JPH0515691B2 - - Google Patents

Description

[Detailed description of the invention]

"Industrial Application Field" The present invention relates to soft capsules containing a photolabile drug. "Problems to be Solved by the Prior Art and the Invention" Some drugs with various physiological activities are unstable to light, so it is desirable to take measures such as shielding them from light when storing them. This also applies to formulations containing these drugs, and it is necessary to provide the formulation with means to ensure high storage stability, especially means for stabilizing against light. In addition, soft capsules are capsules made by adding glycerin, sorbitate, etc. to gelatin, etc., and enclosing the drug in them.They allow various pharmaceuticals to be administered orally, are convenient to carry, and have rapid pharmacological effects. It has many advantages such as: However, if a photo-labile drug is encapsulated in a soft capsule, it will be decomposed or altered by light and lose its pharmacological effect, making it impossible to utilize the above-mentioned advantages effectively. Therefore, in the past, soft capsules were prepared in which a dye that absorbs light of a specific wavelength and an opacifying agent were uniformly dispersed in the gelatin shell (Japanese Patent Application Laid-open No. 48-28621), and food yellow No. 5 was uniformly dispersed in the soft capsule shell. A soft capsule containing active vitamin D which is extremely unstable to light (Japanese Patent Application Laid-Open No. 55-22645), which stabilizes the photo-labile compound in the soft capsule by dispersing it in the soft capsule. Active vitamins as an example of
D A class ₃ oil-based solution has a wavelength of 0.01 wt% aqueous solution.
A UV absorber with a light transmittance of 10% or less at 310 mμ and absorption in the visible region is added to the coating.
Soft capsules of active vitamin D _{class 3} coated with a shell containing 1.0% by weight or less
-84023] etc. have been reported. However, the dyes and ultraviolet absorbers that have absorption in the visible region that have been used in the past,
They are tar-based synthetic pigments, synthetic colorants, etc., and due to recent advances in science, undesirable substances have been found one after another in these pigments and colorants, and there is a social situation where there is concern regarding their safety to the human body. is getting stronger. Furthermore, due to problems such as the stability of natural coloring agents, there are still no natural colorants suitable for use for this purpose. Furthermore, if general-purpose titanium dioxide or the like with an average particle diameter of about 0.4 μm is used as an opacifying agent for the purpose of blocking light, it will not only make visual inspection of the contents impossible, but also pose manufacturing problems depending on the type of capsule. It is something. ``Means for Solving the Problems'' In order to stabilize photolabile drugs, the present inventors have conducted extensive research and found that an oil-based solution containing a photolabile drug is mixed with gelatin and glycerin or sorbitol. and a soft capsule shell containing water, and in this soft capsule shell, at least 85% of the titanium oxide contains fine particles of titanium oxide with a particle size of 0.1 μm or less at a ratio of 0.001 μm to the total amount of the soft capsule shell components.
The present invention was completed based on the discovery that the desired object could be achieved by producing soft capsules containing 5% to 5% by weight. That is, in the present invention, an oily solution containing a photolabile drug is coated with a soft capsule shell containing gelatin, glycerin or sorbitol, and water, and at least 85% of the titanium oxide particles are contained in the soft capsule shell. The present invention provides a soft capsule containing 0.001% to 5% by weight of fine particles of titanium oxide having a diameter of 0.1 μm or less based on the total amount of the soft capsule skin component. The photolabile drug used in the present invention is
Indomethacin, oxandrolone, clofibrate, colchicine, diazepam, syrosingopine, vitamin E, nifedipine, norethisterone, piretanide, vitamin K, propercyazine, perphenazine, mequitazine, medazepam, vitamin D, active vitamin D, Ubiquinone, riboflavin, reserpine, vitamin A
Vitamin D, lorazepam, 4-carbamoyl-imidazolium-5-oleate, etc. In particular, active vitamin D has particularly strong biological activity, so it is required that the single dose be extremely small and uniform. However, it is extremely unstable to light,
In the present invention, active vitamin Ds include:
1α-hydroxycholecalciferol, 24-hydroxycholecalciferol, 25-hydroxycholecalciferol, 1α,24-dihydroxycholecalciferol, 24,25-dihydroxycholecalciferol, 1α,24,25- Preferred examples include trihydroxycholecalciferol, 1α-hydroxyergocalciferol, 25-hydroxyergocalciferol, and 1α,25-dihydroxyergocalciferol. Furthermore, the fine particle titanium oxide in which at least 85% or more of the titanium oxide used in the present invention has a particle size of 0.1 μm or less, when formulated into soft capsules,
Any drug that is transparent or translucent and capable of photostabilizing the photolabile drug contained in the drug is acceptable, and the maximum particle size is 0.1 μm or less and the average particle size is acceptable.
Fine particle titanium oxide of 0.01 to 0.07 μm is preferable, and for example, rutile type fine particle titanium oxide appropriately produced according to the manufacturing method described in JP-A-59-223231 [patent applicant Teikoku Kako Co., Ltd.] may be used. I can do it. In addition, the upper limit of the amount of fine-particle titanium oxide with a particle size of 0.1 μm or less is that the soft capsule shell becomes opaque, and this affects the wall thickness of the capsule. However, it is sufficient if it is 0.001% by weight or more based on the total amount of the shell components, and considering the photostability of the drug content and the transparency of the soft capsule shell, it should be 0.01 to 5% by weight based on the total amount of the shell components. Weight percent is preferred. The shell of the soft capsule of the present invention has a particle size of 0.1 μm.
In addition to the following microparticle titanium oxide, any material that can form a soft capsule shell may be used, and in general, combinations of gelatin, glycerin, various preservatives, etc. may be used. Fine particles of titanium oxide with a particle size of 0.1 μm or less may be uniformly dispersed in the constituent components other than these fine particles of titanium oxide. Additionally, a coloring agent that is safe for the human body can be used in the coating. The oil solution base can be selected as appropriate depending on the physical properties of the drug, as long as it can produce soft capsules and does not impair the stability of photolabile drugs. When selecting active vitamin D as a drug, tri-medium chain (8 to 10 carbon atoms) saturated fatty acid glyceride ester,
Propylene glycol fatty acid diesters and polyglycerol fatty acid esters are preferred. In addition, in addition to photolabile drugs and oil-based solution bases, one or more stabilizers such as dibutylated hydroxytoluene, butylated hydroxyanisole, tocopherols, gallic acid esters, and carotenoids are added to the oily solution. It's okay. The soft capsules of the present invention are prepared by coating an oily solution of a photolabile drug as described above with a coating agent containing fine particle titanium oxide as described above continuously using, for example, a continuous soft capsule manufacturing machine. It is manufactured by applying "Examples" Hereinafter, the formulation of the present invention will be explained using Examples, but the present invention is of course not limited thereto. Example 1 (1) Production of test sample 10 parts by weight of gelatin, 3 parts by weight of glycerin, 10 parts by weight of distilled water, and 0.2% by weight of gelatin, rutile type fine particle titanium oxide with maximum particle size of 0.1 μm and average particle size of 0.05 μm [ [manufactured by Teikoku Kako Co., Ltd.] (hereinafter sometimes abbreviated as microtitanium) was prepared. In addition, the photolabile drugs shown in Table 1 below were dissolved in propylene glycol dicaprylate ester (trade name "sefzo1228", manufactured by Nikko Chemical Co., Ltd.), and the microtitanium capsules described above were dissolved using a continuous soft capsule manufacturing machine. Seamless soft capsules were prepared by coating them with a solution containing . The resulting soft capsules had an average weight of 200 mg per capsule, an average liquid content of 150 mg, and were transparent, allowing the liquid content to be visually observed. In addition, as a control, soft capsules were produced in the same manner as above except that they did not contain microtitanium.

[Table] (2) Light exposure test 100 capsules of each group of soft capsules prepared in (1) were left under a fluorescent light of 6000 lux, and the average residual amount of these photolabile drugs was determined using high performance liquid chromatography. The results are shown in Table 2. The results showed that the photostable drug was significantly photostabilized.

【table】

[Table] Example 2 Two types of gelatin containing 10 parts by weight of gelatin, 3 parts by weight of glycerin, 10 parts by weight of distilled water, and 0.2% by weight of each of general titanium dioxide (manufactured by Teikoku Kako Co., Ltd.) and microtitanium based on gelatin. A gelatin solution was prepared. Then, using a continuous soft capsule making machine, a solution containing 1α(OH) cholecalciferol 0.001% by weight of propylene glycol dicaprylate was coated with a solution containing titanium dioxide as described above, and the average weight per capsule was applied. is 200mg
Seamless soft capsules with an average liquid content of 150 mg were manufactured. Next, 100 capsules of each group of these two types of soft capsules were left under a fluorescent light at 6000 lux/hour, and the average residual rate of 1α(OH) cholecalciferol was determined using high performance liquid chromatography. Ta. The results are shown in Table 3, and it was found that the same amount of titanium dioxide had a photostabilizing effect compared to when general titanium dioxide was used in the soft capsules of the present invention.

[Table] "Effects of the Invention" A soft capsule in which an oily solution containing the photolabile drug of the present invention is coated with a shell containing fine titanium oxide with a particle size of 0.1 μm or less is a photolabile drug. It photostabilizes stable drugs. Furthermore, the titanium dioxide used is widely acknowledged to be safe for the human body, and is sufficiently effective compared to conventionally used titanium dioxide, making it possible to reduce the amount used. In addition, it has a remarkable effect that soft capsules that are essentially transparent or translucent can be provided.

Claims (1)

[Scope of Claims] 1. An oily solution containing a photolabile drug is coated with a soft capsule shell containing gelatin, glycerin or sorbitol, and water, and at least 85% of titanium oxide is contained in the soft capsule shell. is the particle size
A soft capsule containing 0.001% to 5% by weight of fine particles of titanium oxide of 0.1 μm or less based on the total amount of the soft capsule skin component. 2. The soft capsule according to claim 1, wherein the fine titanium oxide particles having a particle size of 0.1 μm or less are fine particle titanium oxide particles having a maximum particle size of 0.1 μm or less and an average particle size of 0.01 to 0.07 μm. 3. Photolabile drugs include indomethacin, oxandrolone, clofibrate, colchicine, diazepam, syrosingopine, vitamin E, nifedipine, norethisterone, piretanide, vitamin K, propericyazine, perphenazine,
At least one photolabile member selected from the group consisting of mequitazine, megzepam, vitamin Ds, active vitamin Ds, ubiquinone, riboflavin, reserpine, vitamin A, lorazepam, and 4-carbamoyl-imidazolium-5-oleate. The soft capsule according to claim 1, which is a drug. 4 Active vitamin D types include 1α-hydroxycholecalciferol, 24-hydroxycholecalciferol, 25-hydroxycholecalciferol, 1α,24-dihydroxycholecalciferol, 1α,25-dihydroxycholecalciferol , 24,25-dihydroxycholecalciferol, and 1α,24,25-trihydroxycholecalciferol.
Soft capsules as described in section.