JPH0238570B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a patch that is applied directly or indirectly to the body in order to treat diseased areas of the body or administer drugs to the circulatory system.

Conventionally, this type of patch has been made of a non-sol and non-gel polymer containing a drug and a non-volatile solubilizing agent, which usually increases the ability of the drug to dissolve in the base polymer, on a support such as a plastic film. One with layers is known. In such a patch, if the polymer layer has adhesiveness, it can be applied directly to the body surface by utilizing its adhesiveness, or if it does not have adhesiveness, it can be applied by other means such as adhesive tape. After the polymer layer is attached to the body surface, the drug in the polymer layer is transferred or absorbed to the body surface through diffusion and movement over time, thereby treating diseased areas of the body or administering the drug to the circulatory system. It is something.

However, conventional patches with such a structure generally have poor sustained drug release properties, and have the disadvantage that their medicinal efficacy disappears in a short period of time.

This invention aims to solve the above-mentioned drawbacks, and will be explained below with reference to the drawings.

FIG. 1 shows an example of the adhesive patch of the present invention, in which 1 shows a support 2 made of a breathable material such as nonwoven fabric, woven fabric, or porous plastic film, and a drug provided on this support 2. A patch main body consisting of a non-sol and non-gel adhesive polymer layer 3 and a release film 4 bonded to the surface of this layer 3; 5 is a metal film covering the main body 1;
It is a non-breathable envelope such as plastic film.

The above-mentioned adhesive polymer layer 3 contains a drug in the adhesive base polymer and, if necessary, a non-volatile solubilizing agent that increases the solubility of the drug in the base polymer, while containing a volatile compound that reduces the solubility of the drug. It is said to have a configuration that includes. This polymer layer is different from a non-sol and non-gel type, such as a polymer layer in a poultice, in which the polymer solidifies as a gel containing a dispersion medium such as water. It is in the form of a continuous film that does not substantially contain a dispersion medium.

Here, the adhesive base polymers include various conventionally known polymers such as natural rubber, synthetic rubber, styrene-isoprene-styrene block polymer, polyacrylic ester, polyisobutylene, silicone resin, and polyvinyl ether. In short, it can be widely applied as long as it can dissolve the drug and diffuse and move it inside the polymer layer. In addition, the drugs contained in this base polymer can be transferred to or absorbed into the body, such as corticosteroids, anesthetics, antihistamines, antibacterial substances, antifungal agents, analgesic and antiinflammatory agents, and keratin emollients. , vitamins, anticonvulsants, etc., as well as systemic drugs such as antihypertensive agents, antibiotics, central nervous system acting agents, vasodilators, antispasmodics, sedatives, sex hormones, and antidiabetic agents. An appropriate amount of these drugs is selected to obtain the desired treatment or administration effect depending on the type of drug.

Examples of corticosteroids include prezonisolone acetate, presonisolone, hydrocortide acetate, hydrocortide, dexamethasone, fluocinolone acetonide, betamethasone, beclomethasone propionate, fludroxycortide, fluocinonide, and the like. Anesthetics include benzocaine, lidocaine, and ethyl aminobenzoate.
Antihistamines include diphenhydramine hydrochloride, isocypenzyl hydrochloride, and diphenylimidazole, antibacterial agents include benzalkonium chloride and nitrofurazone, antifungal agents include nystatin and undecylenic acid, and analgesic and antiinflammatory agents include indomethacin, methyl salicylate, glycol salicylate, salicylic acid amide,
Examples include sodium salicylate.

In addition, salicylic acid, vitamin A, atropine,
Examples include methscopolamine bromide. In addition, systemic drugs such as antihypertensive agents such as reserpine and clonidine, antibiotics such as erythromycin, chloramphenicol, cephalexin, tetracycline, neomycin sulfate, oxytetracycline, and penicillin, and central nervous system agents such as barbiturates, diazepam, nitrazepam, and chlorpromazine and vasodilators such as nitroglycerin and isosorbite dinitrate.

Non-volatile solubilizers commonly used with the above-mentioned drugs can increase the ability of the drug to dissolve in the base polymer, and may also have the function of promoting transdermal absorption or efficacy of the drug. Typical examples include alcohols such as ethylene glycol, propylene glycol, polyethylene glycol, and ethoxylated stearyl alcohol, higher ester ethers of glycerin, oils and fats such as olive oil, lanolin alcohol, and lanolin, isopropyl myristate, and ethyl laurate. esters, plasticizers such as diisopropyl adipate, phthalate esters, and diethyl sebacate, polar solvents such as dimethylacetamide, dimethylsulfoxide, and dimethylformamide, hydrocarbons such as liquid paraffin,
There are also various other emulsifiers. The amount of these non-volatile solubilizers used is generally 20% of the total polymer layer 3.
% by weight or less.

In addition to such non-volatile solubilizing agents, non-volatile accelerators that do not have the function of increasing the ability of the drug to dissolve in the base polymer but only have the function of promoting transdermal absorption or drug efficacy, such as urea, Squalene, squalane, benzyl nicotinate, sodium laurate, allantoin, etc. can also be used. Furthermore, the polymer layer 3 may contain various additives other than those mentioned above, if necessary.

Next, the volatile compound that is a particularly important component in this invention to be included in the adhesive polymer layer 3 is:
If the substance can reduce the solubility of the drug in the base polymer and is not soluble in the base polymer itself, the above-mentioned non-volatile solubilizing agent is used in combination, and a drug that is compatible with this auxiliary agent is selected and used. be done. Examples of typical volatile compounds include methanol, ethanol, isopropanol, acetone, hexane, heptane, cyclohexane, tetrahydrofuran, dioxane, petroleum ether,
There is water etc. The amount of these compounds used is generally 20% by weight or less of the entire polymer layer 3.

According to the patch having the above structure, the volatile compound contained in the adhesive polymer layer 3 suppresses excessive dissolution of the drug into the base polymer, and some of the drug crystallizes inside the layer. For this reason, when using the patch, from the non-breathable package 5 to the patch body 1.
When the adhesive polymer layer 3 is applied to the body surface M after removing the release film 4 as shown in Fig. 2, only the drug dissolved in the base polymer diffuses and moves within the layer at the beginning of application. It is transferred to or absorbed by the body surface M. That is, the diffusion rate of the drug is determined by its dissolution into the base polymer, and those crystallized within the layer hardly participate in the diffusion movement.

On the other hand, as time passes after pasting, the volatile compound gradually volatilizes into the atmosphere through the breathable support 2, and with this volatilization, the drug crystallized inside the layer gradually dissolves into the base polymer. start. Further, this dissolution is promoted by a nonvolatile dissolution aid used in combination. In other words, since the above-mentioned auxiliary agent is non-volatile, it does not volatilize over time, and therefore its original function is improved over time. Due to the dissolution of the crystallized drug over time, the transfer or absorption to the body surface M continues for a long period of time without being temporarily interrupted.

As is clear from the above explanation, the reason why the support 2 in the adhesive patch of the present invention is made breathable is to facilitate the volatilization of volatile compounds during application, and also to facilitate the volatilization of volatile compounds during application. The reason why the patch body 1 is covered with the non-breathable envelope 5 is as follows.
This is to prevent volatile compounds from volatilizing before use and to crystallize as much of the drug as possible inside the layer 3.

Next, a method for producing a patch having the above structure will be explained. One method is to use a polymer composition in which a tacky base polymer is impregnated with a drug, a nonvolatile solubilizer, and a volatile compound, and this is applied or transferred to a support to form a tacky polymer layer. At the same time, a release film is bonded to this polymer layer and the entire surface is covered by heat sealing using an aluminum film or the like.
As another method, instead of the above polymer composition, a polymerizable or crosslinkable composition consisting of monomers or oligomers alone or a mixture of these and a polymer and optionally containing a polymerization initiator is used, Drugs and other necessary ingredients are added to this and applied or transferred to the support, and then polymerized and crosslinked by irradiation with ionizing radiation or ultraviolet rays to form an adhesive polymer layer, followed by heat sealing in the same manner as above. do. If a solvent (solution polymerization) or dispersion medium (emulsion polymerization) is used in the synthesis of the base polymer, these solvents or dispersion medium should be added to the polymer layer in order to make the polymer layer non-sol and non-gel. Removed during formation.

Note that in the adhesive patch having the above structure, the polymer layer 3 is made of a material that is particularly adhesive, but it may be made of a material that does not exhibit adhesiveness. In this case, the release film 4 is not necessary, and when it is pasted, it is pasted onto the body surface using an auxiliary means such as an adhesive tape. Examples of base polymers that do not exhibit tackiness include soft polyvinyl chloride resin, soft polyamide resin, polyvinyl alcohol, polyolefin resin, silicone rubber, and polyacrylic acid resin. The polymer layer 3 can be formed by the same method as described above.

As detailed above, the patch of the present invention is a non-sol and adhesive patch containing a drug and, if necessary, a non-volatile solubilizing agent that increases the ability of the drug to dissolve in a base polymer, on a breathable support. A non-gel polymer layer is provided to constitute the patch body, and the polymer layer contains a volatile compound that reduces the dissolution ability, while the patch body is wrapped in a non-breathable package. With this, the drug contained in the non-sol and non-gel polymer layer can be gradually dissolved in the base polymer over time, so it can be applied to the body surface. A sustained drug release effect can be obtained, and long-term sustainability of drug efficacy can be achieved.

Examples of this invention will be described below. Note that in the following, parts and % mean parts by weight and % by weight, respectively.

Example 1 100% of the above polymer was added to a 40% ethyl acetate solution of an acrylic polymer with an average molecular weight of about 70,000, consisting of 96 parts of isooctyl acrylate and 4 parts of acrylic acid.
8 parts of indomethacin were added and dissolved and dispersed, and 4 parts of polyethylene glycol (non-volatile solubilizing agent) was further added. Thereafter, ethyl acetate was distilled off under reduced pressure at 40°C, and the mixture was concentrated until the total amount of the polymer and polyethylene glycol was 95 to 98%. Next, 10 parts of a volatile compound consisting of 90 parts of ethanol and 10 parts of hexane was added to 100 parts of the above polymer, kneaded with a sealed roll mixer, and then extruded onto an acetate cloth with a thickness of 80μ using an extruder. A sticky polymer layer was formed. A release-treated 25μ Mylar film was attached to the surface of the adhesive polymer layer of the adhesive patch body thus obtained, and then heat-sealed using an aluminum film to completely cover the patch body.

Example 2 90 parts of polyvinyl ethyl ether, 10 parts of polyvinyl methyl ether, 2 parts of sorbitan monooleate (non-volatile solubilizing agent) and 7 parts of isosorbide dinitrate were thoroughly mixed using a roll, and the mixture was mixed thoroughly with a roll. 5 parts of distilled water (volatile compound) and 5 parts of isobornyl acrylate as reactive diluent were added. This composition was applied to a porous polyethylene film with a thickness of 100μ to create a patch body, and a release-treated mylar film was laminated to the coated surface, followed by exposure to ionizing radiation.
8 Mrad irradiated. Thereafter, the main body was completely covered with heat sealing using an aluminum film.

After each patch of Examples 1 and 2 was stored for several days, the patch itself was removed from the aluminum film to prepare a 2×2 cm test piece. Next, the hair on the rabbit's back was shaved off with a razor, and after one day, the test piece with the Mylar film removed was pasted on the shaved area, and the remaining hair of the drug and volatile compounds in the adhesive polymer layer was removed at regular intervals. I checked the amount.

The volatile compounds (ethanol and hexane) in Example 1 and the drug (isosorbide dinitrate) in Example 2 were determined by gas chromatography. The drug of Example 1 (indomethacin) was quantified by high performance liquid chromatography. Furthermore, the volatile compound (water) in Example 2 was determined by the Karl Fischer method.

The results of these tests were as shown in FIGS. 3 and 4. Figure 3 shows the results of Example 1.
Figure 4 shows the results of Example 2, with 1a and 2 in both figures.
a is the remaining amount of the drug, 1c and 2c are the remaining amounts of the drug when no volatile compound is included in each example, and 1b and 2b are the remaining amounts of the volatile compound.

As is clear from both figures, the patch of the present invention exhibits a sustained release property in which the drug is gradually released as the volatile compound evaporates, and is comparable to the conventional product (curves 1c and 2c). It can be seen that the sustainability of the medicinal effect can be further improved compared to the above.

[Brief explanation of drawings]

FIG. 1 is a cross-sectional view showing an example of the patch of the present invention, FIG. 2 is a cross-sectional view showing the state when the patch is attached to the body surface, and FIGS. 3 and 4 are respectively views of the patch. FIG. 2 is a characteristic diagram showing the residual amount of a drug and a volatile compound over time when applied to the body surface. DESCRIPTION OF SYMBOLS 1...Patch body, 2...Support, 3...Polymer layer, 5...Wrap.

Claims (1)

[Claims] 1. The patch body is provided with a non-sol and non-gel polymer layer on a support that contains a drug and, if necessary, a non-volatile solubilizer that increases the ability of the drug to dissolve in the base polymer. In the patch, the polymer layer contains a volatile compound that reduces the dissolution ability, the support is made of a breathable material, and the patch body is covered with a non-breathable wrapper. A patch that is characterized by: