JP7001332B2 - Granulation - Google Patents

Description

The present invention relates to a granulated product that contains amino acids, has little production loss, and can be produced with high production efficiency. Furthermore, the present invention relates to a tablet that contains amino acids but can suppress tableting disorders and can be produced with high production efficiency. Furthermore, the present invention relates to the granulated product and the method for producing the tablet.

Amino acids are basic substances necessary for life activities and are known to have various functionalities. In addition, among the 20 kinds of amino acids that make up proteins, there are essential amino acids that cannot be synthesized in the body, and ingestion of amino acids is indispensable for maintaining vital functions. In recent years, the number of people who are deficient in amino acid intake due to a biased diet is increasing. Therefore, supplements and energy drinks containing amino acids have been developed to supplement the amino acids deficient in the diet. In addition, amino acids that exert pharmacological action are known and are also used as pharmaceuticals.

As described above, amino acids are widely used in fields such as foods and pharmaceuticals. On the other hand, amino acids have a peculiar property that they are difficult to physically bind to other substances. Therefore, when the amino acid is formulated into a solid form, there is a drawback that the formulation becomes difficult due to the weak binding force of the amino acid. In particular, in the case of tablets, capping (an event in which the top and bottom of the tablet are peeled off), sticking (an event in which a part of the raw material adheres to the pestle or mortar and a part of the tablet is peeled off), binding (in the mortar wall) There is a drawback that tableting problems such as (event of scratching the surface of the tablet due to the rubbing of the tablet) occur. In order to prevent such tableting disorders, it is effective to use a large amount of additives such as binders, but when a large amount of additives are used, amino acids and nutritional components and pharmacological components other than amino acids (hereinafter, "" It may be referred to as "functional ingredient"), which causes a decrease in the content of the ingredient, and the amount of one-time intake is increased, which increases the burden on the ingestor.

Therefore, conventionally, a method for suppressing a tableting disorder when producing a tablet containing an amino acid has been studied. For example, Patent Document 1 discloses that tableting disorders can be suppressed by tableting an amino acid together with lactitol. Further, Patent Document 2 discloses that after granulating isoleucine, leucine, and valine into granules, the granules are coated with a binder and tableted to suppress tableting disorders. .. However, the formulation technique of Patent Document 1 is not yet sufficiently effective, and the formulation technique of Patent Document 2 has a drawback that the production efficiency is lowered due to the increase in the coating process.

Against the background of such conventional techniques, it is desired to establish a technique for efficiently formulating tablets containing amino acids by suppressing tableting disorders.

Japanese Unexamined Patent Publication No. 2001-258509 Japanese Patent Application Laid-Open No. 2003-221326

Conventionally, when producing a tablet, a method is known in which a raw material is once granulated and then subjected to tableting molding. Therefore, the present inventor tried to granulate a raw material containing an amino acid and then tableting it. When the raw material containing an amino acid was granulated and then granulated, the granulated product was subjected to a granulation machine (comil). Remained, and faced a new problem that granulated products could not be obtained efficiently. As a result, it is still impossible to establish a technique for producing tablets containing amino acids by suppressing tableting disorders.

Therefore, one of the objects of the present invention is to provide a technique for producing granulated products from raw materials containing amino acids with high production efficiency. Further, another object of the present invention is to provide a formulation technique for efficiently producing a tablet containing an amino acid by suppressing tableting disorders.

As a result of diligent studies to solve the above-mentioned problems, the present inventor made a granulated product by coexisting pregelatinized starch and / or partially pregelatinized starch with amino acids to produce a granulated product on a granulation machine. It was found that the residue of starch can be suppressed and that granulated products containing amino acids can be efficiently obtained. Furthermore, the present inventor has found that by producing tablets using the granulated product, tableting disorders can be suppressed and tablets containing amino acids can be efficiently produced. The present invention has been completed by further studies based on such findings.

That is, the present invention provides the inventions of the following aspects.
Item 1. A granulated product comprising (A) an amino acid and at least one selected from the group consisting of (B) pregelatinized starch and partially pregelatinized starch.
Item 2. Item 2. The granulated product according to Item 1, which contains the component (B) in a ratio of 0.03 to 6 parts by weight per part by weight of the component (A).
Item 3. Item 2. The granulated product according to Item 1 or 2, wherein the component (B) is pregelatinized starch.
Item 4. Item 2. The granulated product according to any one of Items 1 to 3, wherein the content of the component (A) is 1 to 6% by weight.
Item 5. A tablet containing the granulated product according to any one of Items 1 to 4.
Item 6. A method for producing a tablet, which comprises a step of tableting and molding the granulated product according to any one of Items 1 to 4.

Since the granulated product of the present invention contains amino acids, it is possible to suppress the production loss that occurs during granulation, so that high production efficiency can be realized in industrial production. Further, the tablet of the present invention can be efficiently produced because it can suppress a tableting disorder during tableting molding while containing an amino acid.

1. 1. Granulation The granulation product of the present invention is at least one selected from the group consisting of amino acids (hereinafter, also referred to as component (A)), pregelatinized starch and partially pregelatinized starch (hereinafter, (hereinafter, (hereinafter,). B) It is characterized by containing (sometimes referred to as a component). Hereinafter, the granulated product of the present invention will be described in detail.

(A) Amino acid The granulated product of the present invention contains an amino acid. In the prior art, in the case of granulated products containing amino acids, the granulated products remained in the granulator at the time of granulation, and the granulated products could not be obtained efficiently. However, in the present invention, pregelatinized starch and / or portions thereof. By containing pregelatinized starch, it is possible to efficiently produce granulated products even if they contain amino acids.

The type of amino acid used in the present invention is not particularly limited and may be appropriately set according to the intended use, and may be a constituent amino acid of a protein or a non-constituting amino acid of a protein. ..

Specific amino acids that make up the protein include methionine, cysteine, arginine, isoleucine, leucine, valine, histidine, lysine, phenylalanine, threonine, tryptophan, aspartic acid, aspartic acid, alanine, glutamine, glutamic acid, glycine, proline, and serine. , Tyrosine.

Specific examples of the non-constituent amino acid of the protein include ornithine, citrulline, hydroxyproline, γ-aminobutyric acid, cystine, theanine and the like.

Among these amino acids, protein constituent amino acids are preferable, and methionine, cysteine, and arginine are more preferable.

In the granulated product of the present invention, these amino acids may be used alone or in combination of two or more.

The content of the component (A) in the granulated product of the present invention is not particularly limited, and examples thereof include 1 to 6% by weight, preferably 1 to 5.5% by weight, and more preferably 1 to 5% by weight. Be done. In the prior art, there is a drawback that the production loss of the granulated product becomes large when the component (A) is contained, but in the granulated product of the present invention, such a problem of the prior art is overcome. Therefore, even when the component (A) is contained in the above-mentioned content, the production loss is small, and when the tablet is produced, it is possible to suppress the tableting disorder.

(B) Pregelatinized starch and / or partially pregelatinized starch The granulated product of the present invention contains pregelatinized starch and / or partially pregelatinized starch. By containing pregelatinized starch and / or partially pregelatinized starch, it is possible to overcome the drawbacks of conventional granulated products containing amino acids, reduce production loss, and suppress tableting problems when used for tablet production. become.

Pregelatinized starch refers to starch having a degree of pregelatinization of 90% or more. The degree of pregelatinization of the pregelatinized starch used in the present invention is not particularly limited, but it is said that the production loss is further reduced and the tableting disorder when subjected to tableting molding is further effectively suppressed. From the viewpoint, it is preferably 92% or more, more preferably 94% or more, and particularly preferably 96% or more. In the present invention, the degree of pregelatinization refers to a value measured according to the glucoamylase method (edited by Jiro Futakuni, "Starch Science Handbook", Asakura Shoten, 1977, p.242).

Further, the partially pregelatinized starch refers to starch having a degree of pregelatinization of 50% or more and less than 90%. The degree of pregelatinization of the partially pregelatinized starch used in the present invention is not particularly limited, but the production loss is further reduced, and the tableting disorder when subjected to tableting molding is further effectively suppressed. From this point of view, preferably 55% or more and less than 90%, more preferably 60% or more and less than 90%, and particularly preferably 65% or more and less than 90%.

In the present invention, the type of raw material starch for pregelatinized starch and / or partially pregelatinized starch is not particularly limited, and for example, corn starch, wheat starch, horse bell starch, tapioca starch, rice starch, sweet potato starch, sago starch, and the like. Examples thereof include soramame starch, green bean starch, soybean starch, and small bean starch. Among these raw material starches, corn starch is preferable from the viewpoint of more effectively suppressing tableting disorders.

Further, the pregelatinized starch and / or partially pregelatinized starch used in the present invention may be chemically processed, if necessary. The type of such chemical processing treatment is not particularly limited, and is, for example, hydroxypropylation, hydroxypropylated phosphoric acid cross-linking, phosphorylation cross-linking, phosphorylation, phosphorylation monoesterified phosphate cross-linking, and acetylated adipic acid. Cross-linking, acetylation, acetylated phosphate cross-linking, octenyl succi oxidation, acetication, bleaching and the like can be mentioned.

Among pregelatinized starches and partially pregelatinized starches, pregelatinized starches are preferable from the viewpoint of reducing production loss and further effectively suppressing tableting disorders when subjected to tableting molding. Preferred is pregelatinized corn starch.

In the granulated product of the present invention, one kind of pregelatinized starch and partially pregelatinized starch may be selected and used, or two or more kinds of these may be used in combination. May be good.

In the granulated product of the present invention, the ratio of the component (A) to the component (B) is not particularly limited, but the production loss is further reduced, and the tableting obstacle when the tablet is produced is further reduced. From the viewpoint of effective suppression, the total amount of the component (B) is 0.03 to 6 parts by weight, preferably 0.2 to 5.5 parts by weight, more preferably 0.2 part by weight, per 1 part by weight of the total amount of the component (A). 0.2 to 5 parts by weight may be mentioned.

The content of the component (B) in the granulated product of the present invention may be appropriately set within a range that satisfies the ratio of the above-mentioned amino acid to the pregelatinized starch and / or the partially pregelatinized starch. 2 to 6% by weight, preferably 1 to 5.5% by weight, still more preferably 1 to 5% by weight.

Other Ingredients In addition to the above-mentioned ingredients, the granulated product of the present invention may contain other additives, if necessary, as long as the effects of the present invention are not impaired. Examples of such additives include excipients, fluidizers, lubricants, disintegrants, binders, pre-existing agents, acidulants, sweeteners, flavors, colorants and the like.

Specific examples of such additives include sugars such as lactose, glucose, malt sugar, sucrose, and sucrose: sugar alcohols such as mannitol, sorbitol, xylitol, trehalose, and erythritol; corn starch, horse bell starch, wheat starch, and the like. Starch such as rice starch, dextrin, carboxymethyl starch and its derivatives; cellulose such as cellulose, crystalline cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose and its derivatives; Arabic gum, dextran, purulan, light anhydrous silicic acid, synthetic Examples thereof include aluminum silicate, magnesium aluminometasilicate, calcium phosphate, calcium carbonate, calcium sulfate, crospovidone, croscarmellose sodium, carmellose calcium, calcium stearate, magnesium stearate and the like. These additives may be used alone or in combination of two or more.

The granulated product of the present invention may contain a functional component in addition to the above-mentioned components. Such functional ingredients are not particularly limited as long as they can be used in foods and pharmaceuticals, but for example, antacids, stomachic agents, digestive agents, intestinal regulators, antispasmodics, mucosal repair agents, anti-inflammatory agents, astringents, etc. Antiemetics, antitussives, astringents, anti-inflammatory enzyme agents, sedative hypnotics, antihistamines, caffeines, cardiotonic diuretics, antibacterial agents, vasoconstrictors, vasodilators, local anesthetics, crude drugs, crude drug extract powders, vitamins, Mentors, glucosamine compounds, chitin, chitosan and the like can be mentioned. These nutritional components and pharmacological components may be used alone or in combination of two or more. Further, the content of these components is appropriately set according to the type of the component to be used and the like.

When the granulated product of the present invention contains a component other than the component (A) and the component (B), the content thereof may be appropriately set, but for example, the component other than the component (A) and the component (B) is used. The total amount of the components is 88 to 98.8% by weight, preferably 89 to 98.8% by weight, and more preferably 89 to 98% by weight.

Average particle size The average particle size of the granulated product of the present invention is not particularly limited, and examples thereof include 20 to 500 μm, preferably 30 to 400 μm, and more preferably 40 to 250 μm. Here, the average particle size of the granulated product is a value measured by a laser diffraction type particle size distribution measuring device.

Applications The granulated product of the present invention is preferably used as a raw material for producing tablets by being subjected to tableting molding, but may be used as it is as granules or fine granules, and further, a water-soluble polymer or the like. It may be coated and provided as a coating preparation, or it may be filled in a capsule and provided as a capsule.

Method for Producing Granulated Product The granulated product of the present invention can be produced by mixing and granulating the component (A) and the component (B). In addition, when the granulated product of the present invention contains other components added as needed, the other components are mixed together with the component (A) and the component (B) to perform granulation. Just do it. Examples of the granulation method include wet granulation.

The solvent used for wet granulation is not particularly limited, and examples thereof include water, ethanol, and isopropanol. These solvents may be used alone or in combination of two or more. Among these solvents, water is preferable.

The amount of the solvent added for wet granulation is not particularly limited, but for example, 3 to 10 parts by weight, preferably 4 to 9 parts by weight, and further, per 100 parts by weight of the total amount of the components to be subjected to granulation. Preferred are 4 to 8 parts by weight.

It is preferable that the granulated product obtained by wet granulation is dried as necessary and then granulated to a desired average particle size using a granulator.

2. 2. Tablets The tablets of the present invention are characterized by containing the granulated product. In the prior art, amino acids have been a factor in causing tableting disorders during tableting and molding, but in the present invention, by tableting and molding using the granulated product, even if amino acids are contained, the amino acids are beaten. It is possible to suppress tablet damage and obtain tablets efficiently.

The content of the granulated product in the tablet of the present invention is not particularly limited, and examples thereof include 66 to 100% by weight, preferably 66 to 97% by weight, and more preferably 70 to 97% by weight.

The content of the component (A) in the tablet of the present invention is determined according to the content of the granulated product in the tablet and the content of the component (A) in the granulated product, but specifically. Is 0.66 to 6% by weight, preferably 0.66 to 5.5% by weight, and more preferably 0.66 to 5% by weight.

The content of the component (B) in the tablet of the present invention is determined according to the content of the granulated product in the tablet and the content of the component (B) in the granulated product, but specifically. Is 0.13 to 6% by weight, preferably 0.66 to 5.5% by weight, and more preferably 0.66 to 5% by weight.

Further, in addition to the granulated product, the tablet of the present invention may contain other additives necessary for formulation into the tablet, if necessary, as long as the effect of the present invention is not impaired. good. Examples of such additives include excipients, fluidizers, lubricants, disintegrants, binders, pre-existing agents, acidulants, sweeteners, flavors, colorants and the like. Specific examples of these additives are the same as those exemplified in the above-mentioned "1. Granulation".

Further, the tablet of the present invention may contain a functional ingredient, if necessary. Specific examples of such functional components are the same as those exemplified in the above-mentioned "1. Granulation". Further, the content of these components is appropriately set according to the type of the component to be used and the like.

The content of additives and functional components added to the tablets of the present invention other than the granulated product may be appropriately set. For example, the additives and functionality added to the tablets other than the granulated product. The total amount of the components (however, the amount excluding the additives and functional components contained in the granulated product) is 0 to 34% by weight, preferably 3 to 34% by weight, and more preferably 3 to 30% by weight. ..

The tablet of the present invention can be obtained by subjecting the granulated product to tableting and molding. By using the granulated product, the tablet of the present invention can be efficiently produced by suppressing tableting obstacles such as sticking, capping, and binding during tableting molding.

When producing the tablet of the present invention, the granulated product may be coated, if necessary, before being subjected to tableting molding. Further, when producing the tablet of the present invention, a part or all of other components (for example, a binder) added to the granulated product as needed before being subjected to tableting molding. May be coated with.

In addition, when the tablet of the present invention contains other components (additives, nutritional components, and / or pharmacological components) to be added as needed, the other components are mixed with the granulated product. It may be tableted.

The method of tableting is not particularly limited, but for example, it can be performed using an apparatus such as a single-shot tablet machine, a rotary tablet machine, or a high-speed rotary tablet machine. The pressing force during tablet forming is not particularly limited as long as tablet forming is possible, but is usually about 0.9 to 2.0 tons, preferably about 1.0 to 2.0 tons, more preferably about 1.0 to 2.0 tons. It may be set to about 1.2 to 2.0t.

The tablets of the present invention are used as foods and pharmaceuticals because they provide useful physiological functions by amino acids. The tablet of the present invention may be used in the state of an uncoated tablet, but may be used as a coated tablet by applying a coating such as a sugar coating or a film coating, if necessary.

The weight of the tablet of the present invention per tablet may be appropriately set according to the dose per dose, the content of amino acids, and the like, and examples thereof include about 120 to 350 mg.

Hereinafter, the present invention will be specifically described with reference to Examples, but the present invention is not limited to these Examples.

In the following test examples and production examples, the pregelatinized corn starch uses the trade name "Amicol C" (manufactured by Nissho Kagaku Co., Ltd .; pregelatinization degree 98.4), and the partially pregelatinized corn starch is a commercial product. The name "PCS" (manufactured by Asahi Kasei Chemicals Co., Ltd .; pregelatinization degree 70.0) was used.

Test Example 1
1. 1. Production of Granulated Products Granulated products having the composition shown in Table 1 were produced. The specific manufacturing method is as shown below. First, each component and water shown in Table 1 were mixed, and wet granulation was performed with a stirring granulator. The amount of water added was set to be 6 parts by weight per 100 parts by weight of the total amount of each component shown in Table 1. Then, the granulated product was dried at 40 ° C. for 10 minutes to obtain a granulated product. The obtained granulated product was sized with a combil (opening 1 mm).

2. 2. Measurement of recovery rate The weight of the granulated product (granulated product that passed through the combil) recovered by sizing was measured, and the recovery rate was calculated according to the following formula.

The calculated recovery rate was classified according to the following criteria, and the manufacturing efficiency was evaluated.
<Judgment criteria>
◎: Recovery rate is 95% or more ○: Recovery rate is 80% or more and less than 95% △: Recovery rate is 70% or more and less than 80% ×: Recovery rate is 50% or more and less than 70% × ×: Recovery rate is less than 50%

3. 3. Results The results obtained are shown in Table 1. In the granulated product containing amino acids and corn starch, hydroxypropyl cellulose, hypromellose, or xylitol, the granulated product adhered to the combil and remained, so that the recovery rate was as low as less than 50%. On the other hand, in the granulated products containing amino acids and pregelatinized starch and / or partially pregelatinized starch, the recovery rate was 70% or more, showing high production efficiency. Further, as is clear from the comparison between Examples 1 and 5, the recovery rate was higher when the pregelatinized starch was used than when the partially pregelatinized starch was used.

Test Example 2
1. 1. Production of tablets (Example 9 and Comparative Example 6)
A predetermined amount of the components having the composition shown in Table 2 are mixed and subjected to tableting molding by setting a tableting pressure of 1.8 tons and a rotation speed of 40 rpm using a tableting machine (rotary method, VIRGO, Kikusui Seisakusho Co., Ltd.). As a result, tablets (φ9 mm, 3000 tablets in total) were manufactured. In Example 9, the granulated product of Example 1 was used as methionine, pregelatinized corn starch, and glucosamine. Further, in Comparative Example 6, the granulated product of Comparative Example 1 was used as methionine and glucosamine.

(Comparative Example 5)
Each component shown in Table 2 is mixed and subjected to tableting molding by setting a tableting pressure of 1.8 tons and a rotation speed of 40 rpm using a tableting machine (rotary method, VIRGO, Kikusui Seisakusho Co., Ltd.). (Φ9 mm, 3000 tablets in total) was manufactured. In Comparative Example 5, the granulation was not used.

2. 2. Presence or absence of tableting disorder Table 2 shows the results of observing the presence or absence of tableting disorder when each tablet was tableted and molded. Even if amino acids and pregelatinized starch are contained, if they are subjected to tableting without granulation in advance, sticking (an event in which a part of the raw material adheres to a pestle or a mortar and a part of the tablet is peeled off) is observed. (Comparative Example 5). In addition, when tableting was performed using the granulated product of Comparative Example 1 containing no pregelatinized starch, binding (an event in which the tablet surface was scratched by friction on the mortar wall) was observed (an event in which the tablet surface was scratched). Comparative Example 6). On the other hand, when tableting was performed using the granulated product of Example 1 containing amino acids and pregelatinized starch, no tableting problems such as sticking, binding, and capping were observed, and tablets could be efficiently produced. (Example 9).

Production Example 1: Granulation A granulated product having the composition shown in Table 3 was produced under the same conditions as in Test Example 1. In all of the obtained granulated products, adhesion to the combil was suppressed and the recovery rate was high.

Production Example 2: Tablet A tablet having the composition shown in Table 4 was produced under the same conditions as in Test Example 2. No tableting problems such as sticking, binding, and capping were observed in the production of any of the tablets.

Claims (6)

Contains (A) amino acids and (B) pregelatinized starch,
A wet granulated product (provided to contain a DPP-4 inhibitor), wherein the component (A) is selected from the group consisting of methionine, cysteine, arginine, valine, isoleucine, leucine, and theanine. except). The wet granulated product according to claim 1, wherein the component (B) is contained in a ratio of 0.03 to 6 parts by weight per part by weight of the component (A). The wet granulated product according to claim 1 or 2, further comprising partially pregelatinized starch. The wet granulated product according to any one of claims 1 to 3, wherein the content of the component (A) is 1 to 6% by weight. A tablet comprising the wet granulated product according to any one of claims 1 to 4. A method for producing a tablet, which comprises the step of tableting and molding the wet granulated product according to any one of claims 1 to 4.