JPS63165322A - Activated vitamin d composition - Google Patents

Abstract

PURPOSE:To obtain the titled composition having improved stability to light, by adding carotenoids to an oily solution of activated vitamin D. CONSTITUTION:Carotenoids (e.g. lycopene, beta-carotene, xanthophyll, etc.) are added to an oily solution of active vitamin D selected from 1alpha-, 24- or 25- hydroxycholecalciferol, 1alpha,24-, 1alpha,25- or 24,25-dihydroxycholecalciferol and 1alpha,24,25-trihydroxycholecalciferol. 10,000-1,000,000pts.wt. of an oily base is used based on 1pt.wt. of the active vitamin D and the amount of the carotenoids is 0.1-0.001wt% of the oily base. The composition is preferably further incorporated with dibutylhydroxytoluene, tocopherols, gallic acid esters, etc., as a stabilizer for carotenoids.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a photostable active vitamin D-containing pharmaceutical composition.

[Problems to be solved by conventional techniques and inventions] In recent years,
Active vitamin D compounds with strong vitamin D-like biological activity, such as 1α-hydroxycholecalciferol, have been developed, and their application to various diseases caused by vitamin D metabolic disorders, such as rickets and osteomalacia, is attracting attention. has been done. Since these active vitamin Ds have extremely strong biological activity, the amount administered at one time is very small, and therefore, the uniformity and stability of the content in the preparation are particularly required. As a method for preparing this formulation, active vitamin D is dissolved in an oily base such as triglyceride to form an oily solution, which is then encapsulated into a soft capsule to form a preparation for oral administration.

However, active vitamin D types cannot be stimulated by heat, light,
It is unstable to oxygen, etc., and is particularly sensitive to light, for example, activated vitamin D in a glass bottle.
When exposed to sunlight, an oily solution of 50% may be deactivated in 30 minutes. Therefore, although the formulation work is carried out with such considerations in mind, it is practically impossible to carry out the work under complete shielding from light, and the influence of light cannot be avoided.

For this reason, various proposals have been made for photostabilizing active vitamin D. For example, a method of adding dibutylhydroxytoluene, gallic acid esters, or tocopherols as a stabilizer (Japanese Patent Application Laid-Open No. 53-12414
), a method of adding dibutylhydroxyanisole as a stabilizer (JP-A-57-40414), a method of adding hydroquinone as a stabilizer (JP-A-57-4),
0415) etc. However, neither of these methods has yielded fully satisfactory results.

The present invention was made in view of the above circumstances, and an object of the present invention is to provide a pharmaceutical composition containing active vitamin D that has improved stability against light.

[Means for Solving the Problems] The present invention achieves the intended purpose of photostabilizing active vitamin D by incorporating carotenoids into an oily solution of active vitamin D. be.

That is, the present invention relates to a stable active vitamin D-containing pharmaceutical composition comprising carotenoids contained in an oily solution of active vitamin D.

The active vitamin D used in the present invention is 1α
-Hydroxycholecalciferol, 24-hydroxycholecalciferol, 25-hydroxycholecalciferol, 1α,24-dihydroxycholecalciferol, 1α,25-dihydroxycholecalciferol, 24.25-dihydroxycholecalciferol,
1α, 24.25-trihydroxycholecalciferol, 25-hydroxyergocalciferol, 1α
, 25-dihydroxyergocalciferol, etc. The amount of active vitamin D @ added to the oil base is 1 part by weight of active vitamin D to 1 part by weight of the oil base.
The proportion is 0.000 to 10.000.000 parts by weight.

Further, carotenoids used in the present invention include lycopene, β-carotene, and xanthophyll.

Capsanthin, β-apo-8'-rotinal.

Bixin, etc., and natural pigments containing these as main ingredients can also be used. However, carotenoids that are as pure as possible are effective, and therefore commercially available highly pure β-carotene, bixin, etc. are preferable to those containing impurities derived from natural pigments. In addition, dibutylhydroxytoluene is used as a stabilizer for carotenoids, as carotenoids themselves are subject to deterioration due to light.

When one or more of butylhydroxyanisole, tocopherols, gallic acid esters, etc. are added, the effect is greatly improved. Carotenoids may be in a state in which they are not completely dissolved in the oily base, that is, in a suspended state, but it is preferable that they are completely dissolved. Therefore, the amount used is preferably 0.1 to 0.001% by weight based on the oil base.

The oily base to be used may be any oily substance that can dissolve active vitamin D in the above-mentioned ratio, such as natural oil, especially medium-chain (8 to 10 carbon atoms) triglycerides, propylene glycol fatty acid diesters, etc. , polyglycerin fatty acid ester, etc. are preferred.

The pharmaceutical composition of the present invention may be prepared by adding active vitamin D and carotenoids to an oily base simultaneously or sequentially, for example, adding carotenoids to an oily solution in which active vitamin D is dissolved in an oily base. However, the use form as a pharmaceutical is obtained by filling capsules filled with this pharmaceutical composition, such as filling such a composition into hard capsules or coating such a composition with a waste agent mainly composed of gelatin. A soft capsule formulation is preferred. The above-mentioned waste agent is made of, for example, gelatin, modified fused gelatin treated with an acylating agent, glycerin, propylene glycol, and sorbitol.
The ultraviolet absorber or ultraviolet remover described in No. 023 may be added to reduce the effect of ultraviolet rays on active vitamin Ds. As the ultraviolet absorber, in addition to conventional ultraviolet absorbers, it is also preferable to use caramel, and good results can be obtained by adding 1 to 40% by weight of the waste agent. For this purpose, a coloring agent having absorption in the visible region may be added as necessary.

Next, the present invention will be specifically described with reference to Examples, but the present invention is not limited by these in any way.

[Example] Example 1 Propylene glyconyl caprylic acid ester (trade name "Cefsol 228 J" manufactured by Nikko Chemical Co., Ltd.) was used as an oily base, and 1α-hydroxycholecalciferol was added to it at a concentration of 10 μQ/rd. Various stabilizers shown in Table 1 below were further dissolved in this solution, and the bottles were placed in a colorless and transparent glass bottle, sealed, and placed in a place where direct sunlight could enter through the glass window. For each sample, the residual rate of 1α-hydroxycholecalciferol (denoted as "D3 residual rate" in the table) after 3 days, 7 days, and 14 days was measured by high performance liquid chromatography. The results are shown in Table 1.

As is clear from Table 1, when β-carotene, bixin, and xanthophyll were added as stabilizers, the results were higher at each measurement time than when dibutylhydroxytoluene (BHT), α-tocopherol, and their combinations were added. It can be seen that the stability against light is clearly improved.

(The following is a blank space) Table 1 Example 2 Using propylene glycol caprylic acid ester (trade name [Cefsol 228J: manufactured by Nikko Chemical Co., Ltd.) as an oily base, 0.02% by weight of β-carotene was dissolved therein, and BHT and α-tocopherol were dissolved. In this solution, 1α-hydroxycholecariciferol was dissolved at a concentration of 10 μg/d, and as in Example 1, the bottle was placed in a colorless transparent glass bottle, sealed, and placed in a place where direct sunlight could enter through the glass window. The residual rate of 1α-hydroxycholecalciferol (“D3 residual rate”) was measured in the same manner after 1 day, 7 days, and 14 days.

In addition, samples in which the stabilizer was only BHT and only β-carotene were similarly prepared and measured in the same manner. The results are shown in Table 2.

As is clear from Table 2, photostability is improved more when BHT or α-tocopherol, which is a carotenoid stabilizer, is added roughly than when only β-carotene is added as a stabilizer. There was found.

Table 2 Example 3 The following experiment was conducted to examine the stability of the stabilizer of the present invention on various oily bases.

Nα1...Glycerin straight chain saturated fatty acid ester (0,
D, O,: Nisshin Seyuu Co., Ltd.) Nα2... Propylene glycol linear saturated fatty acid ester (Cefsol 228: Nikko Chemical Co., Ltd.) ~03... Hexaglycerin linear saturated fatty acid ester (Cefsol 668: Nikko Chemical Co., Ltd.) (manufactured by) Nα4...Diglycerin straight chain saturated fatty acid with 8 carbon atoms]
Ester (manufactured by Nikko Chemical Co., Ltd.) 0.02% by weight of β-carotene in each of the above oily bases, 8H
T@0.02% was dissolved, and 1α-hydroxycholecalciferol was dissolved in a colander to a concentration of 10 μg/ml. This solution was placed in a colorless transparent glass bottle as in Example 1, sealed, and placed in a place where direct sunlight could enter through the glass window. After 3 days, 7 days, 1 for each sample
The residual rate of 1α-hydroxycholecalciferol (“D3 residual rate”) after 4 days was measured. In addition, as a control, a sample containing no stabilizer (β-carotene and BHT) was similarly prepared and measured in the same manner. The results are shown in Table 3.

As is clear from Table 3, the stabilizer of the present invention was found to be stable against the various oily bases mentioned above.

Table 3 Example 4 Using propylene glycol cacryl ester as an oily base, β-carotene and dibutylhydroxytoluene were each dissolved in an amount of 0.02% by weight, and then 1α
-Hydroxycholecalciferol was dissolved. This oily solution was filled into capsules mainly composed of gelatin at 150 mg per capsule using a rotary set soft capsule filling machine to form light-stabilized soft capsules containing 1 μQ of 1α-hydroxycholecalciferol per capsule. Manufactured.

Example 5 Soft capsules photostabilized in the same manner as in Example 4 except that triglyceride of a fatty acid having 8 to 10 carbon atoms (Panasate 810: manufactured by NOF Corporation) was used instead of propylene glycol cycaprylic acid ester. was manufactured.

Example 6 Example 4 except that propylene glycol caprilate (Cefsol 220: manufactured by Nikko Chemical Co., Ltd.) was used instead of propylene glycol caprilate.
A photostabilized soft capsule was produced in the same manner as above.

Example 7 Light-stabilized soft capsules were produced in the same manner as in Example 4, except that a mixture of the same amount of propylene glycol caprilate and vanasate 810 was used instead of propylene glycol caprilate.

Example 8 Using propylene glycol cacryl ester as an oily base, β-carotene and dibutylhydroxytoluene were each dissolved in an amount of 0.02% by weight, and then 1α
-Hydroxycholecalciferol was dissolved. Using a hard capsule filling machine, this oily solution was filled with 15 ml per capsule.
Photostabilized hard capsules filled with 0 #Ig and containing 1 # of 1α-hydroxycholectoluciferol per capsule were prepared.

[Effects of the Invention] As explained above, according to the present invention, by adding carotenoids to an oily solution of active vitamin Ds, the stability of active vitamin Ds against light can be significantly improved. It is possible to provide an active vitamin D pharmaceutical preparation with high photostability.

(8733) Agent: Yoshiaki Inomata, patent attorney (and others)
1 person)

Claims (4)

[Claims] (1) A stable active vitamin D-containing pharmaceutical composition comprising an oily solution of active vitamin D containing carotenoids. (2) Active vitamin D types include 1α-hydroxycholecalciferol, 24-hydroxycholecalciferol, 25-hydroxycholecalciferol, 1α,24
- At least one active vitamin D selected from the group consisting of dihydroxycholecalciferol, 1α,25-dihydroxycholecalciferol, 24,25-dihydroxycholecalciferol, and 1α,24,25-trihydroxycholecalciferol The stable active vitamin D-containing pharmaceutical composition according to claim 1, which is a type of vitamin D. (3) A patent in which the carotenoid is at least one carotenoid selected from the group consisting of lycopene, β-carotene, xanthophyll, capsanthin, β-apo-8'-carotenal, and bixin, or a natural pigment containing these as a main component. A stable active vitamin D-containing pharmaceutical composition according to claim 1. (4) The stable active vitamin D-containing pharmaceutical composition according to claim 1, which contains carotenoids and a drug that stabilizes carotenoids.