JP2565334B2 - Drug release variable patch preparation - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (a) Field of Industrial Use The present invention relates to a drug-releasing variable patch preparation capable of transdermally administering a drug by applying it to the skin. Considering the relationship between the moisture permeability of the body, that is, the percutaneous absorption of drugs by the ODT effect and the skin irritation due to swelling (the expression level of irritation varies from person to person), the therapeutic purpose and skin of each patient The present invention relates to a drug release variable patch preparation capable of controlling drug release so as to reduce side effects such as irritation. (B) Conventional Techniques Various patches have been proposed for applying a drug to a skin locally or systemically to apply a drug to the skin to treat or prevent a disease.

Transdermal or transmucosal administration of drugs is less troublesome during administration than oral, injection, suppository, etc., is less susceptible to liver metabolism, does not cause gastrointestinal disorders, and has a limited drug release rate. Since it has a medicinal effect over a long period of time, it has an advantage that the number of administrations can be reduced, and it is expected that more and more various drugs will be transdermally or transmucosally administered in the future.

(C) Problems to be Solved by the Invention However, all conventional patches have a drug release characteristic of the formulation that cannot be changed, and some side effects (skin irritation) occur. But especially,
If you want to prioritize the therapeutic effect, or if you want to reduce the skin irritation even if the therapeutic effect is sacrificed to some extent because the skin sensitivity is very high and skin irritation is likely to occur, the same patch preparation should not be used. It was very difficult.

Further, in the conventional patch, a drug release control layer is mainly laminated on the drug storage layer as a means for achieving sustained release of the drug, but this further limits the moisture permeability, There are drawbacks such that the drug migrates to the controlled release layer during storage and the release characteristics change, and the release characteristics cannot be changed to suit the therapeutic purpose of each patient.

(D) Means for Solving Problems In view of the problems of the above conventional preparations, the present inventors have a relatively simple structure as a patch-type pharmaceutical preparation,
As a result of repeated studies to obtain a drug product that can control the drug release characteristics and skin stuffiness at the application site according to the degree of individual patient's symptom and the degree of skin irritation sensitivity, the carrier has two or more layers. The present invention has been completed by finding that the ODT effect can be changed by forming a laminated structure and peeling between the arbitrary layers, thereby solving the above-mentioned problems, and completed the present invention.

That is, in the drug-releasing variable type patch preparation of the present invention, the carrier provided on one side of the drug-containing pressure-sensitive adhesive layer has a laminated structure of two or more layers, and the drug-releasing property is obtained by peeling between the arbitrary layers. It is characterized by controlling.

 Hereinafter, the present invention will be described in detail.

The carrier used in the present invention may be laminated without any particular limitation as long as it can support the drug-containing pressure-sensitive adhesive layer in the form of a film or a sheet, but when it is attached to the skin surface, it expands and contracts the skin. As described above, it is preferable to use a material having flexibility and elasticity.

A feature of the present invention is that the above-mentioned carrier has a laminated structure of two or more layers, and is peeled off between these arbitrary layers to control the drug release property.

In this case, it is desirable to have an interlayer adhesive force that allows the carriers to be peeled from each other and does not spontaneously peel due to rubbing of clothes or the like at the time of sticking. Adhesion via the carrier is considered, but considering that part of the carrier is peeled off after sticking the patch preparation to the skin, the adhesive force between the carriers is more than that of the drug-containing pressure-sensitive adhesive layer to the skin. The lower is also preferable, and in this case, the adhesive force can be controlled by controlling the effective bonding area by using an embossed sheet or an embossed film.

In addition, it is preferable to provide each of the stacked support members with a portion that can be easily pinched in order to facilitate the peeling of any support member.

Specific examples of the carrier used in the present invention include polyurethane, polyethylene, ethylene-vinyl acetate copolymer, polyvinyl chloride, polybutadiene, polypropylene, cellophane, polychloroprene, polyamino acid, nitrile rubber, butyl rubber, and silicone rubber. One or two or more selected from the formed film or sheet, paper, woven fabric, non-woven fabric, etc. can be used by laminating two or more layers.

Of the above supports, those with relatively low moisture permeability, that is, OD
Films and sheets formed of polyethylene, polyvinyl chloride, polybutadiene, polypropylene or the like can easily exhibit the T effect, and polyurethane, paper, woven cloth, non-woven cloth, etc. can be mentioned as those having high moisture permeability. Further, an ethylene-vinyl acetate copolymer is preferable because a film or sheet having various moisture permeability can be obtained by changing the copolymerization ratio.

In the present invention, the carrier provided on one side of the drug-containing pressure-sensitive adhesive layer is formed by laminating one or more films and / or sheets of two or more layers, and each film and / or sheet is pre-pasted or pasted. It can be peeled off later and is configured to be peeled between any layers, thereby changing the moisture permeability of the patch preparation, that is, the ODT effect, thereby
It is characterized in that the release property of a drug can be controlled.

And, a preferred embodiment of the present invention is to use two or more kinds of films and / or sheets having different moisture permeability as a carrier, and a film and / or sheet having lower moisture permeability from the drug-containing pressure-sensitive adhesive layer to the outer layer. It is configured.

With such a constitution, it is possible to control so as to obtain a desired ODT effect by peeling between arbitrary layers.

The drug-containing pressure-sensitive adhesive layer used in the present invention is one in which a transdermal drug is contained in the pressure-sensitive adhesive layer, and the drug contained as the pressure-sensitive adhesive used in the drug-containing pressure-sensitive adhesive layer diffuses and transfers. There is no particular limitation as long as it can be released to the skin surface by a natural polymer or a synthetic polymer.

Examples of the pressure-sensitive adhesive include (meth) acrylic acid butyl ester, (meth) acrylic acid pentyl ester,
(Meth) acrylic acid hexyl ester, (meth) acrylic acid heptyl ester, (meth) acrylic acid octyl ester, (meth) acrylic acid nonyl ester, (meth)
Acrylic acid decyl ester, (meth) acrylic acid undecyl ester, (meth) acrylic acid dodecyl ester,
(Meth) such as acrylic acid tridecyl ester (meth)
Examples of the acrylic pressure-sensitive adhesive include a polymer composed of at least one kind of alkyl acrylate and a copolymer composed of a monomer copolymerizable with the ester.

Examples of the copolymerizable monomer include (meth) acrylic acid, itaconic acid, crotonic acid, maleic acid, maleic anhydride, and carboxyl group-containing monomers such as fumaric acid, styrenesulfonic acid, and allylsulfonic acid. , Sulfopropyl acrylate, (meth) acryloyloxynaphthalene sulfonic acid, acrylamidomethyl propane sulfonic acid, acryloyloxybenzene sulfonic acid-containing monomers, (meth) acrylic acid hydroxyethyl ester, (meth) acrylic acid hydroxypropyl Hydroxyl group-containing monomers such as esters, amide group-containing monomers such as (meth) actylamide, dimethyl (meth) acrylamide, N-butylacrylamide, tetramethylbutylacrylamide, N-methylol (meth) acrylamide. Contains an alkylaminoalkyl group such as a ril monomer, (meth) acrylic acid aminoethyl ester, (meth) acrylic acid dimethylaminoethyl ester, (meth) acrylic acid diethylaminoethyl ester, (meth) acrylic acid tert-butyl ester Acrylic monomer, (meth) acrylic acid methoxyethyl ester, (meth) acrylic acid ethoxyethyl ester, (meth) acrylic acid butoxyethyl ester, (meth) acrylic acid tetrahydrofurfuryl ester, (meth) acrylic acid methoxyethylene Glycol ester, (meth)
Acrylic acid methoxydiethylene glycol ester,
(Meth) acrylic acid methoxy polyethylene glycol ester, (meth) acrylic acid methoxy polypropylene glycol ester, an alkoxy group (or an ether bond in the side chain) -containing monomer, N- (meth) acryloyl amino acid, a vinyl monomer Functional monomers such as acrylic monomers such as urethane of acrylic acid, urea, and isocyanate ester, and (meth) acrylonitrile, vinyl acetate, vinyl propionate, vinylpyrrolidone, vinylpyridine, vinylvirazine, vinylpiperazine, vinylpiperidone. , Vinylpyrimidine, vinylpyrrole,
Vinyl monomers such as vinyl imidazole, vinyl caprolactam, vinyl oxazole, vinyl thiazole, vinyl morpholine, styrene, a-methyl styrene, and bis (N, N'-dimethylaminoethyl) maleate are listed. Can be blended in the pressure-sensitive adhesive composition in an amount of 2 to 60% by weight, preferably 5 to 50% by weight, and polymerized. Outside of these ranges, sufficient tackiness and internal cohesiveness may not be obtained, which is not preferable.

Other usable adhesives include, for example, silicone rubber, polyisoprene rubber, preisobutylene rubber, polybutadiene, styrene-butadiene (or isoprene).
-Styrene block copolymer rubber, acrylic rubber, rubber-based adhesive material mainly composed of natural rubber, polyvinyl alkyl ether, polyvinyl acetate, partially saponified product of polyvinyl acetate, vinyl-based adhesive material mainly composed of polyvinyl alcohol , Cellulose derivatives such as methyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, polysaccharides such as pullulan, dextrin, agar, polyacrylic acid (or their salts), polymethacrylic acid (or their salts), carboxyvinyl polymer Water-soluble polymer such as, polyhydric alcohols such as glycerin, cross-linking agent such as triglycidyl isocyanate, and water-containing gel-like ones that contain a gel-like substance depending on the type of drug, the desired adhesive strength, etc. Can be appropriately selected.

Further, when using the above-mentioned pressure-sensitive adhesive, after sticking to the skin due to lack of internal cohesive force, if the drug-containing pressure-sensitive adhesive layer may cause cohesive failure or adhesive residue on the skin surface due to this, It is also possible to mix a commonly used cross-linking agent, to mix a cross-linkable monomer as a copolymerization component to improve cohesive force, or to cross-link by irradiation with electron beams, ultraviolet rays or the like.

The adhesive used in the present invention does not decompose the contained drug as much as possible, and thus it is necessary to select variously depending on the drug species used, but generally a highly reactive carboxyl group, amino group, or acid amide group. When a monomer having a reactive site such as is used, the reactivity can be reduced by reducing the compounding amount or masking the site.

The drug contained in the drug-containing pressure-sensitive adhesive layer may be one that can be transdermally absorbed into the living body, and the following drugs can be used, for example.

B) Corticosteroids: For example, hydrocortisone, prednisolone, parameterzone, beclomethasone propionate, flumethasone, betamethasone, betamethasone valerate, dexamethasone, triamcinolone, triamcinolone acetonide, fluocinolone, fluocinolone acetonide, fluocinolone acetonide acetate. B) analgesic and anti-inflammatory agents such as clobetasol propionate: eg acetaminophen, mefenamic acid, flufenamic acid, indomethacin, diclofenac, diclofenac sodium, alclofenac, oxyphenbutazone, phenylbutazone, ibuprofen, flurbiprofen, ketoprofen, Salicylic acid, methyl salicylate, l-menthol, camphor, sulindac, tolmetin Thorium, naproxen, etc. fenbufen, c) hypnotic sedatives: For example phenobarbital, amobarbital, cycloalkyl phenobarbital, triazolam, nitrazepam, flunitrazepam, lorazepam, haloperidol, etc., d) tranquilizers: e.g. fluphenazine, Teoritajin, diazepam,
Fludiazepam, flunitrazepam, chlorpromazine, etc. e) Antihypertensive agents: eg clonidine, clonidine hydrochloride, pindolol,
Propranolol, propranolol hydrochloride, bufanol, indenolol, nivadipine, nimodipine, lofedixin, nitrendipine, nipradilol, bucumolol, nifedipine, etc.)) Antihypertensive diuretics: For example, hydrothiazide, bendroflumesiazide, cyclobenchazide, etc.) Antibiotics: For example, penicillin, tetracycline, oxytetracycline, fradiomycin sulfate, erythromycin, chloramphenicol, etc.) Anesthetics: eg lidocaine, dibucaine hydrochloride, benzocaine,
Li) antibacterial substances such as ethyl aminobenzoate: eg benzalkonium chloride, nitrofurazone, nystatin, acetosulfamine, clotrimazole, etc.) antifungal agents: eg pentamycin, amphotericin B, pyrrolenitrin, clotrimazole , Etc.) Vitamin preparations: Vitamin A, Vitamin E, Vitamin K, ergocalciferol, cholecalciferol, octothiacin, riboflavin butyrate, etc. w) Antiepileptic agents: eg nitrazepam, meprobamate, clonazepam, w) coronary vessels Extender: For example, nitroglycerin, nitroglycol, isosorbide dinitrate, erythritol tetranitrate, pentaerythritol tetranitrate, propacyl nitrate, dipyridamole, Molysidomine, etc. Ka) Antihistamines: For example, diphenhydramine hydrochloride, chlorpheniramine, diphenylimidazole, etc. Yo) Antitussives: For example, dextromethorphan hydrobromide, dextromethorphan, terbutaline, terbutazone sulfate, ephedrine, ephedrine hydrochloride, salbutamol sulfate,
Salbutamol, isoproterenol hydrochloride, isoproterenol, isoproterenol sulfate, etc. Ta) Sex hormones: eg progesterone, estradiol, etc.) antidepressants: eg doxepinso) Cerebral circulation improvers: eg hidergine, ergot alkaloids, ifenprodil , Etc.) Antiemetics, anti-ulcer agents: eg metoclopramide, clevopride, domperidone, scopolamine, scopolamine hydrobromide, etc.)) biomedicals: eg polypeptides (TRH, derivatives of LHRH), etc.) For example, fentanyl, desmopressin, digoxin, 5-fluorouracil, mercaptopurine, etc., such a drug is contained in the adhesive layer in an amount of 0.05 to 40% by weight,
2-80 as the content per unit area of the medicated patch
The drug is contained in the range of 0 μg / cm ² , but two or more of these drugs may be used in combination depending on the purpose of treatment, action and the like.

Further, in the present invention, it is preferable to absorb the drug into the living body by percutaneous absorption of the drug alone from the viewpoint of production and stability of the drug, but when absorption of an effective amount is not expected, Auxiliary agents that promote skin absorbability, such as glycols and their alkyl esters, alkyl ethers, oils and fats, urea derivatives, various polar solvents (dimethyl sulfoxide, dodecylpyrrolidone, etc.), various surfactants, etc. It is possible to improve the absorption of a drug by incorporating it in a range that does not impair the skin adhesive property or the stability of the drug.

In the medicated patch configured as described above, the thickness of each layer is not particularly limited, but the drug-containing pressure-sensitive adhesive layer is
The support has a thickness of 10 to 100 μm, and the carrier has a total thickness of 10 to 10 after laminating various films and / or sheets.
Good adhesion can be achieved by setting the thickness to 2000 μm, preferably 50 to 1000 μm.

(E) Action The drug-releasing variable patch preparation of the present invention has the above-mentioned constitution, the carrier provided on one surface of the drug-containing pressure-sensitive adhesive layer has a laminated structure of two or more layers, and It is configured so that it can be peeled between the layers, and it has the effect of changing the ODT effect by peeling one by one from the outside of the carrier.

(F) Examples Hereinafter, the present invention will be described in detail based on Examples, but the present invention is not limited thereto.

In the following text, "parts" means "parts by weight".

[Preparation of Polymer Solution] A pressure-sensitive adhesive solution (hereinafter, abbreviated as polymer solution) used in each example was prepared as follows.

Polymer A 85 parts of 2-ethylhexyl acrylate (2-EHA) and N-vinyl-2 in a flask under an atmosphere of an inert gas.
-Preparation of 15 parts of pyrrolidone and 0.3 part of azobisisobutyronitrile (AIBN) as a polymerization initiator to start the polymerization reaction,
Polymerization was performed while maintaining the reaction temperature at about 60 ° C. while adding ethyl acetate dropwise to obtain a polymer solution.

Polymer B 65 parts of 2-EHA, 15 parts of 2-methoxyethyl acrylate, 20 parts of vinyl acetate, 0.3 parts of benzoyl peroxide (BPO) as a polymerization initiator were charged, and the same procedure as that of the polymer A was used. A combined solution was obtained.

Polymer C Polyisobutylene (weight average molecular weight 1.6 million) 100 parts, polyisobutylene (weight average molecular weight 60,000) 70 parts, alicyclic saturated hydrocarbon resin (weight average molecular weight 700, melting point 100 ° C) 30 parts dissolved in toluene To obtain a polymer solution.

 The carrier used in each example was prepared as follows.

Carrier A A polyester nonwoven fabric (40 g / m ² ) and a polyethylene film (thickness 30 μm) were thermocompression bonded at about 100 ° C. to obtain a peelable two-layer carrier.

Carrier B Polyurethane film with a release treatment on one side (thickness 30μ
m) treated surface and ethylene-vinyl acetate copolymer film with one side stripped (vinyl acetate content 28%) (thickness 50
of the ethylene-vinyl acetate copolymer film and the polyethylene film (thickness: 30 μm) are laminated via a pressure-sensitive adhesive layer (polymer B) having a thickness of 10 μm.
m) was laminated via a pressure-sensitive adhesive layer (polymer B) having a thickness of 10 μm to obtain a three-layer laminated carrier.

Example 1 Diclofenac was added to and mixed with a solution of the polymer A, coated on a release liner so that the thickness after drying was 40 μm, and dried to obtain a drug-containing pressure-sensitive adhesive layer (Diclofenac 400
μg / cm ² ) was obtained.

The drug-containing pressure-sensitive adhesive layer was transferred to the polyester non-woven fabric of the carrier A to obtain the drug-releasable variable patch preparation of the present invention.

Example 2 A drug release-controllable patch preparation of the present invention was obtained in the same manner as in Example 1 except that clonidine was added and mixed to the polymer C solution.

Example 3 Timolol was added to and mixed with the solution of the polymer B, coated on a release liner so that the thickness after drying was 40 μm, and dried to obtain a drug-containing pressure-sensitive adhesive layer (400 μg / cm ^{2 of} timolol). .

The drug-containing pressure-sensitive adhesive layer was transferred to the polyurethane film side of the carrier B to obtain the drug-releasable variable patch preparation of the present invention.

[Human patch test] The polyethylene film of the carrier was peeled off from the drug release variable patch preparations obtained in Examples 1 to 3 and the drug release variable patch preparations of Examples 1 and 2 on the backs of 10 volunteers. What was removed, and further, in the drug release variable patch preparation of Example 3, the polyethylene film or the polyethylene film and the ethylene-vinyl acetate copolymer film were peeled and removed (both size 30 mmφ).
It was applied for 24 hours, and the skin irritation was determined 1, 24 and 48 hours after the removal.

 The judgment was based on Japanese patch test standards.

 The results are shown in Table 1.

Blood Concentration Measurement Ventral region (5 cm long, 3 cm wide) of rats from which the same drug-releasing variable patch preparations [7 types of (I) to (VII)] used in the human patch test were previously hair-removed The blood concentration of the drug after a certain period of time was measured by gas chromatography.

 The results are shown in FIGS.

It can be seen from Table 1 that moisture permeability is improved and skin irritation is significantly improved by sequentially peeling the carrier.

It is also recognized from FIGS. 1 to 3 that the partial release of the carrier improves the sustained release of the drug.

(G) Effect of the Invention The drug-releasing variable patch preparation of the present invention has the above-mentioned constitution, and the carrier provided on one surface of the drug-containing pressure-sensitive adhesive layer comprises one or two or more films and / or sheets. It has a structure in which more than one layer is laminated, and each film and / or sheet can be peeled off, and the ODT effect can be changed by sequentially peeling off each film and / or sheet. As a result, a kind of preparation It has an effect that can be prepared and applied in an optimal manner from the viewpoints of both skin rashiness of each patient and therapeutic effect.

Also, by changing the moisture permeability of the carrier, that is, the ODT effect, the release of the drug can be controlled, and since it has the effect that one type of formulation can be used by selecting either immediate-effect or long-acting. is there.

[Brief description of drawings]

FIG. 1 is a diagram showing the sustained-release properties of a drug when applied as it is in Example 1 and the sustained-release properties of a drug when the polyethylene film on the outside thereof is peeled off, and FIG. 2 is when applied as it is in Example 2. Showing the drug release property of the drug and the drug release property when the polyethylene film on the outside thereof is peeled off, and FIG. 3 is the drug release property when applied as it is in Example 3 and the polyethylene film on the outside thereof. FIG. 3 is a view showing the sustained-release property of a drug when peeled off, and further showing the sustained-release property of a drug when the polyethylene film and the ethylene-vinyl acetate copolymer are peeled off.

Claims (2)

(57) [Claims] 1. A drug characterized in that a carrier provided on one surface of a drug-containing pressure-sensitive adhesive layer has a laminated structure of two or more layers and is peeled off between these arbitrary layers to control drug release. Controlled release patch preparation. 2. A laminated body of a carrier having a laminated structure is a film and / or sheet having different moisture permeability, and the film and / or sheet having lower moisture permeability from the drug-containing pressure-sensitive adhesive layer to the outer layer. The drug-releasing variable patch preparation according to claim 1, which is composed of a sheet.