JPH05255077A - Anti-inflammatory analgesic plaster - Google Patents

Abstract

PURPOSE:To obtain the subject plaster having low side effect and excellent drug-releasability, durability of drug action and transcutaneous absorbability by including a specific oxyalkylene polymer and a tackifier resin in a tacky adhesive composition containing an anti-inflammatory analgesic agent and laminating the layer. CONSTITUTION:An oxyalkylene polymer containing silicon atom bonded with hydroxyl group or a hydrolyzable group, cross-linkable by forming a siloxane bond and having a silicon-containing group of formula (X is hydroxyl group or hydrolyzable group; R<2> is 1-20C univalent hydrocarbon group, etc.; (a) is 0-3; (b) is 0-2; 1<=a+mb; (m) is 0-19) and a tackifier resin (e.g. rosin-based resin) is added to a tacky adhesive composition layer containing an antiinflammatory analgesic agent such as indomethacin (in an amount of preferably 50-1,500mug/cm<2>) and the layer is laminated to a substrate such as cellulose acetate to obtain the objective plaster. The thickness of the tacky adhesive composition layer is preferably 30-200mum.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an anti-inflammatory analgesic patch which exhibits an anti-inflammatory analgesic effect by percutaneous absorption.

[0002]

[Problems to be Solved by the Related Art] Rheumatoid arthritis, osteoarthritis, degenerative spondylosis, various diseases such as periarthritis of the shoulder and shoulder, and other treatments for inflammation and swelling after surgery or trauma. Although steroidal and non-steroidal anti-inflammatory analgesics have been widely applied, it has become a problem in the pharmaceutical industry that they have some side effects. For example, it is known that non-steroidal anti-inflammatory analgesics show various side effects including gastrointestinal disorders, even though they do not show the serious side effects as seen in steroid anti-inflammatory analgesics. In recent years, various dosage forms for reducing such side effects have been studied under the concept of a drug delivery system.

[0003] In particular, in order to solve the above-mentioned problem of side effects and to maintain the potency of the drug, an administration method in which a medicinal component is transdermally absorbed from the outer skin has attracted attention, and in order to carry out such administration method. Various types of ointments and patches containing medicinal components have been investigated as dosage forms, but no satisfactory ones have been developed yet. For example, in the case of an ointment, the dose of the drug is reduced by being scraped off by clothes after being applied to the body surface, and the defects such as contaminating clothes and the release of the drug in the ointment are insufficient. However, the release rate is not constant, which makes it difficult to accurately control the dose to the body. A patch has been proposed as a solution to the drawbacks of such an ointment, but the fact is that a satisfactory patch has not been obtained in terms of drug release.

In the skin of human body, the stratum corneum is mainly composed of keratin containing a large amount of fat-soluble components such as fat, wax and cholesterol, and this keratin substance has a defense function against the external environment and an in vivo component. Since it has a so-called "barrier function" for controlling the release of the drug, it is difficult to percutaneously absorb the drug. As described above, patches have various factors such as drug release from the preparation, drug distribution to the skin after release, drug percutaneous absorption, and safety of the base to the skin. In order to obtain a satisfactory anti-inflammatory analgesic patch, technical ideas have been tried by those skilled in the art.

As the pressure-sensitive adhesive used in these patches, pressure-sensitive pressure-sensitive adhesive materials made of rubber-based, acrylic-based and silicon-based polymer substances are used, but these are generally soluble in drugs and It is poorly soluble and may interfere with the percutaneous absorption of the drug in the prepared patch, and it also has problems such as skin irritation. Currently, the choice must be made very carefully. Is.

The object of the present invention is to solve the above-mentioned conventional problems, and the object is to improve the release and transdermal absorbability of a drug having an anti-inflammatory and analgesic effect contained in the base of a patch. Another object of the present invention is to provide an anti-inflammatory analgesic patch that is highly safe.

[0007]

Means for Solving the Problems The present inventors have improved the solubility, compatibility, drug transfer to the skin surface (drug release) and transdermal absorbability of anti-inflammatory and analgesic drugs, and We have conducted intensive studies to obtain a patch showing an effective therapeutic effect against the above diseases. As a result, they have found a base that allows an anti-inflammatory analgesic in the base to efficiently penetrate to the stratum corneum, and have completed the present invention. That is, the gist of the present invention is (1) an anti-inflammatory analgesic patch comprising a pressure-sensitive adhesive composition layer containing an anti-inflammatory analgesic laminated on a support, wherein the adhesive composition layer comprises a hydroxyl group or a hydrolyzable group. An anti-inflammatory analgesic patch comprising an oxyalkylene polymer having a silicon-containing group which contains a bonded silicon atom and can be crosslinked by forming a siloxane bond, and a tackifying resin, and (2)
A second pressure-sensitive adhesive composition layer containing or not containing an anti-inflammatory agent on the pressure-sensitive adhesive composition layer according to (1), wherein the layer contains a silicon atom to which a hydroxyl group or a hydrolyzable group is bonded, The present invention relates to an anti-inflammatory and analgesic patch, which is characterized by further laminating a layer containing an oxyalkylene polymer having a silicon-containing group that can be crosslinked by forming a siloxane bond and a tackifying resin.

The oxyalkylene polymer having a silicon-containing group in the molecule, which is used in the pressure-sensitive adhesive composition layer or the second pressure-sensitive adhesive composition layer of the present invention, has been disclosed so far. No. 46-12154, No. 49
-32673, JP-A-50-156599, 51-73561, and
54-6096, 55-82123, 55-123620, 55-
125121, 55-131022, 55-135135, 55-13
Known polymers proposed in Japanese Patent No. 7129 and the like can be used and are not particularly limited.

[0009] molecular chain of the oxyalkylene polymer is essentially the general formula ^{(I) -R 1 -O- (I} ) wherein, R ¹ is a divalent organic group. ] Those having a repeating unit represented by the above formula are preferred, and most preferred are those in which most of R ¹ is a hydrocarbon group having 3 or 4 carbon atoms.
As a specific example of R ¹ ,

[Chemical 3] Etc., but especially

[Chemical 4] Is most preferable in terms of tackiness.

The molecular chain of the oxyalkylene polymer may be composed of only one type of repeating unit or may be composed of two or more types of repeating units. The repeating unit represented by -R ¹ -O- in the general formula (I) is usually used in the polymer.
50% (weight%, the same below) or more, preferably 70% or more,
More preferably, it is contained at 80% or more.

The silicon-containing group referred to in the present invention is a well-known functional group, and a typical example thereof is represented by the general formula (II)

[Chemical 5] [In the formula, X is a hydroxyl group or a hydrolyzable group, and when two or more are present, they may be the same or different. R ² is a monovalent hydrocarbon group having 1 to 20 carbon atoms or (R ′) ₃ SiO— (R ′ is a monovalent hydrocarbon group having 1 to 20 carbon atoms, and three R ′ are the same. May be
Which may be different), and when two or more R ² are present, they may be the same or different. a is 0, 1, 2
Alternatively, 3 and b represent 0, 1 or 2. However, 1 ≦ a +
mb, and m

[Chemical 6] B in need not be the same. m is 0 or 1
Represents an integer of 19. ] The group represented by this is shown.

Of the silicon-containing groups as described above, m is 0.
In the case of the general formula (III)

[Chemical 7] Wherein, R ² are as defined above, n represents represents 1, 2 or 3. The group represented by the following is preferable from the viewpoint of economical efficiency.

Specific examples of the hydrolyzable group in the general formula (II) include, for example, halogen atom, hydrogen atom, alkoxy group, acyloxy group, ketoximate group, amino group, amide group, aminooxy group, mercapto group, alkenyl group. An oxy group etc. are mentioned. Among these, alkoxy groups such as methoxy group and ethoxy group are preferable from the viewpoint of mild hydrolyzability.

Further, the number of carbon atoms in R ² in the general formula (II) is 1
Specific examples of the monovalent hydrocarbon group having 1 to 20 carbon atoms to 20 hydrocarbon group or (R ') ₃ SiO- of R', for example a methyl group, an alkyl group such as ethyl group, cyclohexyl group And cycloalkyl groups, aryl groups such as phenyl groups, and aralkyl groups such as benzyl groups.
Of these, a methyl group is particularly preferable from the viewpoint of reactivity.

The number of silicon-containing groups in the oxyalkylene polymer is usually 1 or more, preferably 1.1 or more, and more preferably on average from the viewpoint of obtaining sufficient curability.
1.5 or more. Further, the silicon-containing group may be present in the side chain of the molecular chain of the oxyalkylene polymer, but it is preferably present at the terminal. The number average molecular weight of the oxyalkylene polymer is usually 500 to 30,000, preferably 30.
It is from 00 to 15000. The oxyalkylene polymer may be used alone or in combination of two or more kinds.

The pressure-sensitive adhesive composition layer in the present invention is a layer in which a pressure-sensitive adhesive composition containing an anti-inflammatory analgesic is laminated on a support, and such a pressure-sensitive adhesive composition includes the above-mentioned oxyalkylene polymer, pressure-sensitive adhesive. It can be prepared by dissolving the imparting resin, the curing catalyst, the antioxidant and other additives in a solvent. The tackifying resin used here is not particularly limited as long as it is compatible with the above-mentioned oxyalkylene polymer, rosin resin (rosin, rosin ester or hydrogenated rosin), phenol resin, terpene phenol. Known resins such as resin, xylene resin, aliphatic petroleum resin, aromatic petroleum resin, terpene resin and coumarone resin can be used, but rosin ester resin and terpene phenol resin are preferable.

As the curing catalyst, known tin-based or aluminum-based catalysts, amines such as dibutylamine-2-ethylhexoate, and other acidic catalysts and basic catalysts can be used. Aluminum-based catalysts such as chelates and aluminum alcoholates are preferred. As the antiaging agent, known ones such as BHT (benzenehydroxytoluene) and vitamin E can be used.

The amount of the tackifying resin compounded is usually 10 to 140 parts by weight with respect to 100 parts by weight of the oxyalkylene polymer, and 1 to 30 parts by weight of the curing catalyst and 0.1. 1 to 10 parts by weight can be blended. If the tackifying resin is less than 10 parts by weight, the tackiness becomes insufficient, and if it exceeds 140 parts by weight, the effect corresponding to the blending amount cannot be obtained, and the adhesive remains on the adherend, which is not preferable. .

In the present invention, as long as the above-mentioned pressure-sensitive adhesive composition is used as a constituent component of the pressure-sensitive adhesive composition layer, the anti-inflammatory analgesic incorporated in the pressure-sensitive adhesive composition has improved solubility and compatibility, Although the drug release property is also good, other additives, auxiliaries and the like can be further mixed with the above-mentioned pressure-sensitive adhesive composition for the purpose of further improving the solubility, compatibility, absorbability and the like. Examples of such additives and auxiliaries include isopropyl palmitate, isopropyl myristate, propylene glycol, mineral oil, dimethylsiloxane, dimethylsulfoxide, dimethylformamide, polyethylene glycol, glycerin and various other surfactants. . These additives and auxiliaries are usually added in an amount of 0.5 to 100 parts by weight of the adhesive composition.
It can be added in a proportion of 20 parts by weight. In addition, when these pressure-sensitive adhesive compositions are laminated on a support and used as a base of a patch, other known bases ordinarily used can be appropriately added.

The solvent is not particularly limited, but the above-mentioned oxyalkylene polymer, tackifying resin,
It is preferable to use one that is capable of dissolving a curing catalyst, an antioxidant, etc., and has low toxicity and low irritation to the skin. Examples of such substances include organic solvents having a relatively low boiling point (100 ° C. or lower) such as ethyl alcohol, isopropyl alcohol, ethyl acetate, acetone, methyl ethyl ketone, n-hexane and n-heptane, but irritation to the skin. Ethyl alcohol, isopropyl alcohol and the like are preferable from the viewpoints of sex and safety. The pressure-sensitive adhesive composition thus obtained has low toxicity and low irritation to the skin, has improved drug solubility and compatibility, and is also excellent in drug release.

As the anti-inflammatory and analgesic agent contained in the pressure-sensitive adhesive composition of the present invention, those exhibiting good solubility in the above-mentioned solvents are preferable from the viewpoint of operability in production. When the solubility of the anti-inflammatory analgesic contained in the solvent is not good, the solubility in the solvent is increased by using an additive together for the purpose of improving the compatibility, and the release property of the drug from the adhesive composition layer is improved. Can be controlled. Alternatively, when the solubility of the anti-inflammatory analgesic in the solvent is not good as described above, the sticking property of the adhesive composition layer to the skin is deteriorated, and therefore, on the adhesive composition layer in which the anti-inflammatory analgesic is dissolved and dispersed. In addition, a layer made of an adhesive composition may be further laminated for the purpose of retaining and improving the adhesiveness to the skin. In the present invention, such a layer is referred to as a second pressure-sensitive adhesive composition layer, and the above-mentioned layer laminated on the support is particularly referred to as a first pressure-sensitive adhesive composition layer in this case.

Here, the composition of the pressure-sensitive adhesive composition constituting the second pressure-sensitive adhesive composition layer is not particularly limited as long as the above-mentioned retention and improvement of the adhesiveness to the skin can be achieved. For example, containing a silicon atom bonded to a hydroxyl group or a hydrolyzable group constituting the adhesive composition layer (first adhesive composition layer) from the viewpoint of less irritation to the skin,
A layer having the same structure as the oxyalkylene polymer having a silicon-containing group that can be crosslinked by forming a siloxane bond and the tackifying resin is preferable. In this case, the layer may contain the same or similar anti-inflammatory analgesic as the drug dissolved and dispersed in the first adhesive composition layer, or may not contain the anti-inflammatory analgesic. When the second adhesive composition layer contains the same or similar anti-inflammatory analgesic as the drug dissolved and dispersed in the first adhesive composition layer, the adhesiveness of the second adhesive composition layer is not impaired. It is necessary that the compounding amount be When the second pressure-sensitive adhesive composition layer is further laminated on the first pressure-sensitive adhesive composition layer as described above, it takes some time for the drug to be released from the first pressure-sensitive adhesive composition layer, but By containing the same or similar anti-inflammatory analgesic in the adhesive composition layer of
Until the release of the drug from the first adhesive composition layer starts, an effective anti-inflammatory and analgesic action can be expected due to the release of the anti-inflammatory and analgesic agent in the second adhesive composition layer.

In the present invention, with such a constitution, it can be applied to various antiphlogistic and analgesic agents without being limited by the solubility of the antiphlogistic and analgesic agent in a solvent. In particular, indomethacin, flufenamic acid, mefenamic acid, tolfenamic acid, ketoprofen, ibuprofen, flurbiprofen, naproxen, sulindac,
Non-steroidal agents such as piroxicam, phenylbutazone, oxyphenbutazone, diclofenac sodium and aspirin, or steroid agents such as hydrocortisone have excellent compatibility with the adhesive composition of the present invention, and are clinically used as anti-inflammatory analgesics. These salts are preferable because they are highly useful, and these salts can also be applied to the anti-inflammatory and analgesic patch of the present invention.

The compounding amount of the anti-inflammatory analgesic in the present invention with respect to the pressure-sensitive adhesive composition layer (or the first pressure-sensitive adhesive composition layer when the second pressure-sensitive adhesive composition layer is further laminated) is such that a pharmacological effect is exerted. There is no particular limitation as long as it is present, but it is generally in the range of 1 to 40% by weight, preferably 5 to 30% by weight, and 20 to 2000 μg per unit area in the adhesive composition.
/ Cm ² , and preferably 50 to 1500 μg / cm ² . If the antiphlogistic analgesic is less than 1% by weight or less than 20 μg / cm ² per unit area, the pharmacological effect is not sufficient, and if it exceeds 40% by weight or more than 2000 μg / cm ² per unit area, the compounding amount is increased. You can't get the right effect. In the present invention, the anti-inflammatory analgesic to be blended may be one kind or a combination of two or more kinds, and is not particularly limited.

The anti-inflammatory analgesic patch of the present invention contains an anti-inflammatory analgesic in the pressure-sensitive adhesive composition layer (or the first pressure-sensitive adhesive composition layer when the second pressure-sensitive adhesive composition layer is further laminated). The dosage form is not particularly limited as long as it is a patch, and the preparation method is also not particularly limited. For example, it contains an anti-inflammatory analgesic prepared by dissolving the above-mentioned oxyalkylene polymer, tackifying resin, anti-inflammatory analgesic, additive for improving transdermal absorbability / solubility, and other auxiliaries in a solvent. The adhesive composition can be prepared as a patch by laminating it on a flexible support. Alternatively, it can be prepared as a patch by further laminating the second pressure-sensitive adhesive composition layer on the first pressure-sensitive adhesive composition layer.

Generally, the physical properties required for an external patch are as follows:
It is required that there is no migration or permeation of the drug to the support, that it has appropriate water vapor permeability and flexibility, that it has hydrophobicity and chemical resistance, that it has stability to heat and light, etc. As the material of the support satisfying these conditions, cellulose acetate, ethyl cellulose, polyethylene terephthalate, plastic polyvinyl chloride, polyurethane, polyethylene, aluminum, plastic films such as polyvinylidene chloride, non-woven fabric,
Examples thereof include woven cloth, paper, metal foil and foamed film, or a combination thereof. The material for the support of the anti-inflammatory analgesic patch of the present invention is not particularly limited, and the supports used for the above-mentioned usual patches are used.

The anti-inflammatory and analgesic patch of the present invention is prepared by laminating an adhesive composition layer containing the anti-inflammatory and analgesic agent on the surface of the above-mentioned support, or by further applying an adhesive layer to the skin thereon. Prepared by laminating a second adhesive composition layer containing the same or similar drug as the lower layer (first adhesive composition layer) or a second adhesive composition layer containing no drug for the purpose of improvement. be able to. In order to laminate the pressure-sensitive adhesive composition layer on the surface of the support, for example, an oxyalkylene polymer, a tackifying resin, a curing catalyst, an antiaging agent and other additives constituting the pressure-sensitive adhesive composition used in the present invention. Is diluted with a suitable solvent, and this is applied to the surface of the support and then dried. At this time, if the above-mentioned drug and other optional additives and auxiliaries are uniformly mixed with the pressure-sensitive adhesive composition, a pressure-sensitive adhesive composition layer containing them can be formed on the surface of the support. . It is also possible to coat the pressure-sensitive adhesive composition diluted with a solvent on a release paper coated with a high-molecular polymer, dry it, and then bring the pressure-sensitive adhesive composition into close contact with the surface of the support. In order to laminate the second pressure-sensitive adhesive composition layer on the first pressure-sensitive adhesive composition layer, the pressure-sensitive adhesive composition for the second pressure-sensitive adhesive composition layer is directly applied onto the first pressure-sensitive adhesive composition layer. A release paper which is dried or coated with a polymer is coated with the second adhesive composition and dried,
It can be formed by pressure bonding with the first pressure-sensitive adhesive composition layer laminated on the surface of the support in advance.

The thickness of the pressure-sensitive adhesive composition layer (or the first pressure-sensitive adhesive composition layer when the second pressure-sensitive adhesive composition layer is further laminated) to be formed on the support is not particularly limited. From the viewpoint of obtaining an appropriate feeling of use, it is usually formed so that the thickness after lamination is 30 to 200 μm. When the second pressure-sensitive adhesive composition layer is further laminated, the total thickness of the second pressure-sensitive adhesive composition layer is appropriately adjusted to the same thickness as described above, but the second pressure-sensitive adhesive composition layer is preferably as thin as possible.

With the anti-inflammatory and analgesic patch of the present invention having the above-mentioned constitution, the contained anti-inflammatory and analgesic agent is easily released and rapidly transdermally absorbed to treat inflammation and analgesic diseases. In addition to being more effective than in the past, there are few side effects and its medicinal effect is sustained. The method of using the anti-inflammatory / analgesic patch of the present invention may vary depending on the drug used, that is, a pharmaceutical compound as an active ingredient, and the type of disease to be applied. It

[0030]

The present invention will be described in more detail with reference to the following examples and test examples, but the present invention is not limited to these examples.

Production Example of Oxyalkylene Polymer The production of an oxyalkylene polymer having a silicon atom containing a silicon atom to which a hydroxyl group or a hydrolyzable group is bonded and capable of being crosslinked by forming a siloxane bond in the present invention. Can be performed as follows, for example. First, a pressure-resistant reaction vessel with a 1-liter stirring bar, in which 320 g of polyoxypropylene glycol having an average molecular weight of 3200 (15% of allyl ether groups in all terminal groups, 3% of propenyl ether groups, and 82% of hydroxyl groups) was substituted with nitrogen, with a stirring rod I took it. Subsequently, 40.8 g of powdered caustic soda (purity 98%) was added, and then the temperature was raised to 60 ° C. Then, 7.76 g of bromochloromethane was added and the reaction was carried out at 60 ° C. for 10 hours. Then, the temperature of the reaction section is set to
And add 9.2 g of allyl chloride, and add 10 at 50 ° C.
A time reaction was performed. After the reaction was completed, the contents were taken out in a beaker and diluted with 1000 g of normal hexane,
It was treated with 0 g of aluminum silicate at room temperature for 1 hour under stirring. Then, the mixture was filtered and the cake was washed several times with normal hexane. By removing volatiles from the filtrate by distillation, the propylene oxide polymer having an average molecular weight of 8000 was reduced to 3
00 g was obtained. The terminal group of the polymer was 90% allyl ether group, 8% propenyl ether group and 2% hydroxyl group. 84 g of the polymer obtained was placed on a 500 ml pressure resistant reactor equipped with a stir bar. 0.05 ml of a catalyst solution of chloroplatinic acid (a solution of ₂ g of H ₂ PtCl ₆ .6H ₂ O dissolved in 20 ml of isopropanol and 78 ml of tetrahydrofuran) and 2.1 g of methyldimethoxysilane were added, and after reacting at 100 ° C. for 8 hours, When volatile matter is removed, 82% of the end groups

[Chemical 8] An alkylene oxide polymer, which is a group represented by, was obtained.

Example 1 Oxyalkylene polymer having a silicon-containing group represented by -SiCH ₃ (OCH ₃ ) ₂ having a molecular weight of 8500 at the end
(SILYL 5A01 manufactured by Kanegafuchi Chemical Industry Co., Ltd.) 80 parts by weight of a rosin ester (ester gum AAG manufactured by Arakawa Chemical Co., Ltd.) as a tackifying resin to 100 parts by weight of a curing catalyst (manufactured by Kawaken Fine Chemical Co., Ltd.) Aluminum chelate AL
CH) 10 parts by weight and anti-aging agent BHT 0.5 parts by weight were added to prepare an adhesive composition with isopropyl alcohol, and indomethacin dissolved in isopropyl alcohol was adjusted to 5 parts indomethacin per 100 parts by dry weight. Is added and coated on polyethylene terephthalate.
Curing molding was performed at 0 ° C. to obtain the anti-inflammatory analgesic patch of the present invention.

Example 2 Oxyalkylene polymer having a silicon-containing group represented by -SiCH ₃ (OCH ₃ ) ₂ having a molecular weight of 8500 at the terminal
(SILYL 5A01 manufactured by Kanegafuchi Chemical Industry Co., Ltd.) 80 parts by weight of a rosin ester (ester gum AAG manufactured by Arakawa Chemical Co., Ltd.) as a tackifying resin to 100 parts by weight of a curing catalyst (manufactured by Kawaken Fine Chemical Co., Ltd.) Aluminum chelate AL
CH) 10 parts by weight and anti-aging agent BHT 0.5 parts by weight were added to prepare an adhesive composition with isopropyl alcohol, and ketoprofen dissolved in isopropyl alcohol was prepared so that the dry weight was 100 parts by weight and ketoprofen was 5 parts by weight. Is added and coated on polyethylene terephthalate.
Curing molding was performed at 0 ° C. to obtain the anti-inflammatory analgesic patch of the present invention.

Example 3 Oxyalkylene polymer having a silicon-containing group represented by -SiCH ₃ (OCH ₃ ) ₂ having a molecular weight of 8500 at the terminal
(SILYL 5A01 manufactured by Kanegafuchi Chemical Industry Co., Ltd.) 80 parts by weight of a rosin ester (ester gum AAG manufactured by Arakawa Chemical Co., Ltd.) as a tackifying resin to 100 parts by weight of a curing catalyst (manufactured by Kawaken Fine Chemical Co., Ltd.) Aluminum chelate AL
CH) 10 parts by weight and anti-aging agent BHT 0.5 parts by weight are added to prepare an adhesive composition with isopropyl alcohol, and indomethacin 10 parts and isopropyl palmitate 5 parts are added to 100 parts by dry weight thereof. Indomethacin and isopropyl palmitate dissolved in isopropyl alcohol were added, applied to polyethylene terephthalate, and cured and molded at 40 ° C. to obtain an anti-inflammatory and analgesic patch of the present invention.

Example 4 Oxyalkylene polymer having a molecular weight of 8500 and having a silicon-containing group represented by -SiCH ₃ (OCH ₃ ) ₂ at the terminal
(SILYL 5A01 manufactured by Kanegafuchi Chemical Industry Co., Ltd.) 80 parts by weight of a rosin ester (ester gum AAG manufactured by Arakawa Chemical Co., Ltd.) as a tackifying resin to 100 parts by weight of a curing catalyst (manufactured by Kawaken Fine Chemical Co., Ltd.) Aluminum chelate AL
CH) 10 parts by weight and anti-aging agent BHT 0.5 parts by weight were added to prepare an adhesive composition with isopropyl alcohol, and hydrocortisone succinate 5 was added to 100 parts by weight of this dry weight.
Parts were added, and hydrocortisone succinate dissolved in isopropyl alcohol was added and applied to polyethylene terephthalate and cured and molded at 40 ° C. to obtain an anti-inflammatory analgesic patch of the present invention.

Test Example 1 Evaluation of drug release property The drug release properties of the indomethacin or ketoprofen patches for anti-inflammatory and analgesic preparations obtained in Examples 1 and 2 were compared with those of indomethacin or ketoprofen prepared using a silicone elastomer as an adhesive base. The release of the drug in each anti-inflammatory analgesic patch was compared. As a silicone elastomer, the product 2920 (Dow Co
Indomethacin or ketoprofen was added so that each drug would be 5 parts with respect to 100 parts of this dry weight, followed by curing and molding at room temperature. The size of each sample was 30 μm for this test, and each sample was placed in a horizontal membrane cell (Fran).
40% polyethylene glycol 400 after mounting in z-type cell)
A release test was carried out using a physiological saline solution containing as an elution solvent. At that time, the cumulative release amount of each of indomethacin and ketoprofen over time was measured by the HPLC method.
HPLC measurement was carried out by Inertsil ODS-2 (Gaskuro Kogyo: 4.6
mm x 150 mm) and methanol / 5 mM KH ₂
Indomethacin and ketoprofen were measured in a solvent system of PO ₄ aqueous solution at a flow rate of 1.0 ml / min.

The results are shown in FIG. Example 1 from FIG.
The drug release from the formulations obtained in and 2 was better than the drug release from the formulation using the comparative silicone elastomer. This tendency was similarly observed in the formulations obtained in Example 3 and Example 4, which are not shown in the figure. For example, the release property of the preparation obtained in Example 4 was tested by the same method as described above, and as a result, after 0.5 hour, 1 hour, 2 hours, 4 hours, 6
The cumulative release amounts of hydrocortisone succinate after 6.2 hours, 12 hours, and 24 hours were 6.2 μg / c, respectively.
m ² , 11.7 μg / cm ² , 18.9 μg / cm ² ,
29.7 μg / cm ² , 42.1 μg / cm ² , 64.
8μg / cm ^2, (measured value of n = 3) 89.2μg / cm ² good data was obtained.

Test Example 2 Evaluation of Drug Transfer to the Skin Acrylic adhesive was used as a control for the transfer to the skin when the indomethacin patch for anti-inflammatory and analgesia obtained in Example 1 was applied to the upper arm of a human. It was compared with the indomethacin patch prepared by using. As the acrylic adhesive, 95 parts of 2-ethylhexyl acrylate, 5 parts of acrylic acid, 0.2 parts of benzoyl peroxide and 150 parts of ethyl acetate,
The mixture was charged into a reactor having a reflux condenser and a stirrer, and polymerized at 60 ° C. for 8 hours in a nitrogen gas atmosphere. 5 parts of indomethacin was added to and mixed with 100 parts of the dry weight of the acrylic pressure-sensitive adhesive solution, and the mixture was cured and molded at room temperature. The size of each sample was 30 mm thick for this test.
μm, and applied to the upper arm of human (3 cases) in a size of 4 cm ² for 8 hours, and then the above-mentioned patch was peeled off and the content of indomethacin remaining in the adhesive layer was measured by the HPLC method. The skin transfer rate (%) of indomethacin was calculated from the comparison with the content. The HPLC measurement is Inertsil O
The indomethacin content was measured by using DS-2 (manufactured by Gas Chloro Industrial: 4.6 mm × 150 mm) in a solvent system of methanol / 5 mM KH ₂ PO ₄ aqueous solution at a flow rate of 1.0 ml / min. As a result, the skin transfer rate of indomethacin in the anti-inflammatory and analgesic patch of the present invention was 38.
2%, which was a good skin transfer rate compared to the skin transfer rate of 20.0% in the control patch using the acrylic pressure-sensitive adhesive.

Test Example 3 Evaluation of Carrageenin Intradermal Edema Inhibition Rate The carrageenin intradermal edema inhibition of the patch of indomethacin prepared by using the patch obtained in Example 1 and the acrylic adhesive of Test Example 2 A rate test was conducted. Male Wistar rats weighing about 250 g were made into groups of 10 and the hair on the back of each rat was shaved. After 15 hours, they were obtained as test pieces in Example 1 at two places on the right and left sides of the back. The patch was used as a control piece, and the patch obtained in Test Example 2 was cut into a size of 4 cm ² and applied. Two hours after the application, these were peeled off, and 0.05 ml of 0.5% carrageenin physiological saline solution was intradermally injected into both peeling marks. After 4 hours, the rat was killed, the skin of the injected part was peeled off, and a fragment with a diameter of 12 mm was produced centering on the edema part, the skin weight was measured, and the part between the test piece attachment part and the control piece attachment part was measured. The carrageenin intradermal edema inhibitory rate was calculated according to the following formula, with the weight difference of edema as the edema weight. Carrageenin intradermal edema inhibition rate (%) = [(V _C -V _S) /
V _C ] × 100 (In the formula, V _C and V _S represent the intradermal edema weights of the control piece and the test piece application group, respectively). It was 50.0%, which was a better inhibition rate than the carrageenin intradermal edema inhibition rate of 35.0% in the control patch using an acrylic adhesive.

[0040]

EFFECTS OF THE INVENTION The anti-inflammatory and analgesic patch of the present invention has excellent release of a drug from the pressure-sensitive adhesive composition layer by containing the specific oxyalkylene polymer and the tackifying resin in the pressure-sensitive adhesive composition. There is. Therefore, the patch for anti-inflammatory and analgesia of the present invention can absorb a necessary and sufficient amount of drug through the skin, and thus can more effectively treat inflammation and analgesic diseases and also has side effects. It is possible to exert its medicinal effect little and continuously.

[Brief description of drawings]

FIG. 1 is a diagram showing the cumulative release amount of a drug in an anti-inflammatory and analgesic patch of the present invention obtained in Examples and a control patch.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI technical display location A61K 31/405 ABE 7252-4C 31/57 7252-4C

Claims (3)

[Claims] 1. An anti-inflammatory analgesic patch comprising an adhesive composition layer containing an anti-inflammatory analgesic laminated on a support, wherein the adhesive composition layer contains a silicon atom to which a hydroxyl group or a hydrolyzable group is bonded. An anti-inflammatory analgesic patch comprising: an oxyalkylene polymer having a silicon-containing group that can be crosslinked by forming a siloxane bond; and a tackifying resin. 2. A second pressure-sensitive adhesive composition layer containing or not containing an anti-inflammatory analgesic on the pressure-sensitive adhesive composition layer according to claim 1, wherein the layer is a silicon having a hydroxyl group or a hydrolyzable group bonded thereto. An anti-inflammatory and analgesic patch, further comprising a layer containing an oxyalkylene polymer having a silicon-containing group that contains atoms and can be crosslinked by forming a siloxane bond, and a tackifying resin. 3. The silicon-containing group according to claim 1 or 2 has the general formula (II): [In the formula, X is a hydroxyl group or a hydrolyzable group, and when two or more are present, they may be the same or different. R ² is a monovalent hydrocarbon group having 1 to 20 carbon atoms or (R ′) ₃ SiO— (R ′ is a monovalent hydrocarbon group having 1 to 20 carbon atoms, and three R ′ are the same. May be
Which may be different), and when two or more R ² are present, they may be the same or different. a is 0, 1, 2
Alternatively, 3 and b represent 0, 1 or 2. However, 1 ≦ a +
mb and m m B in need not be the same. m is 0 or 1
Represents an integer of 19. ] The anti-inflammatory analgesic patch according to claim 1, which is represented by the formula