JP3081413B2 - Method for producing patch containing isosorbide dinitrate using mixed adhesive - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION The present invention relates to a method for producing a sustained-release and transdermal administration pharmaceutical patch of the isosorbide dinitrate, more particularly, the present invention recone based adhesive and polyvinyl acetate-based adhesive the mixture-based adhesive Ru is contained isosorbide dinitrate in the adhesive layer containing the agent, excellent in sustained release, and to a method for producing a patch having a good percutaneous absorption property.

[0002]

2. Description of the Related Art It is known that isosorbide dinitrate is absorbed transdermally, and a number of products have already been developed and sold as patches for transdermal absorption.

[0003] It is disclosed in, for example, JP-A-57-116011 that the adhesive used for the patch is preferably a silicone-based, rubber-based, or acrylic-based adhesive. Annual Meeting (September 26-28, 1989)
On the other hand, Oguni et al. Compared patches based on isosorbide dinitrate with those based on acrylic, silicone, and rubber, and reported that the three groups had almost the same transdermal absorbability. Wherein, in the application according to JP 57-11601 1 JP, then especially acrylic adhesives from various pressure-sensitive adhesive is preferred, it corrects the specification are Application Publication (KOKOKU 4-74329).

[0004] One of the problems with the patch is the occurrence of skin rash, and various proposals have been made as a method for reducing this. As one of the methods, there is a method of reducing the size of the preparation, and for that purpose, it is necessary to increase the transdermal absorbability per unit area. In order to enhance transdermal absorbability, addition of various absorption enhancers such as isopropyl myristate has been proposed. However, since such absorption enhancers are generally of low molecular weight, many of them have skin irritation, and the addition of such absorption enhancers in large amounts reduces the adhesive strength of the resulting pressure-sensitive adhesive composition. There are also problems such as doing, and it is not always successful.

[0005]

SUMMARY OF THE INVENTION An object of the present invention is to provide a method for producing a sustained-release patch containing isosorbide dinitrate which is less irritating to the skin and has good percutaneous absorption.

[0006]

SUMMARY OF THE INVENTION The present invention is directed to a silicone-based
It consists of an adhesive (A) and a polyvinyl acetate adhesive (B).
And mixed isosorbide dinitrate (C)
Adhesive set that does not contain enough or does not contain a sufficient amount
Make an adhesive layer consisting of a product, and then isosol nitrate
Isosol nitrate for diffusing and permeating bide (C) into the adhesive layer
This is a method for producing a bide-containing patch .

[0007] In the present invention, isosorbide dinitrate means isosorbide dinitrate or isosorbide dinitrate, and is abbreviated as ISDN.

In the present invention, the silicone-based pressure-sensitive adhesive (A) has the following general formula:

Embedded image And an adhesive comprising a condensation reaction product of a linear silanol-functional dimethylpolysiloxane having a two-dimensional structure and a silicate resin having a three-dimensional structure represented by the following formula, and which is a firmtech Japan 7 (7), 51-55 ( 1991), which has excellent properties as a pressure-sensitive adhesive for transdermal absorption preparations. of course,
In the above general formula, some or all of R and / or R 'may be substituted with another alkyl group, vinyl group, alkoxy group, aryl group or the like within a range that hardly affects the adhesive properties.

A typical silicone-based pressure-sensitive adhesive (A) is Dow Corning Bio-PSA (registered trademark) 3
55, Bio-PSA® Q7-2920. Even if the chemical structure of the skeleton or the substituent is partially changed, neither the transdermal absorbability nor the adhesive property is practically affected. Therefore, such a silicone-based pressure-sensitive adhesive can also be used.
The silicone adhesive may be used alone or in combination of two or more.

In the present invention, the polyvinyl acetate-based pressure-sensitive adhesive (B) is a homopolymer of vinyl acetate; a copolymer of vinyl acetate and an alkyl (meth) acrylate and / or (meth) acrylic acid; It refers to a copolymer of vinyl acetate with vinyl ethers such as vinyl butyl ether, and the like, and refers to a polymer in which the copolymerization ratio of vinyl acetate is at least 50% by weight or more.

Here, the alkyl (meth) acrylate includes an average of 3 to 14 carbon atoms of (meth) acrylic acid.
Preferred are the alkyl esters of
For example, butyl (meth) acrylate, amyl (meth) acrylate, hexyl (meth) acrylate, heptyl (meth) acrylate, octyl (meth) acrylate, nonyl (meth) acrylate, decyl (meth) acrylate, 2-ethylhexyl (meth) acrylate And the like.

In the present invention, a mixture of such a silicone-based pressure-sensitive adhesive (A) and a polyvinyl acetate-based pressure-sensitive adhesive (B) is used. The advantage of this combination is that IS
The percutaneous absorption of DN is extremely high, and there is little skin irritation.

As described above, it is known to use a silicone-based adhesive for an ISDN patch. However, a mixed system of different kinds of pressure-sensitive adhesives is hardly actually used, except for a rubber-based pressure-sensitive adhesive which is difficult to exhibit its properties unless originally mixed. In particular, a patch obtained by mixing a mixture of a silicone adhesive and a polyvinyl acetate adhesive has not been known. This is considered to be due to the fact that the two adhesives use different solvents and that they are very different in chemical structure, so that there is no need to mix them.

A patch using a mixed pressure-sensitive adhesive of a silicone pressure-sensitive adhesive (A) and a polyvinyl acetate pressure-sensitive adhesive (B) obtained by the production method of the present invention is another preferable pressure-sensitive adhesive. It exhibits good transdermal absorbability equivalent to that of a patch obtained using an adhesive such as an acrylic pressure-sensitive adhesive. Further, the adhesive strength to the skin is good. This is because the mixed pressure-sensitive adhesive obtained by mixing different types of pressure-sensitive adhesives has a so-called sea-island structure, and has specificity in adhesiveness to HIFF, precipitation of ISDN crystals, and its release property. Conceivable.

Particularly, a mixture of a silicone-based pressure-sensitive adhesive (A) and a polyvinyl acetate-based pressure-sensitive adhesive (B) is mixed with ISDN.
, The transdermal absorbability changes specifically, and the maximum value of the transdermal absorbability is about 7% by weight when the mixture ratio (weight ratio) of A and B is about 7.
It has a surprising effect that it is near 0:30 and its percutaneous absorption is almost twice as high as that of the single system. Even if it is not this maximum value, A: B is 85:15
Also at 60:40, the transdermal absorbability increases to such an extent that the merits of mixing can be sufficiently enjoyed.

When the ratio of A: B exceeds 60:40 and the ratio of B is increased, the adhesive strength of the obtained patch obviously decreases, and there is a concern that the obtained patch can be stably applied for a long time. .

In the pressure-sensitive adhesive composition for a patch of the present invention, the ratio of ISDN (C) to the mixed pressure-sensitive adhesive is determined by the total weight of the silicone pressure-sensitive adhesive (A) and the polyvinyl acetate pressure-sensitive adhesive (B). On the other hand, ISDN (C) is blended or contained so that the weight of (A + B): C = 90: 10 to 60:40 is satisfied. ISDN (C)
If the ratio is less than 10, the effect as a drug is insufficient, while if it exceeds 40, the crystallized IS
Although the DN increases, the adhesive strength of the resulting patch decreases, and the flexibility of the patch decreases. Further, even if ISDN is increased beyond 40, the percutaneous absorption rate per unit area of ISDN does not increase, so that the drug utilization rate also decreases.

[0018] In the present invention, silicone-based adhesive (A) and polyvinyl acetate-based adhesive and (B), ethyl acetate, hexane, chloroform, xylene, toluene <br/> down, acetone, methanol, fluorocarbon IS dissolved or dispersed in a single or mixed solvent such as solvent
Mixing with DN (C) or without adding ISDN (C), coating on release paper or release film so that the thickness after drying becomes a predetermined thickness, that is, 5 to 100 μm. And remove the solvent sufficiently by evaporation.

When ISDN (C) is mixed with the adhesive solution, applied, and dried to obtain an adhesive layer containing ISDN (C), the adhesive layer containing ISDN (C) is softened. A patch can be obtained by attaching to a support and cutting it to a desired size.

On the other hand, when the coating is performed without mixing ISDN or a sufficient amount without mixing, and dried,
An adhesive layer containing no or insufficient N is obtained.

A particularly preferred patch obtained by the present invention is obtained when the pressure-sensitive adhesive solution is applied and dried without mixing ISDN or a sufficient amount thereof. A sufficient amount refers to an amount that does not substantially exert a medicinal effect.

That is, as is known, the smaller the residual solvent in the final patch, specifically, 100 ppm or less,
Preferably, the more the residual solvent amount is 50 ppm or less, the less the skin irritation of the patch. Therefore, in order to obtain a patch with less residual solvent, a solution or dispersion of the pressure-sensitive adhesive is applied on a release film or the like, and when dried,
It is necessary to reduce the residual solvent by applying sufficient heat and / or allowing sufficient drying time, or by heating the obtained adhesive layer or keeping it under reduced pressure.
Since ISDN is a sublimable drug, it is not easy to reduce the residual solvent from the adhesive layer containing ISDN. However, in the case of a pressure-sensitive adhesive layer containing no ISDN, it is not necessary to consider the sublimation of ISDN at all, and a pressure-sensitive adhesive layer with a sufficiently low residual solvent can be easily produced.

Accordingly, in the preferred method for producing a patch of the present invention, a solution or dispersion of an adhesive mixture is applied without first mixing ISDN or in a sufficient amount, and then containing ISDN. An adhesive layer that does not or does not contain enough is obtained, and then an ISDN solution dissolved in a highly volatile solvent such as acetone, methanol, ethanol, or ethyl acetate at a high concentration is dropped, sprayed, applied, or the like on the adhesive layer. Alternatively, a desired ISDN is attached by immersion or the like. Next, ISDN can be diffused into the adhesive layer by leaving it for a long time or by heating or the like to obtain a patch.

[0024] Even if the solvent used for forming the adhesive layer by coating and drying is the same as the solvent used for dissolving the ISDN, the solvent is used for dissolving the ISDN, and the solvent is used in the manner described above. When the preparation is obtained, the residual solvent of the patch can be reduced much more easily.

In the present invention, in addition to the above-mentioned components A to C, other pressure-sensitive adhesives such as rubber-based pressure-sensitive adhesives may be used as long as they do not affect the properties of these compositions practically.
A single or a mixture of vinyl ether-based adhesives may be used in combination, and if necessary, a known absorption promoter, a dissolution aid,
A diffusion aid, a filler, and the like may be contained alone or in a mixture.

When an absorption enhancer is used, the absorption enhancer is particularly preferably isopropyl myristate, and when isopropyl myristate is used, ISDN (C)
It is preferable to use 0.1 to 2 parts by weight with respect to 1 part by weight.

[0027] As another absorption enhancer or diffusion aids such as sodium lauryl sulfate, sodium dodecylbenzenesulfonate, sodium alkyl diphenyl ether sulfonate, dioctyl sulfosuccinate, polyoxyethylene alkyl phenyl ether sulfate ammonium salt Surfactants such as glycerin, diethylene glycol, propylene glycol, polyethylene glycol, higher aliphatic alcohols; dimethyl sulfoxide and alkylmethyl derivatives; salicylic acid, urea, dimethylacetamide, dimethylformamide, lanolin, allantoin, squalene, and carbopol , Diisopropyl adipate, lauryl pyroglutamate, ethyl laurate, methyl nicotinate, sol Pyrrolidone derivatives such as tall and dodecyl pyrrolidone, olive oil, castor oil, liquid paraffin, vaseline, gelatin, amino acids, lactic acid,
Ethyl lactate, benzyl nicotinate, L-menthol, camphor, dodecylazacycloheptan-2-one and the like can be used. Such additives are preferably used in an amount of 0.05 to 2 parts by weight per 1 part by weight of ISDN.

In the patch obtained by the production method of the present invention, the pressure-sensitive adhesive layer comprising a pressure-sensitive adhesive composition containing a silicone pressure-sensitive adhesive (A), a polyvinyl acetate pressure-sensitive adhesive (B) and ISDN (C) is used. , Formed on a flexible carrier,
As such a flexible carrier, a fabric such as a film, a woven fabric, a knitted fabric, or a nonwoven fabric, or a composite of a film and a fabric is used.

As the material of such a film or fabric, polyester such as polyethylene terephthalate; polyolefin such as polyethylene or polypropylene; polyamide such as nylon 6; ethylene-vinyl acetate copolymer and the like can be used. Among these materials, polyester is preferred from the viewpoint of stability and safety.

In particular, when a film is used on the outer surface of the patch as a flexible carrier that makes it difficult for ISDN to escape from the patch and has high stability, the film is used for the purpose of improving the handleability of the patch. When a mode is adopted in which a fabric such as a woven fabric, a knitted fabric, or a nonwoven fabric is attached to the inner or outer surface via an adhesive or a pressure-sensitive adhesive , the resulting patch has high stability and good handleability. As described above, the thickness of the film is preferably 0.5 to 10 μm, and the weight of the fabric is preferably 8 to 100 g / m ² . 5-4.9
With a polyester film of μm, the fabric weight is 8-60.
g / m ² of polyester is preferred.

Particularly preferred embodiments of the patch are shown below.
That is, the patch comprises (a) a film layer, (b) an adhesive layer, (c) a cloth, (d) an adhesive layer, and (e) a release film layer, and the outermost layer is (a), and (a), (b) ),
The layers are stacked in the order of (c), (d), and (e). When used, (e) is discarded.

(A) is a polyester film layer having a thickness of 0.5 to 4.9 μm. Examples of the film include an ultrathin polyester film (trade name, Teijin Tetron) developed and sold by Teijin Limited for use in capacitors. Film F type) is particularly preferred. (B) is an adhesive layer having a thickness of 5 to 40 μm, such as a silicone-based adhesive, an acrylic-based adhesive, a rubber-based adhesive, a polyvinyl acetate-based adhesive, or an ethylene-vinyl acetate copolymer-based adhesive. (C) has a basis weight of 8 to
60 g / m ² polyester fabric. (D) is an adhesive layer comprising a mixture of a silicone-based adhesive (A) and a polyvinyl acetate-based adhesive (B), wherein the weight ratio of A to B is 8;
5:15 to 60:40 and a thickness of 10 to 60 μ
m, and (e) is a 30-100 μm thick polyester film-based release film layer coated with a fluororesin. ISDN (C) is mainly present in (d) the adhesive layer, but may be present in (b) the adhesive layer and (c) the fabric.

In the production of a patch of such a preferred embodiment, (b) an adhesive layer and (d) an adhesive layer which do not sufficiently contain ISDN are produced, and (a) a film layer and (c) a fabric are used in (b) To form a composite layer, and ISDN dissolved in a solvent such as acetone is added dropwise to the cloth portion of the composite layer by dropping, spraying, dipping, or the like, and thereafter,
The solvent of ISDN is removed by evaporation, and then (d) the adhesive layer is pressed. The patch thus obtained has (e) a release film layer.

The patch thus obtained is left for a long time.
Or by heating ISDN to (d) adhesive layer
Spread well. Naturally, in this process, (b) the adhesive layer
ISDN spreads inside. Patches containing ISDN
Always 10-100cm in size ^TwoUsed by cutting into
However, such cutting may be performed before heating, or performed after heating.
Is also good.

[0035]

The present invention will be described in more detail with reference to the following examples. All parts, percentages and ratios in the examples are on a weight basis. The blood ISDN concentration was measured by the following method. That is, after separating plasma from 1 ml of collected blood, ISDN was extracted with 4 ml of n-hexane, concentrated, and 100 μl of ethyl acetate was added to the concentrate to obtain a sample. To GC-ECD
Quantified by the method.

As the polyvinyl acetate-based pressure-sensitive adhesive used in the examples, in addition to the reagent polyvinyl acetate (manufactured by Wako Pure Chemical Industries), a copolymer with 2-ethylhexyl acrylate was used. Was synthesized by the method described above. That is, 50 parts of vinyl acetate, 97 parts of 2-ethylhexyl acrylate, 3 parts of acrylic acid, 1.0 part of benzoyl peroxide, and 100 parts of ethyl acetate were charged into a reaction vessel having a reflux condenser and a stirrer. While stirring slowly, polymerization was continued for 12 hours. The polymerization conversion was 99.9%. 500 parts of ethyl acetate was added to the obtained polymer solution to adjust the solid content concentration to about 20%. This is called an acrylic ester copolymerized polyvinyl acetate adhesive sample.

A fabric sample was prepared by the following method.
That is, 297 parts of dimethyl terephthalate, 265 parts of ethylene glycol, 53 parts of sodium 3,5-di (carbomethoxy) benzenesulfonate (11.7 mol% based on dimethyl terephthalate), and 0.1% of manganese acetate tetrahydrate.
084 parts and 1.22 parts of sodium acetate trihydrate were placed in a glass flask equipped with a rectification column, and a transesterification reaction was carried out in accordance with a conventional method. In a condensation flask, 0.090 parts of a 56% aqueous solution of orthophosphoric acid as a stabilizer and 0.135 parts of antimony trioxide as a polycondensation catalyst were added.
The reaction was carried out at 5 ° C. under normal pressure for 20 minutes and under reduced pressure of 30 mmHg for 15 minutes, and then reacted under high vacuum for 100 minutes. The final internal pressure was 0.39 mmHg, the intrinsic viscosity of the obtained copolymer was 0.402, and the softening point was about 200 ° C. After completion of the reaction, the copolymer was formed into chips according to a conventional method.

15 parts of this copolymer chip and 85 parts of polyethylene terephthalate chips having an intrinsic viscosity of 0.640 were mixed in a Nauta mixer (manufactured by Hosokawa Iron Works) for 5 minutes, and then mixed at 110 ° C. in a nitrogen stream. For 2 hours and further at 150 ° C. for 7 hours, and then melt-kneaded at 285 ° C. using a twin screw extruder to form chips. This chip had an intrinsic viscosity of 0.535 and a softening point of 261 ° C.

The chip is dried by a conventional method, and a spinneret having a circular slit having a width of 0.05 mm and a diameter of 0.6 mm and having two closed circular arcs is used, and spinning is performed according to a conventional method. Then, a hollow fiber having a ratio of outer diameter to inner diameter of 2: 1 (hollow ratio: 25%) was produced. The obtained hollow fiber had fine holes scattered throughout the hollow fiber cross section and arranged in the fiber direction, and at least a part of the fine holes was connected to the hollow portion. The original yarn is 300 denier / 24 filaments, and the original yarn is used and a draw ratio of 4.
The film was stretched by a factor of 2 to obtain a multifilament of 71 denier / 24 filaments. The single yarn of this multifilament had a diameter of 11 μm.

The multifilament is knitted into a knitted fabric, scoured and dried by a conventional method, and then treated with a 1% aqueous sodium hydroxide solution at a boiling temperature for 2 hours to reduce the alkali weight by 2%.
0% knit was obtained. The obtained knitted fabric was stretched 1.5 times in the machine direction and heated at 100 ° C. for 1 minute to heat set to obtain a knitted fabric having a basis weight of 17 g / m ² , that is, a fabric sample.

Examples 1 to 3 and Comparative Examples 1 to 3 Dow Corning Bi as a silicone-based pressure-sensitive adhesive (A)
o-PSA (registered trademark) 355 (solid content 18.5%) was used, and polyvinyl acetate (Wako Pure Chemical Industries, Ltd., n = 1400 to 1600) was used as the polyvinyl acetate-based adhesive (B). The mixing ratio of the silicone-based pressure-sensitive adhesive (A) and the polyvinyl acetate-based pressure-sensitive adhesive (B) was changed, and both were sufficiently stirred to obtain a mixed dope. Regarding the level, two types of pressure-sensitive adhesive layers of 15 μm (adhesive layer b) and 40 μm (adhesive layer d) were obtained.

A 2.5 μm-thick polyethylene terephthalate film (Teijin Tetron film F type) was used as the film a. First, an adhesive layer b was pressure-bonded on the film a to form a free surface of the adhesive layer b. The fabric sample was crimped on top. Next, an acetone solution of ISDN (C) was continuously dropped on the free surface of the fabric sample such that the amount of ISDN (C) became 8 g / m ² . The acetone was evaporated by air drying, and the adhesive layer d was pressed against the free surface of the fabric to obtain a laminate. At this time, a thickness of 50 μm
m had a release film coated with a milky fluorine-based release agent. The obtained laminate is sized 7 cm x 7 cm
After slicing each piece into aluminum, this was heated at 65 ° C. for 24 hours.

From the preparation thus obtained, a size of 10 c
make test formulation for animal tests m ^2, attached to the back of hairless rats with an average weight of 200g were shaved (n = 3),
Blood was collected before application, 2 hours after application, 5 hours after application, and 24 hours after application, the ISDN concentration in the blood was measured, and Cmax and AUC were calculated from the obtained blood concentrations. The state of adhesion to the skin was also examined. Table 1 shows the results. In the table, polyvinyl acetate is indicated by PVAc.

[0044]

[Table 1]

As is clear from Table 1, when a polyvinyl acetate-based pressure-sensitive adhesive is mixed with a silicone-based pressure-sensitive adhesive, the percutaneous absorption is clearly better than that of a silicone-based pressure-sensitive adhesive alone known to have good percutaneous absorption. Becomes However, when the mixing amount of the polyvinyl acetate-based pressure-sensitive adhesive exceeds a certain value, the adhesive strength becomes insufficient and the once-percutaneous absorbability also decreases.

In some cases, silicone oil was added as a softening agent to the silicone-based pressure-sensitive adhesive. However, even when a test was conducted in a system to which the silicone oil was added, the effect of mixing the polyvinyl acetate-based pressure-sensitive adhesive did not change.

Example 4 An ISDN patch was prepared in the same manner as in Example 3 except that an acrylic acid ester copolymerized polyvinyl acetate pressure-sensitive adhesive sample was used instead of polyvinyl acetate, and a hairless rat was used. AUC was 2887 ng
-Hr / ml, Cmax was 531 ng / ml, there was no skin irritation, and the adhesion to the hairless rat skin was sufficient.

[0048]

The ISD obtained by the production method of the present invention
The N-containing patch has good percutaneous absorption and sustained release properties, has no skin irritation, and can be mainly used as a prophylactic / therapeutic agent for angina pectoris.

────────────────────────────────────────────────── ─── Continued on the front page (72) Inventor Toshiyuki Kato 3-5-5 Midorigaoka, Hamura-shi, Tokyo Inside Teisan Pharmaceutical Co., Ltd. (56) References JP-A-6-329539 (JP, A) (58) Field surveyed (Int.Cl. ⁷ , DB name) A61K 9/70 A61K 31/34

Claims (1)

(57) [Claims] 1. A silicone adhesive (A) and a polyvinyl acetate
It contains a mixed pressure-sensitive adhesive consisting of a neal pressure-sensitive adhesive (B),
Contains no or no isosorbide dinitrate (C)
Create an adhesive layer consisting of an adhesive composition that does not contain
And then add isosorbide dinitrate (C) to the adhesive layer
How to make a patch containing isosorbide dinitrate that can diffuse and infiltrate
Law.