JPS6342602B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a patch that is applied directly to the body for treating diseased areas of the body or for administering medicine to the circulatory system.

Conventionally, this type of patch has been known to have an adhesive polymer layer on a support such as a plastic film, in which a drug and a release auxiliary substance that usually promotes the release of the drug are dissolved. However, they generally have poor sustained drug release properties and have the disadvantage that their drug efficacy disappears in a short period of time.

The present invention aims to provide a method for manufacturing a patch that eliminates the above-mentioned drawbacks, and will be described below with reference to the drawings.

Figure 1 shows an example of a patch manufactured by the method of the present invention, in which 1 is a drug-impermeable support such as a synthetic resin film, a composite film of synthetic resin and metal, or a discontinuous foam sheet. body 2 is a natural rubber-based material comprising a drug provided on this support 1 and, if necessary, a release auxiliary substance for promoting the release of the drug;
Synthetic rubber type, styrene-isoprene-styrene block polymer type, polyacrylic acid ester type,
In an adhesive polymer layer such as polyvinyl ether, polyisobutylene, or silicone resin, the crosslinking density on the outer surface (exposed surface) 3 side (for example, the surface area up to the dashed-dotted line 4 in the figure) is higher than that on the inner surface (supporting surface). body joint surface) is larger than the 5th side.

Here, the adhesive polymer layer 2 is generally formed by applying an adhesive polymer composition containing a drug or the like directly onto the support 1 and drying it, or by once coating it on a release liner and then transferring it to the support 1. Next, it is formed by performing any of the following crosslinking treatments such that the crosslinking density on the outer surface 3 side is greater than that on the inner surface 5 side.

That is, one of the crosslinking treatments is a method of crosslinking the polymer layer by irradiating it with ionizing radiation while covering the surface with a release paper. Another method is to spray a crosslinking agent or a crosslinking aid onto the surface of the polymer layer in advance for crosslinking treatment, such as spraying an appropriate amount of a crosslinking aid such as a polyfunctional acrylic or vinyl monomer or a photosensitive monomer. After irradiating the polymer layer with ionizing radiation or ultraviolet rays, or spraying a known crosslinking agent such as a thiuram compound or a polyfunctional epoxy compound onto the surface of the polymer layer, the polymer layer is left for a predetermined period of time under heating or preferably without heating. This is a method of crosslinking treatment.

In the adhesive polymer layer 2 that has been crosslinked by such a method, the entire layer is not uniformly crosslinked, but the amount of crosslinking bonds that bind the adhesive polymers to each other, that is, the crosslink density becomes larger on the outer surface side. , no or only a small amount of cross-linking is introduced into the inner surface.

The drug contained in the adhesive polymer layer 2 is one that can be dissolved in the polymer component constituting the adhesive polymer layer 2 and transferred or adsorbed to the body surface, such as corticosteroids, anesthetics, antihistamines, antibacterial agents, antifungal agents,
Analgesic anti-inflammatory agents, keratin softeners, vitamins, antispasmodics, etc., as well as systemic drugs such as antispasmodics, sedatives, sex hormones, antidiabetic agents, antihypertensive agents, antibiotics, central nervous system agents, and vasodilators. and so on. 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, fluoroxynolone acetonide, betamethasone, beclomethasone propionate, fludroxycortide, fluoxynonide, and the like. Anesthetics include benzocaine, lidocaine, and ethyl aminobenzoate, antihistamines include diphenhydramine hydrochloride, isocypenzyl hydrochloride, and diphenylimidazole, and antibacterial agents include benzalkonium chloride and nitrofurazone. Examples of the agents include nystatin and undecylenic acid, and examples of analgesic and anti-inflammatory agents include indomethacin, methyl salicylate, glycol salicylate, salicylic acid amide, and 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.

In addition, release aid substances that are sometimes combined with the above drugs can be simply defined as substances that promote the release of drugs to the body surface.
These include those that have the function of improving the solubility and diffusivity of drugs within the adhesive polymer layer, as well as those that have the ability to retain water in the stratum corneum, soften the stratum corneum, and permeate the stratum corneum (loosening).
Those that have functions to improve transdermal absorption, such as functions as penetration aids and pore openers, and functions that change the skin interface condition, and those that have both of the above functions or those that have in addition to these functions. This includes a wide range of drugs that also have the function of promoting drug efficacy to make the drug more effective.

Specific examples of these release auxiliary substances include glycols (mainly drug-soluble) such as diethylene glycol, propylene glycol, and polyethylene glycol, oils and fats (mainly drug-diffusing) such as olive oil, squalene, and lanolin, urea,
Urea derivatives such as allantoin (mainly for the water retention capacity of stratum corneum), dimethyldecyl phosphooxide, methyloctyl sulfoxide, dimethyl laurylamide, dodecylpyrrolidone, isosorbitol, dimethylacetamide, dimethyl sulfoxide,
Polar solvents such as dimethylformamide (mainly keratin permeability), salicylic acid (mainly keratin softening), amino acids (mainly penetration aid), benzyl nicotinate (mainly pore opening agent), sodium lauryl sulfate (mainly (function that changes the skin interface condition), Sarokol (used in combination with drugs that have good transdermal absorption), etc. Others diisopropyl adipate, phthalate ester,
Examples include plasticizers such as diethyl sebacate, hydrocarbons such as liquid paraffin, various emulsifiers, ethoxylated stearyl alcohol, higher ester ethers of glycerin, isopropyl myristate, and ethyl laurate.

FIG. 2 shows another example of a patch manufactured by the method of the present invention, in which the drug-containing adhesive polymer layer 2 provided on the support 1 is a polymer layer having substantially no adhesiveness. 2A and an adhesive polymer layer 2B, and the crosslinking density on the outer surface 3 side of the polymer layer 2B (for example, the surface portion up to the dashed-dotted line 4 position in the figure) was increased by the same method as described above. It is something. Here, the polymer layer 2A having substantially no adhesiveness is made of a polymer composition such as soft polyvinyl chloride, soft polyamide resin, polyvinyl alcohol, polyolefin resin, polyacrylic resin, etc., containing a drug and, if necessary, a release aid. The adhesive polymer layer 2B is formed by applying or transferring a composition containing the same drug or release aid as in the case of FIG. 1 onto the polymer layer 2A. be done.

In addition, FIG. 3 shows that the thickness of the adhesive polymer layer 2B in the adhesive polymer layer 2 having a two-layer structure as described above is made as thin as possible, and the crosslinking density of the entire polymer layer 2B is reduced to the same level as described above. It is made larger by a method.

As described above, the adhesive produced by the method of the present invention has a drug-containing adhesive polymer layer provided on a drug-impermeable support with a higher crosslinking density on the outer surface side than on the inner surface side. According to this patch, the rapid diffusion and movement of the drug within the adhesive polymer layer is suppressed by the exposed surface layer, which has a high crosslinking density and is dense. When the layer is attached to the body surface, drugs can be administered to diseased parts of the body or the circulatory system over a longer period of time, and as a result, the durability of drug efficacy can be improved compared to conventional methods.

In addition, when the crosslinking density of the drug-containing adhesive polymer layer is made uniform throughout the layer, it becomes difficult to adjust the diffusion rate of the drug; However, if the method of densely crosslinking only the outer surface side as in the structure of the present invention is used, there is no need to worry about such problems.

In addition, in this invention, if the outer surface part where the crosslinking density is increased becomes too thick, it becomes impossible to adjust the diffusion rate of the drug appropriately, so generally the thickness of the above part is 1 part of the total thickness of the adhesive polymer layer. It is desirable that the thickness be about /50 to 1/2, or usually about 3 to 20 μm from the outer surface of the polymer layer. This setting can be easily performed by adjusting the amount of crosslinking agent or crosslinking aid sprayed onto the outer surface of the polymer layer, the amount of irradiation, and the like.

EXAMPLES Below, examples of the present invention will be described in more detail. Note that in the following, parts mean parts by weight.

Example 1 A monomer mixture consisting of 90 parts of 2-ethylhexyl acrylate and 10 parts of butyl methacrylate was charged into a small kneader, and after purging with nitrogen, the mixture was reacted at 60°C with 0.1 part of azobisisobutyronitrile as a polymerization initiator for about 15 minutes. Afterwards, the reaction was stopped by rapid cooling. The resulting reaction product had a viscosity of 790 poise and contained a small amount of unreacted monomers or oligomers in addition to the polymer component. This reaction product 100
2.5 parts of isosorbide dinitrate was dispersed and dissolved using a kneader, and this was applied to a thickness of 60 μm on a polyethylene sheet of 80 μm thickness using an extruder to form an adhesive polymer layer. Next, after applying ethylene glycol diacrylate monomer to the surface of this polymer layer at a concentration of 1 g/m ² , ionizing radiation was applied in a nitrogen gas stream.
A patch of the present invention was prepared by irradiating the patch with 5 Mrad to increase the crosslinking density of the exposed surface layer.

Example 2 Two parts of indomethacin are added to an ethyl acetate solution of a polymer consisting of 30 parts of isooctyl acrylate, 65 parts of 2-ethoxyethyl acrylate and 5 parts of acrylic acid, and this is applied to a discontinuous polyvinyl chloride foam sheet after drying. was applied to a thickness of 200 μm and dried at 90° C. for 8 minutes to form an adhesive polymer layer. Next, a release-treated paper was attached to the surface of this polymer layer, and in this state, 8 Mrad of ionizing radiation was irradiated from the release paper surface.
A patch of the present invention was prepared in which the crosslinking density of the exposed surface layer was increased.

In order to examine the sustained drug release properties of the patches of Examples 1 and 2 above, the following underwater release test was conducted.

<Water release test> A 4 x 4 cm test piece was prepared from each patch, immersed in 200 ml of water (30°C), and the amount of drug released was examined at predetermined intervals. In addition, the isosorbide dinitrate of Example 1 was extracted from the test solution using hexane, and was quantified by gas chromatography. In addition, for indomethacin in Example 2, the test solution was directly applied to an ultraviolet spectrometer (320 mμ wavelength) to examine its absorbance, and the drug amount was determined using a previously measured calibration curve.

FIG. 4 and FIG. 5 respectively show the above test results. In Figure 3, curve -1
is the result of Example 1, curve-1a is the result when the ethylene glycol diacrylate monomer of Example 1 is not applied and irradiation with ionizing radiation is not performed, and curve-1b is the result when the ethylene glycol diacrylate monomer of Example 1 is not applied. Add directly to the reaction product together with the drug (the number of parts added depends on the reaction product).
(0.1 parts to 100 parts), the results were obtained when a polymer layer was formed from this and then ionizing radiation was irradiated. Moreover, in FIG. 5, curve-2 is the result of Example 2, and curve-2a is the result when ionizing radiation was not irradiated.

As is clear from both figures above, in the conventional patches 1a and 2a, the amount of drug released reaches saturation in a relatively short period of time and the durability of the drug effect is poor, whereas the patch of the present invention The change in the amount of drug released is gradual, and the drug is still released even after 48 hours, indicating that the durability of the drug's efficacy has been greatly improved. Furthermore, in the patch 1b which has been subjected to crosslinking treatment such that the crosslinking density is uniform throughout the layer, the amount of drug released is too small and sufficient drug efficacy cannot be expected.

[Brief explanation of drawings]

FIG. 1 is a cross-sectional view showing an example of a patch manufactured by the method of the present invention, FIGS. 2 and 3 are cross-sectional views showing other examples of the patch manufactured by the method of the present invention, and FIG. and FIG. 5 are characteristic diagrams showing the drug release characteristics of the patch, respectively. 1...Drug-impermeable support, 2, 2A, 2B
...Drug-containing adhesive polymer layer.

Claims (1)

[Claims] 1. In a method for producing a patch in which a drug-containing adhesive polymer layer is provided on a drug-impermeable support, the adhesive polymer layer is provided on the support, and then the surface of this polymer layer is covered with release paper. The crosslinking density on the outer surface side of the polymer layer can be increased by crosslinking by irradiating ionizing radiation while covered with the polymer layer, or by crosslinking by spraying a crosslinking agent or crosslinking aid onto the surface of the polymer layer. A method for producing a patch characterized in that the patch is larger than the inner surface.