JP3032288B2 - Ketotifen topical formulation - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to an external preparation characterized by stably containing ketotifen or a fumarate thereof as an active ingredient. More specifically, it is an external preparation containing stably ketotifen, which has been conventionally mainly incorporated into oral preparations as an antiallergic agent, and is useful as a therapeutic agent for dermatitis, eczema, atopic eczema, rash and other dermatological fields The present invention relates to an external preparation for ketotifen suitable as a skin external preparation or the like.

BACKGROUND ART Ketotifen {4- (1-methyl-4-piperidylidene) -4H-benzo [4,5] cyclohepta [1,2-b] thiophene-10 [9H] -one} has an antihistamine action, anti-SR
It is a drug having a wide range of anti-allergic actions such as SA action, and fumarate of ketotifen has been widely used as an oral preparation. As the prior art of external preparations containing ketotifen or its fumarate, JP-A-51-32724,
JP-A-51-142543, JP-A-57-181007, JP-A-60-1907
10, JP-A-62-164624, JP-A-62-223119, JP-A-1-
No. 102024, JP-A-1-121218, etc., but no consideration has been given to their stability. That is, conventional preparations containing ketotifen or its fumarate salt in an external preparation are decomposed with time, resulting in a change in color and a satisfactory preparation cannot be obtained.

Ketotifen or its fumarate salt is relatively stable in a powder state, but is unstable in a solution state and causes a color change when blended in a formulation. The preparation having undergone a color change was unfavorable from the viewpoint of safety as well as its brown appearance and poor appearance.

Accordingly, it is an object of the present invention to maintain the stability of ketotifen or its fumarate salt and prevent the color change of the preparation.

DISCLOSURE OF THE INVENTION The present inventors have conducted intensive studies in order to maintain the stability of ketotifen or its fumarate over time in a formulation, and found that ketotifen or its fumarate was 100%.
In external preparations containing parts by weight, as a stabilizer sodium bisulfite, potassium bisulfite, sodium sulfite,
It has been found that the safety of ketotifen or its fumarate salt is remarkably maintained by mixing 2 to 20 parts by weight of at least one sulfite compound selected from the group consisting of potassium sulfite, sodium pyrosulfite and potassium pyrosulfite. The present invention has been completed.

Examples of the dosage form of the external preparation according to the present invention include creams, liquids, lotions, gels, eye drops, aerosols, plasters, poultices, oral preparations, suppositories and the like.

Examples of the bisulfite used as a stabilizer in the present invention include sodium bisulfite and potassium bisulfite. Examples of the sulfite include sodium sulfite and potassium sulfite. Examples of the pyrosulfite include sodium pyrosulfite and potassium pyrosulfite.
These stabilizers are blended in one kind or in combination of two or more kinds, and most preferred is sodium bisulfite, sodium sulfite, sodium pyrosulfite or a combination of these stabilizers with dibutylhydroxytoluene (BHT). .

The compounding amount of these stabilizers is 2 to 20 parts by weight based on 100 parts by weight of ketotifen or its fumarate. If the amount of these stabilizers is too small or too large, the stabilizing effect tends to be hardly exhibited. In particular, when the amount of the stabilizer is larger than the above upper limit, the stabilizer may react with ketotifen, and there is a risk that the preparation may be colored light brown during the production.

BHT alone has little effect, and is more effective when used in combination with at least one selected from the group consisting of bisulfite, sulfite, and pyrosulfite. The combination is based on the sulfite compound 10 to 50 parts by weight per 100 parts by weight of BHT.
A range of 0 parts by weight is preferred.

In practicing the present invention, when bisulfite, sulfite, or pyrosulfite is used as a stabilizer, the stabilizer may be added by dissolving it in purified water or may be added in the form of a powder.

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described more specifically with reference to the following examples.

Example 1 2 g of benzyl alcohol, 5 g of diisopropyl sebacate, 10 g of isopropyl myristate in 0.5 g of ketotifen,
5 g of polyoxyethylene (20) sorbitan monostearate (TS-10, manufactured by Nikko Chemicals) was added and dissolved by heating to 50 ° C. To this was added an aqueous phase in which 5 g of 1,3-butylene glycol and 0.2 g of methylparaben were dissolved at 50 ° C. in 65.88 g of purified water, and emulsified at 50 ° C. 0.8 g of carboxyvinyl polymer was added to this solution, and the mixture was stirred while cooling to room temperature.
Next, a solution prepared by dissolving 0.8 g of diisopropanolamine and 0.02 g of sodium bisulfite in 10 g of purified water was added to this solution, and the mixture was stirred until the mixture became uniform to obtain a cream formulation containing ketotifen.

Example 2 To 0.3 g of ketotifen, 2 g of crotamiton, 5 g of 2-octyldodecanol, 10 g of isopropyl myristate, and polyoxyethylene (20) sorbitan monostearate (TS-
10, 5 g of Nikko Chemicals) and 0.03 g of BHT were added and dissolved by heating to 70 ° C. To this was added an aqueous phase in which 5 g of 1,3-butylene glycol and 0.2 g of methylparaben were dissolved at 50 ° C. in 60.84 g of purified water, followed by emulsification at 50 ° C. 0.8 g of carboxyvinyl polymer was added to this solution, and the mixture was stirred while cooling to room temperature. Next, a solution prepared by dissolving 0.8 g of diisopropanolamine and 0.03 g of sodium bisulfite in 10 g of purified water was added to the solution, and the mixture was stirred until the mixture became uniform to obtain a cream formulation containing ketotifen.

Example 3 1.5 g of benzyl alcohol was added to 0.3 g of ketotifen,
Heated to ° C. to dissolve. White petrolatum 15g, cetostearyl alcohol 10g, polyoxyethylene (23)
Cetyl ether (BC-23, manufactured by Nikko Chemicals), BHT0.0
2 g and 3 g of liquid paraffin were added and dissolved by heating to 75 ° C. to obtain an oil phase. Separately, 60.86 g of purified water was heated to 75 ° C., and 0.3 g of methylparaben and 5 g of 1,3-butylene glycol were added and dissolved. This was added to the previous oil phase and stirred to emulsify. Next, 0.02 g of sodium bisulfite was added, and the mixture was further stirred and cooled to room temperature to obtain a cream formulation containing ketotifen.

Example 4 60 g of 1,3-butylene glycol was added to 0.2 g of ketotifen and 0.01 g of BHT and dissolved by heating to 70 ° C. To this solution, 39.77 g of purified water and 0.02 g of sodium pyrosulfite were added, and stirred to obtain a ketotifen-containing solution.

Example 5 4 g of crotamiton was added to 0.5 g of ketotifen and dissolved by heating to 70 ° C. 85.45 g of white petrolatum, 5 g of glyceryl monostearate, and 5 g of tallow were added thereto, and the mixture was heated to 70 ° C. and dissolved. While stirring this solution, add sodium bisulfite
0.05 g was added, and the mixture was cooled to room temperature with further stirring to obtain a ketotifen-containing ointment.

Example 6 2 g of diisopropyl sebacate and 0.5 g of ketotifen
50 g of 3-butylene glycol was added and dissolved by heating to 70 ° C. 0.7 g of carboxyvinyl polymer was added to purified water 3
The solution swollen to 6.27 g was added and stirred. Next, a solution prepared by dissolving 0.03 g of sodium hydrogen sulfite and 0.5 g of diisopropanolamine in 10 g of purified water was added and stirred to obtain a ketotifen-containing gel.

Example 7 0.3 g of ketotifen, 2 g of crotamiton, 5 g of 2-octyldodecanol, 5 g of isopropyl myristate, and polyoxyethylene (20) sorbitan monostearate (TS-1)
0, Nikko Chemicals) 5g, cholesterol 0.5g, BHT0.
03 g was added and heated to 70 ° C. to dissolve. To 66.74 g of purified water, 5 g of 1,3-butylene glycol and methyl paraben were added.
An aqueous phase in which 0.2 g was dissolved at 50 ° C. was added, and the mixture was stirred while cooling to room temperature. Next, a solution prepared by dissolving 0.2 g of diisopropanolamine and 0.03 g of sodium bisulfite in 10 g of purified water was added to the solution, and the mixture was stirred until the mixture became uniform to obtain a ketotifen-containing lotion.

Example 8 0.05 g of benzalkonium chloride and 2.5 g of chlorobutanol were added to 800 ml of distilled water and dissolved by heating. Then add 2.84 g of sodium dihydrogen phosphate and 5.6 g of disodium hydrogen phosphate
g, sodium bisulfite 0.2 g, and add distilled water
The volume was adjusted to 0 ml and filtered with a filter paper. This is autoclaved (120 ° C,
30 minutes) and stored. Next, 0.1 g of ketotifen / fumaric acid and 0.418 g of sodium chloride were dissolved in a part of this aqueous solution, and the total amount was made 100 ml with this aqueous solution, and the solution was filtered through a 0.22 μm membrane filter. Agent was obtained.

Comparative Example A 4 g of crotamiton was added to 0.5 g of ketotifen and dissolved by heating to 70 ° C. To this, 85.3 g of white petrolatum, 5 g of glyceryl monostearate, and 5 g of tallow were added and heated to 70 ° C. to dissolve. While stirring this solution, add sodium bisulfite
0.2 g was added, and the mixture was cooled to room temperature with further stirring to obtain a ketotifen-containing ointment.

Comparative Example B 30.5 parts by weight of styrene-isoprene-styrene block copolymer Califlex TR-1107 (manufactured by Shell Chemical), 18.0 parts by weight of liquid paraffin, and 46.0 parts by weight of Alcon P-85 (manufactured by Arakawa Chemical) as a tackifier were heated. Then, a mixture of 0.1 parts by weight of ketotifen / fumaric acid, 5.5 parts by weight of peppermint oil as an absorption promoter and 0.03 parts by weight of sodium bisulfite was added and mixed, and then the silicone-treated polyester film was added to a thickness of 10 parts.
It was spread to 0 μm, covered with an aluminum-evaporated nylon-polyester nonwoven fabric, pressure-transferred and cut into a desired size to obtain a ketotifen-containing tape preparation of the present invention. This tape preparation had a high release of the contained drug, had a very high bioavailability, and had no skin irritation.

Example 11 30.0 parts by weight of styrene-isoprene-styrene block copolymer Califrex TR-1107 (manufactured by Shell Chemical), 15.0 parts by weight of liquid paraffin, and 46 parts by weight of arcon (Arakawa Chemical) as a tackifier were heated and dissolved. Next, a solution prepared by dissolving 0.2 parts by weight of ketotifen and 0.02 parts by weight of sodium bisulfite in 5.0 parts by weight of mint oil as an absorption promoter was added and mixed, and then spread to a thickness of 100 μm on a PVC film laminated with a polyester film. Postpone,
It was covered with a silicone-treated polyester film and cut into a desired size to obtain a ketotifen-containing tape preparation of the present invention. This tape preparation also had excellent properties like the tape preparation of Example 10.

Example 12 22.5 parts by weight of styrene-isoprene-styrene block copolymer Califlex TR-1111 (manufactured by Shell Chemical), 35.5 parts by weight of liquid paraffin, and 34.5 parts by weight of YS-resin (manufactured by Yasuhara Yushi) as a tackifier were heated and dissolved. Then, 0.1 parts by weight of ketotifen and 5.0 parts by weight of mint oil as an absorption enhancer and 0.02 parts by weight of sodium bisulfite were added and mixed, and then the silicone-treated polyester film was adjusted to a thickness of 120 μm. , Covered with a polyethylene film, pressure-transferred, and cut into a desired size to obtain a ketotifen-containing tape preparation of the present invention. This tape preparation also had excellent properties like the tape preparation of Example 10.

Example 13 30.0 parts by weight of styrene-isoprene-styrene block copolymer Solprene 418 (manufactured by Philippe Petroleum), 20.0 parts by weight of liquid paraffin, and 36.0 parts by weight of Quinton (manufactured by Zeon Corporation) as a tackifier were heated and dissolved, and then ketotifen was dissolved. 0.3 parts by weight of fumaric acid, 0.3 parts by weight of mint oil as an absorption promoter and 0.02 sodium pyrosulfite
Parts by weight, and then spread on a polypropylene film so as to have a thickness of 80 μm, covered with a silicone-treated polyester film, and cut into a desired size to obtain a ketochain-containing tape preparation of the present invention. . This tape preparation also had excellent properties like the tape preparation of Example 10.

Comparative column 1 2 g of benzyl alcohol, 5 g of diisopropyl sebacate, 10 g of isopropyl myristate in 0.5 g of ketotifen,
5 g of polyoxyethylene (20) sorbitan monostearate (TS-10, manufactured by Nikko Chemicals) was added and dissolved by heating to 50 ° C. An aqueous phase obtained by dissolving 5 g of 1,3-butylene glycol and 0.2 g of methylparaben at 50 ° C. in 61 g of purified water was added thereto, and emulsified at 50 ° C. 0.8 g of carboxyvinyl polymer was added to this solution, and the mixture was stirred while cooling to room temperature. Next, 0.8 g of diisopropanolamine was added to this solution with purified water.
A solution dissolved in 10 g was added, and the mixture was stirred until it became uniform to obtain a ketotifen-containing cream formulation.

Comparative Example 2 Ketotifen 0.5 g, benzyl alcohol 2 g, diisopropyl sebacate 5 g, isopropyl myristate 10 g,
Add 5 g of polyoxyethylene (20) sorbitan monostearate (TS-10, manufactured by Nikko Chemicals) and 0.1 g of BHT, and add
Heated to ° C. to dissolve. An aqueous phase obtained by dissolving 5 g of 1,3-butylene glycol and 0.2 g of methylparaben at 50 ° C. in 61 g of purified water was added thereto, and emulsified at 50 ° C. 0.8 g of carboxyvinyl polymer was added to this solution, and the mixture was stirred while cooling to room temperature. Next, 0.8 g of diisopropanolamine was added to this solution.
Was dissolved in 10 g of purified water and stirred until uniform to obtain a cream formulation containing ketotifen.

Comparative Example 3 0.5 g of ketotifen, 2 g of benzyl alcohol, 5 g of diisopropyl sebacate, 10 g of isopropyl myristate,
5 g of polyoxyethylene (20) sorbitan monostearate (TS-10, manufactured by Nikko Chemicals) was added and dissolved by heating to 50 ° C. An aqueous phase obtained by dissolving 5 g of 1,3-butylene glycol and 0.2 g of methylparaben at 50 ° C. in 61 g of purified water was added thereto, and emulsified at 50 ° C. 0.8 g of carboxyvinyl polymer was added to this solution, and the mixture was stirred while cooling to room temperature. Next, a solution prepared by dissolving 0.8 g of diisopropanolamine and 0.2 g of sodium hydrogen sulfite in 10 g of purified water was added to the solution, and the mixture was stirred until the mixture became uniform to obtain a ketotifen-containing cream formulation.

Test Example 1 (Stability Test) The cream preparations of Examples 1 and 2 and Comparative Examples 1, 2, and 3 were filled in tubes and stored at 60 ° C., and changes in the appearance of the cream were observed. The results are shown in Table 1.

As is clear from the results in Table 1, the cream preparation of the present invention containing an appropriate amount of a stabilizer was superior in heat stability to the cream preparation of the comparative example.

INDUSTRIAL APPLICABILITY The preparation stably containing ketotifen or its fumarate obtained according to the present invention is stable even when stored for a long period of time, and has no change in coloration. It is also excellent in terms of safety because there is no generation.

From the above points, the external preparation of the present invention stably containing ketotifen or its fumarate is industrially very useful, for example, as a therapeutic agent for skin diseases such as dermatitis, eczema, atopic dermatitis and rash.

Continuation of the front page (56) References JP-A-1-121218 (JP, A) JP-A-62-164624 (JP, A) JP-A-62-223119 (JP, A) JP-A-61-275212 (JP, A) , A) JP-A-58-164508 (JP, A) JP-A-59-89621 (JP, A) Pharmaceutical Excipients Research Group, “Practical Pharmaceutical Additives”, Chemical Industry Co., Ltd., (1974), p. . 215-221 (58) Fields investigated (Int. Cl. ⁷ , DB name) A61K 31/445 A61K 47/04 A61K 47/10 A61K 9/107 A61K 9/06 A61K 9/08 A61K 9/70 CA (STN )

Claims (4)

(57) [Claims] 1. An external preparation containing 100 parts by weight of ketotifen or its fumarate as an active ingredient, comprising sodium bisulfite, potassium bisulfite, sodium sulfite, potassium sulfite, sodium pyrosulfite and potassium pyrosulfite as stabilizers. An external preparation for ketotifen comprising 2 to 20 parts by weight of at least one sulfite compound selected from the group. 2. The external preparation of ketotifen according to claim 1, wherein the dosage form is a cream. 3. The external preparation of ketotifen according to claim 1, further comprising dibutylhydroxytoluene as a stabilizer. 4. The external preparation for ketotifen according to claim 3, wherein the compounding amount of the sulfite compound is 10 to 500 parts by weight based on 100 parts by weight of dibutylhydroxytoluene.