JP3122921B2 - Biotin-containing solution for internal use - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a biotin-containing aqueous liquid preparation, a method for producing the same, and a method for stabilizing a biotin-containing aqueous liquid preparation.

[0002]

2. Description of the Related Art Internal preparations containing water-soluble vitamins include syrups and drinks. In these cases, the vitamins include vitamin B group, vitamin C,
It contains nicotinic acid, nicotinamide, and the like. Biotin is a member of the vitamin B group, also called vitamin H, and is necessary for maintaining normal skin and hair. The multivitamin aqueous solution is usually kept at pH 2-5. However, since biotin is hardly soluble at an acidic pH (2 to 4), it is required to improve the solubility and ensure the stability over time after blending when formulating.

[0003] As a method of dissolving biotin, conventionally,
(1) Method of treating biotin with ammonia and lactose (JP-A-61-25668) (2) Method of treating biotin with alkali hydroxide or basic amino acid and lactose
169528). However, these techniques relate to powder formulations and those obtained by these methods are only available in neutral to alkaline. Therefore, even if high-concentration biotin is blended into the aqueous solution of a multivitamin by this method, the aqueous solution of a multivitamin usually has a pH (2 to 5), and biotin precipitates out, making it impossible to formulate a formulation.

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to provide a liquid crystal display device, which has an advantage that even in a region where the liquidity is acidic, compared with the above-mentioned known technology,
An object of the present invention is to provide an excellent preparation capable of maintaining and dissolving biotin at a high concentration in a stable state for a long time.

[0005]

Means for Solving the Problems The present inventors have conducted intensive studies on the solubility and stability of biotin and the economics of aqueous preparations. As a result, the use of polyvinylpyrrolidone as a solubilizing agent achieves the intended purpose. I found to do. Polyvinylpyrrolidone is also called polyvidone or povidone, and is abbreviated as PVP. It is a white to slightly yellow crystal which dissolves in water to form a colloidal solution.

The present inventors have conducted intensive studies and have found that the addition of polyvinylpyrrolidone stably maintains biotin even in an acidic region, thus completing the present invention.

That is, the present invention is a biotin-containing aqueous liquid preparation containing polyvinylpyrrolidone. Further, the present invention provides a biotin-containing aqueous liquid preparation, comprising dissolving polyvinylpyrrolidone and biotin in a neutral or alkaline aqueous solution of an organic or inorganic acid with an alkali metal salt, and then acidifying with an organic or inorganic acid. It is a manufacturing method of.

The aqueous solution containing biotin according to the present invention is stable even when it is stored under acidic conditions for a long period of time or under severe conditions such as a wide range of temperature changes, without generation of scum or fog. Therefore, it is possible to maintain good quality and good quality control. It is an object of the present invention to produce a liquid preparation for internal use containing a high concentration of biotin, which is excellent in stability and which prevents the formation of scum and fog.

The amount of biotin that can be dissolved in the biotin-containing aqueous liquid preparation of the present invention varies depending on the amount of added polyvinylpyrrolidone, pH and the like, but is usually 20 mg / 100 ml or more. When polyvinylpyrrolidone is not added, only a few mg / 100 ml of biotin is dissolved in the low pH range.

The polyvinylpyrrolidone in the present invention is a linear polymer of 1-vinyl-2-pyrrolidone, and has a K value (hereinafter referred to as K value) of Fikenture of 15 to 21, 26 to 26.
35, 50-62, 80-100 compounds.
Specifically, povidone K-15 (PVP K-15), povidone K-30 (PVP K-30), povidone K
-60 (PVP K-60), Povidone K-90 (P
VP K-90).

The above compounds can be used alone or in any combination of two or more kinds.
0.001 to 5.0% by weight, preferably 0.01 to 3.0% by weight
Of polyvinylpyrrolidone is added.

Further, the alkali metal salts of organic acids or inorganic acids that can be contained in the liquid preparation of the present invention include citric acid, malic acid, tartaric acid, lactic acid, gluconic acid,
Examples thereof include alkali metal salts of fumaric acid, phosphoric acid, and carbonic acid, such as sodium salts and potassium salts.

The above salts can be used alone or in any combination of two or more kinds.
0.001 to 2.0% by weight, preferably 0.05 to 1.0% by weight
Is added.

In the present invention, the acid for making the liquid for internal use acidic is not particularly limited as long as it can be used for the liquid for internal use. Preferred examples thereof include citric acid, malic acid, tartaric acid, lactic acid, glucone and the like. Acids, fumaric acid, phosphoric acid, hydrochloric acid and the like can be mentioned.

In order to produce an aqueous solution of a total vitamin, the solution of the present invention may contain water-soluble and fat-soluble vitamins. The water-soluble vitamins used include vitamins B ₁ , B ₂ , B ₆ , B ₁₂ , vitamin C and nicotinamide, and the fat-soluble vitamins include vitamins A, D, E and K. They are,
The selection may be appropriately made according to the purpose, and the combination may be made without any particular limitation. Also, the amount is not particularly limited.

If necessary, the liquid preparation of the present invention may contain a flavoring agent, a coloring agent, a buffer, a preservative and the like which are usually used.

In the method for producing a biotin-containing aqueous liquid in the present invention, usually, first, biotin and polyvinylpyrrolidone are dissolved in a neutral or alkaline solution, and a solution in which various vitamins and acids are separately dissolved is prepared. After mixing the solution, adjust the pH with an acid if necessary. More specifically, for example, biotin and then polyvinylpyrrolidone are dissolved in a sodium citrate solution. Separately, thiamine nitrate (vitamin B ₁ nitrate), sodium riboflavin phosphate (vitamin B ₂ ), pyridoxine hydrochloride (vitamin B ₆ ), nicotinamide, citric acid, sodium benzoate, and other excipients are dissolved in purified water. Let it. Then, the above-mentioned solution containing biotin is mixed with the solution, and the pH is adjusted to 2 to 4 with an appropriate acid to produce a multivitamin-containing aqueous solution.

The liquid preparation for internal use according to the present invention has high stability without the formation of precipitates (stains, fogging, etc.) during storage. This mechanism is thought to be due to the interaction between polyvinylpyrrolidone and biotin. That is, biotin has a ureide ring and a carboxyl group in the molecule, forms an intermolecular interaction with polyvinylpyrrolidone in the acidic region, is stably retained in the matrix of polyvinylpyrrolidone, improves solubility, and precipitates with time. It is thought that the generation of such as is prevented.

This effect is confirmed by measuring the solubility of biotin. The degree of precipitation in the liquid preparation for internal use is determined by visual observation of the appearance over time. This will be described with reference to tables in Examples and Comparative Examples.

Hereinafter, the present invention will be described in detail with reference to Examples and Comparative Examples. However, the present invention is not limited to only these examples.

[0021]

Example 1 4.7 g of sodium citrate was added to 100 parts of purified water.
After dissolving in 0 ml (pH about 8), biotin 650m
g and then a solution (A) in which 30 g of polyvinylpyrrolidone is dissolved.

Separately, thiamine nitrate 1000 mg, sodium riboflavin phosphate 200 mg, pyridoxine hydrochloride 5
00 mg, nicotinamide 2000 mg, citric acid 9
g, sodium benzoate 1.8 g and sucrose 300 g are dissolved in purified water 1000 ml to prepare a solution (B).

The above solution (A) and solution (B) are mixed,
After the addition of apple flavor, citric acid was added to adjust the pH to 3.0, and purified water was added to make the total amount 3000 m.
l. This was sterilized and filtered (0.22 mμ), and dispensed into 100 bottles, 30 ml each, to obtain a biotin-containing aqueous vitamin solution.

[0024]

Example 2 6 g of sodium malate was added to 500 m of purified water
After dissolving in biotin (pH about 7),
Then, a solution (C) is produced by dissolving 18 g of polyvinylpyrrolidone.

Separately, thiamine nitrate 1000 mg, riboflavin sodium phosphate 200 mg, pyridoxine hydrochloride 5
00 mg, nicotinamide 2000 mg, citric acid 9
g, 1.8 g of sodium benzoate, 330 g of sucrose and a solution of vitamin E (3 g of tocopherol acetate in HCO-6
0 or Tween 80) was dissolved in 1000 ml of purified water to prepare a solution (D).

The above solution (C) and solution (D) are mixed,
After adding strawberry flavor, pH 3.5 with hydrochloric acid
And purified water was added to bring the total volume to 3000 ml. This was filled into a container in the same manner as in [Example 1] to obtain a biotin-containing aqueous vitamin solution.

[0027]

COMPARATIVE EXAMPLE 1 Comparative Example 1 was prepared in the same manner as in Example 1 except that polyvinylpyrrolidone was not used to obtain a biotin-containing synthetic vitamin aqueous solution.

[0028]

Comparative Example 2 Comparative Example 2 was carried out in the same manner as in Example 2 except that polyvinylpyrrolidone was not used, to obtain a biotin-containing synthetic vitamin aqueous solution.

Examples 1 and 2 and Comparative Examples 1 and 2
Immediately after production, 1 at 5 ° C. and 40 ° C.
Changes over time in appearance (precipitation, formation of haze) after storage for 3 to 6 months were observed. Table 1 shows the results. In Table 1, the degree of change in appearance is as follows.

-: No change is observed ±: slight change is observed +: change is observed ++, +++: change is remarkable

[0031]

[Table 1] Table 1 Additives Stored at 5 ℃ and 40 ℃ at the time of manufacture (PVP) 1 month 3 months 6 months 1 month 3 months 6 months Comparative Example 1 − − ++ +++ +++ ± ++ Comparative Example 2 − − ++ +++ +++ ± ++ Example 1 1.0 % − − − − − − − Example 2 0.6% − − − − − − −

[0032]

As is evident from Table 1, the aqueous liquid preparation according to the present invention did not produce precipitates or fogging, and it was proved that a high concentration of biotin was maintained in a stable state in an acidic preparation. You.

Continued on the front page (72) Inventor Shigemitsu Osawa 2286-12, Suehiro-cho, Honjo-shi, Saitama (72) Inventor Koichi Sakai 2-5, Hikamachi, Kanazawa-shi, Ishikawa (72) Inventor Yasuo Iwaki Kiyosumi-cho, Toyama-shi, Toyama 108-40 (72) Inventor Ryutaro Ishiguro 2-18, Gobancho, Toyama City, Toyama Prefecture (58) Fields investigated (Int.Cl. ⁷ , DB name) A61K 31/4188 A61K 9/08 A61K 47/12 A61K 47/32 CA (STN) EMBASE (STN) MEDLINE (STN)

Claims (5)

(57) [Claims] 1. A biotin-containing aqueous liquid preparation containing polyvinyl pyrrolidone. 2. A biotin-containing aqueous liquid preparation, comprising dissolving polyvinylpyrrolidone and biotin in a neutral or alkaline aqueous solution of an organic or inorganic acid with an alkali metal salt, and then acidifying with an organic or inorganic acid. Manufacturing method. 3. An alkali metal salt of an organic or inorganic acid that renders a biotin solution neutral or alkaline is citric acid, malic acid, tartaric acid, lactic acid, gluconic acid, fumaric acid,
The method for producing a biotin-containing aqueous liquid preparation according to claim 2, which is one or more sodium salts or potassium salts selected from the group consisting of phosphoric acid and carbonic acid. 4. An organic or inorganic acid which makes a liquid for internal use acidic is citric acid, malic acid, tartaric acid, lactic acid, gluconic acid, or the like.
The method for producing a biotin-containing aqueous liquid preparation according to claim 2, which is selected from the group consisting of fumaric acid, phosphoric acid and hydrochloric acid. 5. A method for stabilizing a biotin-containing aqueous solution for internal use, which comprises polyvinylpyrrolidone.