JPH069394A - External antiphlogistic sedative liquid preparation - Google Patents

Abstract

PURPOSE:To obtain the subject liquid preparation improved in effectiveness, being stable, causing no phase separation, hardly depositing crystal of indomethacin even when allowed to stand at low temperature and capable of storing for a long period. CONSTITUTION:The external antiphlogistic sedative liquid is obtained by blending a lower alcohol-water based base obtained by blending indomethacin with vitamin Es and a middle chain fatty acid ester as a percutaneous absorption promoter with a surfactant selected from a polyoxyethylene hardened castor oil having >=10 ethylene oxide addition mole number, polyoxyethylene alkyl ether having 2-50 ethylene oxide addition mole number and polyoxyethylene alkylphenyl ether having 2-30 ethylene oxide addition mole number.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an external anti-inflammatory analgesic solution, and more particularly to an external anti-inflammatory analgesic solution containing indomethacin and vitamin Es, which has improved efficacy and excellent stability.

[0002]

BACKGROUND OF THE INVENTION Indomethacin has been widely used as an internal medicine for the treatment of osteoarthritis, periarthritis of the shoulder, myalgia, etc. in the field of orthopedics, and its excellent effect has been recognized. On the other hand, since there are side effects such as gastrointestinal disorders and loss of appetite, liquid agents, ointments, patches and the like have been developed in recent years to prevent these side effects (JP-A-53-81616 and JP-A-56).
-135413, JP-A-57-35509, JP-A-55-62013, JP-A-55-62.
014, JP-A-57-140711, and JP-A-63-88125). However, indomethacin is poorly absorbed through the skin and, when administered externally, has not been shown to have a therapeutic effect superior to oral administration.

Therefore, recently, researches on percutaneous absorption enhancers have been actively conducted (JP-A-60-146823, JP-A-61-172833, JP-A-62-6).
1918), and among them, a highly effective accelerator is a medium chain fatty acid ester, particularly isopropyl myristate.

[0004] Drugs such as glycol salicylate, methyl salicylate, and tocopherol acetate are generally well known as active ingredients for external anti-inflammatory analgesics, and in particular,
Vitamin Es typified by tocopherol acetate are added for the purpose of promoting blood flow.

However, as an active ingredient, indomethacin,
In the case of a liquid formulation containing vitamin Es and a medium-chain fatty acid ester as a percutaneous absorption enhancer of indomethacin in a lower alcohol-water base, the effectiveness is high, but it is very unstable, especially at low temperatures. When left to stand, there are problems that phase separation may occur and indomethacin crystals may precipitate.

[0006]

DISCLOSURE OF THE INVENTION The present invention is an external anti-inflammatory analgesic for a lower alcohol aqueous solution containing indomethacin, vitamin Es and medium-chain fatty acid ester, which has improved efficacy and is stable and does not cause phase separation. In addition, the present invention provides an external anti-inflammatory analgesic solution that does not precipitate indomethacin crystals even when left at a lower temperature and can be stored for a long period of time.

[0007]

[Means for Solving the Problems] As a result of intensive investigations by the present inventors to improve the stability of a highly effective external anti-inflammatory analgesic solution containing indomethacin, vitamin Es and medium-chain fatty acid ester, lower alcohols have been obtained. -A polyoxyethylene hydrogenated castor oil with an ethylene oxide addition mole number of 10 or more in an aqueous base, and an ethylene oxide addition mole number of 2
It has been found that the above object can be achieved by blending one or more kinds of surfactants selected from polyoxyethylene alkyl ether of ˜50 and polyoxyethylene alkylphenyl ether of 2-30 moles of ethylene oxide added. It was

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION Indomethacin, which is an anti-inflammatory and analgesic drug used in the present invention, exerts an effect by external administration, and therefore its compounding amount varies depending on the site of inflammation and its symptoms. It is preferable to blend in the range, more preferably 0.5 to 3% by weight.

The vitamin Es of the present invention used as a blood flow promoter include tocopherol, tocopherol acetate, tocopherol nicotinate and tocopherol succinate, and tocopherol acetate is particularly preferred. The amount of vitamin E compounded is 0.1-5
%, Preferably 0.5 to 3% by weight.

As the medium-chain fatty acid ester of the present invention used as a percutaneous absorption enhancer, those having a medium-chain fatty acid residue having 6 to 18 carbon atoms are preferable, and myristic acid which is a kind of monocarboxylic acid ester. Examples thereof include isopropyl, diisopropyl adipate which is a kind of dicarboxylic acid ester, diethyl sebacate and the like, and particularly preferred is isopropyl myristate. Further, although these medium chain fatty acid esters differ depending on the blending amount of indomethacin and the combination of the base components, usually 0.1 to 5% by weight can provide a sufficient accelerating effect.

The surfactant of the present invention has an ethylene oxide addition mole number of 10 or more, preferably 10 to 20.
0 polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ether having an ethylene oxide addition mole number of 2 to 50, ethylene oxide addition mole number of 2 to 30
Polyoxyethylene alkyl phenyl ether can be obtained, for example, from Nikko Chemicals.

Specifically, as polyoxyethylene hydrogenated castor oil having an ethylene oxide addition mole number of 10 or more, Nikkor CO-10, CO-20TX, HCO-
40, HCO-60, HCO-100, etc. can be used.

The number of moles of ethylene oxide added is from 2 to 50.
As the polyoxyethylene alkyl ether, the alkyl group having 10 to 22 carbon atoms is preferable, and
-2, BL-9EX, BC-20TX, BS-4, BO
-10TX or the like can be used.

The number of moles of ethylene oxide added is 2 to 30.
As the polyoxyethylene alkyl phenyl ether, an alkyl group having 6 to 12 carbon atoms is preferable, and NP-2, NP-10, NP-18TX, OP-
3, OP-10, OP-30, etc. can be used. The amount of one or more surfactants selected from these is 0.1 to 10% by weight, preferably 0.5 to 5%.
A sufficiently stable liquid formulation can be obtained at a weight percentage.

Further, examples of the lower alcohol used as the base include ethanol, propanol, isopropanol, etc., and the blending amount of these is preferably 40 to 80% by weight, and 40 to 60% by weight from the viewpoint of skin irritation.

In addition, the external anti-inflammatory analgesic solution of the present invention comprises:
As a cooling agent, 1-menthol, dl-camphor, peppermint oil, borneol and the like can be added, and as a stimulant, capsicum extract, vanillyl amide nonylate, benzyl nicotinate and the like can be added.

Further, as a solvent other than lower alcohol and water, propylene glycol, polyethylene glycol, butylene glycol, glycerin, castor oil and the like, and as a pH adjusting agent sodium hydroxide, potassium hydroxide, triethanolamine and the like, a viscosity imparting agent. As carboxyvinyl polymer, sodium carboxymethyl cellulose,
Polymers such as polyvinyl alcohol, methyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, and polyacrylic acid can be added.

[0018]

INDUSTRIAL APPLICABILITY According to the present invention, a lower alcohol-water base containing indomethacin, vitamin Es and a medium-chain fatty acid ester which is a percutaneous absorption promoter is added to a polyoxyethylene having an ethylene oxide addition mole number of 10 or more. Blended with one or more kinds of surfactants selected from hydrogenated castor oil, polyoxyethylene alkyl ether having 2 to 50 ethylene oxide addition moles, and polyoxyethylene alkylphenyl ether having 2 to 30 ethylene oxide addition moles. Thus, the effectiveness is improved, moreover, stable, phase separation does not occur, crystals of indomethacin do not precipitate even when left at a low temperature, and an external anti-inflammatory analgesic solution that can be stored for a long period of time is obtained.

[0019]

【Example】

Example 1 Comparison between invented products 1, 2, and 3 of Table 1 in which indomethacin, tocopherol acetate as vitamin Es, and isopropyl myristate as a medium-chain fatty acid ester were mixed, and Table 2 in which a surfactant was removed from the present invention Product 1, Comparative product 2 of Table 2 without surfactant and isopropyl myristate,
The stability of each composition of Comparative Products 3, 4, and 5 in Table 2 in which a surfactant other than the product of the present invention was blended was evaluated.

[0020]

[Table 1] Composition of the present invention (g / 100g) 1 2 3 Indomethacin 0.75 0.75 0.75 Tocopherol acetate 1.0 1.0 1.0 Isopropyl myristate 3.0 3.0 3.0 Nikkor HCO-60 2.0-Nikkor BL-9EX-2.0-Nikkor NP-10-2.0 l -Menthol 3.0 3.0 3.0 Sodium hydroxide 0.01 0.01 0.01 Ethanol 15.0 15.0 15.0 Isopropanol 45.0 45.0 45.0 Purified water Remaining amount Remaining amount Remaining amount

[0021]

[Table 2]  CompositionComparative product (G / 100g) 1 2 3 4 5 Indomethacin 0.75 0.75 0.75 0.75 0.75 Tocopherol acetate 1.0 1.0 1.0 1.0 1.0 Isopropyl myristate 3.0 − 3.0 3.0 3.0 Nikkor TS-106 * 1 − − 2.0 − − Nikkor MYS-40 * 2 − − − 2.0 − Nikkor GO-4 * 3 − − − − 2.0 l-Menthol 3.0 3.0 3.0 3.0 3.0 Sodium hydroxide 0.01 0.01 0.01 0.01 0.01 Ethanol 15.0 15.0 15.0 15.0 15.0 Isopropanol 45.0 45.0 45.0 45.0 45.0 Purified water Remaining amount Remaining amount Remaining amount Remaining amount Remaining amount * 1 Sorbitan mono with 6 moles of ethylene oxide added
Stearate * 2 Polyethylene with 40 moles of ethylene oxide added
Glycol monostearate * 3 Solbitteto with 6 moles of ethylene oxide added
Lastearate

In the experimental method, the product of the present invention and the comparative product were transferred to sample bottles and stored at room temperature and low temperature (-20 ° C.) for one week, and the appearance was visually evaluated. The evaluation criteria were ○ which is stable at each temperature, Δ which indicates that the crystals of indomethacin have not precipitated but the liquid is opaque or causes phase separation, and X which causes crystals of indomethacin to precipitate. .

The evaluation results are shown in Table 3. As is clear from Table 3, it was confirmed that the product of the present invention has extremely high stability at both room temperature and low temperature (−20 ° C.) as compared with the comparative product.

[0024]

[Table 3] Inventive product Comparative product Storage condition 1 2 3 1 2 3 4 5 Room temperature ○ ○ ○ △ △ ○ ○ ○ ○ Low temperature ○ ○ ○ × ○ × △ ×

Example 2 Anti-inflammatory experiments were carried out on the products 1, 2 and 3 of the present invention and the comparative product 2 which were stable in Example 1 above, and the anti-inflammatory effects were compared. As the experimental method, Wistar rats (Japan Charles River, male, 5 weeks old) were used as animals, and the test drug 0.
2 ml was administered to the right foot three times before inflammation and once after inflammation, a total of four times.

Further, 1% carrageenin (LAMBA CA
RRAGEENIN, MinseiRikagaku
Co. ) 0.1 ml of the solution was subcutaneously injected into the right leg to cause inflammation, and immediately after the inflammation, a volume measuring device (Ugo Basile) was used.
Company) to measure the foot volume. And after the inflammation 1,2,
The measurement was performed 4 and 6 hours later, and the edema rate and the inhibition rate were calculated from the following formulas.

Edema rate E (%) = (Vt−Vn) / Vn × 100 Vt: paw volume at time t after carrageenin injection Vn: paw volume immediately after carrageenin injection Suppression rate I (%) = (Ec-Et) ) / Ec × 100 Et: edema rate after t hours of the test drug group Ec: edema rate after t hours of the control group

The evaluation results are shown in Tables 4 and 5. As is clear from Tables 4 and 5, the products of the present invention 1, 2, 3
Was confirmed to have a higher anti-inflammatory effect than Comparative Product 2.

[0029]

[Table 4]  Edema rate (%: average value of n = 10) Test drug Weight (g) 1 hour later 2 hours later 4 hours later 6 hours later Invention product 1 145.2 15.3 32.4 41.3 41.8 2 148.3 13.9 30.2 38.5 38.4 3 144.6 14.2 31.5 39.7 40.0 Comparative product 2 145.8 16.7 39.5 55.1 54.7 No treatment 143.8 18.5 45.2 63.4 63.8

[0030]

[Table 5] Suppression rate (%: average value of n = 10) Test drug 1 hour 2 hours 4 hours 6 hours 6 hours Inventive product 1 17.3 28.3 34.9 34.5 2 24.9 33.2 39.3 39.8 3 23.2 30.3 37.4 37.3 Comparative product 2 9.7 12.6 13.1 14.3

Example 3 For the present invention products 1, 2, 3 and comparative product 2 which were stable in the above-mentioned Example 1, a percutaneous absorption test was conducted to compare the serum concentrations of indomethacin. The experimental method was as follows: Hairless rats (Saitama experimental animal, male, 7 weeks old) were tested with 0.
2 ml was administered, 2 hours later, whole blood was collected, serum was separated, and H
Serum concentration of indomethacin was measured by the PLC method.

The results are shown in Table 6. As is clear from Table 6, it was confirmed that the invented products 1, 2 and 3 had a higher serum concentration of indomethacin and a higher transdermal absorbability of indomethacin than the comparative product 2.

[0033]

[Table 6] (Average value of n = 5) Test drug Body weight (g) Serum concentration (ng / ml) Inventive product 1 134.5 224.9 2 129.7 314.3 3 131.6 272.2 Comparative product 2 134.1 51.8

Example 4 An external anti-inflammatory analgesic solution was prepared from the composition shown in Table 7 below. Then, according to the evaluation method of Example 1, the stability was evaluated.

[0035]

[Table 7]  CompositionInvention product (G / 100g) 4 5 6 7 8 Indomethacin 0.5 1.5 1.0 3.0 2.0 Tocopherol acetate 2.0 0.5 1.0 1.5 3.0 Isopropyl myristate 3.0 − − − 1.0 Diisopropyl adipate − 3.0 − 5.0 − Diethyl sebacate − − 3.0 − − Nikkor HCO-60 4.0 − − 0.5 1.0 Nikkor BL-9EX − 3.0 − 3.5 − Nikkor NP-10 − − 3.0 − 1.5 l-Menthol 3.0 3.0 3.0 3.0 3.0 Nonyl vanillylamide 0.005 − 0.01 − − Propylene glycol 5.0 − 10.0 − 5.0 Sodium hydroxide 0.005 0.02 0.01 0.01 0.03 Carboxyvinyl polymer − 0.1 − − 0.1 Ethanol 20.0 10.0 − 25.0 30.0 Isopropanol 35.0 40.0 55.0 25.0 15.0 Purified water Remaining amount Remaining amount Remaining amount Remaining amount Remaining amount

The evaluation results are shown in Table 8. As is clear from Table 8, the products of the present invention have
It was confirmed that the stability was high at room temperature and low temperature (−20 ° C.).

[0037]

[Table 8] Storage condition of the product of the present invention 4 5 6 7 8 room temperature ○ ○ ○ ○ ○ low temperature ○ ○ ○ ○ ○

Example 5 An external anti-inflammatory analgesic solution was prepared from the compounding compositions shown in Tables 9 and 10 below. Then, according to the evaluation method of Example 1, the stability was evaluated.

[0039]

[Table 9] Composition of the present invention (g / 100g) 9 10 11 Indomethacin 0.75 0.75 0.75 Tocopherol acetate 1.0 1.0 1.0 Isopropyl myristate 1.0 1.0 1.0 Nikkor HCO-60 1.0-Nikkor BL-9EX-1.0-Nikkor NP-10-1.0l -Menthol 3.0 3.0 3.0 Sodium hydroxide 0.01 0.01 0.01 Ethanol 15.0 15.0 15.0 Isopropanol 45.0 45.0 45.0 Purified water Remaining amount Remaining amount Remaining amount

[0040]

[Table 10] Blend composition comparison product (g / 100g) 6 7 8 Indomethacin 0.75 0.75 0.75 Tocopherol acetate 1.0 1.0 1.0 Isopropyl myristate 1.0 1.0 1.0 Nikkor TS-106 1.0-Nikkor MYS-40-1.0-Nikkor GO-4--1.0 l- Menthol 3.0 3.0 3.0 Sodium hydroxide 0.01 0.01 0.01 Ethanol 15.0 15.0 15.0 Isopropanol 45.0 45.0 45.0 Purified water Remaining amount Remaining amount Remaining amount

The evaluation results are shown in Table 11. As is clear from Table 11, it was confirmed that the products of the present invention have high stability at room temperature and low temperature (−20 ° C.) in any composition.

[0042]

[Table 11] Inventive product Comparative product Storage condition 9 10 11 6 7 8 Room temperature ○ ○ ○ ○ ○ ○ Low temperature ○ ○ ○ × △ ×

Example 6 An external anti-inflammatory analgesic solution was prepared according to the composition shown in Table 12 below. Then, according to the evaluation method of Example 1, the stability was evaluated.

[0044]

[Table 12]  CompositionInvention product  (G / 100g) 12 13 14 15 16 Indomethacin 0.75 1.0 0.5 1.0 0.75 Tocopherol acetate 1.0 0.5 2.0 0.5 1.0 Isopropyl myristate 1.0 − − 1.0 − Diisopropyl adipate − 4.5 4.0 − − Diethyl sebacate − − − − 2.5 Nikkor HCO-60 − − 2.0 0.5 − Nikkor BL-9EX − 1.5 − − − Nikkor NP-10 − − − 0.3 − Nikkol HCO-100 1.5 − − − − Nikkol OP-10 − − − − 1.5 Nikkor NP-18TX − − − − − 1- menthol 3.0 2.0 3.0 3.0 3.0 dl -Camphor 2.0 1.0 --- Nonyl acid vanillylamide-0.01 --- Propylene glycol-5.0 --- Sodium hydroxide 0.03 0.01 0.008 0.01 0.02 Carboxyvinyl polymer 0.2 ----- Ethanol 15.0 20.0 35.0 30.0 15.0 Isopropanol 48.0 45.0 20.0 25.0 45.0 Purified water Remaining amount Remaining amount Remaining amount Remaining amount Remaining amount Note) Nitsukol HCO-100: POE (100) curing
Castor oil Nitsukol OP-10: POE (10) octylph
Phenyl ether Nitsukol NP-18TX: POE (18) nonylfe
Nyl ether

The evaluation results are shown in Table 13. As is clear from Table 13, it was confirmed that the products of the present invention have high stability at room temperature and low temperature (−20 ° C.) in any composition.

[0046]

[Table 13] Storage condition of the product of the present invention 12 13 14 15 16 Room temperature ○ ○ ○ ○ ○ Low temperature ○ ○ ○ ○ ○

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Office reference number FI technical display location A61K 47/34 H 7433-4C J 7433-4C // (A61K 31/405 31: 355) 9360- 4C

Claims (1)

[Claims] 1. An external anti-inflammatory analgesic for a lower alcohol aqueous solution containing (a) indomethacin, (b) vitamin Es, (c) medium-chain fatty acid ester, and (d) the number of moles of ethylene oxide added is 10 or more. 1 selected from polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ether having an ethylene oxide addition mole number of 2 to 50, and polyoxyethylene alkylphenyl ether having an ethylene oxide addition mole number of 2 to 30.
An external anti-inflammatory analgesic liquid characterized by containing one or more kinds of surfactants.