JPH01143831A - Solution for external use - Google Patents

Abstract

PURPOSE:To obtain a solution for external use having improved absorption characteristics of ketoprofen, excellent safety, feeling in use and stability, containing ketoprofen, polyoxypropylene alkyl ether, isopropyl adipate, etc., in a specific ratio. CONSTITUTION:A solution for external use containing 0.3-5pts.wt. based on 100pts.wt. total amounts of ketoprofen, nonsteroid anti-inflammatory analgesic, 0.5-5pts.wt. (especially 1-3pts.wt.) polyoxypropylene alkyl ether as a surfactant, 0.05-2pts.wt. (especially 0.05-1pt.wt.) hydroxyalkyl cellulose, 0.5-15pts.wt. (especially 1-10pts.wt.) isopropyl adipate and/or isopropyl myristate (improving skin permeation), 0-10pts.wt. humectant, 0-3pts.wt. antiseptic, 0-2pts.wt. ultraviolet light absorber, 0-1pt.wt. perfume, 0-5pts.wt. pH adjuster (the solution has pH value of 4-8) and the rest of a mixed solvent of water and ethanol in the weight ratio of 30:70-70:30.

Description

Detailed Description of the Invention (Field of Industrial Application) The present invention relates to a liquid preparation for external use containing ketoprofen as an active ingredient, which improves the absorption of ketoprofen, and further improves the stability and feel of the liquid preparation for external use. This relates to a formulation with excellent safety.

(Prior art and its problems) Ketoprofen is a non-steroidal anti-inflammatory analgesic that has excellent anti-inflammatory and analgesic effects, and is particularly useful for osteoarthritis, vaginal inflammation, muscle pain, trauma, and post-surgery. Swelling/
It is a drug commonly used to treat pain, etc., and is used not only as an oral medicine, but also as a skewer and external medicine.

Examples of external preparations that have been put into practical use include gel preparations. Although there are some patents for liquid preparations for external use, none of them have satisfactory absorption effects, and there are very few preparations that satisfy the stability, usability, and safety of liquid preparations for external use.

As a result of extensive research in search of a topical solution that satisfies the above requirements, the present inventors discovered a ketoprofen preparation that has excellent absorption of ketoprofen and has excellent stability, range of use, and safety as a topical solution, and has developed the present invention. It has been completed.

(i) The blending amount of ketoprofen is preferably 0.3 to 5 parts by weight per 100 parts by weight of the total amount. Ketoprofen has little pharmacological effect when blended in less than 0.3 parts by weight.
If the amount is more than 5 parts by weight, problems such as irritation of ketoprofen itself and precipitation of ketoprofen will occur.

(ii) Polyoxyethylene polyoxypropylene alkyl ether is a surfactant with the chemical formula: R is an alkyl group, m, n
means a numerical value. Crystalline compounds blended into external liquid preparations, such as the crude drug ketoprofen, as well as ketoprofen decomposition stabilizers, preservatives, etc., must not precipitate and be uniform and stable even when stored at low temperatures (crystal solubilization) After considering and considering the addition of a surfactant, we found that polyoxyethylene polypropylene alkyl ether was particularly suitable. In addition, it has been discovered that the foaming of external liquid preparations can be reduced.

In general, surfactants added to topical solutions include emulsion lotion bases, sodium lauryl sulfate, sorbitan fatty acid esters, etc., but these are insufficient in terms of solubilization and foaming properties of ketoprofen, etc. .

There are more suitable ranges for R, m, and n in the chemical formula of polyoxyethylene polyoxypropylene alkyl ether.

Preferably R is a lauryl group, myristyl group, cetyl group,
m is a stearyl group from 2 to 8. polyoxyethylene polyoxypropylene alkyl ether, where n is 5 to 30;
More preferably, R is a myristyl group, cetyl group, or stearyl group, m is 3 to 6, and n is 10 to 30. More preferably, R is a cetyl group, and the average value of m is 3.5-4
．． 5. Polyoxyethylene with an average value of n of 18 to 22 (
18-22) Polyoxypropylene (3,5-4.5)
It is cetyl ether. When R, m, and n are in this range, the solubilization of ketoprofen etc. is excellent, the foaming property is low,
It was a preferred formulation.

The amount of polyoxyethylene polyoxypropylene alkyl ether added is preferably 0.5 to 5 parts by weight, more preferably 1 to 3 parts by weight, based on 100 parts by weight of the total amount. If less than 0.5 parts by weight is added, the solubilization of ketoprofen etc. will be insufficient, and if more than 5 parts by weight is added, the foaming property will increase, causing a problem.

(tii) The hydroxyalkylcellulose includes hydroxyethylcellulose, hydroxypropylcellulose, etc., and preferably hydroxyethylcellulose. The total amount of hydroxyalkyl cellulose added is 100
It is preferably 0.05 to 2 parts by weight, more preferably 0.05 to 1 part by weight. If it is less than 0.05 parts by weight, it will have poor adhesion to the skin, and the viscosity of the liquid for external use will be low, causing dripping, while if it is added in amounts of 2 parts by weight or more, the viscosity will become high, resulting in stickiness.

(iv) Isopropyl adipate and/or isopropyl myristate is 0.5 to 100 parts by weight of the total amount.
The amount is preferably 15 parts by weight, and more preferably 1 to 10 parts by weight. Addition of less than 0.5 part by weight.

The skin permeability of ketoprofen is insufficient, and when 10 parts by weight or more is added, problems such as stickiness and slow drying occur.

(v) Mixed solvent of water and ethanol When producing the liquid preparation for external use of the present invention, water and ethanol may be added separately in order to improve the efficiency of drug production. This mixed solvent is added in a total amount of 100 parts by weight in addition to the components (i) to (iv) above and the following components that can be added and blended as desired.

The mixing weight ratio of water and ethanol is determined in order to prevent the crystallization of ketoprofen, increase the drying speed after applying the liquid to the skin, the stability of the liquid itself, and skin irritation.
Water: Ethanol = (30:70) ~ (70:30)
(w/w) is preferred, and more preferably water:ethanol = (40:60) to (60:40) (w/w).

Only by selecting and optimally blending the components (i) to (v) above can the present invention be completed as a practical anti-inflammatory and analgesic external liquid preparation.

In addition, the following agents that can be added as desired will be described.

(a) Moisturizing agents include, for example, sodium chondroitin sulfate, 3-butylene glycol, sodium lactate, maltitol, xylitol, etc., and the blending amount is preferably 0 to 10 parts by weight per 100 parts by weight of the total amount.

(b) Preservatives include, for example, benzoic acid and its sodium salt, methylparaben, ethylparaben, propylparaben, butylparaben, sorbic acid and its potassium salt, sodium salt, etc., or mixtures thereof;
The blending amount is preferably 0 to 3 parts by weight per 100 parts by weight of the total amount.

(c) Examples of the ultraviolet absorber include dibutylhydroxytoluene, p-aminobenzoic acid derivatives, benzophenone derivatives (eg, oxybenzone), and the blending amount is preferably 0 to 2 parts by weight per 100 parts by weight of the total amount.

(d) Examples of fragrances include l-menthol, amyl acetate, etc., and the amount blended is preferably 0 to 1 part by weight per 100 parts by weight of the total amount.

(e) Examples of pH adjusters include triethanolamine, triisopropanolamine, sodium hydroxide,
Examples include potassium hydroxide. The amount of pH1 moderating agent is such that the pH value of this liquid preparation is 4 to 8, and the total amount is 10
It is preferably 0 to 5 parts by weight relative to 0 parts by weight.

The external liquid preparation of the present invention can be manufactured, for example, as follows. Polyoxyethylene polyoxypropylene alkyl ether, isopropyl adipate and/or isopropyl myristate, hydroxyalkyl cellulose, water and/or alcohol and other ingredients are placed in a container heated to 70-80°C and uniformly dissolved, then Obtained by adding ketoprofen to make a homogeneous solution.

(Effects of the Invention) The external liquid preparation of the present invention obtained as described above not only has excellent absorption through the skin and excellent anti-inflammatory and analgesic effects, but also has excellent long-term and low-temperature stability, usability, and safety. It is an excellent formulation from all aspects.

The anti-inflammatory effect of the formulation is shown below using a pharmacological test; the safety is shown using a patch irritation test; the usability is shown using a sensory test; and the stability is shown using an accelerated stability test.

(Examples (including test examples)) Test method 1 Drug permeation experiment using excised skin The abdominal skin of hairless rats (purchased from Saitama Experimental Animals) was used to perform the experiment in a Franz type cell.

After fixing the skin on the cell with the stratum corneum side facing upward, each sample is applied.

After fixing the extracted skin dermis side in close contact with physiological saline filled in a receiver container, the amount of ketoprofen that permeated through the extracted skin and moved into the physiological saline solution on the receiver side was measured every hour by high-performance liquid chromatography. Measured over time. Table 1 shows the amount of permeation after 2 and 6 hours.

Test Method 2 Carrageenin - External Edema Suppressive Effect on Rat Paw Edema Experiment One group of 8 male Wistar rats (purchased from Shizuka Dokyo) weighing approximately 130 g were used under non-fasting conditions. After measuring the left hind paw volume of the rat, 100 ml of sample was applied to the left hind paw.
g was applied. After 4 hours, the unabsorbed remaining sample was wiped off with absorbent cotton containing lukewarm water, and 0.11111 of a 1% carrageenin (inflammatory agent)-physiological saline solution was injected under the incised foot skin to induce edema.

The volume of the left foot was measured 3 hours after the treatment on the inflamed side, and the edema rate was calculated from the foot volume before the treatment on the inflamed side. The results are shown in Table-1.

The edema suppression rate was expressed as a percentage by dividing the value obtained by subtracting the edema rate of the sample-applied group from the edema rate of the sample-applied untreated group by the edema rate of the sample-applied untreated group. During the application period, the animals were treated with a primer and housed in individual cages to prevent the sample from being ingested orally.

Test method 3: Measurement of rate of increase in carrageenin inflammation paw pain level. A group of 7 male Wistar rats (purchased from Jidoukyo) weighing approximately 130 g were used, and 100 ml of sample was applied to the left hind paw. After the Ahr, the unabsorbed test substance was wiped off with absorbent cotton containing lukewarm water, and 0 to 1 d of a 1% carrageenan saline solution containing 10% kaolin was injected under the foot in the same area.

Three hours after the injection of the inflammatory agent, pressure stimulation was applied to the left rear using a balance pressure device, and the pain threshold was measured using the leg withdrawal reflex as an index.

The pain threshold increase rate was expressed as a percentage by subtracting the threshold of the sample-untreated group from the threshold after application of the sample, and dividing the value by the threshold of the sample-untreated group.

Table 1 shows the rate of increase in pain level.

Test method 4 Examination of the stability of external liquid preparations The 0 display method, in which external liquid preparations were kept at a constant temperature of 50°C for one month and visually examined for changes in appearance, was ``stable...''
・◎; Separation: × (number of days separated).

The 0 display method for examining the transparency of external liquids that have been kept at -10°C for one month is: "Clear...◎; Cloudy...× (Number of days it started to become cloudy)" I made it.

The results are shown in Table-1.

Test method 5 Foaming property A 301d sample was placed in a 50m polyethylene container (diameter 30mm), set sideways in a reciprocating shaker, shaken at 150 times/min for 10 minutes, and immediately after stopping, foaming property was examined. The zero display method was ``No bubbles ◎ 〃 A little Δ 〃 A lot ×.''

The results are shown in Table-1.

Test method 6 Skin irritation test Using four types of vaseline: Example 1, Example 3, Comparative Example 2, and diurnal vaseline, 48 doses were applied to the upper backs of 33 healthy men in mini batches.
It was applied for 72 hours. Two hours after peeling, the degree of skin irritation was determined. The results are shown in Table-2, and the criteria for evaluation are shown below Table-2.

Example-1 3 parts of ketoprofen, 2 parts of polyoxyethylene (to) polyoxypropylene (4) cetyl ether, 3 parts of isopropyl adipate, 13 parts of 1,3-butylene glycol, 35 parts of ethanol, 0.5 part of oxybenzone, 0.1 part of propylparaben, 0.2 part of menthol, and 1.2 parts of triethanolamine as a pH adjuster were uniformly dissolved at 50°C. (Mixed solution) Add 0.1 part of hydroxyethyl cellulose and 41.9 parts of water to a separate mixing tank and dissolve uniformly at 80°C. After lowering the temperature to 50°C, add the entire mixed solution and cool to room temperature. A homogeneous and transparent liquid preparation for external use was obtained. The solution viscosity of this external solution was 12 cps.

Comparative Examples-1 and 2 A liquid preparation for external use was obtained in the same manner as in Example-1 except that polyoxyethylene (to) polyoxypropylene (4) cetyl ether was removed from the liquid preparation for external use prepared in Example-1 (Comparative Example −
1), polyoxyethylene QΦ polyoxypropylene (
4) A liquid preparation for external use was obtained by using 2 parts of sodium lauryl sulfate instead of cetyl ether (Comparative Example-2).

Comparative Examples 3 and 4 Similar to Comparative Example 1, external solutions prepared in Example 1 were prepared by adding isopropyl adipate or hydroxyethyl cellulose to prepare external solutions in the same manner as in Example 1. It was set to 3°4. Comparative Example 4 had a low solution viscosity of 4 cps, had a lot of liquid shaking, had poor adhesion to the skin, and was unsatisfactory as an external liquid preparation.

Example-2 2 parts of ketoprofen, 50 parts of polyoxyethylene (05) polyoxypropylene (6), 3 parts of myristyl ether, 6 parts of isopropyl myristate, 40 parts of ethanol, 0.2 parts of peppermint oil, and 0.8 parts of triethanolamine It was uniformly dissolved at ℃. (Mixed solution) Add 0.2 parts of hydroxypropyl cellulose and 47.8 parts of water to a separate mixing tank.
After uniformly dissolving at °C and lowering the temperature to 50 °C, the entire mixed solution was added and cooled to room temperature to obtain a uniform and transparent liquid for external use. The solution viscosity was 18 cps. Example-3 3 parts of ketoprofen, 3 parts of polyoxyethylene (30) polyoxypropylene (4) stearyl ether, 3 parts of isopropyl adipate, 3 parts of isoflovir myristate
parts, 101 parts of 1,3-butylene glycol, 4 parts of ethanol
0 part of dibutylhydroxytoluene, 0.1 part of dibutylhydroxytoluene, 0.5 part of oxybenzone, and 0.1 part of methylparaben were uniformly dissolved at 50°C. (Mixed solution) Add 0.1 part of hydroxyethyl cellulose and 37.2 parts of water to another mixing tank and dissolve uniformly at 80°C. After lowering the temperature to 50°C, add the entire mixed solution and cool to room temperature. A homogeneous and transparent liquid for external use was obtained. Solution viscosity was 15 cps.

(Hereafter, margin)

Claims (1)

[Scope of Claims] Ketoprofen 0.3 to 5 parts by weight (hereinafter referred to as A weight part) and polyoxyethylene polyoxypropylene alkyl ether 0.5 to 5 weight parts (hereinafter referred to as B weight part) based on 100 parts by weight of the total amount. 0.05 to 2 parts by weight of hydroxyalkyl cellulose (hereinafter referred to as parts by weight), 0.5 to 15 parts by weight of isopropyl adipate and/or isopropyl myristate (hereinafter referred to as parts by weight D), moisturizer 0 to 10 parts by weight (hereinafter referred to as E parts by weight), preservatives 0 to 3 parts by weight (hereinafter referred to as F parts by weight), ultraviolet absorber 0 to 2 parts by weight (hereinafter referred to as G parts by weight), fragrance 0 ~1 part by weight (hereinafter referred to as H part by weight), 0 to 5 parts by weight of pH adjuster (hereinafter referred to as J part by weight), and a mixture of water and ethanol [The composition of the mixture is (water: ethanol) = (30: 7
0)～(70:30)(w/w)](100-(A+B
+C+D+E+F+G+H+J)) External liquid preparation consisting of parts by weight.