JPH0742228B2 - Pharmaceutical formulation - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a percutaneous absorption-type pharmaceutical preparation containing isosorbitol nitrate (ISDN) in a base, which is effective in suppressing or preventing an attack of angina.

Nitroglycerin is generally known as a drug for angina pectoris (coronary vasodilator), and the drug is used in the form of an ointment that can be sealed and stored.

Recently, a tape preparation has been proposed in which nitroglycerin is mixed with a pressure-sensitive adhesive and formed on a carrier, but it has a problem that it cannot be stored due to its high volatility and it has an excessive transdermal absorbability. Currently, it has not been put to practical use due to side effects such as a sudden drop in blood pressure.

On the other hand, ISDN is known as a drug for suppressing or preventing the attack of angina, and is generally used in the form of tablets.

From the viewpoint of inhibition or prevention, it is desirable that ISDN be provided in the body quantitatively and gradually over a long period of time.

In order to achieve such an object, various attempts have been made to control the dissolution capacity of tablets, but since the absorption capacity of the drug differs depending on the pH in the stomach or intestine, the presence or absence of contents, etc. It is something that is not supplied gradually for a long time in a fixed amount.

Therefore, an object of the present invention is to provide a medicinal preparation of the transdermal administration type, which supplies ISDN quantitatively and gradually over a long period of time.

Another object of the present invention is to provide a pharmaceutical preparation which does not cause skin irritation or cause adhesive residue during use or peeling.

The purpose of these is a pharmaceutical preparation comprising a base layer containing isosorbitol nitrate on the surface of a polyester film, wherein the base layer adhesive surface of the film is coated with a polymer substance layer to which the isosorbitol nitrate can migrate. It is achieved by preparing a pharmaceutical preparation.

The pharmaceutical formulation of the present invention not only solves the various drawbacks of the above-mentioned administration by tablets, but also generally gives an incorrect dose which is often observed when a solution containing a drug is sprayed or an ointment is used. It also solves various problems such as scratches on clothes and clothes, skin irritation, and problems such as adhesive residue.

The present inventors diligently studied from various angles about a transdermal preparation in which ISDN is reliably supplied from the skin and a certain amount is gradually supplied for a long time.

As a result, the formulation was intimately adhered to the skin for a certain period of time, the copolymer composing the base had an appropriate compatibility, and the drug was mostly crystallized in the base. It has been found that the minimum conditions are that they do not, that they have an appropriate release property from the base to the skin, and that they do not cause strong irritation even when applied to the skin for a long time.

And, a pharmaceutical preparation which can satisfy these conditions sufficiently and surely is a base material containing ISDN in an acrylic copolymer, a polymer material layer capable of transferring ISDN to the base adhesive surface of a polyester film. It was found that the film base material is coated on the surface of the substance layer.

The acrylic copolymer is preferably a copolymer of an acrylic acid ester having a C number of 4 to 10 and a polar monomer and / or a vinyl ester monomer copolymerizable with the ester, and the acrylic acid As the ester, n-
Examples thereof include butyl acrylate, isoamyl acrylate, hexyl acrylate, 2-ethylbutyl acrylate, isooctyl acrylate, 2-ethylhexyl acrylate, nonyl acrylate, isononyl acrylate, and decyl acrylate. As polar monomers, acrylic acid and methacrylic acid can be given. Examples of the vinyl ester monomer include vinyl acetate, vinyl propionate, styrenic acid, vinylpydrilones, (meth) acrylonitrile, and vinylimidazole, which have high solubility for drugs.

60-99: 1-40 (weight ratio) of these acrylic acid ester and polar monomer and / or vinyl ester monomer
It is preferable that the copolymerization is carried out at a ratio of, but the amount may exceed this range.

The amount of drug in the base consisting of the copolymer and the drug is 1 to
It is adjusted to be 25% by weight, preferably 2 to 15% by weight.

The base material thus prepared is usually formed on a flexible film substrate with a thickness of 5 to 300 μm.

The base material can be formed on the film entirely or partially, for example, in a streak shape, a lattice shape, a wavy shape, or the like.

One preferable modification of the preparation is to prepare a film base with a base using two or more kinds of acrylic acid ester or a copolymer having different compounding parts such as acrylic acid or methacrylic acid on one film base. On the other hand, it is formed in order from the one end with a predetermined width, alternately formed with a predetermined width, or formed into a sea-island shape. Such a modified base pattern uses a copolymer composed of a single Tg due to a difference in drug release rate or amount due to a slight difference in glass transition temperature (Tg) of the copolymer constituting the base. It has an advantage that the release time can be extended as a whole as compared with the conventional base. The effect of such a pattern can also be obtained by changing the thickness of the base material and / or the drug content.

Another preferred variation is the superposition of multiple base layers on a film substrate. At this time, the amount of the drug in the base layer is increased as it goes inward, and it is devised so that the drug is sequentially supplied to the outer base layer. Such a laminated type has an effect of preventing a large amount of drug from being transdermally absorbed immediately after the preparation is brought into close contact with the skin. It will be appreciated that it can be used as a formulation of

The polyester film that constitutes the film base that holds the base has a thickness of 6 to 9 μm, which does not cause a feeling of strangeness when applied to the skin, can prevent ISDN from scattering, and has flexibility. Is preferable because it does not cause skin irritation, but it may be out of this range.

Therefore, in the present invention, it is important that the polymer material layer to which ISDN can be transferred is provided on the base layer adhesive surface of the polyester film.

Examples of the substance forming the substance layer include ethylene-vinyl acetate copolymer (vinyl acetate content is preferably 22 to 40% by weight), polyvinyl acetate, etc., and the thickness is 100 μm or less. , Preferably 50 μm or less.

These material layers are entirely or partially coated on the surface of the polyester film, and effectively prevent ISDN from being absorbed and crystallized on the surface of the base layer to reduce the adhesive force of the base layer. When ISDN is supersaturated in the base layer, it is temporarily absorbed to prevent crystallization, and when ISDN in the base layer decreases, ISDN migrates from the substance layer to the base layer. . Therefore, the thickness of the base layer can control the ISDN content per unit area.

Further, it is preferable to select a film base material that is stretchable by at least 5% from the viewpoint of reducing peeling of the preparation and discomfort.

In order to more reliably achieve the purpose such as maintaining the shape retention of the base or enhancing the absorption ability of the drug from the skin, the base is blended with a filler or an absorption enhancer. be able to. In addition, a compounding agent such as a general adhesion-imparting resin, a softening agent or another drug such as an anti-itch agent may be added to the base in a small amount.

Examples of the filler include fine powder silica, titanium white, calcium carbonate, and the like. As the absorption promoter, alcohols such as propylene glycol and diethylene glycol, salicylic acid, urea, allantoin, dimethylsulfoxide, dimethylacetamide, dimethylformamide. , Diisopropyl adipate, diethyl sebacate, ethyl laurate, methyl nicotinate, lanolin and the like.

The former can be added in an amount of 20% by weight or less with respect to the base, and the latter can be added in an amount of 30% by weight or less.

The characteristics of the pharmaceutical preparation of the present invention are specifically demonstrated by the following examples, but the fact that ISDN is supplied and absorbed in the skin for a long time in a quantitative manner is remarkable.

Examples of the present invention will be shown below. "Parts in the text" means parts by weight.

Example 1 A four-necked flask was charged with 95 parts of isoamyl acrylate, 5 parts of methacrylic acid and 25 parts of ethyl acetate: heptane (3: 1) and charged with azobisisobutyronitrile as a polymerization initiator.
Add 0.25 part, start the polymerization reaction in an inert gas, and carry out polymerization for 7 hours at a reaction temperature of 58 to 62 ° C while adding ethyl acetate dropwise. Solid content concentration of 34.8% by weight, viscosity (at 30 ° C) of 330 poise A solution of the copolymer is obtained.

To 90 parts of the solid content of the copolymer solution, 10 parts of ISDN was added and stirred, and this was mixed with an ethylene-vinyl acetate copolymer film (EVA, vinyl acetate content 22% by weight) having a thickness of 50 μm and 6 μm. On the EVA surface of the laminated film with the polyester film of (1), the dried film is applied and dried to a thickness of 50 μm to obtain a pharmaceutical preparation.

Example 2 Using 94 parts of 2-ethylhexyl acrylate and 6 parts of acrylic acid, a copolymer solution (solid content concentration 30% by weight, viscosity 280 poise) is obtained in the same manner as in Example 1 below.

13 parts of ISDN was added to 87 parts of the solid content of this copolymer solution, and the EVA surface of the laminated film of the EVA film having a thickness of 40 μm (vinyl acetate content 40% by weight) and the polyester film having a thickness of 6 μm was dried. A pharmaceutical preparation is obtained by coating and drying so that the thickness afterwards becomes 50 μm.

Example 3 The same as Example 1 except that a polyester film having a thickness of 9 μm was used as the carrier.

Tables 1 and 2 show the test results of Examples 1 to 3.

The samples in Table 1 were used 4 days after preparation of the pharmaceutical preparation.

Test method in Table 1 Drug residual rate: Sample (5 cm x 5 cm) was attached to the inside of the upper arm for 24 hours, peeled off, dissolved in 30 ml of ethyl acetate (shake at 40 ° C for 26 hours), and further with ethyl acetate Make up to 50 ml and quantify by gas chromatography. 10 conformations
Calculate as 0%.

Test method in Table 2 A sample (10 cm x 10 cm) was attached to the chest of a human, and after a predetermined time, blood was collected in 3 ml portions, plasma was separated, and 2 ml was collected.
Extracted with n-hexane, centrifuged and placed under an inert gas.
Concentrate to 0.5 ml. It was further extracted with 1 ml of acetonitrile and extracted with acetonitrile, the acetonitrile layer was dried under an inert gas, dissolved in 100 µ of benzene, and measured by gas chromatography.

As is clear from the above examples, the pharmaceutical preparation of the present invention comprises
The fact that the adhesiveness to the skin is excellent and the release property is good is remarkable.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Toshiyuki Yoshikawa 1-2-1, Shimohozumi, Ibaraki City, Osaka Prefecture Inspector, Nitto Electric Industry Co., Ltd. Shoei Hoshino

Claims (5)

[Claims] 1. A pharmaceutical preparation comprising a base layer containing isosorbitol nitrate on the surface of a polyester film, wherein the base material adhesive surface of the film is coated with a polymer substance layer to which isosorbitol nitrate can migrate. The pharmaceutical formulation which is being used. 2. A polyester film having a thickness of 6 to 9 μm.
The pharmaceutical preparation according to claim 1, which is 3. The pharmaceutical preparation according to claim 1, wherein the content of isosorbitol nitrate in the base layer is 1 to 25% by weight. 4. The pharmaceutical preparation according to claim 1, wherein the polymer substance layer is one selected from the group consisting of polyvinyl acetate and ethylene-vinyl acetate copolymer. 5. The pharmaceutical preparation according to claim 4, wherein an ethylene-vinyl acetate copolymer having a vinyl acetate content of 22 to 40% by weight is used.