JPH01157911A - Light shielding capsule pharmaceutical - Google Patents

Abstract

PURPOSE:To obtain a light-shielding capsule pharmaceutical, having high light shielding effects and capable of preventing a change in a contained drug with time, by enclosing a light nontransmitting inorganic substance in microcapsules containing an alkaline earth metal carbonate or silicate as an outer wall mate rial and dispersing the resultant microcapsules in drug shells. CONSTITUTION:The aimed substance obtained by enclosing a light nontransmitting substance (e.g., red iron oxide) in microcapsules containing at least one of an alkaline earth metal carbonate or silicate as an outer shell material, dispersing the resultant microcapsules in gelatin drug shells of a cap sule pharmaceutical and preparing soft capsules by a conventional method. The content of the red iron oxide based on the drug shells is 0.01-20wt.%, preferably 0.1-10wt.%. The direct contact of the light nontransmitting material with the drug in the capsules can be prevented.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a capsule formulation in which a shell contains light-shielding microcapsules.

[Prior Art and Problems] Capsule formulations in which active ingredients such as pharmaceuticals are wrapped in a capsule shell have traditionally had a coloring substance mixed into the capsule to prevent misuse and prevent photodegradation of the active ingredient. There are many things to do. In addition, for capsule formulations such as vitamins (especially I) that require light shielding, an opaque substance is encapsulated in the shell to block light and prevent the decomposition of the medicine in the capsule formulation. There is. Such opaque substances are used to identify the content of a preparation based on its appearance, in order to use different preparations with different contents depending on the patient's disease, age, symptoms, etc. during actual treatment. used.

Soft capsule preparations are manufactured by encapsulating the active substance or the active substance with suitable excipients etc. in a gelatin shell made plastic with glycerin or sorbitol.
Drugs with particularly strong physiological activity (e.g. vitamin D, especially D3)
), it is necessary to uniformly fill a very small amount of the drug, so it is essential to take steps to disperse the drug in a liquid substance such as an oily base to create a soft capsule preparation. . In order to color such soft capsule preparations for the above-mentioned purposes of identification and prevention of photodegradation, attempts have been made to include synthetic tar-based pigments in the shell. However, in recent years, the safety of synthetic tar-based pigments has been questioned, and their use in pharmaceuticals intended for administration to the human body is not desirable.

Therefore, the use of metal oxides such as red iron oxide and titanium oxide, which have a visually pleasing color tone, have an excellent light-shielding effect, and are also biologically safe, has been proposed as a coloring agent to replace synthetic tar-based pigments. (Special Publication No. 57-4.345). However, when red iron is dispersed in the soft capsule skin, the active ingredient comes into direct contact with the red iron in the soft capsule skin, which makes it unstable due to the oxidation effect of red iron.
It is easily deactivated by heat and other influences. For this reason, a method that can be considered is to encapsulate red iron in microcapsules and then disperse it in the soft capsule skin to cut off contact with the drug inside. It was found that during the heating and molding process, the outer wall of the microcapsules and the shell melted together, destroying the structure of the microcapsules.

[Means for Solving the Problems] The present inventors have conducted extensive research in an attempt to protect the drug contents from the oxidation effects of light and light-shielding inorganic substances and to obtain a soft capsule formulation that is stable over time. At least one of an earth metal carbonate or an alkaline earth metal silicate
It is possible to uniformly disperse the microcapsules in which Red Garla is encapsulated in the microcapsules with seeds as the outer wall material in the gelatin shell of the capsule, and that by doing so, it is possible to achieve the purpose of light shielding and also to prevent Red Garla from being contained in the microcapsules. It has been found that it can also block oxidative effects.

[Structure of the Invention] This invention provides a microcapsule in which an opaque inorganic substance is encapsulated in a microcapsule whose outer wall is at least one of an alkaline earth metal carbonate and an alkaline earth metal silicate. The present invention provides a light-shielding capsule formulation in which a microencapsulated light-opaque inorganic substance is dispersed in a shell to prevent direct contact between the light-opaque inorganic substance and the drug in the capsule.

The light-opaque inorganic substance used in the present invention is a substance that blocks the transmission of at least ultraviolet light (100 to 3800 angstroms) and/or visible light (3800 to 7800 angstroms). Here, blocking the permeation means, for example, that the transmittance of a capsule shell material with a thickness of 2 mm is 30
% or less, preferably 10% or less.

Preferred are materials that block the transmission of ultraviolet light between 2900 and 4500 angstroms (optimally about 3100 angstroms). The purpose of this substance is to protect the drug content that is sensitive to light and prevent it from deteriorating, and to make it possible to identify the type and content of the drug content through differences in color and tone, thereby preventing misuse. Of course, this substance must be biologically safe and stable against light and heat, and it is desirable that the color tone can be freely adjusted by adjusting the concentration and combining two or more types. . Specifically, red iron (iron sesquioxide), food red No. 3 aluminum lake, food yellow No. 5 aluminum lake, food green No. 3 aluminum lake, food blue No. 2 aluminum lake, sodium copper chlorophyllin, etc. is desirable. In particular, Red Garla is a fine powder whose main component is iron sesquioxide, so it has high biological safety, has sufficient light-shielding effect and excellent stability against heat, and has a yellow to red or reddish-brown visual appearance. It exhibits a very pleasing color tone. In addition, the color tone can be adjusted freely by adjusting the amount of microcapsules containing red iron, the grade of red iron used, and mixing with extender pigments.
The content of the active ingredient can be easily determined based on the difference in color and tone, making it suitable for use as a pharmaceutical product.

The red iron oxide used in this invention can be commercially available products with different purity, but in particular the content of iron sesquioxide is 9.
It is desirable to use 8% or more, and the content of red iron in the preparation is 0.0% by weight based on the skin.
It is desirable that the amount is 1 to 20% by weight (preferably 0.1 to 10% by weight).

The microcapsules used in this invention are particles with a diameter of 12 to 20 μm (preferably 0.00 μm), which have a core material coated with an outer wall material.
Microspheres of 5 to 10 μm (optimally 1 to 5 μm) are meant. The microcapsules used in the present invention use an alkaline earth metal carbonate or an alkaline earth metal silicate as the outer wall material, and use an opaque inorganic substance such as red red iron as the core material, This is manufactured by known methods.

That is, a pigment powder having a predetermined particle size that does not react with the aqueous solution of the inorganic compound is suspended in an aqueous solution containing an alkali metal silicate or carbonate. Next, an organic solvent having a solubility in water of 5% or less is mixed to form a W10 type emulsion, and then the aqueous solution of the alkaline earth metal halide is mixed with the above W10 emulsion.
Mix with Type 10 emulsion. In this way, spherical microcapsules containing the pigment are obtained. Examples of organic solvents with solubility in water of 5% or less include aliphatic saturated hydrocarbons such as hexane, decane, and hexadecane; aliphatic unsaturated hydrocarbons such as hexene, dimethylbutadiene, and heptyne; and aromatic carbons such as benzene and toluene. Hydrogen; cyclohexane,
Examples include alicyclic hydrocarbons such as cyclohexene and cyclononane, which may be used alone or in combination of two or more. In addition, these organic solvents usually contain about 10% by weight.
There is no problem even if alcohol, etc.

The amount of the organic solvent used is not particularly limited as long as the resulting emulsion is of the W2O type, but it is usually 50% by weight or more of the emulsion. The emulsification method can be carried out by a conventional method such as a stirring method or a shaking method, and a known emulsifier can be added during emulsification. As an emulsifier, preferably MLB is 3.
, 5 to 6.0, and typical examples include polyquine ethylene sorbitan monooleate, polyquine ethylene sorbitan monooleate, sorbitan monostearate, and sorbitan triolate. Be it. These emulsifiers are usually 5% by weight or less, preferably O, Ql to 3% by weight based on the organic solvent.
It is best to use it in moderation.

Alternatively, hollow pigment-free microspheres are prepared from alkali metal silicates or carbonates and alkaline earth metal halides or nitrates as described above, which are then combined into lo-3 After leaving the hollow body under a high vacuum for more than 1 hour and evacuating the air inside the hollow body, an aqueous solution of a water-soluble inorganic compound selected from alkali metals and alkali metal sulfates, nitrates, and halides was added for 12 hours. By leaving it as is, the hollow part of the hollow body is filled with the solution. After washing this, the hollow body is added to an aqueous solution of a compound capable of forming a water-insoluble precipitate by reaction with the solution,
Mix under stirring for 15-30 minutes and leave for 12 hours or more. A water-insoluble precipitate is thus formed within the hollow body. Next, the spherical porous inorganic hollow body containing the precipitate is subjected to heat treatment and/or oxidation treatment and/or reduction treatment to obtain microcapsules containing the inorganic pigment.

The microcapsules of the present invention use an alkaline earth metal carbonate or an alkaline earth metal silicate for the outer wall material, which prevents the opaque inorganic substance from coming into direct contact with the drug content, and prevents the opaque inorganic substance from directly contacting the drug content. Prevents oxidation caused by inorganic substances.

Particularly in soft capsule formulations, the drug content is usually liquid or oily, so when microcapsules are not used, the drug content comes into contact with the opaque inorganic substance within the skin of the capsule, compared to hard capsule formulations. Since the possibility of such contact is increased, the capsule formulation of the present invention that can prevent such contact is more useful.

The alkaline earth metal carbonates used in this invention include:
Beryllium carbonate, calcium carbonate, magnesium carbonate,
Barium carbonate and magnesium calcium carbonate are included, with calcium carbonate being particularly preferred.

The alkaline earth metal silicates used in this invention include beryllium silicate, calcium silicate, magnesium silicate, barium silicate, and magnesium calcium silicate, with calcium silicate being particularly preferred.

In addition, ordinary gelatin and glycerin may be used as the shell base, and other colors such as preservatives, antifungal agents, plasticizers, antioxidants, or titanium oxide, etc., which are usually added to the shell of soft capsule formulations, may be used. Pigments or extender pigments can also be used as appropriate. This preparation is encapsulated in soft capsules by conventional methods.

The contents of the drug contained in the capsule formulation of this invention are as follows:
Although there are no particular limitations on the active ingredient as long as it can be administered as a capsule preparation, drugs that are particularly suitable for use in the present invention are drugs that are easily altered by light and easily oxidized. Specifically, lα-hydroxyvitamin D3, lα,
25-Dihydroxyvitamin D3.21-True 20-
Oxa-1α, 25-dihydroquine vitamin D3.22
- Active vitamin D3s such as oxa-Iα and 25-dihydroxyvitamin D3, other vitamin D3, vitamin A agents such as vitamin A oil and cod liver oil, vitamin B agents such as thiamine tetrahydrofurfuryl disulfide and bisbenziamine, Vitamin B2 agents such as riboflavin sodium phosphate, vitamin B8 agents such as pyridoxine chloride
These include vitamin C agents such as ascorbic acid, vitamin A agents such as dianocobalamin, vitamin E agents such as tocopherol, and vitamin agents such as menatetrenone and menadione.

The capsule formulation of this invention is manufactured by a conventional method. In other words, in the case of soft capsule preparations, a gelatin sheet is made by spreading a gelatin solution containing glycerin and microcapsules, and a flat plate or roller mold (heated as appropriate) is placed so that the drug solution is sandwiched between the two sheets. Punch out and dry. In the case of hard capsules, the drug (powder/granules) is filled into capsule shells containing microcapsules manufactured in advance.

The shell is manufactured, for example, by immersing a capsule-shaped mold in a gelatin solution containing microcapsules, drying it, and peeling off the shell formed on the mold.

This invention places the light-opaque black iso material in the capsule into microcapsules that do not interact with the capsule skin, are biologically safe, and are stable over time against light, heat, and oxidation.
It is advantageous in that by using at least one of alkaline earth metal carbonates or alkaline earth metal silicates as the outer wall material, it is possible to avoid direct contact of the opaque black iso material with the drug content. ing.

[Example 1 The present invention will be described in detail below with reference to Examples, but the present invention is not limited thereto.

Example 1 (Production of microcapsules) Sodium silicate (concentration 170 g/p) IQ
Benzene solution of OCC and polyoxyethylene sorbitan mo7 stearate (concentration 20 g/p) 200
Shake the cc mixture vigorously to create an emulsion. The obtained emulsion was added to 100 cc of a mixed solution of calcium chloride (111s/R) and magnesium chloride (95 g/ff) with stirring, left for 1 hour, filtered, washed, and dried to obtain a particle size of 3. ~5μ porous hollow microspheres were obtained.

100 g of the porous hollow silica spheres produced above were placed in a container, and the air was evacuated under a reduced pressure of 10-3 torr for 1 hour. Then, 300 g of a saturated aqueous solution of iron sulfate (n) was added under reduced pressure to fill the hollow part of the silica spheres. Infiltrate the aqueous solution and further under normal pressure for 2
The mixture was left to stand for 4 hours, filtered, and washed with water. Then, the silica spheres were dissolved in a 1.5 mol/I2 aqueous solution of sodium hydrogen carbonate at 120 mol/l.
0m (2), stirred for 30 minutes, left for 24 hours, filtered, washed with water, washed with methanol, and heated at 110'C.
It was dried for 24 hours. Next, the silica spheres were heat-treated at 500°C for 20 hours to obtain red silica spheres containing α-iron oxide. The iron oxide content was 25% by weight.

(Manufacture of soft capsule preparation) 1.0 mg of lα-hydroxyvitamin D was dissolved in 400 g of fatty oil under a nitrogen gas stream to form an oily solution. A shell is prepared by uniformly dispersing the red iron oxide encapsulating microcapsules produced above in a soft capsule shell base consisting of gelatin and glycerin so that the content of red iron oxide is 3% by weight based on the shell base. According to the method, a drug solution was placed between two shell sheets and formed under heat and pressure to form soft capsules so that each capsule contained 0.5 .mu.g of .alpha.-hydroquine vitamin D3.

Example 2 Soft capsules were produced in the same manner as in Example 1, except that the colorant was replaced with food red No. 3 aluminum lake.

Example 3 Soft capsules were produced in the same manner as in Example I, except that the colorant was replaced with food yellow No. 5 aluminum lake.

Example 4 Soft capsules were produced in the same manner as in Example 1, except that the colorant was replaced with food green No. 3 aluminum lake.

Example 5 Soft capsules were produced in the same manner as in Example 1, except that the colorant was replaced with food blue No. 2 aluminum lake.

Example 6 Soft capsules were produced in the same manner as in Example 1, except that the colorant was replaced with edible steel chlorophyllin sodium.

Test Example 1 A non-transparent soft capsule was placed under an indoor fluorescent light of 1000 Lux, and changes over time in the amount of lα-hydroxyvitamin D3 were measured. The residual rate (%) of lα-hydroxyvitamin D3 was investigated, taking the value at the start of the test as 100%. The results are shown in Table 1. As a control, soft capsules without colorants or opacifying agents were used.

Table 1 Test Example 2 Contents Drug Power α, 25-dihydroxyvitamin D31.
The residual rate (%) of the soft capsule preparation was examined in the same manner as in Test Example 1 except that the amount was 0 mg. The results are shown in Table 2.

Table 2 Test Example 3 Using the soft capsule preparation used in Test Example I and a soft capsule preparation of lα-hydroxyvitamin D3 consisting of a shell containing 3% by weight of non-microencapsulated Red Red Garlic based on the weight of the shell. Changes in the contents of the drug over time were measured at a temperature of 60° C. and under light-shielding conditions. The results are shown in Table 3.

Table 3 Test Example 4 Changes in the drug content over time were measured in the same manner as in Test Example 3, except that a soft capsule formulation containing lα,25-dihydroxyvitamin D3 was used. The results are shown in Table 4.

As described in Table 4 and above, the soft capsule preparation of the present invention has a high light-shielding effect and can prevent the activity of the drug contained therein from decreasing even when the temperature changes.

Patent applicant: Fuso Pharmaceutical Co., Ltd. Representative Patent Attorney Aoyama Aoyama and 1 other person

Claims (6)

[Claims] (1) Opaque microcapsules in which an opaque inorganic substance is encapsulated in microcapsules whose outer wall material is at least one of alkaline earth metal carbonate or alkaline earth metal silicate. A light-shielding capsule preparation in which a transparent inorganic substance is dispersed in the shell to prevent direct contact between the light-opaque inorganic substance and the drug inside the capsule. (2) The light-shielding capsule preparation according to claim 1, wherein the light-opaque inorganic substance is red iron. (3) The content of the microencapsulated light-opaque inorganic substance is 0.1 to 10% by weight based on the total weight of the shell of the capsule preparation. The light-shielding capsule formulation according to item 1 or 2. (4) The light-shielding capsule preparation according to claim 1, wherein the outer wall material is calcium silicate or calcium carbonate. (5) The light-shielding capsule preparation according to claim 1, wherein the capsule preparation is a soft capsule preparation. (6) The light-shielding capsule preparation according to claim 5, wherein the capsule shell contains gelatin as a main component.