JP6456533B2 - Loxoprofen-containing external preparation composition - Google Patents

Description

  The present invention does not attenuate the superior analgesic and anti-inflammatory properties of loxoprofen, such as muscle pain, low back pain, joint pain, shoulder pain, etc. in bruises, sprains, after intense sports, tendonitis, so-called tennis elbow and aging, etc. The present invention relates to an external preparation composition for improving symptoms. More specifically, the present invention relates to an external anti-inflammatory analgesic that further improves the anti-inflammatory action by further adding nonyl acid vanillylamide, which is a specific local warming stimulating component, to the external preparation composition containing loxoprofen.

  Loxoprofen, which is a propionic non-steroidal antipyretic analgesic / anti-inflammatory agent (NSAID), has antipyretic / analgesic / anti-inflammatory effects based on the inhibitory action of prostaglandin biosynthesis, similar to other NSAIDs. Loxoprofen is a prodrug that is absorbed from the gastrointestinal tract and remains active in the body as an intact substance with weak gastric mucosal irritation after oral administration. However, it is also known (for example, refer nonpatent literature 1).

  In recent years, loxoprofen has been clinically used as a topical anti-inflammatory analgesic, such as a poultice, a tape, and a gel (see, for example, Non-Patent Document 2). Loxoprofen is known to be converted to a trans-OH form (active form) by ketone reductase in the skin (see, for example, Patent Document 1).

  On the other hand, pepper extract, capsaicin, nonylic acid vanillylamide, nicotinic acid benzyl ester and the like may be added to an OTC external analgesic / anti-inflammatory agent as a component having a local warming stimulating action (see, for example, Non-Patent Document 3).

  There is no known external preparation composition containing loxoprofen and nonylic acid vanillylamide. There is a description that a product can be blended (see, for example, [0029] of Patent Document 2).

JP 2008-074873 A JP 2010-280634 A

Pharmacology and Treatment Vol.16 No.2 1988 p.611-619 JAPIC Ethical Drug Collection 2013 Maruzen 2012 OTC Pharmaceutical Dictionary 2010-11 Jiho 2010

  An object of the present invention is to provide a loxoprofen-containing external analgesic / anti-inflammatory composition which further improves the analgesic / anti-inflammatory activity of loxoprofen.

  As a result of this study, the present inventors have found that the anti-inflammatory action of loxoprofen is enhanced only when nonyl acid vanillylamide, a specific warming sensation component, is added to loxoprofen, and the present invention has been completed.

That is, the present invention
(1) An external anti-inflammatory analgesic composition containing loxoprofen and nonylic acid vanillylamide,
(2) The anti-inflammatory analgesic composition for external use according to (1) above, wherein the anti-inflammatory action of loxoprofen is enhanced.

  The external preparation composition containing nonyl acid vanillylamide in loxoprofen of the present invention is useful because it can further enhance the excellent anti-inflammatory action of loxoprofen.

  The loxoprofen of the present invention is listed in the 16th revised Japanese Pharmacopoeia as loxoprofen sodium hydrate. Nonyl acid vanillylamide (also referred to as nonanoic acid vanillylamide or nonyl acid vanillylamide) is described in the Pharmaceutical Additives Dictionary 2005.

  The weight% of loxoprofen contained in the external preparation composition of the present invention is usually 0.1 to 10%, preferably 0.5 to 5%. This is applied or affixed once to several times a day. The amount of nonyl acid vanillylamide added is not particularly limited, but a concentration that imparts warmth and does not cause skin irritation is desirable, and is preferably 0.01 to 5%.

Specific dosage forms of the external anti-inflammatory analgesic composition of the present invention can include, for example, liquids, creams, ointments, gels, patches, aerosols, etc., and suitable additions for each dosage form It can be produced according to the usual methods described in the Japanese Pharmacopoeia using appropriate agents and base materials.

  In each of the above dosage forms, a commonly used base or various additives can be used depending on the dosage form. For example, in the case of a solution, lower alcohol such as ethanol, propanol, isopropanol, etc .; water; propylene glycol, polyethylene glycol, butylene glycol, glycerin, castor oil, etc. as a solvent, sodium hydroxide, potassium hydroxide, triethanolamine, etc. as pH As a regulator, a polymer such as carboxyvinyl polymer, sodium carboxymethylcellulose, polyvinyl alcohol, methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyacrylic acid, etc. can be used as a viscosity imparting agent. Hydrocarbons; esters; triglycerides; higher alcohols such as cetanol and stearyl alcohol as oil phase components, sodium alkylbenzene sulfonate Anionic surfactants such as potassium stearate, sodium cetyl sulfate, sodium polyoxyethylene lauryl ether phosphate, dioctyl sodium sulfosuccinate; cationic surfactants such as benzalkonium chloride and benzethonium chloride; sucrose fatty acid ester, stearin Nonionic surfactants such as polyoxyl acid 40, ethylene glycol monostearate, sorbitan sesquioleate, propylene glycol fatty acid ester, polyoxyethylene hydrogenated castor oil, polysorbate, glyceryl monostearate as surfactants, glycerin, propylene glycol Sorbitol, etc. can be used as a moisturizer. In the case of an ointment, petrolatum, liquid paraffin, paraffin wax, microcrystalline wax, etc. Plastics; Lanolins such as purified lanolin, lanolin alcohol, hydrogenated lanolin; animal and vegetable oils; natural waxes; waxes and the like can be used as an ointment base. In the case of gels, aluminum stearate, fatty acid dextran Esters can be used as oily gel bases, carboxyvinyl polymers, bentonites, etc. can be used as aqueous gel bases. In the case of patches, polyacrylic acid, sodium polyacrylate, gelatin, pectin, polyvinylpyrrolidone, vinyl acetate Copolymers, polyethylene oxide, methyl vinyl ether / maleic anhydride copolymer, sodium alginate, sodium carboxymethyl cellulose, xanthan gum, gum arabic, tragacanth, etc. , Propylene glycol, polyethylene glycol, polypropylene glycol, etc. as adhesive polymer, potassium aluminum sulfate, magnesium aluminate silicate, aluminum hydroxide, magnesium magnesium aluminate, magnesium metasilicate aluminate, synthetic hydrotalcite, dihydroxyaluminum Aminoacetate, triglycidyl isocyanate, polyethylene glycol diglycidyl ether, ethylene glycol diglycidyl ether, glycerin diglycidyl ether, triglycerin diglycidyl ether, etc. as curing agents, kaolin, silicic anhydride, zinc oxide, titanium oxide, etc. As body, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene glycerin fat Acid esters, polyethylene glycol fatty acid esters, polyoxyethylene glycol ethers, polyoxyethylene alkylphenyl ethers, polyoxyethylene polyoxypropylene alkyl ethers, polyoxyethylene phytosterols, sorbitan fatty acid esters, glycerin fatty acid esters, etc. are used as surfactants. In the case of aerosol agents, chlorofluorocarbons; chlorofluorocarbons; liquefied petroleum gases; dimethyl ethers as liquefied gas propellants, nitrogen gas, carbon dioxide gas, nitrous oxide gas as compressed gas It can be used as a propellant.

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

(Formulation Example 1) Solution (Table 1)
In 100 g (g) a b c
―――――――――――――――――――――――――――――――
Loxoprofen sodium 0.5 1 2
Nonyl acid vanillylamide 0.1 0.3 1
Ethanol 50 50 50
Purified water Remainder Remainder Remainder ―――――――――――――――――――――――――――――――
Taking the above ingredients and amounts, prepare the liquid according to the section “General preparation for external use”.

(Formulation Example 2) Gel (Table 2)
In 100 g (g) a b c
―――――――――――――――――――――――――――――――
Loxoprofen sodium 0.5 1 2
Nonyl acid vanillylamide 0.1 0.3 1
Carboxyvinyl polymer 2 2 2
Hypromellose 1.5 1.5 1.5
Ethanol 50 50 50
Purified water Remainder Remainder Remainder ―――――――――――――――――――――――――――――――

  Taking the above components and amounts, a gel is prepared according to the section “General Gel Preparation” in Japanese Pharmacopoeia.

(Test Example 1) Anti-inflammatory effect test (1) Test substance Loxoprofen sodium dihydrate was manufactured by Daiichi Sankyo, and nonyl acid vanillylamide and nicotinic acid benzyl ester were manufactured by Wako Pure Chemical Industries, Ltd. . Each test substance was prepared so as to have a concentration of 1% for loxoprofen using 50% ethanol as a solvent, and 0.5% for nonyl acid vanillylamide and nicotinic acid benzyl ester.
(2) Animals used Wistar Imado male rats 5 weeks old (Animal Breeding Institute) were used after 5 days of quarantine and 2 days of habituation. The animals were housed at 5 animals / cage in a rat breeding room controlled at a temperature of 20-26 ° C., a humidity of 30-80%, and an illumination time of 8-20 hours. Solid samples for mice and rats (Funabashi Farm, F-2) and tap water passed through a filter are freely ingested. After pre-breeding for 1 week, animals with good general symptoms such as fur and weight gain are selected. I tried it.
(3) Test method Fasted from the evening before the test (free to drink), fasted from the morning of the test and continued until the end of the test. On the day of the test, after labeling the animal for identification, weighed the rat's right hind limb using an animal balance, and measured the right hind limb volume of the rat using a foot volume measuring device (Volume Meter TK-105, manufactured by Muromachi Kikai). It was used and measured as a pre-dose value.
Inflammation edema was induced by administering 0.1 mL of a carrageenin (manufactured by Sigma-Aldrich Japan) solution having a concentration of 1% using 50% ethanol as a solvent to the rat right hind limb immediately before application of the test substance.
Immediately after the carrageenin subcutaneous administration (inflammation), 0.1 mL of each test substance was applied to the right hind limb of the rat. After application, the animal was quickly prosthetic with a prosthetic device to avoid licking the applied part.
The volume of the right hind limb was measured 3 hours after subcutaneous administration of carrageenan, and the edema intensity of each solid was calculated by the following formula (N = 5).

The edema suppression rate (%) was calculated from the following formula based on that of the test substance administration group with respect to the average edema intensity of the control group (administered only with 50% ethanol medium).

(4) Test result The result of the edema suppression rate in each test substance group is shown in Table 3 (N = 5).

(Table 3)
Study drug (concentration%) Edema suppression rate (%)
―――――――――――――――――――――――――――――――――――
Loxoprofen (1) 25.8
Nonyl acid vanillylamide (0.5) 0.0
Loxoprofen (1) + nonylic acid vanillylamide (0.5) 38.2
―――――――――――――――――――――――――――――――――――
Nicotinic acid benzyl ester (0.5) 5.2
Loxoprofen (1) + nicotinic acid benzyl ester (0.5) 30.3
―――――――――――――――――――――――――――――――――――

Table 3 shows that when loxoprofen is used in combination with nonylic acid vanillylamide, the edema suppression rate is enhanced, but the combined use of nicotinic acid benzyl ester, which is a stimulating component, does not show any significant enhancement. It was.
From the above results, in the external analgesic / anti-inflammatory agent containing loxoprofen, if nonyl acid vanillylamide is further added, not only the warming effect of nonyl acid vanillylamide is added, but the antiedema effect of loxoprofen is enhanced. found.

(Test Example 2) Anti-inflammatory effect test In order to verify the validity of the result of Test Example 1, the following confirmation test was carried out under the same conditions at a later date.
(1) Test substance Loxoprofen sodium dihydrate was manufactured by Daiichi Sankyo, and capsaicin was manufactured by Wako Pure Chemical Industries. Each test substance was prepared so as to have a concentration of 1% for loxoprofen and 0.5% for capsaicin using 50% ethanol as a solvent.
(2) Animals used Wistar Imado male rats 5 weeks old (Animal Breeding Institute) were used after 5 days of quarantine and 2 days of habituation. The animals were housed at 5 animals / cage in a rat breeding room controlled at a temperature of 20-26 ° C., a humidity of 30-80%, and an illumination time of 8-20 hours. Solid samples for mice and rats (Funabashi Farm, F-2) and tap water passed through a filter are freely ingested. After pre-breeding for 1 week, animals with good general symptoms such as fur and weight gain are selected. I tried it.
(3) Test method Fasted from the evening before the test (free to drink), fasted from the morning of the test and continued until the end of the test. On the day of the test, after labeling the animal for identification, weighed the rat's right hind limb using an animal balance, and measured the right hind limb volume of the rat using a foot volume measuring device (Volume Meter TK-105, manufactured by Muromachi Kikai). It was used and measured as a pre-dose value.
Inflammation edema was induced by administering 0.1 mL of a carrageenin (manufactured by Sigma-Aldrich Japan) solution having a concentration of 1% using 50% ethanol as a solvent to the rat right hind limb immediately before application of the test substance.
Immediately after the carrageenin subcutaneous administration (inflammation), 0.1 mL of each test substance was applied to the right hind limb of the rat. After application, the animal was quickly prosthetic with a prosthetic device to avoid licking the applied part.
The volume of the right hind limb was measured 3 hours after subcutaneous administration of carrageenan, and the edema intensity of each solid was calculated by the following formula (N = 5).

The edema suppression rate (%) was calculated from the following formula based on that of the test substance administration group with respect to the average edema intensity of the control group (administered only with 50% ethanol medium).

(4) Test results Table 4 shows the results of the edema suppression rate in each test substance group (N = 5).

(Table 4)
Study drug (concentration%) Edema suppression rate (%)
―――――――――――――――――――――――――――――――――――
Loxoprofen (1) 28.3
Capsaicin (0.5) 19.9
Loxoprofen (1) + capsaicin (0.5) 22.4
―――――――――――――――――――――――――――――――――――

  From Table 4, even if it combined capsaicin with loxoprofen, the enhancement effect of the edema suppression rate was not recognized, but it attenuated rather. Nonyl acid vanillylamide is a capsaicin derivative, but it was surprisingly found that only the former has an effect of enhancing the anti-edema action of loxoprofen.

  The external analgesic and anti-inflammatory agent containing loxoprofen and nonyl acid vanillylamide of the present invention synergistically improves the anti-inflammatory action of loxoprofen, and the warm feeling of nonyl acid vanillyl amide is added to obtain a preparation with excellent usability and effect. Therefore, it is extremely useful.

Claims (3)

An external anti-inflammatory analgesic composition containing loxoprofen, nonylic acid vanillylamide and water, wherein the dosage form is a patch, liquid or gel, and the content (% by weight) of loxoprofen is 0.5 to 5% Composition.
(However, the following (1) to ( 7 ) are excluded.
(1) Loxoprofen sodium hydrate (1.13 g), glycyrrhetinic acid (0.2 g), nonanoic acid vanillylamide (0.025 g), l-menthol (3 g), chlorpheniramine maleate (0.1 g), Hydroxypropyl methylcellulose (1 g), carboxyvinyl polymer (1.2 g), 1,3-butylene glycol (5 g), triethanolamine (1.5 g), ethanol (20 g), and a total amount of 100 g were added. Gel containing purified water (2) Loxoprofen sodium hydrate (1.13 g), glycyrrhetinic acid (0.1 g), nonanoic acid vanillylamide (0.1 g), peppermint oil (6 g), chlorpheniramine maleate (0.5 g), diisopropyl adipate (5 g), isopropanol (40 g , Hydroxypropyl methyl cellulose (0.1 g), polyethylene glycol (1 g), sodium bisulfite (0.2 g), and the total amount 100g become so Added containing purified water lotion (3) Loxoprofensodium hydrate (1.13 g), horse chestnut seed extract (0.3 g (concentration of crude drug: 3 g)), nonanoic acid vanillylamide (0.1 g), l-menthol (3 g), polyvinyl alcohol (1 g), polyacrylic acid moiety Neutralized product (7 g), methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion (5 g), carmellose sodium (5 g), crotamiton (2 g), concentrated glycerin (25 g), polysorbate 80 (0.3 g), Aluminum hydroxide gel (0.05g), titanium oxide (1g ), Talc (2 g), tartaric acid (0.6 g), sodium edetate hydrate (0.1 g), kaolin (2.5 g), sodium bisulfite (0.3 g), and added to a total amount of 100 g Cataplasm containing purified water
(4) Loxoprofen sodium hydrate 1.13 g, peppermint oil 6 g, magnesium aluminate silicate 0.1 g, nonanoic acid vanillylamide 0.1 g, chlorpheniramine maleate 0.5 g, diisopropyl adipate 5 g, isopropanol 40 g, A lotion preparation containing 0.1 g of hydroxypropylmethylcellulose, 1 g of polyethylene glycol, 0.2 g of sodium hydrogen sulfite, and purified water added to a total amount of 100 g
(5) Loxoprofen sodium hydrate 1.13 g, 1-menthol 3 g, polyvinyl alcohol 2 g, kaolin 2.5 g, nonanoic acid vanillylamide 0.1 g, polyacrylic acid partial neutralized product 7 g, carmellose sodium 5 g, N-methyl 2-pyrrolidone 2 g, concentrated glycerin 25 g, polysorbate 80 0.3 g, aluminum hydroxide gel 0.05 g, titanium oxide 1 g, talc 2 g, tartaric acid 0.6 g, sodium edetate hydrate 0.1 g, sodium hydrogen sulfite 0 .3g and cataplasm containing purified water added to a total amount of 100g
(6) Loxoprofen sodium hydrate 1.13 mg, mint oil 6 mg, nonanoic acid vanillylamide 0.1 mg, chlorpheniramine maleate 0.5 mg, diisopropyl adipate 5 mg, isopropanol 40 mg, hydroxypropyl methylcellulose 0.1 mg, polyethylene glycol Lotion containing 1 mg, 0.2 mg of sodium bisulfite, and purified water added to a total amount of 100 mg
(7) Loxoprofen sodium hydrate 1.13 mg, l-menthol 3 mg, nonanoic acid vanillylamide 0.1 mg, polyvinyl alcohol 1 mg, polyacrylic acid partial neutralized product 7 mg, carmellose sodium 5 mg, crotamiton 2 mg, concentrated glycerin 25 mg, polysorbate 80 0.3 mg, aluminum hydroxide gel 0.05 mg, titanium oxide 1 mg, talc 2 mg, tartaric acid 0.6 mg, sodium edetate hydrate 0.1 mg, kaolin 2.5 mg, sodium bisulfite 0.3 mg, and total amount 100 mg A cataplasm containing purified water added so that The anti-inflammatory analgesic composition for external use according to claim 1, wherein the content (% by weight) of nonylic acid vanillylamide is 0.01% to 5%. The anti-inflammatory analgesic composition for external use according to claim 1 or 2, wherein the anti-inflammatory action of loxoprofen is enhanced.