JPS63135333A - Plaster containing prostaglandins - Google Patents

Abstract

PURPOSE:To obtain a plaster having improved stability, by applying a specific acrylic base layer containing prostaglandins as a drug active component on a substrate. CONSTITUTION:The objective prostaglandin-containing plaster can be produced by applying an acrylic base layer [selected from alkyl (meth)acrylate homopolymer, copolymer of alkyl (meth)acrylate and a monomer having cationic electrolyzable group and/or a nonionic monomer, or their mixture] containing a prostaglandin [e.g. the compound of formula I (A is group of formula II or formula III; X is -CH2CH2-, cis-CH=CH-, etc.; Y is -CH2CH2- or trans-CH= CH-; R1 is H or 1-4C alkyl; R2 is single bond or 1-4C alkylene; R3 is 1-8C alkyl, 4-7C cycloalkyl, phenyl or phenoxy), etc.] as a drug active component to a surface of a substrate (e.g. polyvinyl chloride).

Description

DETAILED DESCRIPTION OF THE INVENTION (a) Industrial Application Field The present invention relates to a prostaglandin-containing patch containing prostaglandins as a medicinal ingredient. Specifically, it is a prostaglandin-containing patch that improves the stability of prostaglandins by incorporating prostaglandins, which are extremely unstable against heat, into a specific acrylic base layer. Regarding.

(b) Prior art Prostaglandins (hereinafter abbreviated as PGs) are derivatives of brostanic acid represented by the following formula, and various types of P (it) are known. It depends on the structure and substituents of the five-shelled ring of brostanoic acid, which is the basic skeleton. For example, PGA, PGE, and PGF have the following five-shelled ring structure.

OH0H (PGA) (PGE) (PGF)
In addition, PGs are classified into 11 according to the position of the double bond in the side chain bonded to the 8th and 12th positions of the 5-shell ring.
Type 1 has a trans-double bond between C1 and C, and type PC-2 has a cis-double bond between Cs and Cs and a trans-double bond between C13C14. For example, PGE, PGF2α, and PGF2α are each represented by the following structural formulas.

0xIOI-1 OH By the way, the above PGMs generally have effects such as stimulating smooth muscle contraction, lowering blood pressure, diuresis, bronchodilation, inhibiting lipolysis, inhibiting platelet aggregation, inhibiting gastric acid secretion, and antitumor activity. Because it has pharmacological effects, hypertension,
It is effective in treating thrombosis, peripheral circulation disorder, asthma and gastrointestinal ulcers, inducing labor and abortion in pregnant mammals, preventing arteriosclerosis, and acting as a diuretic and anti-ulcer agent.

As PG is a very useful medicinal ingredient, it has been administered in a variety of ways, including orally, intravenously, and intravaginally. Transdermal preparations have been proposed with the aim of prolonging the pharmacological action and reducing side effects (Japanese Patent Application Laid-open Nos. 55-36494 and 1982-128327).

In the above proposal, it was confirmed that the hypotensive effect is sustained by local application of PGs, and that local vasodilatory effects can be obtained without I:11 action ('!'). The possibility of formulation has been suggested.

(e) Problems to be solved by the invention However, although PGs have excellent pharmacological effects as described above, they contain double bonds and hydroxyl groups in their structure, so
It is a very unstable substance compared to general medicines. For example, P (P) is extremely unstable to heat, so if it is stored in poor conditions it will immediately decompose.
It is known that about 85 to 90% of E and PGE2 are lost when stored at a temperature of 37° C. for 30 days (Japanese Patent Publication No. Sho Go-54933).

Among PGMs, I'OEM is particularly unstable.
The hydroxyl group present at the 11th position of the 5-shell ring undergoes an elimination reaction under the influence of the carbonyl group at the 9th position, forming a double bond and easily converting into PGAs.

Therefore, various proposals have been made to stabilize PGjlt. For example, a method of including PGM with cyclodextrin (Japanese Patent Publication No. 50-3362, Japanese Patent Publication No. 52-3)
No. 1404), a method for making freeze-dried weeds into an injection by adding citric acid or vitamin C to an aqueous solution of cyclodextrin clathrate compounds of PGs (Japanese Patent Publication No. 54-425
70), a method of dissolving PGEs in vegetable oil (JP-A-50-105815), a method of dissolving PGs in glyceryl acetate to form oral capsules (JP-A-51-112,508) ), aerosols consisting of PGEs and alkali metal sulfates or sulfides (U.S. Pat. No. 5,385,1052), PG
A method of adding citric acid aqueous solution and sugar to cyclodextrin clathrate compounds and freeze-drying them (Japanese Unexamined Patent Publication No. 54-10
No. 3844) and the like have been proposed, and have achieved a corresponding stabilizing effect.

By the way, among transdermal preparations, skin-patch preparations, ie, patches, are being injected from the viewpoint of prolonging pharmacological action, reducing side effects, and ease of use.

Since such patches have the advantage of being easy to use by patients themselves, it is particularly important to store the medicinal ingredients stably at room temperature for long periods of time without leaving complicated storage management to the patients.

Under such request, Japanese Patent Application Laid-Open No. 55-36494 and V
f PG disclosed in Publication No. Sho 59-128327
In order to stabilize PGs in the JIIL for transdermal administration of plastics, adding antioxidants and preservatives to the PGM-containing base material, or including PCI in cyclodextrin are being considered. However, in patches containing PGM, these methods are insufficient to suppress the decomposition of highly unstable PGs; The reality is that no sufficient effects have been obtained because no proposals have been made regarding base materials that positively promote this, and no sufficient studies have been conducted.

(d) Means for solving the problem between m and After many years of intensive study on the relationship between PGXI and the base material that contains and holds PGXI,
It is clear from f1 that in the base layer containing and retaining G, the base containing free carboxylic acid makes PGJ unstable, and the type of base layer has a large effect on the thermal stability of PG. did.

In other words, it was discovered that in a patch containing r(J in an acrylic base made of a specific acrylic polymer, the stability of PGM at room temperature is significantly improved, and it can be put to practical use. , which led to the completion of the present invention.

That is, the first invention of the present application is a patch comprising an acrylic base layer containing prostaglandins as a medicinal ingredient on a support, the acrylic base layer containing (meth) Acrylic acid alkyl ester homopolymer, (meth)
It is formed of one selected from the group consisting of a copolymer of an acrylic acid alkyl ester and a monomer having a cationic electrolytic group and/or a nonionic monomer, or a mixture of these polymers. It is characterized by:

In addition, the invention m2 of the present application is a patch comprising an acrylic base layer containing prostaglandins as a medicinal ingredient on a support, the acrylic base layer comprising (meth)acrylic From the group consisting of acid alkyl ester homopolymers, copolymers of (meth)acrylic acid furkyl esters and monomers having a cationic electrolytic group and/or nonionic monomers, or mixtures of these polymers. It is formed by laminating an acrylic adhesive JC on the exposed part of an acrylic base containing prostaglandin.

Hereinafter, first, the invention @1 of the present application will be explained in detail.

The prostaglandins and compounds used as medicinal ingredients in the present invention include, as mentioned above, (including PGA, PGD, PGE, PGF, PGI or derivatives thereof, each of which has a basic skeleton of brostanic acid, and are preferably The compound represented by the following general formula is used.

11L L, A = CC = 0 or 1. t;C-N-
-011-X = C112CI+2-, cisC
II= ell -matahaY= C112CII2 1
c) 7nX Cll=Cll-91'? ,=II
Also, J, tC, -C, straight m Mata 1.1-branched Er (furkyl group, R2 = single bond or C, -C, straight chain or branched alkylene group, R3 = (i) C + ~ a straight-chain or branched alkyl group at c8, (ii) a cycloalkyl group at 04=C7 which is rIl-substituted or unsubstituted with a straight-chain or branched alkyl group at C,=C1, or (iii) ) represents a phenyl group or a 7eth/oxy group substituted or unsubstituted with a halogen atom, a trifluoromethyl group, or a C1-C1 linear or branched alkyl group.

Further, in the present invention, useful pharmacologically acceptable metal cations, ammonium ions, amine cations, or salts of quaternary ammonium cations of the PGMs are preferably used.

In the present invention, preferred embodiments include:
PGlf[ is included by cyclodextrin 1,
Compounds in which PGjJ[ is thereby stabilized are also useful as medicinal ingredients. As this cyclodextrin,
Examples include α-cycystextrin (phosphorus), β-cyscystextrin, γ-cyscystextrin, a-methylated cyclodextrin, β-methylated cyclodextrin, and the like.

In the present invention, the acrylic base layer containing PGs is one that can stably hold the PGs contained therein over a negative period without decomposing them, that is, one that does not have free carboxylic acid in the base. Yes, specifically, ■ (meth)acrylic acid alkyl ester homopolymer, ■ (meth)acrylic acid alkyl ester and a copolymer with a monomer having a cationic electrolytic group, ■ (meth)acrylic acid alkyl ester Copolymer of ester and nonionic monomer, ■ Copolymer of (meth)acrylic acid alkyl ester, monomer having a cationic electrolytic group, and nonionic monomer, ■ Above ■ to ■
A mixture of two or more types of polymers may be mentioned.

In each of the above copolymers (■ to ■), the blending ratio of the components (monomers) constituting the copolymer is determined in relation to the skin adhesive strength of the patch, but the stability of the PGs Therefore, this blending ratio can be determined at any desired ratio.

Furthermore, in the mixture of polymers in item (1) above, the blending ratio of the components (polymers) constituting the mixture can be determined at any desired ratio as described above.

Examples of monomers for forming the (meth)acrylic acid alkyl ester homopolymer include methyl, ethyl, propyl, butyl, pentyl, (meth)acrylic acid,
Examples include alkyl esters having 1 to 12 carbon atoms such as hexyl, heptyl, octyl, nonyl, decyl, and dodecyl, and these furkyl groups can be used in either a linear or branched form.

The monomer having a cationic electrolytic group to be copolymerized with the above (meth)acrylic acid furkyl ester is not particularly limited as long as it is a polymerizable compound containing a nitrogen atom in the molecule. , for example (meth)acrylamide, trimethyl(meth)acrylamide, N-butyl(meth)acrylamide, tetranotylbutyl(meth)
Amide group-containing acrylic monomers such as acrylic 7mide, N-methylol (meth)acrylamide, aminoalkyl group-containing acrylic monomers such as (meth)acrylic acid amide/ethyl ester, (meth)acrylic acid dimethylamino Ethyl ester, (meth)acrylic acid diethyl 7-minoethyl ester, (meth)acrylic fiLerL-butylamino/ethyl ester, a fulkyl 7-minoalkyl group-containing acrylic monomer, and a nitrogen-containing heterocycle such as vinylpyrrolidone, vinylpyrinone, vinylpiperidone. Examples include monomers having the following.

In addition, specific examples of the nonionic monomer include hydroxyl group-containing monomers such as (meth)acrylic acid hydroxyethyl ester, (meth)acrylic acid hydroxypropyl ester, and methoxy (meth)acrylic acid. Ethyl ester, (meth)acrylic acid ethoxyethyl ester, (meth)acrylic acid butoxyethyl ester, (
meth)acrylic acid tetrahydrofurfuryl ester, (
Alkoxy groups (or (tl
Examples include monomers containing (ether bond to LIT), vinyl ester monomers such as vinyl acetate and vinyl propionate.

In the present invention, the (meth)acrylic acid alkyl ester monomer, the monomer having a cationic electrolytic group, and the nonionic monomer each contain 2 f! from each monomer group. If
A combination of the above can also be used.

The above-mentioned acrylic base is one whose polymer composition is adjusted so that it is sticky at room temperature, and when applied to the skin, an auxiliary means for fixing it to the skin surface, such as surgical tape, is used. This is preferable because it can be easily attached and fixed to the skin surface.

Supports used in the present invention include polyvinyl chloride,
Polyethylene, polypropylene, polyethylene terephthalate, ethylene-vinyl acetate copolymer, polyethylene-polyvinyl acetate laminate, polyethylene (ethylene-
Vinyl acetate copolymer) laminate, polyethylene terephthalate-(ethylene-vinyl acetate copolymer) laminate, polyethylene terephthalate-(ethylene-vinyl acetate copolymer) laminate, polycarbonate, polyacetate, polyacrylic acid ester, polysulfone, cellulose ester formed film Alternatively, examples include sheets, films and sheets obtained by vapor-depositing or laminating aluminum thereon, cloth, nonwoven fabric, paper, and the like.

Then, an acrylic base layer containing the above-mentioned PGM is provided on this support, but the content of this PG is 0.
．． 1 to 400 μg/am2, preferably 0.5 to 100
μg/c spear 2, more preferably 5 to 80 μg/e1m2
It is desirable to do so.

The brostaglancon combination patch of the invention of tjSl of the present application is manufactured by a known method, but in this case, an acrylic base solution containing prostaglandins is coated on the above-mentioned support. The subsequent drying process, or the drying process after coating on the release liner (in this case, after this drying, it is transferred onto the support), the drying time at high temperature, that is, prostagland. It is necessary to avoid drying conditions that would cause decomposition of the gins.

Next, the second invention of the present application will be explained in detail.

The twelfth invention of the present application is an improvement of the first invention.

That is, it is a adhesive tape in which a support is provided with an acrylic base layer containing prostaglandins as a medicinal ingredient, and the acrylic base layer is composed of a (meth)acrylic acid alkyl ester monomer. A type selected from the group consisting of a copolymer of a (meth)acrylic acid alkyl ester and a monomer having a cationic electrolytic group and/or a nonionic monomer, or a mixture of these polymers. The adhesive layer is formed by laminating an acrylic adhesive layer on the exposed surface of the prostaglanson-containing acrylic base layer.

In the first invention, the present invention provides an acrylic adhesive layer, particularly an acrylic adhesive layer for controlling the release properties of PGjji, on the exposed surface side of the PG-containing acrylic base.
In other words, it has a sandwich structure in which the PGMG gold-containing acrylic base layer is sandwiched between a support and an acrylic adhesive layer. It is also possible to make it

By configuring in this way, it is possible to control the release of PGM and to configure the PGs to be released more continuously over the growing period.

Therefore, it is particularly preferable to use an acrylic adhesive layer that has a lower PGM distribution than the PGMG-containing acrylic base layer, and that the PGs are transferred to the skin surface through this acrylic adhesive layer. Since the acrylic polymer is released, it is preferable to select and use one having adhesiveness from among the various acrylic polymers mentioned above, or to use it as the main component polymer.

In this way, this acrylic adhesive layer has the purpose of fixing the adhesive patch on the skin surface, and also transfers from the PG gold-containing acrylic base layer by diffusion transfer (I'G) to the skin. This layer is useful for achieving sustained release over a long period of time by controlling the amount and rate of release onto surfaces, so this layer is made by blending a substance with a low distribution coefficient for PGM into the acrylic polymer. It can be formed by

That is, the acrylic adhesive layer in the present invention is not only made of an acrylic polymer, but also an adhesive containing an acrylic polymer as a main component and a substance having a low distribution coefficient for PGs as a subcomponent, such as those listed below. It also includes layers.

Examples of substances with low distribution coefficients for PGs include rubber-based substances such as silicone rubber, polyisoprene rubber, polyisobutylene rubber, polybutadiene, styrene-butadiene (or isoprene)-styrene block copolymer rubber, and natural rubber. It is particularly preferable to use polyisobutylene rubber, but it is preferable to use a mixture of the above-mentioned acrylic polymer and this rubber-based substance, and the mixture exhibits adhesive properties.

It is preferable for the acrylic adhesive layer containing the above-mentioned rubber-based substances to be used as a patch so as not to cause a decrease in adhesion to the skin surface. It is preferable to mix it with the above-mentioned rubber-based substance and adjust it so as to maintain adhesiveness.

The above tackifying ingredients include ronone, modified ronone, and petroleum-based ingredients? Examples include JJ Zai, coumaron indene resin, methyl indene resin, polyterpene tree layer, polystyrene Ulfra, polybutene, liquid polyisobutylene, etc., and the softeners include machine oil, transformer oil, ronone oil, various liquid paraffins, etc. can be mentioned.

In addition, in the present invention, the various polymers mentioned above can be used as the acrylic adhesive layer, but in this case, P
In order to lower the GM distribution rate and slow down the transfer rate of PGs, it is preferable to perform appropriate chemical crosslinking treatment or physical crosslinking treatment to an extent that does not impair skin adhesion.

Such chemical crosslinking treatment includes, for example, novinylbenzene, ethylene glycol no(meth)acrylate,
Trinotyolpropane tri(meth)acrylate, triethylene glycol di(meth)acrylate, polyethylene glycol di(meth)acrylate, polybrobylene glycol di(meth)acrylate, glycitur(
Vinyl group, acryloyl group such as meth)acrylate,
Alternatively, a treatment method of copolymerizing a monomer having two or more reactive groups such as glycityl groups in the molecule, isocyanate peroxides such as benzoyl peroxide, isocyanate-based crosslinking agents, melamine-based crosslinking agents, epoxy Treatment methods include adding an external crosslinking agent such as a system crosslinking agent or a metal compound.

Examples of the above-mentioned physical crosslinking treatment include electron beams, β rays, γ rays,
Methods include irradiation with ionizing radiation such as X-rays and X-rays, and irradiation with ultraviolet rays after adding an ultraviolet absorber.

By the way, the second invention of the present application is an improvement of the first invention of the present application, and therefore, other conditions for the prostaglandins, the acrylic base layer, and the prostaglandin content 1v are as follows: This is similar to the first invention of the present application.

In the prostaglandin-containing patch of the invention of PJJ2 of the present application, for example, on the exposed surface of the prostaglandin M-containing acrylic base layer in the patch obtained by the above method,
By transferring the acrylic adhesive layer obtained by a known method, that is, the prostaglandin-containing acrylic base layer was sandwiched between the above-mentioned special holiday and the acrylic adhesive layer described in 1. This can be obtained by creating a Santoifti structure.

(e) Effect In the present invention, it is not clear why the stability of prostaglandins is greatly improved when prostaglandins are contained in the specific acrylic group 61 layer, but the present inventors' experiments According to the results, it has been found that acrylic base layers containing free carboxylic acids significantly accelerate the hydrolysis of prostaglancins, resulting in extremely poor thermal stability. The base layer does not contain free carboxylic acid,
It is understood that it has the effect of maximally improving the stability of prostagruncates.

In addition, by incorporating prostaglanculins into a specific acrylic base layer and making it into a patch, it is possible to reduce the contact of moisture from the outside world to the prostaglanculins, and prevent pl.
Since it can also prevent positive fluctuations, it can also suppress the hydrolysis reaction of prostaglancins compared to conventional formulations, and has a single-use formulation with excellent stability.

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

In the following, "parts" and "%" are expressed on a weight basis.

Example 1 100 parts of acrylic acid 2-ethylhexyl ester and 0.3 parts of azobisin butyronitrile were charged into a four-loaf flask, and heated to a temperature of 60 to 63°C under an inert gas atmosphere.
125 parts of ethyl acetate was added dropwise to this while controlling the reaction temperature to continue the reaction for 10 hours, and the acrylic copolymer was further aged for 2 hours at a temperature of 75 to 80°C. A polymer solution was obtained.

Brostag 2-None E1 was added and mixed to the obtained acrylic copolymer solution so that the content after drying was 196, and this was placed on a polyester release liner so that the content of prostaglandin E was 40. A prostaglandin E-containing acrylic base layer was formed by coating and drying to give a ratio of 1 g/ctm2.

Next, the acrylic base layer containing Brostaglanson E1 was coated with ethylene-vinyl acetate copolymer (vinyl acetate f
The adhesive patch of the present invention was obtained by transferring the patch to a film (thickness: 70 μm) made of (fi 18%).

Example 2 65 parts of 2-ethylhexyl acrylate, 35 parts of vinyl acetate
1 part and 0.3 parts of azobisisobutyronitrile were reacted in the same manner as in Example 1 to obtain an acrylic copolymer solution.

Prostaglandin E was added and mixed to the obtained acrylic copolymer solution so that the content after drying was 1%, and this was placed on a polyester release liner so that the content of prostaglandin E1 was 1%. It was coated and dried at a concentration of 80 parts g/ell12 to form an acrylic base layer containing prostaglandin E1.

Next, the acrylic base layer containing prostaglandin E was transferred onto a film (thickness: 70μ+6) made of ethylene-vinyl m'-acid copolymer (vinyl acetate content: 18%) to form the adhesive patch of the present invention. Obtained.

Example 3 50 parts of acrylic acid 2-ethylhexyl ester, acrylic acid methoxyethyl ester 2511S, vinyl acetate 2
5 parts 3 and 7 zobisimptilonitrile 0.3 parts,
'A The reaction was carried out in the same manner as in Example 1 to obtain an acrylic copolymer solution.

Prostaglandin E1 was added and mixed to the obtained acrylic copolymer solution so that the content after drying was 1%, and this was placed on a polyester S2 mold release liner with a prostaglandin E1 content of 40 μl T1011+2. The coating was applied and dried to form an acrylic base layer containing prostaglandin E1.

Next, the prostaglanson E and the acrylic base layer containing ethylene-vinyl acetate copolymer (vinyl acetate content: 1
8%) film (thickness: 70 μm) to obtain a patch of the present invention.

Example 4 55 parts of acrylic acid 2-ethylhexyl ester, 15 parts of N-vinylpyrrolidone, 30 g of vinyl acetate and 0.39 g of zobisisobutyronitrile were reacted in the same manner as in Example 1 to prepare an acrylic copolymer solution. I got it.

Prostaglandin E1 was added and mixed to the obtained acrylic copolymer solution so that the content after drying was 196, and this was placed on a polyester release liner so that the content of prostaglandin El was 10. It was coated and dried to give a part g/cI of 112, thereby forming a prostaglandin E1-containing acrylic group;', qWj.

Next, the prostaglanson E and the acrylic base layer containing ethylene-vinyl acetate copolymer (vinyl acetate content: 1
8%) film (thickness: 70.1J+n) to obtain a patch of the present invention.

Example 5 Equal amounts of the acrylic polymer solutions obtained in Example 3 and Example 4 above were mixed, and prostaglandin E1 was added to the resulting acrylic copolymer solution so that the content after drying was 1.
%, and then coated on a polyester release material so that the content of prostaglandin E was 40 μs/c 2. Prostaglandin E was dried. A grill base layer was obtained.

Next, the prostaglandin E1-containing acrylic base layer was coated with an ethylene-vinyl acetate copolymer (vinyl acetate-containing i
The adhesive patch of the present invention was obtained by transferring the adhesive onto a film (thickness: 70 μm wire) made of 18%).

Example 6 17(S)-methyl-ω-homo-trans-Δ2-prostaglandone E, which is a derivative of prostaglandin E, was added to the copolymer solution of Example 3 so that the content after drying was 0.
．． 25%, and then coated on a polyester mold release liner so that the prostaglandin E derivative content was 10 parts g/el11' and dried to form a prostaglandin E derivative. A derivative-containing acrylic base layer was formed.

Next, the acrylic base layer containing a derivative of prostaglandin E was transferred onto the non-vapor-deposited side of a polyethylene film (thickness: 30μIfi) on which aluminum was vapor-deposited, thereby forming the adhesive patch of the present invention. I got it.

Example 7 A patch of the present invention was obtained in the same manner as in Example 3, except that prostaglandin F2 (2) was used instead of prostaglandin E1 as the prostaglandin.

Example 8 Using 17(S)-methyl-ω-homo-trans-Δ2-prostaglandin C+, which is a derivative of prostaglandin E1, as a prostaglandin, and including it with α-cyclodextrin, Example A patch of the present invention was obtained in the same manner as in Example 6, except that the copolymer solution in Example 6 was replaced with the copolymer solution obtained in Example 2.

Example 9 As a prostaglandin, 17(S)-methyl-ω-homo-trans-Δ2-prostaglandin E1, which is a derivative of prostaglandin E1, was clathrated with a-cyclodextrin, and after drying. A patch of the present invention was obtained in the same manner as in Example 6, except that the content (as a derivative of prostaglandin E) was 0.5% and the content was 20 parts g/cra2.

Example 10 The acrylic copolymer solution of Example 3 had a solid content of 10
0 parts to 1 part of benzoyl peroxide (crosslinking agent) was added and mixed, and this was applied onto a polyester release liner and dried to obtain an acrylic pressure-sensitive adhesive layer (thickness: 20 μm).

This acrylic adhesive layer was laminated on the exposed surface of the patch obtained in Example 9 to obtain the patch of the present invention. However, the content rate and content of the clathrated prostaglandin E derivative were 0.25% and 1/'10 μg/cm 2 , respectively.

Example 11 Polyisobutylene rubber (viscosity average molecular weight 1.2 million) 20
Part, polyisobutylene rubber (viscosity average molecular weight 350,000)
30 parts, 20 parts polybutene? ! IS, 30 parts of petroleum resin (Wt cyclic saturated hydrocarbon υf fat) were dissolved and mixed in toluene, and the resulting adhesive solution and the acrylic copolymer obtained in Example 3 were dissolved in toluene. -7 II
n-s entry meeting h'# old 6 end shi
t, Vegetable (3; Kenohe l zuP) Apply the tanned acrylic adhesive solution onto a polyester release liner and dry to form an acrylic adhesive layer (thickness 20 μm).
theory) was obtained.

A patch of the present invention was obtained in the same manner as in Example 10, except that the obtained acrylic adhesive layer was laminated instead of the acrylic adhesive ICJ of Example 10.

Comparative Example 1 50 parts of acrylic acid 2-ethylhexyl ester, 50 parts of acrylic acid, and 0.3 parts of 7zobisin butyronitrile were reacted in the same manner as in Example 1 to obtain an acrylic copolymer solution.

Prostaglandin E1 was added and mixed to the obtained acrylic copolymer solution so that the content after drying was 1%, and this was placed on a polyester mold release liner so that the content of prostaglandin E1 was 40%. A prostaglandin E1-containing acrylic base layer was formed by coating and drying to give a ratio of 1 g/Cm.

Next, the prostaglandin E, f-containing acrylic base layer was coated with an ethylene-vinyl acetate copolymer (vinyl acetate content: 1
8%) g1 film (thickness: 70 μm) was used.

Comparative Example 2 Prostaglandin E140 in 100g of white petrolatum
After adding ++g, the mixture was sufficiently crushed to produce a white petrolatum ointment.

Comparative Example 3 In accordance with a conventional method, a parent tree ointment with the following formulation was prepared, and the ointment 1
After adding 40-g of prostaglandin E to 00 g, the mixture was thoroughly mashed to produce a parent tree ointment preparation.

[Prescription] White petrolatum 25g Ste 7
Lyle alcohol 22 g Propylene glyfur 12 g Sodium lauryl sulfate 1.5 g Ethyl paraoxybenzoate 0
．． 025g paraoxybenzoic acid pill 0.015
Made by g1 39.46 total f
IL 100g Table f51 shows the results of investigating the stability (storability) of prostaglandins using each of the above-mentioned Examples and Comparative Examples.

The numerical values in Table 1 are for each example and each comparative example at a temperature of 4.
The sample was stored in a sealed container at 0°C for 3 months, and the decomposition rate of prostaglandins after storage for 3 months is shown in weight % compared to immediately after production.

In addition, the patches obtained in Examples 6, 9, and 11 were administered to spontaneously hypertensive rats (male, weight 3).
After a certain period of time, rat tail artery pressure was measured using a non-invasive blood pressure measuring device (dose: 200 μg/kg).

The blood pressure lowering values are shown in Table 1.

(The following is a blank space) Table 1 of PtS1 shows that the stability of prostaglandins in Examples is better than that in Comparative Examples.

Also, according to the results of the rat tail artery pressure test, in Example 6 and Example r9a9, after about 2 hours (values in the table), Example 1
In Example 1, the blood pressure lowering value reached its maximum after about 4 hours (the value in the table), and in Example 11, it was observed that the release of prostaglandins was controlled.

Furthermore, a patch with a sandwich structure in which a prostaglandin M-containing acrylic base layer is interposed between a support and an acrylic adhesive layer controls the release of Brostaglandin M2 resins and lasts for a long time. It is recognized that the sustainability of the drug's efficacy is maintained.

In the above example, the case was described in which unstable prostaglandin E and its derivatives and relatively stable prostaglandin F2α were used as prostaglandins, but other prostaglandins may also be used. Similar results were obtained, and it was observed that prostaglandins were stabilized in the specific acrylic base layer used in the present invention.

(g) Effects of the Invention The patch of the present invention contains prostaglandins in a specific acrylic base layer, and the prostaglandins are stabilized in this acrylic base, improving storage stability. This results in the effect of significantly improving the

In particular, the patch of the second invention of the present application, that is, the patch having a sandwich structure in which a prostaglanson-containing acrylic base layer is interposed between a support and an acrylic adhesive layer, is a patch having a sandwich structure in which a prostaglandin-containing acrylic base layer is interposed between a support and an acrylic adhesive layer. The release properties of the drugs are controlled, the persistence of the medicinal effect is maintained over a long period of time, and the drug exhibits excellent pharmacological effects.

Claims (7)

[Claims] (1) A patch comprising an acrylic base layer containing prostaglandins as a medicinal ingredient on a support, wherein the acrylic base layer is a (meth)acrylic acid alkyl ester homopolymer. , a copolymer of (meth)acrylic acid alkyl ester and a monomer having a cationic electrolytic group and/or a nonionic monomer, or a mixture of these polymers. A prostaglandin-containing patch characterized by: (2) The prostaglandin-containing patch according to claim 1, wherein the acrylic base layer is a polymer that is adhesive at room temperature. (3) Prostaglandins have the following general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ However, A=>C=O or >C■OH, X=-CH_2CH_2-, cis-CH=CH- or ▲
There are mathematical formulas, chemical formulas, tables, etc.▼, Y=-CH_2CH_2- or trans-CH=CH-
, R_1=H or a straight chain or branched chain alkyl group of C_1 to C_4, R_2=single bond or a straight chain or branched chain alkylene group of C_1 to C_4, R_3=(i) a straight chain or branched chain of C_1 to C_8 a chain alkyl group, (ii) a C_4 to C_7 cycloalkyl group substituted or unsubstituted with a C_1 to C_4 linear or branched alkyl group, or (iii) a halogen atom, a trifluoromethyl group, or Indicates a phenyl group or phenoxy group substituted with a straight chain or branched chain alkyl group of C_1 to C_4 or unsubstituted. The prostaglandin-containing patch according to claim 1 or 2, which is represented by: (4) The prostaglandin-containing patch according to any one of claims 1 to 3, wherein the prostaglandin is included in cyclodextrin. (5) A patch comprising an acrylic base layer containing prostaglandins as a medicinal ingredient on a support, the acrylic base layer being a (meth)acrylic acid alkyl ester homopolymer. , a copolymer of (meth)acrylic acid alkyl ester and a monomer having a cationic electrolytic group and/or a nonionic monomer, or a mixture of these polymers. A prostaglandin-containing patch comprising: an acrylic adhesive layer laminated on the exposed surface of the prostaglandin-containing acrylic base layer. (6) Prostaglandins have the following general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ However, A=>C=O or >C■OH, X=-CH_2CH_2-, cis-CH=CH- or ▲
There are mathematical formulas, chemical formulas, tables, etc.▼, Y=-CH_2CH_2- or trans-CH=CH-
, R_1=H or a straight chain or branched chain alkyl group of C_1 to C_4, R_2=single bond or a straight chain or branched chain alkylene group of C_1 to C_4, R_3=(i) a straight chain or branched chain of C_1 to C_8 a chain alkyl group, (ii) a C_4 to C_7 cycloalkyl group substituted or unsubstituted with a C_1 to C_4 linear or branched alkyl group, or (iii) a halogen atom, a trifluoromethyl group, or Indicates a phenyl group or phenoxy group substituted with a C_1 to C_4 linear or branched alkyl group or unsubstituted. The prostaglandin-containing patch according to claim 5, which is represented by: (7) The prostaglandin-containing patch according to claim 5 or 6, wherein the prostaglandin is included in cyclodextrin.