JP3506474B2 - Psoriasis treatment with improved stability - Google Patents

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a therapeutic agent for psoriasis with improved stability. More specifically, the present invention contains 1α, 24 (R) containing purified white petrolatum as a base.
-The present invention relates to a therapeutic agent for psoriasis, which contains an oily and ointment having improved stability, which contains dihydroxycholecalciferol as an active ingredient.

[0002]

2. Description of the Related Art 1α, 24 (R) -dihydroxycholecalciferol is a compound belonging to the active vitamin D ₃ class. 1α-hydroxycholecalciferol, 1
α, 24-dihydroxycholecalciferol, 1α,
It is known that active vitamin D ₃ such as 25-dihydroxycholecalciferol has an action of regulating calcium level in the body and is useful for so-called osteopenia such as osteoporosis and osteomalacia. [Basic Research and its Clinical Applications],
1099-1106 (1979)].

On the other hand, in recent years, a new pharmacological action of active vitamin D ₃ has been found, and its potential as a therapeutic agent for patients other than osteopenia has been investigated. For example, a therapeutic agent for rheumatoid arthritis (JP-A-56-26820),
The application of active vitamin D ₃ to a cancer cell differentiation inducer (JP-A-57-149224) is being studied.

In view of the above situation, the present inventors have earnestly studied the possibility of active vitamin D ₃ as a new therapeutic agent, and as a result, 1α, 24 (R) -dihydroxycholecalciferol [hereinafter referred to as " 1α, 24 (R)-(O
H) ₂ -D ₃ "] is effective as a therapeutic agent for psoriasis, which is a type of skin disease.
When 24 (R)-(OH) ₂ -D ₃ is used as a therapeutic agent for psoriasis, it has been found that an ointment comprising a specific solvent and a specific lipophilic base is particularly suitable, and it has already been reported that 1α ，
A type containing 24 (R) -dihydroxycholecalciferol as an active ingredient and having a dosage form of 1α, 24 (R) -dihydroxycholecalciferol, which is selected from the group consisting of fatty acid esters, higher alcohols and propylene carbonate Alternatively, it is composed of a hydrophobic or anhydrous solvent which is a mixture of two or more kinds, and a lipophilic base which is one or a mixture of two or more kinds selected from white petrolatum, yellow petrolatum, liquid paraffin and polyethylene gel of liquid paraffin. An ointment, wherein the amount of the hydrophobic or anhydrous solvent is 0.01 to 25.0 of the ointment.
We proposed a psoriasis therapeutic agent that is wt% (Japanese Patent Publication No. 3-680).
09 gazette).

The ointment contains 1α, 24 (R)-(O
H) ₂ -D ₃ must be dissolved in the oily ointment. To dissolve 1α, 24 (R)-(OH) ₂ -D ₃ in the oily ointment, the oily ointment must be dissolved. Need to have polarity, in order for the oily ointment to have polarity, it is necessary to add a polar solvent to the oily base, and the added solvent must be hydrophobic or anhydrous,
If the polarity of the solvent to be added is too high, the compatibility of the solvent and the oily base becomes poor, and there is a limit to the amount of the solvent to be added in order to maintain the form of the ointment. The above publication discloses room temperature one year stability data of the ointment, and it is shown that a stable preparation is provided.

[0006]

DISCLOSURE OF THE INVENTION The inventors of the present invention have included 1α, 24 (R) -dihydroxycholecalciferol as an active ingredient in the oily ointment disclosed above,
A hydrophobic or anhydrous solvent whose dosage form is one or a mixture of two or more selected from the group consisting of fatty acid esters capable of dissolving 1α, 24 (R) -dihydroxycholecalciferol, higher alcohols and propylene carbonate; , An ointment consisting of white petrolatum or a lipophilic base which is a mixture of white petrolatum and liquid paraffin, wherein the amount of the hydrophobic or anhydrous solvent is 0.01 to 25.0% by weight. As a result of the progress, we have experienced that under severe conditions, the content of 1α, 24 (R) -dihydroxycholecalciferol decreases. It should be noted that the decrease in content was not observed under ordinary storage conditions, and it cannot be said that the ointment composition of this publication has a practical problem.

However, it is important for quality assurance that stability can be guaranteed even when stored under unexpected conditions. Therefore, an object of the present invention is to provide a therapeutic agent for psoriasis, which comprises the above-mentioned ointment containing 1α, 24 (R) -dihydroxycholecalciferol, whose stability is guaranteed even under severe conditions, as an active ingredient. To do.

[0008]

Means for Solving the Problems The inventors of the present invention have conducted extensive studies to solve the above problems, and as a result, depending on the purity of white petrolatum used for imparting semisolidity to an ointment,
It was found that the stability of 1α, 24 (R) -dihydroxycholecalciferol under severe conditions is greatly affected.

Vaseline, which is separated from petroleum components, is an amorphous ointment-like substance obtained mainly from paraffin-based crude oil. Generally called petrolatum. The manufacturing method is as follows. That is, a crude product is obtained by using a precipitate produced by cooling a residual oil obtained by distilling paraffinic crude oil in petroleum crude oil or a precipitate in a storage tank as a raw material and removing a low boiling point portion by steam treatment. Further, after the cylinder oil is treated by the solvent dewaxing method, the oil is deoiled by allowing it to stand for cooling or centrifuging to obtain a crude product. Refining should avoid heating at high temperature, treatment with strong acid or strong alkali, activated carbon or adsorbed soil fuller's earth
The layer is heated to remove unsaturated hydrocarbons and impurities,
Deodorize and decolorize. By repeating this operation, red,
It begins to decolorize from yellow to white.

The white petrolatum thus obtained is
Although it is widely used as an ointment, as described above, it is not possible to completely remove a trace amount of an aromatic compound, a compound having an aldehyde group, or a colored resinous substance, although it has undergone the purification step. Therefore, when the normally available white petrolatum was used as a 0.5 (w / v)% isooctane solution and the absorbance at 275 nm was measured, absorption that was thought to be due to these impurities was observed, and the absorbance (OD) ) Records a value in the range of 0.4 to 1.1.

The present inventors have found that these white petrolatums contain a decrease in the content of 1α, 24 (R) -dihydroxycholecalciferol in an ointment base consisting mainly of white petrolatum under severe conditions. It was presumed that it was due to trace amounts of impurities, and similar stability was investigated using purified white petrolatum with further reduced amounts of these impurities. As a result, surprisingly, when using highly purified white petrolatum,
Specifically, when 0.5 (w / v)% isooctane solution was used and white petrolatum whose absorbance at 275 nm was 0.4 or less was used, 1α, 24 (R ) -Dihydroxycholecalciferol content was found to be almost undecreased and the present invention was reached.

Thus, the present invention is based on 1α, 24 (R)-
One or more kinds selected from the group consisting of fatty acid esters containing dihydroxycholecalciferol as an active ingredient and dissolving 1α, 24 (R) -dihydroxycholecalciferol, higher alcohols and propylene carbonate A mixture of a hydrophobic or anhydrous solvent and a lipophilic base which is a mixture of white petrolatum or white petrolatum and liquid paraffin, and the amount of the hydrophobic or anhydrous solvent is 0.01 to 25.0. In a psoriasis therapeutic agent, which is an ointment in a weight percentage, white petrolatum dissolves it in isooctane to give a concentration of 0.5 (w / w
v) A therapeutic agent for psoriasis with improved stability, which is characterized by being 0.4 or less when measuring the absorbance at 275 nm of the solution adjusted to%.

In the present invention, the fatty acid esters include diisopropyl adipate, decyl oleate, diethyl sebacate, isopropyl myristate, triacetin, glycerin tricaproate, glyceryl tricaprylate, glyceryl tricaprate, glyceryl trilaurate, trilinoleic acid. One or a mixture of two or more selected from the group consisting of glycerin, propylene glycol dicaprylate, propylene glycol dipelargonate and propylene glycol dicaprate is preferable.

The higher alcohols are preferably one or a mixture of two or more selected from the group consisting of octyldodecanol, hexadecyl alcohol and oleyl alcohol.

The amount of the solvent is 0.01 to 0.01 of the ointment.
It is 25.0% by weight. If the amount of the solvent exceeds 25.0% by weight in the ointment, the ointment fluidizes at a relatively high temperature or during long-term storage, which is not preferable. Furthermore, 1α, 24
Considering the stability and percutaneous absorbability of (R) -dihydroxycholecalciferol, 0.1 to 1 is preferable.
It is 0.0% by weight.

The amount of 1α, 24 (R) -dihydroxycholecalciferol added to the ointment can be appropriately increased or decreased.
Usually, it is 1 ng to 2 mg per 1 g of the ointment. further,
More preferably, it is 5 ng / g to 0.5 mg / g.

Purified white petrolatum, which is used in the present invention and which has an absorbance at 275 nm of 0.4 or less when dissolved in isooctane and adjusted to a concentration of 0.5 (w / v)%, is usually, for example, In the presence of a catalyst obtained by coprecipitating the white vaseline of the present invention with an oxide of a Group IV metal and reduced nickel, or a stabilized Raney-Nickel catalyst containing a Group IV metal and aluminum at a reaction temperature of 150- 230
At a temperature of 50 to 150 kg / cm ^{2 of} hydrogen pressure,
It can be produced by a method such as collecting microcrystalline or amorphous paraffin that does not contain an aromatic compound and a colored resinous substance (see Japanese Patent Publication No. 61-11992), and in Japan, for example, Nikko Rica It is available as white petrolatum of sun white grade manufactured by Kogyo Co., Ltd. In the present invention, the absorbance of a 0.5% (w / v)% isooctane solution of white petrolatum at 275 nm is 0.4 or less, but it is 0 to improve the stability of 1α, 24 (R) -dihydroxycholecalciferol. It is preferably 0.3 or less.

The lipophilic base includes the above-mentioned purified white petrolatum or a mixture thereof with liquid paraffin. In the case of the mixture, the ratio of white petrolatum: liquid paraffin is 99.5: 0.5 to 70: 30 is preferable, and 99: 1 to 90:10 is more preferable.

The therapeutic agent for psoriasis of the present invention comprises 1α, 24 (R)
Prepared by dissolving dihydroxycholecalciferol in a hydrophobic or anhydrous solvent and then mixing the resulting solution with a lipophilic base. It is also possible to dissolve 1α, 24 (R) -dihydroxycholecalciferol in a mixture prepared by previously mixing a lipophilic base with a hydrophobic or anhydrous solvent to prepare an oily ointment.

If desired, a preservative, an antioxidant, etc. may be added to the therapeutic agent for psoriasis of the present invention. Examples of the preservative include paraoxybenzoic acid ester, sodium benzoate, sorbic acid, boric acid and the like. Examples of the antioxidant include butylhydroxyanisole,
Dibutyl hydroxytoluene and the like can be mentioned.

[0021]

EXAMPLES The effects of the present invention will be described in more detail below with reference to examples, but the present invention is not limited thereto.

Examples 1 to 5, Control Examples 1 to 7 90 parts by weight of white petrolatum, 5 parts by weight of liquid paraffin [made by Yoshida Pharmaceutical Co., Ltd.] and 5 parts by weight of isopropyl myristate [made by Nikko Chemicals Co., Ltd.] A base is prepared, and 1α, 24 (R) -dihydroxycholecalciferol is dissolved at 2.0 μg / g to prepare 1α, 24
An (R) -dihydroxycholecalciferol ointment was prepared. As white petrolatum, those having various purities were used. The obtained ointment was placed in a glass bottle and stored at 50 ° C. for 1 month, and the residual rate (%) at the start of 1α, 24 (R) -dihydroxycholecalciferol was examined. Also, after storing the white petrolatum used in the same manner,
The absorbance at 275 nm of a 0.5 (w / v)% isooctane solution was measured. The results are shown in Table 1. Note that 1α, 24
The residual ratio (%) of (R) -dihydroxycholecalciferol at the start is a ratio when the residual amount one day after the start of storage is 100.

[0023]

[Table 1]

─────────────────────────────────────────────────── ─── Continuation of front page (56) References JP 62-26223 (JP, A) JP 63-99014 (JP, A) JP 53-32129 (JP, A) (58) Field (Int.Cl. ⁷ , DB name) A61K 31/593 A61K 9/06 A61K 47/06 A61P 17/06 BIOSIS (STN) CAPLUS (STN) MEDLINE (STN) EMBASE (STN)

Claims (3)

(57) [Claims] 1. A formulation containing 1α, 24 (R) -dihydroxycholecalciferol as an active ingredient and having a dosage form of 1α,
A hydrophobic or anhydrous solvent which is one or a mixture of two or more selected from the group consisting of fatty acid esters capable of dissolving 24 (R) -dihydroxycholecalciferol, higher alcohols and propylene carbonate, and white petrolatum or white. In the therapeutic agent for psoriasis, which is an ointment comprising a lipophilic base which is a mixture of petrolatum and liquid paraffin, and the amount of the hydrophobic or anhydrous solvent is 0.01 to 25.0% by weight, the white petrolatum Is 0.4 or less when the absorbance at 275 nm of a solution prepared by dissolving it in isooctane and adjusting the concentration to 0.5 (w / v)% is 0.4 or less. Agent. 2. Fatty acid esters include diisopropyl adipate, decyl oleate, diethyl sebacate, isopropyl myristate, triacetin, glyceryl tricaproate, glyceryl tricaprylate, glyceryl tricaprate, glyceryl trilaurate, glyceryl trilinoleate, dicapryl. The therapeutic agent for psoriasis with improved stability according to claim 1, which is one kind or a mixture of two or more kinds selected from the group consisting of propylene glycol acid, propylene glycol dipelargonate, and propylene glycol dicaprate. 3. The therapeutic agent for psoriasis with improved stability according to claim 1, wherein the higher alcohol is one kind or a mixture of two or more kinds selected from the group consisting of octyldodecanol, hexadecyl alcohol and oleyl alcohol.