WO2005113002A1 - ムスカリン受容体作動薬を含有する眼科用経皮吸収型製剤 - Google Patents
ムスカリン受容体作動薬を含有する眼科用経皮吸収型製剤 Download PDFInfo
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- WO2005113002A1 WO2005113002A1 PCT/JP2005/009709 JP2005009709W WO2005113002A1 WO 2005113002 A1 WO2005113002 A1 WO 2005113002A1 JP 2005009709 W JP2005009709 W JP 2005009709W WO 2005113002 A1 WO2005113002 A1 WO 2005113002A1
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- receptor agonist
- ophthalmic
- absorption
- eyelid skin
- muscarinic receptor
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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
-
- 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
Definitions
- the present invention relates to an ophthalmic transdermal absorption preparation containing a muscular force receptor agonist for administration to the eyelid skin surface to promote lacrimation.
- the present invention also relates to a method for promoting lacrimal secretion by administering an ophthalmic transdermal preparation containing a muscarinic receptor agonist to the surface of the eyelid skin.
- Dry eye is a pathological condition caused by a decrease in the amount of lacrimal secretion and a change in tear components, which may cause erosion of the cornea and conjunctival epithelium, and a foreign body sensation.
- dry eye include dry eye associated with eye diseases such as Siedalen syndrome, Stevens-Johnson syndrome, blepharitis, and meibomian adenitis, VD T (V isua 1 D islay Thermal) work, contact lens wear, etc. Dry eye and the like.
- Common methods for preventing and treating dry eye include supplementation of tears by administration of artificial tears or administration of eye drops containing viscoelastic substances such as hyaluronan chondroitin sulfate. However, the effects of these methods are temporary and require frequent administration.
- preservatives are often added to eye drops, which may cause side effects due to the preservatives.
- Mus force phosphorus receptor also called Mus force phosphorous acetylcholine receptor
- Mus force phosphorous acetylcholine receptor is involved in neurotransmission and stimulation in parasympathetic innervating organs, nicotinic receptors (autocotyl acetyl chloride choline) at autonomic ganglia and ganglion junctions. Also called a receptor).
- Muscarinic receptors are 7-transmembrane G protein-coupled receptors and are classified into five subtypes, M1 to M5.
- Muscarinic receptors are widely distributed in ocular tissues and are involved in various functions such as lacrimation, changes in lens curvature, and aqueous humor outflow. However, when a muscarinic receptor agonist is instilled, tears are secreted, but this causes the side effect of miosis.
- a drug containing a drug intended to reach the posterior eye region including the lens, vitreous body, choroid and retina and a transdermal absorption enhancer in a base matrix As a percutaneous absorption preparation for treating eye diseases, for example, a drug containing a drug intended to reach the posterior eye region including the lens, vitreous body, choroid and retina and a transdermal absorption enhancer in a base matrix
- An ophthalmic transdermal patch having a content layer has also been reported (see International Publication No. 01 26648, pamphlet, EP 122131 5).
- An object of the present invention is to provide an ophthalmic transdermal absorption preparation capable of maintaining a therapeutically effective concentration of a muscular phosphorus receptor agonist for promoting lacrimation and having few side effects such as miosis. is there.
- the present invention allows the muscarinic receptor agonist to be transcutaneously directly transcutaneously from the eyelid skin rather than being transferred to the local eye tissue via the systemic circulation. It is an object of the present invention to provide an ophthalmic transdermal absorption-type preparation which is superior to the effect of promoting continuous lacrimal secretion compared with administration to a site other than the surface of the eyelid skin by shifting to the ocular local tissue. Another object of the present invention is to provide a method for promoting lacrimation by administering an ophthalmic transdermal preparation containing a muscular force receptor agonist to the surface of the eyelid skin. is there.
- the present inventor has continuously administered lacrimal fluid by administering an ophthalmic transdermal absorption preparation containing a muscarinic receptor agonist to the surface of the eyelid skin.
- the present invention was completed by further research based on this finding, and found that there were few side effects such as miosis.
- the present invention is as follows.
- An ophthalmic transdermal preparation containing a muscarinic receptor agonist characterized by being administered to the surface of the eyelid skin to promote lacrimation.
- the compounding amount of the muscarinic receptor agonist is 0.1 to 40 weight 0 /.
- muscarinic receptor agonist is pilocarpine or cevimeline, or a pharmaceutically acceptable salt thereof.
- the ophthalmic transdermal preparation according to any one of (1) to (7), which is a gel.
- a lacrimal secretion promoter for eyelid skin surface administration containing a muscular force receptor receptor agonist (12) A lacrimal secretion promoter for eyelid skin surface administration containing a muscular force receptor receptor agonist.
- the lacrimal secretion promoter according to any one of (12) to (14), further comprising an absorption promoter.
- a tear secretion promoter for eyelid skin surface administration containing 1 to 40% by weight of pilocarpine or cevimeline, or a pharmaceutically acceptable salt thereof, and 5 to 60% by weight of isopropyl myristate .
- a method for promoting lacrimal secretion which comprises administering to the surface of the eyelid skin of a patient an amount of a muscular force receptor receptor agonist effective to promote lacrimation.
- a pharmaceutical composition for surface administration of eyelid skin for promoting tear secretion comprising a muscarinic receptor agonist.
- a commercial product comprising a tear secretion promoter for eyelid skin surface administration containing a muscular force receptor receptor agonist, an absorption promoter, and a description describing the use for the pharmaceutical use. Package.
- the ophthalmic percutaneous absorption preparation of the present invention may be any preparation that can deliver a muscular force receptor agonist to the local tissue of the eye by being administered to the skin surface including the eyelid, for example, a patch.
- External preparations such as ointments, gels and creams can be mentioned, and patches, ointments and gels are preferred.
- the patch means a preparation to be affixed to the skin such as a poultice, a patch, a tape, a plaster.
- the ophthalmic transdermal preparation of the present invention has an excellent tear secretion promoting effect. That is, the present invention provides a transdermal absorption-type lacrimal secretion promoter containing a muscular force receptor receptor agonist.
- the surface of the eyelid skin means the upper and lower eyelids and the skin surface in the vicinity thereof.
- the ophthalmic percutaneous absorption preparation of the present invention can continuously promote lacrimation by adjusting the type, amount, etc. of the muscular phosphorus receptor agonist contained in the preparation.
- the ophthalmic transdermal preparation of the present invention can easily adjust the dose of a muscular force receptor agonist effective for promoting lacrimation.
- any substance having the ability to act on the muscular force receptor to activate the muscular force receptor may be used. Synthetically synthesized. Examples thereof include pilocarpine, cevimeline, carbachol, mussels phosphorus, or pharmaceutically acceptable salts thereof. Pilocarpine, cevimeline, or a pharmaceutically acceptable salt thereof is preferable. Examples of the pharmaceutically acceptable salt of pilocarpine include salts with hydrochloric acid, sulfuric acid, nitric acid, acetic acid and the like, and hydrochloride is preferable. Also, Sevi Examples of the pharmaceutically acceptable salt of melin include salts with hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid and the like, and hydrochloride is preferable.
- the ophthalmic transdermal absorption preparation of the present invention can be appropriately added with any component usually used in the production of pharmaceuticals as long as the effects of the present invention are not impaired.
- examples include ointment bases, gel bases, patch base matrices, solvents, oils, surfactants, adhesives, resins, absorption enhancers, and wetting agents.
- ointment bases include oil bases such as petrolatum, paraffin, plastibase, silicone, vegetable oil, pig oil, waxes, and simple ointments; hydrophilic ointments (burnishing cream), hydrophilic petrolatum, purified lanolin, water-absorbing ointments, Examples include emulsion bases such as hydrolanolin, purified lanolin, and hydrophilic plastic base (cold cream).
- gel bases include carboxybule polymer, polyacrylic acid, polyacrylic acid sodium, methylcellulose, polybulal alcohol, polybulurpyrrolidone, polyethylene oxide, polyacrylamide, sodium alginate, gelatin, gum arabic, tragacanth gum, guar gum, Thickening polymers such as xanthan gum and agar; fatty acid esters such as isopropyl myristate, isopropyl palmitate, propylene glycol oleate; fatty acids such as lactic acid, lauric acid, oleic acid, linoleic acid, linolenic acid; Aliphatic alcohols such as alcohol and oleyl alcohol; and hydrocarbons such as squalene and squalene.
- the solvent include purified water, ethanol, lower alcohols, ethers, pyrrolidones, and ethyl acetate.
- oil agent examples include volatile and non-volatile oil agents, solvents, resins and the like which are usually used for external preparations for skin, and any of liquid, paste and solid can be used at room temperature.
- higher alcohols such as cetyl alcohol and isostearyl alcohol
- fatty acids such as isostearic acid and oleic acid
- polyhydric alcohols such as glycerin, sorbitol, ethylene glycol, propylene glycol, and polyethylene glycol
- myristyl myristate and lauric acid examples include esters such as xylyl, decyl oleate, isopyristyl myristate, and glyceryl monostearate.
- surfactant examples include an anionic surfactant, a cationic surfactant, and a non-ionic surfactant.
- Biionic surfactants and amphoteric surfactants can be used.
- Examples of the cation surfactant include fatty acid salts, alkyl sulfates, polyoxyethylene alkyl sulfates, alkyl sulfocarboxylates, and alkyl ether carboxylates.
- Examples of the cationic surfactant include ammine salts and quaternary ammonium salts.
- nonionic surfactant examples include polyoxyethylene hydrogenated castor oil, polyoxyethylene fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, and the like.
- amphoteric surfactants examples include alkyl betaines, dimethylalkyl glycines, and lecithins.
- Examples of the adhesive and resin include sodium polyacrylate, cellulose ether, calcium alginate, carboxybule polymer, ethylene-acrylic acid copolymer, vinyl pyrrolidone polymer, butyl alcohol-butyl pyrrolidone copolymer, nitrogen-substituted acrylamide.
- Cationic polymers such as polymer, polyacrylamide, cationized gar gum, dimethyl acrylammonium polymer, methacrylic acid acrylic acid copolymer, polyoxyethylene-polypropylene copolymer, poly vinyl Alcohol, Pullulan, Agar, Gelatin, Tamarind Seed Polysaccharide, Xanthan Gum, Carrageenan, Jaime Toxino Lepetatin, Lome Toxino Lepectin, Gargum, Gum Arabic, Crystalline Cellulose, Arabinogalata , Kara gum, Tragacanto gum, Alginic acid, Albumin, Casein, Curdlan, Diellan gum, Dextran, Cellulose, Polyethyleneimine, Highly polymerized polyethylene glycol, Cationized silicon polymer, Synthetic latex, Acrylic silicon, Trimethylsiloxychelic acid, Fluorine And siliconized resin.
- Absorption enhancers include, for example, 1-dodecylazakine heptane-2-one, pyrothiodecane, oleyl alcohol, lauric acid, oleic acid, sodium lauryl sulfate, d-limonene, 1-mentholore, 2-pyrrolidone, 1-methinole 2-pyrrolidone, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl Sulfoxide, decylmethyl sulfoxide, N-lauroyl sarcosine, isopropyl myristate, no.
- Isopropyl propyl noremitate, fumaric acid, maleic acid, lactic acid myristinole, cetyl lactate, polyoxyethylene oleyl ether, ethanol laurate, polyalkanols, glycerin, propylene glycol, diethylanolamine, triisopropanolamine, triethanolamine Min etc. are mentioned. You can use a combination of two or more of these. Preferably, it is isopropyl myristate.
- Examples of the base matrix of the patch include acrylic pressure-sensitive adhesives, silicon-based pressure-sensitive adhesives, rubber-based pressure-sensitive adhesives, and the like.
- Matritas is a tape formulation. You may hold
- acrylic pressure-sensitive adhesives include acrylic acid mono-octyl acrylate copolymer, acrylic ester mono-acetic acid butyl copolymer, 2-ethylhexylhexyl pyrrolidone acrylate copolymer, and methacrylic acid mono-acrylolic acid butyl copolymer. Etc.
- silicone-based pressure-sensitive adhesive examples include polymethylphenylsiloxane copolymer and acrylic acid / dimethylsiloxane copolymer.
- rubber-based adhesives examples include styrene-isoprene-styrene block copolymer, natural rubber, polyisobutylene, polybutene, ethylene monoacetate copolymer (EVA), etc. And the like obtained by adding an agent or the like.
- wetting agent examples include glycerin, polyethylene glycol, sorbitol, maltitol, propylene dallicol, 1,3-butanediol, and reduced maltose starch syrup.
- the ophthalmic transdermal preparation containing the muscular force receptor agonist of the present invention can be produced by a conventional method.
- muscarinic receptor agonists and ointment bases and, if necessary, solvents, oils, surfactants, adhesives, resins, absorption enhancers It can be produced by adding a wetting agent and mixing well.
- a genore agent add a solvent to the gel base and neutralize it with a pH adjuster, and then add a solvent, oil agent, surfactant, viscosity agent, resin, absorption accelerator, wetting agent, etc. as necessary.
- a muscarinic receptor agonist can be produced by mixing and adding a muscarinic receptor agonist to this and kneading well.
- patches patches, patches, tapes, plasters
- muscarinic receptor agonists based on matrix and Z or adhesives and if necessary, solvents, oils, surfactants, resins, absorption enhancement
- Add the agent, wetting agent, etc. mix well, spread this plaster on a support such as non-woven fabric, woven fabric, plastic film (including sheet) or composite film of these, and cover with a release liner.
- a support such as non-woven fabric, woven fabric, plastic film (including sheet) or composite film of these, and cover with a release liner.
- it can be produced by spreading on a release liner and pressure transfer onto the support.
- the support preferably has a flexibility that can be applied to the surface of the eyelid skin, and the thickness is appropriately selected depending on the dosage form, but considering the strength of the preparation, the uncomfortable feeling at the time of application
- the ophthalmic transdermal absorption-type preparation containing the muscular force receptor receptor agonist of the present invention includes, in addition to the above components, a stabilizer, an antioxidant, an antiseptic, A crosslinking agent, pH adjusting agent, ultraviolet absorber, etc. can be added.
- the muscarinic receptor agonist is usually used in a proportion of 0.1 to 60 parts by weight, preferably 0.2 to 20 parts by weight, based on 100 parts by weight of the base.
- the blending amount of the muscular force receptor receptor agonist in the ophthalmic transdermal preparation of the present invention is usually 0.1 to 40% by weight, more preferably 1 to 30% by weight, particularly preferably. Is from 5 to 30% by weight.
- the amount of the muscarinic receptor agonist is preferably in the range of 1 to 40% by weight, more preferably 5 to 30. % By weight, particularly preferably 15 to 30% by weight.
- the amount of the muscular phosphorus receptor agonist is preferably in the range of 0.1 to 40% by weight, more preferably 1 to 30% by weight. / 0 , particularly preferably 5 to 30% by weight.
- the blending amount of the absorption enhancer in the ophthalmic transdermal preparation of the present invention is usually 1 to 60% by weight, preferably 5 to 50% by weight, and particularly preferably 10 to 40% by weight.
- the amount of the absorption accelerator is preferably in the range of 5 to 60% by weight, more preferably 10 to 50% by weight, particularly preferably. Is 20 to 40% by weight.
- the amount of absorption promoter is preferably in the range of 1 to 60% by weight, more preferably 5 to 50% by weight / 0 , and particularly preferably 10 to 40%. weight. / 0 .
- the mixing ratio of the muscarinic receptor agonist and the absorption promoter is usually 1 to 20 parts by weight of the absorption promoter with respect to 1 part by weight of the muscarinic receptor agonist.
- the absorption promoter is preferably 1 to 10 parts by weight, more preferably 1 part by weight of the muscarinic receptor agonist, with respect to 1 part by weight of the muscular phosphorus receptor agonist.
- the agent is 1 to 5 parts by weight.
- the absorption ratio of the muscular phosphorus receptor agonist and the absorption enhancer is 1 part by weight of the muscarinic receptor agonist.
- the agent is preferably in the range of 1 to 20 parts by weight, more preferably 1.5 to 10 parts by weight, particularly preferably the muscarinic receptor agonist, with respect to 1 part by weight of the muscular phosphorus receptor agonist.
- the absorption enhancer is 2 to 10 parts by weight per 1 part by weight of the drug.
- the mixing ratio of the muscular force receptor agonist and the absorption enhancer is 1 to 20 parts by weight.
- the absorption promoter is 1 to 10 parts by weight with respect to 1 part by weight of the muscular force phosphorus receptor agonist, and particularly preferably 1 part by weight of the muscular phosphorus receptor agonist.
- the accelerator is 1 to 5 parts by weight.
- the ophthalmic transdermal preparation of the present invention contains pharmaceutical ingredients other than the muscular force receptor agonist, such as steroidal or non-steroidal anti-inflammatory agents, antibacterial agents, and the like, unless they are contrary to the object of the present invention.
- An antiallergic agent, antihistamine agent, antiviral agent, vasoconstrictor, cataract treatment agent, glaucoma treatment agent, mydriatic agent, etc. may be formulated.
- the dose of the muscular force receptor agonist varies depending on the patient's condition, age, and administration mode, but it is usually 0 for adults.
- the ophthalmic percutaneous absorption type preparation of the present invention can continuously promote lacrimation, and has fewer side effects such as miosis compared with eye drops, so dry eyes, eg tears Liquid deficiency, dry eye, Siedalen syndrome, dry keratoconjunctivitis, Stevens-I Johnson syndrome, blepharitis, dry eye associated with meibomian adenitis, VDT work, contact lens It is useful as a prophylactic / therapeutic agent for dry eye caused by wearing.
- the administration target of the ophthalmic percutaneous absorption preparation and pharmaceutical composition of the present invention is not particularly limited, and various mammals such as sanore, mouse, rat, monoremot, rabbit, peta, inu, horse, and ushi, including humans. Useful for treating dry eye in animals.
- Pilocarpine hydrochloride (manufactured by Nacalai Testa Co., Ltd.) 0.3 g
- Pilocarpine hydrochloride (manufactured by Nacalai Testa Co., Ltd.) 0.3 g
- Pilocarpine hydrochloride (Nacalai Testa Co., Ltd.) 0 3 g Sodium polyacrylate 0 4 5 g Glycerin 0 3 g Heart force oil 0 0 1 g Purified water-_
- Purified water is mixed well with sodium polyatalylate and glycerin to make a hydrous paste. Add katsu oil and pilocarpine hydrochloride and mix well. The mixed plaster is spread-molded on a support (polyester non-woven fabric, etc.), and a release liner is applied to make a catalyzing agent for pyrrole hydrochloride / lepin.
- Pilocarpine hydrochloride (Nacalai Testa Co., Ltd.) 0.3 g Isopropyl myristate 1. g Acrylic copolymer 1.4 8 5 g Polyisocyanate compound 0.0 0 15 5 g _ ⁇ -ethyl ester
- a cevimeline hydrochloride-containing gel is prepared in the same manner as in Example 2 using cevimeline hydrochloride instead of pilocarpine hydrochloride of Example 2.
- a cevimeline hydrochloride-containing tape preparation is prepared in the same manner as in Example 4 using cevimeline hydrochloride instead of pilocarpine hydrochloride of Example 4.
- a carbachol-containing ointment is prepared in the same manner as in Example 1 except that carbachol is used instead of pilocarpine hydrochloride in Example 1.
- a carbachol-containing gel is prepared in the same manner as in Example 2 using carbachol instead of pilocarpine hydrochloride of Example 2. [Example 1 1] Powered Norabacol-containing cataplasm
- a carbachol-containing cataplasm containing a carbachol was prepared in the same manner as in Example 3 using carbachol instead of pilocarpine hydrochloride of Example 3.
- Acrylic copolymer 1 485 g Polyisocyanate compound 0. 0015 g _Ethyl oxalate
- a carbachol-containing tape is prepared in the same manner as in Example 4 except that force rubaco and -l are used instead of pilocarpine hydrochloride of Example 4.
- Acrylic copolymer PE—300 (solid content)
- Polyisocyanate compound CK401 (solid content)
- Cevimeline hydrochloride (extracted from Evozac (registered trademark) capsules) l g Isopropyl myristate 2 g
- Cevimeline hydrochloride was extracted according to the following method.
- Epozak (registered trademark) capsule 30 mg (Product No. XAAAE 20, 1 capsule containing 3 Omg cevimeline hydrochloride) Suspend the contents of 200 capsules (approx. 42 g) in purified water (500 mL) and stir vigorously at room temperature did. The insoluble material was filtered off, adjusted to pH 10 with 1N aqueous sodium hydroxide solution, and extracted with black mouth form (100 mLX4). The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution (100 mLX 2) and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was dried under reduced pressure at room temperature for 20 hours to obtain a pale yellow oil.
- the obtained oil was dissolved in jetyl ether and crystallized by adding equimolar 4N hydrochloric acid Z-dioxane.
- the crystals were filtered off, washed with jetyl ether, air-dried at room temperature, and then dried under reduced pressure at room temperature for 20 hours to obtain cevimeline hydrochloride (5.78 g).
- the chemical structure, physical properties, and purity of the obtained cevimeline hydrochloride were confirmed by nuclear magnetic resonance ( ⁇ H-NMR) and melting point measurements.
- Sodium hydrogen phosphate dihydrate 0.0.01 g Sodium chloride 0.09 g Sodium hydroxide Purified water Appropriate amount Total volume 10 mL (pH 5) To about 7 mL of purified water, sodium hydrogenphosphate dihydrate and sodium chloride were added and dissolved. Pilocarpine hydrochloride was added to this solution and dissolved, and sodium hydroxide was added; adjusted to H5. Purified water was added to make up a total volume of 1 OmL to give pilocarpine hydrochloride-containing eye drops.
- Acrylic copolymer PE—300 782 g (solid content)
- Polyisocyanate compound CK401 0018 g (solid content)
- Isopropyl myristate was weighed into a disposer puller cup. Next, an talyl copolymer as an adhesive base and a polyisocyanate compound as a cross-linking agent were sequentially added and mixed well. After degassing the mixture, it was spread on a release liner using a doctor knife or a single ablator, and allowed to stand until the organic solvent volatilized. Subsequently, the substrate was covered and pressure-bonded with a roller, followed by crosslinking in a constant temperature bath at about 40 ° C. for 8 to 12 hours to obtain a base patch.
- cevimeline hydrochloride was used instead of pilocarpine hydrochloride of Comparative Example 1 and prepared in the same manner as Comparative Example 1 to give a cevimeline hydrochloride-containing eye drop.
- the pilocarpine hydrochloride-containing ophthalmic preparation prepared in Comparative Example 1 was 50 ⁇ m per eye.
- Example 1 As shown in FIG. 1, in the administration group of Example 1, a large amount of lacrimation was observed and a sustained effect was observed. On the other hand, the amount of lacrimal secretion was smaller in the administration group of Comparative Example 1 than in the administration group of Example 1 which is the percutaneous absorption preparation for ophthalmology of this subject.
- the ophthalmic transdermal absorption preparation of the present invention is more effective in promoting lacrimation and has a sustained effect than an eye drop administered directly to the eye.
- the pupil diameter was measured. Using the pupil diameter before application as the standard (O mm), the change in pupil diameter after application and application was measured. For the measurement, an electronic digital caliper (MA X—CA L, manufactured by Nihon Keizai Kogyo Co., Ltd.) was used.
- the percutaneous absorption preparation for ophthalmology of this invention has fewer side effects such as miosis and darkness associated therewith than eye drops administered directly to the eye.
- the ophthalmic percutaneous absorption preparation of the present invention is administered to the surface of the eyelid skin, and tears due to the muscular force receptor agonist contained in the preparation It is a highly safe and highly safe formulation that promotes fluid secretion continuously and has few side effects such as miosis.
- the amount of increased lacrimal secretion after administration was measured based on the amount of lacrimal secretion before administration (Omm / min).
- the lacrimal fluid secretion was observed in the eyes attached to the upper eyelid administration group of Example 13 as compared with the eye drops of the administration group of Comparative Example 3.
- the lower eyelid administration group had a patch eye that showed a greater amount of tear secretion than the opposite eye (non-stick). From this, it can be seen that the ophthalmic transdermal absorption preparation of the present invention is more effective in promoting lacrimal secretion than eye drops administered directly to the eye.
- the pupil diameter was measured. Using the pupil diameter before administration as a reference (0 mm), the change in pupil diameter after administration was measured. The measurement was performed using an electronic digital caliper (MA X—CA L, manufactured by Nihon Keizai Kogyo Co., Ltd.).
- the amount of increased lacrimal secretion after administration was measured using the amount of lacrimal secretion before administration as a reference (O mmZmin).
- the ophthalmic transdermal absorption preparation of the present invention has fewer side effects such as miosis and darkness associated therewith than eye drops administered directly to the eye.
- the ophthalmic percutaneous absorption preparation of the present invention is more excellent in promoting lacrimal secretion than eye drops administered directly to the eye. From the results of the above Test Examples 1 to 5, the ophthalmic transdermal absorption preparation of the present invention was administered to the surface of the eyelid skin, whereby the tear fluid content by the muscular force receptor agonist contained in the preparation was determined. It is a highly safe and highly safe formulation that is continuously promoted and has few side effects such as miosis. Industrial applicability
- an ophthalmic transdermal absorption preparation containing a muscular force receptor agonist which can be administered to the eyelid skin surface to promote lacrimation, and a muscular force receptor receptor agonist
- a muscular force receptor receptor agonist By administering an ophthalmic percutaneous absorption preparation containing A method of promoting lacrimation can be provided.
- the ophthalmic transdermal preparation of the present invention is a highly safe preparation with very little side effects such as miosis observed when using a preparation directly administered to the eye such as eye drops.
- the ophthalmic transdermal preparation of the present invention can be administered to the surface of the eyelid skin so that the muscarinic receptor agonist is substantially removed from the eyelid skin rather than being transferred to the local eye or tissue through the systemic circulation.
- transcutaneously transferring directly to the eye local tissue it is a formulation that has an excellent effect of promoting sustained lacrimal secretion compared to administration to sites other than the eyelid skin surface.
- the ophthalmic transdermal preparation of the present invention can continuously promote tear secretion and has few side effects such as miosis, so dry eyes such as tear reduction, dry eye disease, etc.
- Dry eye associated with eye diseases such as Siedalen syndrome, dry keratoconjunctivitis, Steepsson-Johnson syndrome, blepharitis, meibomian adenitis, VDT (V isua 1 D is 1 ay Termina 1) work, dry eye with contact lens wearing It is useful as a preventive-therapeutic agent.
- This application is based on Japanese Patent Application No. 20 0 4-1 5 1 2 4 8 filed in Japan, the contents of which are incorporated in full herein.
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JP2006519565A JP4308255B2 (ja) | 2004-05-21 | 2005-05-20 | ムスカリン受容体作動薬を含有する眼科用経皮吸収型製剤 |
PL05743236T PL1754491T3 (pl) | 2004-05-21 | 2005-05-20 | Preparat do oczu do wchłaniania przezskórnego zawierający agonistę receptora muskarynowego |
AT05743236T ATE459351T1 (de) | 2004-05-21 | 2005-05-20 | Ophthalmologische perkutan absorbierbare zubereitung enthaltend einen muscarin-rezeptor- agonist |
US10/569,772 US20070053964A1 (en) | 2004-05-21 | 2005-05-20 | Ophthalmic percutaneously absorbed preparation containing muscarinic receptor agonist |
EP05743236A EP1754491B1 (en) | 2004-05-21 | 2005-05-20 | Ophthalmic percutaneously absorbed preparation containing muscarinic receptor agonist |
DE602005019724T DE602005019724D1 (de) | 2004-05-21 | 2005-05-20 | Ophthalmologische perkutan absorbierbare zubereitung enthaltend einen muscarin-rezeptor-agonist |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2004-151248 | 2004-05-21 | ||
JP2004151248 | 2004-05-21 |
Publications (1)
Publication Number | Publication Date |
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WO2005113002A1 true WO2005113002A1 (ja) | 2005-12-01 |
Family
ID=35428256
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2005/009709 WO2005113002A1 (ja) | 2004-05-21 | 2005-05-20 | ムスカリン受容体作動薬を含有する眼科用経皮吸収型製剤 |
Country Status (9)
Country | Link |
---|---|
US (1) | US20070053964A1 (ja) |
EP (1) | EP1754491B1 (ja) |
JP (1) | JP4308255B2 (ja) |
CN (1) | CN1819846A (ja) |
AT (1) | ATE459351T1 (ja) |
DE (1) | DE602005019724D1 (ja) |
ES (1) | ES2342085T3 (ja) |
PL (1) | PL1754491T3 (ja) |
WO (1) | WO2005113002A1 (ja) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008026756A1 (en) * | 2006-08-28 | 2008-03-06 | Senju Pharmaceutical Co., Ltd. | Ophthalmic percutaneous absorption type preparation |
WO2016159351A1 (ja) * | 2015-04-03 | 2016-10-06 | 参天製薬株式会社 | 涙腺ドラッグデリバリーシステム |
WO2016182032A1 (ja) * | 2015-05-12 | 2016-11-17 | 参天製薬株式会社 | アゾール系抗真菌薬の眼瞼皮膚への投与 |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
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CN101123948A (zh) * | 2005-02-17 | 2008-02-13 | 千寿制药株式会社 | 眼科用固体外用药剂 |
US20110217387A1 (en) * | 2008-05-16 | 2011-09-08 | Axis, Inc. | Pharmaceutical composition for treatment of fibromyalgia |
US20100298335A1 (en) * | 2009-05-22 | 2010-11-25 | Kaufman Herbert E | Preparations and Methods for Ameliorating or Reducing Presbyopia |
US8299079B2 (en) | 2009-05-22 | 2012-10-30 | Kaufman Herbert E | Preparations and methods for ameliorating or reducing presbyopia |
PT2493474T (pt) * | 2009-10-30 | 2019-11-26 | Intratus Inc | Métodos e composições para libertação prolongada de fármacos |
US8900626B2 (en) | 2011-06-20 | 2014-12-02 | Senju Usa, Inc. | Transdermal drug delivery system and method of using the same |
CN102846607A (zh) * | 2012-04-09 | 2013-01-02 | 珠海亿邦制药股份有限公司 | 一种以盐酸西维美林为活性成分的固体制剂及其应用 |
WO2019209955A2 (en) | 2018-04-24 | 2019-10-31 | Allergan, Inc. | Presbyopia treatments |
US20210369686A1 (en) * | 2018-10-06 | 2021-12-02 | Biotheravision Llc | Ophthalmic preparations of muscarinic agonist and methods of use |
TWI809317B (zh) * | 2020-09-29 | 2023-07-21 | 美商百歐賽那生技公司 | 蕈毒鹼性促效劑眼用製劑及其用途 |
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2005
- 2005-05-20 DE DE602005019724T patent/DE602005019724D1/de active Active
- 2005-05-20 JP JP2006519565A patent/JP4308255B2/ja not_active Expired - Fee Related
- 2005-05-20 EP EP05743236A patent/EP1754491B1/en not_active Not-in-force
- 2005-05-20 WO PCT/JP2005/009709 patent/WO2005113002A1/ja not_active Application Discontinuation
- 2005-05-20 US US10/569,772 patent/US20070053964A1/en not_active Abandoned
- 2005-05-20 CN CNA2005800005733A patent/CN1819846A/zh active Pending
- 2005-05-20 AT AT05743236T patent/ATE459351T1/de not_active IP Right Cessation
- 2005-05-20 ES ES05743236T patent/ES2342085T3/es active Active
- 2005-05-20 PL PL05743236T patent/PL1754491T3/pl unknown
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CN101528211B (zh) * | 2006-08-28 | 2012-10-10 | 千寿制药株式会社 | 眼用经皮吸收型制剂 |
WO2016159351A1 (ja) * | 2015-04-03 | 2016-10-06 | 参天製薬株式会社 | 涙腺ドラッグデリバリーシステム |
WO2016182032A1 (ja) * | 2015-05-12 | 2016-11-17 | 参天製薬株式会社 | アゾール系抗真菌薬の眼瞼皮膚への投与 |
Also Published As
Publication number | Publication date |
---|---|
JPWO2005113002A1 (ja) | 2008-03-27 |
PL1754491T3 (pl) | 2010-08-31 |
JP4308255B2 (ja) | 2009-08-05 |
EP1754491A1 (en) | 2007-02-21 |
EP1754491A4 (en) | 2008-09-03 |
US20070053964A1 (en) | 2007-03-08 |
EP1754491B1 (en) | 2010-03-03 |
ATE459351T1 (de) | 2010-03-15 |
ES2342085T3 (es) | 2010-07-01 |
CN1819846A (zh) | 2006-08-16 |
DE602005019724D1 (de) | 2010-04-15 |
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