JP2527934B2 - Patch - Google Patents

Description

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

[Prior art and its problems]

Conventionally, ointments, liquids, poultices, plasters and the like are known as external preparations applied to the skin. All of these external preparations are intended for the therapeutic effect by absorption of the drug in the local affected area to which they are applied,
It was exclusively used for drugs having actions such as anti-inflammatory, antibacterial, antipruritic and antiallergic. However, in recent years, it has been proposed to improve the bioavailability of drugs that have a large first-pass effect on the liver by oral administration, drugs that easily cause gastrointestinal injury, drugs that are easily decomposed in the gastrointestinal tract by digestive fluids, etc. An external preparation that has been conventionally used only for local diseases has been taken up, and a so-called transdermal therapeutic system, which is expected to have a systemic action by transdermal absorption of a drug, is being developed by utilizing the external preparation.

The ideal conditions for external preparations intended for percutaneous absorption are, in general, that even a small amount of drug is efficiently absorbed and the amount of drug remaining in the base is small, and the drug release rate and release time are Controllability, repeated application to the same site causes less skin irritation, does not cause side effects such as rash and rash, and can accurately determine the dose,
That the drug is stably retained in the base material for a long period of time, and the like. Among the external preparations, in the case of ointments and the like, the dose of the drug varies depending on the applied area and thickness, and it is difficult to determine an accurate dose. On the other hand, among external preparations, patches are less of the above-mentioned drawbacks in ointments and the like, so they are used for transdermal absorption of drugs such as nitroglycerin and scopolamine,
It has already been used for actual medical care. Some examples of these practical patches are shown in the following: Nitroglycerin is impregnated into a diffusion matrix of cross-linked silicone polymer, and the drug is contained in a viscous silicone liquid and the drug release rate is controlled. Examples include those using a porous membrane, those containing a drug in a diffusion matrix of a gel composed of polyvinyl alcohol, polyvinylpyrrolidone, and glycerin water.

However, all of these conventional patches are so-called monolithic preparations, and the drug release energy depends exclusively on diffusion. In the conventional patch, a drug having a saturated solubility or higher is mixed in a polymer matrix having a single constitution, and the drug is released by diffusion through the solvent in the polymer matrix. In the case of a water-soluble drug, it is either directly incorporated into the polymer matrix in a powder state or dispersed in the form of a coprecipitate with the polymer compound. , When the matrix does not contain water, when it is applied to the skin, water penetrates into the matrix due to TWL (unsensitized evaporation) of the skin, dissolves the drug, and the drug migrates to the skin side by diffusion. It is like this. Therefore, the conventional patch has the following various problems.

Low energy for drug release.

b. In order to increase the efficiency of drug release, it is necessary to make the thickness of the matrix as thin as possible, but if it is too thin, it is difficult to mix the drug in an amount sufficient to obtain a sufficient therapeutic effect.

c. In order to reduce the thickness of the matrix as much as possible and to obtain a drug dose sufficient to obtain a sufficient therapeutic effect, it is necessary to increase the area of application to the skin. In some cases, the patch may be applied to the body. I have to put it on, which is annoying.

d. When the concentration of drug in the matrix is increased and the concentration gradient is increased, it becomes difficult to mix the absorption-promoting component of the drug, etc., and the adhesiveness of the matrix to the skin is reduced, and the drug does not serve as a patch. In addition, there is a possibility that the drug may be wasted because there is a region where the dose dependence is not established at a certain concentration or higher, and thus it cannot be used except for the administration of a drug in which a very small dose is sufficient.

[Object of the Invention]

The object of the present invention is to sufficiently satisfy the ideal conditions described above for a patch intended for percutaneous absorption,
In particular, it is to provide a patch capable of efficiently and reliably administering a drug of an appropriate type and a sufficient amount depending on the purpose of treatment.

[Structure of Invention]

In order to achieve the above-mentioned object, the present invention comprises a drug storage layer consisting essentially of a water-containing hydrophilic polymer matrix, and an auxiliary layer consisting of a water-containing hydrophilic polymer matrix laminated on the drug storage layer. It is a patch with a layered structure in which layers are pasted, and unlike the conventional patches that depended solely on diffusion of the drug release energy, the moisture in the drug storage layer and the auxiliary layer was absorbed by the body temperature during application. Utilizing contraction of each matrix and system change associated with transpiration to the outside through a layer to positively release the drug and achieve efficient and reliable release and transfer of the drug to the surface of the applied skin. The main point is to be able to do. That is, the patch of the present invention comprises a drug storage layer comprising a water-containing hydrophilic polymer matrix containing at least a drug which is almost insoluble or poorly soluble in water and a dissolution agent thereof and a transdermal absorption enhancer, and the drug storage layer. And an auxiliary layer composed of a water-containing hydrophilic polymer matrix which is laminated on the back surface of the auxiliary layer and contains at least a percutaneous absorption enhancer and does not contain the drug and its dissolving agent, and is bonded to the back surface of the auxiliary layer to have air permeability. And a support layer.

More specifically, the patch of the present invention is formed to have a layered structure in which a drug storage layer 1, an auxiliary layer 2 and a support layer 3 are laminated in this order as shown in the drawings.

The drug storage layer 1 is applied to the skin surface, and contains at least a drug that is almost insoluble or hardly soluble in water, its solubilizer, and a transdermal absorption enhancer, and they formed a stable dispersion system. A sheet-like water-containing hydrophilic polymer matrix, which is preferably composed mainly of a viscous material obtained by dissolving or swelling one or more hydrophilic polymer compounds in water, and which itself has adhesiveness to the skin. It consists of a matrix. An auxiliary layer 2 is laminated on the back surface of the drug storage layer 1, that is, the surface opposite to the surface applied to the skin. The auxiliary layer 2 is composed of a sheet-like water-containing hydrophilic polymer matrix, which also contains a percutaneous absorption enhancer and the like in a stable dispersion system. The water-containing hydrophilic polymer matrix forming the auxiliary layer 2 may be a matrix of the water-containing hydrophilic polymer which is substantially the same as or similar to the drug storage layer 1, but in the present invention, the auxiliary layer 2 is It is important not to include the drug and its solubilizers. If the auxiliary layer 2 contains a dissolving agent for the drug, the drug in the storage layer 1 diffuses into the auxiliary layer 2, and the drug concentrations in the storage layer 1 and the auxiliary layer 2 become equal and the concentration gradient decreases. To do. Therefore, when a liquid component such as a plasticizer is added to the auxiliary layer 2, a substance that does not dissolve the drug used is selected.

The hydrophilic polymer matrix forming the drug storage layer 1 and the auxiliary layer 2 needs to contain water. The water content of the drug and its dissolving agent,
The amount is preferably 40 to 90% by weight, more preferably 50 to 85% by weight, although it depends on the amount and type of the transdermal absorption enhancer, hydrophilic polymer and the like. If the water content is low, the contraction rate of the matrix due to water evaporation is reduced, and the drug release force is reduced, which is not preferable. Further, the drug storage layer 1 may be formed in a layered form of two or more layers. For example, when the drug storage layers 1 themselves have different drug concentrations, or when two or more drugs are blended, it is useful to form the drug storage layer 1 into two or more layers.

The method of laminating the auxiliary layer 2 on the drug storage layer 1 is not particularly important in the present invention. The matrixes forming the drug storage layer 1 and the auxiliary layer are both hydrophilic polymer matrices containing water and have a mutual mutual adhesiveness corresponding to each other. Therefore, they may be simply stacked, and if necessary, stored. A tacky component may be added to both or one or both of the layer 1 and the auxiliary layer 2, or the laminated state may be maintained by using, for example, an adhesive tape. Further, the drug storage layer 1, the auxiliary layer 2 and the support layer 3 may be stored separately before being actually applied to the skin, and may be laminated and used at the time of actual application.

On the back surface of the auxiliary layer 2 laminated on the drug storage layer 1, a support layer 3 having air permeability is further attached. This support layer 3 has the function of allowing the evaporation of the water in the storage layer 1 and the auxiliary layer 2 and controlling the evaporation rate, and is made of cloth, non-woven fabric, paper, synthetic resin film, etc., depending on the purpose. Can be arbitrarily selected. The material itself may have no air permeability, may be made porous to have air permeability, or may be a laminate of two or more materials if necessary.

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 having stability confirmed to be usually used in pharmaceuticals, cosmetics, foods, etc. Any substance can be used as long as it can act as a paste or gel to form a matrix. Examples of such hydrophilic polymer compounds include polyacrylic acid and salts thereof, carboxyvinyl polymer, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, alginic acid and salts thereof, gelatin, starch, agar, Examples include dextrin. The hydrophilic polymer compound is not limited to one kind, and two or more kinds may be used, and the hydrophilic polymer compound used in the storage layer 1 and the auxiliary layer 2 may be the same or similar kind. However, different types may be used as needed.

The transdermal absorption enhancer used in the drug storage layer 1 and the auxiliary layer 2 of the present invention can be any one as long as it has an effect of promoting the percutaneous absorption of the drug to be used, and it is necessary. Depending on the requirement, two or more kinds of components can be used. Such transdermal absorption enhancers include, for example, urea, diisopropyl adipate, diethyl adipate, isopropyl myristate, isopropyl palmitate, octyldodecyl oleate, fatty acid mono- or polyhydric alcohol esters such as glycerin fatty acid esters, Examples include higher alcohols such as isostearyl alcohol and 2-octyldodecanol, vegetable oils, animal oils, and mineral oils. The same or different types of percutaneous absorption enhancers can be used for the drug storage layer 1 and the auxiliary layer 2, but the auxiliary layer 2 is selected so that it is difficult to dissolve the drug used. The water-insoluble transdermal absorption enhancer is emulsified and dispersed by adding an appropriate surfactant so as to form a stable dispersed phase in the matrix.

The drug used in the present invention is not particularly limited as long as it is a drug that is almost insoluble or hardly soluble in water, which has transdermal absorbability, and this includes both a drug applied locally and a drug applied systemically. included. Topically applied drugs are mainly expected to exert local drug effects, and conventionally used skin disease therapeutic agents, anti-inflammatory analgesics, anti-pruritic agents,
Local anesthetics, antibacterial agents, etc. can be used. In addition, a drug applied systemically is a drug expected to have a systemic effect, for example, a drug that is absorbed from the skin, which is the application site, and reaches the tissues and organs in the body through the blood to exert its drug effect. Is. Specific examples of some of these drugs are as follows.

Anti-inflammatory analgesics: acetaminophen, aspirin, salicylic acid, methyl salicylate, glycol salicylate, l
-Menthol, camphor, mefenamic acid, flufenamic acid, indomethacin, diclofenac, ibuprofen, ketoprofen, naproxen, pranoprofen, fenoprofen, sarindac, flurbiprofen, piroxicam, phenylbutazone, mepyrizole and the like.

Steroid anti-inflammatory agents: hydrocortisone, prednisolone, dexamethasone, triamcinolone acetonide, fluocinolone acetonide, hydrocortisone acetate, etc.

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

Local anesthetics: benzocaine, procaine.

Antibacterial agents: antifungal agents, antifungal agents, tetracycline antibiotics, cephalosporin antibiotics, macrolide antibiotics, chloramphenicol, sulfonamides,
Such as phenols.

Antihypertensive agents: clonidine, α-methyldopa, reserpine, syrongopine, resinamine, cinnarizine, hydralazine, prazosin, etc.

Antiarrhythmic agents: ginidine, lidocaine, procainamide, disobruamide, etc.

Antihypertensive diuretics: theophylline, trichloromethiazide,
Furosemide, tribacide, methiclothiazide, penfluzide, hydrothiazide, spironolactone, metrazone, etc.

β-blocker: pindolol, propranolol, etc.

Calcium antagonists: diltiazem, nifedipine, nicardipine, verapamil, bencyclane, dilazep, etc.

Antiepileptic agents: Nitrazepam, mebrobamate, phenytoin, etc.

Antivertigo: isoprenaline, betahistine, scopolamine, etc.

Sedatives and hypnotics: phenobarbital, secobarbital, cyclobarbital, amobarbital.

Mentatives: chloropromazine, promazine, prochloroperazine, reserpine, meprobamate, benzodiacepines, etc.

Respiratory agents: Codin, ephedrine, isoproterenol, etc.

If necessary, two or more kinds of the above drugs can be used in combination. The compounding amount is sufficient if the drug effect is exerted, and in many cases, it is 0.1 to 10.0% by weight based on the water-containing hydrophilic polymer matrix constituting the drug storage layer 1.
Although the amount is mixed, it can be appropriately increased or decreased depending on the kind of drug, the purpose of treatment, the degree of disease and the like. Further, in the case of a drug that is extremely hardly soluble in water, it is preferable to add, for example, a surfactant to emulsify and disperse it in the matrix.

As the dissolving agent to be mixed in the drug storage layer 1 together with the drug which is almost insoluble or hardly soluble in water, it is sufficient to use a known and pharmaceutically acceptable dissolving agent for the drug. For example, polyhydric alcohols, oils and fats such as peppermint oil, olive oil, and squalene, or fatty acid esters are generally used as solubilizers of drugs that are almost insoluble or hardly soluble in water, and it is also possible to use them in the present invention. it can.

In the patch of the present invention, in each matrix forming the drug storage layer 1 and the auxiliary layer 2, if necessary,
A plasticizer for imparting or increasing the plasticity of the matrix, a preservative having a function of preventing deterioration by microorganisms or preserving, and other components can be added. Examples of the plasticizer include glycerin and 1,3-
There are butylene glycol, polyethylene glycol and the like, and the addition amount thereof is appropriately within the range that does not impair the quality as a patch, preferably less than 25% by weight. When the water content in the matrix evaporates, its excessive addition may make the matrix a hard thin film, reduce the adhesive force to the skin, and lose the flexibility of the matrix to reduce the shrinkage rate of the matrix. Therefore, when the liquid component such as the absorption enhancer or the solubilizer is selected from the components having a function as the plasticizer of the matrix, it is not necessary to add the plasticizer. Examples of the preservatives include paraoxybenzoic acid alkyl ester (parabens), sorbitans, devidroacetic acid, etc., and the addition amount thereof is, for example, 0.01 to 2.0 of the whole matrix.
It can be wt%. Further, in the present invention, in order to improve the shape retention of each hydrous matrix forming the drug storage layer 1 and the auxiliary layer 2, a crosslinking agent for the hydrophilic polymer matrix may be added. In particular, various aluminum salts for the --COOH group in the functional group of the hydrophilic polymer are effective in enhancing the shape retention of the matrix.

When the patch of the present invention is stored before being actually applied to the skin, the surface of the drug storage layer 1 to be applied to the skin is releasably covered with a film or a film 4 such as a plastic film. Is preferred. If the drug storage layer 1 and the auxiliary layer 2 and the support layer 3 are separately stored, it is necessary to store them in a non-breathable material such as aluminum foil in a confidential manner, and to store for a long time. The same applies to the case.

[Action]

Since the patch of this invention is constituted as described above, when the drug storage layer is applied to the skin, the water content in each matrix forming the drug storage layer and the auxiliary layer laminated on the drug storage layer changes depending on the body temperature. Evaporate through the support layer.
Then, with the evaporation of water, the stable dispersion system of each matrix changes, and in particular, the transdermal absorption enhancer in the drug storage layer, the dissolving agent dissolving the drug, the transdermal absorption enhancer in the auxiliary layer, etc. The liquid component separates from each matrix, and the contraction of each matrix itself promotes the positive separation of the liquid component from the matrix. In this case, the liquid component containing the drug of the drug storage layer tries to be separated on both the skin contact surface side and the opposite side of the matrix forming the drug storage layer, but the drug storage layer skin contact surface side Since the auxiliary layer is laminated on the opposite side, and the auxiliary layer does not contain the drug and its dissolving agent but only the transdermal absorption enhancer, the separation on the opposite side is prevented by the auxiliary layer. On the contrary, the liquid component in the auxiliary layer is transferred to the drug storage layer. At the same time, even a drug that is almost insoluble or extremely insoluble in water will be solubilized by increasing its solubility as the water content decreases. As a result, the liquid component containing the separated drug in the drug storage layer is blocked from moving to the opposite side, moves to the contact surface side with the skin, and is efficiently absorbed on the skin surface. In addition, as described above, the evaporation of water in the drug storage layer and the auxiliary layer, the contraction of the polymer matrix and the change of the system, the separation of the liquid component and the accompanying separation of the drug, and the release of the drug to the patch skin surface are different from each other. Being related, the rate of water evaporation changes the rate of contraction of the matrix and also changes the rate of drug separation. Therefore, in the present invention, there are a plurality of rate controlling means, namely, drug separation rate, that is, drug release rate-contraction rate of polymer matrix-water evaporation rate, and the release rate of the drug can be finely controlled. Become.

〔Example〕

Aluminum hydroxide gel 0.2g, hydroxypropylmethylcellulose 0.3g, carboxymethylcellulose sodium 1.5g, while stirring with distilled water 65g, high speed stirrer
0.5 g of carboxyvinyl polymer and 3.5 g of sodium polyacrylate are sequentially added and mixed to obtain a pasty hydrophilic polymer composition. Separately, propranolol, a poorly water-soluble drug
A solution prepared by adding 1.5 g to 1.5 g of propylene glycol, which is a solubilizer, at 37 ° C. with stirring is prepared, and this solution is added to the above hydrophilic polymer composition and further kneaded by a kneader.
Then, lactic acid was added to adjust the pH of the above composition to around 6.
Add 5 g little by little and knead, and then add 10 g of octyldodecanol, a transdermal absorption enhancer, to 0.5 g of polyoxyethylene sorbitan tetraoleate and 0.5 g of sorbitan monooleate.
The solution added with is added to the above composition adjusted to around PH6 and kneaded. 6 g of the polymer composition produced was 1.0 mm in thickness and 8.0 in diameter.
It is poured into a frame of cm and compressed from both sides to prepare a disk having a uniform thickness, which is used as a drug storage layer. Next, the drug propranolol and its solubilizer propylene glycol were not added, and the same method as the above-mentioned preparation method was used except that glycerin was used as a plasticizer, and a disk with a uniform thickness of 1 mm in diameter and 8 cm in diameter was prepared. Is prepared, and this is used as an auxiliary layer.
Then, the drug storage layer and the auxiliary layer are laminated and laminated,
Furthermore, after laminating a non-woven fabric made of a mixture of polyester and rayon with polyethylene film, and adhering a support with fine holes so that the air permeability is 70 cc / cm ² / sec on one side of the auxiliary layer, A releasable polyethylene film was coated on the surface to be applied to the skin to obtain a patch.

To examine the drug transdermal absorbability of the patches obtained in the experimental examples,
The following four types of samples were prepared, and a percutaneous absorption experiment using rabbits of each sample was tried. As a rabbit, a Japanese white male rabbit weighing 2.5 to 3.5 kg was used, each sample was applied after abdominal hair removal, and the blood concentration of propranolol was measured by the HPLC method every 2 hours. The results of the measurement are shown in Table 1.

Sample 1 ... A laminate of the drug storage layer and the auxiliary layer of the example, which is laminated with a non-breathable support having no pores.

Specimen 2 ... A drug storage layer of the example was directly laminated with a breathable support having an air permeability of 70 cc / cm ² / sec as in the example, without an auxiliary layer.

Sample 3 ... of the example.

Sample 4 ... A non-air-permeable support directly attached to the drug storage layer of the Example, without an auxiliary layer.

Table 2 shows the AuCo- ₁₂ obtained from the blood concentration-time curve of each sample.

As is clear from Tables 1 and 2, the patches using the breathable support (Samples 2 and 3) are more comparable to the patches using the non-breathing support (Samples 1 and 4). However, in Sample 2 as well, Cmax was about 2.5 times higher, and AuCo- ₁₂ was about 3.2 times higher. In particular, in Sample 3 of the example, Cmax was about 3.3 times higher, and AuCo-
_{At 12} , the increase was about 4.7 times, confirming that the patch using the breathable support layer has excellent absorbency. Also,
Similarly, the sample 3 of the example in which the auxiliary layer was laminated even if a support having air permeability was used, was about 1.4 times in Cmax and about 1.5 times in AuCo- _{12 as} compared to the sample 2 in which the auxiliary layer was not laminated. It shows a high value, the blood concentration of the patch of the example, Cmax, AuCo- ₁₂
It is recognized that both are high and have extremely excellent absorbability.

Furthermore, when the appearance change due to application was examined for Samples 1 to 4, the color tone before application was milky white, but the color tone after application was Samples 1 and 4 using a non-breathable support. In contrast to the sample that remained milky white, Samples 2 and 3 using the breathable support became transparent. The change in transparency of Samples 2 and 3 indicates that the emulsion was broken by evaporation of water from the air-permeable support during application and phase separation occurred.

〔The invention's effect〕

As described above in detail, according to the present invention, the drug release is not dependent only on diffusion, and the driving hose of changing and contracting the system of the matrix forming the drug storage layer and the auxiliary layer is utilized. The drug can be released more efficiently than that of the above patch, and a patch having excellent absorbability can be obtained. Moreover, since the release rate of the drug can be finely controlled by various means, the drug can be administered extremely effectively depending on the purpose and content of the treatment. In addition, since the auxiliary layer is laminated on the drug storage layer that is applied to the skin surface and stores the drug, even if the transdermal absorption enhancer is insufficient in the drug storage layer due to the relationship of the compounding amount of the drug, etc. This can be supplemented by containing a sufficient amount of an absorption enhancer, etc., and accordingly, a sufficient amount of the drug can be contained in the drug storage layer. It has an excellent effect that it can be used for transdermal treatment of diseases.

[Brief description of drawings]

The drawings are schematic side views showing an embodiment of the present invention. 1 ... Drug storage layer, 2 ... Auxiliary layer 3 ... Support layer, 4 ... Release film

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Shigeko Shibata 8-1, Minamieicho, Kasukabe City Watanabe Yakuhin Kogyo Co., Ltd. (56) References JP-A-57-9714 (JP, A) JP-A-58-35112 (JP, A) JP-A 61-12621 (JP, A) Actually developed Shou 54-167587 (JP, U)

Claims (2)

(57) [Claims] 1. A drug storage layer comprising a water-containing hydrophilic polymer matrix containing at least a drug which is almost insoluble or hardly soluble in water, a dissolving agent thereof, and a transdermal absorption enhancer, and a layer laminated on the back surface of the drug storage layer. And an auxiliary layer comprising a hydrous hydrophilic polymer matrix containing at least a percutaneous absorption enhancer and not containing the drug and its dissolving agent, and a support layer laminated on the back surface of the auxiliary layer and having air permeability. An adhesive patch comprising: 2. The drug storage layer and the auxiliary layer are of one type or two types.
The patch according to claim 1, which is mainly composed of a viscous material obtained by dissolving or swelling one or more hydrophilic polymer compounds in water.