JPS63313723A - External cataplasm - Google Patents

Abstract

PURPOSE:To obtain an external cataplasm improved in stability of medicine and suppressed in skin irritation which propyl gallate has, by incorporating propyl gallate and medicine to a high polymer substrate layer. CONSTITUTION:A pressure-sensitive adhesive layer is laminated at skin face side of a high polymer substrate containing a medicine and propyl gallate which is a stabilizing agent for the medicine on a support such as film, sheet or tape to provide the external cataplasm. The distribution ratio to pressure-sensitive adhesive layer of propyl gallate is smaller than the distribution ratio to a high polymer substrate layer and the ratio is <=0.3. The ratio of release speed of the medicine from the high polymer substrate layer is preferably <=0.5. Propyl gallate is preferably kept to a concentration of >=1%.

Description

DETAILED DESCRIPTION OF THE INVENTION (1) Field of Industrial Application The present invention relates to an external patch that improves drug stability by adding propyl gallate and suppresses the skin irritation properties of propyl gallate. It is something.

(b) Conventional technology Transdermal administration of drugs is less troublesome during administration than oral administration, injections, suppositories, etc., and also does not undergo liver metabolism, does not cause gastrointestinal disorders, and does not release drugs. Since the speed is limited, it has the advantage of reducing the number of administrations, and it is expected that more and more types of drugs will be administered transdermally in the future. In particular, tape preparations using transdermal administration are attracting attention because of their long-lasting pharmacological effects and ease of dosage adjustment.

However, it is often seen that the stability of the drug itself is impaired when the drug is made into a tape formulation, and therefore various stabilizers have been investigated.

The conditions for this stabilizer include that it does not react immediately with the drug (1 (being inactive), that it is non-toxic, and that it is relatively inexpensive).

Propyl gallate is generally known as an oil and fat antioxidant and is added to edible oils, butter, lipsticks, and the like.

Since this propyl gallate has a strong antioxidant effect, it exhibits a strong stabilizing effect on various drugs for transdermal administration, especially drugs that are susceptible to decomposition due to oxidation.

(c) Problems to be Solved by the Invention When propyl gallate is used as a food additive, it is usually used at a concentration of 0.1% by weight or less due to toxicity.

Furthermore, when it is added to cosmetics such as lipsticks and creams, it is reported that it is preferable to use it at 1% by weight or less due to the skin irritation of gallic acid (JOUNAL OFAMERICAN C0
LLEGE OF TOXICOLOGY Vo
1, 4, Number 3.198523-57).

On the other hand, when added to a drug for transdermal administration, if the amount is less than 1% by weight, the drug stabilizing effect is poor and it is necessary to increase the concentration, but this has the disadvantage of increasing skin irritation.

(d) Means for Solving the Problem In order to solve this drawback, the present inventors have conducted intensive studies and found that the concentration of propyl gallate necessary for stabilizing the drug was maintained at 1% or more. At the same time, we have discovered a method to reduce the skin irritation caused by propyl gallate.

In other words, a transdermally absorbable drug and propyl gallate, which stabilizes the drug, are added to the polymer base layer, thereby improving the stability of the drug. By laminating a pressure-sensitive adhesive layer on the skin, the release properties of propyl gallate are controlled to prevent the propyl gallate from reaching the skin surface, thereby reducing the skin irritation derived from propyl gallate. It is something that

That is, the external patch of the present invention is formed by laminating, in this order, a polymer base layer containing a drug and propyl gallate, which is a stabilizer for the drug, and a pressure-sensitive adhesive layer on a support. It is characterized by:

The present invention will be explained in detail below.

As the support used in the present invention, any flat material such as a film, sheet, tape, or cloth can be used, but it does not substantially allow moisture to pass through or cause skin or mucous membrane irritation, whitening, etc. Various plastic films and sheets made of materials such as polyolefin, polyester, polyurethane, polyvinyl alcohol, polyvinylidene chloride, and polyamide, which are designed to adjust the degree of moisture permeability to a degree that does not cause side effects Foamed sheets, metal foils, woven fabrics, laminates of nonwoven fabrics and plastic films, etc. are suitably used.

The polymer base layer used in the present invention is not limited as long as it contains a transdermally absorbable drug, but in particular polyvinyl acetate, ethylene-vinyl acetate copolymer, polyvinylpyrrolidone - A layer formed of a polymeric material containing vinyl acetate units, such as a vinyl acetate copolymer, is desirable in terms of flexibility and drug retention.

Further, the pressure-sensitive adhesive layer used in the present invention may be a layer formed of a material having pressure-sensitive adhesive properties at room temperature, and a layer formed of a pressure-sensitive adhesive as described below may be used. It is suitably used in terms of skin adhesion and drug transferability.

The pressure-sensitive adhesive may be an acrylic adhesive that is lipophilic and has pressure-sensitive adhesive properties at room temperature, such as butyl (meth)acrylate, pentyl (meth)acrylate, (
Hexyl (meth)acrylate, 2-ethylbutyl (meth)acrylate, heptyl (meth)acrylate, inoctyl (meth)acrylate, 2-ethylhexyl (meth)acrylate, decyl (meth)acrylate, (meth)acrylate Such as dodecyl acid, tridecyl (meth)acrylate (
Examples include homopolymers of meth)acrylic acid esters, and copolymers of these esters with monomers copolymerizable.

As the copolymerizable moamer, for example, (meth)
Acrylic acid, (anhydrous) maleic acid, (anhydrous) itaconic acid, hexamaric acid, hydroxyethyl (meth)acrylate,
Hydroxypropyl (meth)acrylate, (meth)acrylamide, trimethyl (meth)acrylamide, N-butyl (meth)acrylamide, N-methylol (meth)
Acrylamide, aminoethyl (meth)acrylate, (
Dimethylaminoethyl (meth)acrylate, methquinethyl (meth)acrylate, ethoxyethyl (meth)acrylate, butoxyethyl (meth)acrylate, hydrofurfuryl (meth)acrylate, methoxyethylene glycol (meth)acrylate, ( methoxydiethylene glycol acrylate, methoxypolyethylene glycol (meth)acrylate, methoxypolybutylene glycol (meth)acrylate, styrene sulfonic acid, allyl sulfonic acid, sulfopropyl (meth)acrylate, (meth)acryloyloxynaphthalene sulfonic acid, Acrylamidomethylpropanesulfonic acid, acryloyloxybenzenesulfonic acid, N-(meth)acryloyl amino acid, urethane/urea/incyanate ester of acrylic acid, (meth)acrylonitrile, vinyl acetate, vinyl propionate, vinyl versatate, styrene, α−
Methylstyrene, vinylpyrrolidone, vinylpyridine,
Vinylpyrazine, vinylpiperazine, vinylpiperidone, vinylpyrimidine, vinylpyrrole, vinyloxazole, vinylpiperazine, vinyloxazole, vinylthiazole, vinylmorpholine, vinyl chloride, bis(
Examples include N,N'-dimethylaminoethyl)malenate.

Examples of other polymers that are lipophilic and have pressure-sensitive adhesive properties at room temperature include silicone adhesives, polyisoprene rubber, polyisobutylene rubber, polybutadiene, and styrene-butadiene (or isoprene)-styrene block copolymers. Examples include synthetic rubber adhesives such as rubber and acrylic rubber, and natural rubber adhesives.

In a preferred embodiment of the present invention, the distribution ratio of propyl gallate to the pressure sensitive adhesive layer is smaller than the distribution ratio to the polymer base layer, and it is desirable that the ratio is 0.3 or less.

Further, in the polymer base layer and the pressure-sensitive adhesive layer, it is more desirable that the ratio of the release rate of propyl gallate to the release rate of the drug from the polymer base layer is 0.5 or less. .

Moreover, by controlling the release rate and distribution rate of propyl gallate, it is possible to further improve the stability of the drug and prevent irritation of the skin or mucous membranes.

Further, as the drug contained in the polymer base layer in a dissolved or dispersed state, it is preferable to use a drug that is oxidized and decomposed in the polymer base layer to cause a decrease in content, and the drug itself is It is absorbable through the skin and mucosa.

Examples of such drugs include those listed below.

b) Flutifosteroids [=e.g. hydrocortiscin, prednisolone, beclomethasone propionate,
flumethacin, triamcinolone, triamcinolone acetonide, fluocinolone, fluocinolone acetonide, fluocinolone acetonide acetate, clobetasol propionate, etc.) Analgesic anti-inflammatory agents: e.g. acetamino-7ene, mefenamic acid, flufenamic acid, indomethacin, diclo 7-enatsuc, diclofenac sodium, alcro-7enatsuc, oxy-7-enbutazone, 7-eluptazone, ibuprofen, flurbipro-7en, salicylic acid, methyl salicylate,! - Menthol, Can7ar, Slingtsk, Tolmetin Sodium, Naproxen, 7-en, etc.; c) Hypnosedatives: for example, phenobarbital, amoparbital, ciquaparbital, triapram, nitrazepam, lorazepam, haloperidol, etc.; ) Tranquilizers: e.g. fluphenazine, teolitasin, diazepam, fludiazepam, flunitrazebam, haloperidol, chlorpromazine, etc. e) Antihypertensive agents: e.g. clonidine, clonidine hydrochloride, etc.
pindolol, propranolol, propranolol hydrochloride, pr7ranolol, indenolol, nipazibine, nimodipine, roanidixine, nitrendipine, nipradilol, bucumolol, nifedipine, etc. f) Antihypertensive diuretics: e.g. hydrothiazide, pendroflunathiazide, cyclobenziazide, etc. ) Antibiotics: e.g. penicillin, tetracycline,
Oxytetracycline, 7-radiomycin sulfate, erythromycin, chloramphenicol, etc.; 1) Anesthetic agents, such as lidocaine, dibucaine hydrochloride, pensicaine, ethyl amyl-7 benzoate, etc.; Nystatin, acetosulfamine, clotrimazole, etc., n) Antifungal substances: e.g. pentamycin, amphotericin B1 virolnidoline, clotrimazole, etc. l) Vitamin preparations: e.g. vitamin A1 ergocalciferol, cholecalciferol, off) f) antiepileptic drugs such as nitrazepam, mepropamate, clonazepam, troglycol, isosorbide dinitrate, erythritol tetranitrate, pentaerythritol tetranitrate, propyl nitrate, etc.) Antihistamines: e.g. diphenhydramine hydrochloride,
chlorpheniramine, diphenylimiguzole, etc. ii) Antitussives: e.g. dextromethorphan hydrobromide, terbutasone sulfate, ephedrine, ephedrine hydrochloride, salbutamol sulfate, isoprotenol hydrochloride, isoprotenol sulfate, etc. ri) Sex hormones: e.g. propsterone , estradiol, etc., ii) Anti-surgical drugs: e.g. doxepinso) Cerebral circulation improving agents: e.g. videlgin, nilgott alkaloids, embrozil, etc., t) Anti-emetics, anti-ulcer agents: e.g. metoclopramide, clebopride, tonberitone, scopolamine, etc. Scopolamine hydrobromide, 5-
Examples include fluorouracil and mercaptopurine.

The mixing ratio of the drug and the polymer base material, which is mainly composed of a polymer material, varies depending on the type of polymer material, drug, and additive, but the ratio of the drug to the entire polymer base layer is 0.01 to 0.01.
It is best to adjust the amount to 30% by weight, preferably within the range of 0.2 to 20% by weight.If it is less than 0.01% by weight, the therapeutic effect will be poor, while if it exceeds 30% by weight, there will be a limit to the therapeutic effect and crystallization will occur. may precipitate and be difficult to absorb through the skin, which is economically disadvantageous.

In addition, in the present invention, propyl gallate is added to the polymer base layer, but its concentration may be any amount that can stabilize the drug, and although it varies depending on the type of drug, the proportion of propyl gallate in the entire composition may vary. is 1.0 to 5% by weight, preferably 1.0
It is desirable to adjust the amount within the range of ~3% by weight; if it is less than 1.0% by weight, it may not be effective in stabilizing the drug; on the other hand, if it exceeds 5% by weight, there is no difference in the stabilizing effect. This is not preferable as it may cause skin irritation.

The external patch of the present invention has a polymeric base layer formed on a support and a pressure-sensitive adhesive layer laminated on the exposed surface of the polymeric base layer as essential components. It is desirable to protect the surface of the pressure-sensitive adhesive layer by laminating a flexible release film or paper that has been subjected to a release treatment on the exposed surface of the pressure-sensitive adhesive layer.

The external patch of the present invention is entirely water-impermeable,
It is preferable to store them one by one or all at once in a bag made of a light-impermeable packaging material, such as a laminate film of aluminum foil and plastic film, for storage and distribution.

(e) Effect The external patch of the present invention contains a physiologically active drug and propyl gallate that stabilizes the drug in a polymer-based composition as a polymer base layer, thereby achieving the following effects: It has the effect of stabilizing drugs and improving the reliability of external patches.

Furthermore, when the topical patch of the present invention is applied to the skin or mucous membranes, propyl gallate is not transferred into the pressure-sensitive adhesive layer or is transferred at a very low concentration, so irritation to the skin or mucous membranes does not occur. It has an effect that allows the drug to be safely administered into the body with little to no effect.

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

In addition, parts and % in the text indicate parts by weight and weight %.

Example 1 55 parts of acrylic acid 2-ethylhexyl ester, 30 parts of acrylic acid methoxyethyl ester, 15 parts of vinyl acetate, and 0.3 parts of azobisisobityronitrile were charged into four flasks and heated under an inert gas atmosphere. 60-63℃
The polymerization reaction was started by raising the temperature to
The reaction was continued for 10 hours while controlling the reaction temperature while dropping 5 parts, and further aged at a temperature of 75 to 80°C for 2 hours to obtain a copolymer solution.

In the obtained copolymer solution, the contents of dichloro-7enac sodium and citric acid after drying were 20% and 4%, respectively.
The mixture was added and mixed so that the drug content was 100 μg/Cl112 on a polyester mold release liner, and dried to form a pressure-sensitive adhesive layer.

Polyvinyl acetate resin (number average molecular weight 1800.20%
Add and mix dichloro-7enac sodium, citric acid, and propyl gallate to a methanol solution) so that the dry contents are 20%, 4%, and 3%, respectively, and place the drug content on a polyester release liner. is 300μg/cl
o2 and dried to form a polymer base material layer.

This polymeric base material layer is thermocompression bonded to a polyethylene film as a support at a temperature of 100°C, and the above-mentioned pressure-sensitive adhesive layer is pasted from the exposed side of the polymeric base layer to form an external adhesive according to the present invention. obtained the drug.

When the propyl gallate content in this topical patch was measured using the measuring method described below [Note 5)], it was found that the content of propyl gallate in the polymer base layer was 2.
3%, and 0.7% in the pressure sensitive adhesive layer.

Example 2 95 parts of acrylic acid 2-ethylhexyl ester, 5 parts of acrylic acid, and 0.2 parts of benzoyl peroxide were charged into 4 flasks, and the temperature was raised to 62 to 65°C under an inert gas atmosphere to polymerize. Start the reaction and add 125% of ethyl acetate to it.
The reaction was continued for 8 hours while controlling the reaction temperature while adding the same amount dropwise, and further aged for 2 hours at a temperature of 75 to 80°C to obtain a copolymer solution.

Haloperidol was added and mixed to the obtained copolymer solution so that the content after drying was 20%, and the mixture was coated on a polyester release liner so that the drug content was 100 μg/cm2, dried, and sensitized. A pressure adhesive layer was formed.

Ethylene-vinyl acetate copolymer (vinyl acetate content 40%)
) Haloperidol and propyl gallate in a toluene solution containing 20 parts of resin, each with a dry content of 20%.
, 2%, and coated on a polyester mold release liner so that the drug content was 700 μg/c, m2, and dried to form a polymeric base material layer.

This polymeric base layer was laminated onto a nonwoven fabric as a support, and the above-mentioned pressure-sensitive adhesive layer was attached from the exposed side of the polymeric base layer to obtain an external patch of the present invention.

When the propyl gallate content in this topical patch was measured using the measurement method described below [Note 5)], it was found that the content of propyl gallate in the polymer base layer was 1.
6%, and 0.4% in the pressure sensitive adhesive layer.

Comparative Example 1 The copolymer solution obtained in Example 1 was added with dichloro-7enac sodium and citric acid at a dry content of 2% each.
The drug content was 400IIg/cI.
112 and dried to form a pressure-sensitive adhesive layer, and the pressure-sensitive adhesive layer was attached to a polyethylene film.

Comparative Example 2 To the copolymer solution obtained in Example 1, dichloro-7enac sodium, citric acid, and propyl gallate were added and mixed so that the contents after drying were 20%, 4%, and 3%, respectively. This was applied onto a polyester mold release liner so that the drug content was 400 μg/cm2, dried to form a pressure-sensitive adhesive layer, and the pressure-sensitive adhesive layer was attached to a polyethylene film. I used something like

Comparative Example 3 Haloperidol was added and mixed to the copolymer solution obtained in Example 2 so that the content after drying was 20%, and this was placed on a polyester release liner with a drug content of 800μ.
g/cm 2 and dried to form a pressure-sensitive adhesive layer, and the pressure-sensitive adhesive layer was attached to a nonwoven fabric.

Comparative Example 4 The content of haloperidol and propyl gallate in the copolymer solution obtained in Example 2 after drying was 20%, respectively.
2%, and coated on a polyester mold release liner so that the drug content was 800 μg/cI112, and dried to form a pressure-sensitive adhesive layer. A material made by pasting on a non-woven fabric was used.

and 4 correspond to Example 2, respectively.

Regarding the external patches obtained in each example and each comparative example, the stability of the drug over time, the skin migration property of the drug, the skin adhesion property,
An irritation test was conducted on the applied skin surface, and the results are shown in Table 1.

Table 1 The method for measuring each characteristic shown in Table 1 is as follows.

Note 1) Oral stability Each sample piece cut into length 5ea+ and width 3cI11 was heated to temperature 4.
The samples were stored at 0° C. for 3 and 6 months, and then each sample piece was extracted with methanol and quantified using high performance liquid chromatography.

○...Residual rate 95% or more, Δ...Residual rate 90% or more but less than 95%, ×...Residual rate less than 90%.

Note 2) Drug skin migration: Each sample piece cut vertically into 5 am and li 3 en+ was applied to the human skin surface for 24 hours and then peeled off. The drug remaining in each sample piece was extracted with methanol and subjected to high performance liquid chromatography. It was quantified using graphics.

The transfer amount to the skin surface was calculated from the initial content of this sample piece, and the transfer amount of each drug in Comparative Example 1 and Comparative Example 2 was set as 1.0, and the ratio was expressed.

Note 3) Skin adhesion Each sample piece cut into 5 cm x 30 x 11 pieces was applied to the human skin surface for 24 hours, and the state of adhesion to the skin was visually determined.

O...Adhesive area 90% or more, Δ...Adhesive area 50%
or more, less than 90%, ×... less than 50% of adhesive area.

Note 4) Skin irritation Each sample piece (3 cm φ) was pasted on the back of a person for 24 hours, and the skin condition was visually determined 1 hour after it was removed. Scores were given as shown below, and the evaluation was based on the average value of 10 people. did.

○...Average i, o less than 1, Δ...Average 1.0 points or more and less than 2.0 points, ×...Average 2.0 points or more.

0 points...no reaction 0.5 points...slight erythema 1.0 points...obvious erythema 2.0 points...erythema and papules or edema 3.0 points...erythema and edema Papules or small varicella 4.0 points...major varicella Note 5) Measurement method of distribution ratio between base material layers of propyl gallate The polymer base material layer containing the drug shown in Examples 1 and 2 has the same thickness. Samples with a pressure-sensitive adhesive layer that does not contain the drug, propyl gallate, and other additives were incubated at room temperature, 40°C, and 70°C until the migration of the drug and propyl gallate reached an equilibrium state. saved.

After cutting this sample into 5 cm long and 3 cm wide, the polymer base material layer and pressure sensitive adhesive layer were separated, and after methanol extraction,
The content of propyl gallate contained in the polymer base material layer and the pressure-sensitive adhesive layer was determined using high performance liquid chromatography 7 Roughy to determine the distribution ratio.

From Table 1, it can be seen that the Example products have good oral stability of the drug, good skin transferability and skin adhesion of the drug, and skin irritation is controlled as much as possible.

On the other hand, in Comparative Example 1 and Comparative Example 2, the oral stability of the drug was poor, and decomposition of the drug was observed during storage, resulting in problems in terms of storage stability.

In addition, in Comparative Example 3, the drug stability, skin migration and skin adhesion of the drug are good, but the skin irritation is strong and may cause pain to the user. It has problems in terms of daily stability and skin irritation, and is expected to cause pain to some users.

(g) Effects of the Invention The external patch of the present invention has the above-mentioned structure, and achieves long-term stability of the drug by containing a physiologically active drug and propyl gallate in the polymeric base layer. Moreover, this polymeric base material layer hardly restricts the transfer of the drug to the skin or mucous membrane surface, and also controls and suppresses the release of propyl gallate, which causes skin and mucous membrane irritation, as much as possible. A pressure-sensitive adhesive layer is provided, which allows for
The skin irritation caused by the transfer of propyl gallate to the skin is eliminated, and the drug is efficiently absorbed into the body, resulting in an effect that can be used by many people with peace of mind. .

Claims (2)

[Claims] (1) An external patch characterized by laminating a drug and a polymeric base layer containing propyl gallate, which is a stabilizer for the drug, and a pressure-sensitive adhesive layer on a support in this order. . (2) The external patch according to claim 1, wherein the distribution ratio of propyl gallate to the pressure-sensitive adhesive layer is smaller than the distribution ratio to the polymer base layer, and the ratio is 0.3 or less.