CN105326817A - Percutaneous-absorption preparation for treating eye diseases - Google Patents

Abstract

The invention relates to a percutaneous-absorption preparation for treating eye diseases. The percutaneous-absorption preparation comprises a carrier and a paste layer arranged on the carrier, the paste layer is an adhesive layer containing eye disease treating drug, the adhesive layer further contains a viscose-based agent, a percutaneous absorption promoting agent and a tackifier, the viscose-based agent contains polyisobutylene and polyisoprene, the tackifier is chosen from rosin resin, terpene resin, coumarone-indene resin and petroleum-based resin, and the preparation is used for being pasted on the surface of skin containing the front surface of an eyelid. Polyisobutylene and polyisoprene are adopted too replace styrene-isoprene-styrene segmented copolymer in the prior art, so that the eye disease treating drug in the paste layer is enabled to permeate local tissue of a drug receiving eye through skin without through blood flow of the whole body basically, and the preparation has better conjunctival transitivity.

Description

A kind of percutaneous absorption type preparation being used for the treatment of ophthalmic

Technical field

The present invention relates to the technical field of pharmaceuticals for the treatment of ophthalmic, particularly relate to a kind of percutaneous absorption type preparation being used for the treatment of ophthalmic.

Background technology

The preparation of known treatment ophthalmic has eye drop, eye ointment and oral agents etc.Eye drop containing Eye disease treating medicine, though quick-acting is good, easily flows out with tear, and lacks lasting medicine.In addition, in general, in order to long-term preservation, add antiseptic in eye drop of being everlasting, antiseptic easily becomes the reason producing and stimulate.Though eye ointment lasting medicine compared with eye drop is good, be difficult to the dosage accurately adjusting Eye disease treating medicine.And use eye ointment to cause visual deterioration sometimes.Though oral agents lasting medicine is good, easily cause side effect beyond affected part because acting on whole body.

Concerning Eye disease treating, for improving therapeutic effect, endeavouring to seek one always and both to the Eye disease treating medicine of the effective therapeutic dose of the eye such as conjunctiva or cornea local organization sustainable supply (topical), and can need not worry the Eye disease treating preparation of side effect.Such as, treatment anaphylaxis conjunctivitis or infect disease, to prevent after cataract operation complication etc., expecting can at long period constant drug effect.But also not having motion to go out at present can fully corresponding to the Eye disease treating preparation of this requirement.

In addition, this kind of as inflammation diminishing and pain easing plaster etc., there will be a known the percutaneous absorption type preparation of the adhesive Rotating fields being provided with drug containing on carrier.This percutaneous absorption type preparation in general belong to for Formulations for systemic administration Systemic formulations or stick on the preparation that the skin surface such as elbow, knee joint, waist, shoulder uses.

At present, in the technical field of Eye disease treating preparation, it is also proposed percutaneous absorption type preparation.Such as, motion Transcutaneous Therapeutic System, it has carrier layer, pressure sensitive caking property storage layer and strippable protective layer, this storage layer contains base or its salt of polymeric material and pilocarpine.This Transcutaneous Therapeutic System is not local application, but reduces intraocular pressure by making the pilocarpine as active substance be discharged into whole body from skin surface.

In addition, WO01/26648 proposes ophthalmic percutaneous absorption and sticks agent, has the medicated layer containing medicine and short transdermic absorbent in base substrate, thus can arrive any position comprising crystal, vitreous body, choroid and amphiblestroid rear eye.This ophthalmic percutaneous absorption sticks agent owing to medicine being made to arrive the illness portion of rear eye by the skin at other positions, thus belongs to the one of Systemic formulations.

In United States Patent (USP) No. 6277855 description, for dry eye treatment medicine, except the therapy of the topicals such as eye drop, eye ointment, also proposed by the patch of percutaneous or the therapy of dosage administration having liner.The patch of this percutaneous or liner agent by systemic Absorption dry eye treatment medicine and make it circulation and with tear contact tissue, thus also belong to the one of Systemic formulations.

When percutaneous absorption type preparation is Systemic formulations, the skin surface under agent permeates therethrough sticks by Intradermal capillary absorbance, and plays drug effect by this blood capillary through systemic blood flow.That is, drug percutaneous is discharged into whole body by systemic blood flow, and wherein a part arrives illness portion.This percutaneous Systemic formulations is as described below, and the treatment may not suffered from the ophthalmic as eye local organization illness is effective.

First, existing percutaneous Systemic formulations makes Eye disease treating medicine percutaneous be discharged into whole body by systemic blood flow, and thus medicine needs the local organization that could arrive eye for a long time, and the medicine of effective therapeutic dose is difficult to the local organization arriving eye.

The second, existing percutaneous Systemic formulations, is the local organization making the medicine of effective therapeutic dose arrive eye, to whole body release high amount of drug, probably can has side effects to the position beyond illness.

3rd, existing percutaneous Systemic formulations, the medicine of effective therapeutic dose is difficult to optionally arrive the outer part tissue of eye such as conjunctiva, tear tissue, cornea such as reaching posterior aspect of eyelids.That is, percutaneous Systemic formulations is unsuitable for as eye drop, and selectivity delivers medicine to outer part tissue of eye and plays drug effect.

On the other hand, when percutaneous absorption type preparation is topical formulations, be stick to use in the pars affecta skin such as elbow, knee joint, waist, the shoulder surface of human body for the purpose of anti-inflammatory analgesic etc. in general, but not treat for the purpose of ophthalmic trouble.

CN103127033A discloses a kind of percutaneous absorption preparation for treating ophthalmic disease, its use and the Eye disease treating medicine transfer method to eye local organization, described percutaneous absorption type preparation has the structure being provided with the paste layer containing Eye disease treating medicine on carrier, stick on the skin surface containing eyelid front surface, make Eye disease treating medicine in paste layer substantially not by systemic blood flow by transdermal administration eye local organization.Although this percutaneous absorption type preparation has good drug administration targeting, its effect need further raising.

Summary of the invention

The object of the present invention is to provide a kind of percutaneous absorption type preparation being used for the treatment of ophthalmic, its not only can make Eye disease treating medicine in paste layer substantially not by systemic blood flow by transdermal administration eye local organization, and its conjunctiva transitivity result of the test display effect is more excellent than prior art.

The present invention includes following content:

A kind of percutaneous absorption type preparation being used for the treatment of ophthalmic, comprise carrier and be located at the paste layer on described carrier, described paste layer is the viscose glue oxidant layer containing Eye disease treating medicine, also containing viscose glue base, short transdermic absorbent and viscosifier in described viscose glue oxidant layer, described viscose glue base contains polyisobutylene and polyisoprene, and described viscosifier are selected from rosin based resin, terpene resins, coumarone-indene resin and petroleum line resin; Described preparation is for sticking on the skin surface containing eyelid front surface.

The present invention mainly replaces the styrene isoprene styrene block copolymer (SIS) in CN103127033A with polyisobutylene and polyisoprene, and furthers investigate, and finds that its conjunctiva transitivity result of the test is more excellent.

In the present invention, the content of described polyisobutylene and polyisoprene accounts for the 10-90% of described viscose glue oxidant layer, preferred 20-70%, more preferably 40-60%.

In the present invention, described Eye disease treating medicine is 0.1 ~ 60 weight portion relative to the ratio of viscose glue oxidant layer 100 weight portion, preferred 0.3-20 weight portion.

In the present invention, viscose glue oxidant layer is the rubber-like viscose glue oxidant layer containing polyisobutylene and polyisoprene 100 weight portion, viscosifier 10-400 weight portion, short transdermic absorbent 1-50 weight portion and Eye disease treating medicine 0.1-60 weight portion.

In the present invention; described short transdermic absorbent is fatty alcohol, fatty acid, fatty acid ester, hydramine, polyol alkyl ether, polyoxyethylene alkyl ether, glyceride, polyhydric alcohol medium chain fatty acid ester, lactic acid alkyl ester, alkyl dicarboxylate, acylated amino, pyrrolidinone compounds, lactic acid, tartaric acid, 1; 2,6-hexanetriol, benzyl alcohol, lanoline, potassium hydroxide, three (methylol) aminomethanes or their mixture of more than two kinds.

In the present invention, described Eye disease treating medicine is antiviral agent, antibacterial, antifungal, anti-allergic agent, antiinflammatory, nonsteroidal anti inflammatory agent, analgesic agent, the agent of antiinflammatory enzyme, antibiotic, sulfa drug, syncillin, therapeutic agent for glaucoma, agent for treating cataract, miotic, mydriatic, local convergence agent, vasoconstrictor, intraocular pressure rising preventing agent, ocular hypertension therapeutic agent, topical anesthetic cream, α 1 receptor blocking agent, beta-blocker, β1receptorblocker, carbonic acid dehydrogenase blocker, local selectivity H1 receptor blocking agent, adrenocortical hormone, vitamin B12, coenzyme type vitamin B2, anticholinesterase or organic iodine preparation.

In the present invention, described Eye disease treating medicine is the compound of molecular weight less than 1000.

In the present invention, described Eye disease treating medicine is ketotifen fumarate or Diclofenac.

In the present invention, described percutaneous absorption type preparation has can along the shape comprising upper eyelid, the skin surface of palpebra inferior or two eyelid front surfaces sticks.

In the present invention, described carrier is selected from non-woven fabrics, weaves cotton cloth, the complex of thin film, porous plastid, foaming body, paper, non-woven fabrics or upper laminated film of weaving cotton cloth;

Preferably, the material of described non-woven fabrics is selected from polyolefin resin, polyester resin, artificial silk, polyamide, polyester ether, polyurethane, polyacrylics, polyvinyl alcohol, styrene-isoprene-styrene copolymer-and styrene ethylene-propylene-styrol copolymer.

Beneficial effect of the present invention is: the present invention adopt polyisobutylene and polyisoprene replace of the prior art in styrene isoprene styrene block copolymer (SIS), further investigation, it is more excellent than using the percutaneous absorption type preparation of styrene isoprene styrene block copolymer (SIS) to find its conjunctiva transitivity result of the test.Therefore, percutaneous absorption type preparation of the present invention not only can make Eye disease treating medicine in paste layer substantially not by systemic blood flow by transdermal administration eye local organization, and its conjunctiva transitivity is better.

Detailed description of the invention

The typical example of percutaneous absorption preparation for treating ophthalmic disease of the present invention can enumerate adhesive tape preparation.Adhesive tape preparation is the percutaneous absorption type preparation arranging the adhesive Rotating fields containing Eye disease treating medicine on carrier.Adhesive tape agent, by the bonding force of viscose glue oxidant layer, can directly be applied at the skin surface containing eyelid by note, therefore more easy to operate and use than application.

In rubber-like adhesive, polyisobutylene and polyisoprene rubber shape elastomer are as the adhesive of adhesive base.Rubber-like adhesive is the compositions of adding the viscosifier such as such as rosin based resin, terpene resins, coumarone-indene resin, petroleum line resin in the rubber-like elastic body as adhesive base.As required, various additive can be added in adhesive base, the softening agents such as such as liquid polybutene, liquid polyisobutene, Dormant oils; The filler such as titanium oxide, zinc oxide; The antioxidant such as BHT, propyl gallate (stabilizing agent) etc.

Viscosifier are relative to rubber-like elastic body 100 weight portion, and usage ratio is generally 10 ~ 400 weight portions, preferably 50 ~ 300 weight portions, more preferably 70 ~ 200 weight portions.When using softening agent, relative to rubber-like elastic body 100 weight portion, usage ratio is generally 1 ~ 90 weight portion, preferably 5 ~ 50 weight portions.

When manufacturing the adhesive tape preparation (also claiming " sticking agent ") using rubber-like adhesive, the general rubbing method, hot fusion method, rolling process etc. adopting adhesive solution.The rubbing method of adhesive solution is utilize to stick agent peeling off the solution of the organic solvent containing Eye disease treating medicine and adhesive composition of coating on backing or carrier and make it dry method preparation.Organic solvent can list such as toluene, ethyl acetate, hexane etc.

Hot fusion method, such as, after heated and stirred, heat are melted under nitrogen permutizer condition by the adhesive composition beyond Eye disease treating medicine, adds ingredient mix homogeneously after temperature declines.Then, utilize and the adhesive compositions containing ingredient to be utilized heat to melt coating machine peeling off backing to extend and the method for laminate carrier thereon, preparation sticks agent.

Rolling process, such as, by after rubber-like elastic body mastication, after temperature declines, adds viscosifier and carries out mixing.Then, after temperature declines further, add softening agent and carry out mixing.Finally, add ingredient and carry out mixing, be prepared into adhesive compositions.Utilize and this adhesive compositions is extended on stripping backing, and the method preparation of laminate carrier sticks agent thereon.Temperature conditions or mixing time etc. carry out suitable change by the kind of rubber-like elastic body and the proportioning prescription etc. of adhesive compositions.Usually, stripping backing is coated with adhesive compositions, also can according to expectation, on carrier, the rear lamination of coating is as the stripping backing of lining material.

Carrier preferably has the material of the flexibility of the degree of the skin surface that can be bonded in containing the eyelid front surface having fluctuating.Carrier does not more preferably adsorb medicine and can discharge the material of medicine from carrier side.The object lesson of carrier can be enumerated non-woven fabrics, weaves cotton cloth, the complex of thin film (sheet-containing), porous plastid, foaming body, paper, non-woven fabrics or upper laminated film of weaving cotton cloth, but is not limited thereto.

As the material of the non-woven fabrics that carrier uses, include, for example out the polyolefin resin such as polyethylene, polypropylene; The polyester resins such as polyethylene terephthalate, polybutylene terephthalate (PBT), PEN; Artificial silk, polyamide, polyester ether, polyurethane, polyacrylics, polyvinyl alcohol, styrene-isoprene-styrene copolymer-, styrene ethylene-propylene-styrol copolymer etc.The material of weaving cotton cloth can enumerate cotton, artificial silk, polyacrylics, polyester resin, polyvinyl alcohol, but is not limited thereto.

As the material of the thin film that carrier uses, include, for example out the polyolefin resin such as polyethylene, polypropylene; The polyester resins such as the polyacrylics such as polymethyl methacrylate, polyethyl methacrylate, polyethylene terephthalate, polybutylene terephthalate (PBT), PEN; Cellophane cover, polyvinyl alcohol, ethylene-vinyl alcohol copolymer, polrvinyl chloride, polystyrene, polyurethane, polyacrylonitrile, fluororesin, styreneisobutylene-styrol copolymer, SBR styrene butadiene rubbers, polybutadiene, ethene-vinyl acetate copolymer, polyamide, polysulfones, but be not limited thereto.

Paper can list such as impregnation paper, coated paper, good quality paper, kraft paper, Japanese paper, cellophane cover, synthetic paper.Complex can be enumerated and press at above-mentioned non-woven fabrics or upper strata of weaving cotton cloth the complex stating thin film.

The present invention uses Eye disease treating medicine as medicine.As Eye disease treating medicine, all the time, the various medicines used such as eye drop or eye ointment are widely used.About the object lesson (drug effect classification) of this Eye disease treating medicine, as required, antiviral agent (keratitis that herpes simplex causes) can be enumerated together with indication, antibacterial (infects disease: conjunctivitis, blepharitis, corneal tumor, dacryocystisis), antifungal, anti-allergic agent (anaphylaxis conjunctivitis, pollinosis, vernal conjunctivitis), antiinflammatory (conjunctivitis, surface cornea is scorching, blepharitis, scleritis), nonsteroidal anti inflammatory agent (anaphylaxis conjunctivitis), analgesic agent, antiinflammatory enzyme agent (chronic conjunctivitis), antibiotic (infects disease: trachoma, conjunctivitis, blepharitis, blepharitis, keratitis, hordeolum, corneal ulcer, meibomitis, dacryocystisis), sulfa drug (trachoma, conjunctivitis, blepharitis, blepharitis, corneal ulcer, keratitis), syncillin (infecting disease), therapeutic agent for glaucoma, agent for treating cataract, miotic, mydriatic, local convergence agent, vasoconstrictor, intraocular pressure rising preventing agent, ocular hypertension therapeutic agent, topical anesthetic cream, α 1 receptor blocking agent (glaucoma, ocular hypertension), beta-blocker (glaucoma, ocular hypertension), β1receptorblocker (glaucoma, ocular hypertension), carbonic acid dehydrogenase blocker, local selectivity H1 receptor blocking agent (anaphylaxis conjunctivitis), adrenocortical hormone (outer eye, the heteropathy of the inflammatory disease of front eye), vitamin B12 (eyestrain), coenzyme type vitamin B2 (keratitis, blepharitis), anticholinesterase (glaucoma, accommodative esotropia, myasthenia gravis), organic iodine preparation (centrality omentitis).

In these Eye disease treating medicines, particularly preferably antibacterial, anti-allergic agent, nonsteroidal anti inflammatory agent (anti-inflammatory agent).In addition, object disease preferred eye infections disease anaphylaxis conjunctivitis, pollinosis, vernal conjunctivitis.Percutaneous absorption preparation for treating ophthalmic disease of the present invention also can be preferred for the prevention and therapy of post-operation inflammatory, postoperative infection.

Concrete medicine name used in eye drop or eye ointment etc., include, for example out acyclovir, 3'-(1H-Tetrazol-5-yl)oxanilic acid hydrate, azulene, anthranilic acid ascorbic acid, amlexanox, Isopropyl Unoprostone, idoxuridine, ibudilast, indometacin, epinephrine, erythromycin, chlorine lysozyme, hydrochloric acid apraclonidine, Oxybuprocaine, carteolol hydrochloride, cyclopentolate hydrochloride, dipivefrine hydrochloride, Abbott 50192, dorzolamide hydrochloride, pilocarpine hydrochloride, phenylephrine hydrochloride, E-643, betaxolol hydrochloride, Befunolonum, hydrochloric acid levocabastine, Levobunolol Hydrochorid, lomefloxacin hydrochloride, ofloxacin, carbachol, glycyrrhetinic acid dipotassium, glutathion, sodium cromoglicate, chloromycetin, hydrocortisone acetate, prednisolone acetate, vitamin B12, diclofenac sodium, distigmine bromide, homatropine hydrobromide, silver nitrate, privine, iodo calcium stearate, ganda, kedacillin, dexamethasone, tobramycin, tranilast, holder bicalutamide, nipradilol, norfloxacin, natamycin, pirenoxine, ketotifen fumarate, pranoprofen, flavin adenine dinucleotide (FAD), fluorometholone, prednisolone, bromine phenolic acid sodium hydrate, the special potassium of pyridine department, hederin, timolol maleate, neostigmine, first sulfosalicylic acid sodium dexamethasone, ecostigmine, latanoprost, lignocaine, lidocaine hydrochloride, atropine sulfate, gentamycin sulfate, sisomicin sulfate, sulphuric acid dibekacin, Micronomicin Sulfate, DEXAMETHASONE SODIUM PHOSPHATE, Betamethasone phosphate sodium, levofloxacin magnitude.

In these Eye disease treating medicines, from the angle of Percutaneously absorbable and skin permeability, the medicine of the compound composition of preferred molecular weight less than 1000.In addition, in these Eye disease treating medicines, the more preferably antibacterial of molecular weight less than 1000, anti-allergic agent and nonsteroidal anti inflammatory agent.The molecular weight of these Eye disease treating medicines more preferably less than 800, particularly preferably less than 600 or 500.

And, in these Eye disease treating medicines, ketotifen fumarate (anti-allergic agent, antihistaminic; Molecular weight 425.5) and diclofenac sodium (nonsteroidal anti inflammatory agent: molecular weight 318.13) is from the angle of Percutaneously absorbable, skin permeability and drug effect particularly preferably.

In the present invention, when needing to make Eye disease treating medicine be soluble in adhesive or application base (moisture mastic), when modulating the coating fluid or coating composition that contain each composition, cosolvent can be used.Cosolvent can list fatty acid ester, Menthol, the Herba Menthae wet goods of such as crotamiton, ethanol, carbamide, water-soluble organic amine, propylene glycol.Cosolvent can be used alone or two or more combinationally uses.

In the present invention, for promoting the Percutaneously absorbable of Eye disease treating medicine, short transdermic absorbent can be used.Short skin of the present invention not only can make percutaneous drug absorption through absorbent, also makes drugs through skin, therefore also cries transdermal promoter.

Short transdermic absorbent can list such as fatty alcohol, fatty acid, fatty acid ester, hydramine, polyol alkyl ether, polyoxyethylene alkyl ether, glyceride (i.e. the fatty acid ester of glycerol), polyhydric alcohol medium chain fatty acid ester, lactic acid alkyl ester, alkyl dicarboxylate, acylated amino, pyrrolidinone compounds, but is not limited thereto.These short transdermic absorbents can be used alone or two or more combinationally uses.Aliphatic alcohols is as the saturated or undersaturated higher alcohol of the carbon numbers 12 ~ 22 such as preferred oleyl alcohol, lauryl alcohol.Fatty acids is as listed linoleic acid, oleic acid, linolenic acid, stearic acid, isostearic acid, Palmic acid.Hydramine can list such as triethanolamine, Triethanolammonium chloride, diisopropanolamine (DIPA).Fatty acid ester can list such as isopropyl myristate, diisopropyl adipate, isopropyl palmitate.Polyol alkyl ether can list the alkyl ether of the polyhydric alcohol such as such as glycerol, ethylene glycol, propylene glycol, 1,3 butylene glycol, two glycerol, polyglycereol, diethylene glycol, Polyethylene Glycol, dipropylene glycol, polypropylene glycol, sorbitan, Sorbitol, methyl glucosamine, oligosaccharide, reduction oligosaccharide.The carbon number of the moieties of polyol alkyl ether preferably 6 ~ 20.The carbon number of polyoxyethylene alkyl ether preferred alkyl part is 6 ~ 20, and the repetitive (-O-CH2CH2-) of polyoxyethylene chain number is the polyoxyethylene alkyl ether of 1 ~ 9.The concrete example of this polyoxyethylene alkyl ether, can list polyoxyethylene lauryl ether, Polyoxyethylene cetyl ether, polyoxyethylene stearyl base ether, polyoxyl 10 oleyl ether.The glyceride of the fatty acid of the preferred carbon number 6 ~ 18 of glyceride.Glyceride is distinguished as monoglyceride, two glyceride, triglyceride according to the fatty acid number combined, but all can use.In addition, their mixture (such as, the mixture of list and two-glyceride) can also be used.The preferred fatty acid composition forming glyceride can enumerate such as sad, capric acid, dodecylic acid, tetradecanoic acid, hexadecanoic acid, octadecanoid acid (i.e. stearic acid), oleic acid.

In addition, the various short transdermic absorbent such as lactic acid, tartaric acid, 1,2,6-hexanetriol, benzyl alcohol, lanoline, potassium hydroxide (KOH), three (methylol) aminomethane can suitably be used.

In these short transdermic absorbents (transdermal promoter), the polyoxyethylene alkyl ethers such as fatty acid ester, polyoxyl 10 oleyl ether such as the hydramine such as fatty acid, diisopropanolamine (DIPA), isopropyl myristate, isopropyl palmitate such as aliphatic higher alcohol, isostearic acid such as preferred lauryl alcohol; The compound of KOH, three (methylol) aminomethane etc.; Or their mixture of more than two kinds.

Eye disease treating medicine is relative to mastic base 100 weight portions such as adhesives, and usage ratio is generally 0.1 ~ 60 weight portion, preferably 0.3 ~ 20 weight portion.Eye disease treating medicine containing proportional too small, be difficult to obtain and continue and drug effect fully, containing proportional excessive, sometimes crystallization, cause bonding force to decline.

Cosolvent is relative to adhesive 100 weight portion, and usage ratio is generally 0 ~ 60 weight portion, preferably 0 ~ 20 weight portion.Short transdermic absorbent (transdermal promoter) is relative to mastic base 100 weight portions such as adhesives, and usage ratio is generally 1 ~ 50 weight portion, preferably 2 ~ 40 weight portions.Only otherwise hinder the drug effect of Eye disease treating medicine and the cohesive of adhesive, various additives etc. known containing the art in the paste layers such as viscose glue oxidant layer can be made as required.

Percutaneous absorption preparation for treating ophthalmic disease of the present invention can manufacture by existing described method.Here, more specific description is carried out by preferred Production Example.Percutaneous absorption preparation for treating ophthalmic disease of the present invention has the structure being provided with the paste layer containing Eye disease treating medicine on carrier.The paste layers such as viscose glue oxidant layer are typically provided with stripping backing.The application target peeling off backing is protection paste layer, can list the material that such as polyethylene coating good quality paper, polyolefin coating cellophane cover, siloxane treated such as one side such as polyethylene terephthalate (polyester) thin film, polypropylene film etc. are crossed.

When percutaneous absorption preparation for treating ophthalmic disease of the present invention is application, can utilizes and manufacture being coated on carrier containing the moisture mastic of medicine or peeling off on backing in base.When percutaneous absorption preparation for treating ophthalmic disease of the present invention is patch (adhesive tape preparation), by the manufacture method of general patch---solvent coating method, hot fusion method, rolling process etc. manufacture.

Percutaneous absorption preparation for treating ophthalmic disease of the present invention preferably employs the viscose glue banding pattern preparation of rubber-like adhesive.Solvent coating method such as, to in glass-lined metal groove, add the organic solvents such as normal hexane, toluene, ethyl acetate, then add various rubber-like elastic body, viscosifier, antioxidant etc. wherein, stir 2 ~ 10 hours, preferably 3 ~ 7 hours until uniform dissolution.Then, in this adhesive solution, add the Eye disease treating medicine of ormal weight, add cosolvent, short transdermic absorbent etc. as required.Continue stirring about 10 ~ 120 minutes.The coating machines such as doctor knife coater, oppositely coating machine will be used, even spread ormal weight on carrier by gained coating fluid thus.After coating, place about 1 ~ 10 minute under the uniform temperature atmosphere of 40 ~ 120 DEG C, organic solvent is volatilized.Suitable drying condition is set according to the kind of organic solvent and coating layer thickness.The mylar that siloxane treated is crossed in the laminating of the surface of viscose glue oxidant layer or polyethylene coating good quality paper etc. peel off backing, are cut into given size as patch.Also coating fluid can be coated, at the surface laminated carrier of viscose glue oxidant layer after drying on the one side peeling off backing.

When using the adhesive that can hot melt, heat can be carried out and melt coating.In hot fusion method, the adhesive composition beyond ingredient after heated and stirred, dissolving, is added ingredient mix homogeneously under nitrogen displacement, at temperature 100 ~ 150 DEG C after reducing the temperature to 100 ~ 120 DEG C.Then, melt rubbing method by heat and the adhesive compositions containing ingredient extended on stripping film, laminate carrier makes patch thereon.Temperature conditions etc. preferably set the suitableeest scope according to the kind etc. of adhesive base.

When adopting rolling process, such as, temperature after about 5 ~ 20 minutes, is dropped to about 100 ~ 120 DEG C, adds viscosifier, mixing about 5 ~ 10 minutes by rubber-like elastic body mastication at 130 DEG C.Then, after till temperature drops to about 70 ~ 90 DEG C, add softening agent, mixing about 5 ~ 10 minutes, finally, add Eye disease treating medicine, cosolvent, short transdermic absorbent etc. mixing about 5 ~ 10 minutes, obtain ointment-containing body.It is extended on the mylar crossed through siloxane treated the thickness of 0.1mm, then, by viscose glue oxidant layer upper strata ballast carrier, can be made into patch.Temperature or mixing time etc. can set suitable preferable range according to the kind of adhesive base used etc.

Percutaneous absorption preparation for treating ophthalmic disease of the present invention sticks on the skin surface containing eyelid front surface, for the Eye disease treating medicine percutaneous in paste layer being given the local organization of eye.Skin surface containing eyelid front surface refers to upper eyelid, the front surface (skin surface) of palpebra inferior or two eyelids or the skin surface of above-mentioned eyelid and the skin surface of its periphery.

Therefore, percutaneous absorption preparation for treating ophthalmic disease of the present invention preferably have can along upper eyelid, the shape that sticks of the skin surface of palpebra inferior or two eyelids.The object lesson of these shapes, can enumerate along the such shape such as tetragon, ellipse, triangle, circle, the shape of a hoof, ring-type of the shape of eyelid front surface.

Percutaneous absorption preparation for treating ophthalmic disease of the present invention can stick on the skin surface containing eyelid front surface, makes Eye disease treating medicine in paste layer substantially not by systemic blood flow, but the local organization of administration through skin eye.

As mentioned above, in percutaneous absorption preparation for treating ophthalmic disease of the present invention, so-called make the Eye disease treating medicine in paste layer substantially not by systemic blood flow but the local organization of administration through skin eye refer to by Eye disease treating medicine from the skin surface sticking percutaneous absorption preparation for treating ophthalmic disease mainly through cutaneous metastatic to part tissue of eye such as conjunctiva, tear tissue, corneas, before systemic blood flow arrives eye local organization, just play the mode administration of drug effect with a part for this Eye disease treating medicine.

More particularly, when percutaneous absorption preparation for treating ophthalmic disease of the present invention is sticked on the skin surface containing eyelid front surface, to stick the transfer amount (unit: μ g/gtissue) of the outside part tissue of eye of medicine under the sticking within latter 8 hours be medicine by usual more than 4 times of the transfer amount of the outside part tissue of eye of systemic blood flow, preferably more than 5 times, more preferably more than 7 times, particularly preferably more than 8 times.

Below in conjunction with embodiment, embodiment of the present invention are described in detail.It will be understood to those of skill in the art that following examples are only the preferred embodiments of the present invention, so that understand the present invention better, thus should not be considered as limiting scope of the present invention.For a person skilled in the art, the present invention can have various modifications and variations, within the spirit and principles in the present invention all, and any amendment done, equivalent replacement or improvement etc., all should be included within protection scope of the present invention.Experimental technique in following embodiment, if no special instructions, is conventional method; Experiment material used, if no special instructions, is and is purchased available from routine biochemistry chemical reagent work.

Embodiment 1: polyisobutylene and polyisoprene are as rubber-like elastic body

Be dissolved in as the polyisobutylene 18.5g of rubber-like elastic body and polyisoprene 22g, the terpene resin 40.5g as viscosifier, the BHT 1g as antioxidant, the ketotifen fumarate 10g as Eye disease treating antiallergic agent, the lauryl alcohol 3g as absorption enhancer and diisopropanolamine (DIPA) 5g in toluene 150g, obtain the adhesive solution (coating fluid) of solid constituent 40 % by weight.Peeling paper makes dried thickness reach 40 μm this coating solution, sticking carrier (mylars of thick 12 μm) after drying becomes patch.

Comparative example 1: styrene isoprene styrene block copolymer (SIS) is as rubber-like elastic body

Using the styrene isoprene styrene block copolymer (SIS) 40.5g as rubber-like elastic body, terpene resin 40.5g, the BHT 1g as antioxidant as viscosifier, the ketotifen fumarate 10g as Eye disease treating antiallergic agent, be dissolved in toluene 150g as the lauryl alcohol 3g of absorption enhancer and diisopropanolamine (DIPA) 5g, obtain the adhesive solution (coating fluid) of solid constituent 40 % by weight.Peeling paper makes dried thickness reach 40 μm this coating solution, sticking carrier (mylars of thick 12 μm) after drying becomes patch.

Test example 1: to the transitivity of conjunctiva

The test preparation that hair part sticks the tetragon being cut into 1 × 4cm is shaved at rabbit palpebra inferior.Disbonded test preparation after after 1h with 12 hours, peels off the skin of eyelid part under anaesthesia, takes conjunctiva.By quantitative by high performance liquid chromatography (HPLC) for the amount of the medicine contained in conjunctiva.For eye drop, after dripping 1 to rabbit eye, also carry out same operation.Conjunctiva transitivity result of the test is as shown in table 1.

Table 1 conjunctiva transitivity result of the test

N=7, average ± SE

Embodiment 2: polyisobutylene and polyisoprene are as rubber-like elastic body

Till being bonded to evenly as the polyisobutylene 200g of rubber-like elastic body and polyisoprene 200g, the terpene resin 400g as viscosifier, the liquid paraffin 125g as softening agent, the Diclofenac 5g as Eye disease treating nonsteroidal antiinflammatory drug, the refining of the isostearic acid 60g heated type mixing roll as absorption enhancer.After refining is closed, it is 200 μm that the siloxanes face of the stripping backing being used by mixture calender to cross in one side siloxane treated extends into thickness, and then sticking carrier (mylars of thick 12 μm) becomes patch.

Comparative example 2: styrene isoprene styrene block copolymer (SIS) is as rubber-like elastic body

Using the styrene isoprene styrene block copolymer (SIS) 400g as rubber-like elastic body, terpene resin 400g, the liquid paraffin 125g as softening agent as viscosifier, the Diclofenac 5g as Eye disease treating nonsteroidal antiinflammatory drug, as till the isostearic acid 60g heated type mixing roll refining of absorption enhancer is bonded to evenly.After refining is closed, it is 200 μm that the siloxanes face of the stripping backing being used by mixture calender to cross in one side siloxane treated extends into thickness, and then sticking carrier (mylars of thick 12 μm) becomes patch.

Test example 2: to the transitivity of conjunctiva

The test preparation that hair part sticks the tetragon being cut into 1 × 4cm is shaved at rabbit palpebra inferior.Disbonded test preparation after after 1h with 12 hours, peels off the skin of eyelid part under anaesthesia, takes conjunctiva.By quantitative by high performance liquid chromatography (HPLC) for the amount of the medicine contained in conjunctiva.For eye drop, after dripping 1 to rabbit eye, also carry out same operation.Conjunctiva transitivity result of the test is as shown in table 2.

Table 2 conjunctiva transitivity result of the test

N=7, average ± SE

The above results shows: the present invention adopt polyisobutylene and polyisoprene replace of the prior art in styrene isoprene styrene block copolymer (SIS), its conjunctiva transitivity result of the test is more excellent than using the percutaneous absorption type preparation of styrene isoprene styrene block copolymer (SIS).Therefore, percutaneous absorption type preparation of the present invention not only can make Eye disease treating medicine in paste layer substantially not by systemic blood flow by transdermal administration eye local organization, and its conjunctiva transitivity is better.

Embodiment 3: polyisobutylene and polyisoprene are as rubber-like elastic body

Be dissolved in as the polyisobutylene 20.5g of rubber-like elastic body and polyisoprene 29.5g, the terpene resin 50g as viscosifier, the BHT 1g as antioxidant, the ketotifen fumarate 10g as Eye disease treating antiallergic agent, the lauryl alcohol 3g as absorption enhancer and diisopropanolamine (DIPA) 5g in toluene 150g, obtain the adhesive solution (coating fluid) of solid constituent 40 % by weight.Peeling paper makes dried thickness reach 40 μm this coating solution, sticking carrier (mylars of thick 12 μm) after drying becomes patch.

Use above-mentioned gained patch (percutaneous absorption preparation for treating ophthalmic disease), carry out medicine ketotifen fumarate with reference to following method and test to the transitivity of conjunctiva.

1. test method

1) animal

Animal adopts and combines by the rugged foster rabbit of good fortune the male rabbit of Japanese white that the body weight bought is about 2kg, by it respectively in the receptacle of general areas, raises under the condition of temperature 23 ± 3 DEG C, humidity 55 ± 10%.

2) pretreatment of animal

For sticking percutaneous absorption type preparation, use in advance through the rabbit of depilation process.Depilation process is also with under Ketoprofen/xylazine (xylazine) anesthesia, uses clippers and electric shaver to carry out in the mode not injuring skin lagophthalmos periphery and back.

3) administration

Ketotifen percutaneous absorption type preparation is pasted 4cm at the upper and lower eyelid skin of rabbit after depilation process and skin of back place ².

The situation of upper and lower eyelid skin: will 1cm × 2cm=2cm be cut into ²

The percutaneous absorption type preparation of size sticks on each up and down 2cm of the eyelid of a branch hole respectively ².

The situation of skin of back: will 2cm × 2cm=4cm be cut into ²the percutaneous absorption type preparation of size sticks on skin of back.

4) ocular tissue is taked

Take tear every predetermined following time point blood capillary, with overdose of sodium pentobarbital solution, euthanasia is implemented to rabbit.After front eye brine, under the state of possessing conjunctiva, win out eyeball, gather conjunctiva.

Take time point: 4,8,24 hours

5) pretreatment of ocular tissue's sample

Conjunctiva: add phosphate sodium dihydrogen buffer solution 1mL and fritter conjunctiva.Add after 4mL acetonitrile shakes 10 minutes at 300 rpm, centrifugalize 10 minutes at 3,000 rpm.Then get supernatant 4mL in another in vitro carry out decompression solid after, dissolve again in HPLC mobile phase.This solution filter membrane (0.22 μm) is filtered, using filtrate as HPLC working sample.

Tear: after adding HPLC mobile phase 150 μ L stirring, as HPLC working sample.

6. concentration determination

High performance liquid chromatography is used to measure ketotifen fumarate concentration by following HPLC condition.

Detector: ultraviolet spectrophotometer (measuring wavelength 300nm)

Chromatographic column: CapcellpakC18MGS5 μm, 4.5 × 250mm, Shiseido guard column (TOSOH, 80Ts)

Column temperature: the uniform temperature near 40 DEG C

Mobile phase: 0.1M tri-(methylol) aminomethane buffer solution (pH9): acetonitrile=30:70

Flow velocity: 1.0mL/ minute

Injection rate: 50 μ L

The ketotifen fumarate of the percutaneous absorption preparation for treating ophthalmic disease using embodiment 3 to modulate is as shown in table 3 to the transitivity result of the test of conjunctiva.

Table 3 conjunctiva transitivity result of the test

Unit: [μ g/gtissue]

The result of table 3 shows: when percutaneous absorption preparation for treating ophthalmic disease of the present invention is sticked on animal subject skin of back, medicine (ketotifen fumarate) through the skin surface under sticking by Intradermal capillary absorbance, the amount of two conjunctivas is arrived again through systemic blood flow, even if the level through maintaining 0.01 ~ 0.03 μ about g/g from sticking for 4 hours, 8 hours and 24 hours from this blood capillary.That is, the amount that medicine is shifted to eye local organization (conjunctiva of outer ocular tissue) by systemic blood flow is minute quantity.

On the other hand, when percutaneous absorption preparation for treating ophthalmic disease of the present invention is sticked on the skin surface of upper palpebra inferior, the medicine of the high concentration reaching 4.60 μ g/g is had after 4 hours to the conjunctiva place transfer under sticking from sticking, subsequently, its transfer amount is 3.02 μ g/g after 8 hours, be 0.15 μ g/g after 24 hours, maintain high level.

On the other hand, do not stick the eye (relative eye) of percutaneous absorption preparation for treating ophthalmic disease of the present invention although medicine reach the higher level of 0.38 μ g/g after 4 hours to the transfer amount of conjunctiva, only stick lower to conjunctiva transfer amount 4.60 μ g/g about 8.5 about % by weight level.And the transfer amount of medicine is significantly reduced to 0.03 μ g/g after 8 hours, and be significantly reduced to 0.01 μ g/g after 24 hours, the persistence of drug effect is poor.

Above-mentioned experimental result display: percutaneous absorption preparation for treating ophthalmic disease of the present invention can make Eye disease treating medicine in viscose glue oxidant layer substantially not by systemic blood flow, but administration through skin eye local organization.More particularly, when percutaneous absorption preparation for treating ophthalmic disease of the present invention is sticked on eyelid by the display of above-mentioned experimental result and when sticking on back, there were significant differences for the conjunctiva concentration of medicine, and the display of this experimental result, by invention formulation is sticked on eyelid, medicine can continue and shift in high concentration.

And, the drug level not sticking the relative eye conjunctiva of eyelid is significantly lower than the drug level of the eye conjunctiva sticking eyelid, and blood drug level (<0.005 μ g/mL) below detection limit value shows, when invention formulation being sticked on eyelid position, medicine shifts to conjunctiva compared to through systemic blood flow, and from sticking, eyelid position percutaneous shifts to conjunctiva especially.

Applicant states, the present invention illustrates detailed features of the present invention and method detailed by above-described embodiment, but the present invention is not limited to above-mentioned detailed features and method detailed, namely do not mean that the present invention must rely on above-mentioned detailed features and method detailed could be implemented.Person of ordinary skill in the field should understand, any improvement in the present invention, to equivalence replacement and the interpolation of auxiliary element, concrete way choice etc. that the present invention selects component, all drops within protection scope of the present invention and open scope.

Claims (10)

1. one kind is used for the treatment of the percutaneous absorption type preparation of ophthalmic, comprise carrier and be located at the paste layer on described carrier, described paste layer is the viscose glue oxidant layer containing Eye disease treating medicine, also containing viscose glue base, short transdermic absorbent and viscosifier in described viscose glue oxidant layer, described viscose glue base contains polyisobutylene and polyisoprene, and described viscosifier are selected from rosin based resin, terpene resins, coumarone-indene resin and petroleum line resin; Described preparation is for sticking on the skin surface containing eyelid front surface.

2. percutaneous absorption type preparation according to claim 1, is characterized in that, the content of described polyisobutylene and polyisoprene accounts for the 10-90% of described viscose glue oxidant layer, preferred 20-70%, more preferably 40-60%.

3. percutaneous absorption type preparation according to claim 1 and 2, is characterized in that, described Eye disease treating medicine is 0.1 ~ 60 weight portion relative to the ratio of viscose glue oxidant layer 100 weight portion, preferred 0.3-20 weight portion.

4. the percutaneous absorption type preparation according to any one of claim 1-3, it is characterized in that, viscose glue oxidant layer is the rubber-like viscose glue oxidant layer containing polyisobutylene and polyisoprene 100 weight portion, viscosifier 10-400 weight portion, short transdermic absorbent 1-50 weight portion and Eye disease treating medicine 0.1-60 weight portion.

5. the percutaneous absorption type preparation according to any one of claim 1-4; it is characterized in that; described short transdermic absorbent is fatty alcohol, fatty acid, fatty acid ester, hydramine, polyol alkyl ether, polyoxyethylene alkyl ether, glyceride, polyhydric alcohol medium chain fatty acid ester, lactic acid alkyl ester, alkyl dicarboxylate, acylated amino, pyrrolidinone compounds, lactic acid, tartaric acid, 1; 2,6-hexanetriol, benzyl alcohol, lanoline, potassium hydroxide, three (methylol) aminomethanes or their mixture of more than two kinds.

6. the percutaneous absorption type preparation according to any one of claim 1-5, it is characterized in that, described Eye disease treating medicine is antiviral agent, antibacterial, antifungal, anti-allergic agent, antiinflammatory, nonsteroidal anti inflammatory agent, analgesic agent, the agent of antiinflammatory enzyme, antibiotic, sulfa drug, syncillin, therapeutic agent for glaucoma, agent for treating cataract, miotic, mydriatic, local convergence agent, vasoconstrictor, intraocular pressure rising preventing agent, ocular hypertension therapeutic agent, topical anesthetic cream, α 1 receptor blocking agent, beta-blocker, β1receptorblocker, carbonic acid dehydrogenase blocker, local selectivity H1 receptor blocking agent, adrenocortical hormone, vitamin B12, coenzyme type vitamin B2, anticholinesterase or organic iodine preparation.

7. the percutaneous absorption type preparation according to any one of claim 1-6, is characterized in that, described Eye disease treating medicine is the compound of molecular weight less than 1000.

8. the percutaneous absorption type preparation according to any one of claim 1-7, is characterized in that, described Eye disease treating medicine is ketotifen fumarate or Diclofenac.

9. the percutaneous absorption type preparation according to any one of claim 1-8, is characterized in that, described percutaneous absorption type preparation has can along the shape comprising upper eyelid, the skin surface of palpebra inferior or two eyelid front surfaces sticks.

10. the percutaneous absorption type preparation according to any one of claim 1-9, is characterized in that, described carrier is selected from non-woven fabrics, weaves cotton cloth, the complex of thin film, porous plastid, foaming body, paper, non-woven fabrics or upper laminated film of weaving cotton cloth;

Preferably, the material of described non-woven fabrics is selected from polyolefin resin, polyester resin, artificial silk, polyamide, polyester ether, polyurethane, polyacrylics, polyvinyl alcohol, styrene-isoprene-styrene copolymer-and styrene ethylene-propylene-styrol copolymer.