JP6253495B2 - External preparation composition containing loxoprofen - 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 effect by containing loxoprofen in a specific essential oil component, thymol or eucalyptus oil.

  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, menthol, camphor, thymol, and eucalyptus oil, which are essential oil components, may be added to the OTC external analgesic / anti-inflammatory agent as a cooling sensation stimulating component (see, for example, Non-Patent Document 3).

As an external preparation composition containing loxoprofen and an essential oil component, compositions containing loxoprofen and menthol have been disclosed in Patent Document 2 (Example 10) and Patent Document 3 (Tables 4 and 7). ing.
However, an external preparation composition containing loxoprofen and camphor, thymol or eucalyptus oil is not known.

JP 2008-074873 A WO93 / 04677 brochure JP 2008-163017 A

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

  An object of the present invention is to provide a new loxoprofen-containing external analgesic anti-inflammatory agent composition that further improves the effectiveness of loxoprofen and also has a refreshing or cool feeling.

  As a result of this study, it was found that the anti-inflammatory action of loxoprofen is enhanced only when thymol or eucalyptus oil, which is a specific cooling sensation component, is added to loxoprofen, and the present invention has been completed.

That is, the present invention
(1) An external preparation composition containing loxoprofen and at least one selected from thymol and eucalyptus oil,
(2) An external preparation composition as described in (1) above for application to the skin,
(3) The external preparation composition according to (1) or (2), which is an analgesic / anti-inflammatory agent, or (4) the external preparation composition according to (1) or (2), which is an anti-inflammatory agent. is there.

  The external preparation composition containing thymol or eucalyptus oil in loxoprofen of the present invention is useful because it not only has a cool feeling, but can further enhance the excellent anti-inflammatory effect of loxoprofen.

  The loxoprofen of the present invention is listed in the 16th revised Japanese Pharmacopoeia as loxoprofen sodium hydrate. Timol and eucalyptus oil are also listed in the 16th revised Japanese pharmacopoeia.

  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 pasted once to several times a day. Moreover, although the addition amount of thymol and eucalyptus oil is not specifically limited, the density | concentration which a refreshing feeling is given and a skin irritation is not induced is desirable, and it is 0.01 to 5% suitably.

  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 inorganic powder 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
Thymol 1 1 −
Eucalyptus oil 1-1
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
Thymol 1 1 −
Eucalyptus oil 1-1
Carboxyvinyl polymer 2 2 2
Hypromellose 1.5 1.5 1.5
Ethanol 5 5 5
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) Anti-inflammatory effect test (1) Test substance Loxoprofen sodium dihydrate is from Daiichi Sankyo, L-menthol, D-camphor, thymol and eucalyptus oil are from Wako Pure Chemical Industries It was used. Each test substance was prepared to a concentration of 1% 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 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) 27.6
D-Camphor (1) 17.5
Loxoprofen (1) + D-camphor (1) 46.8
―――――――――――――――――――――――――――――――
Eucalyptus oil (1) -4.9
Loxoprofen (1) + Eucalyptus oil (1) 38.8
―――――――――――――――――――――――――――――――
Thymol (1) 6.9
Loxoprofen (1) + Thymol (1) 47.8
―――――――――――――――――――――――――――――――
L-Menthol (1) 21.5
Loxoprofen (1) + L-menthol (1) 30.9
―――――――――――――――――――――――――――――――

From Table 3, it was found that when thymol or eucalyptus oil, which is a specific essential oil component, was used in combination as compared with loxoprofen alone, the edema inhibitory action was enhanced.
On the other hand, even with the same essential oil component, when L-menthol was used in combination, only a slight enhancement of the anti-edema effect was observed, and D-camphor only had an additive effect.

  The combination of loxoprofen with thymol or eucalyptus oil, which is a specific essential oil component, of the present invention further improves the anti-inflammatory action of loxoprofen, and also adds the cooling sensation (cool feeling) of each essential oil. It is extremely useful because it provides a superior formulation.

Claims (4)

External composition containing Rokisopurofe down及 beauty eucalyptus oil.   The external preparation composition of Claim 1 for applying to skin.   The external preparation composition of Claim 1 or 2 which is an analgesic anti-inflammatory agent.   The external preparation composition of Claim 1 or 2 which is an anti-inflammatory agent.