JP4626202B2 - Piroxicam-containing external anti-inflammatory analgesic composition - Google Patents

Description

The present invention relates to an external anti-inflammatory analgesic composition having an increased skin permeability of piroxicam .

  Non-steroidal anti-inflammatory analgesics are used for rheumatoid arthritis, osteoarthritis, musculoskeletal acute and chronic pain, and the like. However, since it generally has side effects such as gastrointestinal disorders, various dosage forms such as external preparations and suppositories have been developed in addition to oral preparations and have been used in the medical field. However, in the case of an external preparation, since the skin permeability of the drug is remarkably suppressed by the effect of the biological barrier due to the keratin, there are cases where a satisfactory effect cannot be obtained.

  Conventionally, a percutaneous absorption enhancer has been studied in order to increase the skin permeability of a drug. For example, nicotinic acid ester (patent document 1), lactic acid and polyoxyethylene alkyl ether phosphate and lauric acid diethanolamine salt (patent document 2), ethylene oxide addition type nonionic surfactant (patent document 3), polyoxy Ethylene alkyl ether agents and polyoxyethylene phenyl ether agents (Patent Document 4), 1- [2- (decylthio) ethyl] azacyclopentan-2-one and cyclodextrins (Patent Document 5), polyoxyethylene derivatives and polyethylene Glycol (Patent Document 6), polyethylene glycol stearate ester or polyoxysorbitan stearate ester (Patent Document 7), alkylene glycol derivative, 1-alkylazacycloheptan-2-one, fatty acid and derivatives thereof, fatty acid alkanolamide Class And polyethylene glycol derivatives (Patent Document 8), epezoline or tolperisone (Patent Document 9), 1-alkylazacycloheptan-2-one and cis-olefin compounds (Patent Documents 10 and 11), N-substituted morpholine (Patent Document 12) ) And absorption accelerator blending techniques such as oleates (Patent Document 13) are disclosed.

  In addition, a percutaneous absorption enhancer containing a powder that increases the longitudinal relaxation time of the NMR spectrum of the oil as an active ingredient is also known (Patent Document 14).

  However, when these percutaneous absorption enhancers are blended, adding a sufficient amount of the percutaneous absorption enhancer to produce an effect is still satisfactory because it tends to cause skin irritation and the effect is insufficient. It was not possible.

  Furthermore, a skin-type external preparation for skin application is disclosed in which a relatively large amount of a polyhydric alcohol, a polymer compound and solid particles are blended in the preparation to enhance the feeling of use (Patent Document 15). However, this technique is troublesome because it requires rubbing after application, and has a drawback that if it is not wiped off after application, it will stain the clothes.

  Further, an external preparation is disclosed in which the percutaneous absorbability of the drug is enhanced by blending scrub (Patent Document 16). However, this technique has a problem that the scrub is a particulate matter that peels off the stratum corneum of the skin or causes minute scratches, so that it is likely to cause skin irritation and the feeling of use is poor.

JP 61-27920 JP 5-186371 JP-A-6-279289 JP 58-79918 JP 4-275235 JP 4-103528 JP 10-87494 A Special table flat 8-500365 JP2000-143510 7-57725 7-68147 JP 2-59528 JP-A-63-313731 JP-A-11-189545 JP2003-81881 JP-A-11-80031

An object of the present invention is to provide an external anti-inflammatory analgesic composition that exhibits an excellent effect by increasing the skin permeability of piroxicam .

As a result of intensive studies to solve such problems, the present inventors have found that the addition of a certain powder component in the composition increases the skin permeability of piroxicam , thereby completing the present invention.

That is, the present invention is an external anti-inflammatory analgesic composition characterized by containing one or two selected from (1) piroxicam and (2) calcium hydrogen phosphate and anhydrous calcium hydrogen phosphate.

According to the present invention, it has become possible to provide an external anti-inflammatory analgesic composition having an increased skin permeability of piroxicam .

A nonsteroidal anti-inflammatory analgesic having an effect in the present invention is piroxicam .

In the present invention, the compounding amount of piroxicam is preferably 0.1 to 20% by mass, and more preferably 0.5 to 5% by mass of the whole preparation. However, it can be appropriately changed depending on the dosage form.

The mechanism of action for promoting percutaneous absorption of the present invention is unclear, but the use of zinc oxide having a skin astringent action significantly suppresses percutaneous absorption, and therefore the effect of the present invention is effective for the use of piroxicam and phosphorus used in the present invention. It is considered to be specific to the combination of calcium oxyhydrogen phosphate or anhydrous calcium hydrogen phosphate.

  In the present invention, the blending amount of calcium hydrogen phosphate or anhydrous calcium hydrogen phosphate is preferably 0.1 to 20% by mass, and most preferably 0.1 to 10% by mass based on the entire preparation.

This is because if it is less than 0.1% by mass, the skin absorption promoting effect of piroxicam is insufficient, and if it is 20% by mass or more, the properties of the preparation are greatly affected and the feeling of use is lowered.

  The average particle size of calcium hydrogen phosphate or anhydrous calcium hydrogen phosphate used in the present invention is preferably 0.001 to 150 μm, and most preferably 1 to 100 μm. Finer calcium phosphate or anhydrous calcium hydrogen phosphate is preferable, but fine particles of 0.001 μm or less are difficult to produce, and if it exceeds 150 μm, a rough feeling may occur after the formulation is applied. .

  In the present invention, no particular rubbing is required, and percutaneous absorption is promoted.

  The external anti-inflammatory analgesic composition of the present invention can be prepared as a liquid preparation such as cream, ointment, lotion, semi-solid preparation such as gel, aerosol, tic, etc., but calcium hydrogen phosphate And / or a gel agent is the most preferable from the point of holding | maintaining anhydrous calcium hydrogenphosphate uniformly, the point of a usability | use_condition, etc. These can be produced by conventional methods.

  Here, the gel agent is a commonly used gelling agent (alginic acid, propylene glycol alginate, ethyl cellulose, methyl cellulose, carboxyvinyl polymer, acrylic acid / alkyl methacrylate copolymer, carbomer, carboxymethyl cellulose, xanthan gum, carrageenan, hydroxy Propylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydrophobized hydroxypropylmethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, aluminum stearate, dextran fatty acid ester, salts and derivatives thereof, etc. can be used. Preferred from the properties of the gel are carboxyvinyl polymer and alkyl-modified carbo One or more selected from the group consisting of civinyl polymer, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydrophobized hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, carboxymethylcellulose or a salt thereof, alginic acid or a salt thereof, xanthan gum and carrageenan Among these, one or more selected from carboxyvinyl polymer, hydroxypropylmethylcellulose, hydroxyethylcellulose and hydrophobized hydroxypropylmethylcellulose are most preferable.

  Moreover, when mix | blending a polyhydric alcohol with the external anti-inflammatory analgesic composition of this invention, the compounding quantity has preferable 20 mass% or less of the whole formulation. This is because when it exceeds 20% by mass, not only the feeling when applied but also the clothes, bedding, etc. are soiled if not wiped off after being applied to the skin.

  The viscosity of the gel used for producing the gel preparation in the present invention is preferably 30 mPa · s to 5000 mPa · s, and most preferably 100 mPa · s to 500 mPa · s in view of the usability such as ease of application.

The liquid preparation can also be prepared according to a conventional method. For example, after dissolving piroxicam in a liquid such as lower alcohol, polyhydric alcohol, water or a mixed solution thereof, calcium hydrogen phosphate or anhydrous calcium hydrogen phosphate is added. Obtained by dispersing. When an appropriate gelling agent is blended with the liquid obtained here, a gel can be obtained. The addition of calcium hydrogen phosphate or anhydrous calcium hydrogen phosphate may be performed before or after the addition of the gelling agent.

It is preferable from the viewpoint of medicinal effect that the anti-inflammatory analgesic composition for external use of the present invention contains a drug capable of improving symptoms such as rheumatoid arthritis, osteoarthritis and musculoskeletal acute / chronic pain in addition to the ingredients. Such drugs include camphor, turpentine oil, peppermint oil, menthol and its derivatives, eucalyptus oil, lactic acid menthyl and other refreshing agents, nonyl acid vanillylamide, capsaicin and other local irritants, glycyrrhizic acid and other anti-inflammatory agents, Diphenylimidazole, diphenhydramine and its salts, antihistamines such as chlorpheniramine maleate, blood circulation promoters such as tocopherol acetate and benzyl nicotinate, arnica tincture, agaric extract, sushi extract, horse chestnut extract, funnel extract, belladonna extract, toki extract, Herbal medicines such as coconut extract, salamander extract, and pepper extract are listed.

  In the external anti-inflammatory analgesic composition of the present invention, various base components that can be blended with pharmaceuticals and quasi-drugs can be blended within a range that does not impair the effects of the present invention.

  Hereinafter, the present invention will be described in more detail with reference to examples and test examples.

Example 1: 0.5 g of gel piroxicam
Ethanol 30g
Propylene glycol 15g
Carboxyvinyl polymer 1.0g
pH adjuster appropriate amount anhydrous calcium hydrogen phosphate 7.0g
100g of purified water
After swelling carboxyvinyl polymer in purified water, add propylene glycol, add ethanol solution in which piroxicam is dissolved, pH adjuster, mix uniformly, and then disperse in anhydrous calcium hydrogen phosphate dispersed in ethanol Was added and mixed so as to be uniformly dispersed to obtain a gel.

Example 2: Gel agent piroxicam 0.5 g
l-Menthol 3.0g
Ethanol 45g
1,3-butylene glycol 10g
Carboxy vinyl polymer 0.5g
Hydroxypropyl methylcellulose 0.5g
pH adjuster appropriate amount calcium hydrogen phosphate 0.5g
100g of purified water
A carboxyvinyl polymer and hydroxypropylmethylcellulose were swollen in purified water, 1,3-butylene glycol was added, and an ethanol solution in which a pH adjuster, piroxicam and l-menthol were dissolved was added and mixed uniformly. Further, calcium hydrogen phosphate dispersed in ethanol was added and mixed so as to be uniformly dispersed to obtain a gel.

Example 3: 0.5 g of gel agent piroxicam
l-Menthol 3.0g
Anhydrous calcium hydrogen phosphate 2.0g
Octyldodecyl myristate 5.0g
Sorbitan monostearate 2.0g
Polysorbate 60 2.0g
Glycerol monostearate 1.0g
Diisopropyl adipate 3.0g
Hydroxypropyl methylcellulose 0.5g
Carboxy vinyl polymer 0.5g
Isopropanol 16g
Ethanol 20g
Edetate appropriate amount sodium bisulfite appropriate amount pH adjuster appropriate amount purified water 100g
Carboxyvinyl polymer, hydroxypropylmethylcellulose was swollen in purified water, heated to 80 ° C with stirring, and oily components and drugs that had been preheated and melted were added from the hopper and cooled to 50 ° C. . After adding aqueous components and homogenizing, add anhydrous calcium hydrogen phosphate dispersed in isopropanol from the hopper, cool to room temperature while stirring with a scraping mixer, and finally add a pH adjuster to prepare a gel did.

Example 4: 0.5 g cream piroxicam
Tocopherol acetate 0.5g
l-Menthol 3.0g
dl-Camphor 0.5g
Anhydrous calcium hydrogen phosphate 5.0g
Propylene glycol 10.0g
Sorbitan monostearate 4.0g
Polysorbate 60 6.0g
Liquid paraffin 30.0g
Isopropyl myristate 4.0g
Cetostearyl alcohol 6.0g
Benzyl alcohol 3.0g
Xanthan gum 0.1g
Dimethylpolysiloxane 0.5g
Dibutylhydroxytoluene 0.1g
L-Arginine Appropriate amount edetate salt Appropriate amount of parabens Appropriate amount Sodium pyrosulfite Appropriate amount of purified water 100g
Xanthan gum was dissolved in purified water, a drug dissolved in an aqueous component was added, and the mixture was heated to 80 ° C. while stirring with a desktop emulsifier. An oily component that had been heated and melted in advance was added thereto from the hopper and cooled to 50 ° C. After homogenizing at 8000 rpm for 3 minutes and homogenizing, anhydrous calcium hydrogen phosphate dispersed in an aqueous component was added from a hopper, and cooled to room temperature while stirring with a scraping mixer to prepare a cream.

Example 5: Lotion agent Piroxicam 0.5 g
l-Menthol 3.0g
Tocopherol acetate 0.5g
dl-Camphor 0.5g
Calcium hydrogen phosphate 1.0g
1,3-Butylene glycol 5.0g
Benzyl alcohol 1.0g
Purified water 20.0g
Polysorbate 80 2.0g
Sodium bisulfite Appropriate edetate Appropriate dibutylhydroxytoluene Appropriate ethanol Total 100 mL
Among the components described above, components other than calcium hydrogen phosphate were stirred and dissolved uniformly, and then calcium hydrogen phosphate was added to prepare a solution for external use.

Example 6: Lotion preparation Piroxicam 0.5g
l-Menthol 3.0g
Tocopherol acetate 0.5g
dl-Camphor 0.5g
Anhydrous calcium hydrogen phosphate 1.0g
1,3-Butylene glycol 5.0g
Benzyl alcohol 1.0g
Purified water 20.0g
Polysorbate 80 2.0g
Sodium bisulfite Appropriate edetate Appropriate dibutylhydroxytoluene Appropriate ethanol Total 100 mL
Components other than anhydrous calcium hydrogen phosphate among the above components were stirred and dissolved uniformly, and then anhydrous calcium hydrogen phosphate was added to prepare an external solution.

Example 7: Lotion preparation Piroxicam 0.5g
l-Menthol 3.0g
Tocopherol acetate 0.5g
Calcium hydrogen phosphate 3.0g
1,3-Butylene glycol 5.0g
Benzyl alcohol 1.0g
Purified water 20.0g
Polysorbate 80 2.0g
Sodium bisulfite appropriate amount edetate appropriate amount dibutylhydroxytoluene appropriate amount ethanol 20mL
100 ml of isopropanol
Among the components described above, components other than calcium hydrogen phosphate were stirred and dissolved uniformly, and then calcium hydrogen phosphate was added to prepare a solution for external use.

Example 8: Lotion agent Piroxicam 0.5g
l-Menthol 3.0g
Tocopherol acetate 0.5g
Anhydrous calcium hydrogen phosphate 5.0g
Purified water 20.0g
Polysorbate 60 1.0g
Sodium bisulfite Appropriate edetate Appropriate dibutylhydroxytoluene Appropriate ethanol Total 100 mL
Components other than anhydrous calcium hydrogen phosphate among the above components were stirred and dissolved uniformly, and then anhydrous calcium hydrogen phosphate was added to prepare an external solution.

Example 9 Gel:
To the lotion obtained in Example 6, 0.5 g of carboxyvinyl polymer and 0.5 g of hydroxypropylmethylcellulose were further added and dissolved, and then a suitable amount of a pH adjuster was added to prepare a gel.

Example 10: Gel Agent After adding 0.5 g of carboxyvinyl polymer and 1.0 g of hydroxypropylmethylcellulose to the lotion obtained in Example 6, the gel was prepared by adding an appropriate amount of a pH adjuster.

Example 11: Gel agent After adding 0.5 g of carboxyvinyl polymer and 0.5 g of hydroxypropylmethylcellulose to the lotion obtained in Example 7, the gel was prepared by adding an appropriate amount of a pH adjuster.

Example 12: Gel Agent A gel agent was prepared by further adding 1.0 g of carboxyvinyl polymer and 0.5 g of hydroxypropylmethylcellulose to the lotion obtained in Example 7 and dissolving it, and then adding an appropriate amount of a pH adjuster.

Example 13: Gel Agent After adding 0.5 g of carboxyvinyl polymer and 0.5 g of hydroxypropylmethylcellulose to the lotion obtained in Example 8, the gel was prepared by adding an appropriate amount of a pH adjuster.

Example 14: Gel agent After adding 0.5 g of carboxyvinyl polymer and 1.0 g of hydroxypropylmethylcellulose to the lotion obtained in Example 8, the gel was prepared by adding an appropriate amount of a pH adjuster.

Example 15: Gel Agent A gel agent was prepared by further adding 1.0 g of hydroxyethyl cellulose to the lotion obtained in Example 6 and dissolving it.

Example 16: Gel agent A gel was prepared by further adding 1.0 g of hydrophobized hydroxypropylmethylcellulose to the lotion obtained in Example 8 and dissolving it.

Example 17: Aerosol agent An aerosol agent was prepared by putting 40% of the lotion agent of Example 6 and 60% of dimethyl ether gas into an aluminum pressure vessel.

Example 18: Aerosol Agent An aerosol agent was prepared by putting 40% of the lotion agent of Example 7 and 60% of a liquefied petroleum gas / dimethyl ether mixed gas into a pressure vessel made of aluminum.

Example 19: Aerosol Agent An aerosol agent was prepared by putting 40% of the lotion agent of Example 8 and 60% dimethyl ether gas into a pressure vessel made of aluminum.

Example 20: Tick agent Piroxicam 0.5 g
l-Menthol 3.0g
Tocopherol acetate 0.5g
Anhydrous calcium hydrogen phosphate 4.0g
1,3-butylene glycol 25.0g
Benzyl alcohol 1.0g
Purified water 5.0g
Polysorbate 80 1.0g
Glycerol monostearate 1.0g
Hydroxypropyl methylcellulose 0.5g
Sodium stearate 10.0g
Sodium bisulfite appropriate amount edetate appropriate amount ethanol 100g
After the above components were dissolved by heating, they were filled into a cylindrical container, cooled to room temperature by slow cooling to the extent that anhydrous calcium hydrogen phosphate did not settle, and solidified to prepare a tic agent.

Example 21: Ointment piroxicam 0.5 g
Glycyrrhetinic acid 0.02g
l-Menthol 3.0g
Tocopherol acetate 0.5g
Anhydrous calcium hydrogen phosphate 10.0g
White petrolatum 20.0g
Dextrin palmitate 15.0g
Dimethylpolysiloxane 0.05g
100g liquid paraffin
After the oil component and the drug were uniformly dissolved or dispersed while heating, anhydrous calcium hydrogen phosphate was added and cooled to room temperature with good stirring to prepare an ointment.

  With the formulations shown in the following table, gel agents of Examples and Comparative Examples were produced by ordinary methods.

（試験例１）ラット摘出皮膚透過性試験
（方法）
電気シェーバーで腹部を剃毛したヘアレスラット（雄、8〜10週齢）の腹部剃毛部より左右2箇所から皮膚を摘出した。摘出した皮膚を平均有効面積0.98cm^２の横型拡散セルに装着した後、ドナー側のセル内に表1に示した各検体を一定量ずつ塗布し、レシーバー側のセルにpH7.4リン酸緩衝液3mLを加えた。レシーバー層の外層には37℃の恒温水を還流し、レシーバー液は撹拌子により撹拌した。

(Test Example 1) Rat Percutaneous Permeability Test (Method)
Skin was extracted from the left and right sides of the abdominal shaved part of a hairless rat (male, 8 to 10 weeks old) shaved with an electric shaver. After the extracted skin is attached to a horizontal diffusion cell with an average effective area of 0.98 cm ^2, a certain amount of each sample shown in Table 1 is applied to the cell on the donor side, and pH 7.4 phosphate buffer is applied to the cell on the receiver side. 3 mL of the solution was added. Constant temperature water at 37 ° C. was refluxed to the outer layer of the receiver layer, and the receiver liquid was stirred with a stirring bar.

  A fixed amount of the receiver solution was collected over time, the measurement wavelength was 255 nm, and the amount of drug was measured by high performance liquid chromatography using propyl paraoxybenzoate as the internal standard substance.

  The results are shown in FIG. It was found that the permeability was drastically increased as compared with Comparative Example 1 by adding anhydrous calcium hydrogen phosphate.

  Further, FIG. 2 shows the cumulative permeation amount of piroxicam after 10 hours in Example 1 when the cumulative permeation amount after 10 hours of Comparative Example 1 is 100%. It can be seen that Example 1 is increased by the blending of anhydrous calcium hydrogen phosphate.

  The present invention provides an external anti-inflammatory analgesic composition that exhibits excellent effects. More specifically, the present invention provides an external anti-inflammatory analgesic composition that promotes skin permeability of piroxicam and has an excellent anti-inflammatory analgesic effect.

It is the figure which showed the measurement result of the piroxicam accumulation | transmission amount of Example 1 and Comparative Example 1, and the accumulation amount (microgram / cm < ² >) was shown on the vertical axis | shaft and time was shown on the horizontal axis | shaft. (Average of hairless rats n = 3-4) It is the figure which showed the measurement result (average of hairless rat n = 3-4) of each comparative example and the piroxicam accumulated permeation amount of Example 1 when Comparative Example 1 was set to 100.

Claims (7)

An external anti-inflammatory analgesic composition comprising (1) piroxicam, and (2) one or two selected from calcium hydrogen phosphate and anhydrous calcium hydrogen phosphate. The anti-inflammatory analgesic composition for external use according to claim 1, wherein the amount of piroxicam is 0.1 to 20% by mass of the whole preparation. 2. The anti-inflammatory analgesic composition for external use according to claim 1, wherein the amount of one or two selected from calcium hydrogen phosphate and anhydrous calcium hydrogen phosphate is 0.1 to 20% by mass of the whole preparation. The external anti-inflammatory analgesic composition according to any one of claims 1 to 3, which is a gel. Selected from the group consisting of carboxyvinyl polymer, alkyl-modified carboxyvinyl polymer, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydrophobized hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, carboxymethylcellulose or salt thereof, alginic acid or salt thereof, xanthan gum and carrageenan The anti-inflammatory analgesic composition for external use according to claim 4, wherein the composition is gelled by one or more kinds. A skin absorption enhancer for piroxicam , characterized by comprising one or two selected from calcium hydrogen phosphate and anhydrous calcium hydrogen phosphate. An external anti-inflammatory analgesic comprising 1 or 2 types selected from calcium hydrogen phosphate and anhydrous calcium hydrogen phosphate, wherein the calcium hydrogen phosphate and anhydrous calcium hydrogen phosphate promote skin absorption of piroxicam Composition.

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