JP5023546B2 - Oral solid preparation - Google Patents

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. In addition, when it coexists with other drugs (for example, vitamin B ₁ , vitamin B ₆ , vitamin C, nicotinamide amides), the content decreases, and in fact, the conventional combination of other vitamins. vitamin B ₁₂ in the formulation, processes for became unstable (Comparative example 6).

In order to use such unstable vitamin B ₁₂ as a medicine or food, it is essential to stabilize vitamin B ₁₂ and, in fact, there is a technology for stabilizing vitamin B ₁₂ through formulation 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) The composition mixture according to (1) to (4), wherein at least one selected from light aluminum oxide is used. (6) The different vitamins are thiamine hydrochloride, thiamine nitrate, bisthiamine nitrate, thiamine disulfide, thiamine dicel sulfate, dicetiamine hydrochloride, and fursulfuric chloride. Thiamine, octothiamine, chicotiamine, bisibutamine, 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 provide a mucopolysaccharide blending agent.

By blending silicic acid and / or magnesium oxide with vitamin B ₁₂ , heterogeneous vitamins and mucopolysaccharide, vitamin B ₁₂ is stable and an excellent solid preparation that can be produced in a simple process is, 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 sodium chondroitin sulfate, 100 g of tocopherol calcium succinate, 100 g of benfotiamine, 120 g of nicotinamide, 108 g of calcium silicate, 64 g of lactose, 150 g of carmellose calcium and powdered powder are 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 example in terms of the ratio at the start, higher than the comparative example, 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 Can be manufactured by a simple manufacturing method, and can be applied to pharmaceuticals, quasi drugs, cosmetics, foods, and the like.

Claims (2)

(A) Chondroitin sulfate or a salt thereof, (B) methylcobalamin, (C) thiamine hydrochloride, thiamine nitrate, bisbenchamine, benfotiamine, pyridoxine hydrochloride, pyridoxal phosphate, nicotinamide, and tocopherol calcium succinate A solid preparation containing vitamins and a component selected from (D) silicon dioxide, light anhydrous silicic acid, calcium silicate, aluminum silicate, sodium aluminate metasilicate, magnesium silicate and magnesium oxide. The solid preparation according to claim 1, wherein the weight ratio of component (D) to component (A) is 1: 2 to 1:20.