JPH06696B2 - Tape preparation - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to isosorbide dinitrate (ISDN) as an active ingredient,
The present invention relates to a transdermal tape preparation containing a nitrite-based coronary vasodilator such as pentaerythritol tetranitrate (PETN) and nitroglycerin (GTN).

(Prior Art) Nitrite drugs such as ISDN, PETN, and GTN are known as effective coronary vasodilators for angina and the like. Since these drugs have a short duration of effect in the body, for example, from the viewpoint of suppressing or preventing angina, it is desirable to administer a prescribed amount in the body over a long period of time. From the viewpoint of controlling and releasing such drugs, sustained-release tablets (sustained-release capsules), ointments, tape preparations, etc. of the above-mentioned nitrite-based drugs are used. In particular, the above-mentioned tape preparation, which is a transdermal preparation in the form of an adhesive tape, has a lower dosage frequency than sustained-release tablets (sustained-release capsules); the dosage is clearer than ointment, and administration and discontinuation of administration are easy And so on; it is very preferably used.

In such a tape preparation, an adhesive layer containing the nitrite-based drug is usually formed on a support, and the support is impermeable to the drug to prevent loss of the drug in the tape preparation. Sexual material is used. As a material for the support which is difficult for the nitrite type coronary vasodilator to migrate or penetrate, cellophane, cellulose acetate,
Polyester, polypropylene, polyamide, polyvinylidene chloride, polyvinyl alcohol and metals are mentioned. The use of the support made of such a material suppresses the migration or permeation of the nitrite-based drug into the support, but these supports do not always give a sufficient function to the obtained tape preparation. For example, sheets made of the above materials are all relatively stiff and poor in extensibility,
And it is a so-called strong seat. Therefore, when a tape preparation using these sheets as a support is applied to the skin surface, the application site is stimulated to cause redness due to the application for a long time; it gives a tight feeling because it cannot follow the flexible movement of the skin. It causes inconvenience. Polyurethane can be mentioned as a material that is difficult to penetrate nitrite-based chemicals and has flexibility, but it is poor in dimensional stability and inferior in operability during processing because it is too soft. Polyethylene and ethylene-vinyl acetate copolymer (EVA) are examples of materials having appropriate flexibility and hardness, but they cannot be used alone because they have migration or permeability of nitrite drugs. Of the materials listed in the above publication, considering sweating and bathing when applying a tape formulation, polyvinyl alcohol (PVA) is not suitable as a support because it is water-soluble, and it also has dimensional stability during storage. Considering it, a polyamide that is deformed by moisture absorption is also not preferable.

In this way, in addition to the property of drug impermeability, considering the processability of the tape preparation during manufacturing, the shape and dimensional stability of the tape preparation during storage, the feeling of sticking, and the safety to the skin, these items are At present, no satisfactory support has been obtained.

(Problems to be Solved by the Invention) The present invention solves the above-mentioned conventional drawbacks, and an object of the present invention is to prevent permeation of a nitrite-based drug and to improve processability during the production of a tape preparation, An object of the present invention is to provide a nitrite-based coronary vasodilator-containing tape preparation having excellent properties, which uses a support excellent in shape and dimensional stability during storage, sticking feeling, and safety to the skin.

(Means and Actions for Solving Problems) The inventor paid attention to nitrite-based drug-impermeable polyvinyl alcohol (PVA) as a support material, and confirmed that the vinyl alcohol unit [-CH ₂ -CH (OH)- Is a polymer containing a certain proportion, if not 100%, the impermeability of the above-mentioned drug is achieved and the water resistance is improved, and such a polymer has various excellent properties as a support. The present invention has been completed and the present invention has been completed.

The tape preparation of the present invention is a preparation in which an adhesive layer containing a nitrous acid-based coronary vasodilator as an active ingredient is formed on a support, and the support comprises a vinyl alcohol unit [-CH ₂
-CH (OH)-] in the proportion of 20-45 mol% ethylene-
It is composed of a vinyl alcohol copolymer, which achieves the above object.

The ethylene-vinyl alcohol copolymer, which is a material for the support of the tape preparation of the present invention, is produced by saponification of ethylene-vinyl acetate copolymer (EVA). The higher the degree of saponification is, the more preferable, but the degree of saponification is 90% or more. The minimum required content of the vinyl alcohol unit contained in the ethylene-vinyl alcohol copolymer is somewhat different depending on the thickness of the support and the kind of the nitrite type drug, but is usually about 20 mol% as described above. If the content of the vinyl alcohol unit is too low, the impermeability of the nitrite-based drug cannot be achieved, and if it is too high, the water resistance and dimensional stability of the support are poor.

Such an ethylene-vinyl alcohol copolymer can be made into a polymer having an appropriate glass transition temperature by appropriately selecting the content of vinyl alcohol units. For example, the content rate of vinyl alcohol unit is 40 mol%
The polymer has a glass transition temperature of about 30 ° C. If such a polymer sheet is used as a support, the polymer is in a relatively rigid state at an average room temperature of 15 to 25 ° C, which facilitates the production of the tape preparation and the operation of applying the tape preparation onto the skin. is there. After sticking to the skin surface, the polymer becomes flexible because it exceeds the glass transition temperature of the polymer. As a result, it is possible to follow the movement of the skin, and it is possible to prevent irritation or a feeling of tightness on the skin. The vinyl alcohol unit content of the polymer that gives such excellent properties is
It is usually 35 to 45 mol%, although it varies depending on individual differences in the body surface temperature of the human and the thickness of the adhesive layer.

The thickness of the support (the above ethylene-vinyl alcohol copolymer) sheet used in the tape preparation of the present invention is not particularly limited, but it is usually 10 to 20 in consideration of drug permeability and the like.
It is 0 μm. If necessary, a film made of a flexible material such as polyethylene, EVA, or polyurethane is laminated on the surface of the sheet for the purpose of improving tensile strength and water resistance. It is also recommended to perform surface treatment such as corona discharge treatment on the adhesive surface with the adhesive layer.

Examples of the nitrite-based coronary vasodilator used in the present invention include:
Examples include amyl nitrite, nitroglycerin, pentaerythritol tetranitrate, triethanolamine trinitrate, and isosorbide dinitrate. In addition to this, any nitrite-based drug that can be transdermally administered can be used, and is not limited to the above compounds. Nitrite drugs are usually used in the adhesive layer.
It is contained in a proportion of 5 to 30% by weight.

As the adhesive base, any material that allows the tape preparation to be applied to the skin surface and that has high stability and does not cause skin damage can be used. For example, a rubber-based, acrylic-based, or silicon-based adhesive base material can be used. Considering the stability in the state of containing a nitrite-based drug and the releasability of the drug, an acrylic pressure-sensitive adhesive base is preferable. In particular, a (meth) acrylic acid ester (co) polymer containing (meth) acrylic acid ester in a proportion of 50 mol% or more and having an ester portion of the (meth) acrylic acid ester having 2 to 14 carbon atoms ， Preferable because of its high stability.

The tape preparation of the present invention is prepared by a conventional method using the above-mentioned support, adhesive base and drug. For example, it can be obtained by applying an organic solvent solution containing the above-mentioned drug and the above-mentioned adhesive base on the surface of the support and drying. The solution may be applied onto a separately prepared release liner, dried and then brought into close contact with the support.

In the tape preparation thus obtained, the support is substantially impermeable to the nitrite-based drug, so that the drug may be leached or volatilized through the support or transferred into the support and lost during storage. Is extremely small. The support contains a vinyl alcohol unit as a polymer component, but it has excellent water resistance and humidity resistance compared to PVA, so dimensional stability during storage is ensured, and sweating and bathing during use. It does not dissolve due to. By selecting the polymer composition that constitutes the support, an even better tape preparation can be obtained. Since this support is relatively stiff at room temperature, it is easy to handle during the production and application of the tape preparation, and has excellent dimensional stability during storage. Further, since it has appropriate flexibility after being applied on the skin surface, it does not irritate the skin or give a feeling of strangeness.

(Example) Hereinafter, the present invention will be described with reference to Examples.

Example 1 A polyester film having a thickness of 45 μm was prepared. A mixed solution of 90 parts by weight of an adhesive base (a copolymer consisting of 96% by weight of 2-ethylhexyl acrylate and 4% by weight of acrylic acid), 10 parts by weight of isosorbide nitrate and 300 parts by weight of ethyl acetate was thinly and uniformly applied on the support. It was applied and dried at 60 ° C for 30 minutes to obtain a tape having an adhesive layer with a thickness of 30 µm. Attach the film shown in Table 1 to the adhesive side of this tape, and
A tape was cut into a size of 5 cm to prepare a sample. This sample was placed in an aluminum laminate film bag with three sides sealed, sealed and stored at room temperature for about 1 month.
The sample was carefully removed from the bag and visually inspected to see if isosorbide dinitrate crystals were found on the back surface of the laminated film. Table 1 shows the drug impermeability when the crystals were not observed, and x when the crystals were observed.

From Table 1, vinyl alcohol (V
It is clear that the ethylene-vinyl alcohol copolymer film and polyurethane film containing A) have excellent ISDN impermeability.

Example 2 A polyethylene film and a high-quality paper were laminated, and the same adhesive base as in Example 1 was used on a release liner whose surface was subjected to a silicone release treatment. It was formed to a thickness. ISDN in Example 1
Four types of films and polyester films (12 μm thick), which were confirmed to be impermeable, were attached to the release liner, respectively, and cut into a size of 5 × 5 cm to prepare a tape preparation sample. Twelve volunteers conducted an 8-hour application test of 5 kinds of samples. We evaluated the ease of applying the tape preparation, the feeling of discomfort during application, and the degree of skin irritation. The position of application was on the chest and abdomen, and each individual was randomly placed as far as possible. Table 2 shows the problems during the application of the sample and the number of occurrences.

From Table 2, vinyl alcohol content of 20 mol% and 40
It is clear that the tape formulation using a mol% ethylene-vinyl alcohol copolymer film as a support has the smallest number of problems in each evaluation item.

Example 3 Films of ethylene-vinyl alcohol copolymer having vinyl alcohol contents of 35, 40 and 45 mol% (thickness: 24 μm
m) was prepared. Each film was stored in two thermostats set at 20 ° C and 35 ° C and left for 2 hours. The film was taken out and the hardness of each film was evaluated by touch. The results are shown in Table 3.

It is clear from Table 3 that when the vinyl alcohol content is in the range of 35 to 45 mol%, a rigid support film is obtained during production and application (room temperature), and soft during application (body surface temperature). is there.

Example 4 A copolymer of 80 mol% butyl acrylate, 20 mol% N-vinyl-2-pyrrolidone and 0.05 mol% 1,6-hexanediol dimethacrylate was prepared and used as an adhesive base. A solution of nitroglycerin in ethyl acetate was added to this adhesive base to form a uniform solution. This was uniformly applied on a polyester film release liner and dried to form a pressure-sensitive adhesive layer having a thickness of 45 μm. The film shown in Table 4 was stuck on the surface of this adhesive layer as a support, and 5
The sample was cut into a size of 5 cm.

Immediately after the production of this sample, the nitroglycerin content per tape excluding the release liner was quantified. This was done by extracting the tape with methanol in a ground-in stopper Erlenmeyer flask for 20 hours and then subjecting it to liquid chromatography. A portion of the remaining sample was enclosed in an aluminum laminate film bag, stored at 40 ° C for 1 month, and the nitroglycerin content was measured by the same method. The results are shown in Table 4.

From Table 4, it can be seen that the ethylene-vinyl alcohol copolymer film having a vinyl alcohol content of 20 mol% or more has a very low transmittance of nitroglycerin and can be used as a support.

(Effects of the Invention) According to the present invention, as described above, the nitrite-based coronary vasodilator does not migrate to the support or permeate the support to be lost. A transdermal tape formulation is obtained. Since the support of this tape preparation is made of ethylene-vinyl alcohol copolymer of a specific composition, in addition to the above-mentioned drug impermeability, processability, dimensional and shape stability of the obtained tape preparation, use of tape preparation Excellent in sticking property at the time. Therefore, the tape preparation can be widely used as a percutaneous preparation for nitrite-based coronary vasodilators such as isosorbide nitrate and nitroglycerin.

Claims (4)

[Claims] 1. A transdermal administration tape preparation comprising a support and an adhesive layer containing a nitrite-based coronary vasodilator as an active ingredient, wherein the support comprises a vinyl alcohol unit [ -CH ₂ -CH (OH)-]
A tape preparation consisting of an ethylene-vinyl alcohol copolymer contained in a proportion of 20 to 45 mol%. 2. The content of the vinyl alcohol unit is 35 to
The tape preparation according to claim 1, which is 45 mol%. 3. The nitrite-based coronary vasodilator is at least one selected from the group consisting of amyl nitrite, nitroglycerin, pentaerythritol tetranitrate, triethanolamine trinitrate and isosorbide dinitrate. The tape preparation according to claim 1. 4. The pressure-sensitive adhesive base of the pressure-sensitive adhesive layer contains (meth) acrylic acid ester in a proportion of 50 mol% or more (co).
The tape preparation according to claim 1, wherein the tape preparation is a polymer and the ester moiety of the (meth) acrylic acid ester has 2 to 14 carbon atoms.