JP2867462B2 - Transdermal formulation - Google Patents

Description

[Detailed description of the invention] "Industrial application field" The present invention relates to the main drug, 2-cyano-6-methyl-4-
(3-nitrophenyl) -1,4-dihydropyridine-3,5
-Absorption selected from 5-isopropyl 3-methyl dicarboxylate and oleyl alcohol, monoolein (glycerol α-monooleate), N, N-diethyl-m-toluamide and azone (1-dodecylazacycloheptan-2-one) A percutaneous absorption preparation comprising an enhancer or the dihydropyridine compound, the absorption enhancer and ethanol, and oleyl alcohol, monoolein, N, N-diethyl which promotes the transdermal absorbability of the dihydropyridine compound The present invention relates to a transdermal absorption enhancer selected from m-toluamide and azone, or a transdermal absorption enhancer comprising the absorption enhancer and ethanol.

Specifically, the present invention comprises the above dihydropyridine compound as an active ingredient, and as a transdermal absorption enhancer of the drug, an absorption enhancer selected from oleyl alcohol, monoolein, N, N-diethyl-m-toluamide and Azone, Alternatively, the present invention relates to a preparation for percutaneous absorption, comprising the absorption enhancer and ethanol.

Further, the present invention provides an absorption enhancer selected from oleyl alcohol, monoolein, N, N-diethyl-m-toluamide and azone, which can enhance the transdermal absorbability of the dihydropyridine compound, or the absorption enhancer and ethanol Percutaneous absorption enhancer comprising:

The dihydropyridine compound as an active ingredient of the present invention is represented by the following chemical formula.

This dihydropyridine compound (I) has a vasodilatory effect and is useful for treating angina pectoris, coronary vascular disorders such as myocardial infarction, or hypertension.

The dihydropyridine compound has a dextrorotatory and levorotatory 2 based on the asymmetric carbon at position 4 of the dihydropyridine ring.
The optically inactive racemates, which include various optically active substances and mixtures thereof, are known under the general name "nilvadipine".

"Problems to be Solved by the Prior Art and the Invention" The dihydropyridine compound (I) used as the main drug of the present invention is poorly soluble in water, has low percutaneous absorbability, and is effective for transdermal administration by transdermal administration. Obtaining medium concentrations has been extremely difficult. In addition, conventional oral preparations achieve a rapid action but have some problems in sustainability, and there has been a demand for development of a preparation for transdermal absorption which releases a drug continuously.

"Means for solving the problems" The inventors of the present invention have conducted intensive studies to overcome the above problems, and as a result, oleyl alcohol, monoolein, N, N-diethyl-m-toluamide and azone,
In addition, they have found that a combination of these compounds and ethanol significantly enhances the transdermal absorbability of the dihydropyridine compound (I), and thus completed the present invention.

Accordingly, one of the objects of the present invention is to provide a dihydropyridine compound (I) as a main drug and oleyl alcohol, monoolein, N, N-diethyl-m as a transdermal absorption enhancer.
-Containing a transdermal absorption enhancer selected from toluamide and azone, or the absorption enhancer and ethanol,
Another object of the present invention is to provide a preparation for percutaneous absorption to which another percutaneous absorption enhancer may be added as a desired component in order to further enhance the absorbability.

Further, another object of the present invention is to significantly promote the transdermal absorbability of the dihydropyridine compound (I). Oleyl alcohol, monoolein, N, N-diethyl-m-
An object of the present invention is to provide a transdermal absorption enhancer selected from toluamide and azone, or a transdermal absorption enhancer comprising the absorption enhancer and ethanol.

Of the above, oleyl alcohol, monoolein, N, N-diethyl-m-toluamide and, among the transdermal absorption enhancers selected from Azone, oleyl alcohol, monoolein and N, N-diethyl-m-toluamide are more preferable, Monoolein is most preferred in terms of stability and the like.

Transdermal absorption enhancers other than oleyl alcohol, monoolein, N, N-diethyl-m-toluamide, azone and ethanol added to the percutaneous absorption preparation of the present invention as a desired component include, for example, diethyl sebacate,
Examples thereof include fatty acid (lower) alkyl esters such as isopropyl myristate, phospholipids such as lecithin, di- or triglycerides, other nonionic surfactants, sulfonic acid esters, pyrrolidone and derivatives thereof.

The preparation for transdermal absorption of the present invention can be produced according to a conventional method.

As the base used in the preparation, a skin-compatible base can be used. As such a skin-compatible base, dihydropyridine compound (I), oleyl alcohol, monoolein, N, There is no contraindication with N-diethyl-m-toluamide, azone and ethanol, and any skin-compatible base can be used as long as it does not adversely affect the dissolution / diffusion of the active ingredient in the base. Examples of such a base include water, a room temperature or thermosetting silicone polymer (eg, a silicone elastomer), a hydrogel composed of a water-soluble polymer or a hydrogelling agent [eg, agar, gelatin, carrageenan, chitosan ,
Agarose, konjac, polyvinyl alcohol, polyvinylpyrrolidone, poly (2-hydroxyethyl) methacrylate, hydroxypropylmethylcellulose, carboxymethylcellulose, hydroxypropylcellulose [hydroxypropylcellulose-H (HPC-H)
Etc.], hydroxyethylcellulose, etc.], and liquid paraffin, triglyceride, etc. gelled with lecithin, ethylcellulose, etc., but are not necessarily limited thereto.

When ethanol is contained in this preparation, it is preferable to use water as a base, and it is preferable to add a hydrogel or a hydrogelling agent as described above to the base to gel the preparation. .

In addition, the base may contain a hydrophilic solvent or a hydrophobic solvent as a drug release aid. Examples of such a hydrophilic solvent include polyhydric alcohols such as propylene glycol, polyethylene glycol (eg, polyethylene glycol 400, polyethylene glycol 4000, etc.), glycerin and the like, and mixtures thereof. Are, for example, glycerides of medium chain fatty acids such as panassate and miglyol,
Examples thereof include liquid paraffin and mixtures thereof.

In this formulation, the rate of transdermal absorption of the active substance can be controlled. For example, such methods include dispersing the active substance in an appropriate skin-compatible sustained-release matrix base, There is a method of controlling the transdermal absorption rate so that diffusion in the substance is rate-limiting. As such a skin-compatible base, for example, the above-mentioned skin-compatible base can be mentioned as it is, and if necessary, by adding the above-mentioned hydrophilic solvent or hydrophobic solvent to the base, the base compound from the base can be obtained. Release rate can be arbitrarily controlled.

 The preparation for transdermal absorption of the present invention can be administered in various dosage forms.

When this preparation is used as a patch, it can be produced, for example, by spreading the preparation on a support such as cloth or aluminum (see FIG. 1), and further adhering an adhesive layer if necessary (see FIG. 2). See figure).

When a tape preparation is prepared, the preparation can be produced by mixing the preparation for transdermal absorption of the present invention with a suitable adhesive and applying the mixture on a suitable support (see FIG. 3). As the adhesive used in this case, any adhesive that can be used for ordinary medical tapes can be used. For example, a silicone adhesive (Silastic 355 Medical manufactured by Dow Corning) can be used.
Adhesive, etc.), rubber-based adhesives (JSR 058 made by Nippon Synthetic Rubber)
5), acrylic adhesives (Nippon Acrylic Chemical's Primal N580S, Nippon Pure Chemical's Julimer ST811, etc.)
It can be appropriately selected according to a desired drug release rate.

Further, the preparation for transdermal absorption of the present invention can be made into a common ointment such as macrogol ointment, FAPG ointment, hydrophilic ointment, absorption ointment, carbopol gel ointment and the like. In this case, it should be filled into a suitable container and adhered to the skin in order to provide sustainability, control the amount of drug absorbed, and prevent adhesion to clothing, or be fixed on a support such as a tape preparation. It is also possible to apply it with a thickness of and apply it to the skin.

When the preparation for transdermal absorption of the present invention is used as a patch, for example, the preparation is developed on a support such as aluminum, and then, if necessary, for example, an ethylene-vinyl acetate copolymer (EV
A) It can be manufactured by sealing a percutaneous absorption enhancer release control membrane composed of a membrane, a microporous membrane (eg, Hypore 1100D, etc.) (see FIG. 4), and further adhering an adhesive layer if necessary (see FIG. 4). (See FIG. 5). In this patch,
In order to maintain the effective concentration of the active ingredient in the blood for a long time, a transdermal absorption enhancer release control membrane can be inserted between the preparation and the adhesive layer or the skin to control the absorption of the drug.
By appropriately changing the thickness of the transdermal absorption enhancer release control membrane, the composition ratio of the EVA membrane, or the pore size and porosity of the microporous membrane, the absorption rate of the drug can be arbitrarily controlled. In addition, if necessary, the adhesive layer may contain a main drug and / or the above-mentioned absorption promoter to enhance transdermal absorbability and maintain absorption of the main drug.

In the case of a patch, the main drug and the transdermal absorption enhancer do not necessarily need to be present in the same layer.For example, a sustained release matrix containing no main drug is developed on a support, and then the transdermal absorption enhancer is released. A patch may be used in which the control film is sealed, and an adhesive layer containing the active ingredient is further adhered thereon (see FIG. 6).

In addition, the preparation for transdermal absorption of the present invention may be in any form capable of absorbing the main drug to the skin, and is not necessarily limited to the above.

Active drug, oleyl alcohol, monoolein, N, N-
In a preparation comprising an absorption enhancer selected from diethyl-m-toluamide and azone, the ratio of the content of the main drug and the absorption enhancer is not particularly limited as long as it can enhance the transdermal absorbability of the main drug. Can be used in any amount, but preferably 0.01%, based on the total weight of the formulation.
-30% by weight and 0.1-50% by weight, more preferably 0.1%
-20% by weight and 0.5-30% by weight.

The main drugs, oleyl alcohol, monoolein, N,
The ratio of the main drug, the absorption enhancer and the content of ethanol in the preparation comprising an absorption enhancer selected from N-diethyl-m-toluamide and azone and ethanol is also not particularly limited as described above, but is preferably the total weight of the preparation. 0.01 to 30% by weight, 0.1 to 50% by weight and 5 to 99% by weight, more preferably 0.1 to 20% by weight, 0.5 to 30% by weight and 30 to 99% by weight, respectively.

Preferred embodiments of the preparation for percutaneous absorption of the present invention include a drug, oleyl alcohol, monoolein, N, N-diethyl-m
-A formulation comprising a transdermal absorption enhancer selected from toluamide and azone and ethanol; a more preferred embodiment is an absorption enhancer selected from the active ingredient, oleyl alcohol, monoolein and N, N-diethyl-m-toluamide And a formulation comprising ethanol, the most preferred embodiment is a formulation comprising the active ingredient, monoolein and ethanol, and may optionally contain other transdermal absorption enhancers.

The preparation for transdermal absorption of the present invention is preferably in the form of a patch as described above.

"Example" Hereinafter, the present invention will be described in more detail with reference to examples, but is not necessarily limited thereto.

Example 1 Nilvadipine 10 parts by weight monoolein 20 {Dulimer ST811 ¹⁾ 70 {(as solid) ethyl acetate 300} [1] Acrylic acid and butyl acrylate (3:97)
After dissolving nilvadipine, monoolein, and julimer ST811 in ethyl acetate, spreading it on release paper so that the thickness after drying would be 100 μm with a knife coater, and drying it to obtain a tape preparation. .

Example 2 nilvadipine 3 parts by weight oleyl alcohol 10 ethanol 51 distilled water 34 HPC-H 2 ethanol oleyl alcohol and nilvadipine were added to ethanol and stirred, and water and HPC-H were further added and stirred to obtain a suspension. Was obtained.

Example 3 Nilvadipine 3 parts by weight Monoolein 10〃 Ethanol 51〃 Distilled water 34〃 HPC-H2〃 Monoethanol and nilvadipine were added to ethanol and stirred, and water and HPC-H were further added and stirred to obtain a suspension. Was obtained.

Example 4 Nilvadipine 1 part by weight monoolein 20〃 ethanol 46.2〃 distilled water 30.8〃 HPC-H2〃 monoolein and nilvadipine were added to ethanol and stirred, and then water and HPC-H were further added and stirred to obtain a solution. A gel formulation was obtained.

Example 5 Nilvadipine 3 parts by weight Monoolein 20〃 Ethanol 45〃 Distilled water 30〃 HPC-H2〃 Monoethanol and nilvadipine were added to ethanol and stirred, and then water and HPC-H were further added and stirred to obtain a suspension. Was obtained. ² per 1cm this to the aluminum support
After spreading to 44.4 mg, Hypore 1100 is placed on the gel.
D was heat-sealed to produce a patch.

Example 6 Nilvadipine 3 parts by weight N, N-diethyl-m-toluamide 10〃ethanol 51〃distilled water 34〃HPC-H 2〃N, N-diethyl-m-toluamide and nilvadipine were added to ethanol, and the mixture was stirred. Water and HPC-
H was added and stirred to obtain a suspension gel preparation.

Example 7 Nilvadipine 3 parts by weight Azone 10 エ タ ノ ー ル Ethanol 51 〃 Distilled water 34 〃 HPC-H 2 ア After adding Azone and Nilvadipine to ethanol and stirring, water and HPC-H were further added and stirred to obtain a suspension gel. A formulation was obtained.

Example 8 5-isopropyl 3-methyl 5-(+)-2-cyano-6-methyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylate 5 {monoolein 10} ethanol 49.8 〃 distilled water 33.2 〃 HPC-H 2 ２ monoolein and (+)-2-cyano-6 in ethanol
-Methyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 5-isopropyl 3-
After adding methyl and stirring, water and HPC-H were further added and stirred to obtain a solution gel preparation.

Example 9 After the suspension gel preparation obtained in Example 3 was spread on an aluminum support so as to be 39.2 mg / cm ² ,
Hipore 1100D (Asahi Chemical Industry Co., Ltd.)
(Thickness: 100 μm) was heat-sealed to produce a patch.

Example 10 After the suspension gel preparation obtained in Example 4 was spread on an aluminum support so as to be 43.3 mg per 1 cm ² ,
Hypore 1100D (100 μm thickness) was heat-sealed to produce a patch.

Example 11 The patch prepared in Example 9 was further added to Hypore 1100
A patch having an acrylic adhesive layer adhered to the D film side was manufactured. The adhesive layer was prepared from the components shown below.

Nilvadipine 10 parts by weight monoolein 20 〃 Julimer ST811 70 〃 (as solid) Ethyl acetate 300 〃 The adhesive layer is prepared by dissolving nilvadipine, monoolein and julimer ST811 in ethyl acetate and drying with a knife coater. Was spread on release paper so as to have a thickness of 100 μm, and this was dried to prepare.

Example 12 The patch prepared in Example 10 was further added to Hypore 1100.
A patch having an acrylic adhesive layer adhered to the D film side was manufactured. The adhesive layer was prepared from the components shown below.

Nilvadipine 10 parts by weight monoolein 20 〃 Julimer ST811 70 〃 (as solid) Ethyl acetate 300 〃 The adhesive layer is prepared by dissolving nilvadipine, monoolein and julimer ST811 in ethyl acetate and drying with a knife coater. Was spread on release paper so as to have a thickness of 100 μm, and this was dried to prepare.

Example 13 Gel Part Ethanol 78.4 parts by weight Water 19.6 {HPC-H 2} HPC-H was added to ethanol and water to prepare a gel part.

Adhesive layer Nilvadipine 10 parts by weight Monoolein 10 〃 Julimer ST811 80 エ チ ル Ethyl acetate 300 〃 Nilvadipine, monoolein and Julimer ST811
Was dissolved in ethyl acetate, spread on release paper so as to have a thickness of 100 μm after drying with a knife coater, and dried to prepare.

The gel was spread on an aluminum support so that the amount of the gel was 51 mg per 1 cm ² . EVA film on gel (vinyl acetate content 1
(9%, thickness 30 μm) was heat-sealed, and the adhesive layer prepared above was adhered to the EVA film to obtain a patch.

Example 14 Gel part Nilvadipine 5 parts by weight Monoolein 20 ethanol 58.4 Water 14.6 HPC-H2 Nilvadipine and monoolein were added to ethanol and dissolved, and then water and HPC-H were added to prepare a gel part.

Adhesive layer Nilvadipine 10 parts by weight Monoolein 10 〃 Julimer ST811 80 〃 (as solid) Ethyl acetate 300 〃 Nilvadipine, monoolein and Julimer ST811
Was dissolved in ethyl acetate, spread on release paper so that the thickness after drying was 100 μm with a knife coater, and dried to obtain a preparation.

The above-mentioned gel in aluminum support, is 1cm ² per gel 68.5mg
It expanded to become. Hypore 1100D (thickness 1
(00 μm) was heat-sealed, and the adhesive layer prepared above was adhered to the Hypore 1100D membrane to obtain a patch.

Example 15 Gel portion Nilvadipine 1 part by weight Ethanol 77.6〃Water 19.4〃HPC-H 2〃 HPC-H was added to ethanol and water to prepare a gel portion.

Adhesive layer Nilvadipine 10 parts by weight Monoolein 10 〃 Silatic 355 Medical Adhesive 80 〃 (as solid) Ethyl acetate 300 〃 Nilvadipine, monoolein and Silatic 355 Medi
After cal Adhesive was dissolved in ethyl acetate, it was spread on release paper so as to have a thickness of 100 μm after drying with a knife coater, and dried.

51.5 mg of gel per 1 cm ^{2 on the} above aluminum support
It expanded to become. An EVA film (vinyl acetate content: 19%, thickness: 30 μm) was heat-sealed on the gel, and the adhesive layer prepared above was bonded to the EVA film to obtain a patch.

Control Example Nilvadipine 3 parts by weight Ethanol 57 〃 Distilled water 38 〃 HPC-H 2 ニ ル After adding nilvadipine to ethanol and stirring, water and HPC-H were further added and stirred to obtain a suspension gel preparation.

"Effect of the Invention" The percutaneous absorption enhancer of the present invention, oleyl alcohol, monoolein, N, N-diethyl-m-toluamide and azone, or a combination of the absorption enhancer and ethanol, the percutaneous absorption of the main drug The properties are significantly improved. In particular, when oleyl alcohol, monoolein or N, N-diethyl-m-toluamide is used in combination with ethanol, the absorbability is extremely remarkably improved.

In order to show the effects obtained by the percutaneous absorption enhancer and the percutaneous absorption preparation of the present invention, test results are shown below.

[A] In vitro skin permeation test Test method: A horizontal membrane-type diffusion cell was used as an apparatus, and rat full thickness skin was used as a permeable membrane. The rats used were SD male rats weighing 200 g to 250 g, and the abdomen had been dehaired with an electric clipper and hair removal cream on the day before the test.

Effective spreading inside of the cell area of 5 cm ² 2% surfactant (BO
-20, trademark: Nippon Chemicals Co., Ltd.), and rat skin is placed. A sample was applied or affixed to the keratin side of the skin, and the amount of drug in the receptor phase was measured over time to determine the skin permeation rate. The amount of sample applied was 100 mg / 5 cm ² as the amount of ethanol. In the case of a polyethylene glycol-containing preparation, the concentration was 50 mg / 5 cm ² .

 In addition, the receptor phase was maintained at 37 ° C.

Test Formulation: Control Formulation Formulation of Example 2 Formulation of Example 3 Formulation of Example 6 Formulation of Example 7 Test Results: [B] In vivo transdermal absorption test in dogs Test method Test preparation 50 was applied to the chest of a beagle dog whose hair had been removed two days before the test.
After attaching cm ² , the concentration of nilvadipine in plasma was measured by gas chromatography with ECD.

Test formulation Patch of Example 10 Test results As is clear from the results of the above in vitro skin permeation test and in vivo percutaneous absorption test, the percutaneous absorption of dihydropyridine compound (I) was oleyl alcohol, monoolein, N, N-diethyl-m-toluamide and It is significantly enhanced by a combination of a transdermal absorption enhancer selected from Azone and ethanol. In addition, by containing the absorption enhancer and ethanol, it was possible to obtain a preparation for transdermal absorption in which the transdermal absorbability of the dihydropyridine compound (I) was dramatically improved.

[Brief description of the drawings]

FIG. 1 is a patch in which drug release is controlled by a sustained release matrix, FIG. 2 is a patch in which drug release is controlled by a sustained release matrix and an adhesive layer is further adhered, FIG. 3 is a tape preparation, FIG. The figure shows a patch in which drug transfer is controlled by membrane permeation, FIG. 5 shows a patch in which drug transfer is controlled by membrane permeation, and an adhesive layer is further adhered, and FIG. 2 shows a patch in which release of a transdermal absorption enhancer in a sustained release matrix containing no is controlled by membrane permeation. (1) ... support (2) ... sustained release matrix containing drug (3) ... adhesive layer (4) ... adhesive layer containing drug (5) ... control of transdermal absorption enhancer release Membrane (6) ... Drug-free sustained release matrix

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 47/14 A61K 47/14 E 47/18 47/18 E 47/22 47/22 E

Claims (1)

(57) [Claims] (1) 5-isopropyl-3-methyl 2-cyano-6-methyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylate and oleyl alcohol, monoolein, N, N -A preparation for transdermal absorption, characterized by containing an absorption enhancer selected from diethyl-m-toluamide and azone, and ethanol.