JPH0826985A - Production of nitroglycerin application agent - Google Patents

Abstract

PURPOSE:To obtain a nitroglycerin application agent capable of readily controlling the thickness of a plaster layer without causing a danger of explosion or deteriorating the tackiness by including nitroglycerin at a high concentration in a plaster coating liquid. CONSTITUTION:This method for producing a nitroglycerin application agent is to dissolve the nitroglycerin and an acrylic tacky agent (e.g. dodecyl methacrylate) in an organic solvent (e.g. ethyl acetate), provide a liquid material containing the nitroglycerin at 5-30wt.% concentration and the tacky agent at 5-50wt.% concentration at (1/10) to (15/10) weight ratio of the nitroglycerin/ tacky agent, further add the tacky agent to the liquid material and prepare a plaster coating liquid, comprising the nitroglycerin and tacky agent at 25-50wt.% plaster ingredient concentration and having 1500-20000cps viscosity at 20 deg.C and then form a plaster layer by a method for directly applying the plaster coating liquid onto a support, drying the applied coating liquid, etc.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a nitroglycerin patch.

[0002]

2. Description of the Related Art Nitroglycerin is known as a seizure preventive for angina and heart failure, and various studies have been conducted to apply it to transdermal preparations. In the percutaneous absorption preparation, in order to improve the drug dose and the persistence of drug effect, it is preferable to add a high concentration of nitroglycerin or to form a thick plaster layer. That is, by increasing the concentration of nitroglycerin in the plaster layer, it is possible to improve the distribution to the skin, and by increasing the thickness of the plaster layer, the supply of nitroglycerin to the surface of the plaster layer. Is sufficiently performed and the decrease in concentration over time can be suppressed, so that continuous drug administration can be achieved with a small-area preparation.

However, since the explosiveness of nitroglycerin increases as the concentration increases, and there is a risk of causing an explosion due to impact or the like, at the production stage of a percutaneous absorption preparation, a safe and efficient production method is examined. There is a need to. As a method of safely blending nitroglycerin, for example,
The following methods have been proposed. (1) Nitroglycerin dissolved in nitroglycerin-soluble oil-and-fat additives such as lanolin, liquid paraffin, and vegetable oil is used as a drug substance (Japanese Patent Publication No. 5).
-21888, JP-A-57-28004). (2) Nitroglycerin is adsorbed on a nitroglycerin-adsorbing excipient or carrier, such as lactose or crystalline cellulose, which is used as a drug substance (JP-A-62-108).
812, JP-A-59-16857). (3) Nitroglycerin dissolved in an organic solvent (ethyl acetate, ethanol, cyclohexane, etc.) in which nitroglycerin and the adhesive are soluble is used as a drug substance.

However, in the above (1), when a large amount of nitroglycerin is blended, (a) the adhesive properties are adversely affected, (b) the plaster layer becomes too soft, and the shape retention becomes poor. ) There is a problem that adhesive residue occurs, and in the above (2), there are problems that (a) the adhesive properties are adversely affected and peeling easily occurs, and (b) it is difficult to be uniform when the plaster composition is mixed. was there.

Further, in the above (3), since only nitroglycerin remains by volatilization of the solvent, a plaster layer having a high concentration of nitroglycerin can be formed without adversely affecting the adhesive property. However, (a) when the nitroglycerin concentration is high, the risk of explosion is high, and (b) when the solvent amount of the plaster composition is large, the thickness control range at the time of coating is narrow and the plaster layer is thick. It becomes difficult to make a formulation.

[0006]

SUMMARY OF THE INVENTION The present invention has been made in view of the above problems, and an object thereof is to allow a high concentration of nitroglycerin to be contained in a plaster coating liquid, and yet to achieve a high concentration. Provided is a method for producing a nitroglycerin patch in which the risk of explosion and the reduction of tackiness are not caused by the concentration of nitroglycerin, and the thickness of the plaster layer can be easily controlled.

[0007]

The method for producing a nitroglycerin patch of the present invention comprises the steps of dissolving nitroglycerin and an adhesive in an organic solvent to prepare a liquid, and then adding the adhesive to the liquid again. To prepare a plaster coating liquid, apply the plaster coating liquid, and dry to form a plaster layer.

As the above-mentioned pressure-sensitive adhesive, when the solubility of nitroglycerin becomes low, not only the concentration of nitroglycerin in the paste coating solution becomes low, but also the volatility of nitroglycerin at the time of coating becomes high. It is preferably one that dissolves by weight or more, and more preferably one that dissolves 10% by weight or more of nitroglycerin. An acrylic adhesive is preferably used as the adhesive having such nitroglycerin solubility.

The above acrylic adhesive is preferably a copolymer having the following (meth) acrylic acid alkyl ester monomer as a constituent component. Examples of the (meth) acrylic acid alkyl ester monomer include (meth) acrylic acid. , Ethyl (meth) acrylate, butyl (meth) acrylate, hexyl (meth) acrylate, octyl (meth) acrylate, isooctyl (meth) acrylate,
Dodecyl (meth) acrylate, heptyl (meth) acrylate, dimethylbutyl (meth) acrylate, stearyl (meth) acrylate, trimethylhexyl (meth) acrylate, 2-hydroxyethyl (meth) acrylate,
Examples thereof include hydroxypropyl (meth) acrylate and isodecyl (meth) acrylate.

The solubility of nitroglycerin can be changed by a combination of the above-mentioned (meth) acrylic acid alkyl ester monomers, but especially 50 mol% of (meth) acrylic acid alkyl ester monomers having an alkyl group having 6 to 12 carbon atoms. The above-mentioned copolymer is preferable because it enables high-concentration dissolution of nitroglycerin, and the obtained pressure-sensitive adhesive also has excellent adhesiveness and transdermal absorbability.

The acrylic pressure-sensitive adhesive is prepared, for example, by mixing the above-mentioned monomers in the presence of a polymerization initiator and carrying out solution polymerization.

The organic solvent is preferably one which dissolves nitroglycerin and the adhesive well and volatilizes quickly during coating, and examples thereof include methanol, ethanol, methyl acetate, ethyl acetate, methyl ethyl ketone, acetone, cyclohexane, and toluene. , Dichloroethane, dichloropropane, tetrahydrofuran, benzene, chloroform and the like, which may be used alone or in combination of two or more kinds.

When the concentration of nitroglycerin in the above liquid is low, the ratio of the nitroglycerin to the adhesive in the plaster coating solution is low and a high concentration of nitroglycerin plaster layer cannot be obtained, or the plaster coating liquid is not coated. The required high plaster component concentration in the liquid cannot be obtained, and the higher the concentration, the higher the risk of explosion. Therefore, the concentration is limited to 5 to 30% by weight.

Further, in the above liquid material, if the concentration of the adhesive is low, the effect of reducing the amount of the solvent cannot be obtained, and it becomes difficult to control the thickness of the plaster layer.
Since it becomes difficult to mix uniformly in the subsequent blending step, it is limited to 5 to 50% by weight.

Further, in the above-mentioned liquid material, when the weight ratio of nitroglycerin / adhesive is small, a plaster layer having a high concentration of nitroglycerin cannot be obtained, and when the weight ratio is large, the risk of explosion becomes high. Limited to ~ 15/10.

If necessary, a percutaneous absorption promoter, a plasticizer, a tackifier, a cross-linking agent, a stabilizer, a filler and the like may be added to the above liquid material.

The plaster coating liquid can be obtained by further adding an adhesive to the liquid material. Further, other additives may be added to the plaster coating liquid, if necessary. The pressure-sensitive adhesive used here is the same pressure-sensitive adhesive as that used for the liquid material.

In the above-mentioned plaster coating liquid, when the concentration of the plaster component composed of nitroglycerin and the pressure-sensitive adhesive is low, it becomes difficult to control the thickness of the plaster layer, and when it is high, uniform coating in a coating device becomes difficult. Therefore, it is limited to 25 to 50% by weight, and preferably 32 to 43% by weight.

When the viscosity of the above-mentioned plaster coating liquid is low, it becomes difficult to control the thickness of the plaster layer, and when it is high, uniform coating with a coating device becomes difficult, so that it is 1,500 to 20,000.
limited to cps, preferably 2,000 to 10,000
It is 0 cps. The above viscosity is a value measured using a B type viscometer under the conditions of 20 ° C. and 50 rpm.

As a method for producing a nitroglycerin patch from the plaster coating solution, the same production method as for adhesive tape can be adopted. For example, the plaster coating solution is directly coated on a support. A method of drying to form a plaster layer, or a method of once coating the above-mentioned plaster coating liquid on a release paper, drying to form a plaster layer, and then transferring and closely adhering the plaster layer to a support. Etc.

The support is not particularly limited, and examples thereof include polyethylene, cellulose acetate, ethyl cellulose, polyethylene terephthalate, plasticized vinyl acetate-vinyl chloride copolymer, nylon, ethylene-vinyl acetate copolymer, ethylene. -A single layer sheet of a material such as a methyl acrylate copolymer, plasticized polyvinyl chloride, polyurethane, polyvinylidene chloride, aluminum or a laminate of two or more kinds of these is used. Furthermore, woven or non-woven fabrics made of materials other than aluminum are also used as the support.

As the above-mentioned release paper, for example, polyethylene-coated high-quality paper, polyolefin-coated glassine paper, polyethylene terephthalate (hereinafter referred to as PET) film, polypropylene film, or the like having one surface treated with silicon is used.

[0023]

Embodiments of the present invention will be described below. Preparation of pressure-sensitive adhesive A 2-ethylhexyl acrylate 1500 g, 2-ethylhexyl methacrylate 7500 g, dodecyl methacrylate 1000 g and 1,6-hexane glycol dimethacrylate 1.2 g were charged in a reactor equipped with a stirrer and a cooling device, and further, Ethyl acetate (5000 g) was added, the temperature was raised to 80 ° C. under a nitrogen stream, and a solution of 8 g of lauroyl peroxide dissolved in 800 g of cyclohexane was added little by little to carry out a polymerization reaction for 6 hours to obtain a solid content concentration of 62% by weight, An ethyl acetate solution of an acrylic pressure-sensitive adhesive having a weight average molecular weight of 1.17 × 10 ⁶ [hereinafter referred to as acrylic pressure-sensitive adhesive A] was obtained. To the ethyl acetate solution of the acrylic pressure-sensitive adhesive A, ethyl acetate was further added to obtain a solid concentration of 40% by weight.
Two kinds of pressure-sensitive adhesive solutions having a solution viscosity of 357,000 cps and 55 wt% (solution viscosity of 715,000 cps) were obtained. The viscosity of the solution is a value measured using a B-type viscometer at 20 ° C. and 50 rpm.

Preparation of Adhesive B 600 g of isoprene-styrene-isoprene copolymer ("Califlex" manufactured by Shell Chemical Co.), 200 g of hydrogenated rosin ester ("Ester gum H" manufactured by Shell Chemical Co.) and saturated alicyclic carbonization Hydrogen (Arakawa Chemical Co., Ltd. "Arcon P-1
00 ") was uniformly mixed with 3000 g of n-cyclohexane to obtain a solution of adhesive B. Further, n-cyclohexane was added to adjust the solid content concentration to 25% by weight.

The above-mentioned pressure-sensitive adhesive A, pressure-sensitive adhesive B, nitroglycerin and ethyl acetate were mixed to prepare the liquid substances shown in Table 1.

[0026]

[Table 1]

(Examples 1 and 2, Comparative Examples 1 to 3) Predetermined amounts of liquid substances, adhesives and other additives shown in Table 2 were mixed, and the compounding bottles were vortexed on a ball mill stand until uniform. Then, a plaster coating liquid was obtained. This plaster coating liquid is applied on a PET film release paper with a comma coater, and the temperature is maintained at 60 ° C. for 20 minutes.
After drying for a minute, the PET / EVA laminated film support was brought into close contact with and transferred to the EVA side to obtain a nitroglycerin patch. In Example 2, a paste coating liquid was obtained by using a dissolver instead of the ball mill.

The plaster coating solutions and nitroglycerin patches obtained in the above Examples and Comparative Examples were evaluated as follows, and the results are shown in Table 2. (1) Solubility When preparing the plaster coating solutions of the above Examples and Comparative Examples with a ball mill or a dissolver, the time until uniform dissolution was measured by visual observation every 15 minutes. (2) Coating thickness After changing the clearance of the comma coater to 200 to 900 μm, the adhesive coating solution was applied on PET film release paper and dried, and then the correlation between the clearance and the thickness of the adhesive layer is shown in FIG. Indicated. In the correlation between the clearance and the thickness of the plaster layer, a straight line is preferable because the thickness of the plaster layer can be easily controlled. (3) Volatilization rate of nitroglycerin A nitroglycerin patch punched out to 10 cm ² was immersed in 30 ml of methanol for 24 hours to extract nitroglycerin, and after measuring nitroglycerin by HPLC (high performance liquid chromatography), The volatilization rate of nitroglycerin was calculated from the formula. Volatilization rate (%) = [(content of nitroglycerin in plaster layer) / (charge of nitroglycerin)] × 100 (4) Appearance of nitroglycerin patch The presence or absence of nitroglycerin bleed was visually observed.

[0029]

[Table 2]

[0030]

The composition of the method for producing a nitroglycerin patch of the present invention is as described above, and a high concentration of nitroglycerin is contained in the plaster coating liquid by using an acrylic adhesive. Moreover, there is no danger of explosion or loss of stickiness due to high concentration nitroglycerin,
Also provided is a nitroglycerin patch in which the thickness of the plaster layer can be easily controlled.

[Brief description of drawings]

FIG. 1 is a graph showing the correlation between the clearance of a comma coater and the thickness of a plaster layer.

Front page continuation (72) Takashi Nakagawa 2-1 Hyakusan, Shimamoto-cho, Mishima-gun, Osaka Prefecture 2-1 Sekisui Chemical Co., Ltd. Mitsushi 22, Shinkawa-cho, Handa-shi, Aichi (72) Inventor Makoto Sato 35, Higashi-tobori-cho, Higashi-ku, Nagoya-shi, Aichi Sanwa Chemical Research Institute

Claims (1)

[Claims] 1. Nitroglycerin and an adhesive are dissolved in an organic solvent to obtain a nitroglycerin concentration of 5 to 30% by weight, an adhesive concentration of 5 to 50% by weight, and nitroglycerin / adhesive = 1.
/ 10 to 15/10 (weight ratio), a liquid material is prepared, and then the above-mentioned adhesive is added to the liquid again so that the concentration of the plaster component composed of nitroglycerin and the adhesive is 25 to 50.
% By weight, viscosity at 20 ° C. is 1,500 to 20,000
A method for producing a nitroglycerin patch, which comprises preparing a plaster coating solution of 0 cps, applying the plaster coating solution, and drying the mixture to form a plaster layer.