HK1084588B - Percutaneous absorption preparations containing 3-methyl-1-phenyl-2-pyrazolin-5-one - Google Patents

Description

Percutaneous absorption preparation containing 3-methyl-1-phenyl-2-pyrazolin-5-one

Technical Field

The present invention relates to a transdermally absorbable preparation of 3-methyl-1-phenyl-2-pyrazolin-5-one, which can be used for the protection of the brain function of a human body including all brain dysfunctions such as cerebral infarction or subarachnoid hemorrhage, the improvement and prevention of brain dysfunction, and the treatment and prevention of diseases such as arteriosclerosis, liver dysfunction, kidney dysfunction, diabetes, gastrointestinal mucosal disorder, and the like.

Background

3-methyl-1-phenyl-2-pyrazolin-5-one is a brain protective agent having a radical scavenging action, and is used in the form of an injection (intravenous drip: intravenous injection by drip) as an agent for improving neurological syndrome, activity disorder in daily life, and dysfunction in a human body in the acute stage accompanying cerebral infarction. In recent years, many people are troubled by brain dysfunction due to aging, diversification of daily foods, increase in pressure in daily life, and the like, and therefore, rapid and accurate measures against brain dysfunction have become one of the medically important problems.

In ischemia such as cerebral infarction and after the blood flow is reopened after ischemia, an excessive amount of free radicals such as hydroxyl free radical (. OH) generated in the human body continuously causes oxidative disorder to the cell membrane of the human body, and the cerebral ischemic disorder is further worsened. In this case, if an injection containing 3-methyl-1-phenyl-2-pyrazolin-5-one (trade name: ラジカツト injection 30 mg; one dose containing 30mg of active ingredient) is used for intravenous drip, the injection can exert an excellent therapeutic effect on cerebral ischemic disorders by eliminating hydroxyl radicals in a human living body.

However, the injection is painful to the patient because the injection needle is inserted into the body (vein) of the patient during intravenous drip, and the patient is restrained for a certain period of time (i.e., the period during which the intravenous drip is performed) because the intravenous drip is usually performed while the patient is lying on a bed. Further, since injection cannot be performed by the patient himself/herself except for some injections such as insulin and interferon, intravenous drip of an injection containing 3-methyl-1-phenyl-2-pyrazolin-5-one cannot be performed by the patient himself/herself, of course, and therefore intravenous drip (administration) by a doctor or a nurse is required. Therefore, the patient must be hospitalized or come and go to the hospital in order to perform the intravenous drip. In the case where a patient is hospitalized or is going to and fro in a hospital for the intravenous drip, the patient feels pain at the time of the intravenous drip, and medical staff such as doctors and nurses need to spend time for the intravenous drip (administration), so that, for example, when the intravenous drip is performed 2 times a day depending on the usage or amount, the patient suffers each time, and the medical staff spends time.

Further, it has been reported that the intravenous drip of the above-mentioned injection has side effects such as liver dysfunction, and one of the reasons for this is that the blood concentration is transiently increased by the intravenous drip. Under such circumstances, development of a preparation containing 3-methyl-1-phenyl-2-pyrazolin-5-one which can be easily administered, can sustain the drug effect for a long period of time, and has few side effects has been desired.

For example, Japanese patent application laid-open No. Sho 61-263917 discloses a method of administration of 3-methyl-1-phenyl-2-pyrazolin-5-one as an agent for normalizing brain function, as an injection, an oral preparation or a suppository (rectal administration), and only injections are clinically used at present. This is because many of the diseases to be treated with the agent for normalizing brain function are diseases accompanied by cerebral infarction, and therefore many patients who are bedridden or unconscious patients are treated with the agent for normalizing brain function, and therefore it is difficult to administer the agent as an oral preparation.

Further, since 3-methyl-1-phenyl-2-pyrazolin-5-one is rapidly metabolized in the liver by glucuronic acid binding or sulfuric acid binding, it is very ineffective due to the first pass effect in the liver when orally administered. Further, 3-methyl-1-phenyl-2-pyrazolin-5-one has been disclosed as a lipid peroxidation inhibitor (see, for example, Japanese patent application laid-open No. 62-108814), an antiulcer agent (see, for example, Japanese patent application laid-open No. 3-215425), a blood sugar increase inhibitor (see, for example, Japanese patent application laid-open No. 3-215426), an ophthalmic preparation (see, for example, Japanese patent application laid-open No. 7-25765), and an acute renal insufficiency treatment/prevention agent (see, for example, Japanese patent application laid-open No. 9-52831), and the like.

Disclosure of the invention

Under such circumstances, the present inventors have intensively studied administration methods other than the above-mentioned administration method involving 3-methyl-1-phenyl-2-pyrazolin-5-one, and as a result, have found that the problems of the prior art can be solved by adopting a transdermal preparation method (including a transdermal patch method) as a preparation method replacing an injection, and that the transdermal preparation has a drug effect equivalent to or better than that of the case where 3-methyl-1-phenyl-2-pyrazolin-5-one is used as an injection, and have completed the invention of a transdermal absorption preparation containing 3-methyl-1-phenyl-2-pyrazolin-5-one.

The transdermal absorption preparation containing 3-methyl-1-phenyl-2-pyrazoline-5-one is characterized by containing 0.1-30 mass% of the following formula as an active ingredient in a matrix:

3-methyl-1-phenyl-2-pyrazolin-5-one or a pharmaceutically acceptable salt thereof. (hereinafter, referred to as i)

The following transdermal absorption preparations of the present invention are preferred.

ii) a transdermal absorption preparation as in i, said matrix being an aqueous matrix.

iii) a transdermal absorption preparation as described in i, wherein the aqueous base contains 1 to 20 mass% of a water-soluble polymer, 0.01 to 20 mass% of a crosslinking agent, 10 to 80 mass% of a polyhydric alcohol, and 1 to 80 mass% of water, based on the total mass of the aqueous base.

iv) a transdermal absorption preparation as in i, said matrix being a rubber-based matrix.

v) a transdermal absorption preparation according to iv, wherein the rubber base comprises 10 to 50 mass% of a rubber polymer, 10 to 50 mass% of a plasticizer and 5 to 50 mass% of a binder based on the total mass of the rubber base.

In addition, the present preparation can be used in the form of a patch.

The transdermal absorption patch containing 3-methyl-1-phenyl-2-pyrazoline-5-one is characterized by being formed by sequentially laminating a support, a matrix layer and a liner, wherein the matrix layer contains 0.1-30 mass% of a compound represented by the following formula:

a matrix of the 3-methyl-1-phenyl-2-pyrazolin-5-one or a pharmaceutically acceptable salt thereof. (hereinafter, referred to as vi)

The transdermal absorption patch of the present invention described below is preferable.

vii) transdermal patch such as vi, the above matrix being an aqueous matrix.

viii) a transdermal patch preparation such as vii, wherein the aqueous base contains 1 to 20 mass% of a water-soluble polymer, 0.01 to 20 mass% of a crosslinking agent, 10 to 80 mass% of a polyhydric alcohol and 1 to 80 mass% of water, based on the total mass of the aqueous base.

ix) transdermal patch such as viii, said matrix being a rubber-based matrix.

x) a percutaneous absorption patch such as ix, wherein the rubber substrate contains 10 to 50 mass% of rubber polymer, 10 to 50 mass% of plasticizer and 5 to 50 mass% of adhesive based on the total mass of the rubber substrate.

The preparation has the following advantages.

a) When the present preparation is used, administration and stopping of administration of 3-methyl-1-phenyl-2-pyrazolin-5-one are convenient, and specifically, for example, administration can be stopped by wiping off (for example, in the case of an ointment or the like) or peeling off (for example, in the case of a patch) the preparation when side effects of the above-mentioned drugs occur.

b) By using (for example, applying to the skin) a certain amount of the present preparation (for example, in the form of an ointment or the like), or by using the present patch (for example, attaching to the skin), the effective blood concentration of the drug can be continuously maintained for a long period of time.

c) Since the effective blood concentration of the drug can be maintained for a long period of time by using the present preparation once (if the drug is administered with the present preparation), the number of times of administration can be reduced as compared with conventional intravenous drip, and thus, the patient compliance during treatment can be improved and the burden on the caregiver can be reduced.

d) When the present preparation is used, the blood concentration can be maintained within a predetermined range, and the blood concentration does not rise to an inappropriate value at a burst as in the case of intravenous drip, so that the side effects of the drug accompanied by a temporary rise in the blood concentration can be avoided.

Brief description of the drawings

FIG. 1 is a graph showing the relationship between the elapsed time after patch application and the cumulative permeation amount of a drug (3-methyl-1-phenyl-2-pyrazolin-5-one) in the case where the patch of example 1 was applied to the skin of a rat.

Best Mode for Carrying Out The Invention

The present preparation and the present patch are explained below.

In the present preparation and the present patch, the 3-methyl-1-phenyl-2-pyrazolin-5-one as an active ingredient varies depending on the formulation, but may be incorporated in an appropriate base in an amount of 0.1 to 30% by mass, preferably 0.5 to 20% by mass, and particularly preferably 0.5 to 10% by mass, based on the total amount of the base.

The preparation may be used in various forms suitable for the purpose, for example, as a solution, a slurry, an ointment, a paste, a gum, etc., or may be used as it is or after being processed into a more suitable form.

If the present preparation is used in the form of a patch, it is preferable in terms of convenience of use since it can be attached to the skin in this manner. The patch can be in the form of various patches such as a cataplasm, a plaster, and a tape, depending on the application.

The adhesive patch can be produced, for example, by adding a predetermined amount of 3-methyl-1-phenyl-2-pyrazolin-5-one suitable for application (e.g., ointment) to a suitable base (e.g., aqueous base or rubber base), pasting the resultant paste on a suitable support in a predetermined thickness, covering the paste with a predetermined backing, and cutting the coated paste into a desired size. The patch can be produced by, for example, pasting a substrate containing 3-methyl-1-phenyl-2-pyrazolin-5-one on a backing in advance to form a matrix layer, covering the upper surface of the matrix layer with a support, and transferring the matrix layer to the support, according to the production method.

As the aqueous base or the rubber-based base, for example, an aqueous base obtained by mixing the following components can be used.

I. Aqueous base

Component 1): water-soluble polymer

Component 2): crosslinking agent

Component 3): polyhydric alcohols

Rubber-based substrates

Ingredient 4): rubber polymer

Ingredient 5): plasticizer

Ingredient 6): adhesive agent

The following describes the components 1) to 6).

Examples of the water-soluble polymer of component 1) include polyacrylic acid, polyacrylate, partially neutralized polyacrylic acid, polyacrylamide, polyethyleneimine, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl cellulose, starch acrylate, ethyl vinyl acetate, gelatin, starch, Eudragid, alginic acid, sodium alginate, and tragacanth. The water-soluble polymer may be used alone, or two or more kinds thereof may be appropriately mixed at a predetermined ratio. The amount of the water-soluble polymer is 1 to 20% by mass, preferably 3 to 6% by mass, based on the total amount of the water-soluble base material.

As the crosslinking agent of the component 2), for example, salts which generate divalent or trivalent metal ions after dissolving in water or the like can be used. Examples of the crosslinking agent include hydroxides such as Aluminum hydroxide and Aluminum magnesium hydroxide, salts of inorganic acids or organic acids such as Aluminum chloride, Aluminum sulfate, Aluminum dihydroxyglycinate, kaolin, Aluminum stearate, magnesium hydroxide, magnesium chloride and magnesium sulfate, or basic salts thereof, complex salts such as Aluminum alum (Aluminum alum), aluminates such as sodium aluminate, inorganic Aluminum complex salts and organic Aluminum chelates, synthetic hydrotalcites, magnesium Aluminum silicate (magnesium aluminate), magnesium aluminate silicate, Aluminum nitrate, Aluminum sulfate, Aluminum-EDTA, Aluminum allantoate aluminate, Aluminum acetate, and Aluminum dihydrogenate (Aluminum glycine). The crosslinking agent can be used in only 1 kind, or can also be according to the predetermined ratio of 2 or more than 2 kinds and use. The amount of the crosslinking agent is 0.01 to 20% by mass, preferably 0.1 to 10% by mass, based on the total amount of the water-soluble base.

The salt that generates a divalent or trivalent metal ion as the crosslinking agent may be a water-soluble substance or a water-insoluble substance. When an aluminum compound which is hardly soluble in water is used as the crosslinking agent, a reaction rate modifier can be added to a reaction system which requires gelation, and the gelation reaction rate can be accelerated particularly by adding an acid. The addition of an organic acid or a salt thereof having a hydroxyl group as an acid significantly accelerates the gelation reaction. Examples of the reaction rate modifier include organic acids, organic acid salts, organic bases, and the like having a chelating ability or a coordinating ability to metal ions, such as citric acid, lactic acid, tartaric acid, gluconic acid, glycolic acid, malic acid, fumaric acid, methanesulfonic acid, maleic acid, acetic acid, EDTA-2N a, urea, triethylamine, and ammonia; and inorganic acids such as hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, hydrobromic acid, and the like.

Examples of the polyhydric alcohol of the component 3) include ethylene glycol, propylene glycol, 1, 3-propanediol, 1, 3-butanediol, ethylene glycol monobutyl ether, triethylene glycol, 1, 4-butanediol, glycerol, trihydroxyisobutane, erythritol, pentaerythritol, xylitol, ribitol, allitol, sorbitol syrup, mannitol, polyethylene glycol, and the like. The above polyols may be used alone in 1 kind, or may be used by mixing 2 kinds or 2 or more kinds appropriately in a predetermined ratio. The amount of the polyhydric alcohol is 10 to 80% by mass, preferably 10 to 60% by mass, based on the total amount of the base material.

Examples of the rubber-based polymer of the component 4) include styrene-isoprene-styrene block copolymers, styrene-butadiene block copolymers, polyisobutylene, raw rubber, polyisoprene, and polybutene. The rubber polymer may be used alone in 1 kind, or may be used by appropriately mixing 2 kinds or 2 or more kinds in a predetermined ratio. The amount of the rubber-based polymer blended is 10 to 70% by mass, preferably 20 to 50% by mass, based on the total amount of the substrate.

Examples of the plasticizer of the component 5) include liquid paraffin, vegetable oil, animal oil, polybutene, low molecular polyisobutylene, vaseline, lanolin, higher fatty acid ester, and the like. The plasticizer may be used alone in 1 kind, or may be used by mixing 2 kinds or 2 or more kinds appropriately in a predetermined ratio. The amount of the plasticizer is 10 to 70% by mass, preferably 20 to 50% by mass, based on the total amount of the base material.

Examples of the binder of component 6) include petroleum resins, rosin resins, hydrogenated rosins, ester rubbers, terpene resins, modified terpene resins, aromatic hydrocarbon resins, and aliphatic hydrocarbon resins. The binder may be used alone in 1 kind, or may be used by mixing 2 kinds or 2 or more kinds appropriately in a predetermined ratio. The amount of the binder is 5 to 50% by mass, preferably 10 to 30% by mass, based on the total amount of the base material.

The support used in the transdermal patch of the present invention is not particularly limited, and materials conventionally used as a support for a transdermal patch can be used. For example, the support may be a woven fabric, a nonwoven fabric, a sheet, a film of a natural or synthetic polymer, or a laminate thereof. Preferable examples of the synthetic polymer include polyvinyl chloride resin, polyethylene resin (e.g., polyethylene resin or a blend of polyethylene resin and another resin), ethylene copolymer resin (e.g., a copolymer of ethylene and another monomer), polypropylene resin (e.g., polypropylene resin or a blend of polypropylene resin and another resin), and polyurethane resin. The size, shape, thickness, etc. of the support can be appropriately selected.

The backing used in the transdermal patch of the present invention is not particularly limited, and materials conventionally used as the backing of the transdermal patch can be used. For example, the spacer may be a sheet, a film or a laminate of natural or synthetic polymers. Preferred examples of the liner include sheets, films or laminates of sheets and films of release paper, cellophane, polyethylene terephthalate, polypropylene, polyester, polyvinylidene chloride, etc., which are treated to facilitate release.

The matrix layer in the transdermal patch of the present invention may contain 0.1 to 30% by mass of 3-methyl-1-phenyl-2-pyrazolin-5-one or a pharmaceutically acceptable salt thereof similar to the above-mentioned preparation, and if necessary, a matrix containing a predetermined amount of the above-mentioned components 1) to 6) may be used, for example, as a layer having a predetermined thickness.

In the present preparation or the present patch, various agents commonly used in the conventional transdermal absorption preparation or transdermal patch, that is, transdermal absorption enhancers, adhesives, softeners, antioxidants, anti-aging agents, preservatives, fragrances, pH adjusters, emulsifiers, dispersants, stabilizers, preservatives, excipients, solubilizers, and the like may be blended at a predetermined ratio as necessary in addition to the above-mentioned essential ingredients (the active ingredient 3-methyl-1-phenyl-2-pyrazolin-5-one or a pharmaceutically acceptable salt thereof) or the above-mentioned components 1) to 6).

The above-mentioned 3-methyl-1-phenyl-2-pyrazolin-5-one or its pharmaceutically acceptable salt as the active ingredient has a radical scavenging action, so that it is highly reactive and therefore has poor stability. Since the number of components of the matrix in the injection is small and the stability of the active ingredient is good when used in the injection, and many other additives are added to the transdermal absorption preparation or the transdermal absorption patch in addition to the above-mentioned essential components when the preparation is performed, the stability of the active ingredient is lowered by the prescription when the active ingredient is used in the transdermal absorption preparation or the transdermal absorption patch. In this case, it is effective to add an antioxidant as a stabilizer for stabilizing the preparation.

Examples of the above antioxidant include ascorbic acid, palmitic acid, sodium hydrogen sulfite, tetrasodium edetate, dried sodium sulfite, citric acid, sodium citrate, tocopherol acetate, dl- α -tocopherol, potassium dichloroisocyanurate, dibutylhydroxytoluene, butylhydroxyanisole, soybean lecithin, sodium metabisulfite, 1, 3-butanediol, benzotriazole, pentaerythritol-tetrakis [3- (3, 5-di-tert-butyl-4-hydroxyphenyl) -propionate ], propyl gallate, and 2-mercaptobenzimidazole. The antioxidant may be used alone in 1 kind, or may be used by mixing 2 kinds or 2 or more kinds appropriately in a predetermined ratio. The amount of the antioxidant is 0.005 to 20% by mass, preferably 0.1 to 5% by mass, based on the total amount of the base material.

The transdermal absorption enhancer is not particularly limited as long as it is an enhancer generally used in a transdermal absorption preparation. Examples of the percutaneous absorption enhancers include alcohols, fatty acids, fatty acid esters, fatty acid ethers, lactic acid esters, acetic acid esters, terpenoids, pyrrolidone derivatives, organic acids, organic acid esters, essential oils, hydrocarbons, azone * ketone (azone) or derivatives thereof, and the like. More specifically, examples of the percutaneous absorption enhancers include ethanol, oleyl alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol, Crotamiton (Crotamiton), cyclodextrin, calcium thioglycolate, N-methyl-2-pyrrolidone, ethyl lactate, cetyl lactate, lactic acid, urea, 1-menthol, peppermint oil, d-limonene, dl-camphor, and the like. The transdermal absorption enhancer, can be used only 1, or according to the predetermined ratio of appropriate mixing of 2 or more than 2. The amount of the percutaneous absorption enhancer is 0.1 to 20% by mass, preferably 0.1 to 5% by mass, based on the total amount of the matrix.

Examples of the solubilizer include N-methyl-2-pyrrolidone, Crotamiton (Crotamiton), polyethylene glycol, isopropyl alcohol, peppermint oil, propylene glycol, butylene glycol, oleyl alcohol, isopropyl myristate, and the like. In particular, when N-methyl-2-pyrrolidone or crotamiton is used, 3-methyl-1-phenyl-2-pyrazolin-5-one has high solubility and is therefore useful as the solubilizer.

< example >

Next, examples of the present invention will be described.

Example 1

The solution A was prepared by mixing 5 parts of sodium polyacrylate, 6 parts of acrylic starch, 12 parts of talc and 29.1 parts of concentrated glycerin. Solution B was prepared by dissolving 2.3 parts of tartaric acid in 30 parts of water. Solution C was prepared by dissolving 3 parts of 3-methyl-1-phenyl-2-pyrazolin-5-one in 8 parts of N-methyl-2-pyrrolidone and 2 parts of crotamiton. To the solution A, solution B and solution C were added, and further, 2.5 parts of methyl acrylate/2-ethylhexyl acrylate copolymer resin emulsion and 0.1 part of aluminum hydroxide gel were added and mixed uniformly. The mixture (present preparation) was stretched in a predetermined thickness on a polyester nonwoven fabric (support) having a predetermined size (length × width × thickness, the same applies hereinafter) to form a matrix layer, and the matrix layer (liner) was covered with a polyethylene film having a predetermined size. This was cut into a predetermined size to obtain a transdermal patch containing 3-methyl-1-phenyl-2-pyrazolin-5-one of example 1.

Example 2

After 20 parts of polybutene, 10 parts of polyisobutylene, 25 parts of a styrene-isoprene-styrene block copolymer, 0.5 part of dibutylhydroxytoluene, 14.5 parts of liquid paraffin, 10 parts of a water-absorbent polymer [ acrylic starch 1000 (trade name: サンウエツト IM1000) ], 17 parts of an adhesive (trade name: アルコン P-100) and 3 parts of 3-methyl-1-phenyl-2-pyrazolin-5-one were dissolved in 60 parts of isohexane, the solution (this preparation) was spread on a polyvinyl chloride sheet (support) of a predetermined size in a predetermined thickness to form a substrate layer, and after drying and removing the solvent, the substrate layer was covered with a polyester film (liner). This was cut into a predetermined size to obtain a transdermal patch containing 3-methyl-1-phenyl-2-pyrazolin-5-one of example 2.

Example 3

20 parts of polybutene, 10 parts of polyisobutylene, 19.5 parts of liquid paraffin, 25 parts of styrene-isoprene-styrene block copolymer, 0.5 part of dibutylhydroxytoluene, and 17 parts of an adhesive (trade name: アルコン P-100) were mixed at 140 ℃ to prepare solution A. 3 parts of 3-methyl-1-phenyl-2-pyrazolin-5-one was uniformly mixed with 5 parts of propylene glycol to prepare a solution B. After heating the solution A at room temperature to 20 ℃, the solution B is added to the solution A and mixed. This mixture (present preparation) was spread on a polyester nonwoven fabric of a predetermined size to form a matrix layer with a predetermined thickness, and after drying to remove the solvent, the matrix layer was covered with a polyethylene film (liner), and after cooling at room temperature, cut into a predetermined size, to obtain a transdermal patch containing 3-methyl-1-phenyl-2-pyrazolin-5-one of example 3.

Experimental example 1: in vitro skin permeation test

1) Test method

The following experiment was performed using 3 samples (sample number 3). Under pentobarbital anesthesia, the abdomen of male rats (7 weeks old) of the Wistar line was shaved, and the skin was excised, and the skin was deeply cut to remove the dermal fat. The skin was attached to a vertical diffusion cell circulating water at 37 ℃ with the dermis side down, and the patch of example 1 punched out to have a diameter of 1cm was attached to the center portion thereof, and then held and fixed using a dome-shaped diffusion cell. Then, the receptor solution which had been kept warm in a thermostatic bath at 37 ℃ was added to the dermis side, a sampling port was installed, and after an L-shaped tube was fixed with an easily stretchable plastic film (パラフイルム), a certain amount of the receptor solution was further added. The receiving solution is stirred by a magnetic stirrer, and then a certain amount of receiving solution is periodically taken out and supplemented with the same amount of receiving solution. The amount of the drug (3-methyl-1-phenyl-2-pyrazolin-5-one) in the taken sample was quantified by High Performance Liquid Chromatography (HPLC), and the skin permeation amount of 3-methyl-1-phenyl-2-pyrazolin-5-one was calculated.

2) Results

The following table 1 and fig. 1 show the relationship between the elapsed time after application of the patch of example 1 and the cumulative permeation amount of the drug (3-methyl-1-phenyl-2-pyrazolin-5-one).

Table 1: relationship between elapsed time after patch application and cumulative drug permeation amount

Elapsed time (hours)	Cumulative penetration (. mu.g/cm))	Standard deviation of
			0	0	0
1	3.41	0.23
			2	10.52	1.04
4	35.79	7.22
			6	78.15	11.30
8	131.03	20.75
			10	190.34	33.25
12	247.59	44.28
			24	643.53	111.28

As is apparent from table 1 and fig. 1 above, the patch of example 1 exhibited good skin permeability, and the skin permeation amount (cumulative permeation amount of the drug) of the drug (3-methyl-1-phenyl-2-pyrazolin-5-one) increased with time (substantially in proportion to time after a prescribed time period elapsed) until 24 hours later.

Test example 2: primary irritation test of rabbit skin

1) Test method

Primary skin irritation test was performed using JW/CSK line male rabbits (12 weeks) with back hair shaved the day before the test, and evaluated using primary irritation index of Draize method. The test was performed by setting a healthy skin area and a damaged skin area abraded with a sterilized injection needle, and evaluating the irritation of each skin. The patch was set to have an attachment area of 5cm²The patches of examples 1, 2 and 3 were applied one by one to each of the healthy skin area and the damaged skin area. Each of the adhesive patches of examples 1, 2 and 3 was peeled off from the healthy skin area and the damaged skin area after 24 hours from the application, and erythema, edema and scab were determined on each area (the healthy skin area and the damaged skin area from which the adhesive patch was peeled) after 1 hour, 24 hours and 48 hours from the peeling according to the determination criteria of the Draize methodAnd (4) obtaining. From the results, a skin irritation index (p.i.i.) was calculated and evaluated according to the evaluation scale.

For comparison, a patch prepared by applying 0.25g of an ointment containing 5 mass% of sodium lauryl sulfate and 95 mass% of white petrolatum to a nonwoven fabric (control 1) and a patch prepared by using a preparation from which the drug (3-methyl-1-phenyl-2-pyrazolin-5-one) in the preparation composition of example 1 was removed (control 2) were evaluated by the same test method as described above.

2) Results

The results are shown in table 2 below.

Table 2: primary irritation test of rabbit skin

Patch preparation	Skin irritation index (P.I.I value)	Level of security
			Example 1	0.06	Weak irritant
Example 2	0.10	Weak irritant
			Example 3	0.10	Weak irritant
Control 1	6.80	Strong irritant
			Control 2	0.06	Weak irritant

The patch preparations of examples 1, 2 and 3 were found to be transdermally absorbable patch preparations having very little skin irritation, as compared with the patch preparation of control 2 containing no drug (3-methyl-1-phenyl-2-pyrazolin-5-one), since they were within the range of weak irritants under the criteria of the Draize method.

Industrial applicability of the invention

The transdermal absorption preparation of the present invention has low skin irritation, and can be applied to the skin of a human, for example, by a transdermal absorption patch, so that a drug (3-methyl-1-phenyl-2-pyrazolin-5-one) as an active ingredient for a brain disorder or the like can be continuously and effectively administered to the human over a long period of time.

The present preparation or the present patch is simple in the method of use (start of administration and stop of administration of the drug), and can maintain the effect of the drug for a long period of time without causing a temporary increase in blood concentration because the drug is stably absorbed through the skin during use.

In addition, unlike conventional injections (intravenous drip), the preparation or the patch does not cause pain to the patient or restrict the patient for a certain period of time during use.

Therefore, the preparation or the patch can be effectively used for protecting the brain function of a human body including all brain functions including cerebral infarction, subarachnoid hemorrhage, and the like, improving and preventing the brain function, and treating and preventing diseases such as arteriosclerosis, liver disorders, kidney disorders, diabetes, gastrointestinal mucosa disorders, and the like.

Claims (4)

1. A transdermal absorption preparation containing 3-methyl-1-phenyl-2-pyrazolin-5-one, characterized by containing 0.1 to 30 mass% of the following formula as an active ingredient in an aqueous medium:

the aqueous base contains 1 to 20 mass% of a water-soluble polymer, 0.01 to 20 mass% of a crosslinking agent, 10 to 80 mass% of a polyhydric alcohol, and 1 to 80 mass% of water based on the total amount of the aqueous base,

the water-soluble polymer is at least one selected from the group consisting of polyacrylic acid, polyacrylate, partially neutralized polyacrylic acid, polyacrylamide, polyethyleneimine, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl cellulose, acrylic starch, ethyl vinyl acetate, gelatin, starch, Eudragid, alginic acid, sodium alginate, and tragacanth,

the crosslinking agent is at least one selected from the group consisting of aluminum hydroxide, aluminum magnesium hydroxide, aluminum chloride, aluminum sulfate, aluminum dihydroxyglycinate, kaolin, aluminum stearate, magnesium hydroxide, magnesium chloride, magnesium sulfate, aluminum alum, sodium aluminate, inorganic aluminum complex salts, organic aluminum chelates, synthetic hydrotalcite, aluminum magnesium silicate, magnesium aluminate silicate, aluminum nitrate, aluminum sulfate, aluminum-EDTA, aluminum allantoate, aluminum acetate, aluminum dihydrogenated aminoacetate,

the polyhydric alcohol is at least one selected from ethylene glycol, propylene glycol, 1, 3-butylene glycol, ethylene glycol monobutyl ether, triethylene glycol, 1, 4-butylene glycol, glycerol, trihydroxy isobutane, butanetetraol, pentaerythritol, xylitol, ribitol, allitol, sorbitol solution, mannitol, and polyethylene glycol.

2. A percutaneous absorption preparation containing 3-methyl-1-phenyl-2-pyrazolin-5-one, characterized by containing 0.1 to 30 mass% of the following formula as an active ingredient in a rubber matrix:

the rubber base material contains 10 to 50 mass% of a rubber polymer, 10 to 50 mass% of a plasticizer and 5 to 50 mass% of a binder based on the total mass of the rubber base material,

the rubber polymer is at least one selected from the group consisting of a styrene-isoprene-styrene block copolymer, a styrene-butadiene block copolymer, polyisobutylene, a raw rubber, polyisoprene and polybutene,

the plasticizer is at least one selected from liquid paraffin, vegetable oil, animal oil, polybutene, low molecular polyisobutylene, vaseline, lanolin, and higher fatty acid ester,

the binder is at least one selected from the group consisting of petroleum resins, rosin-based resins, hydrogenated rosins, ester rubbers, terpene resins, modified terpene resins, aromatic hydrocarbon resins, and aliphatic hydrocarbon resins.

3. A transdermal patch containing 3-methyl-1-phenyl-2-pyrazolin-5-one is characterized by being formed by sequentially laminating a support, a matrix layer and a backing, wherein the matrix layer contains 0.1-30% by mass of a substance represented by the formula

An aqueous base material containing 3-methyl-1-phenyl-2-pyrazolin-5-one or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the aqueous base material contains 1 to 20 mass% of a water-soluble polymer, 0.01 to 20 mass% of a crosslinking agent, 10 to 80 mass% of a polyol and 1 to 80 mass% of water based on the total amount of the aqueous base material,

the water-soluble polymer is at least one selected from the group consisting of polyacrylic acid, polyacrylate, partially neutralized polyacrylic acid, polyacrylamide, polyethyleneimine, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl cellulose, acrylic starch, ethyl vinyl acetate, gelatin, starch, Eudragid, alginic acid, sodium alginate, and tragacanth,

the crosslinking agent is at least one selected from the group consisting of aluminum hydroxide, aluminum magnesium hydroxide, aluminum chloride, aluminum sulfate, aluminum dihydroxyglycinate, kaolin, aluminum stearate, magnesium hydroxide, magnesium chloride, magnesium sulfate, aluminum alum, sodium aluminate, inorganic aluminum complex salts, organic aluminum chelates, synthetic hydrotalcite, aluminum magnesium silicate, magnesium aluminate silicate, aluminum nitrate, aluminum sulfate, aluminum-EDTA, aluminum allantoate, aluminum acetate, aluminum dihydrogenated aminoacetate,

the polyhydric alcohol is at least one selected from ethylene glycol, propylene glycol, 1, 3-butylene glycol, ethylene glycol monobutyl ether, triethylene glycol, 1, 4-butylene glycol, glycerol, trihydroxy isobutane, butanetetraol, pentaerythritol, xylitol, ribitol, allitol, sorbitol solution, mannitol, and polyethylene glycol.

4. A transdermal patch containing 3-methyl-1-phenyl-2-pyrazolin-5-one is characterized by being formed by sequentially laminating a support, a matrix layer and a backing, wherein the matrix layer contains 0.1-30% by mass of a substance represented by the formula

A rubber substrate containing 3-methyl-1-phenyl-2-pyrazolin-5-one or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the rubber substrate contains 10 to 50 mass% of a rubber polymer, 10 to 50 mass% of a plasticizer and 5 to 50 mass% of a binder based on the total mass of the rubber substrate,

the rubber polymer is at least one selected from the group consisting of a styrene-isoprene-styrene block copolymer, a styrene-butadiene block copolymer, polyisobutylene, a raw rubber, polyisoprene and polybutene,

the plasticizer is at least one selected from liquid paraffin, vegetable oil, animal oil, polybutene, low molecular polyisobutylene, vaseline, lanolin, and higher fatty acid ester,

the binder is at least one selected from the group consisting of petroleum resins, rosin-based resins, hydrogenated rosins, ester rubbers, terpene resins, modified terpene resins, aromatic hydrocarbon resins, and aliphatic hydrocarbon resins.