JPH02212419A - Application agent for treating disease - Google Patents

Abstract

PURPOSE:To obtain an application agent for treating, peelable without falling off only a support and causing a residual drug-containing layer even in application for a long period by laminating the drug-containing layer having tackiness at ordinary temperature to the side of a cellular substance of the support formed by laminating a cellular substances to a substrate. CONSTITUTION:A drug-containing layer is laminated to the side of a cellular substance of a support formed by laminating the cellular substance to a substrate. Polyethylene, polypropylene, polyester, etc., are used as the above- mentioned substrate and the thickness thereof is preferably 5-100mum. For example, paper, woven fabric or nonwoven fabric, is preferred as the cellular substance. The afore-mentioned drug-containing layer contains a tacky agent (e.g. acrylic tacky agent) having tackiness at ordinary temperature and a percutaneous absorbable drug (e.g. nifedipine, prednisolone or acetaminophen) as essential ingredients.

Description

DETAILED DESCRIPTION OF THE INVENTION (a) Field of Industrial Application The present invention relates to a disease treatment patch for transdermally administering a drug into a living body.

(b) Conventional technology In recent years, transdermal absorption preparations, which are administered through the skin as a means of administering drugs into living bodies, have been actively developed from the viewpoint of producing sustained pharmacological effects and reducing side effects. Among these, patches are attracting attention due to their ease of handling and strict dosage requirements.

In addition, in such patches, various improvements have been made to the drug-containing layer to improve transdermal absorption, fast-acting properties, and durability.
Various views? ! , has been considered since.

(e) Problems to be Solved by the Invention The characteristic of the above patch is that it maintains its pharmacological effect over a long period of time. Although non-permeability, moisture permeability, and photostability have been studied, there has been no detailed study of the anchoring force between the drug-containing layer and the carrier, which is fundamentally important for a patch. For example, in the case of drugs with excellent transdermal absorption, the drug-containing polymer layer becomes plasticized and no longer has the anchoring force to withstand use, and when removed after application, the drug-containing polymer layer remains on the skin surface to which it is applied. As a result, the product becomes unviable.

In addition, patients want the patch to be as small as possible from the viewpoint of discomfort, skin irritation, etc., and the drug tX inevitably has a high content due to the drug dosage, which can solve the above problems. I'm holding it.

Furthermore, since treatments using patches involve continuous application, if the adhesiveness of the patch is too strong, significant pain, rashes, and skin irritation will be apparent when the patch is removed after application. Control of low adhesion is also required, but this has not yet been investigated in detail.

(d) Means for solving the problem The inventor has determined that the above problem can be solved (after repeated consideration,
If a carrier used in this type of adhesive patch is made by laminating a porous material on a base material, and a drug-containing layer is laminated on the porous material side of the carrier, only the carrier will fall off after long-term application. It was found that the patch could be removed cleanly without leaving any drug-containing layer on the skin surface even when removed after use.

In other words, with this configuration, the surface part of the drug-containing layer penetrates into the gaps of the porous body, improving anchoring properties. Therefore, even if the drug-containing layer is plasticized by containing a plasticizer or transdermal absorption enhancer that exhibits a plasticizing effect (cohesive force decreases), the adhesiveness with the carrier is maintained. (Anchoring property) is improved, and the carrier does not fall off even when pasted for a long period of time.Also, products made by laminating the carrier and drug-containing layer and then pressing them together with (hot) rolls have even better anchoring properties. In addition, it has been found that the appearance is different, and there is no adhesive residue on the skin.

In addition, for drugs with good transdermal absorption that cause mild primary irritation to the skin, the drug contained therein is somewhat adsorbed by the porous material and acts as a drug storage layer, providing mild transdermal absorption. It has also been found that it relieves skin irritation.

The present invention was completed based on these findings,
The present invention will be explained in detail below.

The carrier used in the present invention can be made by laminating a porous material on a base material, or by interposing a hot melt adhesive sheet or film between the base material and the porous material, and then thermally bonding this laminate. Alternatively, the base material and the porous body may be laminated with adhesive material interposed between them, and it is sufficient that the base material and the porous body do not easily separate.

Examples of the base material include films and sheets of polyethylene, polypropylene, polyester, polyvinyl acetate, polyurethane, polyvinyl alcohol, polyvinylidene chloride, polyamide, polyethylene-vinyl acetate laminate, and the like. The thickness of this base material is 5~
A thickness of 100 μm is preferable, and a thickness of less than 5 μm is not preferable because it is difficult to produce a homogeneous laminated film.
If it exceeds 00 μ-, the laminated film becomes too thick, resulting in a strange feeling when applied and poor skin adhesion, which is not preferred.

In addition, the above-mentioned porous material is not limited to porous material as long as it has good adhesion (anchoring property) with the drug-containing layer described below.For military purposes, for example, paper, woven fabric, or non-woven fabric , porous films and sheets obtained by mechanical perforation, and punched films. Among these, paper, woven fabric, or nonwoven fabric is preferable because it provides an anchoring effect with the drug-containing layer described below. , this porous body preferably has a thickness in the range of 20 to 500 μ-;
If it is less than 20μ, the drug-containing layer will not penetrate into the carrier and the necessary anchoring properties will not be obtained.On the other hand, if it is 500μ, the skin [! It is not preferable because the skin adhesion is poor due to the lack of elasticity.

In addition, when preparing a four-handed patch such as a plaster type or adhesive tape-like preparation, it is preferable to use a porous material having a thickness of 20 to 200 μm.

The above paper preferably has a thickness in the range of 20 to 200 μm. If the thickness is less than 20 μm, the drug-containing layer will not penetrate into the paper and the necessary anchoring properties will not be obtained.
If it resembles 00μ bell, it is not preferable because the skin adhesion is poor due to lack of flexibility which gives the carrier a stiff feel when applied to the skin.

The above-mentioned woven or non-woven fabric may be made of cotton, polyester, nylon, vinylon, rayon, acetate, or the like. Of these,
Non-woven fabrics are preferred because the properties of the film or sheet can be freely changed.

The above woven fabrics and non-woven fabrics have a basis weight of 5 to 301y/112
It is preferable to have a weight of 10 to 20 g/m", and most preferably 10 to 20 g/m". If the weight is less than 5 g/aa', the desired anchoring effect cannot be obtained. On the other hand, if the weight is more than 30 g/v2, The overall thickness of the patch may become too large, causing a strange sensation when applied to the skin, or the drug-containing layer may be too press-fitted between the fibers, reducing its adhesion to the skin, which may cause it to lift off the skin when applied. This is undesirable as there is a risk of the adhesive patch falling off or falling off.

Further, the above-mentioned woven fabric or non-woven fabric only needs to have gaps between the fibers to allow the drug-containing layer to enter.

However, like the net, 2 mmX 2 +1!1
This is not preferable because there is a risk that the drug-containing layer will be destroyed on the skin shoulder surface and the carrier surface. Woven or non-woven fabrics with intertwined layers are most desirable.

In the present invention, a drug book is placed on the porous body side of the carrier.

The drug-containing layer has an adhesive that is sticky at room temperature and a transdermally absorbable drug as essential components.

In this case, in order to achieve transdermal absorption and irritation reduction, as well as a balance between the carrier and the drug-containing layer, the drug concentration in the drug-containing layer and the type of porous material used are adjusted.

A typical example of the above adhesive is, for example, an acrylic adhesive.

Examples of this acrylic adhesive include a homopolymer of an alkyl (meth)acrylate in which the alkyl group has 4 or more carbon atoms, or a copolymer containing an alkyl (meth)acrylate as the main monomer. One example is merging.

Examples of the (meth)acrylic acid alkyl esters include n-butyl 7-acrylate, lobutyl methacrylate, hexyl acrylate, 2-ethyl butyl acrylate, inoctyl acrylate, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, Examples include decyl acrylate, dodecyl acrylate, tridecyl acrylate, and tridecyl methacrylate.

Further, other monomers copolymerized with the above (meth)acrylic acid alkyl ester include (meth)acrylic acid,
Carboxyl group-containing monomers such as itaconic acid, maleic acid, maleic anhydride, 7-maric acid, styrene sulfonic acid, 7-lylsulfonic acid, rufobrovir acrylate, (
(meth)acrylic acid hydroxyethyl ester, (meth)acrylic acid hydroxyethyl ester, (meth)acrylic acid hydroxyethyl ester, (meth)acrylic acid hydroxyethyl ester, (
/E) Hydroxyl group-containing monomers such as acrylic acid hydroxypropyl ester, amide group-containing monomers such as (meth)acrylamide, trimethyl(meth)acrylamide, N-butylacrylamide, tetramethylbutylacrylamide, and N-methylol(meth)acrylamide Acrylic monomers, (meth)acrylic acid aminoethyl ester, (meth)acrylic [;, 'methylaminoethyl ester, (meth)acrylic acid diethylaminoethyl ester, (meth)acrylic acid Lert-butylaminoethyl ester, etc. Alkyl7minoalkyl group-containing acrylic monomer, (meth)acrylic acid methoxyethyl ester,
(meth)acrylic acid ethoxyethyl ester, (meth)
(meth)acrylic acid alkoxyalkyl ester such as acrylic acid butoxyethyl ester, (meth)acrylic acid tetrahydrofurfuryl ester, (meth)acrylic acid methoxyethylene glycol ester, (meth)acrylic acid methoxydiethylene glycol ester, (meth)acrylic acid methoxydiethylene glycol ester
Acrylic acid methoxypolyethylene glycol ester,
Monomers containing alkoxy groups (or ether bonds in side chains) such as (meth)acrylic acid methoxypolypropylene glycol ester, vinyl monomers such as N-(meth)acryloyl amino acids, acrylic acid phrethane, urea, and incyanate. Functional monomers such as acrylic monomers such as esters, and (meth)acrylonitrile, vinyl acetate, vinyl propionate, vinylpyrrolidone, vinylpyridine, vinylpyrazine, vinylpiperazine, vinylpiperidone, vinylpyrimidine, vinylpyrrole, vinyl Aerosol, vinyl caprolactam, vinyl oxazole, vinyl aerosol, vinyl morpholine, styrene, alpha
Examples include vinyl monomers such as -methylstyrene and bis(N,N'-trimethylaminoethyl)malenite.

These monomers have the effect of imparting cohesive force and improving drug solubility through copolymerization with the main component monomer, and unless the solubility of the drug is extremely reduced, they will not copolymerize. The polymerization ratio can be arbitrarily selected and used.

In the present invention, the (meth)acrylic acid alkyl ester and the copolymerizable monomer include various isomers in which the alkyl moiety is linear and branched, and fgi isomers and derivatives in which the position of the substituent group is different. This includes the following:

Other adhesives that may be used in the present invention include silicone rubber, polyisoprene rubber, polyisobutylene rubber, polybutadiene, styrene-butadiene (or isoprene)-styrene pro-tox copolymer rubber, acrylic rubber, Examples include rubber-based substances such as natural rubber such as gum arabic, synthetic resins such as polyurethane, polyester, polyamide, and ethylene-vinyl acetate copolymer. Examples of tackifying components include rosin, modified rosin, petroleum-based Examples of the plasticizers include machine oil, transformer oil, rosin oil, and various liquid paraffins.

Examples of other sticky substances include gels 0 For example, water-soluble polymers such as polyvinyl alcohol, polyvinylpyrrolidone, polyacrylic acid and its salts, synthetic systems such as machinic anhydride copolymers, dextran, and natural systems such as pullulan The del base material can be prepared by adding a semi-synthetic compound such as methylcellulose, ethylcellulose, or carboxymethylcellulose to a plasticizer, such as glycerin, propylene glycol, or polyethylene glycol, and if necessary, using a known crosslinking agent.

The above-mentioned adhesive contains a drug, but the drug is not particularly limited as long as it is transdermally absorbable, and specific examples include the following.

()Ca”F antidrugs: dihydropyridine type Ca2÷ antagonists such as nidrenopine, nicardipine, nimodipine, nildipine, nicardipine, nidrenopine, etc.)Fluticosteroid M: 54 examples include hydrocortiscin, firednisolone, beclomethasone propionate, flumethacin , triamcinolone, triamcinolone acetonide, fluocinolone, fluocinolone acetonide, fluocy70 acetonide acetate, clobetasol propiolate, etc. c) Analgesic anti-inflammatory agents: for example acetaminolone, mefenamic acid, flufenamic acid, indomethacin, cyclo7 Enatsuku, diclofenac sodium, flucro7enatsuc, oxy7enbutazone, 7enylbutazone, ibuprofen, flurbib a7ene, salicylic acid, methyl salicylate, !-men)-l, men7ar sulindac, tolmetin sodium, naproxen, 7 2) Hypnotic sedatives: e.g. 7e/barbital, amobarbital, cyfrobarbital, doriapram, nitrazepam, lorazepam, etc.; e) Tranquilizers: e.g. 7e/barbital, amobarbital, cyfrobarbital, doriapram, nitrazepam, lorazepam, etc.; flunitrazebam, haloperidol, chlorpromazine, etc.) Antihypertensive agents: e.g. clonidine, clonidine hydrochloride,
Pindolol, propranolol, propranolol hydrochloride, bupranolol, indenolol, roanidixine, nitrendipine, nibranorol, fucumolol, timolol, metoflorol, etc. g) Antihypertensive diuretics: e.g. hydrothiazide, pendroflunathiazide, cyclobenziazide, etc. g) Antibiotics: For example, penicillin, tetracycline,
Oxytetracycline, 7-radiomycin sulfate, erythromycin, chloramphenicol, etc.; 1) Anesthetic agents, such as docaine, nobuirine hydrochloride, benzicaine, ethyl amylbenzoate, etc.; 2) Antibacterial substances, such as benzalkonium hydrochloride. , nitro-7razone, nyscutin, acetosulfamine, clotrimazole, etc. l) Antifungal substances: e.g. pentamycin, amphotericin B, pyrrolnidoline, clotrimazole, etc. P) Vitamins: e.g. vitamin A1 ergocalciferol , cholecalciferol, octothiazine, riboflavin butyrate, etc.; c) Antiepileptic drugs: e.g., nitrazebam, mebrobamate, clonazebam, etc.; and a) Coronary vasodilators: e.g., nitroglycerin, nitroglycol, insorbidoniitrate, erythritol tetranitrate. , pentaerythritol tetranitrate, propyl nitrate, nianidibin, etc.) Antihistamines: For example, diphenhydramine hydrochloride,
Chlorpheniramine, diphenylimigzole, etc.; ii) Antitussives: For example, dextromethorphan hydrobromide, telbutasone sulfate, ephedrine, ephedrine hydrochloride, salbutamol, imbroterenolol hydrochloride, improterenol 70-sulfate, etc. Hormones: e.g. propsterone, estradiol, etc., 2) Antibiotics, e.g. doxebin, 3) Cerebral circulation improving agents: e.g. bisolquin, nilgot alkaloids, iaenprodil, etc., 4) III.
Anti-tumor wound: e.g. metoclopramide, clevopride,
Tonbelitone, scopolamine, scopolamine hydrobromide, 5-fluorouracil, mercaptopurine, etc. N) Biomedicine: For example, polypeptide M (TRH, LHR
Examples include 7-entanyl, digoxin, desmopressin, nohydroergotamine methanesulfonic acid, nohydroergotamine tartrate, etc.

Among these transdermally absorbable drugs, those having a melting point of 100° C. or lower are preferable because a small amount of drug-containing 1 plasticizes the drug-containing layer.

The mixing ratio of the above drug (A) and adhesive (B) is as follows:
It is preferable that A) is contained in the range of 3 to 40% by weight of the total (A + B), and the content of (A) is 3% by weight.
If the amount is less than 40% by weight, the therapeutic effect may be poor due to the small amount of drug administered to the body, while if the amount is less than 40%, the therapeutic effect will be limited and it will be uneconomical, both of which are undesirable.

In the patch for disease treatment of the present invention, it is desirable to incorporate into the drug-containing layer a substance that acts as a plasticizer to alleviate pain when peeled off after application to the skin. The additive to be used is preferably one with a relatively high melting point among the group of drugs to be melted.This additive functions as a plasticizer and at the same time functions as a transdermal absorption enhancer.

In the present invention, additives that do not act as plasticizers and only have the effect of promoting transdermal absorption may be added, such as lower alcohols such as methanol and ethanol, noethylene glycol, Propylene glycol, polyethylene glycol, polypropylene glycol, glycols such as polyethylene glycol, oils and fats such as olive oil, squalene, lanolin, dimethyldecyl phosphooxide, methyl octyl sulfoxide, dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide, trimethyl lauryl amide , dodecylpyrrolidone, polar solvents such as insorbitol,
Salicylic acid, amino acids, nicotinic acid, pencil ester, diisopropyl anobate, 7-talic acid ester, diethyl sebacate, N-methylpyrrolidone, glycerin ester, 1-dodecyl azacyclohebutan-2-one,
Examples include isopropyl myristate, ethyl laurate, silicone oil, various surfactants, and polymeric polyester plasticizers. These are 2 if necessary.
More than one species can be added.

The amount of the above additive is determined by considering the balance between skin FJ adhesion, cohesive length, and anchoring force, but it is preferably in the range of 0.1 to 40% by weight based on the entire drug-containing layer. Desirably, if the amount added is less than 0.1% by weight, the effect will be poor, and if it exceeds 40% by weight, skin adhesion may be extremely reduced, and cohesive force and anchoring ability may deteriorate. Undesirable.

(e) Effect The patch for disease treatment of the present invention has the above-mentioned structure, and since the surface portion of the drug-containing layer penetrates into the gaps of the porous body, the anchoring property is improved, and therefore, the patch for treating diseases of the present invention is improved. The drug-containing layer is plasticized by containing additives such as skin absorption enhancers,
Adhesion to the carrier (anchoring ability) even if the cohesive force decreases
The adhesive properties of this type of patch are improved, and the carrier does not fall off even after long-term application.Furthermore, if a drug-containing layer containing additives is used to reduce the skin adhesion, this type of patch can be applied easily. It has the effect of reducing skin irritation even if it is repeatedly removed, and does not leave any adhesive residue on the skin surface.

In addition, mild primary sting to the skin: For drugs that are spreadable and have good transdermal absorption, the drug is somewhat adsorbed to the porous material and acts as a drug storage layer, resulting in gentle transdermal absorption. When given, it has the effect of relieving skin irritation.

(r) Examples Next, the present invention will be explained in detail based on Examples, but the present invention is not limited thereto.

In the following, parts or % mean parts by weight or % by weight.

Example 1 In a nitrogen gas atmosphere, 70 parts of octyl acrylate, 30 parts of vinyl acetate, and 100 parts of ethyl acetate were charged into four flasks, and 0.2 parts of azobisisobutyronitrile (AIBN) was added as a polymerization initiator. Add ethyl acetate and stir while maintaining the bath temperature at 59-65℃.
After carrying out the polymerization reaction for 8 hours while controlling the reaction by gradually dropping 3.3 parts, the internal temperature was further lowered to 70°C.
A copolymer solution was obtained by raising the temperature to ~75°C and aging for 3 hours.

The polymerization rate of this copolymer was 91.2%, and the viscosity of the copolymer solution with a solid content concentration of 30% was 52 voids at a temperature of 30°C.

The obtained copolymer solution was added and mixed so that the content of timolol when formed into a timolol sheet was 1200 μm 17 cm, and this was mixed with polyethylene vinyl acetate (polyethylene vinyl acetate).
(EVA) film was laminated with 50 μω paper (porous material), and the paper (porous material) side of the carrier was coated so that the thickness after drying was 40 μm, and the temperature was 90°C.
A drug-containing layer was laminated by drying for 5 minutes to obtain a patch for treating diseases of the present invention.

Comparative Example 1 A patch was obtained in the same manner as in Example 1, using only an EVA film similar to that used in Example 1 as a carrier (therefore, no paper was used).

Example 2 Similarly to Example 1, 90 parts of 2-ethylhexyl acrylate and 10 parts of acrylic acid were copolymerized to achieve a polymerization rate of 98%.
A copolymer solution with a solid content concentration of 30% was obtained. The viscosity of this copolymer solution was 73 voids at a temperature of 30°C.

Nianidipine was added to the obtained copolymer at a content of 300μ.
s/c theory 2.2-octyldecanol with a content of 40
The dried glue was added to the non-woven fabric (porous body) side of a carrier made by laminating a polyethylene terephthalate/EVA (PET/EVA) film with a cotton non-woven fabric (basis weight 4118 g). The patch was coated to a thickness of 50 μm and dried at a temperature of 100° C. for 5 minutes to laminate a drug-containing layer to obtain a patch for treating diseases of the present invention.

Comparative Example 2 PET/EV similar to that used in Example 2 as a carrier
A patch was obtained in the same manner as in Example 2 using Film A (therefore, no nonwoven fabric was used).

Example 3 85 parts of isononyl 7 acrylate, 1 part of butyl acrylate
0 parts of acrylic acid and 5 parts of acrylic acid were copolymerized to obtain a copolymer solution with a polymerization rate of 99% and a solid content of 30%.

The viscosity of this copolymer solution was 98 voids at a temperature of 30°C.

Indomethacin was added to the obtained copolymer at a content of 300%.
gg/Cm", polyester plastic shoulder (product name Polysizer W100OEL>, including 1200μii/
Cm'' and applied to the nonwoven fabric (porous material) side of a carrier formed by laminating a polyester nonwoven fabric (fabric weight ffi 20g) on an EVA film so that the thickness after drying would be 50 μm. , temperature 100℃
The patch was dried for 5 minutes and a drug-containing layer was laminated thereon to obtain a patch for treating diseases of the present invention.

Comparative Example 3a A patch was obtained in the same manner as in Example 3 using only the same E-VA film as used in Example 3 as a carrier.

Comparative example 3b In Example 3a, a patch without additives was obtained.

Using each of the above examples and comparative examples, Table 1 shows the results of investigating the anchor failure rate when measuring the adhesive force to a Bakelite plate, the anchor failure when peeling off after the skin adhesion test, and the adhesive residue.

For Example 1 and Comparative Example 1, the skin irritation when applied to the skin was shown, and for Example 3 and Comparative Example 3b, the presence or absence of pain when peeled off after the skin adhesion trial was shown.

(Leaving space below) 1) The test sample was made into a size of 12+am x 10mm and was crimped onto a Bakelite plate with a load of 850g at a temperature of 23±2°C.However, in Comparative Examples 1 and 3a, the carrier was lined with a polyethylene tele7 tallate tape. The adhesion strength was measured by peeling off beer at 180°C in a shear test.
The rate of anchor failure at that time was expressed as a percentage of the attached area.

2) Place 2 samples of 30nωφ on the inside of the upper arm of a healthy person.
After sticking for 4 hours, the state of the sample when it was peeled off was visually judged for the anchor failure rate and the presence or absence of adhesive residue.

3) Using the same method as in 2), skin irritation was visually determined at 8 hours and 24 hours after peeling.

: None ± : Slight erythema + : Erythema ++ : Floating skin + 10: Vesicles 4) The same method as 2) was used to determine the presence or absence of pain during peeling.

From the results shown in Table 1, in each Example, there was no anchor failure, and there was no anchor failure or adhesive residue when peeled off after adhesion to the skin, and no pain was observed during peeling. On the other hand, in Comparative Example 1, Comparative Example 2, and Comparative Example 3a, anchor failure occurred, while in Comparative Example 3b, there was no anchor failure, but skin pain was observed when peeled off after skin adhesion.

(g) Effects of the invention The patch for disease treatment of the present invention is formed by laminating a drug-containing layer that is adhesive at room temperature on the side of the porous body of a carrier formed by laminating a porous body on a base material. Since the surface part of this drug-containing layer penetrates into the gaps of the porous body, anchoring properties are improved, and therefore even a low-adhesion drug-containing layer containing a plasticizer or transdermal absorption enhancer can be used as a carrier. The adhesive properties of the adhesive have been improved, and the carrier does not fall off even when applied for a long time (Also, even if this type of patch is repeatedly applied and peeled off, there is no skin irritation, and there is no adhesive residue on the skin surface. It has no effect.

In addition, in the patch for disease treatment of the present invention, when it comes to drugs that have mild primary irritation to the skin and have good percutaneous absorption, the drug contained therein is somewhat adsorbed to the porous body and plays the role of drug storage. In fact, it has the effect of alleviating skin irritation by providing gentle percutaneous absorption.

Furthermore, in the patch for disease treatment of the present invention, the one in which the carrier and the drug-containing layer are laminated and then pressed together with a (thermal) roll etc. has further improved anchoring properties and is also aesthetically pleasing. This has the following effect.

Claims (2)

[Claims] (1) A patch for disease treatment, comprising a carrier formed by laminating a porous material on a base material, and a drug-containing layer that is adhesive at room temperature on the side of the porous material. (2) The patch for disease treatment according to claim 1, wherein the drug-containing layer contains an additive that relieves pain when peeled off after application to the skin.