JP2970772B2 - Transdermal gel preparation - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a transdermal absorption gel preparation which is adhered to a skin surface and continuously administers isosorbide dinitrate from the skin surface into a living body.

<Prior Art> In recent years, various skin-adhesive external preparations such as haptics and tapes have been developed as transdermal preparations for administering a drug into a living body through the skin surface.

Such a patch-type preparation is usually provided with an adhesive layer for fixing the skin surface having a relatively strong adhesive force to the skin contact portion of the preparation, or for the purpose of securely fixing the preparation to the applied skin surface, The entire preparation is overcoated with a pressure-sensitive adhesive sheet, and the skin is fixed by the adhesive force of this sheet.

<Problems to be Solved by the Invention> However, the patch-type transdermal preparation must be securely fixed to the skin surface in order to make the drug easily transfer to the skin, but if the skin adhesiveness is too large. When the preparation is peeled off from the skin surface after use, pain or exfoliation due to physical irritation occurs, and sometimes significant skin irritation may occur.

Therefore, skin adhesion is a practically important study item in the development of a patch-type transdermal preparation, but examination of skin irritation is also important, and skin irritation is low and the preparation is well fixed on the skin. In fact, the development of new formulations is desired.

On the other hand, a transdermal preparation containing isosorbide dinitrate has already been developed as a preparation for administering a drug into a living body by transdermal absorption.

This preparation is a so-called tape-like preparation containing isosorbide dinitrate in a specific adhesive, and exhibits a sufficient effect for preventing attacks such as angina pectoris.
However, since this preparation contains isosorbide dinitrate 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> The inventors of the present invention have conducted intensive studies in order to solve the above problems, and as a result, it has been found that acrylate polymers having a good stability and a good release property with respect to isosorbide dinitrate can be obtained. When a large amount of liquid components are blended in a specific ratio and subjected to cross-linking treatment and gelled to an oily gel state, it can prevent the decrease in cohesive force and reduce and disperse the stress applied to the skin surface when the formulation is peeled off, and improve skin adhesion It has been found that the balance of skin irritation is good, and the present invention has been completed.

That is, the present invention is a gel preparation comprising a crosslinked gel layer formed by crosslinking a composition containing the following components (a) to (c) formed on one surface of a support, wherein the components (b) and (c) It is intended to provide a transdermal absorption gel preparation characterized in that the content weight ratio is 1.0: 0.25 to 1.0: 2.0.

(A) isosorbide dinitrate.

(B) Acrylic ester-based polymers.

(C) A liquid component compatible with the component (b).

As a support used in the transdermal absorption gel preparation of the present invention,
It is preferable that the liquid component and isosorbide dinitrate contained in the crosslinked gel layer are not lost from the back surface through the support and cause a decrease in the content. Specifically, polyester,
Nylon, Saran, polyethylene, polypropylene, polyvinyl chloride, ethylene-ethyl acrylate copolymer,
A single film such as polytetrafluoroethylene, Surlyn, or a metal foil, or a laminated film thereof can be used. Among these, in order to improve the adhesiveness (anchoring force) between the support and the later-described crosslinked gel layer, the support is a laminate film of a non-porous sheet and a porous film made of the above-mentioned material, It is preferable to form a crosslinked gel layer on the surface.

Such a porous film is not particularly limited as long as the anchoring force with the crosslinked gel layer is improved, and examples thereof include paper, woven fabric, nonwoven fabric, and a sheet that has been mechanically perforated. Woven and non-woven fabrics are preferred. The thickness of the porous film is in the range of 10 to 500 μm in consideration of the improvement of anchoring force and flexibility of the whole preparation, and 10 to 200 μm in the case of a thin preparation such as a plaster type or an adhesive tape type.

In the case of using a woven fabric or nonwoven fabric as the porous film, 5 to 30 g / m ² of basis weight, and preferably those be 8 to 20 g / m ² from the viewpoint of improvement of anchoring force.

In the present invention, the crosslinked gel layer formed on one surface of the support is provided with isosorbide dinitrate (component (a)),
Acrylic copolymer composed of a specific copolymer (component (b)) and a liquid component compatible with component (b) (component (c))
And has a suitable skin adhesive strength and a cohesive strength. Adhesive strength is 70-250g / 12m in adhesive strength to bakelite plate (measurement method will be described later)
It shows a value of about 20 to 80 g in a m-width and probe tack test.

The acrylic copolymer serves as a main base material for forming a crosslinked gel layer together with a liquid component described below, and maintains a compatible state with the liquid component to provide good adhesion to the skin surface and good shape retention. To demonstrate. Incidentally, rubber-based or silicone-based polymers such as natural rubber and synthetic rubber are not preferred because they have insufficient compatibility with the liquid component used in the present invention, or have extremely low solubility and release properties of drugs. Also,
Such a polymer has a problem that it is difficult to adjust the amount of a functional group involved in a crosslinking reaction and the like in comparison with the acrylic copolymer used in the present invention, and it is difficult to perform a reproducible crosslinking treatment. Not a thing.

As the acrylate polymer (component (b)) used in the present invention, a polymer obtained by polymerizing a (meth) acrylic acid alkyl ester, which is usually used for preparing an adhesive, as a main component monomer can be used. As a polymer particularly preferably used for isosorbide dinitrate among such polymers, a copolymer of an alkyl (meth) acrylate and (meth) acrylic acid is used. As the alkyl (meth) acrylate, an alkyl (meth) acrylate in which the alkyl group has 4 or more carbon atoms is preferable.

As the alkyl (meth) acrylate, specifically, the alkyl group has a linear alkyl group such as butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl or a branched alkyl group ( Examples thereof include alkyl (meth) acrylates, which may be used alone or in combination of two or more.

Further, (meth) acrylic acid is copolymerized with the alkyl (meth) acrylate. The addition of (meth) acrylic acid can improve the cohesion by adding a relatively small amount, and also acts as a useful component in a reaction by a crosslinking means described later.

The amount of each of the above monomers to be copolymerized can be arbitrarily set according to the gel properties of the target gel preparation, the release of isosorbide dinitrate, and the like. / (Meth) acrylic acid = 90-99 / 1-10 (weight ratio), preferably 92-97 / 3-8
(Weight ratio).

The liquid component (component (c)) used in the present invention has a property of being compatible with the acrylic copolymer (component (b)), and provides a soft feeling by plasticizing the crosslinked gel layer. Thus, when the crosslinked gel layer is peeled from the skin surface, it has a role of reducing pain and skin irritation caused by skin adhesion. In addition, since the crosslinked gel layer is plasticized, the free diffusibility of isosorbide dinitrate contained in the crosslinked gel layer is improved, and the releasability is improved. Therefore, the liquid component only needs to have a plasticizing action, but it is also possible to use a liquid component having an absorption promoting action in order to improve the transdermal absorbability of the coexisting drug.

Specific examples of such liquid components include glycols such as ethylene glycol, diethylene glycol, triethylene glycol, propylene glycol, polyethylene glycol, and polypropylene glycol.
Fats and oils such as olive oil, castor oil, squalene, and lanolin, organic solvents such as dimethyldecyl sulfoxide, methyloctyl sulfoxide, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, dimethyllauramide, dodecylpyrrolidone, and isosorbitol, and liquid surfactant. Agents, plasticizers such as diisopropyl adipate, phthalates, diethyl sebacate, hydrocarbons such as liquid paraffin, ethoxylated stearyl alcohol, glycerin esters, isopropyl myristate, isotridecyl myristate, ethyl laurate, N-methyl Pyrrolidone, ethyl oleate, oleic acid, diisopropyl adipate, isopropyl palmitate, octyl palmitate, 1,3-butanediol, etc. It is, used by blending one or more of these. The weight ratio of the acrylic copolymer (component (b)) and the liquid component (component (c)) is 1.0: 0.25.
~ 1.0: 2.0, preferably 1.0: 0.4 ~ 1.0: 2.0, 1.0: 0.6 ~ 1.
It is contained in the crosslinked gel layer at a ratio of 0: 1.8. In addition, the amount of the liquid component blended in the conventional formulation is usually 1.0: 0.25
The liquid component content is lower than that, and such a content may not reach a practical level of skin irritation reduction.

In the present invention, after the components (a) to (c) are blended as described above, a cross-linking treatment is performed by an appropriate cross-linking means to form a gel state, thereby preventing the contained liquid component from flowing out and imparting a cohesive force. . The cross-linking reaction usually occurs on the component (b). Crosslinking treatment is physical crosslinking by irradiation such as ultraviolet irradiation or electron beam irradiation, polyisocyanate compound, organic peroxide, organic metal salt, metal alcoholate,
Chemical cross-linking treatment using a cross-linking agent such as a metal chelate compound and a polyfunctional compound is used. When radiation irradiation or an organic peroxide is used among these crosslinking means, a decomposition reaction may occur depending on conditions, and a highly reactive isocyanate, a metal salt or an organic metal salt used for a usual crosslinking reaction may be used. In this case, the viscosity of the solution may increase after blending, resulting in poor workability. In addition, a method in which a polyfunctional monomer such as diacrylate is previously copolymerized with an acrylate-based polymer can be considered, but also in this case, the solution viscosity may increase during polymerization. Therefore, in the present invention, a metal alcoholate or a metal chelate compound composed of trifunctional isocyanate, titanium or aluminum is preferable from the viewpoint of reactivity and handleability among these crosslinking agents. These cross-linking agents do not cause a thickening phenomenon of the solution until they are coated and dried, and are extremely excellent in workability. In this case, the blending amount of the crosslinking agent is about 0.01 to 2.0 parts by weight based on 100 parts by weight of the acrylic copolymer.

The crosslinked gel layer in the present invention contains isosorbide dinitrate as a medicinal component. Although the content of isosorbide dinitrate can be appropriately set according to the purpose of administration, it is usually contained in the crosslinked gel layer in a range of 2 to 50% by weight, preferably 10 to 40% by weight. Content 2
If the amount is less than 50% by weight, no therapeutically effective amount of isosorbide dinitrate can be expected to be released. If the amount exceeds 50% by weight, the effect of increasing the amount cannot be seen and the effect is not increased. Not only is it disadvantageous, but also poor adhesion to the skin. However, from the viewpoint of imparting sustained release over a long period of time, increasing the amount of release by increasing the content per unit area, and miniaturizing the formulation, regardless of the above weight range, isosorbide dinitrate is a crosslinked gel. It is preferred that the compound is blended at a saturation solubility or higher in the layer.

Further, when isosorbide dinitrate is contained in the crosslinked gel layer, it is preferable to contain it in the crosslinked gel layer as described above, but it is preferable that the isosorbide dinitrate be dissolved in an appropriate solvent without being contained in the crosslinked gel layer. Then, the solution may be in the form of a solution and interposed at the interface between the crosslinked gel layer and the support, so that the periphery of the preparation can be sealed. By separating isosorbide dinitrate from the crosslinked gel layer in this manner, isosorbide dinitrate can be stably maintained even during storage over time. In this case, the release of isosorbide dinitrate can be strictly controlled by interposing a microporous film between the layer containing isosorbide dinitrate and the crosslinked gel layer.

<Effect of the Invention> The percutaneous absorption gel preparation of the present invention is constituted as described above, and the crosslinked gel layer is composed of an acrylate polymer and a large amount of a liquid component compatible therewith in a specific ratio. As a result, skin irritation can be reduced while imparting a soft feeling to the crosslinked gel layer and maintaining cohesion. Therefore, when the preparation of the present invention is peeled off from the skin surface to be applied, pain and skin irritation caused by the adhesive force are small, and a balance between appropriate skin adhesion and skin non-irritation is achieved. In addition, as an index capable of peeling and removing the gel preparation from the skin surface without pain, the product of the present invention has a small amount of exfoliation of keratin,
The amount of exfoliation using volunteers is in the range of 1/5 to 2/3 as compared with the control product containing no liquid component, and other than this range, pain may occur at the time of exfoliation or skin adhesion may be insufficient .

In addition, since it has a gel structure, the degree of freedom of diffusion and movement of isosorbide dinitrate is large, and the release property is good.

<Example> An example of the present invention will be shown below, and will be described more specifically. In the following, parts and% mean parts by weight and% by weight, respectively.

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

Isosorbide dinitrate 20 was added to 40 parts of the solid content of this solution.
Isopropyl myristate, 40 parts of isopropyl myristate, and 99.8 parts of the acrylic copolymer, 0.2 parts of aluminum tris (acetylacetonate) was added as a 10% acetylacetone solution, and ethyl acetate was further added to adjust the viscosity. Done.

The resulting viscous solution was applied on a 75 μm thick polyester separator so as to have a thickness of 40 μm after drying, and dried to form a crosslinked gel layer.

The percutaneous absorption gel preparation of the present invention is obtained by laminating the crosslinked gel layer thus obtained as a support with a nonwoven fabric surface of a laminate film obtained by extrusion-molding a 2 μm thick polyester on a polyester nonwoven fabric (12 g / m ² ). I got

Example 2 A transdermal 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 was changed to 120 μm.

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

Example 4 A transdermal 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 was changed to 120 µm.

Example 5 30 parts of isosorbide dinitrate and 40 parts of isotridecyl myristate were mixed with 30 parts of the solid content of the acrylic copolymer solution prepared in Example 1, and 0.3 part of the above copolymer was mixed with 99.7 parts. Trifunctional isocyanates (Coronate HL,
(Manufactured by Nippon Polyurethane) was added as a 10% ethyl acetate solution, and ethyl acetate was further added to adjust the viscosity.

The resulting viscous solution was dried as in Example 1 and
After forming a crosslinked gel layer having a thickness of μm, the nonwoven fabric surface of the support used in Example 1 was adhered 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 was repeated except that 80 parts of the solid content of the acrylic copolymer solution prepared in Example 1 was mixed with 20 parts of isosorbide dinitrate, and the viscosity was adjusted by adding ethyl acetate. In the same manner as in the above, a cross-linked transdermal preparation containing no liquid component was obtained.

Comparative Example 2 A crosslinked percutaneous absorption preparation containing no liquid component was obtained in the same manner as in Comparative Example 1, except that the thickness of the crosslinked gel layer was changed to 120 μm.

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

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

Comparative Example 5 A gel preparation containing a liquid component but not subjected to a crosslinking treatment was obtained in the same manner as in Example 1 except that the crosslinking agent was not added in Example 1.

In addition, this gel preparation remarkably suffered from cohesive failure, and the test described later could not be performed.

Comparative Example 6 The solid content of the acrylic copolymer in Example 1 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 added.

Experimental Example The preparations obtained in the above Examples and Comparative Examples were applied to 50 cm ² (71 m
(m square) and left for 48 hours at room temperature, and then the following test was performed. In addition, since the dyeing liquid is absorbed by the nonwoven fabric used for the support and the measurement becomes very inaccurate, the sample used for measuring the amount of exfoliation of the stratum corneum is a single-layer film (9
μm thickness).

 The results are shown in Tables 1 and 2.

(Rabbit sticking test)

The samples obtained in each of the Examples and Comparative Examples were affixed to the backs of rabbits whose hair had been removed in advance, and 1.0, 2.5, 4.0, 6.0, 8.0
Each time, 2 ml of blood was collected, and the concentration of isosorbide dinitrate in the blood was measured by gas chromatography.

(Adhesion test)

Each sample on the strip cut to a width of 12 mm was attached to a bakelite plate, and a roller with a load of 300 g was reciprocated once to make close contact, and then peeled at a rate of 300 mm / min in the 180-degree direction. It was measured.

[Tack test]

Evaluation was made by probe tack using a rheometer.

Fix the sample to the metal plate with the skin sticking side up,
After contacting a spherical probe with a diameter of 10 mm with a load of 100 g at a speed of 2 cm / min, maintain the state for 20 seconds, and then measure the peeling force when the spherical probe is separated at the same speed did.

(Pain during peeling)

Attach the sample to the inside of the upper arm of 5 volunteers,
After 30 minutes, it was peeled off and the pain at that time was measured. The evaluation was performed on a five-point scale, and the average score was determined with one point having the least pain as one point. In addition, the thing of the comparative example 1 was judged as five criteria | standards.

(Exfoliating amount)

3 volunteers (A, B, C) inside the upper arm, 16m in diameter
A 30 minute round sample was stuck and peeled off, and then this sample was stained (Gentianviolet 0.5%, Brillian gree
n0.5%, distilled water 98.5%) for 3 minutes, and then washed with water to stain keratinocytes.

These samples were immersed in a 5% aqueous sodium dodecyl sulfate solution for 24 hours to extract the stain, and the absorbance (595 nm) of the extract was measured to compare the exfoliated keratinocytes. That is, it was determined that the higher the measured absorbance, the larger the peeled angular mass.

A good correlation function was confirmed between the number of exfoliated keratinocytes counted by a stereomicroscope and the absorbance.

As is clear from Tables 1 and 2, the percutaneous absorption gel preparation of the present invention has less pain at the time of exfoliation and less exfoliation of the keratin than the comparative example product. Furthermore, it was found that isosorbide dinitrate was rapidly and transdermally absorbed in a large amount.

──────────────────────────────────────────────────続 き Continued on the front page (72) Takashi Kinoshita, Inventor 1-1-2 Shimohozumi, Ibaraki-shi, Osaka Nippon Denko Corporation (72) Miho Hosaka 1-1-2, Shimohozumi, Ibaraki-shi, Osaka (1) 1-2-1 Shimohozumi, Ibaraki-shi, Osaka Nippon Denko Co., Ltd. (56) Reference JP-A-57-21317 (JP, A) JP 57-7409 (JP, A) JP-A-59-219218 (JP, A) (58) Fields investigated (Int. Cl. ⁶ , DB name) A61K 31/34 A61K 9/70 A61K 47/32

Claims (3)

(57) [Claims] 1. A gel preparation comprising a support and a crosslinked gel layer formed on one side of a support by crosslinking a formulation containing the following components (a) to (c), wherein the components (b) and (c) are: Content weight ratio is
A transdermally absorbable gel preparation, wherein the ratio is 1.0: 0.25 to 1.0: 2.0. (A) isosorbide dinitrate. (B) An acrylate polymer obtained by polymerizing an alkyl (meth) acrylate having an alkyl group of 4 or more as a main component monomer. (C) A liquid component compatible with the component (b). 2. The transdermal gel preparation according to claim 1, wherein the component (b) is an acrylic copolymer obtained by copolymerizing an alkyl (meth) acrylate and (meth) acrylic acid. . 3. The component (b) is an acrylic copolymer obtained by polymerizing an alkyl (meth) acrylate and a (meth) acrylic acid at a compounding ratio of 90 to 99/1 to 10 (weight ratio). The percutaneous absorption gel preparation according to claim 1 or 2.