JPS62198613A - Plaster - Google Patents

Abstract

PURPOSE:To provide a plaster having a three-layer structure composed of a drug-storage layer, an assistant layer and a substrate layer and capable of surely and effectively administering a proper kind of drug at a sufficient amount according to the purpose of treatment. CONSTITUTION:The objective plaster is composed of (A) a drug-storage layer composed of a water-containing hydrophilic polymer matrix containing a drug (e.g. anti-inflammatory agent, a local anesthetic, a hypotensor, a hypotensive diuretic, etc.), its dissolving agent and transcutaneous absorbefacient, (B) an assistant layer laminated to said drug-storage layer and composed of a water- containing hydrophilic polymer matrix at least containing a transcutaneous absorbefacient and free from the dissolving agent of the above drug and (C) an air-permeable substrate layer (e.g. porous synthetic resin film, paper, nonwoven fabric, etc.) bonded to the assistant layer. If necessary, various components such as plasticizer, dispersing agent, stabilizer, etc., may be added to the matrix forming the above drug-storage layer and the assistant layer.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a patch, and more particularly to a patch for transdermally administering a drug.

[Prior art and its problems]

Conventionally, as external preparations applied to the skin, ointments,
Liquid agents, poultices, plasters, etc. are known. All of these external preparations were intended to have a therapeutic effect through absorption of the drug in the local affected area, and were mainly used for drugs with anti-inflammatory, antibacterial, antipruritic, and antiallergic effects. . However, in recent years, drugs that have a large first-pass effect on the liver when administered orally,
External preparations, which had previously been used only for localized diseases, have been taken up as a form of administration that aims to improve the bioavailability of drugs that tend to cause gastrointestinal disorders or that are easily degraded in the gastrointestinal tract by digestive juices. A so-called transdermal absorption therapeutic system is being developed, which is expected to have systemic effects through transdermal absorption of drugs.

The ideal conditions for external preparations intended for transdermal absorption are:
In general, ■ Even a trace amount of drug is absorbed efficiently and there is little drug remaining in the base; ■ The release rate and release time of the drug can be controlled; and ■ It can be applied repeatedly to the same site. The drug is less irritating to the skin and does not cause side effects such as rashes or rashes; (1) the dosage can be determined accurately; and (2) the drug is stably retained in the base for a long period of time. Among external preparations, the dosage of ointments and the like varies depending on the area and thickness to which they are applied, making it difficult to determine the exact dosage. On the other hand, among external preparations, patches have fewer of the above-mentioned drawbacks than ointments and the like, so they are used for transdermal absorption of drugs such as nitroglycerin and scopolamine, and are already being used in actual medical care. Some examples of these commercially available adhesive patches include one in which a diffusion matrix of cross-linked silicone polymer is impregnated with nitroglycerin, and one in which a viscous silicone liquid contains a drug and controls the drug release rate. There are those that use a porous membrane, and those that contain drugs in a gel diffusion matrix made of polyvinyl alcohol, polyvinylpyrrolidone, and glycerol water.

However, all of these conventional patches are so-called monolithic preparations, which rely solely on diffusion for drug release energy. Monolithic adhesive patches contain a drug with a saturation solubility or higher in a single polymer matrix, and the drug is released by diffusion through the solubilizing agent in the polymer matrix. In the case of water-soluble drugs, they are blended directly into a polymer matrix in powder form or dispersed in the form of a coprecipitate with a polymer compound; Even if the matrix does not contain water, when applied to the skin, water penetrates into the matrix due to TWL (insensible transpiration) of the skin, dissolves the drug, and the drug is transferred to the skin by diffusion. It is supposed to be done. Therefore, this type of patch has various points of interest, such as primary.

a. Energy for drug release is small.

b. In order to increase the efficiency of drug release, it is necessary to make the matrix as thin as possible; however, if the matrix is made too thin, it becomes difficult to incorporate a sufficient amount of drug to obtain a sufficient therapeutic effect.

In order to reduce the thickness of the C0 matrix as much as possible and obtain a drug dose sufficient to achieve a sufficient therapeutic effect, it is necessary to increase the area of application to the skin, and in some cases it is necessary to apply a patch all over the body. It's necessary and bothersome.

d. If the drug concentration in the 71-rix is increased to create a large concentration gradient, it becomes difficult to incorporate sufficient drug absorption-promoting ingredients, and the adhesion of the matrix to the skin decreases, making it difficult to function as a patch. In addition, there is a risk that the
Above a certain concentration, there is a region where dose dependence does not hold, so there is a risk that the drug will be wasted, and ultimately it cannot be used for anything other than the administration of a drug that only requires administration in a very small amount.

[Objective of the Invention] The object of the present invention is to fully satisfy the above-mentioned ideal conditions for a patch intended for transdermal absorption, and to efficiently administer a drug of the appropriate type and sufficient amount depending on the therapeutic purpose. Another object of the present invention is to provide a patch that can be administered reliably.

[Structure of the invention]

In order to achieve the above object, the present invention comprises laminating an auxiliary layer consisting of a hydrophilic polymer matrix on a drug storage layer consisting essentially of a hydrophilic polymer matrix containing water, and further providing an air-permeable support for the auxiliary layer. The layers are pasted together to form a three-layered patch, and the contraction of each matrix and changes in the system caused by the evaporation of moisture in the drug storage layer and auxiliary layer to the outside world through the support layer are used to release the drug. The main point is to be able to achieve efficient and reliable release of That is, the patch of the present invention includes a drug storage layer made of a water-containing hydrophilic polymer matrix containing at least a drug, its solubilizer, and a transdermal absorption enhancer; It is characterized by comprising an auxiliary layer made of a water-containing hydrophilic polymer matrix that contains an accelerator but does not contain a solubilizer for the drug, and a support layer that is bonded to this auxiliary layer and has air permeability.

More specifically, the adhesive patch of the present invention has a three-layer structure consisting of a drug storage layer 1, an auxiliary layer 2, and a support layer 3, as shown in the drawings.

The drug storage layer 1 is applied to the skin surface, and is preferably a sheet-like water-containing hydrophilic polymer matrix in which a drug, its solubilizer, transdermal absorption enhancer, etc. have formed a stable dispersion system, and is preferably The main ingredient is a viscous substance obtained by dissolving or swelling a seed or two or more hydrophilic polymer compounds in water, and the substance itself is made of a matrix that is adhesive to the skin. An auxiliary layer 2 is laminated on the back side of the drug storage layer 1, that is, on the side opposite to the side to be applied to the skin. The auxiliary layer 2 is made of a sheet-like hydrophilic polymer matrix, which also contains a transdermal absorption enhancer and the like in a stable dispersion system. The hydrated hydrophilic polymer matrix constituting the auxiliary layer 2 can be a hydrated hydrophilic polymer matrix that is substantially the same as or similar to the drug storage layer 1;
In this invention, it is important that the auxiliary layer 2 does not contain a drug solubilizer. If the auxiliary layer 2 contains the above-mentioned solubilizing agent, the drug in the storage layer 1 will diffuse into the auxiliary layer 2,
The drug concentrations in storage layer 1 and auxiliary layer 2 become equal, and the concentration gradient thereof decreases. Therefore, the liquid component such as a plasticizer contained in the auxiliary layer 2 is selected so that it does not dissolve the drug when added.

The hydrophilic polymer 71-lix constituting the drug storage M1 and the auxiliary M2 needs to contain water. The water content is based on the drug and its solubilizer,
Although it depends on the amount and type of transdermal absorbent, hydrophilic polymer, etc., it is preferably 40 to 90% by weight, more preferably 50 to 85% by weight. When the water content is low.

This is undesirable because the shrinkage rate of the matrix due to water evaporation decreases, and the drug release force decreases.

Further, each of the drug storage layer 1 and the auxiliary layer 2 may be formed into two or more layers. For example, when the drug storage layer 1 itself has different drug concentrations, or when two or more types of drugs are mixed, it is useful to form the drug storage layer 1 into two or more layers.

The method of laminating the auxiliary layer 2 to the drug storage layer 1 is not particularly important in this invention.

The matrix forming the drug storage layer 1 and the auxiliary layer is
Both are hydrophilic polymer matrices that contain water and have a certain degree of mutual adhesion, so they can be simply overlapped, and if necessary, an adhesive component can be added to both or one of the storage layer 1 and the auxiliary FvJ2. Alternatively, the laminated state may be maintained using, for example, an adhesive tape. Furthermore, during storage before actually applying it to the skin,
The drug storage layer 1, the auxiliary layer 2, and the support layer 3 may be stored separately and laminated for use during actual application.

On the back side of the auxiliary layer 2 laminated on the drug storage layer 1, a support layer 3 having air permeability is further laminated. This support layer 3 functions to enable the evaporation of moisture in the storage layer 1 and the auxiliary layer 2 and to control the evaporation rate, and is made of cloth, nonwoven fabric, paper, synthetic resin film, etc. depending on the purpose. can be selected arbitrarily. The material itself may not have air permeability, or it may be made porous to provide air permeability, or it may be made by laminating two or more materials as required.

The hydrophilic polymer compound forming the polymer matrix of the drug storage layer 1 and the auxiliary layer 2 of the present invention is a hydrophilic polymer compound whose stability has been confirmed and is commonly used in pharmaceuticals, cosmetics, foods, etc.

Any material that can react with water to form a pasty or gel-like matrix can be used. Examples of such hydrophilic polymer compounds include polyacrylic acid and its salts, carboxyvinyl polymer,
Examples include carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, alginic acid and its salts, gelatin, starch, agar, and dextrin.

The hydrophilic polymer compound is not limited to one type, but two or more types can be used, and the same or similar types of hydrophilic polymer compounds can be used for the storage layer 1 and the auxiliary layer 2. However, different types may be used as required.

Any transdermal absorption enhancer used in the drug storage layer 1 and auxiliary layer 2 of the present invention can be used as long as it is effective in promoting transdermal absorption of the drug used. It is also possible to use two or more types of components, or to use different types of components for the storage layer and the auxiliary layer, if necessary. Examples of such transdermal absorption enhancers include urea, diisopropyl adipate, diethyl adipate, diethyl sebacate, isopropyl myristate, isopropyl palmitate, octyldodecyl oleate, isostearyl alcohol, 2-offtyldodecal, and glycerin. Alcohols such as fatty acid esters, esters, vegetable oils, animal oils, mineral oils, etc. In that case, the water-insoluble transdermal absorption enhancer is
A suitable surfactant is added and emulsified to form a stable dispersed phase in the matrix.

The drug used in this invention is not particularly limited as long as it is transdermally absorbed, and this includes both locally applied drugs and systemically applied drugs. Drugs that are applied locally are expected to primarily exert local medicinal effects.

Traditionally used skin disease treatment drugs, anti-inflammatory analgesics,
Antipruritics, local anesthetics, and antibacterial agents can be used. Also,
Systemically applied drugs are drugs that are expected to have a systemic effect; for example, they are absorbed through the skin where they are applied,
It is a drug that reaches tissues and organs within the body through the blood and exerts its medicinal effects. Specific examples of some of these drugs are as follows.

Anti-inflammatory analgesics: acetaminophen, aspirin, salicylic acid, methyl salicylate, glycol salicylate, Q
- Menthol, camphor, mefenamic acid, flufenamic acid, indomethacin, dizolofenac, ibuprofen, ketoprofen, naproxen, pranoprofen, fenoprofen, salindac, flurbiprofen, piroxicam, phenylbutacin, mepisozole, etc.

Steroid anti-inflammatory agent: Hydrocortiscin.

Prednisolone, dexamethasone, doriamcilone acetonide, fluocinolone acetonide, fludrocorchicin acetate, etc.

Antihistamines: chlorpheniramine, glycyrrhizic acid, diphenhydramine, periactin, etc.

Local anesthetics: Benzicaine, prophylaxis, cephalosporin antibiotics Antibacterial agents: antifungal agents, antifungal agents, tetracyxon antibiotics, aminoglycoside antibiotics, macrolide antibiotics, chloramphenicol, sulfonamides,
such as phenols.

Antihypertensive agents: clonidine, alpha-methyldopa, reserpine, cillongopine, recinamine, cinnarizine, hydrazine, prazosin, etc.

Antiarrhythmic agents: ginidine, lidocaine, protymamide, cymbramide, etc.

Hypotensive drugs: hydralazine, etc.

Antihypertensive diuretics: theophylline, trichloromethiazide,
Furosemide, trivacide, methyclothiazide, penflucito, hydrothiazide, spironolactone, metolazone, etc.

β-blockers: pindolol, propranolol, etc.

Calcium antagonists: diltiazem, nifedipine, nicardipine, verapamil, benzicran, dirazep, etc.

Antiepileptic drugs: nitrazebam, mebrobamate, phenytoin, etc.

Anti-vertigo drugs: isoprenaline, betahistine, sufvoramine, etc.

Sedatives and hypnotics: phenobarbital, secobarbital, cyfrobarbital, amobarbital, etc.

Tranquilizers: chloropromacin, promacin, prochlorperazine, reserpine, mebrobamate, benzocyasebins, etc.

Respiratory agents: Codin, ephedrine, isoproterenol.

Two or more of the above drugs can be used in combination if necessary. The amount of compounding is sufficient as long as the amount is sufficient for the medicinal efficacy to be exerted, and in most cases, the amount is about 0.1 to 10.0% by weight based on the hydrophilic polymer matrix, but depending on the type of drug, The amount can be increased or decreased as appropriate depending on the therapeutic purpose or the severity of the disease. Furthermore, in the case of a drug that is poorly soluble in water, it is preferable to add, for example, a surfactant and emulsify and disperse it in the matrix.

In the patch of the present invention, a plasticizer is optionally added to the matrix forming the drug storage layer 1 and/or the auxiliary layer 2 to impart or enhance the plasticity of the matrix, or to prevent deterioration by microorganisms. Preservatives and other ingredients having functions such as preservatives can be added. Examples of the plasticizer include propylene glycol, glycerin, 1,3-butylene glycol, polyethylene glycol, etc., and the amount added is within a range that does not impair the quality of the patch, preferably less than 25% by weight. be. Its excessive addition causes the matrix to become a hard thin film when the water in the 7 Trix evaporates.
There is a risk that the adhesion to the skin will be reduced, and the matrix will lose its flexibility, resulting in a reduction in the shrinkage rate of the matrix. Therefore, if the liquid component such as the absorption enhancer or solubilizer is selected from components that act as a plasticizer for the matrix, it is not necessary to add a plasticizer. The preservatives include, for example, paraoxybenzoic acid alkyl esters (parabens), sorbitanic acid, dehydroacetic acid, etc., and the amount added thereof can be, for example, 0.01 to 2.0% by weight of the entire matrix. . Furthermore, in this invention, the drug storage layer 1
And/or in order to improve the shape retention of the water-containing matrix forming the auxiliary layer 2, a crosslinking agent for the hydrophilic polymer matrix can be added.

In particular, various aluminum salts for -COOH groups in the functional groups of hydrophilic polymers are effective in improving the shape retention of the matrix.

When storing the patch of the present invention before actually applying it to the skin, it is preferable that the surface of the drug storage RWJ 1 on the side to be applied to the skin is removably covered with a film or film 4 such as a plastic film. preferable. If drug storage layer 1, auxiliary layer 2, and support layer 3 are to be stored separately, each must be stored confidentially in a non-porous material such as aluminum foil, and must be stored for a long period of time. The same applies when doing so.

[Effect]

Since the adhesive patch of this invention is constructed as described above,
When the drug reservoir layer is applied to the skin, the water in each matrix forming the drug reservoir layer and the auxiliary layer laminated thereto evaporates through the support layer due to body temperature. As water evaporates, the stable dispersion system of each matrix changes, especially the transdermal absorption enhancer in the drug storage layer, the solubilizing agent dissolving the drug, and the transdermal absorption enhancer in the auxiliary layer. The liquid component separates from each matrix, and each matrix itself contracts, facilitating separation of the liquid component from the matrix. In this case, the liquid component of the drug reservoir tries to separate both into the skin-contacting surface of the matrix forming the drug-reservoir layer and the opposite side; is laminated with an auxiliary layer,
Moreover, since the auxiliary layer does not contain a drug solubilizer but contains a transdermal absorption enhancer, the auxiliary layer prevents the separation to the opposite side, and the liquid component in the auxiliary layer is instead transferred to the drug storage layer. Visit the temple. At the same time, even drugs that are insoluble or sparingly soluble in water increase in solubility and become soluble as the water content decreases. As a result, the separated drug-containing liquid component of the drug storage layer is blocked from entering the opposite side, enters the skin-contacting surface, and is efficiently absorbed into the skin surface. In addition, since the evaporation of water in the drug storage layer and the auxiliary layer, the contraction of the polymer matrix, the separation of liquid components, and the resulting separation of the drug are each phase-related, the rate of water evaporation depends on the rate of water evaporation in the matrix. The rate of contraction changes, and even the rate of separation of the drug.

Therefore, in this invention, there are multiple rate-limiting means: drug separation rate, i.e., drug release rate - polymer matrix contraction rate - water evaporation rate.
This allows for fine control of the drug release rate.

〔Example〕

Add 0.2 g of aluminum hydroxide gel, 0.3 g of hydroxypropyl methyl cellulose, 1.5 g of sodium carboxymethyl cellulose, 0.5 g of carboxyvinyl polymer, and 3.5 g of sodium polyacrylate to 65 g of distilled water while stirring with a high-speed stirrer. The mixture is added and mixed to obtain a paste-like hydrophilic polymer composition. Separately, prepare a dispersion by adding 1.5 g of propranolol to 1.5 g of propylene glycol while stirring at 37°C, add this dispersion to the above hydrophilic polymer composition, and knead further with a kneader. . Subsequently, in order to adjust the pH of the above composition to around 6, 1.5 g of lactic acid was added little by little and kneaded, and then 0.5 g of polyoxyethylene sorbitan tetraoleate and 0.5 g of sorbitan monooleate were added to 10 g of octyldodecanol. The added solution is added to the above composition adjusted to around P116 and kneaded. 6g of produced polymer composition
The sample was poured into a frame with a thickness of 1.0 cm and a diameter of 8.0 cm, and compressed from both sides to prepare a disk of uniform thickness, which was used as a drug storage layer. Next, the preparation method was the same as that described above, except that the drug propranolol was not added and glycerin was used instead of propylene glycol, and a thickness of 1 mm was prepared.
A disk of uniform thickness with a diameter of 8 cm is prepared and used as an auxiliary layer. Then, the drug storage layer and the auxiliary layer were laminated together, and a support was further laminated with a nonwoven fabric made of a mixture of polyester and rayon and a polyethylene film, and fine pores were formed to have an air permeability of 70 cc/a&/see. was attached to one side of the auxiliary layer, and then the surface of the drug storage layer on the side to be applied to the skin was covered with a peelable polyethylene film to obtain a patch.

In order to examine the drug transdermal absorption of the patches obtained in the experimental examples, the following three types of samples were prepared, and a transdermal absorption experiment using each sample in rabbits was attempted. In addition, rabbits weigh between 2.5 and 3.5 kg.
After removing the abdominal hair, each sample was applied to a Japanese white male rabbit of 1.5 g, and the blood concentration of propranolol was adjusted every 2 hours.
Measured by PLC method. The results of the measurements are shown in Table 1.

Sample 1: A laminate of the drug storage layer and auxiliary layer of Example laminated with an impermeable support without holes.

Sample 2: The drug storage layer of the example has an air permeability of 70 cc/cs, which is the same as that of the example! /see breathable support directly laminated, without auxiliary layer.

Sample 3: Example.

Table 1 AuCo-tz was calculated from the blood concentration time curve of each sample and the result was as shown in Table 2.

Table 2 As is clear from Tables 1 and 2, the patches using a breathable support (Samples 2 and 3) are superior to the patches using a non-breathable support (Sample 1). , in sample 2, Cmax is about 2.5 times higher for Cwax and about 3.2 times higher for AuC0-1z, and in sample 3, Cmax is about 3.3 times higher, and higher for AuCo-1z.
0, it is about 4.7 times higher, confirming that the adhesive patch using an air-permeable support layer has excellent absorbency. In addition, when the auxiliary layer is laminated, Cmax is approximately 1.4 times that of the case where the auxiliary layer is not laminated, and when AuCo-zz is approximately 1
．． The value is 5 times higher, and it is recognized that the patch of Example has extremely excellent absorbency.

〔Effect of the invention〕

As detailed above, according to the present invention, drug release does not rely solely on diffusion, but utilizes the driving horse of changing the matrix system that forms the drug storage layer and the auxiliary layer. It is possible to obtain a patch that releases the drug more efficiently and has excellent absorbability compared to other agents.

Moreover, since the release rate of the drug can be precisely controlled by various means, it is possible to administer the drug extremely effectively depending on the purpose and contents of the treatment. Furthermore, since the auxiliary layer is laminated on the drug storage layer that is applied to the skin surface and stores the drug, even if there is insufficient transdermal absorption enhancer in the drug storage layer due to the amount of drug blended, etc. This can be supplemented by containing a sufficient amount of an absorption enhancer in the drug storage layer, and accordingly, a sufficient amount of drug can be contained in the drug storage layer. It produces excellent effects that can be used for transdermal treatment of diseases.

[Brief explanation of drawings]

The drawing is a schematic side view showing an embodiment of the present invention.

Claims (9)

[Claims] (1) A drug storage layer made of a hydrophilic polymer matrix containing at least a drug, a solubilizer thereof, and a transdermal absorption enhancer; A patch comprising an auxiliary layer made of a water-containing hydrophilic polymer matrix that does not contain a drug solubilizer, and a support layer laminated to the auxiliary layer and having air permeability. (2) The adhesive patch according to claim 1, wherein the drug storage layer and the auxiliary layer are mainly composed of a viscous material obtained by dissolving or swelling one or more hydrophilic polymer compounds in water. (3) The adhesive patch according to claim 1, wherein the drug storage layer and/or the auxiliary layer are two or more layers. (4) The adhesive patch according to claim 1, wherein the drug storage layer and/or the auxiliary layer further contain a plasticizer, a dispersant, and/or a stabilizer. (5) The patch according to claim 4, wherein the plasticizer is one or more of glycerin, propylene glycol, polyethylene glycol, and 1,3-butylene glycol. (6) The adhesive patch according to claim 4, wherein the dispersant and/or stabilizer is a surfactant. (7) The patch according to claim 1, wherein the support layer is a porous synthetic resin film, paper, nonwoven fabric, cloth, or a laminate of one or more of these. (8) The patch according to claim 1, wherein the drug storage layer, auxiliary layer, and support layer are separable during storage. (9) The patch according to claim 1, wherein both or one side of the patch is coated with a removable film or membrane.