JP2007297309A - Oral solid preparation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To stabilize the active ingredients in the preparation, typically chondroitin or the like and obtain a compounding agent that is suitable for the object disease. <P>SOLUTION: In the combination of chondroitin, vitamin B<SB>12</SB>, further different vitamins, silicate salts and/or magnesium oxide are characteristically compounded. Vitamin B<SB>12</SB>is unstabilized, when combined with mucopolysaccharide, but it can be stabilized by this invention to provide the mucopolysaccharide compounds. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

The present invention is, mucopolysaccharides, on Vitamin B ₁₂ and silicic acids and / or solid formulation consisting of magnesium oxide. Particularly Stability good solid preparation of vitamin B ₁₂ included.

Cyanocobalamin, vitamin B ₁₂ such as methylcobalamin, hydroxocobalamin are useful as anti-anemia agent, and various malignant anemia, limbs caused by neuropathy associated therewith numbness, knees and hips pain, facial neuralgia, eye It is given when brain fatigue is observed.

However, vitamin B ₁₂ is known as an unstable vitamin because its content decreases due to the influence of the external environment such as light, moisture, pH, and heat. Also, other drugs (such as vitamin B _1, vitamin B _6, vitamin C, heterologous vitamins nicotinic acid amide) also when coexisting with like, occurs decrease in content, in fact, the conventional blended other vitamins simultaneously vitamin B ₁₂ in the formulation, processes for became unstable (Comparative example 6).

To use such unstable vitamin B ₁₂ such as pharmaceuticals and foods, it is essential to stabilize the vitamin B ₁₂ compounds, currently, it stabilized techniques of vitamin B ₁₂ by pharmaceutically ingenuity Several are disclosed.
For example, a technique is disclosed in which vitamin B ₁₂ is dispersed in a starch and dextrin mixture to form a powder and used as a premix preparation raw material (Patent Document 1). However, in this disclosed technology, there is no mention of specific preparations such as tablets and granules that can be taken by a patient, and when a highly hygroscopic drug or an acidic or basic drug is formulated, In order to overcome the problems that arise, further ingenuity was necessary.
On the other hand, mucopolysaccharides such as sodium chondroitin sulfate are a kind of high-molecular polysaccharides, exist between cells in the living body, and function to supply water and nutrients to cells and retain water in cells. In addition, this function lubricates the cellular tissue connecting the bones and maintains flexibility. Due to the decrease in mucopolysaccharides, bones collide with each other, causing joint pain. For this reason, mucopolysaccharides are taken for relieving arthralgia and are widely used in the fields of pharmaceuticals and foods.

Accordingly, when vitamin B ₁₂ and chondroitin sulfate sodium mucopolysaccharide are taken at the same time, effects such as relief of joint pain and neuralgia can be expected.
However, in general production method, when blended mucopolysaccharide simultaneously, vitamin B ₁₂ is unstable, it is difficult to formulate (Comparative Example 1～5,7).

In the prior art for commercialization, sugar-coated tablets (Patent Document 2) and film-coated tablets (Patent Document 3) that stabilize vitamin B ₁₂ by reducing water content are disclosed. Actually, a film-coated tablet product is commercially available (Non-Patent Document 1). However, in patent document 2, when it preserve | saved under high humidity, the tablet will crack and there existed a problem as a formulation. Further, in Patent Document 3, it is natural that a film coating process is essential, and process management is complicated, that is, a costly manufacturing method has to be selected.

Development of an oral formulation of mucopolysaccharide formulated which solved the stability problem of vitamin B ₁₂ has become as the high cost of production method. Therefore, these conventional preparations are not always satisfactory from the viewpoint of production cost.

That is, in the formulation was blended mucopolysaccharide and vitamin B ₁₂ at the same time, vitamin B ₁₂ is stable, and simple manufacturing method has not been known.
JP-A-3-173823 JP 2002-179559 A JP2003-3000883A “Actage AN lock package insert” Features Takeda Pharmaceutical Company Limited

The present invention was originally simultaneously blended vitamin B ₁₂ and a mucopolysaccharide with a stability problem, be further compounded with different vitamins, and an object thereof is to obtain a possible solid dosage formed by a simple process.

As a result of various investigations on additives to solve the above problems, the present inventors have found that when vitamin B ₁₂ and mucopolysaccharide are mixed with silicic acid and / or magnesium oxide at the same time, vitamin B ₁₂ is stable, And it discovered that the outstanding solid formulation which can be manufactured according to a simple process was obtained, and came to complete this invention.

That is, the present invention provides (1) a mucopolysaccharide, vitamin B ₁₂ and silicic acids and / or composition mixture comprising magnesium oxide, (2) a mucopolysaccharide, vitamin B _12, different vitamins and silicic acids and / or compositions consisting of magnesium oxide (3) The composition mixture according to (1) to (2), wherein the weight ratio of silicic acid and / or magnesium oxide and mucopolysaccharide is 1: 1 to 1:20, (4) the mucopolysaccharide is hyaluronic acid, chondroitin 1 or more selected from glycosamide glycans or salts thereof, (5) composition mixture according to (1) to (3), (5) silicic acid is synthetic aluminum silicate, magnesium silicate, silicon dioxide, hydrous silicon dioxide, silicic acid Calcium, magnesium aluminate silicate, sodium metasilicate aluminate, magnesium silicate aluminum 1 or more selected from light aluminum oxide, (6) The composition mixture according to (4), (6) the different vitamins are thiamine hydrochloride, thiamine nitrate, bisthiamine nitrate, thiamine disulfide, thiamine dicel sulfate, dicetiamine hydrochloride, fursulfuric acid hydrochloride Thiamine, octothiamine, chicotiamine, bisibutiamine, bisbenchamine, prosultiamine, benfotiamine, pyridoxine hydrochloride, pyridoxal phosphate, ascorbic acid, calcium ascorbate, sodium ascorbate, nicotinic acid, nicotinamide, L- One or more selected from cysteine, L-cysteine hydrochloride and aspartic acid, (1) to (5) composition mixture, (1) to (6) solid preparation, (8) mucopolysaccharide is a chondroitin salt, Silicates are silicic acid mugs A Siumu, different vitamins pyridoxal phosphate, tocopherol calcium succinate, about a solid preparation consisting of a bisbentiamine (2) or (3).

According to the present invention, it has become possible to stabilize vitamin B ₁₂ that is destabilized by blending with mucopolysaccharide and to provide a mucopolysaccharide blending agent.

Vitamin B _12, the heterologous vitamins and mucopolysaccharides, by blending silicic acids and / or magnesium oxide, vitamin B ₁₂ is stable and excellent solid preparation can be produced by a simple process, for example, as follows It is.
The active ingredient used in the present invention, vitamin B ₁₂ compound (cyanocobalamin, hydroxocobalamin, hydrochloric hydroxocobalamin acetate hydroxocobalamin, methylcobalamin), and the like. With respect to these, vitamin B ₁₂ compounds, taking into account the supply of stability and the raw materials used, is preferably cyanocobalamin and methylcobalamin, more preferably methyl cobalamin.

  In the present invention, silicic acid means a porous inorganic substance in powder form, silicon dioxide, light anhydrous silicic acid, calcium silicate, aluminum silicate, magnesium silicate, magnesium silicate aluminate, metasilicate aluminate One or more selected from magnesium, magnesium aluminum silicate, or magnesium oxide, preferably calcium silicate, aluminum silicate, magnesium silicate, and magnesium metasilicate aluminate. When these silicic acids and magnesium oxide are added to the preparation, the weight ratio of silicic acid / magnesium oxide and mucopolysaccharide is preferably 1: 1 to 1:20, more preferably 1: 2 to 1:20. More preferably, it is 1: 4 to 1:20, but any weight ratio that achieves the present invention may be used, and the present invention is not limited to this.

In the present invention, different types of vitamins include thiamine hydrochloride, thiamine nitrate, bisthiamine nitrate, thiamine disulfide, thiamine dicel sulfate ester salt, dicetiamine hydrochloride, fursultiamine hydrochloride, octothiamine, chicotiamine, bisbutiamine, bisbenchamine, prosultiamine, Benfotiamine, pyridoxine hydrochloride, pyridoxal phosphate, ascorbic acid, calcium ascorbate, sodium ascorbate, nicotinic acid, nicotinamide, L-cysteine, L-cysteine hydrochloride, and aspartic acid.
Further, the mucopolysaccharide used in the present invention is hyaluronic acid, chondroitin, glycosamide glycans and salts thereof. As the mucopolysaccharide, for example, one or more of sodium chondroitin sulfate listed in the Japanese Pharmacopoeia Standards for Pharmaceutical Ingredients, or oral food grade sodium hyaluronate sold by Kibun Food Chemifa Co., Ltd. can be used. However, the present invention is not limited to this. Among these, it is preferable to use sodium chondroitin sulfate as a medicine.

  Other additives used for the preparation of the preparation of the present invention include excipients such as crystalline cellulose, lactose, starch, mannitol, disintegrants such as low-substituted hydroxypropylcellulose, croscarmellose sodium, carmellose calcium, There are lubricants such as magnesium stearate, calcium stearate, and talc. In addition, glidants, buffers, preservatives, fragrances, pigments, corrigents and the like can be used as necessary.

  Examples of the solid preparation in the present invention include tablets, granules, powders, capsules and the like.

  Examples of the method for producing an oral solid preparation in the present invention include, for example, a preparation machine technology handbook (formulation machine technology study group establishment 10th anniversary publication editorial committee, Jijinshokan), powder compression moldability technology (powder engineering / Direct powder compression methods and wet granulation methods described in publications such as preparations and particle design subcommittees, Nikkan Kogyo Shimbun) can be used.

  The present invention is further described in detail in the following examples and experimental examples, which are merely illustrative and do not limit the present invention, and may be changed without departing from the scope of the present invention. Good.

  EXAMPLES Hereinafter, although an Example etc. demonstrate this invention further in detail, this invention is not limited to these.

<Example 1>
3 g of methylcobalamin and 540 g of crystalline cellulose were mixed in a plastic bag to prepare a powdered powder. Thereafter, 1800 g of chondroitin sulfate 1800 g, tocopherol calcium succinate 100 g, benfotiamine 100 g, nicotinic acid amide 120 g, calcium silicate 108 g, lactose 64 g, carmellose calcium 150 g, and powdered powder were mixed into a V-type mixer (Dalton Co., Ltd.). , “VM-10”) for 15 minutes. Further, 15 g of magnesium stearate was added and mixed with a V-type mixer for 1 minute to prepare a tableting powder. The obtained tableting powder was tableted with a rotary tableting machine (“HT-AP15SSII” manufactured by Hata Seiko Co., Ltd.) to obtain a 9 mm diameter tablet.
Hereinafter, Examples 2 to 13 and Comparative Examples 1 to 7 were formulated as shown in Tables 1 and 2, and each tablet was obtained based on the manufacturing method shown in Example 1.

<Test method>
Each Example and Comparative Example was left in a glass bottle (sealed system) at 50 ° C. for 8 weeks, and then the residual ratio (%) of vitamin B ₁₂ relative to the start of the test was measured. The residual ratio of vitamin B ₁₂ was measured by a liquid chromatography method.

<Test results>
In Table 1, the residual ratio (%) of vitamin B ₁₂ was over 80% in the examples in terms of the ratio at the start, higher than the comparative examples, and excellent in stability.

The present invention uses mucopolysaccharides, vitamin B ₁₂ and silicic acids and / or composition mixture comprising magnesium oxide, more mucopolysaccharides, vitamin B _12, a heterologous vitamin and silicic acids and / or magnesium oxide composition mixture, tablets Etc. can be manufactured by a simple manufacturing method, and can be applied to pharmaceuticals, quasi drugs, cosmetics, foods, and the like.

Claims (8)

Mucopolysaccharides, vitamin B ₁₂ and silicic acids and / or composition mixture comprising magnesium oxide Composition mixture comprising mucopolysaccharide, vitamin B ₁₂ , heterogeneous vitamins and silicic acids and / or magnesium oxide   The composition mixture according to claim 1 or 2, wherein the weight ratio of silicic acid and / or magnesium oxide to mucopolysaccharide is 1: 1 to 1:20.   The composition mixture according to claims 1 to 3, wherein the mucopolysaccharide is selected from one or more of hyaluronic acid, chondroitin, glycosamide glycan or a salt thereof.   The silicic acid is one or more selected from synthetic aluminum silicate, magnesium silicate, silicon dioxide, hydrous silicon dioxide, calcium silicate, magnesium aluminate silicate, sodium aluminate metasilicate, magnesium aluminum silicate, and light aluminum oxide. Composition mixture according to 1-4   Heterogeneous vitamins include thiamine hydrochloride, thiamine nitrate, bisthiamine nitrate, thiamine disulfide, thiamine dicel sulfate ester salt, dicetiamine hydrochloride, fursultiamine hydrochloride, octothiamine, chicotiamine, bisivethiamine, bisbenchamine, prosultiamine, benfotiamine, hydrochloric acid 6. The composition mixture according to claim 2, which is selected from one or more selected from pyridoxine, pyridoxal phosphate, ascorbic acid, calcium ascorbate, sodium ascorbate, nicotinic acid, nicotinic acid amide, L-cysteine, L-cysteine hydrochloride and aspartic acid.   Solid preparation consisting of claims 1-6   The solid preparation comprising 2 or 3, wherein the mucopolysaccharide is a chondroitin salt, the silicic acid is magnesium silicate, and the heterologous vitamin is pyridoxal phosphate, calcium tocopherol succinate, and bisbenchamine.