JP2935113B1 - Indomethacin transdermal absorbent - Google Patents

Abstract

Kind Code: A1 Abstract: Provided is a transdermal indomethacin absorbent which exhibits excellent medicinal properties by improving the absorbability of indomethacin from the skin. Provided is an indomethacin skin absorption enhancer capable of improving and improving the skin absorption of indomethacin. SOLUTION: Indomethacin is used as an active ingredient, and at least one selected from the group consisting of lower alkylene carbonate and ethyl carbonate, or at least one selected from the group consisting of lower alkylene carbonate and ethyl carbonate, and aromatic alcohol A transdermal indomethacin absorbent comprising:

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a transdermal absorbent containing indomethacin as an active ingredient. More specifically, the present invention relates to an anti-inflammatory analgesic external preparation having improved transdermal absorbability of indomethacin.

[0002]

2. Description of the Related Art Indomethacin is widely known as a non-steroidal anti-inflammatory drug having an excellent anti-inflammatory and analgesic effect, but has a drawback that when administered orally, it causes side effects such as gastrointestinal disorders. doing. Therefore, in order to solve such problems, preparation of external preparations (ointments, creams, patches, liquids) for absorbing indomethacin into the living body by transdermal administration has been attempted and developed. .

[0003] However, since the skin has a physiological function as a barrier for preventing invasion of foreign substances from the outside, a sufficient medicinal effect can be obtained simply by applying a medicinal component to a base of the medicament. It is difficult to absorb a sufficient amount of a drug that expresses into the body, and it has conventionally been a problem to improve the therapeutic effect by improving absorption from the skin. Indomethacin is a poorly soluble drug having extremely low solubility in water. For this reason, it is difficult to compensate for poor absorbability by including a large amount of indomethacin in an external preparation.

[0004] As a method of solving such a problem, conventionally,
A method of improving the solubility of indomethacin in a base (JP-A-58-124716, JP-A-4-149131, etc.) and a method of blending a component that promotes absorption from the skin (JP-A-1-279831, JP-A-61-19401
No. 5, JP-A-58-79918, etc.)
Proposed.

[0005]

DISCLOSURE OF THE INVENTION The present invention solves the above-mentioned conventional problems, and provides a transdermal indomethacin having excellent medicinal effects by improving the absorbability of indomethacin from the skin. The purpose is to: In addition, another object of the present invention is to provide an indomethacin skin absorption enhancer capable of improving and improving the skin absorbability of indomethacin.

[0006]

Means for Solving the Problems The present inventors have made intensive studies to solve the above-mentioned problems, and found that indomethacin is mixed with a lower alkylene carbonate such as propylene carbonate or ethyl carbonate and applied to the skin. Thereby, compared to the case of using indomethacin alone, found that indomethacin is rapidly absorbed from the skin and its blood concentration is significantly improved, and a lower alkylene carbonate or ethyl carbonate promotes the skin absorption of indomethacin. As useful as. The present inventor further studied
By using an aromatic alcohol in addition to a lower alkylene carbonate as an indomethacin skin absorption promoting component, it has been found that the skin absorption of indomethacin is significantly improved as compared with a case where only a lower alkylene carbonate or ethyl carbonate alone is used in combination. . The present invention has been developed based on such knowledge.

That is, the present invention relates to the following indomethacin transdermal absorption agent: Indomethacin as an active ingredient, further comprising at least one selected from the group consisting of lower alkylene carbonate and ethyl carbonate, or at least one selected from the group consisting of lower alkylene carbonate and ethyl carbonate, and an aromatic alcohol. Characteristic indomethacin transdermal absorbent.

Item 2. 0.1 to 1.5 parts by weight of indomethacin per 100 parts by weight of indomethacin transdermal absorbent,
And at least one selected from the group consisting of lower alkylene carbonate and ethyl carbonate by 5 to 3
Item 4. The indomethacin transdermal absorbent according to item 1, comprising 0 part by weight.

Item 3. 0.1 to 1.5 parts by weight of indomethacin per 100 parts by weight of indomethacin transdermal absorbent,
Item 4. The indomethacin transdermal absorbent according to item 1, comprising 3 to 20 parts by weight of at least one selected from the group consisting of lower alkylene carbonate and ethyl carbonate, and 1 to 10 parts by weight of an aromatic alcohol.

Item 4. Item 4. The transdermal indomethacin absorbent according to any one of Items 1 to 3, wherein the lower alkylene carbonate is propylene carbonate.

Item 5. Item 5. The indomethacin transdermal absorbent according to any one of Items 1, 3 and 4, wherein the aromatic alcohol is benzyl alcohol.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION The percutaneous absorption agent of the present invention is characterized by containing, in addition to indomethacin as an active ingredient, at least one selected from the group consisting of lower alkylene carbonate and ethyl carbonate.

In the present invention, indomethacin may be any one which is usually used as a medicament, regardless of the crystal polymorphism. The compounding amount is not particularly limited because it varies depending on the type of the dosage form, application symptoms, and the like, but is usually 0.1 to 1.5 parts by weight, preferably 0.3 to 1.5 parts by weight per 100 parts by weight of the transdermal absorbent. It can be suitably selected and adjusted from the range of 1 part by weight.

The lower alkylene carbonate used in the present invention means a carbonate compound having an alkylene group having 2 to 6 carbon atoms. Examples of the alkylene group include an ethylene group, a propylene group, an ethylethylene group, a trimethylene group, and a hexamethylene group. More specific examples of the lower alkylene carbonate include ethylene carbonate and propylene carbonate. These carbonate compounds can be used alone or in combination of two or more. In the present invention, use of propylene carbonate is preferred. In the present invention, ethyl carbonate may be used in place of or in combination with lower alkylene carbonate.

The mixing ratio of the lower alkylene carbonate and / or ethyl carbonate is usually 5 to 30 parts by weight, preferably 5 to 25 parts by weight, more preferably 7 to 20 parts by weight, per 100 parts by weight of the transdermal absorbent. Can be mentioned. Indomethacin 1 contained in transdermal absorbent
The mixing ratio of the lower alkylene carbonate and / or ethyl carbonate with respect to parts by weight is not limited,
Usually, it is desirable to be in the range of 1 to 50 parts by weight, preferably 6 to 26 parts by weight.

By using lower alkylene carbonate or ethyl carbonate in such a ratio in combination with indomethacin, the transdermal absorbability of indomethacin can be improved. This means that according to the transdermal absorption agent of the present invention, a smaller or larger amount of indomethacin can exert a therapeutic effect on anti-inflammatory analgesia equal to or greater than that of the conventional art. In addition, lower alkylene carbonate or ethyl carbonate means that it is useful as an agent for improving the percutaneous absorption of indomethacin and an effect enhancer.

In the present invention, lower alkylene carbonate or ethyl carbonate can be used in combination with an aromatic alcohol, whereby the transdermal absorbability of indomethacin can be further improved.

That is, the percutaneous absorbent of the present invention is characterized by containing, in addition to indomethacin as an active ingredient, at least one selected from the group consisting of lower alkylene carbonate and ethyl carbonate, and an aromatic alcohol. It is assumed that.

When an aromatic alcohol is used in combination, it is possible to improve the transdermal absorbability of indomethacin with a smaller amount of lower alkylene carbonate and / or ethyl carbonate. The compounding amount is usually 3 parts by weight or more, preferably 3 to 20 parts by weight, more preferably 5 to 20 parts by weight per 100 parts by weight of the transdermal absorbent. It is of course possible to incorporate 20 parts by weight or more of the lower alkylene carbonate and / or ethyl carbonate in the transdermal absorbent. However, the effect of improving the transdermal absorbability of indomethacin can be sufficiently achieved by a blending ratio of about 20 parts by weight. Can be satisfied.

The aromatic alcohol used here includes:
Although not particularly limited, for example, benzyl alcohol, phenethyl alcohol, cinnamyl alcohol,
-Phenoxyethanol and the like. These aromatic alcohols can be used alone or in combination of two or more. In the present invention, use of benzyl alcohol is preferred.

The mixing ratio of the aromatic alcohol is usually 1 to 10 parts by weight, preferably 2 to 8 parts by weight, per 100 parts by weight of the transdermal absorbent.

The mixing ratio of lower alkylene carbonate or ethyl carbonate and aromatic alcohol to 1 part by weight of indomethacin contained in the percutaneous absorbent is not particularly limited, but lower alkylene carbonate or ethyl carbonate is usually 3 to 80 parts by weight, Preferably 6
To 27 parts by weight, and the aromatic alcohol is 1 to 30 parts by weight.
Parts by weight, preferably in the range of 2 to 10 parts by weight.

The transdermal absorption agent of the present invention has the following
Any dosage form can be employed as long as it is used for external purposes, such as liquids (including lotions and sprays), ointments, creams, gels, emulsions,
Various external preparations such as sticks can be mentioned. In these dosage forms, bases and components commonly used in the art can be blended according to each dosage form, and can be prepared according to a conventional method.

For example, in the case of a liquid (including a lotion and a spray), it can be prepared by dissolving the above-mentioned various components in a solvent as a base. As the solvent,
Water; lower alcohols such as ethanol, denatured ethanol, propyl alcohol, isopropyl alcohol, and butyl alcohol; acetone; polyhydric alcohols such as glycerin, propylene glycol, 1,3-butylene glycol, and polyethylene glycol.
These solvents can be used alone or in combination of two or more. In the present invention, a lower alcohol solvent such as ethanol or isopropyl alcohol is used alone, or a mixed solvent thereof with water is preferable, and a mixed solvent of water and ethanol is more preferable. The mixing ratio of water and lower alcohol (including ethanol) is not particularly limited as long as each component is dissolved, but usually the ratio of lower alcohol contained in the solvent is 50% or more, preferably 60% or more. Desirably.

When an ointment, cream or gel is used as a dosage form, in addition to the above-mentioned essential components, various bases suitable for each external preparation are mixed in accordance with a conventional method to obtain a semisolid having an appropriate consistency. It can be prepared by obtaining a shape. Examples of the base component include an oil component, glycols, a surfactant, a water-soluble polymer, and a solvent. These specific components are not particularly limited and can be in accordance with a conventional method. For example, as an oil component, lanolin, hydrogenated oil, lecithin, plastibase, liquid paraffin, oleic acid,
Stearic acid, myristic acid, palmitic acid, beeswax, paraffin wax, microcrystalline wax, diisopropyl adipate, isopropyl sebacate, isopropyl myristate, isopropyl palmitate, squalane, squalene, cetanol, stearyl alcohol, oleyl alcohol, hexadecyl alcohol, Examples of the glycols include glycerin, propylene glycol, polyethylene glycol, and polypropylene glycol. Examples of the surfactant include polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, and polyoxyethylene glycerin fatty acid. Ester, polyethylene glycol fatty acid ester, polyoxyethylene glycol ether, polio Examples thereof include ethylene glycol phenyl ether, polyoxyethylene polyoxypropylene alkyl ether, polyoxyethylene phytosterol, sorbitan fatty acid ester, and glycerin fatty acid ester; examples of the water-soluble polymer include carboxyvinyl polymer, sodium carboxymethylcellulose, polyvinyl alcohol, and methylcellulose. , Hydroxyethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, hydroxypropylmethylcellulose, polyacrylic acid and the like; examples of the solvent include water, ethanol, denatured ethanol, propyl alcohol, isopropyl alcohol, acetone and the like. However, it is not limited to these.

When a patch is employed as the dosage form, the base may be, for example, an adhesive polymer, a humectant, a curing agent, an inorganic powder,
It is prepared according to a conventional method using various components such as a surfactant and a solvent. Adhesive polymers include polyacrylic acid, sodium polyacrylate, gelatin, pectin,
Examples include polyvinylpyrrolidone, vinyl acetate copolymer, polyethylene oxide, methyl vinyl ether / maleic anhydride copolymer, sodium alginate, sodium carboxymethylcellulose, xanthan gum, gum arabic, gum tragacanth, and the like; examples of humectants include glycerin, sorbitol, and propylene. Glycol, polyethylene glycol, polypropylene glycol and the like; examples of the curing agent include aluminum potassium sulfate, magnesium aluminate silicate, aluminum hydroxide, magnesium aluminate hydroxide, aluminum hydroxide, magnesium hydroxide aluminate, magnesium aluminate metasilicate, Synthetic hydrotalcite, dihydroxyaluminum aminoacetate, triglycidyl isocyanate, polyethylene Glycol diglycidyl ether, ethylene glycol diglycidyl ether, glycerol diglycidyl ether, triglycerol diglycidyl ether are illustrated; as the inorganic powder kaolin,
Examples thereof include silicic anhydride, zinc oxide, and titanium oxide; examples of the surfactant and the solvent include those described above. However, it is not particularly limited to these.

The indomethacin transdermal absorption agent of the present invention may be added to the above-mentioned components for the purpose of maintaining and improving the effectiveness (stability) of indomethacin, improving the feeling of use, etc., as long as the effects of the present invention are not impaired. May contain arbitrary components. Optional components include, for example, pharmaceuticals such as external preparations,
Examples thereof include additives such as stabilizers, preservatives, dissolution aids, emulsifiers, suspending agents, pH adjusters, and antioxidants used in quasi-drugs and cosmetics.

The indomethacin transdermal absorption agent of the present invention is excellent in absorption from the skin and is used for treating orthopedic diseases such as arthritis, shoulder periarthritis, myalgia, sprain, tendonitis, lumbago, and bruise. And show excellent effect.

The amount of the transdermal absorption agent of the present invention varies depending on the type of the disease, the degree of the symptom, and the size of the affected part, and cannot be specified unconditionally. It is usually used once or several times a day by applying an appropriate amount to the affected area.

[0030]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Examples and Experimental Examples, but the present invention is not limited to the Examples and the like.

Examples 1 and 2 Liquid preparations (products 1 and 2 of the present invention) in which propylene carbonate was mixed with indomethacin were prepared, and indomethacin transdermal absorbent containing no propylene carbonate (comparative control product)
And the transdermal absorbability (absorption effect) of indomethacin as an active ingredient were compared (Table 1).

The transdermal absorbability of indomethacin was evaluated by measuring the blood concentration of indomethacin after a certain period of time after applying the solution to the skin. Specifically, about 0.8 ml of each of the product 1, 2 or the comparative product of the present invention,
Hairless rats (male, 6 weeks old, 6 rats per group)
One hour after that, the rat was anesthetized and laparotomy was performed. About 3 ml of blood was collected from the aorta and the amount of indomethacin in the blood was measured. The amount of indomethacin in the blood was measured by centrifuging the blood collected from the rat (3000 rpm, 10 minutes), removing the protein from the obtained supernatant, adding naphthalene as an internal standard substance, and applying the following conditions. Performed by subjecting to HPLC. Similarly, a solution containing a known amount of indomethacin (including an internal standard substance) was used as a standard solution, and HPL was similarly used.
Subjected to C analysis.

<HPLC> Mobile phase: acetonitrile: 0.13% 1-octanesulfonic acid Na / acetic acid (100: 100: 1) mixed solution Stationary phase: ODS C18 (5C18: manufactured by Nacalai Tesque) Flow rate: 1 ml / 1 min Column temperature: 40 ° C. Measurement wavelength: 254 nm The results are shown in Table 1.

[0034]

[Table 1]

As can be seen from Table 1, the product of the present invention in which propylene carbonate was added to indomethacin had a significantly higher blood concentration of indomethacin at a certain time after application than the control product. This indicates that the indomethacin transdermal absorbent of the present invention is excellent in transdermal absorbability through the skin, and the absorbability is not limited to transfer to the epidermis, but to blood, muscle, and joints. It has been found that it can also promote transferability and has excellent pharmacological effects.

Examples 3 to 6 Liquid preparations (products of the present invention 3 to 6, Table 2) in which propylene carbonate and benzyl alcohol were blended with indomethacin were prepared, and the active ingredient indomethacin was prepared in the same manner as in Example 1. The skin absorbability (absorption effect) was evaluated. As a comparative example, indomethacin transdermal absorbent containing no propylene carbonate (comparative control product, comparative example 1) and a liquid formulation in which benzyl alcohol was added to indomethacin (comparative product, comparative examples 2 to 4) were used. The transdermal absorbability was evaluated. Table 2 shows the results.

[0037]

[Table 2]

From Table 2, it can be seen that the product of the present invention in which propylene carbonate and benzyl alcohol are blended with indomethacin has a remarkably higher blood concentration of indomethacin and a remarkably improved transdermal absorption than indomethacin alone (Comparative Example 1). You can see that In addition, the degree of improvement in the transdermal absorbability of indomethacin in this example was much larger than in Examples 1 and 2 in which only propylene carbonate was blended with indomethacin. From this fact, a composition comprising a combination of propylene carbonate (lower alkylene carbonate) and benzyl alcohol (aromatic alcohol) is extremely useful as an enhancer for promoting percutaneous absorption of indomethacin and, consequently, an action enhancer for indomethacin. I understand.

As described above, by blending propylene carbonate (lower alkylene carbonate) and benzyl alcohol (aromatic alcohol) with indomethacin, the transdermal absorbability of indomethacin can be remarkably increased, and as a result, the amount of indomethacin can be reduced. Can exert a pharmacologically effective anti-inflammatory analgesic effect. The ability to reduce the amount of indomethacin incorporated into the formulation is extremely significant for poorly soluble indomethacin.

Formulation Example 1 The indomethacin transdermal absorption agent (solution) of the present invention was prepared in the same manner as in Example 1, except that ethylene carbonate was used instead of propylene carbonate.

Formulation Example 2 The indomethacin transdermal absorption agent (solution) of the present invention was prepared in the same manner as in Example 1, except that ethyl carbonate was used instead of propylene carbonate.

Formulation Example 3 The indomethacin transdermal absorption agent (solution) of the present invention was prepared in the same manner as in Example 3, except that ethylene carbonate was used instead of propylene carbonate.

Formulation Example 4 In the formulation of Example 4 , an indomethacin transdermal absorption agent (solution) of the present invention was prepared by using ethyl carbonate instead of propylene carbonate.

Formulation Example 5 Gel Ointment A composition having the following formulation was mixed to prepare a gel ointment according to a conventional method.

Indomethacin 1.0 g Propylene carbonate 10.0 g Benzyl alcohol 4.0 g l-menthol 3.0 g Carboxyvinyl polymer 1.0 g Hydroxypropyl cellulose 0.2 g Propylene glycol 10.0 g Sodium edetate 0.01g triethanolamine 0.3 g ethanol 60.0 g purified water Balance total 100.0 g

Formulation Example 6 Cream A composition having the following formulation was mixed to prepare a cream according to a conventional method.

Indomethacin 1 g Propylene carbonate 5 g Benzyl alcohol 4 g 1-Menthol 5 g Stearyl alcohol 7 g Beeswax 2 g Squalane 10 g Self-emulsifying propylene glycol monostearate 3 g Polyoxyethylene cetyl ether 1 g Propylene glycol 8 g purified water Balance total 100 g

Formulation Example 7 Patch Indomethacin, l-menthol, castor oil and polysorbate 80 were dissolved to prepare an indomethacin solution.
Then, the mixture was mixed with other components, kneaded, and spread on a polyester nonwoven fabric to prepare a patch.

Indomethacin 0.5 g Propylene carbonate 5.0 g Benzyl alcohol 2.0 g l-menthol 1.0 g Crotamiton 1.0 g Polyacrylic acid 4.0 g Sodium polyacrylate 1.0 g Carboxymethylcellulose Na 3.0 g glycerin 20.0 g sorbitol solution 15.0 g kaolin 6.0 g Jihido b alkoxy aluminum aminoacetate 0.2 g polysorbate 80 1.0 g castor oil 1.0 g purified water Balance total 100.0 g

Claims (5)

(57) [Claims] Claims: 1. An inactive component comprising indomethacin as an active ingredient and at least one selected from the group consisting of lower alkylene carbonate and ethyl carbonate, or at least one selected from the group consisting of lower alkylene carbonate and ethyl carbonate, and an aromatic alcohol. A transdermal indomethacin absorbent comprising: 2. Per 100 parts by weight of indomethacin transdermal absorbent, 0.1 to 1.5 parts by weight of indomethacin and 5 to 30 parts by weight of at least one selected from the group consisting of lower alkylene carbonate and ethyl carbonate. The indomethacin transdermal absorption agent according to claim 1, which is contained in a ratio of: (3) per 100 parts by weight of indomethacin transdermal absorbent, 0.1 to 1.5 parts by weight of indomethacin, 3 to 20 parts by weight of at least one selected from the group consisting of lower alkylene carbonate and ethyl carbonate, The indomethacin transdermal absorbent according to claim 1, further comprising an aromatic alcohol in a ratio of 1 to 10 parts by weight. 4. The transdermal indomethacin absorbent according to claim 1, wherein the lower alkylene carbonate is propylene carbonate. 5. The transdermal indomethacin absorbent according to claim 1, wherein the aromatic alcohol is benzyl alcohol.