JPS597115A - Anti-inflammatory and antipyretic drug for external use - Google Patents

Abstract

PURPOSE:An anti-inflammatory and antipyretic drug, prepared by incorporating pranoprofen with a base consisting of a lower aliphatic alcohol, etc., a gelling agent, a water-soluble basic substance and water, containing the pranoprofen in the dissolved state, and capable of giving a sufficient drug efficay. CONSTITUTION:An anti-inflammatory and antipyretic drug prepared by incorporating (A) 0.5-5wt%, preferably 1-3wt%, pranoprofen expressed by the formula with (B) 10-90wt% at least one selected from a uni--trivalent aliphatic lower alcohol, polyethylene glycol having 200-1,000 average molecular weight and acetone, (C) 0.1-5wt% gelling agent, e.g. carboxyvinyl polymer, carboxymethyl cellulose (CMC) or aliginic acid, and (D) a water-soluble basic substance, e.g. ammonia, NaOH or an organic amine, in an adequate amount necessary to dissolve the component (A) in the base and keep the pH of the base at a neutral value, preferably 6-8, and (E) 10-90wt% water, preferably purified water.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an anti-inflammatory and analgesic external preparation containing pranoprofen as an active ingredient.

Pranoprofen is a benzopyranopyridinyl acetic acid derivative represented by formula (I) and has been shown to have excellent anti-inflammatory, analgesic, and antipyretic effects, and is currently available in capsule form as an anti-inflammatory agent for chronic arthritic rheumatoid arthritis. - It is sold by the applicant as an analgesic, an analgesic/antipyretic for acute upper respiratory tract inflammation, an anti-inflammatory analgesic after tooth extraction, etc. When pranoprofen is administered orally, it is known that side effects such as gastrointestinal disorders are considerably less than indomethacin and other non-steroidal anti-inflammatory drugs, but they are not completely eliminated.

In addition, in the case of localized diseases such as arthritis, muscle pain, and post-traumatic pain, local administration is not only more effective than systemic administration such as oral administration, but also prevents unknown and unexpected side effects. It is also advantageous from above.

From this point of view, the development of external preparations is desired, but sufficient medicinal efficacy has not been observed just by incorporating them into bases such as vaseline, parent ointment, water-absorbing ointment, and macrogol ointment, which have been widely used in the past. There wasn't.

Therefore, the present inventors conducted various studies and found (a) Planoproa, which is an active ingredient! -n o, 5 to 5 wt% t-(bl
l~Trivalent aliphatic lower alcohol, average molecular weight 200~
10 to 90% by weight of at least one selected from the group consisting of polyethylene glycol, methyl ethyl ketone, and acetone;
When blended into a base consisting of (d) an appropriate amount of a water-soluble basic substance (the amount required to neutralize the external wood preparation) and (e) 10 to 90% by weight of water, pranopro-7ene exists in a dissolved state, The inventors have discovered that it is possible to obtain a product that is not only significantly superior to indomethacin ointment, which has already been used clinically, but also has excellent physical properties as an external preparation, leading to the present invention.

As the mono- to trivalent lower aliphatic alcohol used in the present invention, those commonly used in pharmaceutical preparations, such as ethanol, impropatol, propylene glycol, and glycerin, are desirable. Examples of the gelling agent include carboxyvinyl polymer, hydroxyethyl cellulose, alginic acid, carboxymethyl cellulose, and the like. Among these, carboxyvinyl polymer is preferred, and the amount added varies depending on the molecular weight, but is 0.1 to 1% by weight, preferably 0.5 to 2% by weight. Water-soluble basic substances include ammonia, sodium hydroxide, potassium hydroxide, and organic amines (triethanolamine, jetanolamine, diisopropanolamine, triisopropanolamine, triethylamine, etc.); i means that the active ingredient pranoprofen is dissolved in the base, and p)l of the base is neutral (pH 5 to 9,
It is necessary to adjust the pH to preferably 6 to 8). Moreover, purified water is preferable as water.

The effective effect of pranoprofen, which is an active ingredient, can be expected to be sufficient at 0.5 to 511% by weight, particularly 1 to 3% by weight. If desired, transdermal absorption enhancers (isopropyl myristate, diisopropyl adipate, diethyl sepacate, propylene glycol dibucanate, etc.), stabilizers (
Digtylated hydroxytoluene, etc.), surfactants, fragrances, preservatives, etc. may also be added.

The external preparation of the present invention includes, for example, pranoprofen, a mono- to trivalent aliphatic lower alcohol, and an average molecular weight of ff1200 to 10.
00 polyethylene glycol, methyl ethyl ketone and acetone together with some water and a water-soluble basic substance;
It can be prepared by adding the gelling agent to the remaining water and then mixing them.
There is no problem even if the order of blending the compounds is slightly changed.

Example Carrageenin - Topical anti-inflammatory effect on rat paw edema Weight 15
Separate Donryu rats weighing around 0g [Nippon Flare Co., Ltd.]
6 to 14 mice per group were used. After measuring the paw volume of rat hind paws using the water displacement method, the placebo control group received only the ointment base, and the treatment group received the 1% ointment base prepared in Example 2.
The test ointment containing pranopro7ene was applied to the entire area below the ankle (1004/rat). To prevent rats from licking, the application site was covered with Bacfilm (manufactured by American Can Company) and an occlusive dressing technique (ODT) was performed. After 2 hours, the rose film was removed, the ointment was soaked in hot water and washed off with gauze, and then a 0.5% methylcellulose solution (5rnl/2θO) was added to equalize the edema rate.
g rat body weight) was orally administered, and immediately injected with 1% carrageenan (
Pycnin A (manufactured by Vasco International Company) 0.05% of physiological saline was subcutaneously injected into the hind paw gland of the rat. Three hours after inoculation with the inflammatory agent, the paw volume was measured, the edema rate (%) was calculated, and the inhibition rate (%) was determined in comparison with the 2-sebo control group. The results were statistically processed using the one-way method.

The results are shown in Table 1, and the external preparation of the present invention was superior to the conventional preparation prepared by adding Prapro-7ene to the base.

Table 1: p<o,ot Example Comparison of carrageenan with commercially available indomethacin ointment for foot edema An experiment was conducted in the same manner as in Experimental Example 1. However, the results were compared with the Sham control group treated only with Parafilm.
The inhibition rate (%) was determined.

As the results are shown in Table 2, the external preparation of the present invention was significantly superior to the commercially available indomethacin ointment.

Table 2 Umbrella Umbrella: 8 - Significant difference at p<o, ot + compared to control group
: Significant difference in p<o, os compared to indomethacin ointment Example 1 Pranopro7ene Ig was mixed with triisopropanolamine2
Dissolve in 52 g of ethanol together with 30 g of 5% Hibis Wako 104 [trade name of carboxyvinyl polyamide manufactured by Wako Pure Chemical Industries, Ltd., the same applies hereinafter] and 15 g of purified water to make an anti-inflammatory analgesic external preparation. I got it. The pH of this external preparation was 6.6, and the viscosity (measured using a BH type viscometer manufactured by Tokyo Keiki Seisakusho at 20° C. and a rotor speed of 7.20 rpm) was 46,000 centivoise.

This topical preparation is transparent, spreads easily on the skin, has a cooling sensation, and has an excellent feeling of use.

Example 2 2 g of diisopropyl diisopropanol 1322 acid and 37 g of ethanol are added and dissolved in pranoprofen Ig. Separately, 2 g of Carboball 934 (trade name of carboxyvinyl polymer manufactured by Gutdrich Chemical Co., Ltd., hereinafter the same) was mixed with 48 g of purified water to obtain an anti-inflammatory and analgesic external preparation of centipoise.

Example 3 Furanoflofen Ig was dissolved in 14 g of 2N hydroxide, mixed with 10,430 g of 5% Hibiswako, and further mixed with 12 g of ethanol and 43 g of purified water.

Wood: The external preparation is colorless and transparent with a pH of 8.0 and a viscosity of 67.00.
The voice was 0 centimeters.

Example 4 3 g of pranoprofen was mixed with 5 g of triisopropanolamine
The mixture was dissolved in a mixed solvent of 40,020 g of polyethylene glycol and 32 g of ethanol, and mixed with 4% Hibiswako 104 4'Ogt'' to obtain an anti-inflammatory and analgesic external preparation.

The main rule is colorless and transparent, pH 7.2, viscosity 25,000-1
! It was an anti-voice.

Example 5 Planopro7ene 3 g tl” triisopropaturamine 5 g together with 20 g glycerin and 32 g ethanol
g of mixed solvent, and add 5% Hibis Wako 10 to this.
30 g of dibutylhydroxytoluene and 0.1 g of dibutylhydroxytoluene were mixed, and purified water was further added to make a total amount of 100 g.

This external preparation was colorless and transparent, had a pH of 6.7, and a viscosity of 6LOOO centipoise.

Example 6 Furanoflofen 2g) Diisopropaturamine 4
34 g of acetone and 20 g of 5% Hibis Wako 104 and 40 g of purified water were dissolved to obtain a colorless and transparent anti-inflammatory and analgesic external preparation having a pH of 7.3 and a viscosity of 31.000 centipoise. .

Example 7 0.5 g of pranobrofen and 2 g of triethanolamine
with 20g of methyl ethylgtone and 1 ethanol
It was dissolved in 7.5 g of a mixed solvent, and 20 g of 5% Hibis Wako 104 and 40 g of purified water were mixed therewith. This external preparation had a pH of 7.3 and a viscosity of 22,000 cants.

Example 8 Pranoprofen Igt= was dissolved in 10 g of 5% aqueous ammonia, and 40 g of purified water and 29 g of isopropyl alcohol were added. 5% power to this - Bopol 934
When 20g was mixed, the pH was 8.7 and the viscosity was 16.4.
A colorless and transparent external preparation of No. 00 was obtained.

Example 9 0.5 g of pranoprofen and 1.5 g of jetanolamine
The mixture was dissolved in a mixed solvent of 46 g of ethanol and 30 g of propylene glycol, and a gelling agent containing 1031 g of Hibisfuco-1 and hydroxyethyl cellulose Ig in 20 g of purified water was mixed therein. This external preparation had a pH of 6.7 and a viscosity of 36,000 centiboise.

Example] 0 0.5 g of pranoprofen was dissolved in 20 g of ethanol together with 2 g of diisopropanolamine. To this was mixed 1042 g of Hibiswako dissolved in a mixture of 10 g of purified water and 40 g of glycerin, and further glycerin was added to give a total fk l 00 g. This external preparation had a pH of 6.8 and a viscosity of 58,000 centiboise.

Agent: Patent Attorney Masaru Takamiyagi

Claims (1)

[Claims] (al pranoprofen 0.5-5%, (b)
Average molecular weight: 200 to mono- to trivalent aliphatic lower alcono
10 to 90% by weight of at least one member selected from the group consisting of polyethylene glycol, methyl ethyl ketone, and acetone, (c) a gelling agent of 0.1 to 5% by weight, (d) an appropriate amount of a water-soluble basic substance, and (e) Water about 1
An anti-inflammatory and analgesic external preparation containing θ~90%.