JPH0327535B2 - - Google Patents

Description

[Detailed description of the invention]

<Industrial Application Field> The present invention is directed to the use of active vitamin D ₃ as an active ingredient.
The present invention relates to a soft capsule of active vitamin D type ₃ stabilized by type 3. More specifically, the present invention is a soft capsule containing a metabolite of vitamin _D3 currently known as an active form and a synthetic analogue compound as an active ingredient, and a natural coloring agent contained in the shell of the capsule. This invention relates to a soft capsule of active vitamin D type ₃ , which is stabilized against light. <Prior art> 1α,25-dihydroxycholecalciferol,
1α,24-dihydroxycholecalciferol,
Active vitamin D ₃ , such as 1α-hydroxycholecalciferol, helps in absorption of calcium in the small intestine,
It is a hormone that promotes transport, regulates bone resorption and bone formation in the bones, and suppresses the secretion of parathyroid hormone in the parathyroid glands. Therefore, the deficiency of active vitamin D type ₃ can cause kidney failure and osteomalacia, where calcium absorption is reduced, or osteoporosis, which is a disease of abnormal bone metabolism, or deficiency of active vitamin D type ₃ . _Three active forms of vitamin D are said to be effective in treating conditions such as rickets. However, since all of these compounds are unstable to heat and light and easily oxidized, it is desirable to take measures such as cooling, shielding from light, and replacing with an inert gas when storing them. This means that
The same applies to formulations containing these, and it is necessary to provide the formulation with means to ensure high storage stability, especially means for stabilizing against light. <Problems to be solved by the invention> Conventionally, methods for photostabilizing formulations containing unstable drugs as active ingredients have involved dispersing food tar-based pigments such as Food Yellow No. 4 in a film to form soft capsules. Methods of
13511) is known. However, recently,
The safety of food tar-based dyes has been questioned and is becoming a problem. On the other hand, as an alternative to the photostabilization method, a method is known in which caramel, which is a natural coloring agent, is contained in the film to form a soft capsule (Japanese Patent Laid-Open Publication No. 127448/1982). However, caramel has the disadvantage that when exposed to light, the caramel itself discolors, and as a result, the photostability of the active ingredient drug deteriorates. JP-A-54-138119 discloses gelatin capsules containing a natural coloring selected from carminic acid, latsukaic acid, cacao pigment, and carminic acid lake, which is safe and has good coloring stability. However, it has not been clarified whether these natural pigments are effective in photostabilizing active vitamin _D3 . <Means for Solving the Problems> As a result of intensive research into soft capsules that are safe for the human body and have stabilized active vitamin D ₃ , the present inventors found that cacao pigment, apigenin, and carmine. The present invention was accomplished by discovering that a soft capsule containing one or more natural coloring agents selected from the group consisting of acid, carminic acid lake, latsukaic acid, and shikonin in the film achieves the above object. In other words, the present invention provides active vitamins as drugs.
A soft capsule containing D ₃ , which contains one or more natural coloring agents selected from the group consisting of cacao pigment, apigenin, carminic acid, carminic acid lake, latcaic acid, and shichonic acid. This is a soft capsule containing active vitamin D type ₃ . Active vitamin D ₃ used in the present invention
Examples include 1α-hydroxycholecalciferol (1α-OH-D ₃ ), 1α,25-dihydroxycholecalciferol (1α,25-(OH) ₂
-D ₃ ), 1α,24-dihydroxycholecalciferol (1α,24-(OH) ₂ -D ₃ ), 1α,24,25-trihydroxycholecalciferol (1α,24,25
-(OH) ₃ -D ₃ ), 1α-hydroxy-24-oxocholecalciferol, 1α,25-dihydroxy-
24-oxocholecalciferol, 1α,25-dihydroxycholecalciferol-26,23-lactone, 1α,25-dihydroxycholecalciferol-26,23-peroxylactone, 26,26,
Active vitamin D ₃ having a hydroxyl group at the 1α position such as 26, 27, 27, 27-hexafluoro-1α, 25-dihydroxycholecalciferol; or
25-hydroxycholecalciferol (25-OH
_-D3 ), 24-hydroxycholecalciferol (24-OH- _D3 ), 24-oxocholecalciferol, 24,25-dihydroxycholecalciferol (24,25-(OH) ₂ - _D3) ), 25-hydroxy-24-
Active vitamin D ₃ types that do not have a hydroxyl group at the 1α position, such as oxocholecalciferol, 25-hydroxycholecalciferol 26,23-lactone, and 25-hydroxycholecalciferol-26,23-peroxylactone, etc. can be mentioned. Natural coloring agents used in the present invention include cocoa pigment, apigenin, carminic acid, carminic acid lake, latukaic acid, and shikonin. Cocoa pigment is a water-soluble thiokolate color pigment obtained from cocoa beans, and is already used in thiokolate, drops, ice cream, etc.
Apigenin is a brown pigment obtained from Kouriyan. Carminic acid is extracted from Coccus cacti, a cactus-parasitic insect that grows naturally in Central and South America.
It is the main component of the red pigment nocochineal, which is obtained from the dried powder of the female body of the female body, and is used in jams, etc. Carminic acid lake is the above-mentioned carminic acid made into aluminum or calcium lake. Lactukaic acid is a water-soluble red pigment obtained from the scales secreted by females of the Lacciter accakerr, which is native to Thailand and India, and is used in the same way as carminic acid. Shikonin is a reddish-purple naphthoquinone pigment obtained from Shicon and is used in lipsticks and other products. Among these natural colorants, one type may be used, or two or more types may be used in combination. Among these natural colorants, cacao pigment and apigenin are preferred from the viewpoint of consistency of color tone, but this is not the case if a slight difference in color tone is acceptable. The amount of natural colorants commonly used is up to 2% by weight of the soft capsule coating, preferably from 0.01 to 1%. Preferably, the natural colorant is uniformly dispersed in the film. Alternatively, the natural colorant may be dispersed only on the surface of the capsule membrane. The soft capsule membrane is made of commonly used gelatin,
It consists of ingredients selected from gum arabic, glycerin, sorbitol, etc.
Other additives may be added to the film as desired. Examples of additives include preservatives such as paraoxybenzoate, benzyl alcohol, and sorbic acid; plasticizers such as glycerin and propylene glycol; and colorants such as talc, titanium oxide, alumina, and calcium carbonate. It is usually preferable that active vitamin D ₃ is dissolved in an oily base and contained in a soft capsule. Examples of oily bases include fatty acid glycerides, corn oil, vegetable oils such as olive oil, etc. Any fatty oil that is oily at room temperature and does not impair the stability of active vitamin D ₃ can be used. Can be used. The soft capsule of the present invention is a soft capsule containing a natural coloring agent, and can be produced by wrapping the contents of the soft capsule by a conventional method such as a plate method, a rotary method, or a dropping method. . It can also be obtained by placing softened capsules in a sugar-coating pan, fluidized bed, etc., and spraying an aqueous solution of a natural coloring agent with a spray gun. <Effects of the Invention> According to the soft capsule of the present invention, active vitamin D type ₃ , which is an active ingredient, is photostabilized, and there are no safety problems for the human body, and the soft capsule contains active vitamin D type ₃ . The present invention has great significance. <Examples> The present invention will be explained in more detail below using examples. Example 1 1α-Hydroxycholecalciferol was dissolved in fatty oil (fractionated coconut oil) to obtain a solution with a concentration of 7 μg/ml, and this was mixed with cocoa pigment (polyphae(71)-standose: standose sugar).
Co., Ltd.) (), Apigenin (Sun Brown K: Sanei Chemical Co., Ltd.)
(), Carminic acid (Powder Sunretsu No. 1: Sanei Chemical Co., Ltd.)
A shell containing 0.45% by weight of carmine (manufactured by Tokyo Kasei Co., Ltd.) (), latsukaic acid (Sunretsudo LN: manufactured by Sanei Chemical Co., Ltd.) (), and 0.45% by weight (gelatin 100
20 parts by weight of glycerin, 0.2 parts by weight of ethyl paraoxybenzoate, 0.2 parts by weight of propal paraoxybenzoate, and 80 parts by weight of purified water) to obtain soft capsules containing 1 μg of 1α-hydroxycholecalciferol. An accelerated light exposure test was performed by irradiating these for up to 10.5 hours with a carbon arc weather meter, and the residual rate of 1α-hydroxycholecalciferol was determined by high performance liquid chromatography. For comparison, soft capsules consisting of a shell without any natural coloring agent and a shell using caramel (FA: Showa Kagaku Kogyo Co., Ltd.) were tested at the same time, and the results shown in the table below were obtained. .

[Table] Example 2 The same procedure as in Example 1 was carried out except that 1α,24-dihydroxycholecalciferol was used instead of 1α-hydroxycholecalciferol in Example 1, and the results shown in the table below were obtained. Ta.

【table】

[Table] Example 3 1α-hydroxycholecalciferol was dissolved in fractionated coconut oil to obtain an oily solution with a concentration of 7 μg/ml. A coating agent is prepared by heating and dissolving shell components consisting of 100 parts by weight of gelatin, 20 parts by weight of glycerin, 0.2 parts by weight of ethyl paraoxybenzoate, 0.2 parts by weight of propyl parahydroxybenzoate, 0.5 parts by weight of cacao pigment, and 80 parts by weight of purified water. and 1μg of 1α-hydroxycholecalciferol per capsule.
A continuous soft capsule making machine was used to apply a shell to produce soft capsules containing the following ingredients.

Claims (1)

[Claims] 1 A soft capsule containing active vitamin D type ₃ as a drug, which contains cacao pigment,
A soft capsule of active vitamin D type ₃ containing one or more natural colorants selected from the group consisting of apigenin, carminic acid, carminic acid lake, latukaic acid, and shikonin.