JPH0687750A - Medicine composition - Google Patents

Abstract

PURPOSE:To obtain a medicine composition useful for treating osteoporosis, vitamin D dysbolism, chronic renal insufficiency, etc., comprising 1alpha,25- dihydroxycholecalciferol and a tocopherol. CONSTITUTION:A medicine composition comprises 0.00001-0.001wt.% 1alpha,25- dihydroxycholecalciferol and 0.01-5wt.% tocopherol. The medicine composition is properly mixed with various additives useful for pharmaceutical preparation of common medicines such as crystalline cellulose, lactose, starch, mannitol, silicic anhydride, hydroxypropyl cellulose, magnesium stearate and anhydrous ethanol and pharmaceutically manufactured. The medicine composition can pharmaceutically be manufactured into a dosage form such as tablet, granule, fine granule or capsule. By addition of a tocopherol as a stabilizer, 1alpha,25- dihydroxycholecalciferol as an active ingredient can be prevented from decomposing and maintained stably.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention
It relates to a pharmaceutical composition containing α, 25-dihydroxycholecalciferol.

[0002]

2. Description of the Related Art Vitamin D ₃ is metabolized in vivo and the 1α and 25 carbons in its structure are hydrogenated to 1α, 25-dihydroxycholecalciferol, which exerts its physiological activity. It is said that.
At present, this 1α, 25-dihydroxycholecalciferol has been highly evaluated medically for patients with abnormal vitamin D metabolism as the active vitamin D ₃ inherently in the living body.

However, 1α, 25-dihydroxycholecalciferol is unstable to heat, air, humidity and light and is easily oxidized, and its activity is lowered when a commonly used formulation is stored as it is. Methods such as using aluminum bag packaging for the purpose of blocking humidity and light were used.

However, in such a method, stability against heat and air cannot be secured, and the stability is insufficient.

[0005]

Therefore, there has been a demand for the development of a formulation which does not have the above-mentioned drawbacks and which can ensure sufficient stability such that it can be stored for a long period of time.

[0006]

[Means for Solving the Problems] Under the circumstances, as a result of intensive studies by the present inventors, the above requirements were satisfied by incorporating tocopherols as stabilizers into 1α, 25-dihydroxycholecalciferol preparations. The present invention has been completed based on the finding that a pharmaceutical preparation that can be obtained is obtained.

That is, the present invention provides a pharmaceutical composition containing 1α, 25-dihydroxycholecalciferol and tocopherols.

The tocopherols incorporated as a stabilizer in the pharmaceutical composition of the present invention are free tocopherols or tocopherol derivatives, and they may be any homologues of α, β, γ, σ and the like. Examples of the tocopherols include DL-α-tocopherol and DL-α-tocopherol acetate.

In order to prepare the pharmaceutical composition of the present invention, the above-mentioned tocopherols are blended with 1α, 25-dihydroxycholecalciferol as an active ingredient according to a conventional method,
It may be formulated.

The compounding amount of 1α, 25-dihydroxycholecalciferol in the pharmaceutical composition of the present invention is 0.0000.
It is desirable to set the amount to about 1 to 0.001% by weight (hereinafter, simply referred to as "%"), and the tocopherols should be 0.001%.
It is preferable to add about 01 to 5%, particularly about 0.05 to 1%. When the amount of the tocopherols is less than the above, the effect as a stabilizer becomes low, and when it is too large, color change is likely to occur, which may reduce the commercial value of the formulation, and therefore both are not preferable. .

The preparations prepared as described above are prepared in various dosage forms such as tablets, granules, fine granules, hard capsules,
It may be a soft capsule or the like.

In the formulation of these, various additives usually used in the formulation of pharmaceuticals can be added within a range that does not impair the effects of the present invention. For example, crystalline cellulose, lactose, starch, mannitol, silicic acid anhydride, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose calcium, magnesium stearate, anhydrous ethanol, medium chain fatty acid triglyceride, corn oil,
Soybean oil, sesame oil, gelatin, glycerin, D-sorbitol and the like can be blended and formulated.

[0013]

The present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

Example 1 A 1α, 25-dihydroxycholecalciferol preparation was prepared according to the following formulation. The obtained 1α, 25-dihydroxycholecalciferol preparation was placed in a vial,
It was stored at 60 ° C., and the residual amount of 1α, 25-dihydroxycholecalciferol was measured over time. The results are shown in Table 1.

(Method) Formula I Formula II Formula III Formula IV 1 α, 25-dihydroxycholecalciferol (μg) 0.25 0.25 0.25 0.25 0.25 Absolute ethanol (mg) 0.1 0.1 0 .0.1 0.1 Acetic acid-DL-α-tocopherol (mg) -0.05 0.1 1.0 Medium chain fatty acid triglyceride (mg) 99.9 99.85 99.8 98.9 Total (mg) 100 100 100 100

(Production method) 1α, 25 in absolute ethanol
-A solution of dihydroxycholecalciferol dissolved and dissolved in medium-chain fatty acid triglyceride together with acetic acid-DL-α-tocopherol was filled in a vial.

(Result) As is clear from this result, in the preparation containing no acetic acid-DL-α-tocopherol, almost 1α, 25-dihydroxycholecalciferol was decomposed by the storage for 2 weeks, but the acetic acid-DL-α-tocopherol was added. Almost no decomposition was done with the ones that were made.

Example 2 A soft capsule was produced according to the following formulation. (Process) 1α, 25-dihydroxycholecalciferol 0.25 μg absolute ethanol 0.1 mg DL-α-tocopherol 0.1 mg Medium chain fatty acid triglyceride 99.8 mg Subtotal 100 mg

Gelatin 62.5 mg Concentrated glycerin 12.5 mg D-sorbitol solution (70%) 9.37 mg Titanium oxide 0.63 mg Subtotal 85 mg Total 185 mg

(Production method) 1α, 25 in absolute ethanol
-Dissolve dihydroxycholecalciferol, DL
A mixture of α-tocopherol and medium-chain fatty acid triglyceride was dissolved in gelatin, concentrated glycerin, D-
It was filled in a soft capsule made of sorbitol liquid and titanium oxide. The obtained soft capsule was stable even when stored at room temperature for 6 months or more.

[0021]

The pharmaceutical composition prepared according to the present invention is
1α, 2 which is an active ingredient by the action of tocopherols
Prevents the decomposition of 5-dihydroxycholecalciferol,
Since it can be kept stable, it can be stored for a long period of time and is extremely advantageous as a drug for treating osteoporosis, vitamin D metabolism abnormality, chronic renal failure, hypoparathyroidism, rickets, osteomalacia, etc. It is a thing. that's all

Claims (3)

[Claims] 1. A pharmaceutical composition containing 1α, 25-dihydroxycholecalciferol and tocopherols. 2. The content of tocopherols in the composition,
The pharmaceutical composition according to claim 1, which is 0.01% to 5%. 3. The pharmaceutical composition according to claim 1, wherein the tocopherols are DL-α-tocopherol or DL-α-tocopherol acetate.