JPH03223212A - Gel preparation for transcutaneous absorption - Google Patents

Abstract

PURPOSE:To obtain a gel preparation for transcutaneous absorption having well-balanced skin adhesivity and skin stimulation by including an acrylic acid ester polymer and a large amount of a liquid component compatible to the polymer at a specific ratio in a crosslinked gel layer containing isosorbide dinitrate. CONSTITUTION:The objective gel preparation for transcutaneous absorption is produced by compounding (A) isosorbide dinitrate with (B) an acrylic acid ester polymer having high stability and releasability to the component A, preferably an acrylic copolymer produced by copolymerizing an alkyl (meth)acrylate and (meth)acrylic acid and (C) a liquid component compatible to the component B at a weight ratio (B:C) of 1.0:(0.25-2.0), crosslinking the composition and forming the crosslinked gel layer on one surface of a substrate. The preparation can be peeled off from the applied skin while giving little pain or skin irritation caused by the bonding force of the preparation. It has proper and balanced skin adhesivity and non-stimulating property to the skin and exhibits sufficient effect on the prevention of fit of e.g. stenocardia.

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to a transdermal absorption gel preparation that is applied to the skin to continuously administer isosorbide dinitrate from the skin into the living body.

<Prior Art> In recent years, various transdermal absorption preparations such as poultices and tapes that are applied to the skin have been developed for administering drugs into living bodies through the skin.

In order to securely fix the preparation to the skin surface to which it is applied, such patch-type preparations usually have an adhesive layer on the skin-contacting part of the preparation that has a relatively strong adhesive force, or a strong adhesive layer. The entire formulation is overcoated with a sticky adhesive sheet, and the adhesive force of this sheet is used to fix it on the skin.

<Problem to be solved by the invention> However, patch-type transdermal absorption preparations need to be firmly fixed to the skin surface in order to improve the transdermal transfer of the drug, but on the other hand, if the skin adhesiveness is too large, When the preparation is peeled off from the skin after use, pain and exfoliation due to physical irritation may occur, and sometimes severe skin irritation may occur.

Therefore, while skin adhesion is an important consideration from a practical point of view when developing patch-type transdermal absorption preparations, it is also important to consider skin irritation. The actual situation is whether the development of good formulations is desired.

On the other hand, transdermal absorption preparations containing isosorbitone nitrate have already been developed as preparations for administering drugs into living bodies through transdermal absorption.

This preparation is a so-called tape-like preparation containing isosorbide dinitrate in a specific adhesive, and is sufficiently effective in preventing attacks such as angina pectoris. However, since this preparation contains isosolhydrodinitrate in the adhesive, sufficient care must be taken in preparing the preparation so as not to cause the above-mentioned skin irritation.

<Means for Solving the Problems> Therefore, the present inventors have conducted intensive research to solve the above problems, and have found that an acrylic ester polymer with relatively good stability and release properties against isosorbide dinitrate has been developed. When a large amount of liquid ingredients are mixed in a specific ratio and cross-linked to form an oily gel, it prevents a decrease in cohesive force and also relieves and disperses the stress applied to the skin surface when the formulation is peeled off, improving skin adhesion. It was discovered that the skin irritation was well balanced, and the present invention was completed.

That is, the present invention includes the following (a). (c) A gel preparation in which a crosslinked gel layer formed by crosslinking a formulation containing the component (b) is formed on one side of a support, wherein the weight ratio of the component (bl component and the component (c) (b)) is , 1.0:0.25~1.0:2
．． The purpose of the present invention is to provide a transdermal absorption gel preparation characterized in that:

(al isosorbide dinitrate.

(bl acrylic ester polymer . (c) (b1 (liquid component that is compatible with the bl component).

The support used in the transdermal absorption gel preparation of the present invention is preferably one that does not cause a decrease in the content of the liquid component or isosolpid dinitrate contained in the crosslinked gel layer as it passes through the support and is lost from the back side. .

Specifically, single films such as polyester, nylon, saran, polyethylene, polypropylene, polyvinyl chloride, ethylene-ethyl acrylate copolymer, polytetrafluoroethylene, Surlyn, metal foil, etc., or laminate films of these may be used. can. Among these, in order to improve the adhesion (anchoring force) between the support and the cross-linked gel layer described below, the support is made of a laminate film of a non-porous sheet made of the above material and a porous film, and the porous sheet side is It is preferable to form a crosslinked gel layer.

Such a porous film is not particularly limited as long as it can improve the anchoring force with the cross-linked gel layer, such as paper,
Examples include woven fabrics, non-woven fabrics, and mechanically perforated notebooks, with paper, woven fabrics, and non-woven fabrics being particularly preferred. The thickness of the porous film is 10 to 500 μm in consideration of improvement in anchoring power and flexibility of the entire formulation, and in the case of thin formulations such as plaster type or adhesive tape type, the thickness is in the range of 10 to 200 μm.

In addition, when using woven fabric or non-woven fabric as the porous film,
The basis weight is 5 to 30 g/rd, preferably 8 to 20 g
/m is preferable from the viewpoint of improving anchoring power.

In the present invention, the crosslinked gel layer formed on one side of the support is composed of isosorbide dinitrate (component (a)), an acrylic copolymer (component (b)) made of a specific copolymer, and (component (b)). liquid component that is compatible with the component (. (c) (b1
It is a layer with a crosslinked structure containing ingredients), and has appropriate skin adhesive strength and cohesive strength. The adhesive strength to Bakelite board (measurement method will be described later) is 70~
250g/12 width, 20-80 in probe tack test
It shows a value of about g.

The acrylic copolymer serves as the main base material that constitutes the crosslinked gel layer together with the liquid component described below, and maintains a compatible state with the liquid component to provide good adhesion and shape retention to the skin surface. It is something that can be demonstrated. Note that rubber-based polymers such as natural rubber and synthetic rubber, and silicone-based polymers are not preferred because they may not have sufficient compatibility with the liquid component used in the present invention, or the solubility and release properties of the drug may be extremely low. Furthermore, compared to the acrylic copolymer used in the present invention, it is difficult to adjust the amount of functional groups involved in the crosslinking reaction with such polymers, and it is difficult to perform crosslinking treatment with reproducibility. It cannot be said that it is suitable for

Acrylic ester polymer used in the present invention ((b)
As the component), a polymer obtained by polymerizing a (meth)acrylic acid alkyl ester, which is usually used in the preparation of adhesives, as a main monomer can be used.

Among such polymers, a copolymer of a (meth)acrylic acid alkyl ester and (meth)acrylic acid is particularly preferably used for isofluvitodinitrate.

As the (meth)acrylic acid alkyl ester, (meth)acrylic acid alkyl esters having an alkyl group having 4 or more carbon atoms are preferable.

Specifically, the (meth)acrylic acid alkyl ester has an alkyl group, a straight chain alkyl group or a branched alkyl group such as butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undenol, dodecyl, tridecyl, etc. Examples include (meth)acrylic acid alkyl esters, and one or more types of these can be used.

In addition, the above (meth)acrylic acid alkyl ester is (
Copolymerized with meth)acrylic acid. (Meth)acrylic acid can improve cohesive force when added in a relatively small amount, and also acts as a useful component in the reaction by crosslinking means described below.

The amount of each of the above monomers in copolymerization can be arbitrarily set depending on the gel properties of the desired gel preparation and the release properties of isosolpid dinitrate, but (meth)
Acrylic acid alkyl ester/(meth)acrylic acid = 9
0-99/1-10 (weight ratio), preferably 92-97
/3 to 8 (weight ratio).

The liquid component (components (c) and (b)) used in the present invention has properties that are compatible with the above-mentioned acrylic copolymer (component (b)), and it plasticizes the crosslinked gel layer to create a soft feel. By providing this, it has the role of reducing pain and skin irritation caused by skin adhesive force when the crosslinked gel layer is peeled off from the skin surface.

Furthermore, since the cross-linked gel layer is plasticized, the isosorbide dinitrate contained in the cross-linked gel layer has good free diffusivity and release properties are also improved.

Therefore, this liquid component may be one that has a plasticizing effect, but in order to improve the percutaneous absorption of the coexisting drug, a liquid component that has an absorption promoting effect may also be used.

Specifically, such liquid components include ethylene glycol, diethylene glycol, triethylene glycol, propylene glycol, polyethylene glycol,
Glycols such as polypropylene glycol, oils and fats such as olive oil, castor oil, squalene, lanolin, dimethyldenyl sulfoxide, methyl octyl sulfoxide, dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide, dimethyl lauryl amide,
organic solvents such as dodecylpyrrolidone, isosorbitol, liquid surfactants, plasticizers such as diisopropyl adibate, phthalate esters, diethyl sebacate,
Hydrocarbons such as liquid paraffin, ethoxylated stearyl alcohol, glycerin esters, isopropyl myristate, isotridecyl myristate, ethyl laurate, N-methylpyrrolidone, ethyl oleate, oleic acid, diisopropyl adipate, isopropyl palmitate, palmitin. Octyl acid, 1. Examples include 3-butanediol, and one or more of these are used in combination. The acrylic copolymer (component (b)) and the liquid component (component (c) and (b)) have a weight ratio of 1
．． 0: 0.25-1.0+2.0. Preferably 1.
0:0.4~1.0:2.0, 1.0+0.6~
It is contained in the crosslinked gel layer at a ratio of 1.0:1.8.

In addition, the amount of liquid ingredients contained in conventional formulations is usually
The amount of liquid component is less than 1.00.25, and such a content may not reach a practical level of reducing skin irritation.

In the present invention, after the components (al to (c)) are blended as described above, they are crosslinked using an appropriate crosslinking means to form a gel state, thereby preventing the contained liquid components from flowing out and imparting cohesive force. The crosslinking reaction usually occurs on the above (bl component).Crosslinking treatment includes physical crosslinking by radiation irradiation such as ultraviolet ray irradiation and electron beam irradiation, and polyisocyanate compounds, organic peroxides, organometallic salts, Chemical crosslinking treatment using crosslinking agents such as metal alcoholades, metal chelate compounds, and polyfunctional compounds is used. Among these crosslinking methods, when radiation irradiation or organic peroxides are used, decomposition may occur depending on the conditions. Reactions may occur, and metal salts and organic metal salts used in highly reactive isocyanate formation and normal crosslinking reactions may cause a thickening phenomenon of the solution after blending, resulting in poor workability. A method of copolymerizing a polyfunctional monomer such as diacrylate with an acrylic acid ester polymer may also be considered, but in this case as well, there is a possibility that the solution viscosity increases during polymerization. Among these crosslinking agents, trifunctional isonoanates, metal alcoholades made of titanium or aluminum, or metal chelate compounds are preferred from the point of view of reactivity and handling. It does not cause thickening phenomenon and has excellent workability.

In this case, the blending amount of the crosslinking agent is 100% of the acrylic copolymer.
The amount is about 0.01 to 2.0 parts by weight.

The crosslinked gel layer in the present invention contains isosorbide dinitrate as a medicinal ingredient. The content of isoenorhydrocinitrate can be set appropriately depending on the purpose of administration, but it is usually 2 to 50% by weight in the crosslinked gel layer.
It is preferably contained in a range of 10 to 40% by weight. If the content is less than 2% by weight, it cannot be expected that a therapeutically effective amount of isosol dinitrate will be released, and if it is contained in an amount exceeding 50% by weight, the effect may be increased by increasing the amount. Not only is this economically disadvantageous as it cannot be seen, but it also has poor adhesion to the skin. However, from the viewpoint of providing sustained release properties over a long period of time, increasing the amount of release by increasing the content per unit area, and miniaturizing the formulation, isosolhuman nonitrate is used regardless of the above weight range. It is preferable to blend the compound at a saturation solubility or higher in the crosslinked gel layer.

In addition, when containing isosorbide dinitrate in the crosslinked gel layer, it is preferable to contain it in the crosslinked gel layer as described above, but it is preferable to contain isosorbide dinitrate in a suitable solvent without containing it in the crosslinked gel layer. It is also possible to form a solution by dissolving it in a solution and interposing it at the interface between the crosslinked gel layer and the support, and sealing the periphery of the preparation. By separating isosolhiton nitrate from the crosslinked gel layer in this manner, it is possible to stably retain isosolhiton nitrate even during oral storage. In this case, by interposing a microporous film between the isosorbitocinitrate-containing layer and the crosslinked gel layer, it is also possible to strictly control the release of isosorbitocinitrate.

<Effects of the Invention> The transdermal absorption gel preparation of the present invention has the above-mentioned structure, and consists of a cross-linked gel layer or an acrylic acid ester polymer and a large amount of liquid component compatible with this in a specific ratio. Since it contains the crosslinked gel layer, it is possible to reduce skin irritation while imparting a soft feel to the crosslinked gel layer and maintaining cohesive force.

Therefore, when the preparation of the present invention is peeled off from the skin surface to which it is applied, there is less pain and skin irritation caused by the adhesive force, and a balance between appropriate skin adhesion and non-irritation is achieved. In addition, as an indicator that the gel preparation can be peeled off and removed from the skin surface without pain, the product of the present invention has a lower amount of exfoliation of keratin, and the amount of exfoliation of keratin using Hollandia is 115 to 2/2 compared to the control product that does not contain a liquid component. 3. Outside this range, it may cause pain when peeled off or lack skin adhesion.

Moreover, since it is a gel structure, the degree of freedom of diffusion and movement of isosorbitocinitrate is large, and the release property is good.

<Examples> Examples of the present invention will be shown below and explained in more detail. In addition, in the following, parts and % mean parts by weight and weight %.

Example 1 2-ethylhexyl acrylate 9 under an inert gas atmosphere
5 parts of acrylic acid and 5 parts of acrylic acid were copolymerized in ethyl acetate to prepare an acrylic copolymer solution.

20 parts of inosolhydrocynitrate and 40 parts of isopropyl myristate were mixed with 40 parts of the solid content of this solution, and 0.2 parts of aluminum tris(acetylacetate) was mixed with 99.8 parts of the above acrylic copolymer. ester) was added as a 10% acetylacetone solution, and ethyl acetate was further added to adjust the viscosity.

The obtained viscous solution was applied onto a polyester separator having a thickness of 75 μm so as to have a dry thickness of 40 μm, and dried to form a crosslinked gel layer.

The transdermal absorption gel preparation of the present invention was prepared by laminating the nonwoven surface of a laminate film obtained by extruding 2 μm thick polyester onto a polyester nonwoven fabric (12 g/rrr) as a support to the thus obtained crosslinked gel layer. Obtained.

Example 2 A transdermal absorption gel preparation of the present invention was obtained in the same manner as in Example 1, except that the thickness of the crosslinked gel layer in Example 1 was changed to 120 μm.

Example 3 A transdermal absorption gel preparation of the present invention was obtained in the same manner as in Example 1 except that isopropyl myristate was replaced with octyl valmitate.

Example 4 A transdermal absorption gel preparation of the present invention was obtained in the same manner as in Example 3, except that the thickness of the crosslinked gel layer in Example 3 was changed to 120 μm.

Example 5 30 parts of solid content of the acrylic copolymer solution prepared in Example 1 was mixed with 30 parts of isosolpitodinitrate and 40 parts of ittrizotul myristate, and 99 parts of the above copolymer was mixed.
．． To 7 parts, 0.3 parts of trifunctional isocyanate (Coronate HL, manufactured by Nippon Polyurethane Co., Ltd.) was added as a 10% ethyl acetate solution, and ethyl acetate was further added to adjust the viscosity.

The resulting viscous solution was dried in the same manner as in Example 1, and
After forming a crosslinked gel layer with a thickness of μm, the nonwoven fabric surface of the support used in Example 1 was bonded to this crosslinked gel layer to obtain a transdermal absorption gel preparation of the present invention.

Example 6 A transdermal absorption gel preparation of the present invention was obtained in the same manner as in Example 5, except that the thickness of the crosslinked gel layer was changed to 120 μm.

Comparative Example 1 Example 1 except that 20 parts of isosorbide dinitrate was mixed with 80 parts of the solid content of the acrylic copolymer solution prepared in Example 1, and ethyl acetate was further added to adjust the viscosity. In the same manner as above, a crosslinked transdermal absorption preparation containing no liquid component was obtained.

Comparative Example 2 A cross-linked transdermal preparation containing no liquid component was obtained in the same manner as in Comparative Example 1, except that the thickness of the cross-linked gel layer was 120 μm.

Comparative Example 3 Instead of the acrylic copolymer prepared in Comparative Example 1, 10 parts of polyisobutylene (viscosity average molecular weight 990,000), 15 parts polyisobutylene (viscosity average molecular weight 60,000), polyisobutylene (viscosity average molecular weight 1260) The liquid component was prepared in the same manner as in Comparative Example 1, except that a polyisobutylene rubber-based polymer consisting of 3 parts of ) and 7 parts of an alicyclic petroleum resin (softening point 100''C) was used, and toluene was used instead of ethyl acetate. A rubber-based preparation containing no .

Comparative Example 4 A transdermal absorption preparation containing no liquid component and not subjected to crosslinking treatment was obtained in the same manner as in Comparative Example 1 except that no crosslinking agent was added.

Comparative Example 5 A gel preparation containing a liquid component or not subjected to crosslinking treatment was obtained in the same manner as in Example 1 except that no crosslinking agent was added.

It should be noted that this gel preparation significantly suffered from cohesive failure and could not be subjected to the tests described below.

Comparative Example 6 In Example 1, the solid content of the acrylic copolymer was 65 parts,
A crosslinked gel preparation containing a liquid component was obtained in the same manner as in Example 1, except that 20 parts of isosorbide dinitrate and 15 parts of isopropyl myristate were blended.

Experimental Example The preparations obtained in the above Examples and Comparative Examples were used at 50aI! (
71mm square) and store it at room temperature.
After leaving it for a while, the following test was conducted. In addition, since the dyeing solution will be absorbed by the nonwoven fabric used as the support, making the measurement very inaccurate, we used a single-layer film (9 μm thick) with no nonwoven fabric laminated as the support for the sample used to measure the amount of keratin exfoliation. It was used.

The results are shown in Tables 1 and 2.

[Rabbit patch test]

The samples obtained in each Example and Comparative Example were pasted on the back of a rabbit whose hair had been removed in advance, and 0.2, 5.4, 0.6
．． Two blood samples were collected at each lapse of time of 0.8.0, and the concentration of isosorbide dinitrate in the blood was measured by gas chromatography.

[Adhesion test]

Each sample on a strip cut to a diameter of 12 mm was pasted on a Bakelite plate, and a roller with a load of 300 g was moved back and forth once to bring it into close contact, and then it was peeled off in a 180 degree direction at a speed of 300 strokes/min. The force was measured.

[Tack test]

Evaluation was made by probe tack using a rheometer.

The sample was fixed on a metal plate with the side to be applied to the skin facing up, and a spherical probe with a diameter of 10 mm was attached to it with a load of 100 g.
After making contact at a speed of cm/min, this state was maintained for 20 seconds, and then the peeling force was measured when the spherical probe was pulled away at the same speed.

[Pain during peeling]

The sample was pasted on the inside of the upper arm of 5 volunteers, and 3
It was peeled off after 0 minutes and the pain at that time was measured. The evaluation was on a five-point scale, with the least painful score being one point, and the average score was calculated. Note that Comparative Example 1 was evaluated as a standard with 5 points.

[Amount of exfoliation]

A circular sample cut into a diameter of 16 mm was pasted on the inner side of the upper arm of three volunteers (A, B, and C) for 30 minutes, and after peeling off, the sample was soaked in a staining solution (Gentian V
ioleto, 5%, Br1llian green
The cells were immersed in 98.5% distilled water) for 3 minutes, and then washed with water to stain the corneocytes.

These samples were immersed in a 5% sodium dodecyl sulfate aqueous solution overnight to extract a staining solution, and the absorbance (595 nm) of this extract was measured to compare the number of exfoliated corneocytes. That is, it was determined that the higher the measured absorbance, the greater the exfoliated corneal mass.

Note that a good correlation was confirmed between the number of exfoliated corneocytes counted using a stereomicroscope and the above absorbance.

[Margin below]

Table 1 Table 2 As is clear from Tables 1 and 2 above, the transdermal absorption gel preparation of the present invention causes less pain when peeled off compared to the comparative example product, and also reduces the amount of exfoliated dead skin. There are few. Furthermore, it was found that isosorbitocinitrate is absorbed rapidly and in large quantities through the skin.

Claims (2)

[Claims] (1) A gel preparation in which a crosslinked gel layer formed by crosslinking a formulation containing the following components (a) to (c) is formed on one side of a support, and the content weight of components (b) and (c) The ratio is 1.0
:0.25 to 1.0:2.0. (a) Isosorbide dinitrate. (b) Acrylic acid ester polymer. (c) A liquid component that is compatible with component (b). (2) The transdermal gel formulation according to claim 1, wherein component (b) is an acrylic copolymer obtained by copolymerizing a (meth)acrylic acid alkyl ester and (meth)acrylic acid.