JP3037654B2 - Easy-absorbable folic acid preparation, production method thereof and feed containing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an easily absorbable folate preparation, a method for producing the same, and a feed containing the same. INDUSTRIAL APPLICABILITY The easily absorbable folate preparation of the present invention is excellent in stability of folic acid and excellent absorption of folic acid by livestock, and thus is useful as a compounding agent for feed of livestock and pets.

[0002]

2. Description of the Related Art Folic acid and its related compounds are anti-anemic vitamins of humans, monkeys and chicks, ie, prevention and treatment of dietary megaloblastic anemia of humans and monkeys present in yeast extract and liver extract. It is one of the group B vitamins that has been found as a factor and as a growth factor for chicks and certain lactic acid bacteria. Chemically synthesized folic acid is used as a pharmaceutical, food or feed additive.

[0003] However, the amount of folic acid is extremely small compared to other nutrients, and it is often used as a fine crystalline powder in order to uniformly mix it.
It is susceptible to chemical changes depending on temperature and other components such as minerals incorporated at the same time. Further, folic acid is extremely poorly soluble in water, and therefore has poor absorption in pigs and the like, and a folic acid preparation which is chemically stable and excellent in absorption is desired.

Conventionally, as a method of stabilizing folic acid, a method of coating with a high melting point oil or the like (Japanese Patent Publication No. 59-768).
No. 5), a method of microencapsulation by a "phase separation method" using an organic solvent (JP-A-53-81387), and a method of forming an inclusion compound with cyclodextrin (JP-A-62-281855). ), A method of coating with dextrin, gelatin or the like (JP-A-6-19773).
No. 3) is disclosed, but few of these techniques improve both stability and solubility, and the method of using toxic and harmful organic solvents is safe for livestock and the like. There is a problem with the properties, and the cost is not practical.

[0005]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel easily absorbable folic acid preparation having excellent stability and high solubility, a method for producing the same, and a feed containing the same.

[0006]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies for improving the bioavailability of folic acid,
In addition to finding a safe and novel method for producing folic acid and casein coprecipitate that does not use any toxic and harmful organic solvents, this coprecipitate has remarkably high bioavailability and good stability Thus, the present invention has been completed.

That is, the present invention provides a folic acid preparation comprising folic acid and a coprecipitate of casein and / or a casein-containing substance. Further, the present invention provides the method for producing a folate preparation of the present invention, which comprises a step of adding an acid to an alkaline solution containing at least folic acid and casein and / or a casein-containing substance to coprecipitate folic acid and casein. . Further, the present invention provides a feed containing the folic acid preparation of the present invention.

[0008]

As described above, the folate preparation of the present invention contains a coprecipitate of folic acid and casein and / or a casein-containing substance. The folic acid used here can be any of powders, crystals or final synthesized products in the form of a slurry before drying, and is not particularly limited. Also,
The casein and / or casein-containing material is coprecipitated with folic acid to form at least a portion, preferably at least 50%, more preferably at least 90%, and most preferably the entire amount of folic acid in an amorphous state. It is used for maintaining, and as casein-containing substances, sodium caseinate, milk, skim milk powder, fermented milk, yogurt and the like can be used.

The ratio of folic acid to casein and / or casein-containing material in the coprecipitate is not particularly limited. However, if the amount of folic acid is too large, dispersion of folic acid becomes insufficient and crystalline folic acid is contained. It is not preferable because the stability and the absorbability decrease. Therefore, the compounding ratio of folic acid and casein and / or a casein-containing material is 1% by weight or more of casein to 1 part by weight of folic acid in a ratio of folic acid and casein,
It is more preferably at least 2 parts by weight. On the other hand, there is no limitation on the lower limit of the amount of folic acid, but if the amount of folic acid is too small, it is uneconomical to administer a large amount of folic acid preparation to administer the required amount of folic acid, Usually, the mixing ratio of folic acid and casein is not more than 1000 parts by weight, preferably not more than 200 parts by weight, as casein per 1 part by weight of folic acid.

The above coprecipitate can be produced by adding an acid to folic acid and an alkaline solution of casein and / or a casein-containing substance to coprecipitate folic acid and casein. For example, an alkaline solution is added to one or more formulations of folic acid and casein and / or casein-containing,
Is adjusted to 8 or more, preferably 10 or more, and folic acid and casein are dissolved.
To 5 or less, preferably 4 or less, and coprecipitate folic acid and casein. As a method of preparing an alkaline solution of folic acid and casein and / or a casein-containing substance, folic acid and casein and / or a casein-containing substance are individually dissolved or dispersed in an alkaline solution or water, and an alkaline aqueous solution is added. Then pH
May be 8 or more to dissolve folic acid and casein,
Further, an alkaline aqueous solution may be added to a mixture of folic acid and casein and / or a casein-containing substance to dissolve the mixture. The total concentration of folic acid and casein in the prepared alkaline solution is not particularly limited, but is usually about 1 to 15% by weight.

The alkali used here is not particularly limited as long as it dissolves both folic acid and casein. Preferred examples thereof include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, and alkaline earth metals. Hydroxides, as well as alkali metal carbonates such as sodium carbonate. Also, as the acid used,
There is no particular limitation, and inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as citric acid, lactic acid and acetic acid can be preferably used.The organic acids are both chemically synthesized products and natural acids prepared by microbial fermentation and the like. Can be used.

The step of producing the coprecipitate is preferably carried out at 0 ° C. to 4 ° C.
Although it can be carried out at 0 ° C., it can be carried out at room temperature, so that it is most economical and preferable to carry out at room temperature. Further, an inert carrier such as silicic acid, diatomaceous earth, kaolin or the like which serves as a nucleus for precipitation can be added. The use amount of these inert carriers is not particularly limited, but is usually preferably about 0.1 to 10% based on the weight of the mixture after adding the acid.

Suitable methods for drying the coprecipitate include:
For example, a method in which a precipitate is taken out by a method such as a spray drying method, filtration, or centrifugal separation and then heated and dried under normal pressure or reduced pressure can be employed.

The folate preparation of the present invention may consist of only the above-mentioned coprecipitate, or may be made into a dosage form suitable for oral administration, such as powdering, granulating, tableting, and pilling, by a conventional method. It can also be prepared, and if necessary, a coloring agent, a flavoring agent,
Suitable additives such as a flavoring agent, an excipient and the like may be included.

The folic acid preparation of the present invention is excellent in solubility and absorbability, has high storage stability, has good fluidity, is excellent in mixing with various powdered drugs, and is useful as an additive for feed and food. When used as an additive for livestock or pet feed, the amount of the folic acid preparation of the present invention is not particularly limited, and varies depending on the type and condition of the livestock and pets. It is preferable to mix the amount so that the daily intake is about 1 μg to 250 μg.

[0016]

The present invention will be described more specifically below with reference to examples. However, the present invention is not limited to the following examples.

Example 1 A solution of a mixture of 1 g of folic acid and 99 g of casein in 1500 ml of water was added to a solution of about 1N aqueous sodium hydroxide solution.
0 ml was added to adjust the pH to about 12. After dissolving folic acid and casein, about 1N hydrochloric acid solution (220 ml) was added to adjust the pH to about 12.
Was adjusted to about 3, and folic acid and casein were coprecipitated. Next, the precipitate was filtered and dried to obtain about 98 g of folic acid-casein coprecipitate. In the obtained coprecipitate, substantially all folic acid was in an amorphous state.

Example 2 A liquid obtained by dispersing a mixture of 2 g of folic acid and 98 g of casein in 1500 ml of water was mixed with about 1 M aqueous potassium hydroxide solution 180
After adding f.l. ml to dissolve folic acid and casein, about 1N hydrochloric acid solution (210 ml) was added to coprecipitate folic acid and casein. Next, the precipitate was filtered and dried to obtain about 95 g of a folic acid-casein coprecipitate. In the obtained coprecipitate, substantially all folic acid was in an amorphous state.

EXAMPLE 3 A solution prepared by dispersing a mixture of 2 g of folic acid and 98 g of casein in 1500 ml of water was mixed with about 1 M aqueous sodium carbonate solution.
After dissolving folic acid and casein, add about 1N
Was added, and folic acid and casein were co-precipitated. Next, the precipitate was filtered and dried to obtain about 99 g of a folate-casein coprecipitate. In the obtained coprecipitate, substantially all folic acid was in an amorphous state.

Example 4 To a liquid obtained by dispersing 99 g of skim milk powder in 1500 ml of water was added a solution obtained by dissolving 1 g of folic acid in 20 ml of an about 1 N aqueous sodium hydroxide solution, and further added 180 ml of an about 1 N sodium hydroxide solution. After dissolving folic acid and casein, about 1N hydrochloric acid solution (220 ml) was added to coprecipitate folic acid and casein. Next, the precipitate was filtered and dried to obtain about 40 g of a folate-casein coprecipitate. In the obtained coprecipitate, substantially all folic acid was in an amorphous state.

Example 5 A solution prepared by dispersing a mixture of 2 g of folic acid and 98 g of casein in 1500 ml of water was added to a solution of about 1N aqueous sodium hydroxide solution.
After 0 ml was added to dissolve folic acid and casein, 350 ml of an aqueous fermented lactic acid solution was added to coprecipitate folic acid and casein. Next, the precipitate was filtered and dried to obtain about 97 g of a folate-casein coprecipitate. In the obtained coprecipitate, substantially all folic acid was in an amorphous state.

Example 6 To 999 g of yogurt, a solution prepared by dissolving 1 g of folic acid in 20 ml of a 1N aqueous sodium hydroxide solution was added.
After adding 180 ml of an N aqueous sodium hydroxide solution to dissolve folic acid and casein, 220 ml of a 1N hydrochloric acid solution was added.
Was added to co-precipitate folic acid and casein. Next, the precipitate was filtered and dried to obtain about 45 g of a folic acid-casein coprecipitate. In the obtained coprecipitate, substantially all folic acid was in an amorphous state.

Example 7 A liquid obtained by dispersing a mixture of 5 g of folic acid and 95 g of casein in 1500 ml of water was mixed with about 1N aqueous sodium hydroxide solution 21.
After dissolving folic acid and casein, add about 1N
Was added, and folic acid and casein were coprecipitated. Next, the precipitate was filtered and dried to obtain about 97 g of a folate-casein coprecipitate. In the obtained coprecipitate, substantially all folic acid was in an amorphous state.

Example 8 A mixture of 20 g of folic acid and 80 g of casein was mixed with 1500 ml of water.
Is added to an aqueous solution of about 1 M potassium hydroxide 25
After dissolving folic acid and casein, add about 1N
Was added, and folic acid and casein were coprecipitated. Next, the precipitate was filtered and dried to obtain about 96 g of a folate-casein coprecipitate. In the obtained coprecipitate, substantially all folic acid was in an amorphous state.

Example 9 Stability of folic acid in the vitamin-mineral mixture to which the coprecipitates obtained in Examples 1 and 7 were added and, as a comparative example, the raw folic acid powder used for producing these coprecipitates was added Sex was tested.

(1) Mixing ratio The mixing ratio of each component was as shown in Table 1 below.

[0027]

[Table 1]

(2) Stability test conditions 500 g of each sample was put in a polyethylene bag and sealed.
It was stored at 0 ° C. and 75% relative humidity.

(3) Determination of folic acid Feed analysis standard comment (second edition) 10.17 Determined by folic acid determination (published by Japan Feed Association).

(4) Test Results Table 2 below shows the residual ratio (%) of folic acid after storage.

[0031]

[Table 2]

From the above results, it can be seen that the folic acid preparation of the present invention has much better storage stability than the folic acid bulk powder of the comparative example.

Example 10 The dissolution rates of the coprecipitates obtained in Examples 1 and 7 and the raw folic acid powder used for producing these coprecipitates in artificial gastric juice as a comparative example were tested.

(1) Solubility test conditions A 3 g sample was added to 100 ml of the test solution of the Japanese Pharmacopoeia (13th revision) disintegration test method, and after shaking for 1 hour in a thermostat at 20 ° C. The suspension is centrifuged (10000 rpm
m, 30 minutes), and the folic acid content in the supernatant was measured.

(2) Determination of folic acid Feed analysis standard comment (second edition) 10.17 Determined by folic acid (published by Japan Feed Association).

(3) Test results Table 3 below shows the amount of folic acid eluted in each case.

[0037]

[Table 3]

From the above results, it is clear that the folic acid preparation of the present invention has a very good dissolution property, so that the folic acid absorption rate is high and the bioavailability is excellent.

Example 11 Pigs were orally administered the coprecipitate obtained in Example 1 and, as a comparative example, the raw folic acid powder used for producing this coprecipitate, and the change in blood concentration was examined.

(1) Test Conditions for Blood Concentration Three pigs (body weight: 85 to 100 kg) which had been fasted for one day were orally administered with each sample mixed with about 300 g of a mixed feed for 1 hour and 2 hours after administration. The total folate concentration in plasma was measured by microbioassay after 4, 6, 8, 10 and 24 hours.

(2) Determination of folic acid A microbioassay method using Lactobacillus casei ATCC7469 was used.

(3) Test Results The results are shown in FIGS. 1 and 2. From these results, it was found that the folic acid preparation of the present invention was far superior to the control folic acid preparation in both the maximum plasma concentration and the area under the plasma concentration curve. That is, by coprecipitating folic acid and casein and causing folic acid to be present in the casein in a substantially non-crystalline state, the solubility and translocation to blood are significantly improved, and the bioavailability is significantly improved. It was ok.

[0043]

Industrial Applicability According to the present invention, folic acid preparations having excellent solubility and absorbability, high storage stability, good flowability, excellent mixing with various powdered drugs, and useful as additives for feeds and foods. Was provided.

[Brief description of the drawings]

BRIEF DESCRIPTION OF DRAWINGS FIG. 1 is a graph showing changes over time in plasma total folate concentration when a folic acid preparation of the example of the present invention or an original folic acid powder as a control is orally administered to pigs.

FIG. 2 is a diagram comparing the areas under the plasma total folate concentration curve shown in FIG. 1;

Continuation of the front page (58) Fields surveyed (Int.Cl. ⁷ , DB name) A23K 1/16 301 A23K 1/16 303 A61K 31/505 A61K 47/42 BIOSIS (DIALOG) CA (STN) JICST file (JOIS ) REGISTRY (STN) WPIDS (STN)

Claims (6)

(57) [Claims] 1. A folate preparation comprising folic acid and a co-precipitate of casein and / or casein-containing substances. 2. The coprecipitate comprises folic acid, casein and / or
The folate preparation according to claim 1, which is produced by adding an acid to an alkaline solution of a casein-containing substance and coprecipitating folate and casein. 3. The folate preparation according to claim 1, wherein the weight ratio of folic acid to casein in the coprecipitate is from 1: 1 to 1: 1000. 4. The folate preparation according to claim 1, wherein the casein-containing substance is sodium caseinate, milk, skim milk powder, fermented milk, or yogurt. 5. The method for producing a folate preparation according to claim 1, comprising a step of adding an acid to an alkaline solution containing at least folate and casein and / or a casein-containing substance to coprecipitate folate and casein. 6. A feed containing the folic acid preparation according to claim 1.