JPH02221221A - External preparation - Google Patents

Abstract

PURPOSE:To obtain an external preparation for treating dermatosis, readily handleable and safe, containing alpha-tocopherol vitamin A acid ester having granulation formation promoting action and antitumor action, dibutylhydroxytoluene (antioxidant) and an oil-based raw material. CONSTITUTION:An external preparation containing (A) 2.0-40.0wt.% alpha-tocopherol vitamin A acid ester shown by the formula, (B) 0.01-5.0wt.% dibutylhydroxytoluene and (C) an oil-based raw material as active ingredients. When the preparation is used, the viscosity of the external preparation at room temperature is preferably <=1,000 centipoise. When the external preparation is used as an ointment, 0.05-5.0wt.% component A is blended with the components B and C. When used as a cream, 0.05-5.0wt.% component A is mixed with the components B and C and further an oil, wax, surfactant and water and pharmaceutically manufactured.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a topical preparation for the treatment of skin diseases, and more particularly, α- This invention relates to an external preparation containing tocopherol vitamin A acid ester as an active ingredient.

The present invention also relates to a drug substance that facilitates the handling of the α-tocopherol vitamin A acid ester represented by the above formula (1) and allows preparation of external preparations without impairing stability.

[Prior art and problems] α-tocopherol vitamin A represented by the above formula (1)
The acid ester is a well-known compound whose chemical name is tocopheryl retinoate (hereinafter referred to as tocopheryl retinoate) (Japanese Patent Publication No. 49-26632). This formula (
Tocopheryl retinoate (hereinafter sometimes referred to as compound (1)) represented by I) has an anti-ulcer effect, and its application as a therapeutic agent for gastrointestinal ulcers has been proposed (Japanese Patent Publication No. 6 O.
-26770), expected to further prevent skin deterioration,
It has been proposed to be used as an ingredient in cosmetics (Japanese Unexamined Patent Publication No. 5
l-173137).

A therapeutic agent for skin diseases containing compound (1) as an active ingredient has also been proposed (Japanese Patent Application Laid-Open No. 61-207332).

Compound (1) in the above-mentioned JP-A-61-207332
The formulation for external use can be in the form of an ointment, lotion, liniment, or aerosol, and its formulation can be done using conventional pharmaceutical methods. It is used. For example, in the production of ointment, the raw materials used are oily substances such as liquid paraffin, vaseline, silicone oil, aliphatic higher alcohols, higher fatty acids, fatty acid esters, vegetable oil, castor oil, lanolin and its derivatives, squalene,
Squalane, etc.; Emulsifiers/dispersants, such as polyhydric alcohol ester type nonionic surfactants, polyoxyethylene type nonionic surfactants, etc.; Wetting agents, such as glycerin, propylene glycol, sorbitol, amino acids, etc.;
Stabilizers, such as antioxidants, preservatives, etc.; other agents, such as polyethylene gelcol, polyethylene, suspending agents, etc., selected as appropriate and used in combination with compound (1);
This is done through steps such as mixing, emulsifying, and dispersing each component.

The present inventors have been earnestly pursuing the development of a clinically applicable practical external preparation for the treatment of skin diseases, but due to the viscosity of compound (1), We realized that it is difficult to formulate an external preparation that exhibits the clinically desired therapeutic effect using formulation technology. For example, since compound (1) is a viscous substance, it is difficult to handle it when weighing it when adjusting its content, and when formulating it, heating operations are required to reduce the viscosity of compound (1) itself. After that, standard formulation techniques need to be applied. However, compound (1) has low chemical stability (oxidation and
Because tocopheryl retinoate has the property of being easily decomposed, high-temperature operations during the formulation process change tocopheryl retinoate, making it difficult to effectively secure the originally intended concentration of compound (1) in the formulation. It becomes difficult.

Therefore, it has been desired to develop more effective formulation techniques.

Therefore, the present inventors believe that if it is possible to obtain a drug substance in which the viscosity of compound (1) itself is lowered in advance, when preparing an external preparation containing compound (I), , does not require high-temperature operation that would cause isomerization or oxidative decomposition of compound (1), and
We thought that it might be possible to ensure the chemical stability of ).

Based on this viewpoint, the present inventors investigated the preparation of a low-viscosity drug substance that is easy to handle and stably contains Compound (I), and also used the drug substance as a basic formulation. We investigated the preparation of an external preparation that is not irritating to the skin and can most effectively exert the medicinal effects of compound (I).

The present inventors focused on the fact that compound (1) has the property of being well soluble in appropriate organic solvents such as ethyl acetate, chloroform, cyclohexane, acetone, or animal/vegetable oils,
A method for preparing a drug substance with low viscosity by dissolving compound (I) in these solvents was investigated. However, although this method allows the desired low-viscosity drug substance to be obtained, when an organic solvent is used, there are problems with residual concentration, toxicity, and skin irritation when formulated as an external preparation. Therefore, it could not be a clinically applicable formulation. Furthermore, even when animal or vegetable oils are used, the drug substance itself becomes rancid with the passage of time, resulting in a lack of stability of the preparation itself, making it impossible to provide a desirable preparation.

Therefore, as a result of investigating solvents for drug substances instead of the above-mentioned organic solvents or animal/vegetable oils, we found that a formulation consisting of a compound (D) mixed with an oily raw material, and dibutylhydroxytoluene as an antioxidant, was found. The present inventors have discovered that a drug substance that satisfies the above conditions have been completed, and have completed the present invention.The present inventors have also found that when this drug substance is used as a basic formulation and is made into external preparations such as ointments, creams, and lotions. In particular, the present inventors have confirmed that an external preparation in the form of a cream is effective as a therapeutic agent for skin diseases such as bed sores, burns, and wounds, leading to the completion of the present invention.

[Structure of the Invention] The first object of the present invention is to provide a drug substance that stably contains tocopheryl retinoate and that greatly facilitates the preparation of external preparations. A, based on the total weight of the drug substance (a) α-tocopherol vitamin A acid ester 2 represented by the following formula (I):
．． (b) dibutylhydroxytoluene 0.01 to 5.0% by weight, and (c) an oily raw material;

The second object of the present invention is to provide an external preparation for treating skin diseases, and in detail, based on the total weight of the preparation: (a) α-tocopherol vitamin A acid ester represented by the above formula (1) 0. 05 to 5.0% by weight, (b)
An object of the present invention is to provide an external preparation for treating skin diseases, which contains at least 0.002 to 0.2% by weight of dibutylhydroxytoluene and (c) an oily raw material.

In this case, the external preparation for treating skin diseases is preferably prepared using the external preparation drug substance provided as described above.

As the external preparation, in particular, a skin disease treatment preparation in the form of an ointment, a cream, or a lotion is provided.

Specifically, the ointment containing compound (1) is: B. based on the total weight of the preparation; (a) 0.05 to 5.0% by weight of compound (1);
An ointment comprising b) dibutylhydroxytoluene and (c) an oily raw material is provided.

In addition, the cream containing Compound (I) specifically includes: Based on the total weight of C1 preparation; (a) Compound (1) 0.05 to 5.0% by weight; (
A cream agent is provided which is blended with b) dibutylhydroxytoluene, (c) an oily raw material, (d) oil, (e) wax, (f) surfactant, and (g) water.

Furthermore, as a lotion containing compound (1),
Specifically: D, based on the total weight of the preparation; (a) Compound (1) 0.05 to 5.0% by weight, (
A lotion is provided which contains b) dibutylhydroxytoluene, (c) an oily raw material, (d) oil, (e) wax, (f) surfactant, and (g) water.

[Effect] As mentioned above, the chemical name of the compound (1) to be incorporated into the external preparation of the present invention is tocopheryl retinoate,
It has been attempted to be used as a therapeutic agent for gastrointestinal ulcers due to its granulation-promoting and anti-ulcer effects, and as an ingredient in cosmetics due to its anti-skin deterioration effect.Recently, its use as a therapeutic agent for skin diseases has also been considered. There is.

The physical properties of compound (1) are described below.

Compound (1) is a clear yellow viscous substance, has no odor or has a slightly unique odor, and is unstable to light and air. Also, it is slightly soluble in ethanol and difficult to dissolve in methanol. Almost insoluble in water. Compound (1) is miscible with organic solvents such as ethyl acetate, chloroform, cyclohexane, and acetone, as well as vegetable oils such as soybean oil and sesame oil, but as mentioned above, it is not advisable to formulate formulations using these solvents. In addition, in the method of directly mixing compound <r> with a suitable cosmetic raw material base to form a topical preparation, when high temperature operation is performed to reduce the viscosity of compound (1), the heat causes the crude drug to It is difficult to formulate a formulation as a therapeutic agent for skin diseases using this method because the main compound (I) is susceptible to oxidative decomposition (and the target concentration cannot be secured).

Many topical preparations for the treatment of skin diseases that have a granulation-promoting effect have been proposed for the treatment of skin ulcers such as burns and decubitus ulcers, freeze-healing, wounds, etc. The pharmacological effect of external preparations is to form new skin tissue on the skin ulcer surface and increase the therapeutic effect due to the anti-ulcer effect, anti-keratinization effect, or wound surface healing promoting effect of the drug contained as an active ingredient. Ointments are the mainstream formulation for this purpose.

In general, skin changes due to bedsore healing, burns, etc., are caused by chickenpox,
They correspond to plaques, ulcers, erosions, etc., and from the viewpoint of treatment of these primary rashes, treatments based on oil ointment bases, emulsion ointment bases, or water-soluble ointment bases (in the form of ointments) are recommended. These three types of ointments have not only the therapeutic effects of the active ingredients contained in them, but also the unique effects of the bases themselves. For example, the characteristics of an oily base basically have the effect of softening the skin, removing the skin, and promoting the formation of the epidermis.Furthermore, the emulsion ointment base has 0/ There are two types of ointment: W-type hydrophilic ointment and W2O-type water-absorbing ointment, but both are used for dry skin diseases, and conversely, they are used for moist diseases such as chickenpox, sores, ulcers, etc. When applied to the skin, it has the disadvantage of absorbing exudate and worsening the symptoms, but it has the advantage of excellent penetration into deep ulcers.On the other hand, water-soluble ointment bases are similar to hydrophilic ointments. Unlike emulsion ointments, it has stronger water solubility and water absorption than emulsion ointments, so it is used on moist surfaces such as chickenpox and sores, and has the effect of absorbing moisture and secretions and drying the affected area, but it has less water absorption. Too strong, the lesion surface becomes too dry, causing cracks,
On the contrary, there are many concerns that the symptoms may worsen.

Therefore, even within the scope of external preparations for treating skin diseases, the types of external preparations themselves used vary depending on the symptoms to which they are applied. When planning to formulate a topical preparation for the treatment of skin diseases that effectively exhibits the granulation-promoting effect and anti-ulcer effect of 1), it is important to consider formulations that can be used to prepare various types of topical preparations. It is considered good.

From the above points of view, the present inventors investigated the formulation of a drug substance for preparing a topical preparation containing compound (1) as an active ingredient. We have newly discovered that the drug substance is extremely effective as a drug substance for preparing various target external preparations.In addition, such drug substance formulations
It can be applied not only to ointments but also to creams or lotions.

Therefore, the present invention relates to a drug substance containing compound (1) and an external preparation based on this drug substance formulation. According to the present invention, by dissolving compound (1) in an oily raw material and further adding dibutylhydroxytoluene (hereinafter also referred to as BHT) as an antioxidant, compound (I) can be stabilized during formulation. This provided an effective means of making it possible to formulate it into an external preparation without compromising its properties.

The above-mentioned oily raw materials are preferably pharmaceutically acceptable liquid paraffin, squalane, squalene, medium-chain fatty acid triglyceride, isopropyl valmitate, isopropyl myristate, octyldodecyl myristate, etc. Among them, compound (I) in a polar state ( Liquid paraffins, which are generally non-polar), are particularly preferred from the viewpoint of solubility.

In addition, liquid paraffin can also be used in JP-A-61-207 mentioned above.
Compared to the liquid paraffin disclosed in No. 332, light liquid paraffin which is a low molecular weight component is preferable, and when compound (1) which is viscous due to its low viscosity is mixed, compound (D The viscosity of the liquid paraffin can be lowered, making it easier to handle.This light liquid paraffin product uses Moresco, a high-purity product with less contamination of unsaturated substances that can cause irritation when used clinically. Bioless■ (pine wood oil) is suitable.

In addition, since compound (1) is easily decomposed by light and heat, dibutylhydroxytoluene is used as an antioxidant.
Stability can be maintained particularly advantageously by adding butylhydroxyanisole, df-α-tocopherol, and especially dibutylhydroxytoluene.

Therefore, the present invention is characterized by the combination formulation of tocopheryl retinoate oily raw material, preferably light liquid paraffin-dibutyl hydroxytoluene. The properties and chemical properties have been resolved. The use of the obtained drug substance facilitates formulation into ointments, creams, or lotions, which will be described later, and has made it possible to develop especially clinically useful creams for treating skin diseases.

External preparations in the form of bulk formulations, ointments, creams, and lotions containing compound (1) will be described below.

A,! 111 difference The drug substance of the present invention contains: (a) Compound (I) 2 to 40% by weight, preferably 1% by weight, based on the total weight of the drug substance;
(b) dibutylhydroxytoluene 0.01 to 5% by weight, more preferably 20 to 30% by weight;
0% by weight, preferably 0.05 to 4.01% by weight
, more preferably 0.07 to 2.0% by weight, and (c) light liquid paraffin, squalane, squalene,
Oily raw materials such as medium chain fatty acid triglycerides, isopropyl valmitate, isopropyl myristate, octyldodecyl myristate, preferably light liquid paraffin (
Moresco Bioless■: Matsumura Sekiyu).

The light liquid paraffin used in the preparation of the drug substance of the present invention is a drug substance listed in the Japanese Pharmacopoeia,
Compared to liquid paraffin, which is also listed in the pharmacopeia, the number of carbon atoms in the hydrocarbon compound contained therein is lower. Among them, those with high purity and low skin irritation (
Moresco Bioless (Matsumura Sekiyu) is preferably used. Examples of antioxidants include dibutylhydroxytoluene (BHT), butylhydroxyanisole, and dl-
Antioxidants such as α-tocopherol can be mentioned, but BHT is preferred among them in terms of antioxidant power, low irritation, etc., in the range of 0.01 to 5.0% by weight (compound (I)
The stability of compound (i) is ensured by the amount of (adjusted by the amount of).

The amount of compound (I) in the drug substance of the present invention is an amount sufficient to exhibit sufficient effects when the obtained drug substance is formulated into a topical preparation for treating skin diseases. In addition, it is necessary that the drug substance be applicable to the intended formulation, and as a result of studies by the present inventors, it has been found that the above-mentioned blending amount is preferable.

As described above, the drug substance provided by the present invention consists of a compound formulation of compound (I)-BHT-oil-based raw material, preferably light liquid paraffin, and this combination stabilizes compound (I) itself. The drug substance with guaranteed properties is easy to handle, so it can be used for ointments,
This has made it easier to consider formulating creams or lotions, and has made it possible to create creams that are particularly clinically useful.

A second object of the present invention is to provide ointments, creams, and lotions that are external preparations for treating skin diseases. It is preferable to use a drug substance that is

In this case, the above-mentioned A used for formulation
The blending amount of the drug substance obtained in step 1 is determined by the content of compound (1) in the target preparation that effectively exhibits an effect as a therapeutic agent for skin diseases. According to the studies of the present inventors, in view of the granulation-promoting effect and anti-ulcer effect possessed by compound (I) itself, compound (1) is present at 0.05 to 5.0% by weight based on the total weight of the preparation. Preferably 0.
1 to 3.0% by weight, more preferably 0.2 to 1
．． It has been found that sufficient effects can be exhibited if the amount equivalent to 0% by weight is blended. Therefore, in the following explanation, the drug substance obtained in the above A will be used as a basic formulation, and the explanation will be given in terms of the converted amount contained as compound (1) in the drug substance.

It should be noted that in preparing the following specific formulations, it is sufficient to ensure the desired blending amount of each ingredient, and it is not necessary to use the drug substance itself obtained in A above. Needless to say.

B, tJJl The ointment of the present invention contains (a) 0.05 to 5.0% by weight, preferably 0.1 to 3% by weight of the drug substance obtained in A above as compound (1), based on the total weight of the preparation. .0% by weight,
More preferably 0.2 to 1.0% by weight, and (b) the balance is an oil or water-soluble polymer compound, preferably white petrolatum or macrogol.

In this case, the ointments provided as described above are basically of two types: lipophilic ointments (hydrophobic ointments) and hydrophilic ointments. When a hydrophilic ointment is desired, it is preferable to use white petrolatum as the oil, and when a hydrophilic ointment is desired, macrogol is preferably used. Regarding macrogols,
Its consistency is 400 macrogol, 4000 macrogol
It can be adjusted by adding appropriate amounts of the following.

As described above, a hydrophobic or hydrophilic ointment stably containing the desired compound (1) can be prepared.

The vaseline-based or macrogol-based ointment prepared as described above is an extremely good formulation with no skin irritation and excellent compatibility.

C1ku1nim1 The cream of the present invention contains (a) 0.05 of the drug substance obtained in A above as compound (1), based on the total weight of the preparation.
5.0% by weight, preferably 0.0% by weight. (b) Wax, 1 to 20% by weight; (c) Oil, 1 to 25% by weight; (d) Surfactant, 0 to 10% by weight; % by weight, and (e) residual water.

The cream of the present invention is particularly preferably in an oil-in-water type (0/W) formulation, and the wax includes self-emulsifying wax, spermaceti, Japanese wax, white beeswax, and other waxes. When a self-emulsifying wax (Borawax GP-200) is used, it is not necessary to add a surfactant because it itself has a surfactant effect. Further, fatty acid esters such as isopropyl myristate, octyldodecyl myristate, and isopropyl palmitate are preferable as the oil, and one type or a combination of two or more of these can be added. The above-mentioned oil may be used in an amount sufficient to achieve the purpose, and is usually blended in an amount of 25% by weight to 25% by weight based on the total amount of the cream. Furthermore, as the surfactant, nonionic surfactants are preferred, and one type or a combination of two or more types from among Spans and Tweens are blended. The amount to be blended may be any amount that satisfactorily achieves the purpose, and can be blended within a range of 1 to 10% by weight based on the total weight of the cream.

The cream of the present invention basically consists of the drug substance obtained from A above, wax, oil, surfactant, and water, but it also contains ingredients that are blended in ordinary creams, i.e. Moisturizers, preservatives, etc. can be added as appropriate.

As described above, various O/W type creams stably containing the target compound (I) can be prepared. When applied to the healing surface of bedsores, this combination formula has a unique medicinal effect that is not found in other external preparations, which is to dissolve hematomas that occur in bedsores. This is a formulation that can release Compound (I) well.

It has also been found that among these O/W type creams, those with particularly high water content are excellent in the above-mentioned effects.

D. Lotion The lotion of the present invention contains (a) the drug substance obtained in A above as a compound (as D), based on the total weight of the preparation;
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 10% by weight, (c) oil, 0.
(b) 1 to 2% by weight, and (b) the balance water. Considering the physical properties of compound (1), the form of an emulsion lotion is preferable.

As the wax, self-emulsifying wax (Borawax GP-200) is preferably used, and Borawax C
P-200 alone can be expected to have a sufficient emulsifying effect. Also,
The above-mentioned oil is preferably a fatty acid ester such as isopropyl myristate, octyldodecyl myristate, or isopropyl palmitate, and these are used alone or in combination of two or more.

The above-mentioned oil is blended in an amount sufficient to achieve the purpose (usually within the range of 0.1 to 2% by weight based on the total weight of the lotion).

The external preparation of the present invention may contain other ingredients used in conventionally known external preparations.

That is, a suitable combination of solubilizers, thickeners, humectants, emulsifiers, etc. can be used depending on the purpose, and the necessary amount can be added. In addition, as a preservative, parabens such as methyl, ethyl, and propyl paraoxybenzoate, chlorobutanol, benzyl alcohol, and the like may be used alone or in combination of two or more depending on the purpose.

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

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

Compound (I) Solubility of tocopheryl retinoate in various solvents Test compound (■) The solubility of tocopheryl retinoate in various solvents was determined by the amount of solvent required to dissolve compound (1) Ig. A comparative study was conducted.

The results are shown in Table 1.

Table 1 Solvent Amount required for dissolution. Therefore, when preparing a drug substance for compound (1), it is expected that organic solvents, vegetable oils, or cosmetic raw material bases will be good solvents. However, as mentioned earlier, organic solvents pose problems such as evaporation during storage, their toxicity, and residual concentration when manufactured into products, while vegetable oils have problems with stability due to rancidity of the formulation itself, making it difficult to use them. I can't. Therefore, light liquid paraffin can be said to be satisfactory as a solvent for compound (I) also from the viewpoint of good solubility shown in Table 1.

From Table 1 above, it can be seen that compound (1) is hardly soluble or hardly soluble in polar solvents.

On the other hand, in organic solvents, vegetable oils, and cosmetic raw material bases, the viscosity measurement of test compound (1), which shows good solubility in organic solvents, vegetable oils, and cosmetic raw materials (D), was compared with white petrolatum. A measurement test was conducted.

Weigh out approximately 0.4 cc of Tomonuki Compound (I) and use an E-type viscometer (3
The viscosity was measured under conditions set at 40°C, 50°C, and 60°C. In addition, as a comparison, 40
The viscosity of white petrolatum under ℃ conditions was also measured.

■； The results are shown in the figure.

As is clear from the results shown in the figure, compound (I) exhibits Newtonian flow having an intrinsic viscosity at each temperature. Moreover, even at 60°C, it shows a viscosity of about 25,000 centipoise, and when compared with white petrolatum at the same temperature at 40°C, the viscosity of compound (I) is about 200 centipoise.
It exhibits twice the consistency.

From the above, the drug substance prepared by mixing and dissolving compound (1) in light liquid paraffin (viscosity: about 200 centipoise) is valuable because it solves the above-mentioned viscosity problem.

ULf2! u: Preparation example 1 of drug substance Compound (1) 25.0 gBHT
O,5 Perfun 745 Total amount 1000 g After dissolving BHT in light liquid paraffin heated to about 50°C, this solution was added to compound (1) heated to the same temperature, and gradually cooled while stirring. , compound (I) 2
A drug substance containing 5% was obtained.

Formulation example 2 (comparative example) Compound (I) 25.0 g Butylated hydroxyanisole (BHA) 74.5 Total amount 100.0 g Butylated hydroxyanisole (hereinafter referred to as BHA) as an antioxidant
A drug substance was prepared containing the following ingredients (sometimes referred to as A).

The preparation method was similar to that of Prescription Example 1 above.

Formulation example 3 (comparative example) Compound (1) 25.0 g Mixed tocopherol 0.5 Concentrate part 74.5 Total amount 100.0 g Pharmaceutical ingredient containing mixed tocopherol concentrate as an antioxidant created a body. The preparation method was similar to that of Prescription Example 1 above.

Formulation Example 4 (Comparative Example) Compound (1) 25.0 g Bar 7 76.0 Total amount 100.0 g A drug substance containing no antioxidant was prepared. The preparation method was similar to that of Prescription Example 1 above.

Table 2 "1 Milk A" - Stability test of compound (1) in bulk drug product In order to confirm the stability of compound (I) in bulk drug product, the compound (I) obtained in Example 3 was tested. Four formulations of drug substance were investigated. That is, approximately 5 g of the drug substance of each formulation was weighed into a screw tube and left under severe conditions for 6 months at 40.50°C and 2 months at 60°C, and α-
Tocopheryl retinoate 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 (1) in light liquid paraffin is relatively good (formulation example 4), but the stability of compound (1) in light liquid paraffin is relatively good (formulation example 4).
, Formulation Example 2: BHA) shows that the stability is further improved. When comparing the efficacy of antioxidants, BHT showed particularly excellent effects. Regarding appearance, no change in appearance was observed in Formulation Example 1 containing BHT, but it was observed at a relatively early stage in other Formulation Examples.

As a result of the above test, the drug substance (Formulation Example 1), which uses light liquid paraffin as a base and specifically contains BHT as an antioxidant, is stable under harsh conditions, so it can be used at room temperature. It was estimated that its stability would be ensured for a long time under the following conditions.

Real “fly”! Preparation of L five knee ointment (hydrophobic ointment) Example 3
A hydrophobic ointment was prepared using the drug substance obtained in Formulation Example 1.

Compound (I) 25% containing drug substance 2.0g Wase 1
98.0 Total amount 100.0 g White petrolatum was heated to about 70°C and melted, then the drug substance containing 25% compound (1) heated to the same temperature was added,
Mix uniformly in a vacuum, shielded from light.

The mixture was then cooled to room temperature while being mixed under the same conditions to obtain a hydrophobic ointment containing 0.5% of compound (1).

Preparation of ``Mitsu'' 11L Aburi-ichi ointment (hydrophilic ointment) Example 3
A hydrophilic ointment was prepared using the drug substance obtained in Formulation Example 1.

Drug substance containing 25% compound (I) 2.0g Macrogol 400 58.0 Macrogol 40
00 40.0 Total amount 100.
0 g Macro goal 400 and macro goal 4000 at about 70°
Compound (I) heated to C and melted, then heated to the same temperature
) A 25%-containing drug substance was added and the following procedure was carried out in the same manner as in Example 5 to obtain a hydrophilic ointment containing 0.5% Compound (I). Preparation of LL knee cream (I) A cream was prepared using the drug substance obtained in Formulation Example 1 of Example 3.

(^) Pharmaceutical drug substance containing 25% of compound (I) 2. OO
g Borawax GP-20015,00 Isopropyl myristate 3.00 Methyl p-oxybenzoate 0.24 Propyl p-oxybenzoate 0.06 (B) Concentrated glycerin
4.00 Sorbitol liquid 5
．． 00 total amount 100.00 g (A) is heated to about 70° C. and melted in the dark. (
After heating and mixing B) to about 70°C, add it to (A) and mix in a vacuum state while shielding from light. Next, under the same conditions, the mixture was cooled to room temperature, and 0.5% of compound (I) was added.
A cream containing the following ingredients was obtained.

Preparation of Cream (I) A cream was prepared using the drug substance obtained in Formulation Example 1 of Example 3.

(A) Drug substance containing 25% compound (I) 2.00
g Octyldodecyl myristate 23.00 Cetyl alcohol 7.00 Whale wax
2.00 Methyl paraoxybenzoate
0.24 Propyl oxybenzoate 0.0
6 (B) Concentrated glycerin 4.00 Sorbitol solution 5.00 (c) Polyoxyethylene (20) Sorbitan monostearate 2.65 Sorbitan monostearate 2.35 Total amount 100.00 g (A) and (c) Heat to about 70° C. to melt and mix in the dark. Next, heat (B) and (D) at about 70°C,
After melting, add to the previous mixture and mix in vacuum under light shielding. The mixture was then cooled to room temperature while being mixed under the same conditions to obtain a cream containing 0.5% of compound (1).

Fruit” Yoshi! Preparation of a lotion using the drug substance obtained in Formulation Example 1 of Example 3.

(A) Drug substance containing 25% of compound (I) 2. OO
g Borawax GP-2004,00 Isopropyl Valmitate 0.64 Benzyl Alcohol 1.00 (B) Concentrated Glycerin
3.00 Sorbitol liquid
4.00 total amount 100.00 g (A) is heated to about 70°C and melted in the dark.

After heating (B) to about 70℃ and mixing, add it to (^),
Mix in a vacuum, shielded from light. Next, under the same conditions, the mixture was cooled to room temperature, and compound (1) was added to 0.5
A lotion containing % was obtained.

Release test of compound (1) from external preparations Hydrophobic ointment, hydrophilic ointment, cream (1), cream (■ ), the release properties of compound (1) from each lotion formulation were investigated.

1; Measurement was carried out using a TMS-103 type device manufactured by Toyama Sangyo ■. Add 3g of each of the above external preparations to a phosphoric acid-ethanol mixture (
0.01M phosphate buffer (pH 6.0): ethanol = 2:8) 500ml (37°C50
Artificial membrane (millibore filter: FSLWO4700, pore size 3.0μ) placed in contact with the solution surface of
m), the buffer solution was stirred at 15 Orpm, and the compound (I) released into the buffer solution through the artificial membrane was measured over time by an absorbance method.

Class l: The results are shown in Table 3.

Unit: mg As is clear from the results in Table 3, the cream formulation shown in type (1) among the five formulations has particularly excellent release ability and is likely to be an effective drug when applied clinically. is expected.

Support 1 and Eyu: Efficacy study of topical preparations containing tocopheryl retinoate in progress; bedsores, burn ulcers, radiation ulcers, traumatic ulcers, leg ulcers,
The effectiveness of the hydrophobic ointment, hydrophilic ointment, cream (I), and cream (II) obtained from the above examples was investigated in patients with diabetic ulcers, varicose vein syndrome, and general intractable skin ulcers. .

After wiping and disinfecting the ulcer surface once a day for patients with the above-mentioned disease, an appropriate amount of the above-mentioned external preparation was applied to a lint cloth or gauze depending on the size of the lesion.

■: Both formulations have a good effect on promoting granulation formation on the wound surface, but both hydrophobic and hydrophilic ointments have a poor effect on hematoma removal on the wound surface. On the other hand, among cream preparations, cream preparation (I), which has a particularly high water content, had good hematoma removal action and associated epidermal formation action, and showed particularly excellent clinical efficacy among the test drugs. In addition, cream (I) was preferable compared to other ointments, as it was particularly easy to apply to deep ulcers.

In addition, no side effects were observed in any of the above four preparations, and it was found that this preparation was excellent in both efficacy and safety.

Example 12: Compound (I) in rats by transdermal administration
), blood concentration, urinary/fecal excretion, and tissue concentration.The left center of the back of two rats was shaved with clippers, and a group of damaged skin animals with skin peeling and a normal skin group without skin peeling were created. A 14C-labeled tocopheryl retinoate-containing ointment prepared by the preparation method described below was applied in a sealed manner for 24 hours using the sealed application method. For each test item, the concentration of compound (I) was measured by the following procedure.

11 Main 11: Four rats were used in each of the damaged skin group and the normal skin group, and ointment doses of 5 and 50 mg/kg body weight were administered, and after administration 1.
4.8 hours, 1.2.3.4.5.7°10, 15.2
Blood was collected on day 5.30. The collected blood was absorbed into a filter paper, air-dried, and then radioactivity was measured by the combustion method.

Contest 1 - Administer ointment at 5 mg/kg body weight to the injured skin group, and collect naturally excreted urine and feces. Both urine and feces were collected every 24 hours from 0 to 6.6 hours after administration, and every 24 hours thereafter. Urine was appropriately diluted, tT-21 scintillator was added to measure radioactivity, and feces was measured by the combustion method.

Group J111 - Ointment 5+ag/kg body weight was administered to the injured skin group, and 0.5.2.6.24.72.120 hours after administration, the brain, eyeball, submandibular gland, heart, and lung 1. Kidney, tile, testis, small intestine (ileum), muscle, fat, skin, blood, plasma, and tissues from the administration site were collected, and radioactivity was measured by the combustion method.

0.5.5% tocopheryl retinoate ointment was prepared according to the following formulation.

0.5% Tocopheryl Retinoate Ointment; 14C) Copheryl 0.50g (6p Ci/mg) Retinoate Light Liquid Paraffin 1.48 BHT O,02 Selenium 98.00 Total 100. OOg (30 μCi/g ointment) HT 0.02 Total amount of Guse1 98.00 ioo, 00 g (30 μCi/g ointment) Radioactivity was below the detection limit at all measurement times for both the damaged skin group and the normal skin group. No migration into the blood from either administration site was observed.

,′.

The results are summarized in Table 4.

5% Tocopheryl Retinoate Ointment; 14C-Tocopheryl 5. OOg (3μCi
/mg) Retinoate light liquid paraffin 1.48 As is clear from Table 4, it was not detected in the urine even after 120 hours. Although it was detected in feces after 24 hours, the amount excreted was very small.

Group M Watari” 4 The results are summarized in Table 5.

As is clear from Table 5, no radioactivity was detected in tissues other than the damaged skin where it was applied.

From the above test results, it is considered that compound (1) is only distributed at the administration site and does not migrate throughout the body.

[Effects of the invention] In general, drugs intended for application to injured areas have problems with irritation at the administration site and systemic effects associated with absorption of the drug from the administration site, but preparations containing compound (I) No irritation was observed at the application site, and as is clear from the test in Example 12, no systemic transfer of compound (I) was observed.

That is, the preparation containing compound (I) according to the present invention stays only at the application site, exhibits excellent medicinal efficacy at the application site, and exhibits no systemic effects (side effects) associated with absorption from the application site. Therefore, it can be said that it is an extremely useful external preparation from the standpoint of safety.

In addition, in terms of clinical pharmacological effects, cream formulation (I) with a particularly high water content exhibits the granulation-promoting effect of tocopheryl retinoate and the hematoma removal effect derived from cream formulations. It has an excellent healing promoting effect.

As described above, the external preparation of the present invention not only makes preparation of the external preparation extremely easy without impairing the stability of compound (1), but also serves as a therapeutic agent useful for skin diseases, especially for deep ulcers. Ointments including creams that can be applied;
This can be said to be of great significance as it provides a lotion.

(XI, 00Dcps)

[Brief explanation of the drawing]

The figure shows the results of Example 2. Patent applicant: Nippon Ledary Co., Ltd. times Rotation number

Claims (6)

[Claims] (1) (a) The following formula (I): ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) α-tocopherol vitamin A acid ester 2
．． 0 to 40.0% by weight; (b) dibutylhydroxytoluene 0.01 to 5.
0% by weight, and (c) an oily raw material. (2) The external preparation drug substance according to claim 1, which has a viscosity at room temperature of 1000 centipoise or less. (3) Based on the total weight of the preparation: (a) 0.05 to 5.0% by weight of α-tocopherol vitamin A acid ester represented by formula (I) according to claim 1, (b) 0.0% by weight of dibutylhydroxytoluene. 002 to 0
．． 2% by weight, and (c) an oily raw material. (4) Based on the total weight of the preparation: (a) 0.05 to 5.0% by weight of α-tocopherol vitamin A acid ester represented by formula (I) according to claim 1 (b) 0.002% of dibutylhydroxytoluene or 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)
An external preparation for treating skin diseases, which contains at least 1 to 5% by weight of a medium-chain fatty acid ester and (f) water. (5) The external preparation for treating skin diseases according to claims 3 and 4, which is obtained using the drug substance according to claim 1. (6) The external preparation for treating skin diseases according to claims 3 to 5, which is in the form of a cream.