JPH0745400B2 - External pharmaceutical preparation - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (a) Field of Industrial Application The present invention relates to a pharmaceutical preparation for external use, which is applied onto the skin of a body and transdermally administers a drug into a living body.

(B) Conventional Technology Conventionally, a drug such as a methyl salicylate-containing pressure-sensitive adhesive or a menthol-containing pressure-sensitive adhesive has been used as a pharmaceutical preparation for treating or preventing a local or systemic disease by transdermally administering a drug from the skin surface. A tape-shaped or sheet-shaped pressure-sensitive adhesive has been proposed.

As described above, in the pharmaceutical preparation intended for percutaneously administering the drug to the body by sticking it on the body skin, the skin adhesiveness, internal cohesiveness, and the stability with time against the decomposition reaction of the drug Acrylic pressure-sensitive adhesives are used.

(C) Problems to be Solved by the Invention When a drug is transdermally administered, the drug is a pressure-sensitive adhesive (adhesive) from the viewpoints of diffusibility of the drug and transfer to the skin.
It is desirable that it is in a dissolved state.

However, many acrylic pressure-sensitive adhesives generally have poor hydrophilicity, and when a hydrophilic drug is used, if the drug is contained to the extent that drug efficacy can be expected, the drug will crystallize in the pressure-sensitive adhesive layer. May occur, and problems may occur with respect to adhesiveness, diffusibility, and release to the living body.

(D) Means for Solving the Problems As a result of intensive investigations by the present inventors to solve the above problems, the pressure-sensitive adhesive obtained by copolymerizing aminoalkyl (meth) acrylamide has excellent skin adhesion. In addition, by using this type of acrylamide, the polarity of the pressure-sensitive adhesive itself becomes remarkably high, and it becomes possible to allow a high content of the drug to exist in the pressure-sensitive adhesive layer in a dissolved state. Moreover, when used for the purpose of transdermal administration of a drug,
We found that drug release and skin permeability were improved,
The present invention has been completed.

That is, the present invention is a pharmaceutical preparation comprising a layer of a pressure-sensitive adhesive containing a drug on a flexible carrier, wherein the pressure-sensitive adhesive contains aminoalkyl (meth) acrylamide as a copolymerization component. It is characterized by being contained.

The present invention will be described in detail below.

The carrier used in the present invention holds a layer of a pressure-sensitive adhesive containing a drug, and can follow its movement when applied to the skin surface, and gives a strange feeling even when applied to a curved surface. A material having appropriate flexibility is selected so that it can be applied without any problem.

Examples of these carriers include polyolefins such as polyethylene, polyester, polyvinyl chloride, polyvinylidene chloride, polyamide, ethylene-vinyl acetate copolymer, polyurethane and other plastic films and sheets, foams made of rubber and / or synthetic resin. Sheet / film,
Examples thereof include non-woven fabric, woven fabric, paper, metal foil, and various laminated films formed by laminating these materials.

The pressure-sensitive adhesive for containing a drug in the present invention has a skin adhesive property that can be applied to a skin surface for a long time, and has the greatest feature in that it contains an aminoalkyl (meth) acrylamide as a copolymerization component. Is to have.

Further, the pressure-sensitive adhesive is an alkyl (meth) acrylate whose alkyl group has 4 to 12 carbon atoms in consideration of skin adhesiveness, internal cohesiveness, stability against drug decomposition reaction and drug retention. Acrylic pressure sensitive adhesives containing at least 50% by weight of ester are preferred.

Specifically, for example, (meth) acrylic acid butyl ester, (meth) acrylic acid pentyl ester, (meth) acrylic acid hexyl ester, (meth) acrylic acid heptyl ester, (meth) acrylic acid octyl ester,
(Meth) acrylic acid nonyl ester, (meth) acrylic acid decyl ester, (meth) acrylic acid undecyl ester, (meth) acrylic acid dodecyl ester, (meth)
Acrylic acid such as 2-ethylhexyl ester (meth)
Examples thereof include copolymers of one or more kinds of alkyl acrylate and aminoalkyl (meth) acrylamide described later.

Further, for the purpose of adding cohesiveness to the pressure-sensitive adhesive composed of the above monomers, acrylic acid hydroxyethyl ester,
It is possible to copolymerize functional monomers such as hydroxypropyl acrylate, (meth) acrylamide, and dimethylacrylamide, and vinyl-based monomers such as acrylonitrile, vinyl acetate, vinyl propionate, vinylpyrrolidone, and vinylcaprolactam. It is also possible to copolymerize a hydrophilic acrylic acid alkoxyalkyl ester monomer such as acrylic acid methoxyethyl ester, acrylic acid ethoxyethyl ester, or acrylic acid butoxyethyl ester for the purpose of further improving the solubility of the drug. is there.

The aminoalkyl (meth) acrylamide monomer used in the present invention is represented by the following formula. Among them, when the solubility of the drug, the release property and the stability are taken into consideration, R Aminoalkyl (meth) acrylamide monomers having a sum of carbon numbers of ₂ , R ₃ and R ₄ of ₃ to 15 are preferred.

(R ₁ is a hydrogen atom or a methyl group, R ₂ is an alkylene group, R ₃ and R ₄ are a hydrogen atom, an alkyl group or a phenyl group) That is, in the above structural formula, R ₂ is an alkylene group,
Therefore, aminoalkyl (meth) acrylamide is not a urea derivative.

Further, in the above structural formula, R ₃ and R ₄ are a hydrogen atom, an alkyl group or a phenyl group, and therefore, in the present invention,
Aminoalkyl (meth) acrylamide is a concept including these substances.

Specifically, for example, N, N-dimethylaminoethyl (meth) acrylamide, N, N-diethylaminoethyl (meth) acrylamide, N, N-dimethylaminopropyl (meth) acrylamide, N, N-diethylaminopropyl (meth ) Acrylamide, N, N-dipropylaminopropyl (meth) acrylamide, N, N-di-n-butylaminoethyl (meth) acrylamide and the like, and these are polymerizable monomers described above using at least one kind. In particular, it is copolymerized with an alkyl (meth) acrylate to obtain a pressure sensitive adhesive.

It is considered that these monomers exhibit basicity because they have an amide group and an amino group in the molecule, and when used as a copolymerization component, the polarity of the pressure-sensitive adhesive is remarkably increased and good drug solubility is shown. To be

In the above copolymer, the proportion of aminoalkyl (meth) acrylamide is preferably in the range of 5 to 40% by weight, particularly preferably 10 to 30% by weight.

The content of aminoalkyl (meth) acrylamide is 5
If it is less than 10% by weight, the polarity of the copolymer cannot be sufficiently increased, resulting in insufficient solubility of highly polar drugs and easy formation of crystals in the pressure-sensitive adhesive layer, thus releasing or migrating the drugs. On the other hand, if it exceeds 40% by weight, the cohesive force may be too high and the skin adhesiveness may be poor, which is not desirable.

The drug used in the present invention is not particularly limited as long as it is percutaneously absorbed into the body when the external pharmaceutical preparation is applied to the skin.

The following can be illustrated as such a drug.

B) Corticosteroids: eg hydrocortisone,
Prednisolone, beclomethasone propionate, flumethasone, triamcinolone, triamcinolone acetonide, fluocimolone, fluocinolone acetonide, fluocinolone acetonide acetate, clobetasol propionate, etc. Acid, indomethacin, diclofenac, diclofenac sodium, alclofenac, oxyphenbutazone, phenylbutazone, ibuprofen, flurbiprofen, salicylic acid, methyl salicylate, 1-menthol, camphor, sulindac, trimethine sodium, naproxen, fenbufen, etc. C) Hypnotic sedatives: eg phenobarbital, amobarbital, cyclobarbital, lorazepam Haloperidol, etc., d) tranquilizers: e.g. fluphenazine, Teoridajin, diazepam, flunitrazepam, chlorpromazine, etc., e) anti-hypertensive agents: e.g. clonidine, clonidine hydrochloride,
Pindolol, propranolol, propranolol hydrochloride, bufuranolol, indenolol, bumolol,
Nifedipine, diltiazem hydrochloride, etc. f) antihypertensive diuretics: eg hydrothiazide, bondroflunathiazide, cyclopenthiazide, etc.)) antibiotics: eg penicillin, tetracycline,
Oxytetracycline, fludiomycin sulfate, erythromycin, chloramphenicol, etc.) Anesthetics: eg lidocaine, benzocaine, ethyl aminobenzoate, etc.)) Antibacterial substances: eg benzalkonium chloride, nitrofurazone, nystatin, acetosulfamine , Clotrimazole, etc.) Antifungal substances: eg pentamycin, amphotericin B, pyrrole nitrone, clotrimazole, etc.) Vitamin preparations: eg vitamin A, ergocadiphenol, cholecasiphenol, octothiacin, riboflavin butyrate W) antiepileptic agents: eg nitrazepam, mepropamate, clonazepam, etc. w) coronary vasodilators: eg nitroglycerin, nitroglycolol, isosorbide dinitrate, eri Lithol tetranitrate, pentaerythritol tetranitrate, such as prop-chill nitrate, f) antihistamines: e.g. diphenhydramine hydrochloride,
Chlorpheniramine, diphenylimidazole, etc. yo) Antitussives: eg dextromethorphan, terbutamine, ephedrine, ephedrine hydrochloride, etc. Ta) Sex hormones: eg progesterone, estradiol, etc.) Reagents: eg doxepin, so) Others: eg 5-fluorouracil, dihydroergotamine, fentanyl, desmopressin, digoxin, metoclopraside, domperide, scopolamine,
Examples thereof include scopolamine hydrobromide and the like, and two or more kinds of these drugs can be used in combination as necessary.

The compounding ratio of the drug (B) to the pressure-sensitive adhesive (A) is 0.1 to 3 with respect to the total weight of (A) and (B).
It is better to adjust it to 0% by weight, preferably 0.2 to 20% by weight, and if less than 0.1% by weight, the therapeutic effect is poor.
When it exceeds 0% by weight, the therapeutic effect is limited and it is economically disadvantageous.

And, in the present invention, among the above-mentioned drugs, a highly hydrophilic drug having an acid / salt structure is easily dissolved in the above-mentioned acrylic pressure-sensitive adhesive, and further, the diffusibility of the drug and the mobility to the skin are excellent. Is preferred.

Hydrophilic drugs having an acid / salt structure often have one or more acidic groups (eg, carboxyl group) or basic groups (eg, amine group) in the drug molecule and have high polarity.

Therefore, from the viewpoint of skin adhesion and the like, an acrylic adhesive which is usually used as a pressure-sensitive adhesive has too low polarity to dissolve a hydrophilic drug in most cases.

Since the external pharmaceutical preparation of the present invention uses an aminoalkyl (meth) acrylamide monomer whose polarity is enhanced by an amide bond as a copolymerization component in an acrylic pressure-sensitive adhesive, the hydrophilicity of the pressure-sensitive adhesive is It is possible to dissolve the hydrophilic drug in a high concentration without crystallizing in the pressure sensitive adhesive layer.

Further, in the present invention, the above-mentioned drug-containing pressure-sensitive adhesive is applied onto the above-mentioned carrier by a method such as roll coater or casting to provide a layer of the drug-containing pressure-sensitive adhesive. . In this case, the thickness of the layer is appropriately determined in consideration of the skin adhesiveness, the type of drug and the dose.

(E) Action The present invention uses the pressure-sensitive adhesive having the above-mentioned constitution and containing aminoalkyl (meth) acrylamide as a copolymerization component, so that the polarity of the whole pressure-sensitive adhesive becomes extremely high and hydrophilic. The solubility of the drug is extremely improved, and because the solubility of the drug is improved, the drug is not deposited on the surface of the pressure-sensitive adhesive layer (so-called blooming), which prevents the decrease in skin adhesiveness. In addition, there is no skin rash and it has a safe action.

In addition, the high polarity of aminoalkyl (meth) acrylamide enhances the hydrophilicity of the pressure sensitive adhesive, which results in
The daily stability of the drug is extremely high, the formulation is stable for a long period of time and has good storage stability, and further, the adhesion and affinity with the skin are good, and the drug release and the skin permeability are improved. Alternatively, it has a function of easily accommodating water due to perspiration and improving the ODT effect.

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

In addition, in an Example and a comparative example, a part or% means a weight part or weight%.

Example 1 Acrylic acid 2 in a five-necked flask equipped with a stirring bar, a thermometer, a reflux condenser, an inert gas introducing tube and a dropping funnel.
-Ethylhexyl ester 70 parts, methacrylic acid methyl ester 20 parts, N, N- dimethylaminopropyl acrylamide 10 parts of the monomer mixture was thoroughly agitated with an inert gas while stirring, then azobis as a polymerization initiator. After adding 0.2 part of isobutyl nitrile, the reaction rate was controlled at 60 to 65 ° C. by stirring speed, cooling of the outer bath, dropping of ethyl acetate as a diluting solution, etc., and after reacting for 8 hours, further 75 to
The temperature was raised to 80 ° C. and aged for 10 hours to obtain a pressure-sensitive adhesive solution (solid content concentration 40%).

Clonidine, which is an antihypertensive agent, was added to and mixed with the obtained pressure-sensitive adhesive solution, coated on a polyester film so that the thickness after drying was 40 μm, and dried to obtain a topical pharmaceutical preparation of the present invention.

The amount of clonidine used in this example was 400 μg.
/ cm ² (10% clonidine content) was set.

Example 2 A methanol solution of scopolamine hydrobromide, which is an agent for autonomic nerves, was added to and mixed with the pressure-sensitive adhesive solution used in Example 1, and the thickness after drying was measured on a polyester film.
The external pharmaceutical preparation of the present invention was obtained by coating and drying so that the thickness became 50 μm.

The amount of scopolamine hydrobromide used in this example was 1000 μg / cm ² (scopolamine hydrobromide content 20
%).

Example 3 Water in a five-necked flask equipped with a stirring bar, a thermometer, a reflux condenser, an inert gas introducing tube and a dropping funnel was used.
3 parts of polyoxyethylene lauryl ether are dispersed in 70 parts, 70 parts of acrylic acid iso-nonyl ester, 20 parts of methacrylic acid methyl ester and 10 parts of N, N-dipropylaminobutyl methacrylamide are added to this, and an inert gas is added. The temperature is raised to 50 ° C while substituting with 0.1%, 0.1 part of potassium peroxodisulfate and 0.1 part of sodium sulfite are added, polymerization is carried out for 3 hours, and then the temperature is raised to about 80 ° C and aged for 2 hours to obtain a pressure-sensitive adhesive. An emulsion (solid concentration 40%) was obtained.

The obtained pressure-sensitive adhesive emulsion was salted out with an aqueous sodium sulfate solution, washed with water, dried and then dissolved in ethyl acetate to obtain a pressure-sensitive adhesive solution (solid content concentration 30%).

The resulting pressure-sensitive adhesive solution is mixed with a methanol solution of propranolol hydrochloride, which is an antihypertensive agent, and coated on a polyester film so that the thickness after drying is 40 μm, and dried to obtain the external pharmaceutical preparation of the present invention. Obtained.

The addition amount of propranolol hydrochloride used in this example was set to 400 μg / cm ² (propranolol hydrochloride content 10%).

Example 4 Acrylic acid 2 in a 5-necked flask equipped with a stir bar, a thermometer, a reflux condenser, an inert gas introducing tube and a dropping funnel.
-Ethylhexyl ester 60 parts, methacrylic acid t-butyl ester 20 parts, acrylic acid methoxyethyl ester 10
Parts, N, N-dimethylaminopropyl acrylamide a monomer mixture consisting of 10 parts was sufficiently replaced with an inert gas while stirring, and then 0.2 parts of azobisisobutyl nitrile was added as a polymerization initiator. The reaction temperature was adjusted to 60 ~ by cooling the bath and adding ethyl acetate as a diluent.
After controlling the temperature to 65 ℃ and reacting for 8 hours, the temperature is further raised to 75-80 ℃ and aged for 10 hours. Pressure-sensitive adhesive solution (solid content concentration 40%)
Got

To the obtained pressure-sensitive adhesive solution, a methanol solution of clonidine hydrochloride, which is an antihypertensive agent, is added and mixed, and coated on a polyester film so that the thickness after drying is 40 μm, and dried to obtain the external pharmaceutical preparation of the present invention. Obtained.

The amount of clonidine hydrochloride used as an antihypertensive agent in this example was 600 μg / cm ² (the content of clonidine hydrochloride was 15
%).

Comparative Example 1 Polymerization was performed under the same conditions as in Example 1 except that N, N-dimethylaminopropylacrylamide was removed from Example 1, and the obtained pressure-sensitive adhesive solution (solid content concentration 40%) was subjected to antihypertension. Clonidine as an agent was added and mixed, and applied on a polyester film so that the thickness after drying was 40 μm, and dried to obtain a pharmaceutical preparation.

The addition amount of clonidine, which is an antihypertensive agent used in this comparative example, was set to be 400 μg / cm ² (content of clonidine was 10%).

Comparative Example 2 Acrylic acid 2 in a five-necked flask equipped with a stir bar, a thermometer, a reflux condenser, an inert gas introducing tube and a dropping funnel.
-After sufficiently replacing the monomer mixture consisting of 90 parts of ethylhexyl ester and 10 parts of acrylic acid with an inert gas while stirring, 0.2 part of benzoyl peroxide was added as a polymerization initiator, and the stirring speed and the external bath were added. The reaction temperature is controlled at 60 to 65 ° C by cooling the above, dropping ethyl acetate as a diluting solution, and after reacting for 8 hours, the temperature is further raised to 75 to 80 ° C and aged for 10 hours to obtain a pressure-sensitive adhesive solution ( A solid content concentration of 30%) was obtained.

To the obtained pressure-sensitive adhesive solution, a methanol solution of scopolamine hydrobromide, which is an agent for autonomic nerves, is added and mixed, and coated on a polyester film so that the thickness after drying is 50 μm, and dried to prepare a pharmaceutical preparation. Obtained.

The addition amount of scopolamine hydrobromide used in this comparative example was 1000 μg / cm ² (the content of scopolamine hydrobromide was 20
%).

Comparative Example 3 Polymerization was performed under the same conditions as in Example 3 except that N, N-dimethylaminopropylacrylamide was removed from Example 3, and the obtained pressure-sensitive adhesive solution (solid content concentration 30%) was subjected to antihypertension. A methanol solution of propranolol hydrochloride, which is an agent, was added and mixed, and applied on a polyester film so that the thickness after drying was 40 μm, and dried to obtain a pharmaceutical preparation.

The addition amount of propranolol hydrochloride used in this comparative example was set to be 400 μg / cm ² (propranolol hydrochloride content 10%).

Comparative Example 4 Polymerization was carried out under the same conditions as in Example 3 except that N, N-dipropylaminobutylacrylamide was removed in Example 4, and the obtained pressure-sensitive adhesive solution (solid content concentration 40%) was treated with Add a mixture of clonidine hydrochloride, a hypertension drug, in methanol to mix it, and dry it on a polyester film to a thickness of 40
A pharmaceutical preparation was obtained by coating and drying so as to have a thickness of μm.

The amount of clonidine hydrochloride used in this comparative example was 60.
It was set to be 0 μg / cm ² (the content of clonidine hydrochloride was 15%).

With respect to the pharmaceutical preparations of Examples and Comparative Examples, the results of the tests on the solubility of the drug, the stability of the drug over time, the release of the drug, the skin adhesion, and the rash on the applied skin surface are shown as the first display.

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

<Drug solubility> Each sample piece cut into 3 cmφ was allowed to stand at a temperature of 25 ° C for 24 hours, and the presence or absence of drug crystals in each preparation was examined.

○: Dissolution ×: Crystal precipitation on the entire surface <Drug stability over time> Each sample piece cut into 3 cmφ was housed in an aluminum packaging material and sealed, and stored at temperatures of 25 ° C and 50 ° C for 1 month. After that, extraction with methanol was performed, and quantification was performed by high performance liquid chromatography.

<Drug Release> Each sample piece cut into 3 cmφ was attached to rat skin, and the drug release into the distilled water through the skin was measured. High-performance chromatography was used for the quantification, and the total amount of drug released in 24 hours was determined. The value of the corresponding comparative example was set to 1.0 and shown as a relative ratio.

<Skin Adhesion> Each sample piece (3 cmφ) was attached to the inside of the human upper arm, and after 24 hours, the state of adhesion to the skin was visually determined.

○: Adhesive area 90% or more ×: Adhesive area 50% or more and less than 90% <Skin rash> Each sample piece (3 cmφ) was attached to a human back for 24 hours and peeled off 1
The state of the skin after the lapse of time was visually determined, the scores were given as follows, and the average value of 10 persons was used for the determination.

○: Less than 1.0 points on average △: 1.0 points or more on average ×: 2.0 points or more on average 0 points: No reaction 0.5 points ... Slight erythema 1.0 points ... Erythema 2.0 points ... Erythema and papules or edema 3.0 points ... Erythema and edema Pimples or small chickenpox 4.0 points ... Large chickenpox From Table 1, the topical pharmaceutical preparation of the present invention has excellent properties in drug solubility, drug release and skin adhesiveness as compared with Comparative Examples, and moreover Also in terms of stability and skin rash, it is recognized that there is no difference compared to the comparative example.

(G) Effect of the Invention The external pharmaceutical preparation of the present invention has the above-mentioned constitution, and in particular, since the pressure-sensitive adhesive containing aminoalkyl (meth) acrylamide as a copolymerization component is used, the polarity of the pressure-sensitive adhesive is Is extremely high and the solubility of hydrophilic drugs is improved, and the stability of the drug over time is extremely high, the formulation is stable for a long period of time and has good storage stability, and it is safe with no skin rash and safe. Since the pressure-sensitive adhesive has high hydrophilicity, it has good adhesion (adhesiveness) to the skin and hydrophilicity, is easily compatible with water due to perspiration, improves the ODT effect, and ultimately has excellent drug release and skin permeability. It has an excellent effect.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Yusuke Ito 1-2, Shimohozumi, Ibaraki City, Osaka Prefecture Nitto Denki Kogyo Co., Ltd. (56) Reference JP-A-60-66759 (JP, A) JP 61-83119 (JP, A)

Claims (4)

[Claims] 1. A pharmaceutical preparation comprising a layer of a pressure-sensitive adhesive containing a drug on a flexible carrier, wherein the pressure-sensitive adhesive contains aminoalkyl (meth) acrylamide as a copolymerization component. A pharmaceutical preparation for external use characterized by being contained. 2. The pharmaceutical preparation for external use according to claim 1, wherein aminoalkyl (meth) acrylamide has a sum of carbon numbers of alkyl groups of 3 to 15. 3. The external pharmaceutical preparation according to claim 1 or 2, wherein the drug is a hydrophilic drug. 4. The pressure-sensitive adhesive has an alkyl group with 4 to 12 carbon atoms.
At least 50 (meth) acrylic acid alkyl esters
Claim 1 which is a copolymer which is contained by weight%.
The external pharmaceutical preparation according to any one of items 1 to 3.