JP2848529B2 - External preparation - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial application] The present invention relates to an external preparation for the treatment of skin diseases, and more specifically, the following formula (I) having a granulation formation promoting action and an anti-ulcer action: An external preparation containing an α-tocopherol vitamin A acid ester represented by the following formula as an active ingredient:

The present invention also relates to a drug substance capable of facilitating the handling of the α-tocopherol vitamin A ester represented by the formula (I) and preparing an external preparation without deteriorating the stability.

[Conventional Technology and Problems] The α-tocopherol vitamin A ester represented by the formula (I) is a known compound whose chemical name is tocopheryl retinoate (hereinafter referred to as tocopheryl retinoate). (Japanese Patent Publication No. 49-26632). This formula (I)
The tocopheryl retinoate (hereinafter sometimes referred to as compound (I)) represented by the formula (1) has an antiulcer effect, and has been proposed to be applied to a drug for treating gastrointestinal ulcer (Japanese Patent Publication No. 60-1985).
26770) Further, in view of expecting an effect of preventing skin deterioration, use as a component of cosmetics has been proposed (JP-A-51-17313).
7).

Also, a therapeutic agent for skin diseases containing compound (I) as an active ingredient has been proposed (JP-A-61-207332).

The dosage form of compound (I) as an external preparation in JP-A-61-207332 can be in the form of ointments, lotions, liniments or aerosols. The pharmacologic and widely used methods that are in place are used. For example, in the production of ointments, oily substances such as liquid paraffin, petrolatum, silicone oil, higher aliphatic alcohols, higher fatty acids, fatty acid esters, vegetable oil, castor oil, lanolin and its derivatives, squalene, squalane, etc. Emulsifiers and dispersants such as polyhydric alcohol ester type nonionic surfactants, polyoxyethylene-based nonionic surfactants and the like; wetting agents such as glycerin, propylene glycol, sorbite, amino acids and the like; stabilizers such as antioxidants, Preservatives and the like; those which are appropriately selected from others, for example, polyethylene glycol, polyethylene, suspending agents and the like, are used in combination with compound (I), and are subjected to steps such as mixing, emulsifying, and dispersing each component. .

The present inventors have been keenly pursuing the development of a practical external preparation for the treatment of skin diseases which is clinically applicable to compound (I). I have found that it is difficult to formulate an external preparation that exhibits a desired therapeutic effect clinically with the formulation technology. For example, since compound (I) is a viscous substance, it is difficult to handle by weighing or the like at the time of adjusting the content. In addition, when formulating the compound, a heating operation is performed to lower the viscosity of compound (I) itself. After that, it is necessary to carry out usual formulation techniques. However, since compound (I) has a low chemical stability and has a property of being easily oxidized and decomposed, tocopheryl retinoate is changed by a high temperature operation in the formulation process, and the initial purpose in the formulation is changed. It is difficult to effectively secure the concentration of the compound (I).

Therefore, development of a more effective formulation technique has been desired.

In preparing an external preparation containing Compound (I), if the present invention can provide a drug substance in which the viscosity of Compound (I) itself has been reduced in advance, the present inventors have proposed a method for preparing an external preparation. It was conceived that a high-temperature operation that would cause isomerization and oxidative decomposition of the compound (I) was not required, and the chemical stability of the compound (I) could be ensured.

From such a viewpoint, the present inventors have studied the preparation of a low-viscosity drug substance containing compound (I) which is easy to handle and stably. The preparation of an external preparation which was not irritating to the irritated skin and could most effectively exhibit the medicinal properties of the compound (I) was examined.

The present inventors have paid attention to the fact that compound (I) has a property of being soluble well in an appropriate organic solvent such as ethyl acetate, chloroform, cyclohexane, acetone or animal or vegetable oils. A method for preparing a drug substance having a low viscosity by dissolving it was studied. However, in such a method, although a desired low-viscosity drug substance can be obtained, in the case of using an organic solvent, toxicity and skin irritation are problematic as well as its residual concentration when formulated as an external preparation. And could not be a clinically applicable formulation. In addition, even when animal and vegetable oils were used, the drug substance itself became rancid over time, and as a result, the stability of the drug substance itself was lacking, and it could not be a desirable drug.

Therefore, as a result of studying the above-mentioned organic solvent or a solvent for drug substance in place of animal and vegetable oils, a compounding formula comprising compounding compound (I) with an oily raw material and further compounding especially dibutylhydroxytoluene as an antioxidant was proposed. The present invention was found to be a drug substance satisfying the above conditions, and the present invention was completed. In addition, the present inventors, as a basic formulation of this drug substance, ointments, creams, when used as an external preparation such as a lotion, especially for external preparations in the form of a cream, pressure sores, burns, It has been confirmed that the composition is an effective external preparation as a therapeutic agent for skin diseases such as wounds, and the present invention has been completed.

[Constitution of the Invention] The first object of the present invention is to provide a drug substance which stably contains tocopheryl retinoate and which significantly facilitates preparation of an external preparation. A. Based on the total weight of the drug substance (a) The following formula (I): Α-tocopherol vitamin A acid ester represented by 2.
0 to 40.0% by weight, (b) 0.01 to 5.0% by weight of dibutylhydroxytoluene, and (c) an oily raw material.

A second object of the present invention is to provide an external preparation for the treatment of skin diseases, and more specifically, based on the total weight of the preparation: (a) α-tocopherol vitamin A acid ester of the formula (I) from 0.05 to 0.05; 5.0% by weight, (b) 0.002 to 0.2% by weight of dibutylhydroxytoluene, and (c) an external preparation for the treatment of skin diseases comprising at least an oily material.

In this case, the external preparation for skin disease treatment is desirably prepared using the original preparation for external use provided as described above.

As the external preparation, an external preparation for treating skin diseases, which is in any form of an ointment, a cream or a lotion, is provided.

Examples of the ointment containing the compound (I) include: B. based on the total weight of the preparation; (a) 0.05 to 5.0% by weight of the compound (I), (b) dibutylhydroxytoluene, and (c) An ointment containing an oily raw material is provided.

In addition, creams containing compound (I) include:
Specifically: C. based on the total weight of the preparation; (a) 0.05 to 5.0% by weight of compound (I), (b) dibutylhydroxytoluene, (c) oily raw material, (d) oil, (e) wax, There is provided a cream comprising (f) a surfactant and (g) water.

Examples of the lotion containing the compound (I) include: D. based on the total weight of the preparation: (a) 0.05 to 5.0% by weight of the compound (I), (b) dibutylhydroxytoluene, (c) The present invention provides a lotion comprising an oily raw material, (d) oil, (e) wax, (f) surfactant, and (g) water.

[Action] As described above, the compound (I) compounded in the external preparation of the present invention is called a tocopheryl retinoate, and its therapeutic agent for gastrointestinal ulcer is considered to have a granulation formation promoting action and an anti-ulcer action. In view of the effect of preventing skin deterioration, application as a component of cosmetics has been attempted, and provision of the composition as a therapeutic agent for skin diseases has recently been studied.

 The physical properties of compound (I) are described below.

Compound (I) is a clear yellow viscous substance which has no or slightly unique odor and is unstable to light and air. In addition, it is slightly soluble in ethanol and slightly soluble in methanol. Almost insoluble in water. Compound (I) is well miscible with organic solvents such as ethyl acetate, chloroform, cyclohexane and acetone, and vegetable oils such as soybean oil and sesame oil, but it is not advisable to formulate these as solvents as described above. . In the method of directly mixing the compound (I) with a suitable base material for cosmetics and converting it into an external preparation, when a high-temperature operation is performed to reduce the viscosity of the compound (I), the compound as the main drug is heated by the heat. Since oxidative decomposition of (I) is apt to occur and the target concentration cannot be secured, it is difficult to formulate a preparation as a therapeutic agent for skin diseases by this method.

BACKGROUND ART Conventionally, many external preparations for treating skin diseases having a granulation formation promoting effect have been proposed for the purpose of treating skin ulcers such as burns and pressure ulcers or skin diseases based on frost acne, wounds and the like. The pharmacological effect of these external preparations is that the drug contained as an active ingredient possesses a new skin tissue on the skin ulcer surface due to the anti-ulcer action, anti-keratinizing action or wound healing promoting action, etc. Ointments dominate the formulation.

In general, skin changes due to pressure ulcers, burns, etc. correspond to blisters, plaques, ulcers, erosions, etc.From the viewpoint of treatment for these primary rashes, oil-based ointment bases and emulsion ointment bases are considered. This is because those in the form of an ointment based on a base or a water-soluble ointment base are considered preferable. These three types of ointments have not only the therapeutic effect of the active ingredient blended therein, but also the specific effect of the base used itself. The properties basically have the effect of removing crusts with the softening of the skin and promoting the formation of the epidermis. There are two types of emulsion ointment bases: O / W type hydrophilic ointment and W / O type water-absorbing ointment, all of which are used for dry skin diseases. When applied to moist diseases, i.e., blisters, erosions, ulcers, etc., it absorbs exudates and has the disadvantage of exacerbating the symptoms, but has the advantage of excellent penetration into deep ulcers . On the other hand, the water-soluble ointment base is different from the hydrophilic ointment in that it has higher water solubility and water absorption than the emulsion ointment, so it is used for wet surfaces such as blisters and erosions, absorbs moisture and secretions, and dries the lesion. Although it has an effect, it is often observed that the water absorption is too strong and the lesion surface is too dry, causing cracks and worsening the symptoms.

Therefore, even in the category of skin disease treatment external preparation,
Various types of external preparations are used depending on the indication, and the granulation formation-promoting action and anti-ulcer action of compound (I) can be effectively taken into consideration while taking into account the characteristics of the base as described above. When a formulation as an external preparation for treating skin diseases to be exerted is planned, it is considered that it is better to examine a preparation that can prepare various types of external preparations.

From the above viewpoints, the present inventors have studied the formulation of a drug substance capable of preparing an external preparation containing the compound (I) as an active ingredient. As a result, the drug substance for external use was prepared based on the basic formula as described above. Has newly found that it is extremely effective as a drug substance capable of preparing various kinds of desired external preparations. In addition, such a drug substance formulation can be applied not only to ointments but also to creams or lotions.

Accordingly, the present invention relates to a drug substance containing Compound (I) and an external preparation based on the drug substance formulation. According to the present invention, compound (I) is dissolved in an oily raw material, and further compounded with dibutylhydroxytoluene (hereinafter sometimes referred to as BHT) as an antioxidant. This provided an effective means for making it possible to formulate an external preparation without impairing the properties.

 As the oily raw material, a pharmaceutically acceptable liquid paraffin is used.
Quince, squalane, squalene, medium-chain triglyceride
Lido, isopropyl palmitate, isopromyristate
Pill, octyldodecyl myristate, etc.
But the polar state of compound (I) (almost non-polar)
Liquid paraffin that matches
No. Also, liquid paraffin is disclosed in the above-mentioned JP-A-61-2073.
Low molecular weight compared to liquid paraffin disclosed in No. 32
Light liquid paraffin which is an amount component is particularly preferable,
Mixing compound (I) which is viscous due to its low viscosity
When used, lowers the viscosity of compound (I) and makes handling easier
It can be. Made of this soft liquid paraffin
As a product, causes irritation when applied clinically
Morescoby, a high-purity product with low contamination of unsaturated substances
Ores (Matsumura Sekiyu) is appropriate.

In addition, since compound (I) is easily decomposed by light or heat, stability is particularly excellent by adding dibutylhydroxytoluene, butylhydroxyanisole, dl-α-tocopherol, and especially dibutylhydroxytoluene as an antioxidant. Can be maintained.

Therefore, the present invention is characterized by the formulation of tocopheryl retinoate-oil-based raw material, preferably light liquid paraffin-dibutylhydroxytoluene, and such a combination causes physical problems that may cause problems when formulating compound (I) as an external preparation. Properties and chemistry have been resolved. By using the obtained drug substance, it is easy to formulate it into an ointment, cream or lotion as described below, and it has become possible to develop a cream for treating dermatological diseases which is particularly useful clinically.

Hereinafter, an external preparation in the form of a drug substance, an ointment, a cream, or a lotion containing the compound (I) will be described.

A. Drug substance The drug substance of the present invention is based on the total weight of the drug substance; (a) 2 to 40% by weight, preferably 10% by weight of compound (I)
To 35% by weight, more preferably 20 to 30% by weight, (b) 0.01 to 5.0% by weight of dibutylhydroxytoluene
%, Preferably 0.05 to 4.0% by weight, more preferably
0.07 to 2.0% by weight, and (c) light liquid paraffin, squalane, squalene,
Medium chain fatty acid triglyceride, isopropyl palmitate
Isopropyl myristate, octyl myristate
Oily raw materials such as dodecyl, preferably light liquid paraffin
(Moresco Bioless : Matsumura Sekiyu).

 Light flow used in the preparation of the drug substance of the present invention
Paraffin is a drug substance listed in the Japanese Pharmacopoeia.
Compared with liquid paraffin listed in the
With low carbon atoms in hydrocarbon compounds contained in
is there. Among them, high purity and low skin irritation
(Moresco Bioless : Matsumura Oil)
Is done. As an antioxidant, for example, dibutyl hydroxy
Ruene (BHT), butylhydroxyanisole, dl-α
-Mention may be made of antioxidants such as tocopherol
However, BHT is particularly preferred in terms of antioxidant power, hypoallergenicity, etc.
In the range of 0.01 to 5.0% by weight (compound of compound (I)
The amount of compound (I)
Stability is guaranteed.

The compounding amount of the compound (I) in the drug substance of the present invention is as follows:
When the obtained drug substance is formulated into a target external preparation for the treatment of skin diseases, the drug substance is used in an amount sufficient to exert a sufficient effect, and is applied to the target drug substance. It is necessary to be able to do so, and as a result of the study of the present inventors, it has been found that the above-mentioned compounding amount is preferable.

As described above, the drug substance to be provided by the present invention is composed of a compounding formula of compound (I) -BHT-oil-based raw material, preferably light liquid paraffin. The original drug formulation, whose properties are ensured, is excellent in handling, so the ointment described below,
This facilitated the study of formulation into creams or lotions and enabled the realization of creams that are particularly clinically useful.

A second object of the present invention is to provide an ointment, cream or lotion which is an external preparation for the treatment of skin diseases. In preparing these preparations, the preparations prepared as described above are used. It is preferred to use the drug substance.

In this case, the compounding amount of the drug substance obtained in the above-mentioned A used for the preparation of the compound (I) in the preparation of the compound (I) in which the target preparation exhibits an effective effect as a therapeutic agent for skin diseases Determined by the content. According to the study of the present inventors, compound (I) contains 0.05 to 5.0% by weight, preferably 0.1 to 5.0% by weight, based on the total weight of the preparation, in view of the granulation formation promoting action and the anti-ulcer action possessed by compound (I) itself.
It has been found that a sufficient effect can be exerted if an amount corresponding to 3.0% by weight, more preferably 0.2 to 1.0% by weight is added. Therefore, in the following description, the drug substance obtained in the above-mentioned A is used as a basic prescription, and the conversion amount is described as the amount of the compound (I) contained in the drug substance.

In the preparation of the following specific preparations, it is sufficient that the compounding amount of each target component is secured, and it is not necessary to use the drug substance itself obtained in the above A. Needless to say.

B. Ointment The ointment of the present invention is based on the total weight of the preparation.
A preparation comprising 0.05 to 5.0% by weight, preferably 0.1 to 3.0% by weight, more preferably 0.2 to 1.0% by weight, and (b) the remainder containing oil or a water-soluble polymer compound, preferably white petrolatum or macrogol. It is.

In this case, the ointment provided as described above is basically composed of lipophilic ointment (hydrophobic ointment) or hydrophilic ointment.
There are various types and ointments of different types, and it is preferable to use white petrolatum as the oil when a hydrophobic ointment is desired and to use macrogol when a hydrophilic ointment is desired. In the case of macrogol, its consistency can be adjusted by mixing macrogol 400, macrogol 4000 and the like in appropriate amounts.

As described above, a hydrophobic or hydrophilic ointment containing the desired compound (I) stably can be prepared. The vaseline-based or macrogol-based ointment prepared as described above is a very good preparation having no skin irritation and excellent affinity.

C. Cream The cream according to the present invention is prepared by: (a) using the drug substance obtained in the above A as the compound (I)
0.05 to 5.0% by weight, preferably 0.1 to 3.0% by weight, more preferably 0.2 to 1.0% by weight, (b) wax, 1 to 20% by weight, (c) 1 to 25% by weight of oil, (d) surfactant 0 To 10% by weight, and (e) residual water.

As the cream of the present invention, an embodiment of a cream in which the preparation is an oil-in-water (O / W) is particularly preferable. As the wax, a wax such as a self-emulsifying wax, a spermaceti wax, a mocrow, and a beeswax wax are used. In the case of using a self-emulsifying type wax (Polawax GP-200), since this itself has a surface activity,
No additional surfactant is required. In addition, as the oil, fatty acid esters such as isopropyl myristate, octyldodecyl myristate, and isopropyl palmitate are preferable, and one or a combination of two or more of them can be added. The above oil may be used in an amount sufficient to achieve its purpose, and is usually added in the range of 1 to 25% by weight based on the total amount of the cream. Further, as the surfactant, a nonionic surfactant is preferable, and one or more of Spans and Tweens are combined. The compounding amount may be sufficient to achieve the purpose, and is 0% based on the total weight of the cream.
To 10% by weight.

In the cream of the present invention, basically, the aforementioned A
Although it is composed of the obtained drug substance-wax-oil-surfactant-water, the components to be added to ordinary creams, that is, humectants, preservatives and the like can be appropriately added.

As described above, various O / W creams containing the desired compound (I) stably can be prepared. In addition, this combination formula shows a specific drug effect that is not seen in other external preparations that dissolves hematoma generated in pressure ulcer when applied to the pressure ulcer surface, and the compound is applied only to the diseased site It is a preparation that can release (I) favorably.

It was also found that among these O / W creams, those having a particularly high water content were excellent in the above-mentioned effects.

D. Lotion The lotion according to the present invention is: (a) 0.05 to 5.0% by weight, preferably 0.1 to 3.0% by weight of the drug substance obtained in the above A as compound (I), More preferably, it is a lotion composition comprising 0.2 to 1.0% by weight, (b) 1 to 10% by weight of a wax, (c) oil, 0.1 to 2% by weight, and (b) a balance of water. When physical properties are taken into consideration, the form of an emulsion lotion is preferred.

As the wax, a self-emulsifying wax (Polawax GP-200) is preferably used, and Polawax GP-2 is used.
A sufficient emulsifying action can be expected with only 00. In addition, as the oil, fatty acid esters such as isopropyl myristate, octyldodecyl myristate, and isopropyl palmitate are preferable, and one kind or a combination of two or more kinds is used.

The above oil may be used in an amount sufficient to achieve its purpose, and is usually added in the range of 0.1 to 2% by weight based on the total weight of the lotion. In the external preparation of the present invention, other components used in conventionally known external preparations can be blended. That is, a necessary amount of a solubilizer, a thickener, a humectant, an emulsifier, or the like can be appropriately combined and blended in a required amount. As a preservative, parabens such as methyl, ethyl and propyl paraoxybenzoate, chlorobutanol and benzyl alcohol may be used alone or in combination of two or more depending on the purpose.

The preparation for external use of the present invention can be carried out by using the drug substance described in the above A by a conventionally known production method (for details, see Examples below).

[Examples] Examples of the drug substance of the present invention and external preparations in the form of ointments, creams and lotions will be described below.

Example 1: Solubility test of compound (I) tocopheryl retinoate in various solvents The solubility of compound (I) tocopheryl retinoate in various solvents was determined by measuring the amount of solvent necessary to dissolve 1 g of compound (I). Was compared.

 Table 1 shows the results.

From Table 1 above, it can be seen that Compound (I) is hardly soluble or hardly soluble in polar solvents. On the other hand, it shows good solubility in organic solvents, vegetable oils and cosmetic raw materials. Therefore, when preparing a drug substance of the compound (I), it is expected that an organic solvent, a vegetable oil or a cosmetic raw material base will be a good solvent. However, as mentioned above, organic solvents are problematic in terms of evaporation during storage, their toxicity, and residual concentration when commercialized.In vegetable oils, the stability of the formulation itself due to rancidity is a problem, and it must be used. Can not. Therefore, soft liquid paraffin can be said to be satisfactory as a solvent for compound (I) from the viewpoint of good solubility shown in Table 1.

Example 2: Viscosity measurement test of compound (I) A measurement test was performed on the viscosity of compound (I) due to temperature change, using white petrolatum as a control.

Method: About 0.4 cc of the compound (I) was weighed out, and the viscosity was measured at 40 ° C., 50 ° C. and 60 ° C. using an E-type viscometer (3 ° cone). As a control, the viscosity of white petrolatum at 40 ° C. was also measured.

Results: The results are shown in the figure.

As is clear from the results, the compound (I) exhibits a Newtonian flow having an intrinsic viscosity at each temperature. Even at 60 ° C., it exhibits a viscosity of about 25,000 centipoise, and at 40 ° C., the viscosity of compound (I) is about 200 times that of white petrolatum when compared with white petrolatum at the same temperature. .

From the above, a drug substance (viscosity of about 200 centipoise) produced by mixing and dissolving compound (I) in soft liquid paraffin is valuable because it solves the above viscosity problem.

Example 3 Preparation of Drug Substance Formulation Example 1 Compound (I) 25.0 g BHT 0.5 Soft liquid paraffin 74.5 Total 100 0 g BHT was dissolved in soft liquid paraffin heated to about 50 ° C. To the compound (I) heated to the same temperature, the mixture was gradually cooled while stirring to give compound (I) 25%
An active drug substance was obtained.

Formulation Example 2 (Comparative Example) Compound (I) 25.0 g butylhydroxy 0.5 anisole (BHA) light liquid paraffin 74.5 total amount 100 0 g butylhydroxyanisole (hereinafter referred to as BH) as an antioxidant
(Sometimes referred to as A).
The preparation method was in accordance with the production method of Formulation Example 1.

Formulation Example 3 (Comparative Example) Compound (I) 25.0 g mixed tocopherol 0.5 concentrate light liquid paraffin 74.5 total amount 100.0 g A drug substance in which mixed tocopherol concentrate was mixed as an antioxidant was prepared. The preparation method was in accordance with the production method of Formulation Example 1.

Formulation Example 4 (Comparative Example) Compound (I) 25.0 g Light liquid paraffin 75.0 Total amount 100.0 g A drug substance containing no antioxidant was prepared. The preparation method was in accordance with the production method of Formulation Example 1.

Example 4: Stability test of compound (I) in drug substance In order to confirm the stability of compound (I) in the drug substance, the drug substance of four formulations obtained in Example 3 was obtained. Was considered. That is, about 5 g of the drug substance of each formulation was weighed into a screw tube and left under severe conditions of 40 and 50 ° C. for 6 months and 60 ° C. for 2 months, and α-tocopheryl retino at each measurement point. Eate content was measured by HPLC method. In addition, changes in the appearance of the drug substance were also observed.

 The results are shown in Table 2.

As is clear from the results in Table 2, the stability of compound (I) in soft liquid paraffin is relatively good (Formulation Example 4), but the compounding of an antioxidant (Formulation Example 1: BHT, It can be seen that Formulation Example 2: BHA) further improves its stability. When comparing the efficacy of antioxidants, BH
T showed a particularly excellent effect. Regarding the appearance, no change was observed in the appearance of Formulation Example 1 containing BHT, but the appearance was relatively early in the other Formulation Examples.

According to the above test, the drug substance (formulation example 1) containing light liquid paraffin as a base and BHT as an antioxidant is particularly stable under severe conditions. It is presumed that its stability will be ensured for a long time under the following.

Example 5: Preparation of ointment (hydrophobic ointment) Using the drug substance obtained in Formulation Example 1 of Example 3, a hydrophobic ointment was prepared.

Drug substance containing 25% compound (I) 2.0 g white petrolatum 98.0 Total 100.0 g Heating and melting white petrolatum at about 70 ° C., followed by heating to the same temperature and 25% compound (I) drug substance , And uniformly mixed in a vacuum under light shielding. Then, the mixture was cooled to room temperature while mixing under the same conditions to obtain a hydrophobic ointment containing 0.5% of the compound (I).

Example 6: Preparation of ointment (hydrophilic ointment) A hydrophilic ointment was prepared using the drug substance obtained in Formulation Example 1 of Example 3.

Macrogol 400 58.0 Macrogol 4000 40.0 Total amount 100.0 g Macrogol 400 and Macrogol 4000 were heated to about 70 ° C, melted, and then heated to the same temperature. Compound (I) 25%
The preparation containing the active ingredient was added, and the same operation as in Example 5 was performed to obtain a hydrophilic ointment containing 0.5% of compound (I). Example 7: Preparation of cream (I) Formulation example of Example 3 A cream was prepared using the drug substance obtained in 1.

(A) Drug substance containing 25% compound (I) 2.00 g Polawax GP-200 15.00 Isopropyl myristate 3.00 Methyl parahydroxybenzoate 0.24 Propyl paraoxybenzoate 0.06 (B) Condensed glycerin 4.00 Sorbitol solution 5.00 Water qs 100.00 g) Heat (A) to about 70 ° C under light shielding and melt.
(B) is heated to about 70 ° C. and mixed, and then added to (A), and mixed in a vacuum under light shielding. Then, the mixture was cooled to room temperature while mixing under the same conditions to obtain a cream containing 0.5% of compound (I).

Example 8: Preparation of cream (II) A cream was prepared using the drug substance obtained in Formulation Example 1 of Example 3.

(A) Drug substance containing 25% of compound (I) 2.00 g octyldodecyl myristate 23.00 cetyl alcohol 7.00 whale wax 2.00 methyl paraoxybenzoate 0.24 propyl paraoxybenzoate 0.06 (B) concentrated glycerin 4.00 sorbitol solution 5.00 (C) polyoxy Ethylene (20) sorbitan monostearate 2.65 Sorbitan monostearate 2.35 (D) Water qs 100.00 g (A) and (C) are heated to about 70 ° C under light shielding, melted and mixed. Next, (B) and (D) are heated and melted at about 70 ° C., then added to the above mixture, and mixed in a vacuum under light shielding. Then, the mixture was cooled to room temperature while mixing under the same conditions to obtain a cream containing 0.5% of compound (I).

Example 9: Preparation of lotion A lotion was prepared using the drug substance obtained in Formulation Example 1 of Example 3.

(A) Drug substance containing 25% of compound (I) 2.00 g Polar wax GP-200 4.00 Isopropyl palmitate 0.64 Benzyl alcohol 1.00 (B) Condensed glycerin 3.00 Sorbitol solution 4.00 Water Appropriate amount Total amount 100.00 g (A) Heat to about 70 ° C and melt. (B)
Is heated to about 70 ° C, mixed, and added to (A).
Mix under vacuum. Then, the mixture was cooled to room temperature while mixing under the same conditions to obtain a lotion containing 0.5% of compound (I).

Example 10: Test of release of compound (I) from external preparations of hydrophobic ointment, hydrophilic ointment, cream (I), cream (II) and lotion obtained in the above Examples 5 to 9 The release of compound (I) from each preparation was examined.

Method: Measurement was performed using a TMS-103 type device manufactured by Toyama Sangyo Co., Ltd. 3 g of each of the above external preparations was mixed with a phosphoric acid-ethanol mixture (0.
01M phosphate buffer (pH6.0): ethanol = 2: 8) 500ml
Artificial membrane (Millipore filter: FSLWO4700, pore size 3.0μ) placed in contact with the solution surface of (37 ℃ 500)
m), the buffer was stirred at 150 rpm, and the compound (I) released into the buffer through the artificial membrane was measured over time by an absorbance method.

Results: The results are shown in Table 3.

As is clear from the results in Table 3, the cream preparation represented by type (I) among the five preparations has particularly excellent release ability,
It is expected to be an effective drug when applied clinically.

Example 11: Efficacy study test of tocopheryl retinoate-containing topical preparation Method: pressure ulcer, burn ulcer, radiation ulcer, traumatic ulcer, leg ulcer, diabetic ulcer, varicose vein syndrome, general intractable skin ulcer patient as a control The effectiveness of the hydrophobic ointment, hydrophilic ointment, cream (I) and cream (II) obtained from the above examples was examined.

The ulcer surface was wiped and disinfected once a day in principle for the above-mentioned diseased patients, and then an appropriate amount of the above-mentioned external preparation was spread on a lint cloth or gauze according to the size of the lesion and then applied.

Result: In any of the preparation forms, the action of promoting granulation formation on the wound surface is good, but both the hydrophobic and hydrophilic ointments have a poor hematoma removal action on the wound surface, which delays epidermal formation. There is a tendency. On the other hand, the cream preparation (I), which is a preparation having a particularly high water content, also has a good hematoma-removing action and a concomitant epidermis-forming action, showing a particularly excellent clinical effect among the test drugs. Cream (I) was particularly preferable as a preparation easily adaptable to deep ulcers, as compared with other ointments.

In addition, no side effects were observed in any of the above four preparations,
This formulation was found to be both effective and safe.

Example 12: Compound (I) in rats by transdermal administration
Blood concentration, urinary and fecal excretion and tissue concentration of the rat Method: The center of the back of the rat was shaved with a hair clipper, and a group of injured skin animals that peeled the skin and a group of normal skin that did not peel the skin were prepared. The ointment containing tocopheryl retinoate labeled with ¹⁴ C prepared by the preparation method described below was sealed and applied for 24 hours by the method of sealed application. With respect to each test item, the concentration of compound (I) was measured by the following operation.

Blood concentration; using 4 rats each for damaged skin group and normal skin group,
Ointment 5 and 50 mg / kg body weight were administered, and blood was collected 1, 4, 8 hours after administration, 1, 2, 3, 4, 5, 7, 10, 15, 25, and 30 days. The collected blood was absorbed by filter paper, and after drying in air, the radioactivity was measured by the combustion method.

Urinary and fecal excretion rate: 5 mg / kg body weight of ointment is administered to the damaged skin group, and spontaneously excreted urine and feces are collected. Both urine and feces were collected every 0 to 6, 6 to 24 hours after administration, and thereafter every 24 hours. Urine was appropriately diluted, tT-21 scintillator was added to measure the radioactivity, and feces were measured by the combustion method.

Ointment 5 mg / kg body weight was administered to the damaged skin group, and 0.5,
At 2,6,24,72,120 hours brain, eyeball, submandibular gland, heart, lung, kidney,
The spleen, testis, small intestine (ileum), muscle, fat, skin, blood, plasma, and tissues of the administration site were collected, and radioactivity was measured by a combustion method.

Preparation of ointment; 0.5,5% tocopheryl retinoate ointment was prepared according to the following formulation.

0.5% tocopheryl retinoate ointment; ¹⁴ C-tocopheryl 0.50 g (6 μCi / mg) retinoate Light liquid paraffin 1.48 BHT 0.02 Vaseline 98.00 Total 100.00 g (30 μCi / g ointment) 5% tocopheryl retinoate ointment; ¹⁴ C-tocopheryl 5.00g (3μCi / mg) Retinoate Light liquid paraffin 1.48 BHT 0.02 Vaseline 98.00 Total amount 100.00g (30μCi / g ointment) Result: Blood concentration; Radioactivity detected in both damaged and normal skin groups at any measurement time It was below the limit, and there was no migration into the blood from both administration sites.

Urinary and fecal excretion rates; the results are summarized in Table 4.

As is clear from Table 4, it was not detected in urine even after 120 hours. Although excreted in feces after 24 hours, its excretion was very small.

Tissue concentrations; Table 5 summarizes the results.

As is clear from Table 5, no radioactivity was detected in tissues other than the damaged skin as the application site.

From the above test results, it is considered that Compound (I) is distributed only at the administration site and does not migrate to the whole body.

[Effects of the Invention] In general, a drug intended for application to an injured site has problems of irritation at the administration site of the preparation and systemic action associated with absorption of the drug from the administration site, but the preparation containing the compound (I) is problematic. No irritation at the application site was observed, and as is clear from the test in Example 12, no systemic transfer of compound (I) was observed.

That is, the preparation containing the compound (I) according to the present invention stays only at the site of application, exhibits excellent drug efficacy at the site of application, and does not show any systemic action-side effect associated with absorption from the site of application. Therefore, it can be said that this is an extremely useful external preparation from the viewpoint of safety.

In addition, cream (I) having a particularly high water content in clinical pharmacological action is more effective in promoting the granulation formation of tocopheryl retinoate and in removing the hematoma derived from the cream preparation, and healing the wound surface more than other preparation forms. It is excellent in promoting effect.

As described above, the external preparation of the present invention not only facilitates the preparation of the external preparation without impairing the stability of the compound (I), but also as a therapeutic agent useful for skin diseases, especially for deep ulcers. Ointments, including applicable creams,
It can be said that providing a lotion is very significant.

[Brief description of the drawings]

 The figure shows the results of Example 2.

──────────────────────────────────────────────────続 き Continued on the front page (58) Field surveyed (Int.Cl. ⁶ , DB name) A61K 31/355 A61K 47/10 A61K 47/30 CA (STN)

Claims (5)

(57) [Claims] (1) The following formula (I): Α-tocopherol vitamin A acid ester represented by the formula
An original drug substance for external use, comprising 2.0 to 40.0% by weight, (b) 0.01 to 5.0% by weight of dibutylhydroxytoluene, and (c) light liquid paraffin. 2. Based on the total weight of the preparation: (a) 0.05 to 5.0% by weight of α-tocopherol vitamin A ester of formula (I) according to claim 1, (b) 0.002 to An external preparation for treating skin diseases, comprising 0.2% by weight and (c) light liquid paraffin. 3. Based on the total weight of the preparation: (a) 0.05 to 5.0% by weight of the α-tocopherol vitamin A acid ester of formula (I) according to claim 1, (b) 0.002 to 0.2% by weight, (c) 0.1 to 6.0% by weight of light liquid paraffin, (d) 5 to 50% by weight of self-emulsifying wax, (e) 1 to 5% by weight of medium-chain fatty acid ester, and (f) water. An external preparation for treating skin diseases. 4. The external preparation for treating skin diseases according to claim 2 or 3, which is obtained by using the drug substance according to claim 1. 5. The composition according to claim 2, which is in the form of a cream.
An external preparation for treating a skin disease according to any one of the above.