JPH04288016A - Production of soft capsule agent of active type vitamin d3s - Google Patents

Abstract

PURPOSE:To efficiently obtain a soft capsule agent of active type vitamin D3 by extremely shortening a preparation time of a solution of content to be packed into a soft capsule agent (<=1/20 preparation time by conventional method) and preventing deactivation of active vitamin D3 in a production process. CONSTITUTION:Active type vitamin D3 is dissolved in a small amount, preferably gamma10 pts.wt., especially 0.01-1 pts.wt. ethanol, preferably anhydrous ethanol based on 100 pts.wt. middle-chain fatty acid triglyceride, then mixed with well purified middle-chain fatty acid triglyceride composed of 8-12C fatty acid not containing an unsaturated fatty acid, such as tricaprylic acid glyceride, tricapric acid glyceride or trilauric acid glyceride to give a solution of content to be packed into a soft capsule, having uniformly dissolved active type vitamin D3, in an extremely short time. Then the solution is packed into a soft capsule agent film to give a soft capsule agent of active type vitamin D3 in a short time especially advantageously in terms of mass production without deactivating the active type vitamin D3 during preparation of the solution of content.

Description

[Detailed description of the invention]

0001

[Industrial Application Field] The present invention relates to a method for manufacturing soft capsules of active vitamin D3, and more specifically, it can significantly shorten the manufacturing time and prevent deactivation of active vitamin D3 during the manufacturing process. The present invention relates to a method for producing active vitamin D3 type soft capsules.

0002

[Prior Art and Problems to be Solved by the Invention] Vitamin D3 undergoes metabolism in the living body, and carbons at the 1α and 25th positions in its structure are hydroxylated to become 1α,25-dihydroxycholecalciferol, which causes physiological problems. It is said to exhibit activity. At present, 1α,25-dihydroxycholecalciferol is considered to be the most physiologically active metabolite of vitamin D;
It has been highly evaluated medically for patients with metabolic disorders. In addition, similar compounds of this compound include 1α-hydroxycholecalciferol, 1α, which has a hydroxyl group at the 1α position,
24-dihydroxycholecalciferol, 1α,24
, 1α such as 25-trihydroxycholecalciferol
-Hydroxyvitamin Ds are synthesized, these are 1α,
Since it has similar physiological activity to 25-dihydroxycholecalciferol, it is expected to be applied clinically as an active vitamin D3 class. This active form of vitamin D
Class 3 has high physiological activity, so the single dose is 0.5
Since the amount is extremely small (μg), it is preferable to dissolve it in an oily base and make it into a soft capsule to ensure accurate dosage for patients and to make it easy to administer.
No. 1-233618).

However, all active vitamin D3s are unstable to heat and light and easily oxidized, so if they are simply dissolved in a commonly used oil base and made into soft capsules, their activity will not be maintained during storage. It will drop. For this reason, conventionally,
A method of stabilizing the oil base by irradiating it with light in advance (Japanese Patent Laid-Open No. 53-75320), or adding an ultraviolet absorber such as a tar pigment to the coating (Japanese Patent Laid-Open No. 54-8402)
Methods such as No. 3) were used. However, irradiating the oily base with light in advance is complicated and causes high costs, and the use of ultraviolet absorbers is not preferable in view of the adverse effects on the human body.

[0004] In contrast, the present inventors have discovered that a soft capsule in which active vitamin D3 is dissolved in medium-chain fatty acid triglyceride containing substantially no unsaturated acids and filled into the soft capsule shell is available indoors. We previously reported that it is stable with almost no decrease in activity even when stored under scattered light for 30 days (
JP-A-61-189229). However, even with soft capsules using this specific triglyceride, there is a problem that if the content liquid for capsule filling is not prepared as quickly as possible, the active vitamin D3s may be deactivated during the preparation of the content liquid. was there. This problem has been a major obstacle in mass production of active vitamin D3 soft capsules.

[0005]

[Means for Solving the Problems] Under such circumstances, the present inventors have conducted intensive research and found that active vitamin D3
By dissolving D3 in a small amount of ethanol and then mixing it with the medium-chain fatty acid triglyceride, a content solution in which active vitamin D3 is completely and uniformly dissolved can be obtained in an extremely short time, and the active vitamin D3 is dissolved during the preparation of the content. They discovered that vitamin D3s can be mass-produced without deactivation, and completed the present invention.

[0006] That is, the present invention provides active vitamin D3.
of a soft capsule, which is characterized in that after dissolving the same in a small amount of ethanol, the mixture is mixed with medium-chain fatty acid triglyceride substantially free of unsaturated acids, and the resulting content liquid is filled into the soft capsule shell. A manufacturing method is provided.

[0007] In the present invention, first, activated vitamin D
Dissolve Type 3 in a small amount of ethanol. The ethanol used here is preferably anhydrous ethanol. The amount of ethanol used may be the minimum amount necessary to dissolve active vitamin D3 in a short time, but it should not exceed 10 parts by weight per 100 parts by weight of medium-chain fatty acid triglyceride.
Particularly preferred is 0.01 to 1 part by weight. If the amount of ethanol is too large, the soft capsule skin will dissolve, and if the amount of absolute ethanol is too small, it will take a long time to completely dissolve the active vitamin D3, which is not preferable.

[0008] Next, the obtained ethanol solution is mixed with medium chain fatty acid triglyceride to obtain a content liquid for filling soft capsules. The medium-chain fatty acid triglyceride used in the present invention is a well-purified triglyceride composed of a fatty acid having 8 to 12 carbon atoms and substantially free of unsaturated acids, such as tricaprylic acid glyceride, tricapric acid glyceride, trilauric acid glyceride, etc. Examples include glyceride. These may be used alone or in a mixture of two or more, and are commercially available, for example, as Panacet 800, Panacet 810, or Panacet 812 (all brand names of NOF Corporation). The amount of medium-chain fatty acid triglyceride used is not particularly limited as long as it dissolves active vitamin D3s, but is preferably 50,000 to 800,000 parts by weight per 1 part by weight of active vitamin D3s.

The content liquid for filling soft capsules thus obtained is filled into soft capsule shells by means known per se. Here, the soft capsule skin is mainly composed of ingredients used in ordinary soft capsules, such as gelatin, succinated gelatin, etc., and contains glycerin, sorbitol, etc.
Those with added light shielding agents, preservatives, etc. are used.

0010

EXAMPLES Next, the present invention will be explained in detail with reference to Examples, but the present invention is not limited thereto.

Example 1 10 mg of α-hydroxycholecalciferol was dissolved in 2 g of absolute ethanol by stirring under a nitrogen gas stream.
Furthermore, Panacet 810 (manufactured by Nippon Oil & Fats Co., Ltd.) 1998
A soft capsule filling solution was prepared by mixing the mixture with stirring, and soft capsules of 1α-hydroxycholecalciferol were obtained using a capsule shell made of succinated gelatin and glycerin according to a conventional method.

Comparative Example 1 10 mg of α-hydroxycholecalciferol was stirred under the same conditions as in Example under a stream of nitrogen gas.
g of Panasate 810 to prepare a soft capsule filling liquid, and the following procedure was carried out in the same manner as in the Examples to obtain 1α-hydroxycholecalciferol soft capsules.

Test Example During the production of the content liquid for filling soft capsules in the above Examples and Comparative Examples, the liquid was sampled over time while stirring, and the content of 1α-hydroxycholecalciferol in the solution was measured. We compared the time required. The results are shown in Table 1.

[Table 1] As a result, according to the method of the present invention, it was completely dissolved in 5 minutes, whereas in the comparative example, it was not completely dissolved even after 60 minutes, and it took 120 minutes for complete dissolution. did. Further, in the method of the present invention, almost no deactivation of 1α-hydroxycholecalciferol was observed during the preparation of the content liquid.

[0014]

[Effects of the Invention] According to the method of the present invention, the content liquid for filling soft capsules can be obtained in less than 1/20 of the time compared to conventional manufacturing methods, and active vitamin D3 types are deactivated during the manufacturing process. Active vitamin D3 soft capsules can be obtained efficiently. The method of the invention is particularly advantageous for mass production.

Claims (1)

[Claims] [Claim 1] After dissolving active vitamin D3 in a small amount of ethanol, it is mixed with medium-chain fatty acid triglyceride that is substantially free of unsaturated acids, and the resulting content liquid is filled into soft capsule shells. A method for producing a soft capsule, characterized by: