JP2826905B2 - External ointment for skin - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to an ointment stably containing ketotifen or a fumarate thereof as an active ingredient. More specifically, an ointment containing ketotifen formulated in an oral preparation as an antiallergic agent, which is useful as a therapeutic agent for dermatitis, eczema, atopic eczema, rash and other dermatological fields. About.

[Background Art] Ketotifen fumarate [Chemical name: 4- (1-methyl-4-piperidylidene) -4H-benzo [4,5] cyclohepta [1,2-b] thiophene-10H (9H) -one. Fumaric acid] is a drug having a wide range of antiallergic actions such as antihistamine action and anti-SRS-A action, and is currently widely used as an oral preparation.

Prior art ointments containing ketotifen or a fumarate thereof are disclosed in JP-A-51-32724 and JP-A-5-32724.
1-142543, JP-A-57-181007, JP-A-60
-190710, JP-A-62-164624, JP-A-62-164624
223119, JP-A-1-102024, JP-A-1-12
JP-A No. 1218 and JP-A-1-202338.

However, none of these has been sufficiently considered in terms of stability. Among them, JP-A-51-32724 discloses an ointment containing an anionic surfactant or an amphoteric surfactant as a surfactant, and a liquid higher alcohol as a main base. However, in this case, the stability of ketotifen or its fumarate salt is not sufficient, and skin irritation by a surfactant or a higher alcohol may be considered.

As a dermatological drug for treating pathological skin such as atopic dermatitis and eczema, it is not preferable to incorporate a large amount of an ionic surfactant or a higher alcohol which is considered to be highly irritating. Further, JP-A-1-102024 and the like describe ointments and creams in which the pH is adjusted to basic with a basic base, but ketotifen or its fumarate salt is easily decomposed significantly when the pH is increased. Therefore, they inevitably suffer from degradation of ketotifen or its fumarate and coloring of the cream over time. In the case of an ointment containing water, ketotifen or its fumarate salt is further degraded, which is not suitable as a preparation. Japanese Unexamined Patent Publication (Kokai) No. 1-213876 discloses a proposal for improving the stability, in which bisulfite, sulfite, pyrosulfite, and dibutylhydroxytoluene are blended as a stabilizer for ketotifen or its fumarate. is there. Since all of these stabilizers are water-soluble, creams and gels are effective for formulations containing water, but ointments containing ketotifen or its fumarate in an oily ointment base. In the case of the agent, the coloring prevention effect was hardly observed.

Ketotifen or its fumarate salt is relatively stable when stored alone, but ketotifen is susceptible to oxidation reactions, etc., and when it is added to an ointment, it reacts with the base component and degrades over time. The waking content was reduced and the coloring changed. In particular, when the above general surfactant is blended as a dispersant, the color change of the ointment is large,
The stability of ketotifen or its fumarate could not be preserved. In addition, when ketotifen or its fumarate salt was simply blended into an ointment base such as white petrolatum or plastibase, there was a problem that the coloration change was small, but the dispersion was poor, and the quantitative value was largely varied, so that the product was not produced. . When a liquid component or the like is added to further improve the dispersibility or to improve the stickiness of the ointment, the physical properties deteriorate over time, and the dispersibility of ketotifen or its fumarate salt worsens, and the liquid component exudes. There was a problem that occurs.

DISCLOSURE OF THE INVENTION An object of the present invention is to stably blend ketotifen or its fumarate with time, and to have excellent dispersibility thereof,
It is an object of the present invention to obtain an ointment having excellent stability of physical properties without exudation.

The present inventors have conducted intensive studies on a stable ointment containing ketotifen or its fumarate,
In ointments containing ketotifen or its fumarate, HLB (hydrophile-lypohile-balance) is used as a dispersant.
The abbreviation) has been found that an ointment containing a specific surfactant having a value of 4.5 or less can solve the above-mentioned object at once, and completed the present invention.

That is, the present invention relates to ketotifen or fumarate salt thereof as an active ingredient of 0.02 to 1% by weight, and a surfactant having an HLB value of 4.5 or less, sorbitan sesquistearate, sorbitan distearate, sorbitan tristearate or glyceryl monostearate. Dispersant 1 to be selected
Ointment for external use on skin, characterized by containing 20% by weight and 70-95% by weight of white petrolatum.

Surfactants formulated as dispersants in the present invention are HLB
It is appropriately selected from sorbitan sesquistearate, sorbitan distearate, sorbitan tristearate and glyceryl monostearate having a value of 4.5 or less. Although the HLB value of these surfactants is 4.5 or less, especially HLB 3.5
The following sorbitan tristearate or glyceryl monostearate are preferred. When the HLB value is larger than 4.5, the ointment is colored with time, and the effect of the present invention cannot be obtained. These surfactants stabilize ketotifen or its fumarate, prevent coloring of the ointment over time, improve the dispersibility of ketotifen or fumarate in the ointment, and improve the physical properties of the ointment over time. Has a stability effect and the like. These surfactants may be used alone or in combination of two or more kinds.

The composition of the ointment of the present invention comprises ketotifen or its fumarate in an amount of 0.02 to 1% by weight, preferably 0.05 to 0.5% by weight, and a sorbitan sesquistearate, a sorbitan distearate and a sorbitan tristearate having an HLB value of 4.5 or less of a surfactant. It consists of 1 to 20% by weight, preferably 3 to 15% by weight, of a dispersant selected from stearates or glyceryl monostearate, 70 to 95% by weight of white petrolatum, preferably 85 to 95% by weight. When the amount of the surfactant, which is a dispersant, is less than 1% by weight, there is no stabilizing effect, the dispersibility of the ointment base of ketotifen or its fumarate is poor, and the ointment is removed with time. Baring occurs. If it exceeds 20% by weight, the ointment becomes hard and the feeling of use is poor.

The ointment of the present invention may contain, in addition to the essential components described above, a base component that is usually added to an oily ointment. Examples of such are liquid paraffin,
And liquid hydrocarbons such as squalane and liquid isoparaffin. These liquid hydrocarbons are blended for the purpose of improving the feeling of use, dispersibility of ketotifen or its fumarate, etc., and the blending amount thereof is 10% by weight or less,
Preferably, 0.5 to 7% by weight is blended. In addition, methyl paraben, propyl paraben, butyl paraben,
Preservatives such as isopropylmethylphenol, silicone oils such as methylpolysiloxane and methylphenylpolysiloxane, and powders such as talc, styrene powder and silicon powder can be blended.

Next, the production method of the present invention will be described. In order to produce the ointment of the present invention, white petrolatum and a surfactant are dissolved by heating, ketotifen or a fumarate thereof is added thereto while stirring and cooling, and further cooled to room temperature while stirring.

The ointment containing ketotifen or its fumarate obtained in the present invention contains ketotifen uniformly, and there is no variation in ketotifen in the ointment. Moreover, even if stored for a long period of time, ketotifen is not decomposed and is stable, and there is no change in coloring of the ointment, so that commercial value is maintained. Further, since there is no generation of decomposed substances and the like, there is an effect that it is excellent also in terms of safety.

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

Example 1 Ingredients Weight (%) Ketotifen / Fumarate 0.1 Sorbitan tristearate 5.0 [Nikko Chemicals: SS-30 (HLB = 2.1)] Squalane 3.0 White petrolatum 91.9 100.0 White petrolatum, sorbitan tristearate and 80 % squalane Heated to ° C. to dissolve. The dissolution was cooled with stirring, ketotifen / fumarate was added at 60 ° C., and the mixture was cooled with stirring to room temperature to obtain an antiallergic external ointment.

Example 2 Component Weight (%) Ketotifen / Fumarate 0.3 Sorbitan Tristearate 5.0 [Nikko Chemicals: SS-30 (HLB = 2.1)] Liquid paraffin 3.0 Methylpolysiloxane 0.3 White Vaseline 91.4 100.0 White Vaseline, Sorbitan Tristea The rate, liquid paraffin, and methylpolysiloxane were heated to 80 ° C. and dissolved. The solution was cooled with stirring, ketotifen / fumarate was added at 60 ° C, and further cooled to room temperature with stirring to obtain an antiallergic external ointment.

Example 3 Component Weight (%) Ketotifen / Fumarate 0.2 Sorbitan sesquistearate 5.0 [Nikko Chemicals: SS-30 (HLB = 4.2)] Liquid paraffin 3.0 White petrolatum 91.8 100.0 White petrolatum, Sorbitan sesquistearate, Liquid paraffin Was heated to 80 ° C. to dissolve. The dissolution was cooled with stirring, ketotifen / fumarate was added at 60 ° C., and the mixture was cooled with stirring to room temperature to obtain an antiallergic external ointment.

Example 4 Component Weight (%) Ketotifen / Fumarate 0.2 Glyceryl monostearate 5.0 [Nikko Chemicals: MSG-B (HLB = 3.0)] Liquid paraffin 3.0 White petrolatum 91.8 100.0 White petrolatum, glyceryl monostearate, liquid paraffin Was heated to 80 ° C. to dissolve. This solution was cooled with stirring, and ketotifen / fumarate was added at 60 ° C.
The mixture was further cooled while stirring to room temperature to obtain an antiallergic external ointment.

Example 5 Component Weight (%) Ketotifen / Fumarate 0.2 Sorbitan Tristearate 5.0 [Nikko Chemicals: SS-30 (HLB = 2.1)] Squalane 3.0 Methylpolysiloxane 0.2 White Vaseline 91.6 100.0 White Vaseline, Sorbitan Tristearate , Squalane and methylpolysiloxane were heated to 80 ° C. and dissolved.
This solution is cooled with stirring, and ketotifen
The fumarate was added, and the mixture was cooled with stirring to room temperature to obtain an antiallergic external ointment.

Example 6 Component Weight (%) Ketotifen / Fumarate 0.3 Sorbitan Tristearate 5.0 [Nikko Chemicals: SS-30 (HLB = 2.1)] Liquid paraffin 3.0 Talc 1.0 White petrolatum 90.7 100.0 White petrolatum, sorbitan tristearate, The liquid paraffin was heated and dissolved at 80 ° C. This solution was cooled with stirring, ketotifen / fumarate and talc were added at 60 ° C, and further cooled to room temperature with stirring to obtain an antiallergic external ointment.

Example 7 Component Weight (%) Ketotifen Fumarate 0.5 Sorbitan Tristearate 3.0 [Nikko Chemicals: SS-30 (HLB = 2.1)] Liquid Paraffin 3.0 Fine Pearl 3.0 White Vaseline 90.5 100.0 White Vaseline, Sorbitan Tristearate The liquid paraffin was heated to 80 ° C. and dissolved. This solution was cooled with stirring, ketotifen / fumarate and fine pearl were added at 60 ° C., and further cooled to room temperature with stirring to obtain an antiallergic external ointment.

Example 8 Ingredients Weight (%) Ketotifen 0.1 Glyceryl monostearate 7.0 [Nikko Chemicals: MGS-F75 (HLB = 1.5)] Methyl polysiloxane 0.5 White petrolatum 92.4 100.0 White petrolatum, glyceryl monostearate and methyl polysiloxane were 80 Heated to ℃ to dissolve. The solution was cooled with stirring, ketotifen was added at 60 ° C, and further cooled to room temperature with stirring to obtain an antiallergic external ointment.

Example 9 Ingredient Weight (%) Ketotifen / Fumarate 0.1 Sorbitan Tristearate 6.0 [Nikko Chemicals: SS-30 (HLB = 2.1)] Microcrystalline Wax 3.0 Liquid Paraffin 2.0 White Vaseline 88.9 100.0 White Vaseline, Sorbitan Tristea The rate, microcrystalline wax, and liquid paraffin were heated to 80 ° C. and dissolved. The solution was cooled with stirring, ketotifen / fumarate was added at 75 ° C., and further cooled to room temperature with stirring to obtain an antiallergic external ointment.

Example 10 Ingredients Weight (%) Ketotifen / Fumarate 0.1 Sorbitan tristearate 15.0 [Nikko Chemicals: SS-30 (HLB = 2.1)] Squalane 4.0 White petrolatum 80.9 100.0 White petrolatum, sorbitan tristearate and 80 % squalane Heated to ℃ to dissolve. The solution was cooled with stirring, ketotifen / fumarate was added at 70 ° C., and further cooled to room temperature with stirring to obtain an antiallergic external ointment.

Comparative Example 1 Component Weight (%) Ketotifen / Fumarate 0.1 Liquid paraffin 3.0 White petrolatum 96.9 100.0 White petrolatum and liquid paraffin were heated to 80 ° C. and dissolved. The dissolution was cooled with stirring, ketotifen / fumarate was added at 60 ° C., and the mixture was cooled with stirring to room temperature to obtain an antiallergic external ointment.

Comparative Example 2 Ingredient Weight (%) Ketotifen / Fumarate 0.2 Wax 5.0 Liquid Paraffin 3.0 White Vaseline 91.8 100.0 White Vaseline, wax and liquid paraffin were heated to 80 ° C. and dissolved. The dissolution was cooled with stirring, ketotifen / fumarate was added at 60 ° C., and the mixture was cooled with stirring to room temperature to obtain an antiallergic external ointment.

Comparative Example 3 Component Weight (%) Ketotifen / Fumarate 0.1 Sorbitan monooleate 5.0 [Nikko Chemicals: SO-30 (HLB = 1.7)] Liquid paraffin 3.0 White petrolatum 91.9 100.0 White petrolatum, sorbitan monooleate, Liquid paraffin Was heated to 80 ° C. to dissolve. The dissolution was cooled with stirring, ketotifen / fumarate was added at 60 ° C., and the mixture was cooled with stirring to room temperature to obtain an antiallergic external ointment.

Comparative Example 4 Component Weight (%) Ketotifen / Fumarate 0.1 Polyoxyethylene (2) monostearate 5.0 [Nikko Chemicals: MYS-2 (HLB = 4.0)] Liquid paraffin 3.0 White petrolatum 91.9 100.0 White petrolatum, polyoxy Ethylene (2) monostearate and liquid paraffin were heated to 80 ° C. and dissolved. The dissolution was cooled with stirring, ketotifen / fumarate was added at 60 ° C., and the mixture was cooled with stirring to room temperature to obtain an antiallergic external ointment.

Comparative Example 5 Component Weight (%) Ketotifen / Fumarate 0.2 Diglyceryl monoisostearate 5.0 [Nikko Chemicals: DGMIS-30 (HLB = 5.5)] Liquid paraffin 3.0 White petrolatum 91.8 100.0 White petrolatum, diglyceryl monoisostearate rate,
The liquid paraffin was heated and dissolved at 80 ° C. The dissolution was cooled with stirring, ketotifen / fumarate was added at 60 ° C., and the mixture was cooled with stirring to room temperature to obtain an antiallergic external ointment.

Comparative Example 6 Component Weight (%) Ketotifen / Fumarate 0.2 Plastibase 99.8 100.0 Ketotifen / Fumarate was added to Plastibase,
The mixture was stirred to obtain an antiallergic topical ointment.

Comparative Example 7 Component Weight (%) Ketotifen / Fumarate 0.2 Sorbitan Monostearate 5.0 [Nikko Chemicals: SS-10 (HLB = 4.7)] Liquid Paraffin 3.0 White Vaseline 91.8 100.0 White Vaseline, Sorbitan Monostearate, Liquid Paraffin Was heated to 80 ° C. to dissolve. This solution was cooled with stirring, and ketotifen / fumarate was added at 60 ° C.
The mixture was further cooled while stirring to room temperature to obtain an antiallergic external ointment.

Test Example 1 (Stability Test of Physical Properties) The ointments of Examples 1 to 10 and Comparative Examples 3 to 5 and 7 were filled in an aluminum tube, and stored at 50 ° C to observe the coloring state of the ointment. The test results are shown in Table 1.

As can be seen from the results in Table 1, the ointments of Examples 1 to 10
There was no color change over time, and it was stable. On the other hand, Comparative Example 3
The ointments represented by Nos. 5 and 7 were colored over time. Therefore, the ointment shown in the examples can be said to be an ointment containing ketotifen or fumarate more stably than the conventional ointment.

Test Example 2 (Drug stability test) The ointments of Examples 1 to 3, 9 to 10 and Comparative Examples 1, 3, and 5 were filled in aluminum tubes, stored at 40 ° C, and the remaining ketotifen was determined by HPLC. The amount was measured. The results are shown in Table 2.

As can be seen from the results in Table 2, Examples 1-3 and 9-
The ointment of No. 10 was excellent in the stability of ketotifen, but the ointments of Comparative Examples 1, 3, and 5 were inferior in stability, and the quantitative values varied. This indicates that the specific surfactant incorporated as a dispersant in the present invention has an excellent effect as a ketotifen dispersant and a ketotifen stabilizer.

Test Example 3 (Dispersibility of Ketotifen) In order to examine the dispersibility of ketotifen in an ointment, the ointments of Examples 1 to 3 and 9 and Comparative Examples 1 to 2 and 6 were quantified. The results are shown in Table 3.

As can be seen from the results in Table 3, the ointments of Examples 1 to 3 and 9 in which specific surfactants were blended had no problem in quantitative values, but the ointments of Comparative Examples 1 to 2 and 6 Was abnormal in quantitative value, and the coefficient of variation was large.

[Industrial application] From the above points, the skin external preparation of the present invention containing ketotifen is industrially very useful as a therapeutic agent for dermatitis, eczema, atopic dermatitis, rash and the like.

──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor, Kazuichi Nakajima 408, Tashiro Daigakucho, Tosu City, Saga Prefecture Hisamitsu Pharmaceutical Co., Ltd. (58) Field surveyed (Int. Cl. ⁶ , DB name) A61K 31/445 A61K 9/06 A61K 47/14 CA (STN)

Claims (1)

(57) [Claims] 1. An active ingredient comprising ketotifen or its fumarate in an amount of 0.02 to 1% by weight and a surfactant having an HLB value of 4.5 or less, sorbitan sesquistearate, sorbitan distearate, sorbitan tristearate or glyceryl monostearate. An ointment for external use on the skin, comprising 1 to 20% by weight of a selected dispersant and 70 to 95% by weight of white petrolatum.