WO2009154169A1 - ペプチド誘導体およびそれを含む涙液分泌促進組成物 - Google Patents
ペプチド誘導体およびそれを含む涙液分泌促進組成物 Download PDFInfo
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- WO2009154169A1 WO2009154169A1 PCT/JP2009/060873 JP2009060873W WO2009154169A1 WO 2009154169 A1 WO2009154169 A1 WO 2009154169A1 JP 2009060873 W JP2009060873 W JP 2009060873W WO 2009154169 A1 WO2009154169 A1 WO 2009154169A1
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- composition
- lacrimal secretion
- promoting
- acid
- leu
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
- A61K9/0051—Ocular inserts, ocular implants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/04—Artificial tears; Irrigation solutions
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06086—Dipeptides with the first amino acid being basic
- C07K5/06095—Arg-amino acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- the present invention includes a peptide derivative for treating and / or preventing an ocular disease associated with decreased lacrimal secretion, ie, dry eye (dry eye), corneal epithelial detachment, keratitis, corneal ulcer, conjunctivitis and the like, and the like.
- the present invention relates to a composition for promoting lacrimal secretion.
- the present invention relates to a DDS (drug delivery system) preparation, a transdermal absorption preparation, a topical ophthalmic preparation (eye drops, eye ointment, etc.) and a contact lens composition containing the composition for promoting lacrimal secretion.
- Dry eye is a disease that presents with symptoms such as dry eyes, corneal congestion, foreign body sensation, and pruritus, and causes corneal damage mainly due to a decrease in tear secretion. Moreover, it is said that when dry eye becomes severe, it causes visual impairment and eye strain.
- Tear fluid is a thin liquid layer having a thickness of about 7 ⁇ m that exists at the boundary between the eyeball and the atmosphere and covers the outermost layer of the eyeball.
- Tear fluid has a three-layer structure consisting of an oil layer, an aqueous layer, and a mucin layer from the outside, and each layer plays an important role in preventing dryness of the eyeball.
- the aqueous layer occupying most of the thickness of the tears is present between the oil layer and the mucin layer, thereby preventing the aqueous layer from decreasing and maintaining the wettability of the eyeball.
- the oil layer is mainly produced from a gland that exists around the ridge called the meibomian gland and covers the entire water layer to prevent water evaporation.
- the mucin layer is made hydrophilic by covering the surface of the corneal epithelium which is hydrophobic, and has a function of holding the aqueous layer on the surface of the corneal epithelium.
- Tears have various functions as well as dry eye prevention. Other functions of tears include, for example, protection of the cornea and conjunctiva, bacteriostatic action, defense against infection from bacteria, fungi, viruses, etc., supply of oxygen and various nutrients to the cornea, and carbon dioxide and metabolites. Removal, dilution and removal of damaging stimuli in the event of damage to the cornea and conjunctiva, transport of liquid components such as epidermal growth factor involved in wound healing and blood components such as fibronectin to damaged sites, cornea and conjunctival epithelium Cell retention and wound healing regulation.
- Patent Document 1 for example, a peptide having the amino acid sequence Ser-Leu-Ile-Gly-Arg-Leu-NH 2 activates PAR-2, which is a subtype of PAR (Protease-activated receptor).
- PAR-2 Protease-activated receptor
- Patent Document 2 discloses 3 or 4 amino acids of isoleucine (Ile), glycine (Gly), arginine (Arg), and leucine (Leu) that act on parasympathetic nerves to promote tear secretion.
- Ile isoleucine
- Gly glycine
- Arg arginine
- Leu leucine
- an object of the present invention is to provide a composition for promoting lacrimal secretion that is effective over a long period of time. That is, an object of the present invention is to apply a composition having a lacrimal secretion promoting action over a long period of time, which can solve the problem of side effects caused by an artificial tear type eye drop for the purpose of supplementing conventional tear fluid components. And In particular, an object of the present invention is to provide a composition that acts on parasympathetic nerves and promotes lacrimation over a long period of time.
- the present inventors have conducted research to develop a preferable drug as such a composition for promoting lacrimal secretion, and as a result, the general formula (I):
- the present invention was completed by finding that lacrimal secretion is induced for a long time by the peptide derivative represented by
- a peptide derivative represented by [2] A composition for promoting lacrimal secretion comprising the peptide derivative according to the above [1] and formulated so as to be pharmacologically and pharmaceutically acceptable; [3] The composition for promoting lacrimal secretion according to the above [2], further comprising a substance that inhibits inactivation or degradation of the peptide derivative; [4] The composition for promoting lacrimal secretion according to [3] above, wherein the substance that inhibits inactivation or degradation is a peptidase inhibitor; [5] The composition for promoting lacrimal secretion according to [4], wherein the peptidase inhibitor is amastatin; [6] The composition for promoting lacrimal secretion according to any one of the above [2] to [5], which is formulated as a DDS preparation; [7] The composition for promoting lacrimal secretion according to any one of [2] to [6], wherein the composition is transdermally absorbed; [8] The composition for
- a therapeutic or preventive agent for ophthalmic diseases comprising the composition for promoting lacrimal secretion according to any one of [2] to [5] above; [15] The eye disease treatment or prevention agent according to the above [14], wherein the eye disease is dry eye, corneal epithelial detachment, keratitis, corneal ulcer or conjunctivitis.
- the peptide derivative and lacrimal secretion promoting composition of the present invention have an excellent lacrimal secretion promoting action over a long period of time, and are excellent treatment for dry eye caused by side effects of drugs, diseases or reduced lacrimal secretion function, etc. Become a medicine. This also makes it possible to treat or prevent eye dryness, corneal hyperemia, foreign body sensation, pruritus sensation, etc. associated with dry eye, visual impairment, eye strain, discomfort and burning sensation.
- the tear secretion promoting composition of the present invention can also be applied to eye drops for contact lenses, contact lens cleaning solutions, contact lens storage solutions, and contact lens compositions.
- the present invention provides a peptide derivative capable of achieving an excellent tear secretion promoting action over a long period of time.
- the peptide derivative of the present invention is 2-furoyl-L-arginine (Arg) -L-leucine (Leu), which has the formula (I):
- the peptide derivative of the present invention can be synthesized according to a known method described in Carpino, LA et al., J. Org. Chem., 37, 3404-3409, 1972 as follows. Briefly, for L-Arg-L-Leu- NH 2, D-Arg-L-Leu-NH 2, L-Arg-D-Leu-NH 2 and D-Arg-D-Leu- NH 2 is After adding dimethylformamide to commercially available Fmoc-PAL-PEG-PS-resin and allowing the resin to expand, the peptide synthesis column is prepared by filling the peptide synthesis column, and Fmoc-L-Leu- OH, Fmoc-D-Leu-OH, Fmoc-L-Arg (Pbf) -OH and / or Fmoc-D-Arg (Pbf) -OH were weighed and added to HATU (O- (7-azabenzotriazole- 1-yl) -1,1,3,3-t
- the above amino acids are arranged in order from the C-terminus and synthesized using a peptide synthesizer.
- Synthesized peptide - resin TFA-H 2 O-phenol - after treatment with a mixed solution of triisopropylsilane, the resin was filtered, to obtain a recrystallized crude peptide filtrate with cold diethyl ether.
- the crude peptide is purified by HPLC, and the resulting fraction is lyophilized to give the title peptide.
- the above amino acids are arranged in order from the C-terminus and synthesized using a peptide synthesizer.
- the synthesized peptide-resin is removed from the peptide synthesizer and filtered while washing with dichloromethane.
- 2-furoic acid, N, N-diisopropylethylamine, HATU (O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium dissolved in dimethylformamide in this peptide-resin Hexafluorophosphate) is added. After shaking, the resin is filtered and washed with an appropriate amount of dimethylformamide.
- the peptide derivatives of the present invention also include pharmaceutically acceptable salts.
- pharmaceutically acceptable salts include salts with bases such as inorganic bases and organic bases, and acid addition salts such as inorganic acids, organic acids, basic or acidic amino acids, and the like.
- examples of the inorganic base include alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, aluminum and ammonium.
- examples of the organic base include primary amines such as ethanolamine, secondary amines such as diethylamine, diethanolamine, dicyclohexylamine, N, N′-dibenzylethylenediamine, trimethylamine, triethylamine, pyridine, picoline, triethanolamine and the like.
- inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
- organic acids include formic acid, acetic acid, lactic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, benzoic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, ethanesulfonic acid, and benzenesulfone. An acid, p-toluenesulfonic acid, etc. are mentioned.
- basic amino acids include arginine, lysine, ornithine and the like.
- acidic amino acids include aspartic acid and glutamic acid.
- the present invention provides a composition for promoting lacrimal secretion comprising the above-described peptide derivative and formulated so as to be pharmacologically and pharmaceutically acceptable.
- composition for promoting lacrimal secretion of the present invention is useful as a therapeutic or prophylactic agent for eye diseases that can be treated or prevented, such as dry eye, corneal epithelial detachment, keratitis, corneal ulcer, or conjunctivitis.
- eye diseases such as dry eye, corneal epithelial detachment, keratitis, corneal ulcer, or conjunctivitis.
- the composition for promoting lacrimal secretion of the present invention can be used as it is or after being subjected to various treatments such as dilution with water. It can be used by blending it into a composition for transfusion, transmucosal absorption preparation, transdermal absorption preparation and the like.
- the amount of the peptide derivative is appropriately selected depending on the product, but in the case of a systemic preparation, it can be 0.001 to 50% by weight, particularly 0.01 to 10% by weight, If the content is less than 0.001%, there is a possibility that a satisfactory tear secretion promoting action may not be observed, and if it exceeds 50%, properties such as stability and flavor of the product itself may be impaired.
- the amount of lacrimal secretion which is an index for determining the effect of promoting lacrimal secretion, is, for example, the method of Iga et al. (Iga, Y. et al., Jpn. J. Pharmacol., 78, 373-80) using rats. , (1998)). Specifically, the rat was anesthetized with pentobarbital (50 mg / kg intraperitoneal administration), and a human tear secretion test paper and Sirnal test paper (Showa Yakuhin Kogyo Co., Ltd.) cut into 2 mm widths were applied to the rat lower eyelid insert.
- pentobarbital 50 mg / kg intraperitoneal administration
- Sirnal test paper Showa Yakuhin Kogyo Co., Ltd.
- test paper After a certain period of time, the test paper is removed and the wet length of the test paper is measured using a caliper. If a statistically significant increase in tear secretion is observed when a test substance is administered, it can be said that the substance has a lacrimal secretion promoting action.
- the peptide derivative contained in the composition for promoting lacrimal secretion of the present invention is decomposed by a peptidase existing in the living body or administered from the outside, by combining or blending with a drug such as a peptidase inhibitor such as amastatin, The durability of the action can be further increased.
- oral administration topical ocular administration, intravenous administration, transmucosal administration, transdermal administration, intramuscular administration, subcutaneous administration, intrarectal administration and the like can be appropriately selected.
- it can be used as various preparations.
- each formulation will be described, but the dosage form used in the present invention is not limited to these, and can be used as various formulations usually used in the field of pharmaceutical formulations.
- the oral dosage of the peptide derivative is preferably in the range of 3 mg / kg to 300 mg / kg, more preferably 10 mg / kg to 100 mg / kg.
- the effective blood concentration is in the range of 2 ⁇ g / mL to 200 ⁇ g / mL, more preferably 5 ⁇ g / mL to 100 ⁇ g / mL. Should be administered.
- the dosage forms for oral administration include powders, granules, capsules, pills, tablets, elixirs, suspensions, emulsions and syrups, which can be appropriately selected.
- these formulations can be modified according to the purpose, such as sustained release, stabilization, easy disintegration, hardly disintegrating, enteric, and easy absorption.
- dosage forms for oral administration include chewing agents, sublingual agents, buccal agents, troche agents, ointments, patch agents, liquid agents, and the like, which can be appropriately selected.
- modifications such as sustained release, stabilization, easy disintegration, poor disintegration, enteric solubility, easy absorption, etc. can be applied to these preparations.
- DDS drug delivery system
- the DDS preparations referred to in this specification include sustained release preparations, topical preparations (troches, buccal tablets, sublingual tablets, etc.), drug release control preparations, enteric preparations and gastric preparations, etc., administration routes, bioavailability
- the components of DDS basically include drugs, drug release modules, coatings and treatment programs.
- a drug with a short half-life, in which the blood concentration decreases rapidly when release is stopped is preferred.
- a coating that does not react with living tissue at the administration site is preferable, and it is preferable to have a treatment program that maintains the best drug concentration for a set period of time.
- the drug release module basically has a drug reservoir, a release control, an energy source and a release hole or release surface. It is not necessary to have all these basic components, and the best mode can be selected by adding or deleting as appropriate.
- Materials that can be used for DDS include polymers, cyclodextrin derivatives, lecithin and the like.
- Insoluble polymers silicone, ethylene / vinyl acetate copolymer, ethylene / vinyl alcohol copolymer, ethyl cellulose, cellulose acetate, etc.
- water-soluble polymers and hydroxyl gel-forming polymers polyacrylamide, polyhydroxyethyl) Methacrylate cross-linked product, polyacrylic cross-linked product, polyvinyl alcohol, polyethylene oxide, water-soluble cellulose derivative, cross-linked poloxamer, chitin, chitosan, etc.), slow-dissolving polymer (ethyl cellulose, methyl vinyl ether / maleic anhydride copolymer partial ester, etc.)
- Gastric polymer hydroxypropylmethylcellulose, hydroxypropylcellulose, carmellose sodium, macrogol, polyvinylpyrrolidone, dimethylaminoethyl methacrylate,
- silicone, ethylene / vinyl acetate copolymer, ethylene-vinyl alcohol copolymer, methyl vinyl ether / maleic anhydride copolymer partial ester can be used for drug release control
- cellulose acetate is an osmotic pump material.
- Ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, and methylcellulose can be used as membrane materials for sustained-release preparations, and polyacrylic crosslinked products can be used as oral mucosa or ocular mucosa adhesives.
- dosage form known dosage forms such as oral preparations, injections, suppositories, transdermal absorption preparations, etc.
- solvents excipients, coating agents, bases, binders, Lubricants, disintegrants, solubilizers, suspending agents, thickeners, emulsifiers, stabilizers, buffering agents, tonicity agents, soothing agents, preservatives, flavoring agents, fragrances, coloring agents, etc. It can be manufactured by adding an additive.
- each of these additives is exemplified with specific examples, but is not particularly limited thereto.
- the solvent include purified water, water for injection, physiological saline, peanut oil, ethanol, glycerin and the like.
- the excipient include starches, lactose, glucose, sucrose, crystalline cellulose, calcium sulfate, calcium carbonate, talc, titanium oxide, trehalose, xylitol and the like.
- the coating agent include sucrose, gelatin, cellulose acetate phthalate, and the above-described polymers.
- the base include petrolatum, vegetable oil, macrogol, oil-in-water emulsion base, water-in-oil emulsion base and the like.
- binder examples include starch and derivatives thereof, cellulose and derivatives thereof, natural polymer compounds such as gelatin, sodium alginate, tragacanth and gum arabic, synthetic polymer compounds such as polyvinylpyrrolidone, dextrin, hydroxypropyl starch and the like. It is done.
- lubricant examples include stearic acid and its salts, talc, waxes, wheat starch, macrogol, hydrogenated vegetable oil, sucrose fatty acid ester, polyethylene glycol and the like.
- disintegrants include starch and derivatives thereof, agar, gelatin powder, sodium bicarbonate, cellulose and derivatives thereof, carmellose calcium, hydroxypropyl starch, carboxymethylcellulose and salts thereof, and cross-linked products thereof, and low-substituted hydroxypropylcellulose.
- solubilizer examples include cyclodextrin, ethanol, propylene glycol, polyethylene glycol and the like.
- suspending agent examples include gum arabic, tragacanth, sodium alginate, aluminum monostearate, citric acid, and various surfactants.
- thickener examples include carmellose sodium, polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, tragacanth, gum arabic, and sodium alginate.
- Examples of the emulsifier include gum arabic, cholesterol, tragacanth, methylcellulose, various surfactants, lecithin and the like.
- Examples of the stabilizer include sodium bisulfite, ascorbic acid, tocopherol, a chelating agent, an inert gas, and a reducing substance.
- Examples of the buffer include sodium hydrogen phosphate, sodium acetate, boric acid and the like.
- Examples of the isotonic agent include sodium chloride and glucose.
- Examples of soothing agents include procaine hydrochloride, lidocaine, benzyl alcohol and the like.
- Examples of the preservative include benzoic acid and its salts, paraoxybenzoic acid esters, chlorobutanol, reverse soap, benzyl alcohol, phenol, thimerosal, and the like.
- Examples of the corrigent include sucrose, saccharin, licorice extract, sorbitol, xylitol, glycerin and the like.
- Examples of the fragrance include spruce tincture and rose oil.
- Examples of the colorant include water-soluble food dyes and lake dyes.
- DDS preparations such as sustained release preparations, enteric preparations or drug release control preparations
- effects such as sustained effective drug concentration in the blood and improved bioavailability can be expected.
- the active peptide and / or the lacrimal secretion promoting peptide may be inactivated or degraded in vivo, and as a result, the desired effect may be reduced or eliminated.
- many peptides are known to be degraded by aminopeptidases in vivo (Godin, D. et al., Eur. J. Pharmacol., 253, 225-30, 1994).
- a substance that inhibits an active peptide and / or a substance that inactivates or degrades a tear secretion promoting peptide for example, a substance that inhibits aminopeptidase
- the effects of the ingredients can be further sustained.
- aminopeptidase inhibitor As the aminopeptidase inhibitor, astatatin, afamenin A, afamenin B, bestatin and the like are known. These compounds may be incorporated into the formulation or may be administered separately. When the above component is not a peptide, those skilled in the art can appropriately identify a substance that inactivates or decomposes this component, select a substance that inhibits the substance, and combine or use it together.
- components that are used in normal compositions can be used as additives other than those described above, and the amount of these components to be added should be a normal amount within a range that does not interfere with the effects of the present invention. it can.
- the tear secretion promoting composition of the present invention can also be applied to the skin.
- the preparation for skin application is not particularly limited, and is a lotion, cream, gel, ointment, pasta, plaster, patch, patch, patch, tape, transdermal absorption treatment system ( Transdermal® Therapeutic® System (TTS) formulation and the like.
- TTS Transdermal® Therapeutic® System
- the application site is not particularly limited to the chest, lower abdomen, back, lower leg, cheek, heel, lower arm, arm, neck and the like.
- the transdermally absorbable preparation described in the present specification refers to all of them in a broad sense, and in the narrow sense, a preparation having a support such as a plaster, a patch, a patch, a patch, a tape, and a TTS preparation. Point to.
- the pressure-sensitive adhesive polymer used for the percutaneous absorption preparation having a support includes acrylic acid, rubber, and silicone, but is not particularly limited as long as it is biologically acceptable.
- acrylic acid type a (co) polymer mainly composed of (meth) acrylic acid alkyl ester can be suitably used, but it can be copolymerized with (meth) acrylic acid alkyl ester and the (meth) acrylic acid alkyl ester. It may be a copolymer of monomers.
- the proportion of the (meth) acrylic acid alkyl ester is preferably 20% by weight or more.
- Examples of (meth) acrylic acid alkyl esters include methyl acrylate, butyl acrylate, isobutyl acrylate, hexyl acrylate, octyl acrylate, 2-ethylhexyl acrylate, isooctyl acrylate, decyl acrylate, isodecyl acrylate, acrylic Lauryl acid, stearyl acrylate, methyl methacrylate, butyl methacrylate, isobutyl methacrylate, 2-ethylhexyl methacrylate, isooctyl methacrylate, decyl methacrylate, isodecyl methacrylate, lauryl methacrylate, stearyl methacrylate, etc. These may be used alone or in combination of two or more.
- a functional monomer is preferable.
- a monomer containing an alkoxy group having an ether bond in a side chain a monomer having a hydroxyl group, a monomer having a carboxyl group, a monomer having an amide group, an amino group
- Monomer having a sulfoxy group, a monomer having an alkoxy group, a monomer having a nitrogen-containing heterocyclic ring, and the like Specific examples thereof are shown below.
- Examples of the monomer containing an alkoxy group having an ether bond in the side chain include (meth) acrylic acid methoxyethyl ester, (meth) acrylic acid ethoxydiethyl ester, (meth) acrylic acid methoxydiethylene glycol ester, and (meth) acrylic acid methoxy.
- a propylene glycol ester etc. are mentioned.
- Examples of the monomer having a hydroxyl group include hydroxyalkyl (meth) acrylates such as (meth) acrylic acid hydroxyethyl ester and (meth) acrylic acid hydroxypropyl ester.
- Examples of the monomer having a carboxyl group include ⁇ - or ⁇ -unsaturated carboxylic acids such as (meth) acrylic acid, maleic acid monoalkyl esters such as butyl maleate, (anhydrous) maleic acid, itaconic acid, fumaric acid, Examples include crotonic acid.
- Examples of monomers having an amide group include alkyl (meth) acrylamides such as (meth) acrylamide, dimethyl (meth) acrylamide, N-butylacrylamide, and diethylacrylamide, and N-alkoxy (methyl) acrylamides such as butoxymethylacrylamide and ethoxymethylacrylamide. Etc.
- Examples of the monomer having an amino group include dimethylamino acrylate.
- Examples of the monomer having a sulfoxyl group include styrene sulfonic acid, acrylic sulfonic acid, sulfopropyl (meth) acrylate, (meth) acryloyloxynaphthalene sulfonic acid, acrylamidomethylpropane sulfonic acid, and the like.
- Examples of the monomer having an alkoxy group include (meth) acrylic acid methoxyethyl ester, (meth) acrylic acid tetrahydrofurfuryl ester, (meth) acrylic acid methoxyethylene glycol, (meth) acrylic acid methoxypolyethylene glycol ester, and the like. It is done.
- Examples of the monomer having a nitrogen-containing heterocyclic ring include vinyl pyrrolidone, methyl vinyl pyrrolidone, vinyl piperazine, and vinyl imidazole.
- vinyl chloride vinyl acetate, vinyl propionate, styrene, ⁇ -methylstyrene, acrylonitrile, ethylene, propylene, butadiene, and the like can also be used.
- the (co) polymer mainly composed of the above (meth) acrylic acid alkyl ester is usually prepared by blending the above monomers in the presence of a polymerization initiator and performing solution polymerization.
- a polymerization initiator such as an azobis type or peroxide type Under the nitrogen atmosphere, the reaction may be performed at 50 to 90 ° C. for 5 to 100 hours.
- Examples of the organic solvent for polymerization include benzene, ethylbenzene, butylbenzene, toluene, xylene, hexane, heptane, ethyl acetate, hydroxyethyl acetate, methyl benzoate, acetone, methyl cellosolve, ethylene glycol monoethyl ether, methyl alcohol, propyl Alcohol etc. are mentioned.
- Examples of the azobis polymerization initiator include 2,2-azobis-iso-butyronitrile, 1,1′-azobis (cyclohexane-1-carbonitrile), 2,2′-azobis (2,4-dimethylvaleronitrile), and the like.
- Examples of the peroxide polymerization initiator include lauroyl peroxide and benzoyl peroxide.
- the rubber-based adhesive examples include natural rubber, isoprene rubber, polyisobutylene, polyvinyl ether, polyurethane, polyisoprene, polybutadiene, styrene-butadiene copolymer, styrene-isoprene copolymer, styrene-isoprene-styrene block.
- a copolymer or the like is used.
- silicone adhesive silicone rubbers, such as a polyorganosiloxane, are used, for example.
- an adhesive it is commonly used in the production of transdermally absorbable preparations as described in JP-A-9-208605, JP-A-10-94595, JP-A-10-94596, JP-A-10-298068, etc.
- the pressure-sensitive adhesive used in the above can be used.
- the pressure-sensitive adhesive layer as described above can be formed on a sheet-like or tape-like support.
- a material in which the drug for transdermal absorption contained in the pressure-sensitive adhesive layer is lost from the back surface through the support and does not cause a decrease in content, that is, a material impermeable to the drug can be preferably used.
- Nylon polyvinyl chloride, plasticized polyvinyl chloride, polyvinylidene chloride, polyethylene, polyethylene terephthalate, polypropylene, cellulose acetate, ethyl cellulose, plasticized vinyl acetate-vinyl chloride copolymer, ethylene-vinyl acetate copolymer Polymer, ethylene-ethyl acrylate copolymer, polyurethane, polyester-polyethylene / vinyl acetate copolymer laminate, polyethylene / vinyl acetate copolymer-rayon nonwoven fabric laminate, polyester nonwoven fabric-polyester film laminate, vinylon nonwoven fabric- Polyester film laminates (see JP-A-10-310521), films such as aluminum sheets can be used, and these materials may be used as a single layer or as two or more types of laminates. Also good.
- the thickness of the support is preferably 2000 ⁇ m or less, more preferably 2 to 300 ⁇ m.
- the composition for promoting lacrimal secretion of the present invention can also be contained in polymer fine particles dispersed in an adhesive layer.
- the polymer fine particles include cross-linked polyvinyl pyrrolidone, cross-linked cellulose, polystyrene, styrene-divinylbenzene copolymer, and the like, and the material of the polymer fine particles is appropriately selected depending on the type of drug.
- the particle size of the polymer fine particles is preferably 200 ⁇ m or less, more preferably 50 ⁇ m or less.
- the drug contained in the polymer fine particles may be present in a dissolved state or may be present in an undissolved state.
- the solvent used when the polymer fine particles contain a drug is appropriately selected depending on the type of drug and the type of polymer fine particles, and examples thereof include ethyl acetate, toluene, and tetrahydrofuran.
- an ordinary method for producing an adhesive tape can be applied to form an adhesive layer, such as a solvent coating method, a hot melt coating method, an electron beam curable emulsion coating method, and the like. It is done.
- the pressure-sensitive adhesive, drug and other additives as required are dissolved or dispersed in an appropriate solvent, and the resulting solution or dispersion is applied to the surface of the support and dried to obtain a solvent.
- an adhesive layer having a predetermined thickness can be formed on the support.
- the obtained adhesive layer may be stuck to the support surface.
- a percutaneous absorption preparation in which polymer fine particles containing a drug are dispersed in an adhesive layer can be obtained.
- the solvent include benzyl alcohol, butyl benzoate, isopropyl myristate, octanol, propylene glycol, polypropylene glycol, ethylene glycol and the like.
- the above solution or dispersion may not be applied directly to the surface of the support, but may be applied to a release paper coated with a silicone resin or the like, and may be adhered to the support after drying.
- a release paper coated with a silicone resin or the like can be used to protect the adhesive layer surface of a transdermally absorbable preparation such as a tape until use.
- a surface of a polyethylene terephthalate film treated with silicone can be used as the release paper.
- the thickness of the release paper is preferably 1000 ⁇ m or less, and more preferably 10 ⁇ m to 300 ⁇ m.
- the thickness of the pressure-sensitive adhesive layer as described above varies depending on the purpose of use or application site. However, when the thickness is reduced, the drug content per unit area of the transdermally absorbable preparation is insufficient and the adhesive strength is reduced. On the other hand, when the thickness is increased, the drug contained in the pressure-sensitive adhesive layer in the vicinity of the support is not sufficiently diffused, and the drug release rate may be reduced. Specifically, it is preferably prepared between 3 ⁇ m and 1000 ⁇ m, more preferably between 10 ⁇ m and 500 ⁇ m. Furthermore, the pressure-sensitive adhesive layer may be subjected to a crosslinking treatment.
- additives such as a plasticizer, an absorption accelerator, a skin irritation reducing agent, and an antioxidant may be added as necessary.
- the amount of the additive used varies depending on the type, but is preferably 1 to 50% by weight, more preferably 1 to 10% by weight based on the total weight of the pressure-sensitive adhesive layer. If the amount used is less than 1% by weight, the effect of reducing the adhesive strength is reduced.
- the plasticizer can adjust the adhesive force to the skin surface and can reduce irritation when peeling from the skin.
- the plasticizer for example, diisopropyl adipate, phthalate ester, diethyl sebacate, higher fatty acid esters, softeners described in JP-A No. 10-179711 can be used, and two or more of these can be used in combination. You can also.
- a compound that enhances the solubility and dispersibility of the drug in the adhesive layer a compound that changes keratin water retention ability, keratin softening property, keratin permeability, and the like, and a compound that functions as a carrier, etc. may be used. it can.
- examples of compounds that enhance solubility and dispersibility include glycols such as ethylene glycol, diethylene glycol, propylene glycol, triethylene glycol, polyethylene glycol, and polypropylene glycol, and oils such as olive oil, castor oil, squalene, and lanolin, and the like.
- Examples of the compound that functions as a carrier include ethanol, isopropanol, N-methyl-2-pyrrolidone, propylene glycol and the like.
- benzyl nicotinate which is a pore opening agent
- dibutylhydroxytoluene which is an antioxidant, and the like
- an absorption promotion effect can be expected additively or synergistically.
- hydrocarbons various surfactants, fatty alcohols such as myristyl alcohol, pentadecyl alcohol, cetyl alcohol, heptadecyl alcohol, stearyl alcohol, etc., direct decanoic acid, palmitic acid, heptadecanoic acid, stearic acid, oleic acid, etc.
- fatty alcohols such as myristyl alcohol, pentadecyl alcohol, cetyl alcohol, heptadecyl alcohol, stearyl alcohol, etc.
- direct decanoic acid palmitic acid
- heptadecanoic acid stearic acid
- oleic acid etc.
- Examples include aliphatic esters such as chain fatty acids, methyl oleate, ethyl oleate, propyl oleate, methyl stearate, ethyl stearate, propyl stearate, butyl stearate, lauryl stearate, myristyl stearate, and methyl nanodecanoate. It is done.
- aliphatic esters such as chain fatty acids, methyl oleate, ethyl oleate, propyl oleate, methyl stearate, ethyl stearate, propyl stearate, butyl stearate, lauryl stearate, myristyl stearate, and methyl nanodecanoate. It is done.
- Crosslinking methods include physical crosslinking by irradiation with ultraviolet rays, electron beams, X-rays, ⁇ rays, ⁇ rays, polyisocyanate compounds, organic peroxides, organometallic salts, metal alcoholates, metal chelate compounds, isocyanates. Examples thereof include chemical crosslinking treatment using a crosslinking agent such as a compound or an epoxy compound. The amount of the crosslinking agent is 0.001 to 10%, preferably 0.05 to 1% of the pressure-sensitive adhesive layer.
- the amount of the drug contained in the transdermally absorbable preparation is appropriately set according to the drug type and the site of application, but is usually about 1 to 60% by weight, preferably about 2 to 40% by weight in the adhesive layer. It is good to mix
- the drug contained in the transdermally absorbable preparation does not need to be completely dissolved in the pressure-sensitive adhesive layer as long as it does not interfere with the purpose of the present invention.
- the drug may be contained, and the drug may be dispersed in an undissolved state.
- JP-A-9-77658, JP-A-9-12448, JP-A-9-176000, JP-A-9-301853, JP-A-9-169635, JP-A-10-130172 Examples include the techniques described in JP-A-10-179711, JP-A-10-298067, JP-A-10-306023, JP-A-11-92361, JP-A-11-104229, JP-A-11-292794, and the like. Therefore, the composition for promoting lacrimal secretion of the present invention may utilize these known transdermal absorption preparation techniques.
- the composition for promoting lacrimal secretion of the present invention can be used as an ophthalmic composition such as an eye wash, an eye drop, an eye ointment, and an eye gel.
- an ophthalmic composition it can be 0.0001 to 50 w / v%, preferably 0.0001 to 5 w / v%, and particularly preferably 0.001 to 0.01 w / v%. . If it is less than 0.0001 w / v%, a satisfactory tear secretion promoting action may not be observed, and if it exceeds 50 w / v%, properties such as the stability of the product itself may be impaired.
- the osmotic pressure of the aqueous eye drop is preferably 230 to 450 mOsm, preferably 260 to 320 mOsm.
- the pH is about 3.5 to 8.5, preferably about 5.0 to 8.0.
- the amount of tears on the surface of the eye is usually about 7 ⁇ L, and the drug is diluted and discharged by exchanging the tears on the surface, and the half-life is about 7 minutes. Since the amount of drug solution in the conjunctival sac is 10 to 30 ⁇ L and a large amount of drug cannot be stored in a solution state, in the case of aqueous eye drops, it is preferable to perform eye drops once to several times a day.
- dosage forms for topical ocular administration include solutions, ointments, ophthalmic inserts, gels, emulsions, suspensions and solid eye drops, which can be appropriately selected. Further, these formulations can be further modified such as sustained release, stabilization and easy absorption. These are sterilized by, for example, filtration through a sterilization filter, heat sterilization, or the like. In particular, the size of the particles contained in the eye ointment and the like is preferably 75 ⁇ m or less.
- the drug delivery system (DDS) technology can be adopted for the above dosage forms.
- DDS drug delivery system
- Such a DDS preparation can be continuously attached to the inside of the bag, and the drug can be continuously released at a constant rate.
- the release rate is preferably 0.1 ⁇ g / h to 10 mg / h, more preferably 1 ⁇ g / h to 100 ⁇ g / h.
- the release can be sustained as a dosage form such as addition of a thickening agent, oily or aqueous suspension, oily solution or the like.
- a viscous eye drop or eye ointment to which a slowly soluble polymer (povidone and water-soluble polymer) or the like is added can be obtained.
- the durability, absorbability and the like can be remarkably increased by encapsulating the drug in an ointment and liposome.
- the buffer used in the aqueous eye drop is particularly preferably a borate buffer.
- a borate buffer is used as the buffer, a less irritating liquid can be obtained as compared to the case of using another buffer, for example, a phosphate buffer.
- the addition amount of boric acid is 0.01 to 10 w / v%, preferably 0.1 to 4 w / v%, more preferably 0.5 to 2 w / v%.
- solvent examples include distilled water, physiological saline, vegetable oil, liquid paraffin, mineral oil, propylene glycol, p-octyldodecanol, ethanol, ethylene glycol, macrogol, glycerin, olive oil, sesame oil, peanut oil, castor oil, and the like. Is mentioned.
- isotonic agents include sodium chloride, boric acid, sodium citrate, potassium chloride, borax, propylene glycol, glycerin, glucose, sorbitol, mannitol, trehalose and the like.
- buffer examples include boric acid, phosphoric acid, acetic acid, citric acid, carbonic acid, tartaric acid and salts thereof, borax, sodium citrate, sodium glutamate, sodium aspartate and the like.
- stabilizer examples include sodium sulfite and propylene glycol.
- Examples of the chelating agent include edetic acid and its salts, nitrilotriacetic acid and its salts, trihydroxymethylaminomethane, citric acid, sodium hexametaphosphate, and the like.
- Examples of thickening agents include glycerin, carboxyvinyl polymer, chondroitin sulfate, polyvinyl alcohol, polyvinyl pyrrolidone, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose and salts thereof, sodium alginate, macrogol 4000. Arabic gum, gelatin and the like.
- Examples of the base include petrolatum, purified lanolin, xylene 50, plastibase, macrogol, liquid paraffin, polyethylene glycol, carboxymethyl cellulose and the like.
- Examples of the gelling agent include carboxymethylcellulose, methylcellulose, carboxyvinyl polymer, ethylene maleic anhydride polymer, polyoxyethylene-polyoxypropylene block copolymer, gellan gum and the like.
- Examples of the excipient include crystalline cellulose.
- Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, gelatin, polyvinylpyrrolidone and the like.
- Examples of the lubricant include magnesium stearate, hydrogenated castor oil, talc and the like.
- Examples of the stabilizer include edetates, sodium citrate, sodium bisulfite, ethylenediaminetetraacetate and the like.
- Examples of the pH adjuster include hydrochloric acid, sodium hydroxide, phosphoric acid, citric acid, malic acid, tartaric acid, fumaric acid, lactic acid, succinic acid, ascorbic acid, and acetic acid.
- binder examples include hydroxypropylcellulose, hydroxypropylmethylcellulose, gelatin and the like.
- suspending agent include methyl cellulose, sodium carboxymethyl cellulose, carboxy vinyl polymer, hydroxypropyl methyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, polyethylene glycol, sodium chondroitin sulfate, polysorbate 80 and the like.
- bactericides include benzethonium chloride, chlorhexidine gluconate and the like.
- antioxidant include sulfite, ascorbic acid, ⁇ -tocopherol, cysteine and the like.
- colorant include tar pigment, riboflavin, licorice extract, zinc oxide and the like.
- wetting enhancer include terpenoids (menthol, borneol, camphor, geraniol, anethole, limonene, eugenol) and the like.
- composition for promoting lacrimal secretion of the present invention includes, for example, antibiotics, antiviral agents, anti-inflammatory agents, antiallergic agents, vasoconstrictors, local anesthetics, as long as the object of the present invention is not impaired.
- Drugs such as analgesics, intraocular pressure-lowering agents, immunomodulators and vitamins can be added. Examples are shown below.
- antibiotics include aminoglycosides, quinolones, new quinolones, macrolides, cephems, and the like.
- sulfa drugs include sulfamethoxazole, sulfisoxazole, sulfisomidine, sulfadiazine, sulfadimethoxine, sulfamethoxypyridazine, and the like.
- antiviral agent include famciclovir, penciclovir, acyclovir and the like.
- Nonsteroidal anti-inflammatory agents include, for example, indomethacin, diclofenac, pranoprofen, thiaprofenic acid, tolfenamic acid and the like.
- examples of the steroidal anti-inflammatory agent include prednisolone.
- examples of the anti-inflammatory agent include dipotassium glycyrrhizinate, allantoin, ⁇ -aminocaproic acid, berberine chloride, berberine sulfate, sodium azulene sulfonate, zinc sulfate, zinc lactate, lysozyme chloride and the like.
- antiallergic agent examples include ketotifen, oxatomide, cetirizine, cromoglycate sodium and the like.
- antihistamine examples include mequitazine, chlorpheniramine maleate, diphenhydramine hydrochloride and the like.
- vasoconstrictor examples include naphazoline, tetrahydrozoline, oxymetazoline, phenylephrine, ephedrines, epinephrine, and salts thereof.
- local anesthetic examples include lidocaine hydrochloride, procaine hydrochloride, dibucaine hydrochloride and the like.
- anticholinergic agents include belladonna alkaloids, flutropium bromide, tropicamide, and the like.
- anti-inflammatory enzyme examples include lysozyme chloride, serrapeptase, bromelain and the like.
- miotic agent examples include pilocarpine hydrochloride.
- herbal extracts include licorice, licorice, gourd, carrot, yokuinin, touki, psycho, keihi, trash, and chicory.
- fragrance and the refreshing agent include menthols, camphors, borneols, eucalyptus, geraniols, fennel, and peppermint.
- anticholinesterase drug include neostigmine methyl sulfate and the like.
- the composition for promoting lacrimal secretion of the present invention can be formulated as an ophthalmic composition.
- vitamins known vitamins such as vitamin A, vitamin C, vitamin E, vitamin B 1 are used. , B 2 , B 6 , B 12 etc. or their derivatives can be used alone or in combination of two or more.
- Derivatives of vitamin B 2 flavin adenine dinucleotide , derivatives as salts of pyridoxine and pyridoxal vitamin B 6, can be used hydroxocobalamin such as vitamin B 12.
- other vitamins such as nicotinate, pantothenate and biotin can also be used.
- the preferred amount of vitamins in the eye drop is 0.1 to 10 w / v%, preferably 0.25 to 5 w / v% for vitamin A and its derivatives relative to the whole composition for promoting lacrimal secretion of the present invention.
- Vitamin B 1 and derivatives thereof are 0.01 to 0.5 w / v%, preferably 0.03 to 0.3 w / v%, and vitamin B 2 and derivatives thereof are 0.005 to 0.3 w / v.
- Vitamin B 12 and its derivatives are 0.000005 to 0.003 w / v%, preferably 0.0001 to 0.0015 w / v%, and vitamin C and its derivatives are 0.005 to 0.2 w / v%.
- Vitamin E and its derivatives are The range is 0.005 to 0.2 w / v%, preferably 0.01 to 0.1 w / v%.
- concentration is preferably 0.01 to 1 w / v%, and more preferably 0.05 to 0.5 w / v%.
- osmotic pressure regulator amino acids as nutrient sources, osmotic pressure regulator, water-soluble polymer as thickener, etc., neutral salts as osmotic agent, tear fluid component equalizer, etc.
- amino acids include ⁇ -aminocaproic acid, glutamic acid, lysine, histidine, leucine, methionine, phenylalanine and the like.
- amino acids when amino acids are contained in the aqueous eye drop composition of the present invention, they may be added per se or they may be added in the form of a salt. Examples of such salts include sodium glutamate, lysine hydrochloride, histidine hydrochloride and the like.
- the concentration is preferably 0.01 to 1 w / v%, and more preferably 0.05 to 0.5 w / v%.
- water-soluble polymer examples include polyvinyl pyrrolidone, hydroxypropyl methyl cellulose, polyvinyl alcohol, carboxymethyl cellulose and the like.
- concentration of the water-soluble polymer is preferably 0.1 to 5 w / v%, and more preferably 0.3 to 3 w / v%.
- the neutral salt examples include sodium chloride, calcium chloride, magnesium chloride, sodium sulfate, calcium sulfate, magnesium sulfate, sodium nitrate, calcium nitrate, and magnesium nitrate, particularly preferably sodium chloride, calcium chloride, magnesium chloride, Magnesium sulfate.
- concentration of the neutral salt is preferably determined in consideration of the osmotic pressure.
- the ophthalmic composition of the present invention may use a solubilizing agent such as cyclodextrin, polyvinylpyrrolidone, caffeine, propylene glycol, benzyl benzoate, ethanol, trisaminomethane, mannitol, sodium carbonate, citric acid.
- a solubilizing agent such as cyclodextrin, polyvinylpyrrolidone, caffeine, propylene glycol, benzyl benzoate, ethanol, trisaminomethane, mannitol, sodium carbonate, citric acid.
- Nonionic surfactants such as polyoxyethylene sorbitan mono-higher fatty acid esters (polyoxypolyoxyethylene sorbitan monooleate, polyoxyethylene oxystearic acid triglyceride, etc.), polyethylene glycol, polyoxyethylene hydrogenated castor oil, Polyoxyethylene sorbitan monooleate, polyoxyethylene monostearyl, polyoxyethylene lauryl ether, decaglyceryl monolaurate, polyoxyethylene polyoxy B propylene glycol, and the like.
- Nonionic surfactants used in eye drops and the like are known to be relatively weak in irritation to mucous membranes and cornea and are widely used.
- the concentration of the nonionic surfactant is preferably 0.01 to 10 w / v%, more preferably 0.05 to 5 w / v%, and further preferably 0.1 to 2 w / v%. More preferably.
- Other surfactants include anionic surfactants (alkyl sulfates, sodium lauryl sulfate, sodium lauroyl sarcosine sodium), but these have strong solubilizing action but have stimulating action on mucous membranes, etc. It is not preferable to use as.
- the ophthalmic composition preferably contains a preservative and a preservative.
- preservatives include phenolic substances such as phenol, cresol and paraoxybenzoic acid ester, alcohols such as chlorobutanol and propylene glycol, acidic substances such as benzoic acid and dehydroacetic acid or salts thereof, benzalkonium chloride, chloride Examples thereof include quaternary ammonium salts such as benzethonium, polyethylene oxide-containing polymer quaternary ammonium compounds, and thimerosal.
- the preservative is preferably prepared between 0.0001 w / v% and 5 w / v%, for example, quaternary ammonium salts such as benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, methyl paraoxybenzoate, paraoxybenzoate, etc.
- Paraoxybenzoates such as ethyl acetate, propyl paraoxybenzoate, butyl paraoxybenzoate, benzyl alcohol, phenethyl alcohol, chlorobutanol, thiomersal, thimerosal, methylparaben, propylparaben, disodium edetate, sorbic acid and its salts, dehydro Examples thereof include sodium acetate.
- the peptide derivative of the present invention is known to be degraded by peptidase in vivo, for example, the combined use of an aminopeptidase inhibitor can be expected to maintain the effect.
- Amasstatin, afamenin A, afamenin B, bestatin and the like are known as aminopeptidase inhibitors, and these compounds may be included in the preparation or used in combination. Even when the above component is not a peptide, a substance that inhibits inactivation or decomposition of this component can be blended or used together to maintain the effect of the component.
- a minute amount of oil such as castor oil or liquid paraffin can be added to dry eye accompanying lipid secretion abnormality due to meibomian gland dysfunction.
- components that are used in normal compositions can be used as additives other than those described above, and the amount of these components to be added should be a normal amount within a range that does not interfere with the effects of the present invention. it can.
- an insoluble drug or the like is included in the composition for promoting lacrimal secretion of the present invention, a known technique as described in JP-A-11-29463 is used to obtain a stable aqueous suspension. Also good.
- composition for promoting lacrimal secretion of the present invention can also be applied to eye drops for contact lenses, cleaning solutions for contact lenses, storage solutions for contact lenses, and contact lens compositions.
- the composition for promoting lacrimal secretion of the present invention as an ophthalmic solution for contact lenses, a cleaning solution for contact lenses, and a storage solution for contact lenses, it is preferable to add a surfactant.
- a surfactant By blending the surfactant, an effect of preventing adsorption of the phospholipid-like polymer to the contact lens can be expected.
- the types of surfactants are polyoxyethylene polyoxypropylene block copolymer, polyoxyethylene polyoxypropylene substituted ethylenediamine, polysorbate 80, polyoxyethylene hydrogenated castor oil, polyoxyethylene stearate and other nonionic surfactants, alkyl polyamino Examples include amphoteric surfactants such as ethyl glycine, and anionic surfactants such as alkylbenzene sulfonates and alkyl sulfates. Nonionic surfactants are most preferred from the viewpoint of safety to the eyes. Further, the amount of the surfactant that can be blended is preferably 0.001 to 5%, more preferably 0.01 to 1%.
- eye drops for contact lenses cleaning solutions for contact lenses, and preservation solutions for contact lenses
- those having a commonly used composition can be used, and the additives used for these are the above-mentioned preparations for topical ophthalmic administration. It can be used by appropriately selecting from the additives described.
- the eye drop for contact lens, the cleaning solution for contact lens, and the preserving solution for contact lens can be produced by the same production method as the above preparation for topical ophthalmic administration.
- the contact lens can also be set as the chemical
- the contact lens can be manufactured using a known material. For example, a hydrous soft ophthalmic lens material described in JP-A-9-80358, a 2-hydroxyethyl methacrylate polymer described in JP-A-9-124715, an ophthalmic lens material described in JP-A-9-18987, An ophthalmic collagen gel molded product described in Kaihei 11-197234, a hydrogel lens previously coated with a lipid layer described in JP-A-9-101488, and the like can be used.
- a known material such as a methacrylic acid ester polymer, an oligosiloxanylalkyl (meth) acrylate monomer-methacrylic acid ester monomer copolymer may be used.
- a commonly used contact lens such as a hard or hard corneal lens and a gel, hydrogel or soft lens manufactured from these known materials can be used.
- the drug sustained-release contact lens is, for example, a known drug sustained-release composition described in JP-A-8-24325, JP-A-11-24010, JP-A-10-339857 and the like. According to the manufacturing method of a contact lens, it can also be manufactured by making it contain or attach to a contact lens. Specifically, a drug sustained-release agent in the form of a fine powder or gel is prepared from the active peptide of the present invention and / or a tear secretion-promoting peptide and a polymer such as polyvinylpyrrolidone and sodium hyaluronate, and this is used as a contact lens. A drug sustained-release contact lens can be produced by attaching it to a part.
- a drug sustained-release contact lens can be manufactured by forming a contact lens into a shape having a drug reservoir by, for example, manufacturing a contact lens with a member forming a lens front surface part and a member forming a lens rear surface part.
- the contact lens of the present invention can also be manufactured by manufacturing other known drug sustained-release contact lenses.
- HATU O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate
- PIONEER a peptide synthesizer PIONEER
- a column for peptide synthesis was prepared according to the above method, Fmoc-L-Leu-OH 565 mg (Bacchem), Fmoc-D-Arg (Pbf) -OH 1.038 g (Bacchem) were weighed in a test tube, 380 mg of HATU (O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate) (Applied Biosystems) was added thereto. The above amino acids were arranged in order from the C-terminal, and were synthesized using a peptide synthesizer PIONEER (Applied Biosystems).
- HATU O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate
- PIONEER a peptide synthesizer PIONEER
- the synthesized peptide-resin was treated with a mixed solution of TFA-H 2 0-phenol-triisopropylsilane (8.8: 5.0: 0.5: 0.2) for 4 hours, then the resin was filtered, and the filtrate was cooled with diethyl ether (Kishida Chemical Co., Ltd.).
- a column for peptide synthesis was prepared according to the above method, Fmoc-D-Leu-OH 565 mg (Bacchem), Fmoc-D-Arg (Pbf) -OH 1.038 g (Bacchem) were weighed in a test tube, 380 mg of HATU (O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate) (Applied Biosystems) was added thereto. The above amino acids were arranged in order from the C-terminal, and were synthesized using a peptide synthesizer PIONEER (Applied Biosystems).
- the synthesized peptide-resin was treated with a mixed solution of TFA-H 2 0-phenol-triisopropylsilane (8.8: 5.0: 0.5: 0.2) for 4 hours, the resin was filtered, and the filtrate was cooled with diethyl ether (Kishida Chemical Co., Ltd.). ) To obtain a crude peptide. Next, the crude peptide was subjected to HPLC (A: 0.02% TFA-containing H 2 O, B: 0.02% TFA-containing 50% CH 3 CN) and purified. The obtained fraction was freeze-dried to obtain the title peptide.
- HPLC A: 0.02% TFA-containing H 2 O, B: 0.02% TFA-containing 50% CH 3 CN
- HATU O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate
- PIONEER Applied Biosystems
- the rat lacrimation was measured according to the method of Iga et al. (Iga, Y. et al., Jpn. J. Pharmacol., 78, 373-80, 1998). .
- the rat was anesthetized with pentobarbital (50 mg / kg intraperitoneal administration), and a human tear secretion test paper, Sirnal test paper (Showa Yakuhin Kogyo Co., Ltd.) cut into 2 mm widths was inserted into the rat lower eyelid.
- the wet length of the test paper was measured using a caliper, and the length was used as an index of lacrimation. Tear volume was measured 1, 2, 4 and 6 minutes after peptide administration. The results are shown as mean values (mm) ⁇ standard error, and the significance test was performed by Tukey's multiple comparison test.
- Rats were intravenously administered a physiological saline solution (2.5 ⁇ mol / kg) of amastatin, which is an aminopeptidase inhibitor, to the rat, and 1 minute later, the physiology of various peptide derivatives Saline solution (5 ⁇ mol / kg) was administered intravenously. The measurement was started immediately after peptide administration. As a control, the amount of lacrimal secretion when a physiological saline solution (solvent) containing no peptide was intravenously administered was also measured. The measurement results of lacrimal secretion are shown in FIGS.
- D-form amino acids are known to slow down metabolism. It is also known that the activity becomes stronger and the action time is prolonged by making the peptide a cyclic structure or modifying the N-terminus. Therefore, (L) Arg- (L) Leu-NH enhanced 2 tear secretion-enhancing effect or action time extension for the purpose of (D) Arg- (L) Leu -NH 2 (D forms, L Structure), (L) Arg- (D) Leu-NH 2 (L form, D form structure), (D) Arg- (D) Leu-NH 2 (D form, D form structure), cyclo-Arg-Leu In addition, 2-furoyl- (L) Arg- (L) Leu-NH 2 (L-form, L-form structure) in which a furoyl group was introduced at the N-terminus was synthesized and the lacrimal secretion promoting action was examined.
- 2-furoyl- (L) Arg- (L) Leu-NH 2 exhibits a lacrimal secretion promoting action of Ser-Leu-Ile-Gly-Arg-Leu-NH 2 and Ile-Gly-Arg-Leu-NH 2 It was shown to last longer than 2 ( Figure 5).
- 2-furoyl- (L) Arg- (L) Leu-NH 2 has a lower molecular weight than Ser-Leu-Ile-Gly-Arg-Leu-NH 2 and Ile-Gly-Arg-Leu-NH 2 Therefore, it is considered that the absorption into the body, which has been a problem with Ser-Leu-Ile-Gly-Arg-Leu-NH 2 and Ile-Gly-Arg-Leu-NH 2 , is improved.
- 2-furoyl- (L) Arg- (L) Leu-NH 2 has a longer action time than Ser-Leu-Ile-Gly-Arg-Leu-NH 2 and Ile-Gly-Arg-Leu-NH 2 It has been extended and the problem has been improved. From these, 2-furoyl- (L) Arg- (L) Leu-NH 2 is more prominent than Ser-Leu-Ile-Gly-Arg-Leu-NH 2 and Ile-Gly-Arg-Leu-NH 2 It is a therapeutic agent for diseases of abnormal tear secretion such as dry eye or Sjogren's syndrome.
- the peptide derivative and lacrimal secretion promoting composition of the present invention have an excellent lacrimal secretion promoting action over a long period of time, and are excellent treatment for dry eye caused by side effects of drugs, diseases or reduced lacrimal secretion function, etc. Become a medicine. This also makes it possible to treat or prevent eye dryness, corneal hyperemia, foreign body sensation, pruritus sensation, etc. associated with dry eye, visual impairment, eye strain, discomfort and burning sensation.
- the tear secretion promoting composition of the present invention can also be applied to eye drops for contact lenses, contact lens cleaning solutions, contact lens storage solutions, and contact lens compositions.
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Abstract
Description
すなわち、本発明は、従来の涙液成分の補充を目的とした人工涙液型点眼剤等による副作用の問題を解決できる、長時間にわたり涙液分泌促進作用を有する組成物を適用することを目的とする。
特に、本発明は、副交感神経に作用して、長時間にわたり涙液分泌を促進する組成物を提供することを目的とする。
[1]式(I):
[2]前記[1]記載のペプチド誘導体を含み、かつ、薬理学的および薬剤学的に許容されるように製剤化された涙液分泌促進組成物;
[3]さらに、前記ペプチド誘導体の失活化または分解を阻害する物質を配合することを特徴とする前記[2]記載の涙液分泌促進組成物;
[4]前記失活化または分解を阻害する物質がペプチダーゼ阻害薬であることを特徴とする前記[3]記載の涙液分泌促進組成物;
[5]前記ペプチダーゼ阻害薬がアマスタチンであることを特徴とする前記[4記載の涙液分泌促進組成物;
[6]DDS製剤化されていることを特徴とする前記[2]~[5]のいずれか1に記載の涙液分泌促進組成物;
[7]経皮吸収製剤化されていることを特徴とする前記[2]~[6]のいずれか1に記載の涙液分泌促進組成物;
[8]経粘膜吸収製剤化されていることを特徴とする前記[2]~[6]のいずれか1に記載の涙液分泌促進組成物;
[9]眼科用組成物であることを特徴とする前記[2]~[5]のいずれか1に記載の涙液分泌促進組成物;
[10]眼科用組成物が洗眼剤、点眼剤、眼軟膏剤または眼用ゲル剤の形態であることを特徴とする前記[9]記載の涙液分泌促進組成物;
[11]眼科用組成物がコンタクトレンズ用点眼剤、コンタクトレンズ用保存液、またはコンタクトレンズ用洗浄液の形態であることを特徴とする前記[9]記載の涙液分泌促進組成物;
[12]前記[2]~[5]のいずれか1に記載の涙液分泌促進組成物を保持および/または含有することを特徴とするコンタクトレンズ;
[13]前記涙液分泌促進組成物を持続的に放出するように、保持および/または含有することを特徴とする前記[12]記載のコンタクトレンズ;
[14]前記[2]~[5]のいずれか1に記載の涙液分泌促進組成物を含むことを特徴とする眼疾患治療剤または予防剤;
[15]眼疾患が、ドライアイ、角膜上皮剥離、角膜炎、角膜潰瘍または結膜炎であることを特徴とする前記[14]記載の眼疾患治療剤または予防剤
を提供するものである。
また、本発明の涙液分泌促進組成物はコンタクトレンズ用点眼液、コンタクトレンズ用洗浄液およびコンタクトレンズ用保存液さらにはコンタクトレンズ組成物にも応用できるものである。
本発明のペプチド誘導体は、2-フロイル-L-アルギニン(Arg)-L-ロイシン(Leu)であり、式(I):
1H-NMR (D2O):0.605 (d, 3H, J=6.2 Hz), 0.656 (d, 3H, J=6.2 Hz), 1.307-1.742 (m, 7H), 2.973 (t, 2H, J=6.9 Hz), 4.106 (dd, 1H, J=10.2, 4.4 Hz), 4.250 (dd, 1H, J=8.4, 6.0 Hz), 6.378 (dd, 1H, J=3.7, 1.8 Hz), 6.947 (dd, 1H, J=3.7, 0.7 Hz), 7.426 (dd, 1H, J=1.8, 0.7 Hz).
元素分析 C17H28N6O4として
計算値:C,53.67;H,7.42;N,22.09;O,16.82
質量分析
計算値:380.44
実測値:380.22
簡単には、L-Arg-L-Leu-NH2、D-Arg-L-Leu-NH2、L-Arg-D-Leu-NH2およびD-Arg-D-Leu-NH2については、市販のFmoc-PAL-PEG-PS-resinにジメチルホルムアミドを加えて放置して樹脂を膨張させた後、ペプチド合成用のカラムに充填してペプチド合成用カラムを作製し、Fmoc-L-Leu-OH、Fmoc-D-Leu-OH、Fmoc-L-Arg(Pbf)-OHおよび/またはFmoc-D-Arg(Pbf)-OHを秤量し、これにHATU(O-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウムヘキサフルオロホスフェート)を加える。上記のアミノ酸をC末端から順に並べ、ペプチド合成機を用いて合成を行う。合成したペプチド-樹脂はTFA-H2O-フェノール-トリイソプロピルシランの混合溶液で処理した後、樹脂を濾過し、濾液を冷ジエチルエーテルで再結晶して粗ペプチドを得る。この粗ペプチドをHPLCによって精製し、得られたフラクションの凍結乾燥を行って標記ペプチドを得る。
薬剤学的に許容される塩としては、例えば無機塩基、有機塩基等の塩基との塩、無機酸、有機酸、塩基性または酸性アミノ酸などの酸付加塩等が挙げられる。無機塩基としては、例えば、ナトリウム、カリウム等のアルカリ金属、カルシウム、マグネシウム等のアルカリ土類金属、アルミニウム、アンモニウム等が挙げられる。有機塩基としては、例えば、エタノールアミン等の第一級アミン、ジエチルアミン、ジエタノールアミン、ジシクロヘキシルアミン、N,N'-ジベンジルエチレンジアミン等の第二級アミン、トリメチルアミン、トリエチルアミン、ピリジン、ピコリン、トリエタノールアミン等の第三級アミン等が挙げられる。無機酸としては、例えば、塩酸、臭化水素酸、硝酸、硫酸、リン酸等が挙げられる。有機酸としては、例えば、ギ酸、酢酸、乳酸、トリフルオロ酢酸、フマル酸、シュウ酸、酒石酸、マレイン酸、安息香酸、クエン酸、コハク酸、リンゴ酸、メタンスルホン酸、エタンスルホン酸、ベンゼンスルホン酸、p-トルエンスルホン酸等が挙げられる。塩基性アミノ酸としては、例えば、アルギニン、リジン、オルニチン等が挙げられる。酸性アミノ酸としては、例えば、アスパラギン酸、グルタミン酸等が挙げられる。
以下に、各製剤について記載するが、本発明において用いられる剤型はこれらに限定されるものではなく、医薬製剤の分野において通常用いられる各種製剤として用いることができる。
涙液分泌低下の治療薬として用いる場合には、ペプチド誘導体の経口投与量は、3mg/kg~300mg/kgの範囲が好ましく、より好ましくは10mg/kg~100mg/kgである。全身投与を行う場合、特に静脈内投与の場合には老若男女または体型等により変動があるが、有効血中濃度が2μg/mL~200μg/mL、より好ましくは5μg/mL~100μg/mLの範囲となるように投与すべきである。
溶剤としては、例えば、精製水、注射用水、生理食塩水、ラッカセイ油、エタノール、グリセリン等が挙げられる。
賦形剤としては、例えば、デンプン類、乳糖、ブドウ糖、白糖、結晶セルロース、硫酸カルシウム、炭酸カルシウム、タルク、酸化チタン、トレハロース、キシリトール等が挙げられる。
コーティング剤としては、例えば、白糖、ゼラチン、酢酸フタル酸セルロースおよび上記した高分子等が挙げられる。
基剤としては、例えば、ワセリン、植物油、マクロゴール、水中油型乳剤性基剤、油中水型乳剤性基剤等が挙げられる。
結合剤としては、例えば、デンプンおよびその誘導体、セルロースおよびその誘導体、ゼラチン、アルギン酸ナトリウム、トラガント、アラビアゴム等の天然高分子化合物、ポリビニルピロリドン等の合成高分子化合物、デキストリン、ヒドロキシプロピルスターチ等が挙げられる。
崩壊剤としては、例えば、デンプンおよびその誘導体、寒天、ゼラチン末、炭酸水素ナトリウム、セルロースおよびその誘導体、カルメロースカルシウム、ヒドロキシプロピルスターチ、カルボキシメチルセルロースおよびその塩類ならびにその架橋体、低置換型ヒドロキシプロピルセルロース等が挙げられる。
溶解補助剤としては、例えば、シクロデキストリン、エタノール、プロピレングリコール、ポリエチレングリコール等が挙げられる。
懸濁化剤としては、例えば、アラビアゴム、トラガント、アルギン酸ナトリウム、モノステアリン酸アルミニウム、クエン酸、各種界面活性剤等が挙げられる。
粘稠剤としては、例えば、カルメロースナトリウム、ポリビニルピロリドン、メチルセルロース、ホドロキシプロピルメチルセルロース、ポリビニルアルコール、トラガント、アラビアゴム、アルギン酸ナトリウム等が挙げられる。
安定剤としては、例えば、亜硫酸水素ナトリウム、アスコルビン酸、トコフェロール、キレート剤、不活性ガス、還元性物質等が挙げられる。
緩衝剤としては、例えば、リン酸水素ナトリウム、酢酸ナトリウム、ホウ酸等が挙げられる。
等張化剤としては、例えば、塩化ナトリウム、ブドウ糖等が挙げられる。
無痛化剤としては、例えば、塩酸プロカイン、リドカイン、ベンジルアルコール等が挙げられる。
保存剤としては、例えば、安息香酸およびその塩類、パラオキシ安息香酸エステル類、クロロブタノール、逆性石けん、ベンジルアルコール、フェノール、チロメサール等が挙げられる。
矯味剤としては、例えば、白糖、サッカリン、カンゾウエキス、ソルビトール、キシリトール、グリセリン等が挙げられる。
芳香剤としては、例えば、トウヒチンキ、ローズ油等が挙げられる。
着色剤としては、例えば、水溶性食用色素、レーキ色素等が挙げられる。
アクリル酸系としては、(メタ)アクリル酸アルキルエステルを主体とする(共)重合体が好適に使用できるが、(メタ)アクリル酸アルキルエステルおよび該(メタ)アクリル酸アルキルエステルと共重合可能なモノマーの共重合体であってもよい。上記(メタ)アクリル酸アルキルエステルを主体とする(共)重合体の構成成分中、(メタ)アクリル酸アルキルエステルの割合は20重量%以上が好ましい。
水酸基を有するモノマーとしては、例えば、(メタ)アクリル酸ヒドロキシエチルエステル、(メタ)アクリル酸ヒドロキシプロピルエステル等のヒドロキシアルキル(メタ)アクリレートが挙げられる。
アミド基を有するモノマーとしては、(メタ)アクリルアミド、ジメチル(メタ)アクリルアミド、N-ブチルアクリルアミド、ジエチルアクリルアミド等のアルキル(メタ)アクリルアミド、ブトキシメチルアクリルアミド、エトキシメチルアクリルアミド等のN-アルコキシ(メチル)アクリルアミド等が挙げられる。
スルホキシル基を有するモノマーとしては、例えば、スチレンスルホン酸、アクリルスルホン酸、スルホプロピル(メタ)アクリレート、(メタ)アクリロイルオキシナフタレンスルホン酸、アクリルアミドメチルプロパンスルホン酸等が挙げられる。
窒素含有複素環を有するモノマーとしては、例えば、ビニルピロリドン、メチルビニルピロリドン、ビニルピペラジン、ビニルイミダゾール等が挙げられる。
その他、上記にあげたモノマー以外に、塩化ビニル、酢酸ビニル、プロピオン酸ビニル、スチレン、α-メチルスチレン、アクリロニトリル、エチレン、プロピレン、ブタジエン等も使用可能である。
重合用有機溶媒としては、例えば、ベンゼン、エチルベンゼン、ブチルベンゼン、トルエン、キシレン、ヘキサン、ヘプタン、酢酸エチル、酢酸ヒドロキシエチル、安息香酸メチル、アセトン、メチルセロソルブ、エチレングリコールモノエチルエーテル、メチルアルコール、プロピルアルコール等が挙げられる。アゾビス系重合開始剤としては、2,2-アゾビス-イソ-ブチロニトリル、1,1’-アゾビス(シクロヘキサン-1-カルボニトリル)、2,2’-アゾビス(2,4-ジメチルバレリニトリル)等が挙げられ、過酸化物系重合開始剤としては、過酸化ラウロイル、過酸化ベンゾイル等が挙げられる。
上記のシリコーン系粘着剤としては、例えば、ポリオルガノシロキサン等のシリコーンゴムが用いられる。
その他、粘着剤として、特開平9-208605号、特開平10-94595号、特開平10-94596号、特開平10-298068号等に記載されるような、経皮吸収製剤の製造において一般的に用いられる粘着剤を使用できる。
支持体としては、ナイロン、ポリ塩化ビニル、可塑化ポリ塩化ビニル、ポリ塩化ビニリデン、ポリエチレン、ポリエチレンテレフタレート、ポリプロピレン、酢酸セルロース、エチルセルロース、可塑化酢酸ビニル-塩化ビニル共重合体、エチレン-酢酸ビニル共重合体、エチレン-アクリル酸エチル共重合体、ポリウレタン、ポリエステル-ポリエチレン・酢酸ビニル共重合体積層体、ポリエチレン・酢酸ビニル共重合体-レーヨン不織布積層体、ポリエステル不織布-ポリエステルフィルム積層体、ビニロン製不織布-ポリエステル製フィルム積層体(特開平10-310521号参照)、アルミニウムシート等のフィルムを使用することができ、これらの素材は単層で用いてもよく、または、2種以上の積層体として用いてもよい。支持体の厚みとしては2000μm以下が好ましく、2~300μmがより好ましい。
溶解性や分散性を高める化合物としては、エチレングリコール、ジエチレングリコール、プロピレングリコール、トリエチレングリコール、ポリエチレングリコール、ポリプロピレングリコール等のグリコール類、オリーブ油、ヒマシ油、スクアレン、ラノリン等の油脂類等が挙げられ、角質の保水能、角質軟化性、角質浸透性等を変化させる化合物としては、1-ドデシルアゾシクロヘプタン-2-オン(1-dodecylazocycloheptane-2-one)、オレイン酸、ミリスチン酸イソプロピル、中鎖脂肪酸モノグリセリド、モノテルペン類、l-メントール、d-リモネン尿素、アラントイン、サリチル酸、メチルオクチルスルホキシド、ジメチルラウリルアミド、ドデシルピロリドン、イソソルビトール、ジメチルアセトアミド、ジメチルスルホキシド、ジメチルホルムアミド等が挙げられる。キャリアーとして働く化合物としては、例えば、エタノール、イソプロパノール、N-メチル-2-ピロリドン、プロピレングリコール等が挙げられる。また、毛孔開孔剤であるニコチン酸ベンジル、酸化防止剤であるジブチルヒドロキシトルエン等も使用できる。上記吸収促進剤を2種以上併用することにより、相加的あるいは相乗的に吸収促進効果が期待できる。
本発明の涙液分泌促進組成物は、洗眼剤、点眼剤、眼軟膏剤、眼用ゲル剤などの眼科用組成物として用いることができる。
眼科用組成物の場合には、0.00001~50w/v%、好ましくは0.0001~5w/v%とすることができ、特に0.001~0.01w/v%とするのが好ましい。0.00001w/v%より少ないと満足する涙液分泌促進作用が認められない可能性があり、50w/v%を越えると製品そのものの安定性等の特性が損なわれる可能性がある。また、水性点眼剤の浸透圧は230~450mOsm、好ましくは260~320mOsmとなるよう調製するのが好ましい。pHは3.5~8.5、好ましくは5.0~8.0程度とするのがよい。
溶剤としては、例えば、蒸留水、生理食塩液、植物油、流動パラフィン、鉱物油、プロピレングリコール、p-オクチルドデカノール、エタノール、エチレングリコール、マクロゴール、グリセリン、オリーブ油、ゴマ油、ラッカセイ油、ヒマシ油等が挙げられる。
等張剤としては、例えば、塩化ナトリウム、ホウ酸、クエン酸ナトリウム、塩化カリウム、ホウ砂、プロピレングリコール、グリセリン、グルコース、ソルビトール、マンニトール、トレハロース等が挙げられる。
緩衝剤としては、例えば、ホウ酸、リン酸、酢酸、クエン酸、炭酸、酒石酸およびそれらの塩、ホウ砂、クエン酸ナトリウム、グルタミン酸ナトリウム、アスパラギン酸ナトリウム等が挙げられる。
安定化剤としては、例えば、亜硫酸ナトリウム、プロピレングリコール等が挙げられる。
粘稠化剤としては、例えば、グリセリン、カルボキシビニルポリマー、コンドロイチン硫酸、ポリビニルアルコール、ポリビニルピロリドン、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、メチルセルロース、ヒドロキシプロピルメチルセルロース、カルボキシメチルセルロースおよびそれらの塩類、アルギン酸ナトリウム、マクロゴール4000、アラビアゴム、ゼラチン等が挙げられる。
基剤としては、例えば、ワセリン、精製ラノリン、ゼレン50、プラスチベース、マクロゴール、流動パラフィン、ポリエチレングリコール、カルボキシメチルセルロース等が挙げられる。
ゲル化剤としては、例えば、カルボキシメチルセルロース、メチルセルロース、カルボキシビニルポリマー、エチレン無水マレイン酸ポリマー、ポリオキシエチレン-ポリオキシプロピレンブロックコポリマー、ゲランゴム等が挙げられる。
結合剤としては、例えば、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ゼラチン、ポリビニルピロリドン等が挙げられる。
滑沢剤としては、例えば、ステアリン酸マグネシウム、硬化ヒマシ油、タルク等が挙げられる。
安定化剤としては、例えば、エデト酸塩類、クエン酸ナトリウム、亜硫酸水素ナトリウム、エチレンジアミン四酢酸塩等が挙げられる。
pH調整剤としては、例えば、塩酸、水酸化ナトリウム、リン酸、クエン酸、リンゴ酸、酒石酸、フマル酸、乳酸、コハク酸、アスコルビン酸、酢酸等が挙げられる。
結合剤としては、例えば、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ゼラチン等が挙げられる。
懸濁化剤としては、例えば、メチルセルロース、カルボキシメチルセルロースナトリウム、カルボキシビニルポリマー、ヒドロキシプロピルメチルセルロース、ポリビニルアルコール、ポリビニルピロリドン、ポリエチレングリコール、コンドロイチン硫酸ナトリウム、ポリソルベート80等が挙げられる。
抗酸化剤としては、例えば、亜硫酸塩、アスコルビン酸、α-トコフェロール、システイン等が挙げられる。
着色剤としては、例えば、タール色素、リボフラビン、カンゾウエキス、酸化亜鉛等が挙げられる。
濡れ増強剤としては、例えば、テルペノイド類(メントール、ボルネオール、カンフル、ゲラニオール、アネトール、リモネン、オイゲノール)等が挙げられる。
サルファ剤として、例えば、スルファメトキサゾール、スルフィソキサゾール、スルフィソミジン、スルファジアジン、スルファジメトキシン、スルファメトキシピリダジン等が挙げられる。
抗ウイルス剤として、例えば、ファムシクロビル、ペンシクロビル、アシクロビル等が挙げられる。
非ステロイド系抗炎症剤として、例えば、インドメタシン、ジクロフェナク、プラノプロフェン、チアプロフェン酸、トルフェナム酸等が挙げられる。
ステロイド性抗炎症剤として、例えば、プレドニゾロン等が挙げられる。
抗炎症剤として、例えば、グリチルリチン酸ジカリウム、アラントイン、ε-アミノカプロン酸、塩化ベルベリン、硫酸ベルベリン、アズレンスルホン酸ナトリウム、硫酸亜鉛、乳酸亜鉛、塩化リゾチーム等が挙げられる。
抗アレルギー剤として、例えば、ケトチフェン、オキサトミド、セチリジン、クロモグリク酸ナトリウム等が挙げられる。
抗ヒスタミン薬として、例えば、メキタジン、マレイン酸クロルフェニラミン、塩酸ジフェンヒドラミン等が挙げられる。
局所麻酔薬として、例えば、塩酸リドカイン、塩酸プロカイン、塩酸ジブカイン等が挙げられる。
抗コリン薬として、例えば、ベラドンナアルカロイド、臭化フルトロピウム、トロピカミド等が挙げられる。
消炎酵素薬として、例えば、塩化リゾチーム、セラペプターゼ、ブロメライン等が挙げられる。
縮瞳剤として、例えば、塩酸ピロカルピン等が挙げられる。
生薬抽出物として、例えば、イカリソウ、カンゾウ、ゴオウ、ニンジン、ヨクイニン、トウキ、サイコ、ケイヒ、ゴミシ、シコン等が挙げられる。
香料および清涼化剤として、例えば、メントール類、カンフル類、ボルネオール類、ユーカリ類、ゲラニオール類、ウイキョウ類、ハッカ類等が挙げられる。
抗コリンエステラーゼ薬として、例えば、メチル硫酸ネオスチグミン等が挙げられる。
アミノ酸としては、例えば、ε-アミノカプロン酸、グルタミン酸、リジン、ヒスチジン、ロイシン、メチオニン、フェニルアラニン等が挙げられる。また、アミノ酸を本発明の水性点眼組成物に含有させるに当たっては、それら自体を添加してもよく、それらを塩の形で添加してもよい。そのような塩としては、例えばグルタミン酸ナトリウム、塩酸リジン、塩酸ヒスチジン等が挙げられる。アミノ酸を用いる場合、その濃度は0.01~1w/v%とするのが好ましく、さらには0.05~0.5w/v%とするのが好ましい。
防腐剤は0.0001w/v%~5w/v%の間で調製するのが好ましく、例えば、塩化ベンザルコニウム、塩化ベンゼトニウム、塩化セチルピリジニウム等の四級アンモニウム塩類、パラオキシ安息香酸メチル、パラオキシ安息香酸エチル、パラオキシ安息香酸プロピル、パラオキシ安息香酸ブチル等のパラオキシ安息香酸エステル類、ベンジルアルコール、フェネチルアルコール、クロロブタノール、チオメルサール、チメロサール、メチルパラベン、プロピルパラベン、エデト酸二ナトリウム、ソルビン酸およびその塩類、デヒドロ酢酸ナトリウム等を挙げることができる。
不溶性の薬物等を本発明の涙液分泌促進組成物に含有させる場合には、安定な水性懸濁液剤を得るために、特開平11-29463号に記載されるような公知技術を使用してもよい。
本発明の涙液分泌促進組成物は、コンタクトレンズ用点眼液、コンタクトレンズ用洗浄液およびコンタクトレンズ用保存液さらにはコンタクトレンズ組成物にも応用できる。
コンタクトレンズは公知の材料を用いて製造することができる。例えば、特開平9-80358号記載の含水性軟質眼用レンズ用材料、特開平9-124715号記載の2-ヒドロキシエチルメタクリレート系重合体、特開平9-189887号記載の眼用レンズ材料、特開平11-197234号記載の眼科用コラーゲンゲル成形物、特開平9-101488号記載の脂質層で予め被覆されたヒドロゲルレンズ等を用いることができる。その他、メタクリル酸エステル系ポリマー、オリゴシロキサニルアルキル(メタ)アクリレート系モノマー-メタクリル酸エステル系モノマー共重合体等の公知材料であってもよい。
コンタクトレンズは、これらの公知材料から製造される、ハードもしくは硬質角膜型レンズ、および、ゲル、ヒドロゲルもしくはソフト型レンズなどの一般に用いられるコンタクトレンズを用いることができる。
具体的には、本発明の活性ペプチドおよび/または涙液分泌促進ペプチドとポリビニルピロリドン、ヒアルロン酸ナトリウムなどのポリマーから、微粉末状またはゲル状の薬剤徐放剤を調製し、これをコンタクトレンズの一部に付着させることにより、薬剤徐放性コンタクトレンズを製造できる。
また、コンタクトレンズを、レンズ前面部を形成する部材とレンズ後面部を形成する部材とで製造するなどして、薬剤貯蔵部を有する形状とすることによって薬剤徐放性コンタクトレンズを製造できる。これら以外の公知の薬剤徐放性コンタクトレンズの製造によっても、本発明のコンタクトレンズを製造できる。
1.L-Arg-L-Leu-NH2の合成方法
Fmoc-PAL-PEG-PS-resin(アプライドバイオシステムズ社)を1.03g(0.390meq/g)秤取し、これにジメチルホルムアミド20mLを加えて2~3時間放置し、樹脂を膨張させた後、ペプチド合成用のカラムに充填した。
上記の方法に準じてペプチド合成用カラムを作製し、Fmoc-L-Leu-OH 565mg(バッケム社)、Fmoc-L-Arg(Pbf)-OH 1.038g(アプライドバイオシステムズ社)を試験管に秤量し、これにHATU(O-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウムヘキサフルオロホスフェート)(アプライドバイオシステムズ社)を各380mg加えた。上記のアミノ酸をC末端から順に並べ、ペプチド合成機PIONEER(アプライドバイオシステムズ社)を用いて合成を行った。合成したペプチド-樹脂をTFA-H2O-フェノール-トリイソプロピルシラン(8.8:5.0:0.5:0.2)の混合溶液で4時間処理した後、樹脂を濾過し、濾液を冷ジエチルエーテル(キシダ化学社)で再結晶し、粗ペプチドを得た。次にこの粗ペプチドをHPLC(A:0.02%TFA含H2O、B:0.02%TFA含50%CH3CN)に供し精製した。得られたフラクションの凍結乾燥を行い、標記ペプチドを得た。
Fmoc-PAL-PEG-PS-resin(アプライドバイオシステムズ社)を1.03g(0.390meq/g)秤取し、これにジメチルホルムアミド20mLを加えて2~3時間放置し、樹脂を膨張させた後、ペプチド合成用のカラムに充填した。
上記の方法に準じてペプチド合成用カラムを作製し、Fmoc-L-Leu-OH 565mg(バッケム社)、Fmoc-D-Arg(Pbf)-OH 1.038g(バッケム社)を試験管に秤量し、これにHATU(O-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウムヘキサフルオロホスフェート)(アプライドバイオシステムズ社)を各380mg加えた。上記のアミノ酸をC末端から順に並べ、ペプチド合成機PIONEER(アプライドバイオシステムズ社)を用いて合成を行った。合成したペプチド-樹脂をTFA-H2O-フェノール-トリイソプロピルシラン(8.8:5.0:0.5:0.2)の混合溶液で4時間処理した後、樹脂を濾過し、濾液を冷ジエチルエーテル(キシダ化学社)で再結晶し、粗ペプチドを得た。次にこの粗ペプチドをHPLC(A:0.02%TFA含H2O、B:0.02%TFA含50%CH3CN)に供し精製した。得られたフラクションの凍結乾燥を行い、標記ペプチドを得た。
Fmoc-PAL-PEG-PS-resin(アプライドバイオシステムズ社)を1.03g(0.390meq/g)秤取し、これにジメチルホルムアミド20mLを加えて2~3時間放置し、樹脂を膨張させた後、ペプチド合成用のカラムに充填した。
上記の方法に準じてペプチド合成用カラムを作製し、Fmoc-D-Leu-OH 565mg(バッケム社)、Fmoc-L-Arg(Pbf)-OH 1.038g(アプライドバイオシステムズ社)を試験管に秤量し、これにHATU(O-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウムヘキサフルオロホスフェート)(アプライドバイオシステムズ社)を各380mg加えた。上記のアミノ酸をC末端から順に並べ、ペプチド合成機PIONEER(アプライドバイオシステムズ社)を用いて合成を行った。合成したペプチド-樹脂をTFA-H20-フェノール-トリイソプロピルシラン(8.8:5.0:0.5:0.2)の混合溶液で4時間処理した後、樹脂を濾過し、濾液を冷ジエチルエーテル(キシダ化学社)で再結晶し、粗ペプチドを得た。次にこの粗ペプチドをHPLC(A:0.02%TFA含H20、B:0.02%TFA含50%CH3CN)に供し精製した。得られたフラクションの凍結乾燥を行い、標記ペプチドを得た。
Fmoc-PAL-PEG-PS-resin(アプライドバイオシステムズ社)を1.03g(0.390meq/g)秤取し、これにジメチルホルムアミド20mLを加えて2~3時間放置し、樹脂を膨張させた後、ペプチド合成用のカラムに充填した。
上記の方法に準じてペプチド合成用カラムを作製し、Fmoc-D-Leu-OH 565mg(バッケム社)、Fmoc-D-Arg(Pbf)-OH 1.038g(バッケム社)を試験管に秤量し、これにHATU(O-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウムヘキサフルオロホスフェート)(アプライドバイオシステムズ社)を各380mg加えた。上記のアミノ酸をC末端から順に並べ、ペプチド合成機PIONEER(アプライドバイオシステムズ社)を用いて合成を行った。合成したペプチド-樹脂をTFA-H20-フェノールートリイソプロピルシラン(8.8:5.0:0.5:0.2)の混合溶液で4時間処理した後、樹脂を濾過し、濾液を冷ジエチルエーテル(キシダ化学社)で再結晶し、粗ペプチドを得た。次にこの粗ペプチドをHPLC(A:0.02%TFA含H2O、B:0.02%TFA含50%CH3CN)に供し精製した。得られたフラクションの凍結乾燥を行い、標記ペプチドを得た。
L-Leu-PS-resin(ノバビオケム社)を1.00g(0.2meq/g)秤取し、これにジメチルホルムアミド20mLを加えて2~3時間放置し、樹脂を濾過した。この樹脂にジメチルホルムアミド10mLに溶かしたFmoc-L-Arg(Pbf)-OH 0.519g(アプライドバイオシステムズ社)、N,N-ジイソプロピルエチルアミン600μL(アルドリッチ社)、HATU(O-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウムヘキサフルオロホスフェート)(アプライドバイオシステムズ社)を380mg加えた。30分間振とうした後、この樹脂を濾過し、適量のジメチルホルムアミドで洗浄した。さらにこの樹脂にピペリジン(WAKO):ジメチルホルムアミド(2:8)20mLを加え、30分間振とうした後、この樹脂を濾過し、適量のジメチルホルムアミドで洗浄した。このようにして合成したペプチド-樹脂をTFA-H2O-フェノール-トリイソプロピルシラン(8.8:5.0:0.5:0.2)の混合溶液で4時間処理した後、樹脂を濾過し、濾液を冷ジエチルエーテル(キシダ化学社)で閉環後、再結晶し、粗ペプチドを得た。次にこの粗ペプチドをHPLC(A:0.02%TFA含H20、B:0.02%TFA含80%CH3CN)に供し精製した。得られたフラクションの凍結乾燥を行い、標記ペプチドを得た。
Fmoc-PAL-PEG-PS-resin(アプライドバイオシステムズ社)を1.03g(0.390meq/g)秤取し、これにジメチルホルムアミド20mLを加えて2~3時間放置し、樹脂を膨張させた後、ペプチド合成用のカラムに充填した。上記の方法に準じてペプチド合成用カラムを作製し、Fmoc-L-Leu-OH 565mg(バッケム社)、Fmoc-L-Arg(Pbf)-OH 1.038g(アプライドバイオシステムズ社)を試験管に秤量し、これにHATU(O-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウムヘキサフルオロホスフェート)(アプライドバイオシステムズ社)を各380mg加えた。上記のアミノ酸をC末端から順に並べ、ペプチド合成機PIONEER(アプライドバイオシステムズ社)を用いて合成を行った。合成したペプチド-樹脂をペプチド合成機から取り出し、ジクロロメタンで洗浄しながら濾過した。このペプチド-樹脂にジメチルホルムアミド10mLに溶かした2-furoic acid 224mg(アルドリッチ社)、N,N-ジイソプロピルエチルアミン600μL(アルドリッチ社)、HATU(O-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウムヘキサフルオロホスフェート)(アプライドバイオシステムズ社)を380mg加えた。30分間振とうした後、この樹脂を濾過し、適量のジメチルホルムアミドで洗浄した。さらにこの樹脂にピペリジン(WAKO):ジメチルホルムアミド(2:8)20mLを加え、30分間振とうした後、この樹脂を濾過し、適量のジメチルホルムアミドで洗浄した。このようにして合成したペプチド-樹脂をTFA-H2O-フェノール-トリイソプロピルシラン(8.8:5.0:0.5:0.2)の混合溶液で4時間処理した後、樹脂を濾過し、濾液を冷ジエチルエーテル(キシダ化学社)で再結晶し、粗ペプチドを得た。次にこの粗ペプチドをHPLC(A:0.02%TFA含H20、B:0.02%TFA含50%CH3CN)に供し精製した。得られたフラクションの凍結乾燥を行い、標記ペプチドを得た。
(1)使用動物および飼育環境
実験には6週齢のWistar系雄性ラットを使用した。各動物は室温23±2℃、湿度50±5%および12時間の明暗サイクル(明期:07:00から19:00)の環境下で1週間の予備飼育の後、実験に供した。予備飼育期間および実験期間中は水および固形飼料を自由に摂取させた。
ラット涙液分泌量の測定は伊賀らの方法 (Iga, Y. et al., Jpn. J. Pharmacol., 78, 373-80, 1998) に準じて行った。即ち、ラットをペントバルビタール(50mg/kg腹腔内投与)で麻酔し、幅2mmに細切したヒト涙液分泌機能検査紙、シルナル試験紙(昭和薬品化工業株式会社)をラット下眼瞼に挿入し、試験紙の濡れている長さについてノギスを用いて測定して、その長さを涙液分泌の指標とした。涙液量の測定はペプチド投与後1、2、4および6分後に行った。
また、結果は平均値(mm)±標準誤差で示し、有意差検定はTukeyの多重比較検定で行った。
ラットにアミノペプチダーゼ阻害薬であるアマスタチンの生理食塩水溶液(2.5μmol/kg)を静脈内投与し、その1分間後、各種ペプチド誘導体の生理食塩水溶液(5μmol/kg)を静脈内投与した。なお、測定はペプチド投与直後より開始した。
対照として、ペプチドを含有しない生理食塩水溶液(溶媒)を静脈内投与した場合の涙液分泌量も測定した。
涙液分泌量の測定結果を図1~5に示す。
以前に涙液分泌促進作用が示されたSer-Leu-Ile-Gly-Arg-Leu-NH2およびIle-Gly-Arg-Leu-NH2の配列の一部であるArg-Leu-NH2から(L)Arg-(L)Leu-NH2を合成し、その涙液分泌に対する影響を検討した。その結果、(L)Arg-(L)Leu-NH2は涙液分泌を促進した(図1)が、その作用はSer-Leu-Ile-Gly-Arg-Leu-NH2およびIle-Gly-Arg-Leu-NH2よりも弱かった(図2)。
これらのことから、2-フロイル-(L)Arg-(L)Leu-NH2はSer-Leu-Ile-Gly-Arg-Leu-NH2およびIle-Gly-Arg-Leu-NH2よりも顕著に優れた効果を有するドライアイまたはシェーグレン症候群等の涙液分泌異常の疾患に対する治療薬となる。
Claims (15)
- 請求項1記載のペプチド誘導体を含み、かつ、薬理学的および薬剤学的に許容されるように製剤化された涙液分泌促進組成物。
- さらに、前記ペプチド誘導体の失活化または分解を阻害する物質を配合することを特徴とする請求項2記載の涙液分泌促進組成物。
- 前記失活化または分解を阻害する物質がペプチダーゼ阻害薬であることを特徴とする請求項3記載の涙液分泌促進組成物。
- 前記ペプチダーゼ阻害薬がアマスタチンであることを特徴とする請求項4記載の涙液分泌促進組成物。
- ドラッグデリバリーシステム(DDS)製剤化されていることを特徴とする請求項2~5のいずれか1項に記載の涙液分泌促進組成物。
- 経皮吸収製剤化されていることを特徴とする請求項2~6のいずれか1項に記載の涙液分泌促進組成物。
- 経粘膜吸収製剤化されていることを特徴とする請求項2~6のいずれか1項に記載の涙液分泌促進組成物。
- 眼科用組成物であることを特徴とする請求項2~5のいずれか1項に記載の涙液分泌促進組成物。
- 眼科用組成物が洗眼剤、点眼剤、眼軟膏剤または眼用ゲル剤の形態であることを特徴とする請求項9記載の涙液分泌促進組成物。
- 眼科用組成物がコンタクトレンズ用点眼剤、コンタクトレンズ用保存液、またはコンタクトレンズ用洗浄液の形態であることを特徴とする請求項9記載の涙液分泌促進組成物。
- 請求項2~5のいずれか1項に記載の涙液分泌促進組成物を保持および/または含有することを特徴とするコンタクトレンズ。
- 前記涙液分泌促進組成物を持続的に放出するように、保持および/または含有することを特徴とする請求項12記載のコンタクトレンズ。
- 請求項2~5のいずれか1項に記載の涙液分泌促進組成物を含むことを特徴とする眼疾患治療剤または予防剤。
- 眼疾患が、ドライアイ、角膜上皮剥離、角膜炎、角膜潰瘍または結膜炎であることを特徴とする請求項14記載の眼疾患治療剤または予防剤。
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
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EP09766617.6A EP2301951B1 (en) | 2008-06-19 | 2009-06-15 | Peptide derivative and composition for promoting tear secretion comprising the same |
CN2009801230192A CN102066402B (zh) | 2008-06-19 | 2009-06-15 | 肽衍生物以及含有肽衍生物的用于促进泪液分泌的组合物 |
CA2726161A CA2726161C (en) | 2008-06-19 | 2009-06-15 | A peptide derivative and a composition for promoting lacrimal secretion comprising the same |
JP2010517906A JP5421910B2 (ja) | 2008-06-19 | 2009-06-15 | ペプチド誘導体およびそれを含む涙液分泌促進組成物 |
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Cited By (3)
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JP5568174B1 (ja) * | 2013-04-12 | 2014-08-06 | ロート製薬株式会社 | コンタクトレンズパッケージ、およびコンタクトレンズ用パッケージング液 |
JP2014519955A (ja) * | 2011-06-20 | 2014-08-21 | センジュ ユーエスエー、インコーポレイテッド | 経皮薬物送達システムおよびその使用方法 |
JP2020027247A (ja) * | 2018-08-14 | 2020-02-20 | 優▲ニ▼康光學股▲フン▼有限公司 | 機能性成分含有コンタクトレンズ、及びその製品 |
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CN103249429A (zh) * | 2010-11-08 | 2013-08-14 | 希尔洛有限公司 | 缓冲的眼用组合物以及使用其的方法 |
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EP4039263A1 (en) * | 2021-02-04 | 2022-08-10 | Medivis S.r.l. | Formulation for the treatment of asthenopia |
Citations (27)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH0912448A (ja) | 1995-04-28 | 1997-01-14 | Read Chem Kk | 薬物放出制御型経皮吸収製剤 |
JPH0977658A (ja) | 1995-09-08 | 1997-03-25 | Takeda Chem Ind Ltd | 経皮吸収製剤 |
JPH0980358A (ja) | 1995-09-11 | 1997-03-28 | Menicon Co Ltd | 含水性軟質眼用レンズ用材料、それからなる含水性軟質眼用レンズ用成形体、ならびにそれからなる含水性軟質眼用レンズおよびその製法 |
JPH09101488A (ja) | 1995-03-24 | 1997-04-15 | Ocular Res Of Boston Inc | 脂質層で予め被覆されたヒドロゲルレンズ |
JPH09124715A (ja) | 1995-10-30 | 1997-05-13 | Hoya Corp | 2−ヒドロキシエチルメタクリレート系の重合体、ハイドロゲル及び含水ソフトコンタクトレンズの製造方法 |
JPH09169635A (ja) | 1995-12-20 | 1997-06-30 | Sekisui Chem Co Ltd | 経皮吸収製剤 |
JPH09176000A (ja) | 1995-12-28 | 1997-07-08 | Teijin Ltd | 医療用貼付剤 |
JPH09189887A (ja) | 1996-01-09 | 1997-07-22 | Menicon Co Ltd | 眼用レンズ材料 |
JPH09208605A (ja) | 1996-02-02 | 1997-08-12 | Sekisui Chem Co Ltd | 医療用粘着剤の製造方法及び医療用粘着剤 |
JPH09301853A (ja) | 1996-05-14 | 1997-11-25 | Nitto Denko Corp | 貼付剤および貼付製剤 |
JPH1094595A (ja) | 1996-09-25 | 1998-04-14 | Teijin Ltd | 新規な医療用粘着剤及び製剤 |
JPH1094596A (ja) | 1996-09-25 | 1998-04-14 | Teijin Ltd | 医療用粘着剤及び製剤 |
JPH10130172A (ja) | 1996-10-28 | 1998-05-19 | Sekisui Chem Co Ltd | 経皮吸収製剤 |
JPH10179711A (ja) | 1996-12-24 | 1998-07-07 | Teijin Ltd | 医療用貼付材 |
JPH10298067A (ja) | 1997-04-23 | 1998-11-10 | Teijin Ltd | 医療用粘着剤および経皮吸収性粘着製剤 |
JPH10298068A (ja) | 1997-04-24 | 1998-11-10 | Nitto Denko Corp | 医療用粘着剤及び当該医療用粘着剤を用いた医療用粘着シート、経皮吸収製剤並びに当該医療用粘着剤の製造方法 |
JPH10306023A (ja) | 1997-05-06 | 1998-11-17 | Sekisui Chem Co Ltd | 経皮吸収製剤及びその製造方法 |
JPH10310521A (ja) | 1997-05-12 | 1998-11-24 | Teikoku Seiyaku Co Ltd | 経皮吸収貼付製剤 |
JPH10339857A (ja) | 1997-06-05 | 1998-12-22 | Menicon Co Ltd | 薬剤徐放性コンタクトレンズの製法およびそれによってえられた薬剤徐放性コンタクトレンズ |
JPH1124010A (ja) | 1997-06-27 | 1999-01-29 | Menicon Co Ltd | 薬剤徐放性視力矯正用コンタクトレンズの製法およびそれに用いる薬剤徐放剤 |
JPH1129463A (ja) | 1997-05-14 | 1999-02-02 | Senju Pharmaceut Co Ltd | 再分散性の良い水性懸濁液剤 |
JPH1192361A (ja) | 1997-09-16 | 1999-04-06 | Teijin Ltd | 経皮吸収製剤 |
JPH11104229A (ja) | 1997-10-02 | 1999-04-20 | Teijin Ltd | 医療用粘着剤及び製剤 |
JPH11197234A (ja) | 1998-01-09 | 1999-07-27 | Koken Co Ltd | 眼科用コラーゲンゲル成形物 |
JPH11292794A (ja) | 1998-04-03 | 1999-10-26 | Teijin Ltd | 経皮吸収製剤 |
JP2001181208A (ja) | 1999-12-27 | 2001-07-03 | Fuso Pharmaceutical Industries Ltd | 涙液分泌促進組成物 |
JP2005272445A (ja) * | 2004-02-27 | 2005-10-06 | Fuso Pharmaceutical Industries Ltd | 涙液分泌促進ペプチドおよびその組成物 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW506317U (en) * | 2001-07-27 | 2002-10-11 | Wang-Kuan Lin | Adjustment structure for safety catch of nailing gun |
-
2009
- 2009-06-15 CN CN2009801230192A patent/CN102066402B/zh active Active
- 2009-06-15 CA CA2726161A patent/CA2726161C/en active Active
- 2009-06-15 EP EP09766617.6A patent/EP2301951B1/en active Active
- 2009-06-15 WO PCT/JP2009/060873 patent/WO2009154169A1/ja active Application Filing
- 2009-06-15 AU AU2009261285A patent/AU2009261285B2/en active Active
- 2009-06-15 US US12/996,728 patent/US8383595B2/en active Active
- 2009-06-15 KR KR1020107028994A patent/KR101521278B1/ko active IP Right Grant
- 2009-06-15 JP JP2010517906A patent/JP5421910B2/ja active Active
Patent Citations (27)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH09101488A (ja) | 1995-03-24 | 1997-04-15 | Ocular Res Of Boston Inc | 脂質層で予め被覆されたヒドロゲルレンズ |
JPH0912448A (ja) | 1995-04-28 | 1997-01-14 | Read Chem Kk | 薬物放出制御型経皮吸収製剤 |
JPH0977658A (ja) | 1995-09-08 | 1997-03-25 | Takeda Chem Ind Ltd | 経皮吸収製剤 |
JPH0980358A (ja) | 1995-09-11 | 1997-03-28 | Menicon Co Ltd | 含水性軟質眼用レンズ用材料、それからなる含水性軟質眼用レンズ用成形体、ならびにそれからなる含水性軟質眼用レンズおよびその製法 |
JPH09124715A (ja) | 1995-10-30 | 1997-05-13 | Hoya Corp | 2−ヒドロキシエチルメタクリレート系の重合体、ハイドロゲル及び含水ソフトコンタクトレンズの製造方法 |
JPH09169635A (ja) | 1995-12-20 | 1997-06-30 | Sekisui Chem Co Ltd | 経皮吸収製剤 |
JPH09176000A (ja) | 1995-12-28 | 1997-07-08 | Teijin Ltd | 医療用貼付剤 |
JPH09189887A (ja) | 1996-01-09 | 1997-07-22 | Menicon Co Ltd | 眼用レンズ材料 |
JPH09208605A (ja) | 1996-02-02 | 1997-08-12 | Sekisui Chem Co Ltd | 医療用粘着剤の製造方法及び医療用粘着剤 |
JPH09301853A (ja) | 1996-05-14 | 1997-11-25 | Nitto Denko Corp | 貼付剤および貼付製剤 |
JPH1094595A (ja) | 1996-09-25 | 1998-04-14 | Teijin Ltd | 新規な医療用粘着剤及び製剤 |
JPH1094596A (ja) | 1996-09-25 | 1998-04-14 | Teijin Ltd | 医療用粘着剤及び製剤 |
JPH10130172A (ja) | 1996-10-28 | 1998-05-19 | Sekisui Chem Co Ltd | 経皮吸収製剤 |
JPH10179711A (ja) | 1996-12-24 | 1998-07-07 | Teijin Ltd | 医療用貼付材 |
JPH10298067A (ja) | 1997-04-23 | 1998-11-10 | Teijin Ltd | 医療用粘着剤および経皮吸収性粘着製剤 |
JPH10298068A (ja) | 1997-04-24 | 1998-11-10 | Nitto Denko Corp | 医療用粘着剤及び当該医療用粘着剤を用いた医療用粘着シート、経皮吸収製剤並びに当該医療用粘着剤の製造方法 |
JPH10306023A (ja) | 1997-05-06 | 1998-11-17 | Sekisui Chem Co Ltd | 経皮吸収製剤及びその製造方法 |
JPH10310521A (ja) | 1997-05-12 | 1998-11-24 | Teikoku Seiyaku Co Ltd | 経皮吸収貼付製剤 |
JPH1129463A (ja) | 1997-05-14 | 1999-02-02 | Senju Pharmaceut Co Ltd | 再分散性の良い水性懸濁液剤 |
JPH10339857A (ja) | 1997-06-05 | 1998-12-22 | Menicon Co Ltd | 薬剤徐放性コンタクトレンズの製法およびそれによってえられた薬剤徐放性コンタクトレンズ |
JPH1124010A (ja) | 1997-06-27 | 1999-01-29 | Menicon Co Ltd | 薬剤徐放性視力矯正用コンタクトレンズの製法およびそれに用いる薬剤徐放剤 |
JPH1192361A (ja) | 1997-09-16 | 1999-04-06 | Teijin Ltd | 経皮吸収製剤 |
JPH11104229A (ja) | 1997-10-02 | 1999-04-20 | Teijin Ltd | 医療用粘着剤及び製剤 |
JPH11197234A (ja) | 1998-01-09 | 1999-07-27 | Koken Co Ltd | 眼科用コラーゲンゲル成形物 |
JPH11292794A (ja) | 1998-04-03 | 1999-10-26 | Teijin Ltd | 経皮吸収製剤 |
JP2001181208A (ja) | 1999-12-27 | 2001-07-03 | Fuso Pharmaceutical Industries Ltd | 涙液分泌促進組成物 |
JP2005272445A (ja) * | 2004-02-27 | 2005-10-06 | Fuso Pharmaceutical Industries Ltd | 涙液分泌促進ペプチドおよびその組成物 |
Non-Patent Citations (10)
Title |
---|
CARPINO, L.A. ET AL., J. ORG. CHEM., vol. 37, 1972, pages 3404 - 3409 |
GODIN, D. ET AL., EUR. J. PHARMACOL., vol. 253, 1994, pages 225 - 30 |
IGA, Y. ET AL., JPN. J. PHARMACOL., vol. 78, 1998, pages 373 - 80 |
JOURNAL OF CLINICAL AND EXPERIMENTAL MEDICINE, vol. 199, no. 5, 2001, pages 387 - 392 |
KANKE T. ET AL.: "Binding of a highly potent protease-activated receptor-2 (PAR2) activating peptide, [3H]2-furoyl-LIGRL-NH2, to human PAR2", BR. J. PHARMACOL., vol. 145, no. 2, 2005, pages 255 - 263, XP008146069 * |
KAWABATA A. ET AL.: "2-Furoyl-LIGRL-NH2, a potent agonist for proteinase-activated receptor-2, as a gastric mucosal cytoprotective agent in mice", BR. J. PHARMACOL., vol. 144, no. 2, 2005, pages 212 - 219, XP008146097 * |
NISHIKAWA H. ET AL.: "Protease-activated receptor-2 (PAR-2)-related peptides induce tear secretion in rats: involvement of PAR-2 and non -PAR-2 mechanisms", J. PHARMACOL. EXP. THER., vol. 312, no. 1, 2005, pages 324 - 331, XP009099112 * |
PROGRESS IN MEDICINE, vol. 26, no. 4, 2006, pages 853 - 856 |
REFRACTORY DISEASES AND HOME-CARE, vol. 9, no. 12, 2004, pages 61 - 64 |
See also references of EP2301951A4 * |
Cited By (5)
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JP2014519955A (ja) * | 2011-06-20 | 2014-08-21 | センジュ ユーエスエー、インコーポレイテッド | 経皮薬物送達システムおよびその使用方法 |
JP2017048201A (ja) * | 2011-06-20 | 2017-03-09 | センジュ ユーエスエー、インコーポレイテッド | 経皮薬物送達システムおよびその使用方法 |
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WO2014167611A1 (ja) * | 2013-04-12 | 2014-10-16 | ロート製薬株式会社 | コンタクトレンズ用組成物およびそれを用いたコンタクトレンズパッケージ |
JP2020027247A (ja) * | 2018-08-14 | 2020-02-20 | 優▲ニ▼康光學股▲フン▼有限公司 | 機能性成分含有コンタクトレンズ、及びその製品 |
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CA2726161C (en) | 2015-09-08 |
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JPWO2009154169A1 (ja) | 2011-12-01 |
CA2726161A1 (en) | 2009-12-23 |
AU2009261285A1 (en) | 2009-12-23 |
US20110224154A1 (en) | 2011-09-15 |
CN102066402A (zh) | 2011-05-18 |
KR20110043540A (ko) | 2011-04-27 |
KR101521278B1 (ko) | 2015-05-18 |
EP2301951B1 (en) | 2013-04-24 |
CN102066402B (zh) | 2013-11-06 |
EP2301951A1 (en) | 2011-03-30 |
AU2009261285B2 (en) | 2012-12-13 |
US8383595B2 (en) | 2013-02-26 |
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