JP4782438B2 - Patch preparation - Google Patents

Description

  The present invention relates to a patch preparation for transdermal drug administration and a commercial package thereof capable of adjusting the dose of the drug according to the age, weight and symptoms of the patient.

  In recent years, many transdermal drugs that administer drugs through the skin surface have been developed. These transdermal drugs are highly evaluated in terms of compliance, such as effective utilization of administered drugs by avoiding primary metabolism in the liver and sustained pharmacological effects, ease of administration, confirmation of administration, etc. For many other drugs, it is desired to adopt a transdermal administration method through the skin surface, particularly an administration method using a patch preparation in which a pressure-sensitive adhesive layer containing the drug is applied to the skin surface.

  In general, the dose of a drug is adjusted according to the age, weight, and symptoms of the patient to whom the drug is administered. In the case of an oral preparation, it is easily adjusted by adjusting the number of tablets. In the case of a transdermal drug, the adjustment of the dosage includes a method of adjusting the dosage by changing the drug content and drug concentration in the same area, a method of adjusting by changing the dosage area, etc. From the viewpoint of productivity, in general, a plurality of preparations having different areas or a preparation having a certain area is marketed.

  Therefore, conventionally, in contrast to the various conveniences described above, it has not been possible to easily adjust the dose of the drug according to the age, weight and symptoms of the patient.

By the way, a patch preparation used for the purpose of treatment, prevention or inspection of a disease usually has a drug-impermeable membrane (usually a liner) to protect the adhesive substrate surface until it is applied to the skin. .
Japanese Utility Model Publication No. 62-050623

  Therefore, the present invention provides a patch preparation that can use the same preparation regardless of the age, weight, and symptoms of the patient to be administered, and that can adjust the dosage suitable for each individual. And

  As a result of diligent efforts in view of the above-described conventional techniques, the present inventors have found that the above-described problems can be achieved by the following patch.

That is, the present invention is as follows.
(1) At least a pressure-sensitive adhesive layer and a drug-impermeable membrane are sequentially laminated on one side of the support, and the drug is blended in the pressure-sensitive adhesive layer, or / and between the support and the pressure-sensitive adhesive layer. A medicated patch comprising a drug storage layer and a drug permeation control membrane, wherein the drug impermeable membrane is formed of a collection of small pieces that can be selectively peeled off individually at the time of use according to the intended dose. A patch preparation that can adjust the patch area.
(2) The adhesive preparation according to the above (1), wherein the peeling force of the drug-impermeable membrane is 10 to 100 g / 30 mm width.
(3) The patch preparation according to (1) or (2) above, which has a small piece of drug-impermeable membrane that can be peeled along the outer periphery of the patch preparation.
(4) Commercial including a patch preparation according to any one of the above (1) to (3) and a description indicating a drug-impermeable membrane piece to be peeled according to the intended dose package.

The present invention is described in detail below.
1 to 3 show specific examples of the patch preparation of the present invention, FIG. 1 is a plan view of the patch preparation viewed from the drug-impermeable membrane side, and FIG. 2 (matrix type) and FIG. 3 (reservoir type) are respectively diagrams. 1 is a cross-sectional view taken along line AA in FIG.

  In the present invention, the matrix type patch preparation is, for example, laminated in the order of an adhesive layer (2) and a drug-impermeable membrane (1) on one side of a support (5) as shown in the sectional view of FIG. This type of patch preparation contains a drug in the adhesive layer.

  Furthermore, in the present invention, the reservoir-type patch preparation is a drug storage layer (4), a drug permeation control membrane (3), an adhesive layer (on the one side of the support (5), as shown in the sectional view of FIG. 2 ′) shows a patch preparation that is laminated in the order of the drug-impermeable membrane (1). Since this type of patch preparation has a drug storage layer, the adhesive layer contains a drug. It does not have to be.

  In the patch preparation of the present invention, as described above, since the drug-impermeable membrane is made into an aggregate of pieces that can be selectively peeled off individually at the time of use, it is adapted to the age, weight, and symptoms of the patient to be administered. The size of the exposed area of the pressure-sensitive adhesive layer can be adjusted by appropriately and selectively peeling the peeling pieces. Thus, the dose suitable for each individual can be adjusted. Even when the drug is continuously administered, this patch preparation has a relatively large area (that is, a drug containing a large amount of drug). Therefore, it is excellent in sustainability of the effect of the drug, and is also useful when administering the drug for a long time.

  In the present invention, in order to make the drug-impermeable membrane an aggregate of small pieces that can be individually peeled, for example, after preparing a patch preparation, a method of making a cut line in the drug-impermeable membrane, or creating a predetermined shape in advance And a method for forming a drug-impermeable membrane by assembling the individual pieces. FIG. 1 shows that a drug-impermeable membrane is divided into seven small pieces, a-1, a-2, b-1, b-2, c-1, c-2 and d, by cutting lines. It is an example.

  Considering that it is a patch preparation to be applied to the skin, from the point of suppressing peeling when applied to the affected area, the peripheral part of the adhesive preparation is sticky when applied to the skin. It is desirable that it adheres. From this point of view, it is preferable that the small pieces in the small piece aggregate include small pieces that can be peeled at least along the outer periphery of the patch. For example, in the example of FIG. 1, a-1 and a-2 correspond to this. In that case, the width | variety of the direction orthogonal to the outer periphery of a-1 and a-2 is 5-20 mm normally, Preferably it is about 10-15 mm. Thus, sufficient adhesion to the skin is achieved.

  The form of the aggregate of small pieces of the drug-impermeable membrane in the present invention is not particularly limited as long as it can be divided into individual pieces. However, as shown in the specific example shown in FIG. It is preferable.

  The external shape (planar shape) of the patch preparation of the present invention is not particularly limited as long as it is a shape suitable for being applied to the skin, but for the purpose intended by the present invention, it is to be a planar shape such as a square shape or a circular shape. Is desirable.

  The area of each small piece is not particularly limited, and is not particularly limited as long as the object of the present invention can be achieved. The shape of the small piece is not particularly limited, and is not particularly limited as long as the object of the present invention can be achieved.

  In the present invention, the peel force of the drug-impermeable membrane is a value measured according to JIS Z-0237, and is usually 10 to 100 g / 30 mm width, preferably 40 to 100 g / 30 mm width, more preferably 60 to 80 g / The range is 30 mm wide. If the peeling force of the drug-impermeable membrane is 100 g / 30 mm width or less, the drug-impermeable membrane can be easily peeled at the time of use, which is preferable as the drug-impermeable membrane of the present invention. In addition, if the width is 10 g / 30 mm or more, the drug-impermeable membrane that has not been peeled off to adjust the dose will not cause a shift or the like at the time of application of the preparation, and is originally intended to contact (adhere) with the skin. The part of the plaster that is not exposed is exposed, the drug is not absorbed from the part through the skin, and overdose does not occur, which is preferable as the drug-impermeable membrane of the present invention.

  In addition, since the part of the drug-impermeable membrane that did not peel at the time of use does not adhere to the skin, for example, when the part is the peripheral edge of the preparation, there is a concern of peeling from the skin from the part. is there. Therefore, the peripheral edge of the preparation should be peeled off to make it sticky, and the small pieces should be distributed so that a drug-impermeable membrane that does not peel off remains in the central part of the preparation or in the vicinity. Is preferred. For example, in the specific example of FIG. 1, it is desirable to peel in the order of a → b → c → d.

  As the drug-impermeable membrane used in the present invention, those generally used as a patch liner can be used. For example, paper or plastic film (for example, polyester film) that has been subjected to a release treatment by application of silicone resin, fluorine resin, or the like is used. In particular, since the drug-impermeable membrane remaining on the surface of the preparation without peeling off at the time of use comes into contact with the skin, a material having low skin irritation is preferable, and for example, a polyester film or paper is preferably used.

  The thickness of the drug-impermeable membrane is usually 10 to 200 μm, preferably 50 to 100 μm. When the thickness is less than 10 μm, there is a concern that the handleability becomes inferior, and when the thickness exceeds 200 μm, it is not preferable in that the skin adhesion inhibition is caused by the drug-impermeable membrane remaining at the time of use.

  As the adhesive used in the patch preparation of the present invention, an acrylic system that has been used conventionally so as to have adhesiveness at room temperature (about 20 to 30 ° C.) and not to cause fogging when contacting the skin surface. Adhesive, natural rubber adhesive, synthetic rubber adhesive (synthetic isoprene rubber, polyisobutylene rubber, styrene / butadiene rubber, styrene / isoprene / styrene rubber, styrene / butadiene / styrene rubber), silicone adhesive, vinyl ester It is preferable to use a medical pressure-sensitive adhesive such as a vinyl-based pressure-sensitive adhesive or a vinyl ether-based pressure-sensitive adhesive. Among these, it is preferable to use at least one pressure-sensitive adhesive selected from acrylic, rubber-based, and silicone-based from the viewpoint of stability of the pressure-sensitive adhesive quality and ease of adjustment of the pressure-sensitive adhesive properties.

  The acrylic pressure-sensitive adhesive is preferably a polymer obtained by polymerizing (meth) acrylic acid alkyl ester in a proportion of 40% by weight or more. Particularly preferably, a copolymer obtained by copolymerizing one or two or more kinds of (meth) acrylic acid alkyl ester 50 to 98% by weight and one or two or more kinds of copolymerizable monomers 1 to 50% by weight. Is used.

  As such (meth) acrylic acid alkyl ester, it is possible to use an ester obtained from a primary to tertiary alcohol having from 2 to 18, preferably 4 to 12, carbon atoms of an alkyl group and acrylic acid or methacrylic acid. it can.

  On the other hand, the copolymerizable monomer has at least one unsaturated double bond involved in the copolymerization reaction in the molecule and has a carboxyl group (for example, (meth) acrylic acid, itaconic acid, maleic acid, maleic anhydride). Etc.), hydroxyl groups (eg (meth) acrylic acid hydroxyethyl ester, (meth) acrylic acid hydroxypropyl ester, etc.), sulfoxyl groups (eg styrene sulfonic acid, allyl sulfonic acid, (meth) acrylic acid sulfopropyl ester, (meth) ) Acryloyloxynaphthalene sulfonic acid, acrylamidomethylpropane sulfonic acid, etc.), amino group (for example, (meth) acrylic acid aminoethyl ester, (meth) acrylic acid dimethylaminoethyl ester, (meth) acrylic acid tert-butylaminoethyl ester, etc.) Amide groups (eg (meth) acrylamide, dimethyl (meth) acrylamide, N-butyl (meth) acrylamide, N-methylol (meth) acrylamide, N-methylolpropane (meth) acrylamide etc.), alkoxyl groups (eg (meth) Acrylic acid methoxyethyl ester, (meth) acrylic acid ethoxyethyl ester, (meth) acrylic acid methoxyethylene glycol ester, (meth) acrylic acid methoxydiethylene glycol ester, (meth) acrylic acid methoxypolyethylene glycol ester, (meth) acrylic acid methoxy A monomer having a functional group in the side chain, such as polyethylene glycol ester and (meth) acrylic acid tetrahydrofurfuryl ester, can be used. Examples of other copolymerizable monomers include (meth) acrylonitrile, vinyl acetate, vinyl propionate, N-vinyl-2-pyrrolidone, methyl vinyl pyrrolidone, vinyl pyridine, vinyl piperidone, vinyl piperidone, vinyl pyrimidine, vinyl piperazine, and vinyl. Pyrazine, vinyl pyrrole, vinyl imidazole, vinyl caprolactam, vinyl oxazole, vinyl morpholine, and the like can be used.

  These copolymerizable monomers can be copolymerized singly or in combination of two or more. From the viewpoints of adhesion and cohesiveness as adhesive properties, carboxyl group-containing monomers and hydroxyl group-containing monomers Copolymerizing at least one of the essential components in the range of 1 to 50% by weight, preferably 3 to 20% by weight, and if necessary, other monomers exemplified above, such as vinyl acetate and N-vinyl-2- It is preferable to copolymerize a vinyl monomer such as pyrrolidone in a range of 40% by weight or less, preferably 30% by weight or less.

  Specific examples of the acrylic pressure-sensitive adhesive include a copolymer composed of 2-ethylhexyl acrylate and acrylic acid, a copolymer composed of 2-ethylhexyl acrylate and hydroxyethyl acrylate, and 2-ethylhexyl acrylate. Examples thereof include a copolymer composed of vinylpyrrolidone and acrylic acid.

  The acrylic pressure-sensitive adhesive can be used as a cross-linking pressure-sensitive adhesive using a cross-linking agent. Thus, it is possible to suppress the occurrence of cohesive failure in the skin adhesive pressure-sensitive adhesive layer and the occurrence of adhesive residue when the preparation after application is peeled off.

  As the crosslinking agent for the acrylic pressure-sensitive adhesive, various crosslinking agents such as isocyanate, metal salt, and epoxy can be used.

  In the present invention, the pressure-sensitive adhesive may be used alone or a plurality of types of pressure-sensitive adhesives may be mixed as appropriate, and further, rosin, rosin derivatives, polyterpene resins, coumarone-indene resins, petroleum resins, terpene phenol resins, and the like. It can be added as necessary to increase the viscosity.

  First, the drug-impermeable membrane peeling force is usually in the range of 10 to 100 g / 30 mm width, preferably 40 to 100 g / 30 mm width, more preferably 60 to 80 g / 30 mm width. A thing can be obtained by selecting the thing in said range according to the material (kind) of the plastic film to be used, for example, or performing a peeling process and adjusting in the said range.

  The drug used in the present invention is not particularly limited as long as it has transdermal absorbability. Specifically, general anesthetics, hypnotics / sedatives, antidepressants, antipyretic analgesics, antipruritics, neuropsychiatric agents, local anesthetics, skeletal muscle relaxants, autonomic nerve agents, antispasmodics, antiparkinson Drugs, antihistamines, cardiotonic drugs, arrhythmia drugs, diuretics, antihypertensive drugs, vasoconstrictors, coronary vasodilators, peripheral vasodilators, arteriosclerotic drugs, cardiovascular drugs, respiratory stimulants, antitussive expectorants , Hormonal drugs, topical suppurative drugs, analgesic / antipruritic / astringent / anti-inflammatory drugs, parasitic skin disease drugs, hemostatic drugs, gout treatment drugs, diabetes drugs, anticancer drugs, antibiotics, Chemotherapy drugs, narcotics, etc. can be used.

  In the present invention, when the pressure-sensitive adhesive layer contains a drug, the drug is contained in the range of 0.5 to 60% by weight, preferably 1 to 50% by weight, more preferably 3 to 40% by weight. I can do it. When the content is less than 0.5% by weight, it is difficult to absorb a sufficient amount of drug to exert a pharmacological effect, and when it exceeds 60% by weight, the skin adhesiveness is lowered.

  By blending one or two or more long-chain fatty acid esters and long-chain fatty alcohols in the adhesive layer containing the drug, these components are compatible with the adhesive layer, and the adhesive layer is plasticized. Turn into. As a result, the diffusibility of the active ingredient in the pressure-sensitive adhesive layer can be improved, and the skin permeability can be promoted.

  Examples of the long-chain fatty acid esters blended in the pressure-sensitive adhesive layer include isopropyl myristate, diethyl sebacate, octyl palmitate, ethyl oleate, lauric acid ester, glycerin oleic acid monoester, propylene glycol fatty acid ester, and the like. .

  Examples of long-chain aliphatic alcohols include octyl alcohol, decyl alcohol, dodecyl alcohol, oleyl alcohol, isostearyl alcohol, hexyl decanol, octyldodecanol and the like.

  The content of such long-chain fatty acid esters or / and long-chain aliphatic alcohols in the pressure-sensitive adhesive layer is 25 to 200 parts by weight, preferably 40 to 180 parts by weight, particularly preferably 100 parts by weight of the pressure-sensitive adhesive. A range of 50 to 150 parts by weight is desirable. If the content of these components is too small, the skin permeability of the active ingredient cannot be promoted, and a sufficient plasticizing action cannot be exhibited, so that the skin irritation can hardly be reduced. On the other hand, if the content is too high, the surface of the pressure-sensitive adhesive layer will be plasticized too much and the cohesive force will decrease. Shows a tendency to increase.

  The support of the present patch preparation is not particularly limited, but a laminated film of a plastic film and a nonwoven fabric is preferable, and an adhesive layer is laminated on the nonwoven fabric surface of the support. Examples of the plastic film include polyester, ethylene / vinyl acetate copolymer, polyethylene, polyurethane, polyolefin, polypropylene and the like, preferably polyester and polyethylene, but from the property that the drug is difficult to migrate to the support. Polyester is most preferred.

  The thickness of the plastic film is usually 1 to 1000 μm, preferably 2 to 100 μm, and more preferably 5 to 50 μm from the viewpoint of flexibility and operability.

Nonwoven fabrics are manufactured from materials commonly used in the field of patches. Examples of such a material include polyester, polyethylene, polypropylene, polyamide, and the like, and polyester, polypropylene, and polyamide are preferable. The basis weight of the nonwoven fabric is usually 1 to 100 g / ^{m 2,} preferably from the reason that is a 6~50g / ^{m 2,} the adhesion feeling to the skin surface at the time of flexibility and sticking is good, 6～30G / M ² is more preferable.

  If necessary, the drug-containing layer contains additives such as antioxidants, various pigments, various fillers, stabilizers, drug dissolution aids, drug dissolution inhibitors and the like in an amount of 2 to 100 parts by weight of the adhesive. It can mix | blend in the range of about 50 weight part.

  In the case of the reservoir-type patch preparation of the present invention, the amount of the drug in the drug-containing composition enclosed in the drug storage layer can vary depending on the type of the composition. Desirably, it is 0.5 to 50% by weight, 1 to 20% by weight for a gelling agent, and 0.5 to 20% by weight for a water-soluble gel. If the amount is less than this, the therapeutic effect is insufficient, and if it exceeds this amount, it is not preferable from the viewpoint of drug utilization.

  Examples of the drug permeation control membrane used in the present invention include a microporous membrane having an average pore diameter of 0.1 to 1 μm. As the material of the microporous membrane, polyolefin such as polypropylene and polyethylene, polytetrafluoroethylene, and the like are used. The thickness of the drug permeation control membrane is usually 1 μm to 200 μm, and in particular, 10 μm to 100 μm is desirable from the viewpoint of ease of production and appropriate bending resistance.

  The patch preparation of the present invention is produced by a method known per se. For example, a solution containing a polymer compound used for the pressure-sensitive adhesive layer is applied to a drug-impermeable membrane and dried, and then a film used for a support layer, a nonwoven fabric, or the like is bonded to the surface of the pressure-sensitive adhesive layer, or the polymer The solution containing the compound is directly applied to a film, nonwoven fabric or the like used for the support layer and dried, and then a separator is laminated on the surface of the pressure-sensitive adhesive layer, so that the support layer, the pressure-sensitive adhesive layer, and the drug-impermeable membrane are in this order. It can be manufactured by obtaining a laminated raw material, punching it out in the shape of the outer frame of the medicated patch, and cutting the above-mentioned cut lines only with a metal blade or the like only in the drug-impermeable membrane portion. Alternatively, small pieces of drug-impermeable membranes that have been created in a predetermined shape in advance may be assembled.

  In addition, the reservoir-type patch preparation of the present invention having a drug-containing layer and a drug permeation control membrane is formed, for example, by forming an adhesive layer on a drug-impermeable membrane as described above, and forming a drug permeation control membrane thereon. Form. Next, the film used for the support layer is placed on the drug permeation control membrane, and the peripheral part is heat-sealed, leaving a part for injecting the drug storage solution, and punched into a patch preparation, and the drug storage layer solution Can be manufactured by injecting and heat-sealing.

Further, the present invention is that the patch preparation, and the patch preparation should be selectively peeled off and pasted according to the patient's age, weight, symptom, or according to the intended dose. A commercial package containing the description is provided.
Depending on the patient's age, weight and symptoms, the dosage will vary, but depending on the intended dose, the above-mentioned items should leave a small piece at the time of use. It will be described whether it should be affixed.

  Hereinafter, the patch preparation of the present invention will be described in more detail with reference to Examples and Test Examples. Needless to say, various applications can be made without departing from the technical idea of the present invention.

Example 1
A pressure-sensitive adhesive solution was prepared by polymerizing 5% by weight bisoprolol, 30% by weight isopropyl myristate, and 65% by weight acrylic pressure-sensitive adhesive. After applying and drying the above pressure-sensitive adhesive solution to a polyester film having a thickness of 38 μm subjected to silicone release treatment so that the thickness after drying becomes 60 μm, a polyester film having a thickness of 2 μm and a polyester nonwoven fabric having a basis weight of 12 g / m ² The support body which consists of was bonded together, and the sheet-like original fabric was obtained. This was punched out to 50 mm × 50 mm and cut with a metal blade to obtain a patch preparation (matrix type) of the present invention.
The drug-impermeable membrane peeling force of this preparation was 45 g / 30 mm width.

Example 2
The polyisobutylene-based pressure-sensitive adhesive was applied and dried on a 38 μm-thick polyester film subjected to silicone release treatment so that the thickness after drying was 60 μm. A 100 μm-thick Sunmap LC (manufactured by Nitto Denko Corporation, polyethylene porous membrane) is laminated on this, and a 75 μm-thick polyester film support is left on the drug storage layer solution inlet so that it becomes 3 mm × 3 mm. Sheet and punched along the outer periphery of the heel sheet. After injecting 500 μL of a drug storage layer solution consisting of 5% by weight bisoprolol and 95% by weight ethanol (95%) from the injection port, the injection port was completely sealed with a heel sheet, and the patch preparation of the present invention (reservoir type) )
The drug-impermeable membrane peeling force of this preparation was 45 g / 30 mm width.

Test Example The drug-impermeable membrane capable of splitting separation of Example 1 and Example 2 was peeled off by 25%, 50%, and 100%, and the dissolution test was performed. The dissolution test conditions were carried out in accordance with the 14th revised Japanese Pharmacopoeia (JP) dissolution test method 2nd paddle method. However, the temperature was 32 ± 0.5 ° C., the paddle rotation speed was 50 times / minute, and the test solution was 900 mL of phosphate buffer (pH 6.8) (conforming to JP Disintegration Test Method Second Solution).

Results From the results of Example 1 (FIG. 4), the patch preparation (matrix type) of the present invention showed drug release according to the drug-impermeable membrane release area. In other words, by exposing the skin adhesive layer in an arbitrary area and adhering it to the skin, the dosage of the drug can be adjusted according to the age, weight, and symptoms of the patient to be administered even though it is the same preparation. It can be done easily.

  Further, from the results of Example 2 (FIG. 5), the patch preparation (reservoir type) of the present invention showed a drug release rate corresponding to the drug-impermeable membrane peeling area as in Example 1, and Since the drug can move freely in the drug storage layer, the drug was released over a long period of time. In other words, patients who have applied a patch preparation with only a part of the drug-impermeable membrane peeled can extend the application period, thus reducing the time and effort required for the patient to put back the preparation and simplifying the dosage. As well as making adjustments, the patient's QOL can be improved.

The top view (figure seen from the drug impermeable membrane side) of the patch preparation of one embodiment is shown. AA sectional drawing (matrix type) of FIG. 1 is shown. AA sectional drawing (reservoir type) of FIG. 1 is shown. 3 is a graph showing the results of Example 1. The graph which shows the result of Example 2.

Explanation of symbols

a-1 to d Drug-impermeable membrane piece e Cut line for cutting X Liner Y Patch preparation 1 Drug-impermeable membrane 2, 2 ′ Adhesive layer 3 Drug-permeation control membrane 4 Drug storage layer
5 Support

Claims (4)

At least a pressure-sensitive adhesive layer and a drug-impermeable membrane are sequentially laminated on one side of the support, and the drug is blended in the pressure-sensitive adhesive layer or / and a drug storage layer between the support and the pressure-sensitive adhesive layer. A patch preparation comprising a drug permeation control membrane, wherein only the drug non-permeable membrane is formed of a collection of small pieces to be selectively peeled off individually at the time of use according to the intended dose. A patch preparation that can adjust the patch area. Peel strength of the drug-impermeable layer is 10 to 100 g / 30 mm width, the adhesive preparation of claim 1. Collection of small pieces to be selectively stripped to form a drug-impermeable film has a piece to be peeled off along the outer periphery of the patch preparation, a patch preparation according to claim 1 or 2. Patch preparation according to any one of claims 1 to 3, and in accordance with the dosage contemplated, including written matter instructing pieces of the drug-impermeable layer to be peeled, commercial packages.

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