JPH11189528A - Pharmaceutical preparation for application to skin improved in stability - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a pharmaceutical preparation for application to skin capable of formulating a drug unstable in a base in a stable state, excellent in storage stability and usable by a simple method. SOLUTION: This pharmaceutical preparation for application to skin is obtained by forming a drug layer and a base layer reactive with the drug in a separated state on a tacky tape and integrating the drug layer with the base layer at the time of the application to the skin for use. A supporting sheet 5 containing the drug (or a base) is placed on the tacky tape 4 and a container 2 prepared by filling the base (or the drug) 6 in a solution state therein and sealing the container 2 with a breakable sheet 3 is then placed thereon. The edge 7 of the container 2 is bonded to the edge of the tacky tape 4. When using the preparation, the sheet 3 is broken to impregnate the supporting sheet 5 with the solution in the container 2. The container 2 is peeled and the supporting sheet 5 containing the drug is subsequently applied to skin.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a two-layered preparation for skin application in which a base which reacts with a drug is separated from the drug, and which is used by integrating the drug layer and the base layer when applied to the skin.

[0002]

2. Description of the Related Art In the past, administration of drugs to humans has attempted to treat systemic and local diseases by various transdermal means. The dosage forms of these preparations include
There are ointments, liquids, patches, etc., but these dosage forms are unstable because the drug is contained in the base and the drug is easily decomposed by the reaction between the drug and the base component. For,
Many preparations have a short expiration date, and some drugs cannot be formulated because of insufficient stability.

[0003] Conventionally known bilayer preparations in which a drug and a base are separated for the purpose of drug stability include injections and acidic drugs which are used by dissolving the unstable drug in an aqueous solution at the time of use. Suppositories in two layers to suppress the reaction with basic drugs, and in a broader sense include dry syrup used for drugs that are unstable in aqueous solution, but there are no such formulations in skin application preparations. It was not possible to formulate a drug that would be unstable by reaction with the components.

Incidentally, there is a product (Japanese Utility Model Application Laid-Open No. 63-114626) whose shape is somewhat similar to the product of the present invention in an emergency bandage, but this product uses a drug solution dissolved in a base for the wound. In addition, a container for holding the drug solution by the time of use is attached to the bandage, and the drug solution is impregnated with gauze at the time of use. The purpose of this method is only to apply a drug in a solution state to the wound, and the purpose is clearly different from the product of the present invention. As a matter of course, in this emergency bandage system, since the drug is in the base solution, the stability of the drug reacting with the base component cannot be expected.

[0005]

DISCLOSURE OF THE INVENTION The present invention aims to solve the above-mentioned drawbacks of the conventionally known preparations for skin application, and aims at a drug which is conventionally unstable in a base. Is intended to be formulated in a stable state, to provide a preparation for skin application that can be used in a simple manner while ensuring the storage stability of the preparation.

[0006]

Means for Solving the Problems The present invention relates to a preparation for skin application, in which a base layer that reacts with a drug is formulated in a state separated from the drug layer, and the stability of the preparation during manufacture and storage is ensured. In addition, the present invention relates to a preparation that uses a drug layer and a base layer integrally when applied to the skin. The first type of the skin application preparation of the present invention is a solid-state drug layer A containing a drug (A ₁ ) or a drug (A ₂ ) and a base that does not react with the drug, on an adhesive tape.
And a base layer B in the form of a solution containing a base that reacts with the drug. The base layer B is a skin application preparation in which the drug layer A and the base layer B are integrated and used when applied to the skin. The second type of skin application preparation of the present invention comprises a base layer C in a solid state containing a base that reacts with a drug on an adhesive tape.
And a drug layer D in the form of a solution containing the (D ₁ ) drug or the (D ₂ ) drug and a base that does not react with the drug are provided separately, and the base layer C and the drug layer D are integrated when applied to the skin. It is a skin application preparation that is used in the form of a skin. In the above-mentioned preparation for skin application, it is preferable to use a carrier sheet carrying a drug and / or a base for the drug layer A and the base layer C in a solid state. Further, the base layer B and the drug layer D in a solution state
Is preferably placed on a tape in a state where it is separated from the drug layer A and the base layer C in a solid state by being enclosed in a breakable container. All of the above-mentioned skin application preparations of the present invention are two-layer preparations in which a drug layer and a base layer are separately provided on an adhesive tape, and there is no reaction between the drug and the base component until use, and The drug is stable and can be used in a simple manner when applied to the skin.

The adhesive tape used in the present invention includes, in addition to so-called non-aqueous adhesives such as acrylic, silicone, isoprene, polyisobutylene and vinyl, polyacrylic acid and metal salts thereof. An aqueous pressure-sensitive adhesive containing a water-soluble polymer can also be used.

The solid phase of the present invention includes a woven fabric, a nonwoven fabric,
A carrier sheet such as a cloth such as flannel, sponge, absorbent cotton, or gauze can be used. In addition, in order to prevent the exudation of the solution impregnated in these support sheets, gelatin, carboxymethylcellulose, methylcellulose, polyvinyl alcohol, poly-N-vinylacetamide, polyacrylic acid and metal salts thereof are used in advance. A metal cross-linking agent such as a water-soluble polymer, synthetic aluminum silicate, aluminum hydroxide gel, or zinc oxide is contained so that a drug layer or a base layer in a solution state can be rapidly gelled.

In the present invention, the base layers in the solid state and in the solution state include water, surfactants such as polysorbates, sucrose fatty acid esters, polyoxyethylene alkyl ethers, glycerin, butylene glycol, sorbitol, Polyhydric alcohols such as propylene glycol,
Ethanol, isopropyl alcohol, benzyl alcohol, phenylethyl alcohol, alcohols such as butanol, gelatin, carboxymethylcellulose, polyvinylpyrrolidone, polyacrylamide, hydroxyethylcellulose, methylcellulose, polyvinyl alcohol, N-vinylacetamide polymer, polyacrylic acid and these Water-soluble polymers such as metal salts, synthetic aluminum silicate, aluminum hydroxide gel, metal cross-linking agents such as zinc oxide, and various (meth) acrylate-based tackifiers containing alkyl (meth) acrylate as a main component Rubber-based tackifying substances such as silicone rubber, polyisoprene rubber, and natural rubber; vinyl-based tackifying substances such as polyvinyl acetate and polyvinyl alcohol; l, dl-menthol, l, dl Camphor, peppermint oil, essential oil component of peppermint water or the like, organic acids, organic bases, inorganic acids, p such inorganic bases
An H adjuster and other components that can serve as drug solubilizers such as crotamiton, N-methylpyrrolidone, cetyl lactate, liquid paraffin, and urea, stabilizers, humectants, keratin softeners, or absorption promoters can be added.

[0010] The drug used in the present invention includes a drug which is susceptible to a hydrolysis reaction, an oxidation reaction and the like by water in a base;
Drugs that decompose by the reaction of base components other than water (eg, esterification) and drugs that are unstable in the acidity (pH) of the base can also be used. Specifically, drugs that are susceptible to hydrolysis by water include salicylic acid esters having an ester bond, an ether bond, an amide bond, and the like in the molecule, inflammation analgesics such as indomethacin, piroxicam, and tenoxicam, and azelastine hydrochloride and the like. Antiarrhythmic drugs, antiarrhythmic drugs such as atenolol, alprenolol hydrochloride, arotinolol hydrochloride, indenolol hydrochloride, oxprenolol hydrochloride, carteolol hydrochloride, bucmorol hydrochloride, propranolol hydrochloride, nadolol, pindolol, bisoprolol fumarate, and timolol maleate;
Prazosin hydrochloride, reserpine, nilvadipine, felodipine, nicardipine hydrochloride, nicorandil, pindolol, valnidipine hydrochloride, lisinopril, delapril hydrochloride, quinapril hydrochloride, nisoldipine, bopindolol malonate, bunazosin hydrochloride, cilazapril, benazepril hydrochloride, imidaprizine hydrochloride, nitridene dimelidene Betaxolol hydrochloride, trandolapril,
Alacepril, temocapril hydrochloride, nifedipine, antihypertensive drugs such as benidipine hydrochloride, carvedilol, enalapril maleate, cardiovascular drugs such as vinpocetine, nicergoline, diabetes drugs such as glibenclamide, antiparkinson drugs such as bromocriptine mesylate, nifedipine and the like Vasodilators, flurazebam, oxazepam, zopiclone, tandospirone citrate, rilmazahon hydrochloride, lorazepam, lormetazepam, haloxazolam, prazepam, oxazolam, cloxazolam, etc.Anesthetic / hypnotic sedatives, methylanisotropine bromide, methylatropine bromide, bromide Butylscopolamine, N-methylsulfolamine methylsulfate, anticonvulsants such as atropine sulfate, antiepileptics such as clonazepam, antipsychotics such as nemonapride, pimozide, risperidone, Inotropic agents such as Mobendan, mention may be made of hyperlipidemia for medicine such as pravastatin and the like. Drugs that are easily oxidized by water in the base include ketones, hydroxyl groups, double bonds, triple bonds, ketoprofen having an amino group, etc., anti-inflammatory analgesics such as loxoprofen sodium, eperisone hydrochloride, tolperisone hydrochloride, hydrochloric acid Antispasmodic agents such as tizanidine, bromperidol, etizolam, haloperidol, fluphenazine, perphenazine, antipsychotics such as etizolam, thiothixene, timiperone, peptic ulcer drugs such as famotidine, estazolam, alprazolam, diazepam, triazolam, nitrazepam , Nimetazepam, Fludiazepam, Medazepam, Anti-anxiety / hypnotic sedatives such as lorazepam, perlapine, flurazepam, antiallergic drugs such as ketotifen fumarate, piperidene hydrochloride, talipexol hydrochloride, trihexyphenidyl hydrochloride, salt Antiparkinsonian agents such as Pirohepuchin, cardiotonics such as denopamine, mention may be made of terbutaline sulfate, salbutamol sulfate, bronchodilators such as procaterol hydrochloride. Examples of the drug which is easily decomposed by a reaction such as esterification with a component in the base include anti-inflammatory analgesics such as flurbiprofen and diclofenac sodium having a carbonyl group or the like in the molecule.

[0011] The material of the container in which the drug or the base in the solution state is to be put is plastic, such as polyethylene, polypropylene, polystyrene, vinyl chloride resin, polyethylene terephthalate, acrylic resin, and fluorine resin, as well as aluminum, stainless steel, and the like. Glass, paper, etc. can be used.

[0012]

Hereinafter, the present invention will be described specifically with reference to Examples and Comparative Examples. Note that the present invention is not limited to the following embodiments. FIG. 1 is a perspective view of an embodiment of the skin application preparation of the present invention, FIG. 2 is an exploded view thereof, and FIG. 3 is a sectional view thereof. 4 (a) to 4 (d) are explanatory diagrams of a method of using the skin application preparation of the present invention. Figures 1-4
In the formula, 1 is a preparation for skin application, 2 is a container, 3 is a breakable sheet, 4 is an adhesive tape, 5 is a solid phase, 6 is a liquid phase enclosed in the container, 7 is an edge of the container, and 8 is a container. , 9 is the adhesive surface of the adhesive tape, 10 is the protective surface of the adhesive tape, and 11 is the skin surface.

The container 2 is preferably formed by molding a film of a thermoplastic resin such as polyethylene or polypropylene by means of vacuum forming or the like to form a cavity into which a solution can enter. The internal volume of the container is appropriately determined according to the amount of the drug, the base, or the amount of the drug and the base enclosed in the container. The container 2 may have an arbitrary shape such as a dome shape or a trapezoidal shape, but it is preferable to provide a notch 8 for breaking the sheet 3 sealing the container in use. In the figure, a vertical / horizontal cross-shaped notch is provided, but the notch may be one in the vertical or horizontal direction.
May be provided with one conical notch. After filling the container 2 with the solution 6 containing the drug and / or the base,
Sheet 3 that can break the four edges 7 of the container such as aluminum foil
And sealed. On the other hand, the solid phase 5 containing the drug and / or the base is placed on the adhesive surface 9 of the adhesive tape 4, and the container 2 is placed thereon with the sheet 3 sealing the mouth of the container facing down. Then, the four edges of the adhesive tape 4 having no solid phase portion and the four edges of the sheet 3 are bonded to each other. In use, when the sheet 3 is broken and the solution in the container is transferred to the solid phase 5, the vertical and horizontal dimensions of the solid phase 5 are adjusted so that the solution does not protrude from the solid phase. It is better to make it slightly larger than the vertical and horizontal dimensions of the part.

When the skin application preparation of the present invention is used, as shown in FIG. 4A, the container 2 is pushed in the direction of the arrow with a finger, and the skin application preparation is slightly bent along the notch 8 at that time. The sheet 3 is broken by the notch 8, and the solution in the container 2 is moved to the solid phase 5 ((b) in FIG. 4). After the solution is impregnated into the solid phase 5, the adhesive tape 4 is peeled off from the sheet layer 3 as shown in FIG. 4C, and contains the drug and the base as shown in FIG. The solid phase 5 is applied to the skin surface.

Example 1 0.09 g of sodium polyacrylate and 0.05 of dry aluminum hydroxide gel
g in ethanol 1 ml, size 40 mm x 50
mm and a 1 mm thick nonwoven fabric, and dried at room temperature with ethanol. Next, ketotifen fumarate 0.01 g
Was dissolved in 1 ml of ethanol, soaked in the nonwoven fabric, and ethanol was dried at room temperature to form a drug layer. Also, 0.006 g of tartaric acid was dissolved in 1 ml of water: glycerin (7: 3), placed in a polyethylene container, and the aluminum foil was heat-sealed to form a base layer. The drug layer was affixed to an adhesive tape, and the aluminum foil surface of the base layer was further affixed to the adhesive tape so as to coincide with the drug layer, thereby obtaining a sample.

Example 2 0.09 g of sodium polyacrylate and 0.05 of dry aluminum hydroxide gel
g in ethanol 1 ml, size 40 mm x 50
mm and a 1 mm thick nonwoven fabric, and dried at room temperature with ethanol. Next, 0.01 g of nicardipine hydrochloride was dissolved in 1 ml of ethanol, soaked in the nonwoven fabric, and ethanol was dried at room temperature to form a drug layer. Also, 0.006 g of tartaric acid was dissolved in 1 ml of water: glycerin: methylpyrrolidone (5.5: 3: 0.2), placed in a polyethylene container, and heat-sealed the aluminum foil to form a base layer. Thereafter, the same treatment as in Example 1 was performed to obtain a preparation for skin application.

Example 3 0.09 g of sodium polyacrylate, 0.05 g of talc, and 0.05 g of dried aluminum hydroxide gel were dispersed in 1 ml of ethanol, and the resultant was impregnated into a nonwoven fabric having a size of 40 mm × 50 mm and a thickness of 1 mm. To dry the ethanol at room temperature. Next, 0.01 g of methyl salicylate was dissolved in 1 ml of ethanol, soaked in the nonwoven fabric, and ethanol was dried at room temperature to form a drug layer. Thereafter, the same treatment as in Example 1 was performed to obtain a preparation for skin application.

<Comparative Example 1> 0.6 g of tartaric acid was dissolved in 58.35 ml of water to make it tartaric acid, and 1 g of ketotifen fumarate was added and dissolved. Separately, 9 g of sodium polyacrylate was added to 30 g of glycerin for swelling, and the above-mentioned aqueous solution of ketotifen fumarate was added and kneaded well to prepare a mixed solution containing ketotifen fumarate. Then 1g of water
Suspended 0.05 g of dried aluminum hydroxide gel, and added to the ketotifen fumarate-containing suspension and kneaded well,
A plaster containing 1% ketotifen fumarate was obtained. The obtained 1% ketotifen fumarate-containing plaster was 7 g / 10 cm ×
It was plastered on a non-woven fabric so as to have a size of 14 cm, a polyethylene film was laminated, and cut into a size of 40 mm × 50 mm to obtain a specimen.

Comparative Example 2 Tartaric acid (0.6 g) was dissolved in water (58.35 ml). Separately, 1 g of nicardipine hydrochloride was added to and dissolved in 2.0 g of methylpyrrolidone. Separately, 9 g of sodium polyacrylate was added to 30 g of glycerin to swell, the above-mentioned nicardipine hydrochloride methylpyrrolidone solution was added, and the mixture was sufficiently kneaded. Then, the above-mentioned aqueous solution of tartaric acid was further mixed to prepare a mixed liquid containing nicardipine hydrochloride. Then 1g of water
And 0.05 g of dried aluminum hydroxide gel is suspended in the suspension, added to the suspension containing nicardipine hydrochloride, kneaded well, and mixed with 1%
A plaster containing nicardipine hydrochloride was obtained. Hereinafter, the same treatment as in Comparative Example 1 was performed to obtain a preparation for skin application.

Comparative Example 3 Tartaric acid (0.6 g) was dissolved in water (45.85 ml). Separately, 1 g of methyl salicylate was added to 5 g of talc and kneaded, and then added to 9 g of sodium polyacrylate and 30 g of glycerin to swell. Next, the above-mentioned aqueous solution of tartaric acid was mixed to prepare a mixed liquid containing methyl salicylate. Next, 0.05 g of dried aluminum hydroxide gel was suspended in 1 g of water, and the suspension containing methyl salicylate was added to the suspension and kneaded well to obtain a paste containing 1% methyl salicylate. Hereinafter, the same treatment as in Comparative Example 1 was performed to obtain a preparation for skin application.

Comparative Example 4 0.09 g of sodium polyacrylate and 0.05 of dry aluminum hydroxide gel
g in ethanol 1 ml, size 40 mm x 50
mm and a 1 mm thick nonwoven fabric, and dried at room temperature with ethanol. Next, ketotifen fumarate 0.01 g
And 0.006 g of tartaric acid in water: glycerin (7: 3)
The solution was dissolved in 1 ml, placed in a polyethylene container, and the aluminum foil was heat-sealed. The nonwoven fabric was attached to an adhesive tape, and a polyethylene container containing a drug solution was attached to the adhesive tape so that the aluminum foil surface coincided with the nonwoven fabric.

Comparative Example 5 0.09 g of sodium polyacrylate was dispersed in 1 ml of ethanol, and the size was 40 m.
The resultant was impregnated into a nonwoven fabric having a size of 50 mm and a thickness of 1 mm, and ethanol was dried at room temperature. Next, nicardipine hydrochloride 0.0
1 g and tartaric acid 0.006 g were dissolved in 1 ml of water: glycerin: methylpyrrolidone (5.5: 3: 0.2). Thereafter, the same treatment as in Comparative Example 4 was performed to obtain a preparation for skin application.

Comparative Example 6 0.09 g of sodium polyacrylate and 0.05 g of talc were mixed with 1 ml of ethanol.
And ethanol was dried at room temperature by infiltrating into a nonwoven fabric having a size of 40 mm × 50 mm and a thickness of 1 mm. Next, 0.01 g of methyl salicylate and 0.006 g of tartaric acid
Was suspended in 1 ml of water: glycerin (7: 3). Less than,
The same treatment as in Comparative Example 4 was performed to obtain a preparation for skin application.

<Test Examples> Examples 1 to 3 and Comparative Examples 1 to
The sample obtained in 6 was subjected to 40 ° C., 6
After storage for a period of months, the residual amount of the drug was measured. The results are shown in Table 1. Table 1 Stability test (40 ° C, 6 months) 検 体 Sample Drug residual rate ─────────── ─────────── Example 1 99.9% Example 2 98.7% Example 3 99.7% Comparative Example 1 24.2% Comparative Example 2 27.2% Comparative Example 30 % Comparative Example 4 23.8% Comparative Example 5 26.8% Comparative Example 60% ────────────────────── As is clear from Table 1, It can be seen that Examples 1 to 3 have a higher residual ratio of the drug than Comparative Examples 1 to 3, which are preparations containing a drug in the base, similarly to the conventional skin application preparation. Comparative Examples 4 to 6 are described in Japanese Utility Model Laid-Open No. 63-114626.
However, this formulation has low drug stability and cannot be formulated.

[0025]

Industrial Applicability According to the present invention, it is possible to formulate a drug which has been difficult to formulate due to the reaction with the base component, and it is possible to extend the expiration date of a conventional formulation having a short expiration date. It has become possible.

[Brief description of the drawings]

FIG. 1 is a perspective view of one embodiment of the skin application preparation of the present invention.

FIG. 2 is an exploded view of FIG.

FIG. 3 is a sectional view of FIG. 2;

FIG. 4 is an explanatory diagram of a method for using the skin-suitable preparation of the present invention.

[Explanation of symbols]

 1. 1. Skin preparation Container 3. 3. Breakable sheet Adhesive tape 5. Solid phase 6. 6. Liquid phase enclosed in container 7. Edge of container 8. Notch provided on container 9. Adhesive surface of adhesive tape 10. Protective surface of adhesive tape Skin surface

Claims (6)

[Claims] 1. A solid phase drug layer A containing a drug (A ₁ ) or a drug (A ₂ ) and a base that does not react with the drug, and a base in a solution state containing a base that reacts with the drug. A preparation for skin application wherein the agent layer B is provided in a separated state, and the drug layer A and the base layer B are used integrally when applied to the skin. 2. A base layer C in a solid state containing a base that reacts with a drug on an adhesive tape and a drug (D ₁ ) or (D ₂ )
A skin application preparation in which a drug layer D in a solution state containing a drug and a base that does not react with the drug is provided in a separated state, and the base layer C and the drug layer D are used integrally when applied to the skin. 3. The base is water, a surfactant, a monohydric alcohol, a polyhydric alcohol, a water-soluble polymer, a fat-soluble polymer, a pH adjuster, an inorganic dispersant, an essential oil, a metal cross-linking agent, and an adhesive. The preparation for application to the skin according to claim 1 or 2, wherein the preparation is selected from one or more of the imparting substances. 4. A carrier sheet selected from cloth, sponge, absorbent cotton, and gauze is used for the solid phase layer.
Or the preparation for application to the skin according to 2 above. 5. The preparation for skin application according to claim 1, wherein the layer in a solution state is enclosed in a container which can be broken. 6. The preparation according to claim 1, wherein the base is water and the drug is a drug that reacts with water.