JPH06199701A - Anti-inflammatory analgesic agent for external use - Google Patents

Abstract

PURPOSE:To provide an anti-inflammatory analgesic agent for external use, effective for improving the absorption of a drug component through the skin and transfer of the drug component into the deep part of the skin and exhibiting remarkably improved therapeutic effect. CONSTITUTION:The objective anti-inflammatory analgesic agent for external use is composed of (A) a nonsteroidal antiinflammatory agent having at least one asymmetric carbon atom and containing 51.0-100.0wt.% of (S)-isomer, e.g. flurbiprofen, ketoprofen and ibuprofen and (B) a polyhydric alcohol such as ethylene glycol, glycerol, propylene glycol, polyethylene glycol and polypropylene glycol. The technique can be applied to any pharmaceuticals for external use such as liquid, ointment, plaster, etc.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to an external anti-inflammatory analgesic,
Specifically, it has at least one asymmetric carbon and (S)
The present invention relates to an external anti-inflammatory and analgesic agent having a dramatically improved therapeutic effect on inflammation by blending a non-steroidal anti-inflammatory drug containing 51.0 to 100.0% by weight of the body and a polyhydric alcohol.

[0002]

2. Description of the Related Art Currently, many nonsteroidal anti-inflammatory drugs such as flurbiprofen, ketoprofen and ibuprofen are used in the field of orthopedics, and they have excellent effects as internal or external preparations (JP-A-56). -36411,
JP-A-58-124716, JP-A-58-4713, JP-A-59-37412, JP-A-61-12614, JP-A-62-270524, JP-A-58-150508,
JP-A-58-52216, JP-A-60-146823,
JP-A-61-272833, JP-A-61-19401
5, JP-A-56-51412, JP-A-59-2797
8).

Most of these non-steroidal anti-inflammatory drugs have asymmetric centers (mainly asymmetric carbon atoms) in their chemical structures.
And is administered as a racemate "1: 1 mixture of (S)-and (R) -form". In recent years, as the analytical measurement technique for optical isomers has been developed and the pharmacokinetics in the body have been investigated, it has been found that there is a large difference in drug activity between the (S) -form and the (R) -form. (JP-A-63-1468
15, JP-A-63-45234). However, the drug is still supplied as a racemate, and there is a concern that the antagonism of the pharmacological action between the optical isomers and the occurrence of side effects due to the drug may be supplied.

[0004]

DISCLOSURE OF THE INVENTION The present invention aims to improve the effect of a drug by rapidly transferring a nonsteroidal anti-inflammatory drug into blood, muscle and synovial fluid and to reduce the effective dose. To provide an anti-inflammatory drug for external use that can reduce side effects.

[0005]

Means for Solving the Problems The inventors of the present invention sought prompt transfer of a nonsteroidal anti-inflammatory drug into blood, muscle and synovial fluid, and as a result, a nonsteroidal drug having at least one asymmetric carbon atom. In anti-inflammatory drugs, (S) -body 5
It has been found that the above object can be achieved by using a non-steroidal anti-inflammatory drug contained in an amount of 1.0 to 100.0% by weight and incorporating a polyhydric alcohol. That is, the anti-inflammatory agent for external use of the present invention comprises a non-steroidal anti-inflammatory drug having at least one asymmetric carbon atom and 51.0 to 100.0% by weight of (S) -form, and a polyhydric alcohol. Is blended.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION The nonsteroidal anti-inflammatory drug according to the present invention means flurbiprofen, ketoprofen, ibuprofen, pranoprofen, fenoprofen and salts thereof, naproxen, lactylphenetidine, tramadol hydrochloride, suprofen, alumino. Examples include profene, thiaprofenic acid, pentazocine, loxoprofen and salts thereof, ibuprofen piconol and the like.

In order to improve the therapeutic effect, the non-steroidal anti-inflammatory drug preferably contains the (S) -form in an amount of 51.0 to 100.0% by weight, more preferably 70 to 1
It is 00% by weight. The compounding amount of the non-steroidal anti-inflammatory drug in the external anti-inflammatory analgesic is not particularly limited, but is 0.0
1 to 20% by weight is preferable, and more preferably 0.1 to 20% by weight.
It is 10% by weight.

As the polyhydric alcohol, ethylene glycol, glycerin, propylene glycol, polyethylene glycol, polypropylene glycol or the like can be blended. The polyhydric alcohol is preferably added in an external anti-inflammatory analgesic in an amount of 0.1 to 50% by weight,
It is more preferably 1 to 40% by weight.

The external anti-inflammatory and analgesic agent of the present invention preferably uses a liquid agent, an ointment, a cream or a patch as its dosage form in order to make the present invention more effective. Conventional bases and compounding ingredients can be used in these dosage forms depending on the dosage form. For example, for liquids, creams and ointments,
A solvent as a base, an oil component, a surfactant, a water-soluble polymer, etc. are used, but as a solvent, water, ethanol, propyl alcohol, isopropyl alcohol, acetone, benzyl alcohol, etc., and as an oil component, lanolin, curing Oil, lecithin, plastibase, liquid paraffin, oleic acid, stearic acid, myristic acid, palmitic acid, beeswax, paraffin wax, microcrystalline wax, diisopropyl adipate, isopropyl myristate, isopropyl sebacate, isopropyl palmitate, squalane, squalene, Cetanol, stearyl alcohol, oleyl alcohol, hexadecyl alcohol, silicone oil, etc., as the surfactant, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan Fatty acid ester, polyoxyethylene glycerin fatty acid ester, polyethylene glycol fatty acid ester, polyoxyethylene glycol ether, polyoxyethylene alkyl phenyl ether, polyoxyethylene polyoxypropylene alkyl ether, polyoxyethylene phytosterol, sorbitan fatty acid ester, glycerin Fatty acid ester, etc., as the water-soluble polymer, carboxyvinyl polymer, sodium carboxymethyl cellulose, polyvinyl alcohol, methyl cellulose, hydroxyethyl cellulose,
Examples thereof include hydroxypropyl cellulose, polyvinylpyrrolidone, hydroxypropylmethyl cellulose, polyacrylic acid and the like.

In the case of the patch, an adhesive polymer, a moisturizer, a curing agent, an inorganic powder, a surfactant, water and the like are used, and the adhesive polymer is polyacrylic acid or sodium polyacrylate. , Gelatin, pectin, polyvinylpyrrolidone, vinyl acetate copolymer, polyethylene oxide, methyl vinyl ether / maleic anhydride copolymer, sodium alginate, sodium carboxymethyl cellulose, xanthan gum, gum arabic, tragacanth gum, etc. as moisturizers, glycerin, sorbitol , Propylene glycol, polyethylene glycol, polypropylene glycol, etc., as the curing agent, aluminum potassium sulfate, magnesium aluminate silicate, aluminum hydroxide, magnesium aluminate hydroxide, metasilicic acid Magnesium Rumin acid, synthetic hydrotalcite, dihydroxy aluminum aminoacetate, triglycidyl isocyanate, polyethylene glycol diglycidyl ether, ethylene glycol diglycidyl ether, glycerol diglycidyl ether,
Triglycerin diglycidyl ether and the like, inorganic powders such as kaolin, silicic acid anhydride, zinc oxide and titanium oxide, and surfactants such as polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester and polyoxyethylene. Examples thereof include glycerin fatty acid ester, polyethylene glycol fatty acid ester, polyoxyethylene glycol ether, polyoxyethylene alkylphenyl ether, polyoxyethylene polyoxypropylene alkyl ether, polyoxyethylene phytosterol, sorbitan fatty acid ester, and glycerin fatty acid ester.

Further, the external anti-inflammatory and analgesic composition of the present invention has various adjuvants such as l-menthol, dl-camphor, tocopherol acetate, psyllium extract and horse chestnut extract for the purpose of improving the efficacy and the feeling of use. Various stabilizers such as sodium edetate, sodium sulfite, butylhydroxyanisole, and butylhydroxytoluene can be blended for the purpose of stabilizing the active ingredient such as tincture of Arnica.

[0012]

INDUSTRIAL APPLICABILITY According to the present invention, absorption of a nonsteroidal anti-inflammatory drug having at least one asymmetric carbon and containing 51.0 to 100.0% by weight of (S) -form from the skin is absorbed. A therapeutic effect is dramatically improved by increasing the migration to deep skin, and an external anti-inflammatory analgesic agent is obtained which can reduce side effects by reducing the effective dose. Furthermore, the present invention is a technique that can be applied to all dosage forms of external preparations, and is widely used for solutions, ointments, creams, patches and the like.

[0013]

【Example】

Example 1 A liquid preparation (Table 1) containing (S) -form and (S, R) -form of flurbiprofen as an active ingredient was prepared and an anti-inflammatory experiment was conducted to compare the anti-inflammatory effects.

[0014]

TABLE 1: flurbiprofen formulated liquid composition Invention Product comparisons goods Lot 1 1 2 3 component (g / 100g) (S) - flurbiprofen ^{* 1 1.0 1.0 - - (S} , R) - flurbiprofen * ² - - 1.0 1.0 Nikkol ^{HCO-60 * 3 2.0 2.0 2.0} 2.0 l- menthol 3.0 3.0 3.0 3.0 propylene glycol 40.0 - 40.0 - ethanol 10.0 50.0 10.0 50.0 purified water Balance remaining residual remaining * 1 S content> 99.0% * 2 Racemic content 100.4% * 3 Polyoxyethylene hydrogenated castor oil with 60 ethylene oxide addition moles

Experimental method: 1) Experimental group Control (no treatment) Inventive product 1 Comparative product 1 Comparative product 2 Comparative product 3 2) Animal Wistar male rat 5 weeks old 3) Operating method Hair on the back of the rat was clipped. After cutting, 1% carrageenin (LAMBA CARRAGEENIN, Minse
i Rikagaku Co. ) 0.1 ml of the solution was subcutaneously injected into the right leg to cause inflammation. Immediately measure the volume of the paw and add 0.5 m
1 l was applied to the back. Thereafter, the paw volume was measured 1, 2, 3, 4, 5 hours later, and the edema rate was calculated from the following formula and shown in Table 2. Edema rate E (%) = (Vt−Vn) / Vn × 100 Vt: paw volume after t hours of carrageenin injection Vn: paw volume immediately after carrageenin injection

[0016]

[Table 2] Table 2: Mean value of edema rate% at each time (n = 7) hours 1 hour 2 hours 3 hours 4 hours 5 hours Experimental group: No treatment 18.6 37.1 38.9 39.7 37.1 1 12.8 21.3 26.8 26.2 28.2 Comparative product 1 17.8 29.8 32.8 32.0 35.2 Comparative product 2 12.4 27.7 30.5 33.7 33.2 Comparative product 3 18.1 25.4 29.5 29.5 31.9

As a result, looking at the edema rate 4 hours after inflammation, there was a significant difference between the 1 composition group of the product of the present invention containing (S) -flurbiprofen and propylene glycol and the untreated control group. I knew there was a difference.

Example 2 Although the effect of the product of the present invention was confirmed in Example 1, the following controls were added in order to confirm the effect of propylene glycol and also to reconfirm the effect of the product of the present invention in detail. , The number of experimental samples was increased and the experiment was repeated. Among the liquid preparations prepared in Example 1, the product 1 of the present invention and the comparative product 2 were used, and an anti-inflammatory test was conducted by adding a control to compare the anti-inflammatory effects. 1) Experimental group Control (no treatment) Control (only solvent system, ie, composition of the present invention 1 or comparative product 2 excluding flurbiprofen) Invention product 1 comparative product 2 2) Animal Wistar male rat 5 3 weeks old 3) Method of operation After cutting the hair on the back of the rat with hair clippers, 1% carrageenin (LAMBA CARRAGEENIN, Minse)
i Rikagaku Co. ) 0.1 ml of the solution was subcutaneously injected into the right leg to cause inflammation. Immediately measure the volume of the paw and add 0.5 m
1 l was applied to the back. After that, the paw volume was measured 1, 2, 3, 4, and 5 hours later, and Example 1. The edema rate was calculated in the same manner as in and shown in Table 3.

[0019]

[Table 3] Table 3: Mean value of edema ratio% (n = 15) at each time 1 hour 2 hours 3 hours 4 hours 5 hours Experimental group: control (no treatment) 17.4 38.3 51.8 54.7 51.8 Control (solvent) 22.8 38.5 51.3 52.5 50.7 Inventive product 1 12.1 19.7 27.4 28.5 28.6 Comparative product 2 17.9 29.2 40.1 40.6 36.0

As a result, looking at the edema rate 4 hours after inflammation, the untreated control group, the solvent control group and the product 1 of the present invention were examined.
It was also found that there was a significant difference between Comparative Product 2 and Comparative Product 2.
There is also a significant difference between the product 1 of the present invention and the product 2 of comparison, and (S) -flurbiprofen is (S, R)-
It was found to have a high anti-inflammatory effect as compared with flurbiprofen. Furthermore, no side effects such as redness, rash, swelling of the skin of rats were observed in any of the 4 groups.

Example 3 As active ingredients, (S) -form of flurbiprofen, ketoprofen and ibuprofen, (S,
The liquid formulation shown in Table 4 was prepared using the R) -form, and the average value of the edema ratio after 4 hours (n = 13) was obtained in the same manner as in Example 1.
Was measured and the results are shown in Table 4.

[0022]

[Table 4]Table 4: Solution composition and edema rate after 3 hours This product Comparative product 2 3 4 5 4 5 Ingredients (g / 100g): (S) -Flurbiprofen *¹1.0 1.0 − − − − (S, R) -Flurbiprofen − − − − − − (S) -Ketoprofen *²− − 1.0 − − − (S, R) -Ketoprofen − − − − 1.0 − (S) -Ibuprofen *³− − − 1.0 − − (S, R) -Ibuprofen − − − − − 1.0 Nikkor HCO-60 2.0 2.0 2.0 2.0 2.0 2.0 l-Menthol 3.0 3.0 3.0 3.0 3.0 3.0 Propylene glycol − − 40.0 − 40.0 − Glycerin 40.0 − − 40.0 − 40.0 Polyethylene glycol (MW = 300) − 40.0 − − − − Ethanol 10.0 10.0 10.0 10.0 10.0 10.0 Purified water Remaining amount Remaining amount Remaining amount Remaining amount Remaining amount Remaining amount Evaluation: No treatment Edema rate after 4 hours 55.0 30.1 32.4 29.0 35.7 42.7 43.4 * 1) (S) -flurbiprofen content> 99.0% * 2) (S) -ketoprofen content: 95.1% * 3) (S) -ibuprofen content: 99.9%

Example 4 The composition shown in the following Table 5 was prepared and used as an external anti-inflammatory analgesic gel ointment.

[0024]

[Table 5] Table 5: Gel ointment composition This product lot 678 component (g / 100g): (S) -flurbiprofen * ¹ 0.5 − − (S) -ketoprofen * ² − 0.5 − ( S) -Ibuprofen * ³ − − 0.5 l-Menthol 3.0 3.0 3.0 Glycerin 20.0 20.0 20.0 Carboxy vinyl polymer 1.0 1.0 1.0 Hydroxyethyl cellulose 0.1 0.1 0.1 Polyethylene glycol fatty acid ester 2.0 2.0 2.0 Isopropyl alcohol 47.0 47.0 47.0 Triethanolamine 0.2 0.2 0.2 Purified water 26.2 26.2 26.2 * 1) (S) -flurbiprofen content> 99.0% * 2) (S) -ketoprofen content: 95.1% * 3) (S) -ibuprofen content: 99.9%

Example 5 The following formulation composition shown in Table 6 was prepared to give an external anti-inflammatory analgesic cream.

[0026]

[Table 6] Table 6: Composition of cream agent Development lot 9 10 11 Ingredient (g / 100g): (S) -flurbiprofen * ¹ 0.3 − − (S) -ketoprofen * ² − 0.3 − (S ) -Ibuprofen * ³ − − 0.3 Propylene glycol 20.0 20.0 20.0 White petrolatum 16.0 16.0 16.0 Cetanol 6.0 6.0 6.0 Isopropyl myristate 6.0 6.0 6.0 POE Sorbitan monostearate (20E.O.) 3.0 3.0 3.0 Propyl paraoxybenzoate 0.02 0.02 0.02 Purified Water 48.68 48.68 48.68 * 1) (S) -flurbiprofen content> 99.0% * 2) (S) -ketoprofen content: 95.1% * 3) (S) -ibuprofen content: 99.9%

Example 6 Formulations shown in Table 7 below were prepared and used as patches.

[0028]

[Table 7] Table 7: Composition of adhesive patch Development lot 12 13 14 Component (g / 100g): (S) -flurbiprofen * ¹ 0.3 − − (S) -ketoprofen * ² − 0.3 − (S ) -Ibuprofen * ³ − − 0.3 l-menthol 3.0 3.0 3.0 polyacrylic acid 4.5 4.5 4.5 sodium polyacrylate 1.5 1.5 1.5 sodium carboxymethylcellulose 4.0 4.0 4.0 glycerin 15.0 15.0 15.0 propylene glycol 5.0 5.0 5.0 sorbitol 10.0 10.0 10.0 aluminum hydroxide 0.1 0.1 0.1 Synthetic hydrotalcite 0.05 0.05 0.05 Polyoxyethylene glycol ether 1.0 1.0 1.0 Kaolin 6.0 6.0 6.0 Titanium oxide 0.5 0.5 0.5 Purified water 49.05 49.05 49.05 * 1) (S) -flurbiprofen content> 99.0% * 2 ) (S) -Ketoprofen content: 95.1% * 3) (S) -Ibuprofen content: 99.9%

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Reference number within the agency FI Technical indication location A61K 47/32 E 7433-4C (72) Inventor Kazuyuki Miki 1-3, Honjo, Sumida-ku, Tokyo No. 7 within Lion Corporation

Claims (1)

[Claims] 1. Having at least one asymmetric carbon atom, and
(S) -An external anti-inflammatory analgesic comprising a non-steroidal anti-inflammatory drug containing 51.0 to 100.0% by weight of a body and a polyhydric alcohol.