholic acid, cholate, cholic acid, decamethonium, decamethonium bromide, dimethyl sulphoxide, EDTA and disodium EDTA, glycocholate, glycocholic acid, glycodeoxycholic acid, glycyrrhizic acid, paraben, polyoxyethylene, polyoxyethylene ethers of fatty acids such as polyoxyethylene 4-, 9-, 10-, and 23-lauryl ether, polyoxyethylene 10- and 20-cetyl ether, polyoxyethylene 10- and 20-stearyl ether, polyoxyethylated castor oil, polyoxyethylene monolaurate, polyoxyethylene sorbitans such as polyoxyethylene sorbitan monolaurate, polyoxy:

polyoxyethylene stearate, polyoxypropylene 15 stearyl ether, sodium cholate, sodium glycocholate, sodium taurocholate, sodium glycodeoxycholate, sodium taurodeoxycholate, sodium ursodeoxycholate, taurocholic acid, taurodeoxycholic acid, TWEEN 20, urosdeoxycholic acid, and derivatives, esters, salts and mixtures thereof in a greater than accepted concentration.

199. The method of claim 187, said penetration enhancer comprising saponin.

200. The method of claim 187, said composition further comprising an active pharmaceutical ingredient.

201. The method of claim 200, said active pharmaceutical ingredient selected from the group consisting of alpha-2 adrenergic agonists, analgesics, anesthetics, antibiotics, antidepressants, antihistamines, antipsychotics, antivascular agents, antiviral agents, aptamers, artificial tears, beta-adrenergic blocking agents, carbonic anhydrase inhibitors, catalytic antioxidants, chemotherapeutics, cholinesterase inhibitors, corticosteroids, direct acting miotics, hormones, light-activated drugs, non-steroidal anti-inflammatory drugs, ocular lubricants, ophthalmic decongestant agents, ophthalmic antiseptics, ophthalmic antifungals, peptides, prostaglandin analogs, proteins, catalytic antioxidants, sedatives, steroid, stimulants, sulfonamides, vasoconstrictors and vasodilators.

202. A device for ophthalmic administration of a composition, comprising:

a) a nebulizer;

b) an composition reservoir functionally associated with said nebulizer; and

c) a pharmaceutical composition including a highly irritating penetration enhancer and an ophthalmically acceptable carrier contained within said reservoir.

203. The device of claim 202, wherein said penetration enhancer comprises at least 0.05% by weight of said pharmaceutical composition.

204. The device of claim 202, said penetration enhancer being a penetration enhancer that is inherently highly irritating.

205. The device of claim 204, wherein said highly irritating penetration enhancer is selected from the group consisting of benzalkonium chloride, BL-9, deoxycholic acid, digitonin, escin, fusidic acid, fusidate, fusidic acid derivatives, saponin, saponins, sodium deoxycholate, acetone, acyl lactylates, acyl peptides, acylsarcosinates, alcohols, alkanolamine salts of fatty acids, alkyl benzene sulphonates, alkyl ether sulphates, alkyl sulphates, allantoin, anionic surface-active agents, 1-substituted azacycloheptan-2-ones, benzyl benzoate, benzyl salicylate, butan-1,4-diol, butyl benzoate, butyl laurate, butyl myristate, butyl stearate, cationic surface-active agents, citric acid, cocoamidopropylbetaine, decyl methyl sulfoxide, decyl oleate, dibutyl azelate, dibutyl phthalate, dibenzyl sebacate, dibutyl sebacate, dibutyl suberate, dibutyl succinate, dicapryl adipate, didecyl phthalate, diethylene glycol, diethyl sebacate, diethyl-m-toluamide, di(2-hydroxypropyl)ether, diisopropyl adipate, diisopropyl sebacate, N,N-dimethyl acetamide, dimethyl azelate, N,N-dimethyl formamide, 1,5-dimethyl-2-pyrrolidone, dimethyl sebacate, dioctyl adipate, dioctyl azelate, dioctyl sebacate, 1,4 dioxane, 1-dodecylazacycloheptan-2-one, dodecyl dimethyl amine oxides, ethyl caprate, ethyl caproate, ethyl caprylate, 2-ethyl-hexyl pelargonate, ethyl-2-hydroxypropanoate, ethyl laurate, ethyl myristate, 1-ethyl-2-pyrrolidone, ethyl salicylate, glycerol monolaurate, hexyl laurate, 2-hydroxyoctanoic acid, 2-hydroxypropanoic acid, 2-hydroxypropionic acid, isethionates, isopropyl isostearate, isopropyl palmitate, guar hydroxypropyltrimonium chloride, hexan-2,5-diol, khellin, lamepons, lauryl alcohol, lecithin, maypons, metal salts of fatty acids, methyl nicotinate, 2-methyl propan-2-ol, 1-methyl-2-pyrrolidone, 5-methyl-2-pyrrolidone, methyl taurides, miranol, nonionic surface-active agents, octyl alcohol, octylphenoxy polyethoxyethanol, oleic ethanolamide, pleyl alcohol, pentan-2,4-diol, phenoxyethanol, phosphatidyl choline, phosphine oxides, polyalkoxylated ether glycollates, poly(dialkylpiperidinium chloride), poly(dipropyldiallylammonium chloride), polyethylene glycol monolaurate, polyglycerol esters, poly(vinyl pyridinium chloride), propan-1-ol, propan-2-ol, propylene glycol, propylene glycol dipelargonate, propylene glycol monolaurate, pyroglutamic acids, 2-pyrrolidone, pyruvic acids, Quaternium 5, Quaternium 18, Quaternium 19, Quaternium 23, Quaternium 31, Quaternium 40, Quaternium 57, quartenary amine salts, quaternised poly(dimethylaminoethylmethacrylate), quaternised poly(vinyl alcohol), sapamin hydrochloride, sodium cocaminopropionate, sodium dioctyl sulphosuccinate, sodium laurate, sodium lauryl ether sulphate, sodium lauryl sulphate, sorbitan monooleate, sorbitan monolaurate, sugar esters, sulphosuccinate, tetrahydrofuran, tetrahydrofurfuryl alcohol, transcutol, triethanolamine dodecyl benzene sulphonate, triethanolamine oleate, urazole, urea, and derivatives, esters, salts and mixtures thereof.

206. The device of claim 202, said penetration enhancer being a penetration enhancer that is highly irritating at high concentrations.

207. The device of claim 206, wherein said highly irritating penetration enhancer is selected from the group consisting of ammonium glycyrrhizide, Brij 35, Brij 78, Brij-98, cetylpyridium chloride, chenodeoxycholic acid, cholate, cholic acid, decamethonium, decamethonium bromide, dimethyl sulphoxide, EDTA and disodium EDTA, glycocholate, glycocholic acid, glycodeoxycholic acid, glycyrrhizic acid, paraben, polyoxyethylene, polyoxyethylene ethers of fatty acids such as polyoxyethylene 4-, 9-, 10-, and 23-lauryl ether, polyoxyethylene 10- and 20-cetyl ether, polyoxyethylene 10- and 20-stearyl ether, polyoxyethylated castor oil, polyoxyethylene monolaurate, polyoxyethylene sorbitans such as polyoxyethylene sorbitan monolaurate, polyoxy:

polyoxyethylene stearate, polyoxypropylene 15 stearyl ether, sodium cholate, sodium glycocholate, sodium taurocholate, sodium glycodeoxycholate, sodium taurodeoxycholate, sodium ursodeoxycholate, taurocholic acid, taurodeoxycholic acid, TWEEN 20, urosdeoxycholic acid, and derivatives, esters, salts and mixtures thereof in a greater than accepted concentration.

208. The device of claim 202, said penetration enhancer comprising saponin.

209. The device of any of claims 202, said composition further comprising an active pharmaceutical ingredient.

210. The device of claim 209, said active pharmaceutical ingredient selected from the group consisting of alpha-2 adrenergic agonists, analgesics, anesthetics, antibiotics, antidepressants, antihistamines, antipsychotics, antivascular agents, antiviral agents, aptamers, artificial tears, beta-adrenergic blocking agents, carbonic anhydrase inhibitors, catalytic antioxidants, chemotherapeutics, cholinesterase inhibitors, corticosteroids, direct acting miotics, hormones, light-activated drugs, non-steroidal anti-inflammatory drugs, ocular lubricants, ophthalmic decongestant agents, ophthalmic antiseptics, ophthalmic antifungals, peptides, prostaglandin analogs, proteins, catalytic antioxidants, sedatives, steroid, stimulants, sulfonamides, vasoconstrictors and vasodilators.

211. A device for ophthalmic administration of a composition, comprising:

a) a misting unit including

i) a nebulizer, configured to generate a mist from a composition;

ii) a mist director, configured to direct mist generated by said nebulizer at an eye;

b) an eye-state detector, configured to detect if said eye is open or shut; and

c) a switch functionally associated with said misting unit and with said eye-state detector having at least two states, an “

ON”

state wherein a mist is directed at said eye and an “

OFF”

state wherein a mist is not directed at said eye.

212. A device for ophthalmic administration of a pharmaceutical composition to an eye of a subject, comprising:

a) a contact component with a contact surface, said contact surface configured to contact a portion of the body of the subject during the administration; and

b) a reversibly actuatable radiation-source, configured to irradiate said contact surface with sterilizing radiation

wherein said contact component and said radiation source are both integral elements of a single unit of the device.

213. A method of treatment, comprising:

a) contacting a pharmaceutical composition with a posterior section of an eye;

b) shutting said eye with a respective eyelid; and

c) vibrating said eyelid.

214. A device for increasing the bioavailability of an ophthalmically administered API in a pharmaceutical composition, comprising:

a) an eyelid contact component, configured to physically contact an eyelid of an eye and maintain said eyelid in a shut position; and

b) a vibration generator configured to generate vibrations and transfer said vibrations to said eyelid contact component.