JPH0772133B2 - Stable ketoprofen-containing cream formulation - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention is directed to ketoprofen: 2- (3-
It relates to a cream preparation stably containing benzoylphenyl) propionic acid.

More specifically, in a cream preparation containing ketoprofen, which is a non-steroidal analgesic and anti-inflammatory drug having excellent analgesic and anti-inflammatory effects, as an active ingredient, stability and transdermal absorbability of the active ingredient, and The present invention relates to a cream preparation having excellent physical stability and safety.

[Conventional technology]

As a prior art of a cream formulation containing ketoprofen as an active ingredient, Japanese Patent Laid-Open No. 58-1033 is available.
11, the same 58-83622, the same 59-190912, the same 60-209515, and the like.

However, in the above-mentioned known art, higher alcohols, polyhydric alcohols, lower alcohols and the like, which are not incorporated in the preparation of the present invention at all, are incorporated as essential constituents.

Ketoprofen is a weakly acidic compound having a carboxyl group, and easily reacts with a compound having a hydroxyl group such as the above-mentioned higher alcohols, polyhydric alcohols and lower alcohols to form an ester. In particular, this reaction is easily promoted in a cream preparation, and in the above-mentioned known cream preparation, ketoprofen, which is an active ingredient, is inevitably converted into an ester form, and the remaining amount of the active ingredient having activity is very small. is there.

Incidentally, in order to prevent the conversion to this ester form,
Although various studies have been made, one of them is to raise the pH value. However, this method is also not a measure that can be adopted as a preparation for the outer skin, because the transdermal absorbability of the active ingredient decreases as the pH value increases.

In order to enhance transdermal absorbability in cream formulations, it is naturally desirable to create a drug-soluble formulation, but since ketoprofen, the active ingredient, is a highly fat-soluble drug, a large amount of dissolving or It is necessary to add a solvent having strong properties, that is, the above-mentioned higher alcohol, polyhydric alcohol and lower alcohol. However, when these are blended, the active ingredient cannot be stabilized as described above, and further, liquid separation easily occurs in the preparation itself, and it seems difficult to obtain a physically stable cream preparation.

As described above in detail, conventionally known cream preparations have drawbacks such as conversion of ketoprofen to an ester form, low transdermal absorbability, and liquid separation, and development of a cream preparation that solves these problems is strongly desired. It was rare.

Although not related to the invention of the present application, a conventional gel gel preparation containing ketoprofen will be supplementarily described.

Known techniques for gel preparations containing ketoprofen are disclosed in Japanese Patent Laid-Open No. 56-161323, and other therapeutic agents for rheumatoid arthritis, traumatic and non-traumatic inflammatory diseases. As a matter of fact, development is being considered. However, in the case of these gel preparations, since alcohols such as isopropanol and ethanol are contained in a large amount and indispensably, side effects such as skin irritation are caused and it is currently regarded as a problem from the viewpoint of safety.

[Problems to be solved by the invention]

The present invention is intended to provide a cream preparation which overcomes the drawbacks of the conventional cream preparation and gel preparation described in the preceding paragraph.

That is, in conventional cream preparations, it is necessary to create a cream preparation without blending higher alcohols, polyhydric alcohols, and lower alcohols, which are said to be essential ingredients, and prevent the conversion of ketoprofen, which is an active ingredient, into an ester form. However, the first is the problem to be solved.

In addition, transdermal absorbability and pH value, and change of ketoprofen to ester form and pH value are related to each other, but the production of ester form is low, and the transdermal absorbability is high.
Setting the value is the next problem to be solved.

It is also an object of the present invention to solve a physically unstable phenomenon which conventional cream preparations have, such as liquid separation.

Furthermore, the final purpose is to solve side effects such as skin irritation that gel preparations have.

[Means for solving problems]

The inventor of the present application seeks a cream preparation having the object of the preceding paragraph, namely, good stability of ketoprofen and excellent physical stability of the preparation itself, high percutaneous absorption of the active ingredient, and yet low skin irritation. I conducted an earnest research.

As a result, formulate creams without blending alcohols such as higher alcohols and polyhydric alcohols, which are widely used as the base of cream preparations and are commonly used as essential essential ingredients of cream preparations. The present invention was completed by finding out that the cream composition having a compounding composition and a specified compounding ratio, which will be described in detail later, satisfies all the objects of the preceding paragraph.

That is, the present invention comprises ketoprofen as an active ingredient, a hydrophilic polymer, a nonionic surfactant, a fatty acid ester, a pH adjusting agent and water as a base component, and the water content is 70 to 85% by weight. And a ketoprofen-containing cream preparation containing no lower alcohol.

More specifically, ketoprofen 0.5 to 6% by weight, hydrophilic polymer 0.1 to 5% by weight, preferably 0.5 to 1.
5% by weight, nonionic surfactant 0.5-10% by weight, preferably 3-6% by weight, fatty acid ester 2-30% by weight, preferably 10-20% by weight, pH regulator 0.05-3% by weight, preferably Relates to a cream preparation having a composition of 0.5 to 1.5% by weight, 70 to 85% by weight of water, preferably 70 to 80% by weight, and above.

The blending ratio is a particularly important factor in the invention of the present application, and within the specified blending ratio range described above, the following remarkable effects are exhibited. Therefore, if the specified blending ratio is deviated, the cream preparation aimed at in the present application cannot be obtained by any means.

Next, each of the compounding components will be described more specifically.

As the hydrophilic polymer, a carboxyvinyl polymer (for example, Carbopol 934, manufactured by Gutrich Chemical Co.,
940,941 or Hibis Wako 104,105 made by Wako Pure Chemical Industries
Etc.), hydroxyethyl cellulose, hydroxypropyl cellulose, etc., among which carboxyvinyl polymer is most suitable.

Examples of the nonionic surfactant include ester-based nonionic surfactants such as sorbitan fatty acid ester, glycerin fatty acid ester, decaglycerin fatty acid ester, propylene glycol fatty acid ester, polyoxyethylene sorbitan fatty acid ester, and polyoxyethylene cured castor. Oil or the like may also be an ether type nonionic surfactant such as leuoxyethylene alkyl ether,
Examples thereof include polyoxyethylene alkyl phenyl ether. These nonionic surfactants are used in an appropriate amount of 1
It is mixed in one kind or a combination of two or more kinds.

As the fatty acid ester, an alcohol ester of a monocarboxylic acid having ₄ to ₁₈ carbon atoms (eg, isopropyl palmitate, isopropyl myristate, butyl stearate, myristyl myristate, isocetyl myristate, octyldodecyl myristate, etc.), or alcohol diester (e.g. adipic acid diisopropyl, diisopropyl sebacate) of C ₁ -C ₃ a dicarboxylic acid number C ₄ -C ₁₀ carbon atoms, or a glycerine or propylene glycol mono-, di- or tri fatty acid esters (e.g., mono- Glycerin caprate, propylene glycol dicaprylate, glycerin tricaprylate, etc.). These fatty acid esters are appropriately mixed in an appropriate amount of one kind or a combination of two or more kinds.

Examples of the pH adjusting agent include inorganic bases such as sodium hydroxide, potassium hydroxide and aqueous ammonia, and organic bases such as triethylamine, arginine, triethanolamine, triisopropanolamine, diethanolamine and diisopropanolamine.

The above pH adjuster has a pH value of 4 to 7 in consideration of the release of the active ingredient ketoprofen from the base, the percutaneous absorption of the active ingredient, or the skin irritation of the present formulation. It is necessary to mix it so as to preferably set it to 4.5 to 6.0.

In addition to the above-mentioned essential ingredients in designing the cream preparation of the present invention, an absorption promoter, a preservative, a preservative, a silicone oil, a fragrance and the like can be added in an appropriate amount and in an appropriate amount, if necessary.

In addition, as the absorption promoter, Azone, crotamiton, l-
Menthol, peppermint oil, oleic acid, salocol, etc.
Preservatives include parabens such as methylparaben, ethylparaben, propylparaben and butylparaben, thymol, chlorcresol, orthophenylphenol,
Examples of the preservative include phenols such as isopropylmethylphenol and photosensitizers, and examples of the preservatives include ultraviolet absorbers such as oxybenzone and benzoresorcinol; antioxidants such as dibutylhydroxytoluene and dl-α-tocopherol; and sodium edetate. Examples include sequestering agents for metal ions. Examples of silicone oil include methylpolysiloxane, methylphenylpolysiloxane, cyclic dimethylsiloxane and the like.

Next, a method for producing the cream preparation of the present invention will be described.

To produce the cream preparation of the present application, first, a nonionic surfactant and a fatty acid ester are added to ketoprofen and dissolved by heating, and then a hydrophilic polymer is dissolved in water, and the above oil phase component is added thereto, The cream preparation of the present application can be obtained by emulsifying while stirring at an appropriate speed, then gradually adding an aqueous solution of a pH adjusting agent, and further stirring.

As described above, the cream preparation of the present invention described in detail is a novel compounding composition which has not been found in the prior art, and this is a novel finding first found by the inventor of the present application.

There is no known material that suggests such a composition, and of course, there is no material that suggests that the composition has the effects described below.

Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples.

Example 1 3 g of ketoprofen, 5 g of polyoxyethylene (20) sorbitan monostearate, and diisopropyl adipate 3
g, isopropyl myristate 10g, oxybenzone 0.5
g, crotamiton 1 g and methyl paraben 0.1 g, add 70
It was heated to 0 ° C. and dissolved uniformly. On the other hand, 1 g of carboxyvinyl polymer was dissolved in 65.4 g of water. Next, the above oil phase was added to a carboxyvinyl polymer aqueous solution while stirring and emulsified. Next, add 1 g of diisopropanolamine to it.
The solution dissolved in 10 g was added, and the mixture was stirred until it was uniform to obtain the cream preparation of the present invention.

Example 2 3 g of ketoprofen, 3 g of polyoxyethylene (60) hydrogenated castor oil, 5 g of diisopropyl sebacate, 10 g of isopropyl myristate, 1.5 g of peppermint oil, 0.1 g of methylparaben.
And 0.1 g of propylparaben were added, and the mixture was heated to 70 ° C. and uniformly dissolved. On the other hand, 1.2 g of carboxyvinyl polymer is added to water.
It dissolved in 65.6 g. Next, an aqueous carboxyvinyl polymer solution was added and emulsified while stirring the above oil phase. Next, a solution prepared by dissolving 0.5 g of triethanolamine in 10 g of water was added, and the mixture was stirred until it was uniform to obtain the cream preparation of the present application.

Example 3 To 1.5 g of ketoprofen, 3 g of polyoxyethylene (60) hydrogenated castor oil, 10 g of diisopropyl adipate, 2 g of octyldodecyl myristate, 3 g of 1-menthol, and 0.1 g of isopropylmethylphenol were added, and heated to 70 ° C. It dissolved uniformly. On the other hand, carboxyvinyl polymer 0.8g
Was dissolved in 68.6 g of water. Next, the above oil phase was added to a carboxyvinyl polymer aqueous solution while stirring and emulsified. Next, a solution prepared by dissolving 1 g of triethanolamine in 10 g of water was added, and the mixture was stirred until it was uniform to obtain the cream preparation of the present application.

Example 4 5 g of ketoprofen, 5 g of polyoxyethylene (20) sorbitan monooleate and 0. sorbitan monostearate.
5 g, diisopropyl adipate 5 g, glycerin tricaprylate 10 g, salocol 1 g, methylparaben 0.1 g and propylparaben 0.1 g were added, and the mixture was heated to 70 ° C. and uniformly dissolved. On the other hand, 1.5 g of carboxyvinyl polymer was added to 60.3 of water.
dissolved in g. Next, an aqueous carboxyvinyl polymer solution was added and emulsified while stirring the above oil phase. Next, a solution prepared by dissolving 1.5 g of diisopropanolamine in 10 g of water was added, and the mixture was stirred until it became uniform to obtain the cream preparation of the present invention.

Example 5 To 2 g of ketoprofen, 6 g of polyoxyethylene (10) monolaurate, 5 g of diisopropyl adipate, 5 g of crotamiton, 0.2 g of oxyvenzone and 0.2 g of methylparaben were added and dissolved by heating at 70 ° C. On the other hand, 1.0 g of carboxyvinyl polymer was dissolved in 69.8 g of water. Next, the above oil phase was added to a carboxyvinyl polymer aqueous solution while stirring and emulsified. Next, a solution prepared by dissolving 0.8 g of triethanolamine in 10 g of water was added, and the mixture was stirred until it was uniform to obtain the cream preparation of the present invention.

Example 6 To 1 g of ketoprofen, 2 g of polyoxyethylene (23) cetyl ether, 5 g of diethyl sebacate, 10 g of propylene glycol dicaprylate, and 0.1 g of thymol were added, and the mixture was heated to 70 ° C.
It was heated to and dissolved uniformly. On the other hand, 0.7 g of carboxyvinyl polymer was dissolved in 70.6 g of water. Next, the above oil phase was added to the carboxyvinyl polymer aqueous solution with stirring, and the mixture was stirred. Next, triisopropanolamine 0.6 g was added to water 10 g.
The solution dissolved in was added and stirred until uniform to obtain the cream preparation of the present invention.

Example 7 1.5 g of ketoprofen, 3 g of polyoxyethylene (20) sorbitan monostearate, and diisopropyl sebacate
10 g, isopropyl myristate 4 g, crotamiton 0.5
g, oxybenzone 0.3 g, methylpolysiloxane 0.2 g and isopropylmethylphenol 0.05 g were added and heated to 70 ° C. to dissolve. On the other hand, carboxyvinyl polymer 1.0g
Was dissolved in 68.85 g of water. Next, the above oil phase was added to the carboxyvinyl polymer aqueous solution and stirred. Next, a solution prepared by dissolving 0.8 g of diisopropanolamine in 10 g of water was added, and the mixture was stirred until it became uniform to obtain the cream preparation of the present application.

Example 8 3 g of ketoprofen, 3 g of polyoxyethylene (20) sorbitan monostearate and 15 g of diisopropyl adipate
g, squalane 5g and methylparaben 0.2g, 70 ℃
It was heated to dissolve. Meanwhile, carboxyvinyl polymer
1 g was dissolved in 61.8 g of water. Next, the above oil phase was added to the carboxyvinyl polymer aqueous solution and stirred. Next, a solution prepared by dissolving 1 g of triethanolamine in 10 g of water was added, and the mixture was stirred until it was uniform to obtain the cream preparation of the present application.

Next, as reference examples, examples in which higher alcohols, polyhydric alcohols, and lower alcohols are blended and examples in which a hydrophilic polymer is not blended are shown below, and are provided as comparative formulations for the test examples described below.

Reference Example 1 To 3 g of ketoprofen, 5 g of polyoxyethylene (25) monostearate, 10 g of 2-octyldodecanol, 5 g of isopropyl myristate, 5 g of propylene glycol, 0.1 g of methylparaben and 0.1 g of propylparaben were added, and the mixture was heated to 70 ° C.
It was heated to and dissolved uniformly. On the other hand, 1 g of carboxyvinyl polymer was dissolved in 59.8 g of water. Next, the above oil phase was added to the carboxyvinyl polymer aqueous solution with stirring and stirred. Next, a solution prepared by dissolving 1 g of triethanolamine in 10 g of water was added, and the mixture was stirred until it became uniform to obtain a cream preparation.

Reference Example 2 3 g of ketoprofen, 5 g of polyoxyethylene (60) hydrogenated castor oil, 5 g of 2-hexyldecanol, myristyl lactate
5 g, 1,3-butylene glycol 10 g and methyl paraben 0.
2 g was added, and the mixture was heated to 70 ° C. and uniformly dissolved. On the other hand, 1 g of carboxyvinyl polymer was dissolved in 59.8 g of water. Next, the above oil phase was added to the carboxyvinyl polymer aqueous solution and stirred. Next, a solution prepared by dissolving 1 g of diisopropanolamine in 10 g of water was added, and the mixture was stirred until it became uniform to obtain a cream preparation.

Reference Example 3 Ketoprofen 3 g, polyoxyethylene (20) sorbitan monostearate 5 g, isopropyl myristate 10
g, ethanol 7 g, diethyl sebacate 15 g and crotamiton 5 g were added, and the mixture was heated to 70 ° C. and uniformly dissolved. on the other hand,
1 g of carboxyvinyl polymer was dissolved in 41 g of water. Next, a solution prepared by adding 3 g of coconut oil fatty acid diethanolamide to 10 g of water was added and stirred until uniform to obtain a cream preparation.

Reference Example 4 5 g of crotamiton was added to 3 g of ketoprofen, and the mixture was heated to 70 ° C. and dissolved. To this, cetostearyl alcohol 10
g, polyoxyethylene lauryl ether 2 g, white petrolatum 10 g, liquid paraffin 5 g and methylparaben 0.2 g were added, dissolved by heating and kept at 80 ° C. On the other hand, water 64.8 g 80
The temperature was kept at 0 ° C., the above oil phase was added thereto, and the mixture was uniformly emulsified with a homomixer. After emulsification, the mixture was cooled to 30 ° C with stirring to obtain a cream preparation.

Reference Example 5 10 g of cetostearyl alcohol, polyoxyethylene (2
5) 2.5 g of lauryl ether, 10 g of white petrolatum, 5 g of liquid paraffin, and 0.2 g of methylparaben were heated to 80 ° C and dissolved. Meanwhile, 69.3 g of water was heated and kept at 80 ° C. The above oil phase was added to the aqueous phase, 3 g of ketoprofen was further added, and the mixture was uniformly emulsified with a homomixer. After emulsification, the mixture was cooled to 30 ° C with stirring to obtain a cream preparation.

Test Example 1 (Test on stability of ketoprofen in cream preparation) The cream preparation of Example 1 and the cream preparations of Reference Examples 1 and 2 were filled in a tube and the remaining amount of ketoprofen was measured when the tube was stored at 40 ° C. The measurement results are shown in Table 1.

As is clear from Table 1, the cream preparation of Example 1 was very stable even after being stored for a long period of time as compared with the preparation of Reference Example without any change to an ester form or the like.

Test Example 2 (Test on Physical Stability of Cream Formulation) About 4 g of the cream formulation of Example 1 and the cream formulations of Reference Examples 3 and 4 were filled in a transparent glass bottle having a diameter of 13 mm and a height of 45 mm at 40 ° C. and 50 ° C. It was stored in and observed for change in appearance. The results are shown in Table 2.

From the results in Table 2, it is clear that the cream preparation of Example 1 has much better physical stability than the cream preparations of Reference Examples 3 and 4.

Test Example 3 (Test for transdermal absorption) Regarding the cream preparation of Example 8 and the preparation of Reference Example 5,
The percutaneous absorption of ketoprofen was measured using rats.

(Experimental Method) On the previous day, 100 μl (about 95 to 100 mg) of a sample was applied to a male Wistar rat having a body weight of 170 to 180 g, which was shaved on the back in the range of 2.5 × 2.5 cm, and further sealed with an adhesive tape. Blood was collected after 1 hour, 3 hours, and 6 hours, and the content of ketoprofen in the serum was measured by high performance liquid chromatography. The results are shown in Table 3.

From the results in Table 3, it is clear that the cream preparation of Example 8 has better transdermal absorption of ketoprofen than the cream preparation of Reference Example 5.

Test Example 4 (Test on skin irritation) The cream preparation of the present invention of Example 1 was put into a fin chamber (manufactured by Taisho Pharmaceutical Co., Ltd.) of 45 healthy males and stuck on the inside of the upper arm of the test subject for 48 hours. Thirty minutes after the peeling, the skin of the applied part was visually observed. As a result, no skin reaction was observed in 45 subjects.

[Operation and effect of the invention]

As is clear from the test examples described above, the cream preparation of the present invention has the following remarkable actions and effects.

(1) Since ketoprofen, which is an active ingredient, is excellent in stability over time, changes in the active ingredient due to long-term storage of the preparation of the present invention can be prevented, and the drug efficacy of the initial preparation can be expected for a long time.

(2) In commercializing the drug product, the condition of long-term stability under severe conditions is indispensable, but the drug product of the present invention has a physically stable action for a long period of time even under severe conditions. It is satisfactory.

(3) The cream preparation of the present application has a high percutaneous absorption of active ingredients, and can be expected to have excellent medicinal effect of ketoprofen.

(4) Furthermore, since the cream preparation of the present application has little skin irritation, it is useful as a safe drug without side effects.

In addition to the above effects, of course, as a preparation for ketoprofen rind, it has a remarkable anti-inflammatory and analgesic effect, and a great effect as a therapeutic drug for inflammatory diseases such as joint pain, myalgia, and tendonitis. Is.

Claims (2)

[Claims] 1. A ketoprofen-containing cream preparation comprising ketoprofen as an active ingredient, a hydrophilic polymer as a base ingredient, a nonionic surfactant, a fatty acid ester, a pH adjusting agent, water and an absorption enhancer. The accelerator is selected from one or more of Azone, crotamiton, l-menthol, peppermint oil, oleic acid, salocol or squalane, and the water content is 70 to 85% by weight.
And a ketoprofen-containing cream preparation characterized by containing no lower alcohol. 2. Ketoprofen 0.1 to 6% by weight, hydrophilic polymer 0.1 to 5% by weight, nonionic surfactant 0.5.
~ 10 wt%, fatty acid ester 2-30 wt%, pH adjuster 0.05-3 wt%, water 70-85 wt%, absorption promoter 0.
The ketoprofen-containing cream preparation according to claim 1, characterized in that it is incorporated in an amount of 5 to 5.0% by weight.