JP7029244B2 - Patch - Google Patents

Description

The present invention relates to a patch, and more particularly to a patch containing rivastigmine and / or a pharmaceutically acceptable salt thereof.

Transdermal and transmucosal absorption preparations have been developed as preparations for administering drugs in vivo, and among them, patches that are easy to handle and can maintain the effective blood concentration of the drug for a long period of time are attracting attention. ing. For example, rivastigmine (methylethylcarbamitic acid 3-[(S) -1- (dimethylamino) ethyl] phenyl), which is an Alzheimer-type dementia drug, can reduce the burden of medication management on caregivers and enable continuous administration. From this point of view, administration with a patch is preferable.

Examples of the patch containing such rivastigmine include a lining layer, a storage layer containing a pharmaceutically active ingredient and a polymer, a silicone polymer and a tackifier in Japanese Patent Application Laid-Open No. 2009-517468 (Patent Document 1). A transdermal therapeutic system comprising an adhesive layer has been described, including rivastigmine as the pharmaceutically active ingredient. Further, in International Publication No. 2015/087926 (Patent Document 2), a support layer, a specific amount of ribastigmine and / or a pharmaceutically acceptable salt thereof, and an acrylic polymer (A) having a hydroxy group are included. Contains a specific amount of acrylic polymer (B), which is a drug reservoir, a (meth) acrylic acid alkyl ester copolymer having a carboxy group, and / or an acrylic acid homopolymer, and a rubber-based adhesive base. A laminated patch comprising an adhesive layer is described. However, a laminated patch in which a layer containing a drug (drug storage layer) and a layer containing an adhesive base (adhesive layer) for adhering a patch to the skin, such as these patches, are separate layers. Although it is possible to increase the content of rivastigmine in the patch, the thickness of the patch increases, so that the drug reservoir or adhesive layer is exposed during storage or application to the skin, and the skin becomes exposed. There is a concern that it may be irritated by touching the skin, or that it may adhere to the inner layer of the packaging material and be difficult to remove, and that the manufacturing process may be complicated.

Further, as a single-layer type patch containing a drug and a pressure-sensitive adhesive in the same single layer, for example, a support and an alkyl (meth) acrylate that does not contain an acrylic monomer component having a carboxy group. A patch having a pressure-sensitive adhesive layer containing an ester copolymer and rivastigmine is described in International Publication No. 2013/031992 (Patent Document 3). Further, Japanese Patent Application Laid-Open No. 2002-542277 (Patent Document 4) describes a pharmaceutical agent that acts as basic or neutral, and a pressure-sensitive adhesive polymer having an acrylic acid or methacrylic acid unit in its polymer chain. A transdermal therapeutic system containing the above is described, and US Pat. No. 6,316,023 (Patent Document 5) contains rivastigmine, polymethacrylate, an acrylate copolymer containing a carboxy group, and an antioxidant. A transdermal absorption system is described.

Special Table 2009-517468 Gazette International Publication No. 2015/0879226 International Publication No. 2013/031992 Special Table 2002-542277 Publication No. U.S. Pat. No. 6,316,023

In the rivastigmine-containing patch as described in Patent Documents 3 to 4, the present inventors directly contact the skin containing the rivastigmine, and therefore, in order to exhibit sufficient skin permeability, the present inventors use rivastigmine. It has been found that if the content is simply increased, the skin irritation given to the application site may increase in long-term application or the like, and further reduction of such skin irritation is required.

The present invention has been made in view of the above-mentioned problems of the prior art, and an object of the present invention is to provide a patch having sufficiently small skin irritation to an application site.

As a result of intensive studies to achieve the above object, the present inventors have added rivastigmine and / or a pharmaceutically acceptable salt thereof in a single-layer patch having a support layer and a pressure-sensitive adhesive layer. An acrylic polymer having a carboxy group [acrylic polymer (A)] and an acrylic polymer having a hydroxy group and / or an acrylic polymer having substantially no functional group [acrylic polymer (B). )] And at least two acrylic polymers in a specific ratio to be contained in the pressure-sensitive adhesive layer, and rivastigmine and / or pharmaceutically acceptable thereof per unit area of the pressure-sensitive adhesive layer. By keeping the salt content within a specific range, the skin irritation given to the application site is sufficiently reduced while maintaining the medicinal effect as a patch containing ribastigmine and / or its pharmaceutically acceptable salt. We have found that this is possible, and have completed the present invention.

That is, the patch of the present invention is
A patch having a support layer and an adhesive layer.
The pressure-sensitive adhesive layer
At least one drug selected from the group consisting of rivastigmine and its pharmaceutically acceptable salts, and
At least one acrylic polymer (A) made of an acrylic polymer having a carboxy group, and
At least one acrylic polymer (B) made of an acrylic polymer (b2) having substantially no functional group, and
Contains
The content of rivastigmine and / or its pharmaceutically acceptable salt with respect to the total mass of the pressure-sensitive adhesive layer is 6 to 18% by mass in terms of free form.
The content of rivastigmine and / or its pharmaceutically acceptable salt per unit area of the pressure-sensitive adhesive layer is 0.45 to 0.90 mg / cm ² in terms of free form, and
The mass ratio (A: b2) of the acrylic polymer (A) and the acrylic polymer (b2) having substantially no functional group in the pressure-sensitive adhesive layer is 81: 19 to 10:90. be,
It is characterized by that.

Further, as the patch of the present invention, it is preferable that the acid value of the acrylic polymer having a carboxy group is 15 to 55 mgKOH / g.

Further, as the patch of the present invention, the average cumulative skin permeation amount of rivastigmine and / or its pharmaceutically acceptable salt when contacted with the skin of a hairless mouse for 24 hours is 200 to 560 μg / g in terms of free form. It is preferably cm ² .

Further, as the patch of the present invention, it is preferable that the area of the pressure-sensitive adhesive layer is 5 to 40 cm ² .

According to the present invention, it is possible to provide a patch having a sufficiently small skin irritation to the application site.

3 is a graph showing the relationship between the average cumulative skin permeation amount and the content of the acrylic polymer having a carboxy group in each of the patches obtained in Examples 4 to 7 and Comparative Examples 2 to 3. It is a graph which shows the average cumulative skin permeation amount for each time in the patch obtained in Example 10. 3 is a graph showing the relationship between the average cumulative skin permeation amount and the content of the acrylic polymer having a carboxy group in each of the patches obtained in Examples 11 to 15 and Comparative Examples 2 and 5. It is a graph which shows the average cumulative skin permeation amount for each time in the patch obtained in Example 12.

Hereinafter, preferred embodiments of the present invention will be described in detail in line with the preferred embodiments thereof. The patch of the present invention is
A patch having a support layer and an adhesive layer.
The pressure-sensitive adhesive layer
At least one drug selected from the group consisting of rivastigmine and its pharmaceutically acceptable salts, and
At least one acrylic polymer (A) selected from the group consisting of acrylic polymers having a carboxy group, and
At least one acrylic polymer (B) selected from the group consisting of an acrylic polymer (b1) having a hydroxy group and an acrylic polymer (b2) having substantially no functional group,
Contains
The content of rivastigmine and / or its pharmaceutically acceptable salt per unit area of the pressure-sensitive adhesive layer is 0.45 to 0.90 mg / cm ² in terms of free form, and
When the acrylic polymer (B) contains the acrylic polymer (b1) having the hydroxy group, the acrylic polymer (A) and the acrylic polymer having the hydroxy group in the pressure-sensitive adhesive layer are contained. The mass ratio (A: b1) with (b1) is 73: 27 to 5:95, and
When the acrylic polymer (B) contains an acrylic polymer (b2) that does not substantially have the functional group, the acrylic polymer (A) and the functional group in the pressure-sensitive adhesive layer are mixed. The mass ratio (A: b2) with the acrylic polymer (b2) that is substantially nonexistent is 81: 19 to 10:90.
It is a patch characterized by the fact that.

(Support layer)
The support layer according to the present invention is not particularly limited as long as it can support the pressure-sensitive adhesive layer, and a known support layer for a patch can be appropriately adopted. Examples of the material of such a support layer include polyesters such as polyethylene terephthalate, polybutylene terephthalate, and polyethylene naphthalate; polyolefins such as polyethylene and polypropylene; polyurethane; synthetic resins such as ethylene-vinyl acetate copolymer, and aluminum and the like. Metal and paper are mentioned. The form of the support layer made of such a material is, for example, a film; a sheet such as a foam sheet, a porous sheet, a microporous sheet, etc.; a fabric such as a woven fabric, a knitted fabric, a non-woven fabric; a foil; and a laminate thereof. The body is mentioned. The support layer according to the present invention is preferably one that does not allow the drug to permeate, and above all, a polyester film is preferable from the viewpoint of being excellent in drug impermeableness. The thickness of the support layer is not particularly limited, and is usually about 2 to 600 μm.

(Adhesive layer)
The pressure-sensitive adhesive layer according to the present invention is at least one selected from the group consisting of at least one drug selected from the group consisting of ribastigmine and a pharmaceutically acceptable salt thereof, and at least one selected from the group consisting of an acrylic polymer having a carboxy group. At least one selected from the group consisting of a seed acrylic polymer (A), an acrylic polymer having a hydroxy group (b1), and an acrylic polymer having substantially no functional group (b2). Contains an acrylic polymer (B).

[Drug]
The pressure-sensitive adhesive layer according to the present invention contains at least one selected from the group consisting of rivastigmine as a drug and a pharmaceutically acceptable salt thereof. Rivastigmine is a generic name for 3-[(S) -1- (dimethylamino) ethyl] phenyl methylethylcarbamite.

In the present invention, the form of rivastigmine contained in the pressure-sensitive adhesive layer may be a free form (free form) or a pharmaceutically acceptable salt thereof, and is being produced and / or produced. The pharmaceutically acceptable salt of rivastigmine may be desalted into a free form in the preparation, and it may be one of these or a mixture of two or more thereof. Pharmaceutically acceptable salts of rivastigmine include, for example, hydrochloric acid, sulfuric acid, acetic acid, nitrate, hydrobromic acid, phosphoric acid, methanesulfonic acid, fumaric acid, maleic acid, citric acid, tartrate acid, besilic acid, succinic acid. , Acid addition salts of acids such as tannic acid. In the present invention, among these, a free form of rivastigmine (hereinafter, simply referred to as "rivastigmine") is more preferable from the viewpoint that skin permeability tends to be further improved.

In the present invention, the content of rivastigmine and / or its pharmaceutically acceptable salt contained in the pressure-sensitive adhesive layer (the content of rivastigmine or the content of pharmaceutically acceptable salt of rivastigmine, or both. When all of them are contained, the total content thereof, the same applies hereinafter) is preferably 6 to 23% by mass, preferably 6 to 20% by mass, based on the total mass of the pressure-sensitive adhesive layer in terms of free form. It is more preferably by mass%, and even more preferably 6 to 18% by mass. If the content of the pressure-sensitive adhesive layer with respect to the total mass is less than the lower limit, it tends to be difficult to maintain sufficient skin permeability of rivastigmine, and the area of the patch becomes large during the application. The usability tends to decrease. On the other hand, if the upper limit is exceeded, the skin permeability of rivastigmine becomes too high, and it tends to be difficult to sufficiently reduce the skin irritation given to the application site.

Further, in the present invention, the content of rivastigmine and / or a pharmaceutically acceptable salt thereof contained in the pressure-sensitive adhesive layer is the content per unit area of the pressure-sensitive adhesive layer in terms of free form. It needs to be 0.45 to 0.90 mg / cm ² . In the present invention, the content of rivastigmine and / or its pharmaceutically acceptable salt per unit area satisfies such a condition, thereby sufficiently reducing the skin irritation given to the application site, and rivastigmine and / or its. It is possible to maintain the skin permeation amount of the pharmaceutically acceptable salt within a sufficient range where the medicinal effect can be expected. If the content of the pressure-sensitive adhesive layer per unit area is less than the lower limit, the skin permeation amount of rivastigmine decreases, while if it exceeds the upper limit, the skin irritation given to the application site increases. The content of the pressure-sensitive adhesive layer per unit area is more preferably 0.45 to 0.80 mg / cm ² , and even more preferably 0.50 to 0.80 mg / cm ² .

The pressure-sensitive adhesive layer according to the present invention may further contain a drug other than rivastigmine and a pharmaceutically acceptable salt thereof, as long as the effect of the present invention is not impaired. The other drugs are not particularly limited, but are, for example, hypnotic / sedative agents (flurazepam hydrochloride, lyl mazafone hydrochloride, phenobarbital, amobarbital, etc.), antipyretic anti-inflammatory analgesics (butorphanol tartrate, perisoxal citrate, acetaminophen, etc.). Mephenamic acid, diclofenac sodium, aspirin, alcrophenac, ketoprofen, flurubiprofen, naproxene, pyroxicum, pentazocin, indomethacin, glycol salicylate, aminopyrine, loxoprofen, etc.), steroidal anti-inflammatory agents (hydrocortisone, prednisolone, dexamethasone, betamethasone, etc.) Excitement / stimulant (methanefetamine hydrochloride, methylphenidet hydrochloride, etc.), neuropsychiatric agents (imiplamine hydrochloride, diazepam, celtralin hydrochloride, fluboxamine maleate, paroxetine hydrochloride, citaloplum hydrobromide, fluoxetine hydrochloride, alprazolam, haloperidol, clomipramine, amitryptiline , Decipramine, Amoxapin, Maprotyrin, Mianserin, Sepiptyrin, Trazodon, Lofepramine, Milnaciplan, Duroxetine, Benrafaxin, Chlorpromazine hydrochloride, Thioridazine, Diazepam, Meprobamate, Ethizolam, Lisperidone, Miltazapine, etc. Progesterone, norethisterone acetate, metenolone acetate, testosterone, etc.), local anesthetics (lidocane hydrochloride, prokine hydrochloride, tetrakine hydrochloride, dibucaine hydrochloride, propitokine hydrochloride, etc.), urinary organ preparations (oxybutynin hydrochloride, tamthrosin hydrochloride, propiverine hydrochloride, tortellodin tartrate) , Fesoterodine, imidafenacin, etc.), Skeletal muscle relaxant (thizanidin hydrochloride, emerison hydrochloride, prizinol mesylate, schisametonium chloride, etc.), reproductive organ preparation (lithodrin hydrochloride, meladrin tartrate, etc.), antiepileptic acid (sodium valproate, chronazepam , Carbamazepine, etc.), Autonomic nerve agents (carpronium chloride, neostigmine bromide, betanecol chloride, etc.), anti-Parkinson's disease agents (pergolide mesilate, bromocryptin mesylate, trihexyphenidyl hydrochloride, amantazine hydrochloride, ropinilol hydrochloride, talipexol hydrochloride, etc. Cabergoline, droxydopa, viperiden, selegiline hydrochloride, etc.), diuretics (hydroflumethiazide, frosemide, etc.), respiratory promoters (lovelin hydrochloride) , Dimorphoramine, naloxone hydrochloride, etc.), anti-mitiginal pain agents (dihydroergotamine mesylate, sumatriptan, ergotamine tartrate, flunaridine hydrochloride, siproheptazine hydrochloride, etc.), antihistamines (cremastine fumarate, diphenhydramine tannate, chlorpheniramine maleate, etc. Diphenylpyraline hydrochloride, promethazine, etc.), bronchial dilators (turobterol hydrochloride, procaterol hydrochloride, salbutamol sulfate, clinbuterol hydrochloride, phenotelol hydrobromide, terbutalin sulfate, isoprenal sulfate, formoterol fumarate, etc.), cardiotonic agents (isoprenalin hydrochloride, hydrochloric acid, etc.) Dopamine, etc.), coronary vasodilators (zyrthiazem hydrochloride, verapamil hydrochloride, isosorbide nitrate, nitroglycerin, nicolangyl, etc.), peripheral vasodilators (nicamethate citrate, trazoline hydrochloride, etc.), quitting aids (nicotine, etc.), for circulatory organs Agents (flunaridine hydrochloride, nicardipine hydrochloride, nitorenzine, nisoldipine, ferrodipine, amlogipin vesylate, nifedipine, nilvadipine, manidipine hydrochloride, benidipine hydrochloride, enalapril hydrochloride, temocapril hydrochloride, araceptril, imidapril hydrochloride, sirazapril, lysinopril Perindpril erbumin, athenolol, pindrol, bisoprolol fumarate, meteprolol tartrate, betaxolol hydrochloride, timorol maleate, bopindolol malonate, niprazilol, arotinolol hydrochloride, celiprol hydrochloride, carvezilol, amoslalol hydrochloride, carteolol hydrochloride, bevantrol hydrochloride, bevantrol hydrochloride , Bunazocin hydrochloride, prazosin hydrochloride, doxazosin mesylate, balsartane, candesartan cilexetil, rosartan potassium, chronidine hydrochloride, guanfacin hydrochloride, guanabends acetate, etc.) , Nadrol, disopyramide, etc.), Anti-malignant ulcer agents (cyclophosphamide, fluorouracil, tegafur, procarbazine hydrochloride, ranimustin, irinotecan hydrochloride, flulysine, etc.) Depressant (Glybenclamid, Chlorpropamide, Torbutamide, Glymidin Sodium, Glybsol, Buformin Hydrochloride, etc.), Digestive ulcer therapeutic agent (Pro) Glumid, cetraxate hydrochloride, spizoflon, simethidine, glycopyromycin bromide, etc.), biliary agents (ursodesoxycholic acid, osalmid, etc.), gastrointestinal motility improving agents (donperidone, cissupride, etc.), agents for liver diseases (thiopronin) Etc.), antiallergic agents (ketotifen fumarate, azelastine hydrochloride, etc.), antiviral agents (acyclovir, etc.), antispasmodics (betahistin mesylate, diphenidol hydrochloride, etc.), antibiotics (cephaloridine, cefdinyl, cefpodoxime proxetyl, etc.) , Cefaclor, clarithromycin, erythromycin, methylerythromycin, canamycin sulfate, cycloserine, tetracycline, benzylpenicillin potassium, propicillin potassium, cloxacillin sodium, ampicillin sodium, bacampicillin hydrochloride, carbenicillin sodium, chloramphenicol, etc.), customs Sex poisoning agents (cyanamide, etc.), appetite suppressants (magindol, etc.), chemotherapeutic agents (isoniazide, ethionamide, pyrazinamide, etc.), blood coagulation promoters (tyclopidin hydrochloride, walfarin potassium, etc.), anti-Alzheimer agents (phyzostigmin, dongepezil hydrochloride, etc.) , Tacrine, alecholine, xanomerin, etc.), serotonin receptor antagonist anti-vomiting agent (ondansetron hydrochloride, granisetron hydrochloride, ramosetron hydrochloride, azacetron hydrochloride, paronosetron, etc.) Painkillers (fentanyl citrate, morphine sulfate, morphine hydrochloride, codeine phosphate, cocaine hydrochloride, petidin hydrochloride, etc.) can be mentioned. When the pressure-sensitive adhesive layer further contains such other drugs, the content (total content in the case of a mixture of two or more kinds) is 10% by mass with respect to the total mass of the pressure-sensitive adhesive layer. % Or less is preferable.

[Acrylic polymer (A)]
The pressure-sensitive adhesive layer according to the present invention contains at least one acrylic polymer (referred to as "acrylic polymer (A)") selected from the group consisting of acrylic polymers having a carboxy group.

In the present invention, the "acrylic polymer" refers to a polymer or copolymer of a monomer containing (meth) acrylic acid and / or a (meth) acrylic acid derivative, and the above-mentioned (meth) acrylic acid derivative. Examples thereof include (meth) acrylic acid ester. Further, in the present invention, "(meth) acrylic acid" means acrylic acid and / or methacrylic acid, and "carboxy group" means a group represented by the following formula ^: -COOH or a group represented by -COO-. ..

Further, in the present invention, the "acrylic polymer having a carboxy group" refers to an acrylic polymer having a carboxy group content of 3% by mass or more. Further, in the present invention, the "acrylic polymer having a carboxy group" is preferably one that does not substantially have a hydroxy group. In the present invention, substantially no hydroxy group means that the content of the hydroxy group is less than 3% by mass.

The acrylic polymer (A) according to the present invention preferably has an acid value of 15 to 55 mgKOH / g, more preferably 20 to 55 mgKOH / g, and further preferably 25 to 55 mgKOH / g. preferable. If the acid value is less than the lower limit, the skin permeability of rivastigmine tends to be high, and it tends to be difficult to sufficiently reduce the skin irritation given to the application site. On the other hand, if the acid value exceeds the upper limit, sufficient rivastigmine is sufficient. It tends to be difficult to maintain skin permeability. In the present invention, the "acid value" indicates the mass (mg) of potassium hydroxide (KOH) required to neutralize the free fatty acid present in 1 g of the polymer, and is JIS K 0070 (1992). ) Can be measured by a method compliant with. The weight average molecular weight of such an acrylic polymer (A) is not particularly limited and may be 1,000 to 10,000,000.

Examples of the acrylic polymer (A) according to the present invention include -2-ethylhexyl acrylate, vinyl acetate, butyl acrylate, acrylic acid copolymer, -2-ethylhexyl acrylate, methyl acrylate, and acrylic acid. Glycidyl methacrylate copolymer, acrylic acid / acrylic acid-2-ethylhexyl / vinyl acetate copolymer, acrylic acid / butyl acrylate / acrylic acid-2-ethylhexyl copolymer, acrylic acid / methyl acrylate / acrylic acid- Examples thereof include 2-ethylhexyl copolymer, acrylic acid / acrylic acid octyl ester copolymer, and acrylic acid / vinyl acetate copolymer, and one of these may be used alone or in combination of two or more. May be good.

Further, as these acrylic polymers (A), commercially available ones may be used, for example, 87-2051 (acid value: 44 mgKOH) of Duro-Tak (registered trademark) acrylic pressure-sensitive adhesive series (manufactured by Henkel). / G), 87-2194 (acid value: 51 mgKOH / g), 87-2054 (acid value: 49 mgKOH / g), 87-235A (acid value: 41 mgKOH / g, 87-2852 (acid value: 29 mgKOH / g)) , 87-2100 (acid value: 25 mgKOH / g), 87-2677 (acid value: 17 mgKOH / g), 87-2052, 87-2196, 87-2353, 87-207A, 87-200A, 87-2677, 87 -2825; An acrylic polymer contained in GMS 9073 of GELVA (registered trademark) acrylic pressure-sensitive adhesive series (manufactured by Henkel); MAS COS 10 (manufactured by Cosmedi) and the like can be appropriately used.

In the present invention, the content of the acrylic polymer (A) contained in the pressure-sensitive adhesive layer (total content in the case of a mixture of two or more types, the same applies hereinafter) is the entire content of the pressure-sensitive adhesive layer. It is preferably 5 to 84% by mass, more preferably 10 to 79% by mass with respect to the mass. If the content of the acrylic polymer (A) is less than the lower limit, the skin permeability of rivastigmine tends to be high, and it tends to be difficult to sufficiently reduce the skin irritation given to the application site. If the upper limit is exceeded, it tends to be difficult to maintain sufficient skin permeability of rivastigmine.

[Acrylic polymer (B)]
The pressure-sensitive adhesive layer according to the present invention is at least one acrylic polymer selected from the group consisting of acrylic polymers having a hydroxy group (referred to as “acrylic polymer having a hydroxy group (b1)”). In addition, at least one acrylic polymer selected from the group consisting of acrylic polymers having substantially no functional group (referred to as "acrylic polymer (b2) having substantially no functional group"). It contains at least one acrylic polymer (referred to as "acrylic polymer (B)") selected from the group consisting of.). In the present invention, by combining the acrylic polymer (A) and the acrylic polymer (B), the medicinal effect as a patch containing rivastigmine and / or a pharmaceutically acceptable salt thereof is maintained. However, it is possible to sufficiently reduce the skin irritation given to the application site.

-Acrylic polymer having a hydroxy group (b1)
In the present invention, the "acrylic polymer having a hydroxy group" means an acrylic polymer having a hydroxy group content of 3% by mass or more. In the present invention, the "hydroxy group" refers to a group represented by the following formula: -OH or ^-O- . Further, in the present invention, the "acrylic polymer having a hydroxy group" is preferably one that does not substantially have a carboxy group. In the present invention, substantially no carboxy group means that the content of the carboxy group is less than 3% by mass.

The weight average molecular weight of the acrylic polymer (b1) having a hydroxy group according to the present invention is not particularly limited and may be 1,000 to 10,000,000.

Examples of the acrylic polymer (b1) having a hydroxy group according to the present invention include a homopolymer of (meth) acrylic acid hydroxyalkyl ester and a copolymer of (meth) acrylic acid hydroxyalkyl ester and a polymerizable monomer. Examples thereof include a (meth) acrylic acid hydroxyalkyl ester copolymer which is a coalescence. Examples of the (meth) acrylic acid hydroxyalkyl ester include esters of a hydroxy group-containing alcohol having an alkyl group having 2 to 18 carbon atoms and (meth) acrylic acid, and specifically, (meth). Examples thereof include 2-hydroxyethyl acrylate, 2-hydroxypropyl (meth) acrylate, 3-hydroxypropyl (meth) acrylate, and 4-hydroxybutyl (meth) acrylate. Specific examples of the polymerizable monomer include (meth) acrylic acid, (meth) acrylate-2-ethylhexyl, (meth) methyl acrylate, butyl (meth) acrylate, vinylpyrrolidone, and vinyl acetate. ..

Specific examples of the acrylic polymer (b1) having such a hydroxy group include (meth) -2-ethylhexyl acrylate, vinyl acetate, and 2-hydroxyethyl acrylate copolymer (meth). ) 2-Hydroxyethyl acrylate copolymer, (meth) 2-hydroxypropyl acrylate copolymer, (meth) 3-hydroxypropyl acrylate copolymer, (meth) 4-hydroxybutyl acrylate copolymer, Examples thereof include -2-ethylhexyl acrylate, vinyl acetate, hydroxyethyl acrylate, and glycidyl methacrylate copolymer, and one of these may be used alone or in combination of two or more.

Further, as the acrylic polymer (b1) having these hydroxy groups, a commercially available one may be used, for example, 87-202A of Duro-Tak (registered trademark) acrylic pressure-sensitive adhesive series (manufactured by Henkel). 87-2287, 87-2516, 87-2510, 87-4287, 87-2525, 87-201A, 87-202A, 87-208A, 87-502A, 87-503A, 87-504A; GELVA® acrylic Acrylic polymers contained in GMS 788, GMS 737, etc. of the pressure-sensitive adhesive series (manufactured by Henkel) can be appropriately used.

In the present invention, when the pressure-sensitive adhesive layer contains the acrylic polymer (b1) having the hydroxy group as the acrylic polymer (B), the content of the acrylic polymer (A) and the hydroxy group. The mass ratio (A: b1) to the content of the acrylic polymer (b1) having the above (total content in the case of a mixture of two or more kinds, the same applies hereinafter) is 73: 27 to 5:95. It is necessary to be. In the patch of the present invention in which the content of ribastigmine and / or a pharmaceutically acceptable salt thereof per unit area of the pressure-sensitive adhesive layer is within the above range, the acrylic polymer (A) and the hydroxy group are further added. By having the mass ratio with the acrylic polymer (b1) having the above range, the medicinal effect as a patch containing rivastigmine and / or a pharmaceutically acceptable salt thereof is maintained, and the application site is It is possible to sufficiently reduce the skin irritation given. The mass ratio is more preferably 70:30 to 10:90, and even more preferably 70:30 to 20:80.

-Acrylic polymer (b2) that has virtually no functional group
In the present invention, the "acrylic polymer having substantially no functional group" refers to an acrylic polymer in which the content of the functional group in the polymer is less than 3% by mass. Examples of the functional group include a carboxy group, a hydroxy group, a carbonyl group, an amino group, an alkoxy group, a nitro group, a sulfo group and the like. The weight average molecular weight of the acrylic polymer (b2) having substantially no functional group according to the present invention is not particularly limited and may be 1,000 to 10,000,000.

Examples of the acrylic polymer (b2) having substantially no functional group include -2-ethylhexyl-vinylpyrrolidone copolymer of acrylate and -2-ethylhexyl / -2-ethylhexyl / methyl acrylate. Dodecyl acid acid copolymer, -2-ethylhexyl acrylate / vinyl acetate copolymer, -2-ethylhexyl acrylate / methyl methacrylate / butyl acrylate copolymer, -2-ethylhexyl acrylate / methyllate copolymer, Examples thereof include ethyl acrylate / methyl methacrylate copolymer, and one of them may be used alone or two or more thereof may be used in combination.

Further, as the acrylic polymer (b2) having substantially no of these functional groups, commercially available ones may be used, for example, MAS 811 and MAS 683 (manufactured by Cosmed); Duro-Tak ( Registered trademark) Acrylic adhesive series (manufactured by Henkel) 87-900A, 87-901A, 87-9301, 87-4098, 87-9088, 87-9085; GELVA (registered trademark) acrylic adhesive series (manufactured by Henkel) ), The acrylic polymer contained in GMS 3083, GMS 3253, GMS 3235 and the like can be appropriately used.

Further, in the present invention, when the pressure-sensitive adhesive layer contains the acrylic polymer (b2) having substantially no functional group as the acrylic polymer (B), the acrylic polymer (A) The mass ratio (A: b2) to the content of the acrylic polymer (b2) having substantially no functional group (total content in the case of a mixture of two or more kinds, the same applies hereinafter). ) Needs to be 81: 19 to 10:90. In the patch of the present invention in which the content of ribastigmine and / or a pharmaceutically acceptable salt thereof per unit area of the pressure-sensitive adhesive layer is within the above range, the acrylic polymer (A) and the functional group are further added. By having the mass ratio with the acrylic polymer (b2) substantially free of the above range, the medicinal effect as a patch containing ribastigmine and / or a pharmaceutically acceptable salt thereof is maintained. At the same time, it is possible to sufficiently reduce the skin irritation given to the application site. The mass ratio is more preferably 80:20 to 15:85, and even more preferably 80:20 to 20:80.

Further, in the present invention, the content of the acrylic polymer (B) (total content in the case of a mixture of two or more kinds, the same applies hereinafter) is 10 to 10 with respect to the total mass of the pressure-sensitive adhesive layer. It is preferably 89% by mass, more preferably 15 to 84% by mass. If the content of the acrylic polymer (B) is less than the lower limit, it tends to be difficult to maintain sufficient skin permeability of rivastigmine, while if it exceeds the upper limit, rivastigmine permeates the skin. It tends to be difficult to sufficiently reduce the skin irritation given to the application site due to the high sex.

The acrylic polymer (B) according to the present invention is a combination of the acrylic polymer (b1) having a hydroxy group and the acrylic polymer (b2) having substantially no functional group. Also, the mass ratio (b1:) of the content of the acrylic polymer (b1) having a hydroxy group and the content of the acrylic polymer (b2) having substantially no functional group in the pressure-sensitive adhesive layer (b1: b2) may be up to 1: 1.

[Other ingredients]
The pressure-sensitive adhesive layer according to the present invention includes ribastigmine and / or a pharmaceutically acceptable salt thereof, the acrylic polymer (A), and the acrylic polymer as long as the effects of the present invention are not impaired. In addition to (B), other tackifiers and additives such as tackifiers, softeners, antioxidants, solubilizers, fillers and stabilizers may be further contained.

Examples of the other pressure-sensitive adhesive base include a rubber-based pressure-sensitive adhesive base, an acrylic-based pressure-sensitive adhesive base other than the acrylic-based polymer (A) and the acrylic-based polymer (B), and a silicone-based pressure-sensitive adhesive base. One of them may be used alone or two or more of them may be used in combination. When the pressure-sensitive adhesive layer further contains such another pressure-sensitive adhesive, its content (total content in the case of a mixture of two or more kinds) is 30 with respect to the total mass of the pressure-sensitive adhesive layer. It is preferably mass% or less.

Examples of the tackifier include rosin resin, rosin ester resin, terpene resin, terpene phenol resin, C5 petroleum resin, C5 / C9 petroleum resin, DCPD (dicyclopentadiene) petroleum resin, and Kumaron inden resin. Examples thereof include alicyclic saturated hydrocarbon resins and those to which hydrogen is added, and one of these may be used alone or in combination of two or more. When the pressure-sensitive adhesive layer further contains such a tackifier, the content thereof (total content in the case of a mixture of two or more kinds) is 30% by mass with respect to the total mass of the pressure-sensitive adhesive layer. % Or less is preferable.

Examples of the softener include petroleum oils (eg, paraffin process oils such as liquid paraffin, naphthenic process oils, aromatic process oils, etc.), squalanes, squalanes, and vegetable oils (eg, olive oils, camellia oils, castor oils, etc.). , Thor oil, lacquer oil, etc.), Silicone oil, dibasic acid esters (eg dibutylphthalate, dioctylphthalate, etc.), liquid rubber (eg liquid polybutene, liquid isoprene rubber, etc.), liquid fatty acid esters (eg myristic acid) Isopropyl, hexyl laurate, diethyl sebacate, diisopropyl sebacate, etc.), diethylene glycol, polyethylene glycol, glycol salicylate, propylene glycol, dipropylene glycol, triacetin, triethyl citrate, crotamitone, etc. It may be used alone or in combination of two or more. Among these, liquid paraffin, liquid polybutene, isopropyl myristate, diethyl sebacate, and hexyl laurate are preferable, and liquid paraffin is more preferable. When the pressure-sensitive adhesive layer further contains such a softening agent, the content thereof (total content in the case of a mixture of two or more kinds) is 10% by mass with respect to the total mass of the pressure-sensitive adhesive layer. The following is preferable.

Examples of the antioxidant include tocopherol and its ester derivatives, ascorbic acid, ascorbic acid stearate, nordihitolog ayaretinic acid, dibutylhydroxytoluene, butylhydroxyanisole, ascorbic acid palmitate, sodium pyrosulfate, and propyl gallate. , 2-Mercaptobenzimidazole is preferred. When the pressure-sensitive adhesive layer further contains such an antioxidant, the content thereof (total content in the case of a mixture of two or more kinds) is 10% by mass with respect to the total mass of the pressure-sensitive adhesive layer. % Or less is preferable.

The solubilizer may be, for example, fatty acids (eg, capric acid, oleic acid, linoleic acid, etc.), fatty acid esters (eg, isopropyl myristate, isopropyl palmitate, etc.), although it depends on the type of solute to be dissolved. Fatty acid derivatives (eg, propylene glycol monolaurate, diethanolamide, etc.), fatty acid glycerin esters (eg, glycerin monolaurate, glycerin monooleate, etc.), polyhydric alcohol esters of fatty acids (eg, sorbitan monolaurate, etc.), Aliper alcohols (eg, octyldodecanol, isostearyl alcohol, oleyl alcohol, etc.), polyhydric alcohols (eg, propylene glycol, dipropylene glycol, polyethylene glycol, etc.), pyrrolidone derivatives (eg, N-methyl-2-pyrrolidone) Etc.), organic acids (eg acetic acid, lactic acid, etc.), organic acid salts (eg sodium acetate, sodium lactate, etc.), and one of these may be used alone or in combination of two or more. May be. When the pressure-sensitive adhesive layer further contains such a dissolving agent, the content thereof (total content in the case of a mixture of two or more kinds) is 10% by mass with respect to the total mass of the pressure-sensitive adhesive layer. The following is preferable.

Examples of the filler include inorganic compounds such as silica, aluminum oxide, aluminum hydroxide, zinc oxide, titanium oxide, talc, clay, kaolin, glass, barium sulfate, calcium carbonate, hydroxyapatite, and ceramics; cellulose, silk, and polyester. , Polyacrylate, polyacrylic acid ester, polymethacrylic acid ester, polystyrene, and other organic compounds, and one of these may be used alone or in combination of two or more. Examples of the stabilizer include tocopherol, an ester derivative of tocopherol, ascorbic acid, ascorbic acid stearyl ester, nordihydroguayretinic acid, dibutylhydroxytoluene, butylhydroxyanisole, ascorbic acid palmitate, sodium pyrosulfate, and propyl gallate. Examples thereof include propyl and 2-mercaptobenzimidazole, and one of these may be used alone or in combination of two or more. When the pressure-sensitive adhesive layer further contains such a filler and / or the stabilizer, the content thereof (total content in the case of a mixture of two or more kinds) is the entire content of the pressure-sensitive adhesive layer. It is preferably 10% by mass or less with respect to the mass.

In the present invention, the thickness of the pressure-sensitive adhesive layer is preferably 20 to 200 g / m ² , more preferably 20 to 100 g / m ² . When the thickness of the pressure-sensitive adhesive layer is less than the lower limit, the adhesiveness to the skin tends to decrease, while when the thickness exceeds the upper limit, the pressure-sensitive adhesive layer is exposed and adheres to the inner layer of the packaging material. It tends to be difficult to take out.

In addition, the patch of the present invention is the amount of the drug to be administered by appropriately cutting when it is applied to the application site according to the purpose of treatment and the treatment method, that is, rivastigmine and / or its pharmaceutical use in the entire pressure-sensitive adhesive layer. The allowable salt content (specifically, for example, 4.5 mg, 9 mg, 13.5, 18 mg, etc. in terms of free form) can be adjusted. In the patch of the present invention, the area of the sticking surface of the pressure-sensitive adhesive layer is preferably 5 to 40 cm ² , and as described above, rivastigmine and / or a pharmaceutically acceptable salt thereof in the entire pressure-sensitive adhesive layer. When the content of is, for example, 18 mg in terms of free form, it is more preferably 20 to 40 cm ² . When the area of the pressure-sensitive adhesive layer is less than the lower limit, the skin irritation given to the application site tends to increase, while when the area exceeds the upper limit, the skin permeation amount of rivastigmine decreases and the usability during application decreases. I tend to do it. When the content of rivastigmine and / or its pharmaceutically acceptable salt in the entire pressure-sensitive adhesive layer is, for example, 18 mg in terms of free form, the area of the pressure-sensitive adhesive layer may be 22.5 to 40 cm ² . It is more preferably 22.5 to 36 cm ² , and particularly preferably 22.5 to 36 cm 2.

(Attachment and its manufacturing method)
The patch of the present invention preferably has a structure in which the pressure-sensitive adhesive layer is laminated on one surface of the support layer. Further, the patch of the present invention may further include a release liner on the surface of the pressure-sensitive adhesive layer opposite to the support layer. Examples of such a release liner include polyolefins such as polyethylene and polypropylene; ethylene-vinyl acetate copolymers, vinyl acetate-vinyl chloride copolymers, polyvinyl chloride and the like; polyamides such as nylon; polyesters such as polyethylene terephthalate; cellulose derivatives; Examples thereof include synthetic resins such as polypropylene, films and sheets made of materials such as aluminum and paper, and laminates thereof. These mold release liners have a mold release treatment such as a silicone-containing compound coat or a fluorine-containing compound coat on the surface on the side in contact with the pressure-sensitive adhesive layer so that they can be easily peeled off from the pressure-sensitive adhesive layer. It is preferable to have.

According to the patch of the present invention, the average cumulative skin permeation amount of rivastigmine and / or its pharmaceutically acceptable salt when contacted with the skin of a hairless mouse for 24 hours is 200 to 560 μg / cm in terms of free form. It can be ² . The average cumulative skin permeation amount is preferably 200 to 530 μg / cm ² , and more preferably 230 to 500 μg / cm ² . When the average cumulative skin permeation amount is within the above range, the skin irritation given to the application site can be sufficiently reduced.

In the present invention, "the average cumulative skin permeation amount of rivastigmine and / or its pharmaceutically acceptable salt when in contact with the skin of a hairless mouse for 24 hours" can be measured by the following method. That is, first, the three samples of the patch are cut into a size of 3 cm ² each, and the skin of the body of the hairless mouse is peeled off and the patch is attached to the epidermis side from which the fat has been removed. Next, this was set in a Franz-type permeation test cell filled with a flow-through type receptor solution (PBS) so that the dermal side was in contact with the receptor solution, and the receptor solution was sent at a flow rate of about 4 mL / hr for 2 hours. Receptor solution is collected every 24 hours. The concentration of rivastigmin and / or a salt thereof (free form equivalent) in the collected receptor solution was measured by high performance liquid chromatography, and for each sample, rivastigmin and / or 24 hours from the start of application per unit area of the pressure-sensitive adhesive layer. The skin permeation amount (free form equivalent) of the pharmaceutically acceptable salt can be calculated, and the average value thereof can be taken as the average cumulative skin permeation amount [μg / cm ^2/24 hr].

Such a patch of the present invention is not particularly limited and can be produced by a conventionally known method. For example, first, a pressure-sensitive adhesive containing rivastigmine and / or a pharmaceutically acceptable salt thereof, the acrylic polymer (A), the acrylic polymer (B), and if necessary, a solvent and the other components. A layer composition is prepared, applied onto one surface of the support layer to a desired thickness, and then the solvent is removed as necessary to remove the solvent on one surface of the support layer. It can be produced by forming a drug reservoir. When the patch of the present invention further comprises the release liner, the pressure-sensitive adhesive layer composition is first applied on one surface of the release liner to form the pressure-sensitive adhesive layer. , The support layer may be laminated on the surface opposite to the release liner.

The solvent is not particularly limited and may be appropriately selected depending on the drug to be used and the type of each base. For example, lower alcohols such as methanol, ethanol and isopropanol, toluene, xylene, pentane and n-. Examples thereof include hexane, cyclohexane, heptane, octane, methyl acetate, ethyl acetate, propyl acetate, methyl butyrate, ethyl butyrate and propyl butyrate.

Hereinafter, the present invention will be described in more detail based on Examples and Comparative Examples, but the present invention is not limited to the following Examples. In each Example and Comparative Example, the skin irritation evaluation test, the drug transfer amount measurement, the hairless mouse skin permeation test, and the human skin permeation test were carried out by the methods shown below.
<Skin irritation evaluation test>
The skin irritation evaluation test was carried out by the following two methods modified from the Buehler method.

(Skin irritation evaluation test 1)
First, the back shoulder blade of the guinea pig is cut and shaved to a size of 4 cm x 6 cm, and the cut and shaved part is divided into sections A, B, and C (2 cm x 4 cm each), and the four corners of them are physiological. A W / O type emulsion having a volume ratio of 1: 1 between the saline solution and FCA (Freund's Complete Adjuvant) was intradermally administered in 0.1 mL increments. Next, as a sensitization treatment, a patch that was cut to a size of 1.5 cm x 1.5 cm and the release liner was removed was applied to each section, and 24-hour occlusion application was repeated 3 times (once / week). rice field. Next, as an inducing measure, a patch that was cut into a size of 1.5 cm × 1.5 cm and the release liner was removed was applied to the section B or the section C, and after applying the closure for 24 hours, the patch was applied. It peeled off. Draize evaluation criteria for skin reaction 24 hours and 48 hours after exfoliation:
[Erythema and crust formation score]
0: No erythema 1: Minor erythema (slightly recognizable)
2: Obvious erythema (pale red)
3: Moderate to severe erythema (clear red)
4: Severe erythema (burning or deep red) with deep reaction and slight crusting
[Edema formation score]
0: No edema 1: Minor edema (slightly recognizable)
2: Mild edema (skin bumps are apparent at the edge of the target area)
3: Moderate edema (the target area is clear and a ridge of about 1 mm is seen)
4: Severe edema (ridge of 1 mm or more, ridge that exceeds the administration range)
The total score of the erythema and crust formation score and the edema formation score was calculated and used as the evaluation value. The test was conducted on 6 guinea pigs, and the average evaluation value was used as the average skin irritation score.

(Skin irritation evaluation test 2)
First, the back shoulder blade of the hairless rat was cut and shaved to a size of 4 cm x 6 cm, and the cut and shaved part was cut to a size of 1.0 cm x 1.0 cm and the release liner was removed. The agent was applied, closed for 24 hours, and then the agent was peeled off. The skin reaction 0.5 hours after exfoliation was evaluated according to the above-mentioned Draize evaluation criteria, and the total score of the erythema and crust formation score and the edema formation score was calculated and used as an evaluation value. This evaluation was repeated 4 times (once / day) in succession at the same site, and each evaluation value was calculated. In addition, the test was performed on 6 hairless rats, and the average evaluation value was used as the average skin irritation score at each time.

<Measurement of drug transfer amount>
The patch used for the skin irritation evaluation test 1 after 24 hours was placed in a glass centrifuge tube, 10 mL of tetrahydrofuran was added and shaken to dissolve the pressure-sensitive adhesive layer, and then 0.2%. 40 mL of a phosphoric acid aqueous solution / methanol mixed solution (50/50) was added and further shaken to obtain a drug extract. Regarding the obtained extract, a high performance liquid chromatography device (manufactured by Shimadzu Corporation, column: ODS column, solvent: 0.2% phosphoric acid aqueous solution containing 7 mM SDS / methanol mixed solution (40/60), detection wavelength: UV215 nm). ) Was used to measure the amount of rivastigmin and / or its salt remaining in the pressure-sensitive adhesive layer, and the mass of rivastigmin added during the manufacture of the patch and the mass of rivastigmin and / or its salt after 24 hours of application (free). The difference from the body conversion) was calculated. The test was performed on 6 guinea pigs, and the average of the calculated values (differences) obtained was taken as the average drug transfer amount [mg / cm ² ].

<Hairless mouse skin penetration test>
First, the skin of the body of the hairless mouse was peeled off to remove fat, and a patch was applied to the epidermis side by cutting into a size of 3 cm ² and removing the release liner. This was set in a flow-through type Franz type permeation test cell so that the dermis side was in contact with the receptor solution, and the cell was filled with the receptor solution (PBS). Next, the receptor solution was sent at a flow rate of about 4 mL / hr while circulating warm circulating water around the outer periphery so that the receptor solution was kept at 32 ° C., and the receptor solution was collected every 2 hours for up to 24 hours. did. The concentration of rivastigmine and / or its salt in the collected receptor solution (free form equivalent) was measured by high performance liquid chromatography, and rivastigmine and / or its pharmaceuticals per unit area of the pressure-sensitive adhesive layer 24 hours after the start of application. The cumulative amount of salt permeated into the skin (free form equivalent, unit: μg / cm ^2/24 hr) was calculated. The test was performed on 3 or more samples, and the average of the obtained cumulative skin permeation amount was taken as the average cumulative skin permeation amount [μg / cm ^2/24 hr].

<Human skin penetration test>
First, a frozen human skin section was thawed at room temperature to remove subcutaneous fat, and treated with a dermatome to a thickness of about 500 μm. Next, a patch that was cut to a size of 3 cm ² and removed from the release liner was attached to the keratin side of the skin section, and this was applied to a flow-through type Franz type permeation test cell so that the dermis side was in contact with the receptor solution. The cell was set and the cell was filled with a receptor solution (PBS). Next, the receptor solution was sent at a flow rate of about 4 mL / hr while circulating warm circulating water around the outer periphery so that the receptor solution was kept at 32 ° C., and the receptor solution was collected every 2 hours for up to 24 hours. did. The concentration of rivastigmin and / or a salt thereof (free form equivalent) in the collected receptor solution was measured by high performance liquid chromatography, and rivastigmine and / or its pharmaceutically acceptable per unit area of the pressure-sensitive adhesive layer was pharmaceutically acceptable per hour. The cumulative skin permeation amount of the salt (free form equivalent, unit: μg / cm ² ) was calculated. The test was performed on 4 or more samples, and the average of the obtained cumulative skin permeation amount was taken as the average cumulative skin permeation amount [μg / cm ² ].

(Skin irritation score-mean cumulative skin permeation conversion test)
(Comparative Example 1, Examples 1 to 3)
First, an ethyl acetate solution of an acrylic polymer having a carboxy group (acrylic polymer (A), acid value: 51 mgKOH / g, Duro-Tak (registered trademark) 87-2194 (manufactured by Henkel), acrylic polymer). : 37 parts by mass), and ethyl acetate solution of acrylic polymer with substantially no functional group (acrylic polymer (B), acid value: 0 mgKOH / g, MAS811 (manufactured by Cosmedy), acrylic 25 parts by mass of ribastigmine and 1 part by mass of other components (antioxidant) were added to (polymer: 37 parts by mass) to obtain a pressure-sensitive adhesive layer composition.

Next, the obtained pressure-sensitive adhesive layer composition was applied onto one surface of a polyethylene terephthalate film (release liner) that had been subjected to a mold release treatment, and then ethyl acetate was dried and removed to remove a pressure-sensitive adhesive layer having a thickness of 50 μm. Got Next, the obtained pressure-sensitive adhesive layer and a polyethylene terephthalate film (support layer) that has not been subjected to mold release treatment are bonded together, and the support layer / pressure-sensitive adhesive layer / mold-release liner are laminated in this order in the pressure-sensitive adhesive layer. A patch (test patch 1 (Comparative Example 1)) having a rivastigmine content of 1.25 mg / cm ² per unit area was obtained.

The same applies except that the content of rivastigmine was changed and the decrease in the content of rivastigmine was supplemented by the acrylic polymer (A) and the acrylic polymer (B) so that the mass ratio of these was 1: 1. Test patch 2 (Example 1) (rivastigmine content: 0.90 mg / cm ² ), test patch 3 (Example 2) (rivastigmine content: 0.60 mg / cm). ² ), the test patch 4 (Example 3) (rivastigmine content: 0.45 mg / cm ² ). The obtained test patches 1 to 4 were subjected to skin irritation evaluation tests 1 and 2, drug transfer amount measurement, and hairless mouse skin permeation test, respectively. The results obtained are shown in Table 1.

As is clear from the results shown in Table 1, in the test patches 1 to 4, when the rivastigmine content per unit area of the pressure-sensitive adhesive layer is 0.45 to 0.90 mg / cm ² , the average drug transfer amount is It was confirmed that the range was 0.2 to 0.39 mg / cm ² , and when the average drug transfer amount was within the range, the skin irritation given to the application site of the patch could be significantly attenuated. Here, since the average drug transfer amount and the average cumulative skin permeation amount are in a corresponding relationship, if the average cumulative skin permeation amount (when in contact with the skin of a hairless mouse for 24 hours) is within the range of 200 to 560 μg / cm ² . It can be said that the skin irritation given to the application site can be significantly attenuated.

(Example 4)
First, an ethyl acetate solution of an acrylic polymer having a carboxy group (acrylic polymer (A), acid value: 51 mgKOH / g, Duro-Tak (registered trademark) 87-2194 (manufactured by Henkel), acrylic polymer). : 26.1 parts by mass), and ethyl acetate solution of acrylic polymer having hydroxy group (acrylic polymer (B), acid value: 0 mgKOH / g, Duro-Tak (registered trademark) 87-4287 (Henkel) , Acrylic polymer: 60.9 parts by mass), 12 parts by mass of ribastigmine and 1 part by mass of other components (antioxidant) were added to obtain a pressure-sensitive adhesive layer composition.

Next, the obtained pressure-sensitive adhesive layer composition was applied onto one surface of a polyethylene terephthalate film (release liner) subjected to a mold release treatment, and then ethyl acetate was dried and removed to a thickness of 50 g / m ² (release liner). A pressure-sensitive adhesive layer having a rivastigmine content of 0.6 mg / cm ² ) was obtained. Next, the obtained pressure-sensitive adhesive layer and a polyethylene terephthalate film (support layer) that has not been subjected to mold release treatment are bonded together to obtain a patch laminated in the order of support layer / pressure-sensitive adhesive layer / mold release liner. rice field. The obtained patch was cut so that the area of the pressure-sensitive adhesive layer was 3 cm ² , and the patch had a rivastigmine content of 1.8 mg in the entire pressure-sensitive adhesive layer. Composition of the pressure-sensitive adhesive layer (composition, pressure-sensitive adhesive layer area, content of rivastigmine per unit area and in the entire pressure-sensitive adhesive layer, and mass ratio of acrylic polymer (A) to acrylic polymer (B) (A). : B)) is shown in Table 2.

(Examples 5 to 7, Comparative Examples 2 to 3)
Each patch was obtained in the same manner as in Example 4 except that the structure of the pressure-sensitive adhesive layer was set to the structure shown in Table 2. In Table 2, "Duro-Tak 87-2054" is an ethyl acetate solution of an acrylic polymer having a carboxy group (acrylic polymer (A), acid value: 49 mgKOH / g, manufactured by Henkel). , "Duro-Tak 87-2516" is an ethyl acetate solution of an acrylic polymer having a hydroxy group (acrylic polymer (B), acid value: 0 mgKOH / g, manufactured by Henkel), and has a mass in the composition. Each part indicates the mass part of each acrylic polymer.

(Comparative Example 4)
First, 12 parts by mass of ribastigmin and 88 parts by mass of a rubber-based pressure-sensitive adhesive base composition were added to an appropriate amount of a solvent (absolute ethanol and toluene) and mixed to obtain a pressure-sensitive adhesive layer composition. As the rubber-based pressure-sensitive base composition, a mixture of 20 parts by mass of a styrene-isoprene-styrene block copolymer, 5 parts by mass of polyisobutylene, 15 parts by mass of a tackifier, and 48 parts by mass of a softener was used. Then, a patch was obtained in the same manner as in Example 4 except that this pressure-sensitive adhesive layer composition was used.

(Examples 8 to 9)
The structure of the pressure-sensitive adhesive layer is the same as that of Example 4, except that the structure of the pressure-sensitive adhesive layer is set to the structure shown in Table 2 and the content of rivastigmine in the entire pressure-sensitive adhesive layer is 2.7 mg or 1.35 mg. Each patch was obtained individually.

The results of the hairless mouse skin permeation test for each of the patches obtained in Examples 4 to 9 and Comparative Examples 2 to 4 are shown in Table 2 together with the composition of each pressure-sensitive adhesive layer. Further, the average cumulative skin permeation amount in each of the patches obtained in Examples 4 to 7 and Comparative Examples 2 to 3 was y, and the acrylic polymer (A) having a carboxy group in the total acrylic polymer (A + B). FIG. 1 shows an approximate straight line obtained with x in the content [mass%] of. In FIG. 1, the obtained approximate straight line is expressed by the following equation: y = −5.229x + 584.06 ( ^R2 = 0.9447).

(Example 10)
First, an ethyl acetate solution of an acrylic polymer having a carboxy group (acrylic polymer (A), acid value: 51 mgKOH / g, Duro-Tak (registered trademark) 87-2194 (manufactured by Henkel), acrylic polymer). : 34.8 parts by mass), and an ethyl acetate solution of an acrylic polymer having a hydroxy group (acrylic polymer (B), acid value: 0 mgKOH / g, Duro-Tak (registered trademark) 87-4287 (Henkel). , Acrylic polymer: 52.2 parts by mass), 12 parts by mass of ribastigmine and 1 part by mass of other components (antioxidant) were added to obtain a pressure-sensitive adhesive layer composition. Then, a patch was obtained in the same manner as in Example 4 except that this pressure-sensitive adhesive layer composition was used (rivastigmine content: 0.6 mg / cm ² ). The results of a human skin permeation test on the patch obtained in Example 10 are shown in FIG.

From the results shown in Table 2 and FIG. 1, the rivastigmine content per unit area of the pressure-sensitive adhesive layer is 0.45 to 0.90 mg / cm ² , and the carboxy group in the total acrylic polymer (A + B) is used. The content of the acrylic polymer (A) is 73 to 5% by mass, that is, the acrylic polymer having a carboxy group (acrylic polymer (A)) and the acrylic polymer having a hydroxy group (acrylic high molecular weight). When the mass ratio (A: b1) to the molecule (b1)) is 73:27 to 5:95, the average cumulative skin permeation amount (when in contact with the skin of a hairless mouse for 24 hours) is 200 to 560 μg / cm ² described above. It was confirmed that it was within the range of. Therefore, in the patch of the present invention, it can be said that the skin irritation given to the application site is sufficiently small.

(Examples 11 to 15, Comparative Example 5)
Each patch was obtained in the same manner as in Example 4 except that the structure of the pressure-sensitive adhesive layer was set to the structure shown in Table 3. In Table 3, "Duro-Tak 87-2051" is an ethyl acetate solution of an acrylic polymer having a carboxy group (acrylic polymer (A), acid value: 44 mgKOH / g, manufactured by Henkel). , "MAS 811" is an ethyl acetate solution of an acrylic polymer having substantially no functional group (acrylic polymer (B), acid value: 0 mgKOH / g, manufactured by Cosmed), and is in the composition. The mass part of each indicates the mass part of each acrylic polymer.

The results of the hairless mouse skin permeation test for each of the patches obtained in Examples 11 to 15 and Comparative Example 5 are shown in Table 3 together with the composition of each pressure-sensitive adhesive layer. Table 3 also shows the results of a hairless mouse skin permeation test for each of the patches obtained in Comparative Examples 2 and 4, and the composition of the pressure-sensitive adhesive layer. Further, the average cumulative skin permeation amount in each of the patches obtained in Examples 11 to 15 and Comparative Examples 2 and 5 was y, and the acrylic polymer (A) having a carboxy group in the total acrylic polymer (A + B). FIG. 3 shows an approximate straight line obtained with the content [mass%] of the above as x. In FIG. 3, the obtained approximate straight line is expressed by the following equation: y = −5.0923x + 616.35 (R ² = 0.9636). Further, FIG. 4 shows the results of a human skin permeation test on the patch obtained in Example 12.

From the results shown in Table 3 and FIG. 3, the ribastigmine content per unit area of the pressure-sensitive adhesive layer is 0.45 to 0.90 mg / cm ² , and the carboxy group in the total acrylic polymer (A + B) is used. The content of the acrylic polymer (A) is 81 to 10% by mass, that is, the acrylic polymer having a carboxy group (acrylic polymer (A)) and the acrylic polymer having substantially no functional group are high. When the mass ratio (A: b2) with the molecule (acrylic polymer (b2)) is 81: 19 to 10:90, the average cumulative skin permeation amount (when in contact with the hairless mouse skin for 24 hours) is 200 as described above. It was confirmed that the content was within the range of ~ 560 μg / cm ² . Therefore, in the patch of the present invention, it can be said that the skin irritation given to the application site is sufficiently small.

As described above, according to the present invention, it is possible to provide a patch having sufficiently small skin irritation to the application site.

Claims (4)

A patch having a support layer and an adhesive layer.
The pressure-sensitive adhesive layer
At least one drug selected from the group consisting of rivastigmine and its pharmaceutically acceptable salts, and
At least one acrylic polymer (A) made of an acrylic polymer having a carboxy group, and
At least one acrylic polymer (B) made of an acrylic polymer (b2) having substantially no functional group, and
Contains
The content of rivastigmine and / or its pharmaceutically acceptable salt with respect to the total mass of the pressure-sensitive adhesive layer is 6 to 18% by mass in terms of free form.
The content of rivastigmine and / or its pharmaceutically acceptable salt per unit area of the pressure-sensitive adhesive layer is 0.45 to 0.90 mg / cm ² in terms of free form, and
The mass ratio (A: b2) of the acrylic polymer (A) and the acrylic polymer (b2) having substantially no functional group in the pressure-sensitive adhesive layer is 81: 19 to 10:90. be,
A patch characterized by that. The patch according to claim 1, wherein the acrylic polymer having a carboxy group has an acid value of 15 to 55 mgKOH / g. Claims characterized in that the average cumulative skin permeation of rivastigmine and / or its pharmaceutically acceptable salt upon contact with the skin of a hairless mouse for 24 hours is 200-560 μg / cm ² in terms of free form. Item 2. The patch according to Item 1 or 2. The patch according to any one of claims 1 to 3, wherein the pressure-sensitive adhesive layer has an area of 5 to 40 cm ² .

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