JP7426685B2 - tablet - Google Patents

Description

The present invention relates to tablets with excellent sustained release properties.

BACKGROUND OF THE INVENTION With the recent increase in health consciousness, it has become common practice to take ingredients useful for promoting health as supplements in the form of tablets. Among these tablets, there are sustained-release tablets that release useful ingredients gradually and maintain their effects over a long period of time.

As a method for imparting this sustained release property, a method of coating a tablet core and a method of adding a sustained release agent to a tablet core are known (see Patent Document 1).

Special Publication No. 06-104625

The above-mentioned sustained release by coating has the problem of increasing the number of manufacturing steps. Moreover, sustained release by adding a sustained release agent to the tablet core is preferable because it does not increase the number of manufacturing steps, but its sustained release effect is not necessarily sufficient, and there is a demand for tablets with further improved sustained release effects.

An object of the present invention is to provide a tablet with excellent sustained release properties.

As a result of intensive studies to solve the above problems, the present inventors discovered that tablets exhibit excellent sustained release properties by containing a combination of specific ingredients in the tablet core, and have completed the present invention. It's arrived.

That is, the present invention is as follows.
[1] A tablet characterized by comprising a tablet core containing the following components (A), (B) and (C).
(A) Hydroxypropyl methyl cellulose (B) Hydroxypropyl cellulose (C) At least one component selected from cellulose, sugar alcohol, starch, dextrin, and maltose [2] The tablet core contains (C) cellulose, sugar alcohol, The tablet according to [1], characterized in that it contains two or more components selected from starch, dextrin, and maltose.
[3] The tablet according to [1] or [2], which is for sustained release.
[4] A coated tablet having a coating layer, any one of [1] to [3], characterized in that the coating layer does not contain component (A), component (B), or component (C). Tablets listed.
[5] Any one of [1] to [4], wherein the tablet core contains (D) at least one component selected from vitamins, polyphenols, amino acids, peptides, lactic acid bacteria, charcoal, and fragrances. Tablets listed.

The tablet of the present invention has excellent sustained release properties.

The tablet of the present invention is characterized by comprising a tablet core containing the following components (A), (B), and (C).

(A) Hydroxypropyl methylcellulose (HPMC)
(B) Hydroxypropyl cellulose (HPC)
(C) At least one component selected from cellulose, sugar alcohol, starch, dextrin, and maltose

When the tablet core contains component (A), component (B), and component (C), a tablet having excellent sustained release properties can be obtained. That is, the tablet of the present invention has a long disintegration time and has the property that the ingredients intended for sustained release slowly dissolve (sustained release properties), so that the effects of the ingredients can be maintained for a long period of time. For example, even if you take a large amount of useful ingredients such as vitamins at once, more than a predetermined amount cannot be absorbed into the body and will be excreted from the body.However, according to the tablet of the present invention, the desired ingredients are slowly absorbed. Because it dissolves, desired ingredients can be absorbed continuously over a long period of time. Moreover, this makes it possible to reduce the number of times tablets are taken. Furthermore, especially in the pharmaceutical field where side effects are a problem, it is possible to suppress a rapid increase in the concentration of active ingredients in the blood, thereby making it possible to suppress side effects.

The disintegration time of the tablet of the present invention is preferably 20 minutes or more, more preferably 25 minutes or more, and even more preferably 30 minutes or more. In addition, disintegration time means the time until a sample in a solvent disintegrates, and specifically, the method described in "Disintegration test method" in item "6.09" of the 15th edition Japanese Pharmacopoeia. Measured by

The tablet of the present invention may be a coated tablet having a coating layer, or may be a bare tablet consisting of a tablet core without a coating layer. That is, in the present invention, the tablet core means the portion of the tablet from which the coating layer has been removed. In the case of tablets without a coating layer (naked tablets), the tablet consists of only the core. In general, a bare tablet (also referred to as a plain tablet) refers to a tablet without a coating layer formed on its surface. The tablet of the present invention containing component (A), component (B), and component (C) in the core exhibits sufficient sustained release properties even if it is a plain tablet.

When the tablet of the present invention is a coated tablet, the coating layer includes a form containing the above-mentioned components (A), (B), and (C) (a form containing three components), and a form containing the above-mentioned components (A) to (C). A form containing two components, a form containing one of the components (A) to (C), a form not containing the (A) component, the (B) component, and the (C) component (a form not containing the three components) It may be in any form.

Hydroxypropyl methylcellulose (HPMC), the component (A), and hydroxypropylcellulose (HPC), the component (B), contained in the core of the tablet of the present invention are cellulose derivatives used as additives for foods and medicines, and are commercially available. products can be used.

The component (C) contained in the core of the tablet of the present invention is a component selected from cellulose, sugar alcohol, starch, dextrin, and maltose, and at least one of these components may be included. It is preferable to include two or more types, and more preferably three or more types. Moreover, as component (C), cellulose, sugar alcohol, starch, and maltose are preferable among the said components, and sugar alcohol, starch, and maltose are more preferable. It is preferable to include two or more types of these components, and more preferably three or more types. Specifically, a combination of sugar alcohol, starch and maltose is particularly preferred.

Each component of component (C) will be explained below. Commercially available products can be used for each component. Furthermore, two or more of each component may be used in combination.

Examples of cellulose include cellulose derived from plants, cellulose derived from bacteria, cellulose produced by microorganisms, and cellulose produced by animals, and may be powdered or crystallized. Cellulose as component (C) does not contain cellulose derivatives. Therefore, cellulose as component (C) is distinguished from hydroxypropyl methyl cellulose (HPMC) as component (A) and hydroxypropyl cellulose (HPC) as component (B).

Examples of sugar alcohols include xylitol, sorbitol, mannitol, reduced maltose, lactitol, oligosaccharide alcohols, erythritol, low saccharification reduced starch syrup, high saccharification reduced starch syrup, reduced palatinose, etc. Among the above ingredients, reduced maltose, reduced Palatinose is preferred, and reduced maltose is particularly preferred.

Examples of starch include corn starch (starch derived from corn), tapioca starch, potato starch, sweet potato starch, rice starch, wheat starch, etc., and may be pregelatinized starch or partially pregelatinized starch. As the starch, corn starch, tapioca starch, and potato starch are preferred, and corn starch is particularly preferred.

Dextrin in the present invention refers to a starch decomposition product obtained by hydrolyzing starch using an enzyme or an acid, and includes the above-mentioned starch decomposition products. In the present invention, indigestible dextrin obtained by adding a small amount of acid to starch, heating it, and then hydrolyzing it with an enzyme is also included in dextrin in the present invention. Digestible dextrin is particularly preferred as the dextrin.

Maltose is a reducing disaccharide in which two molecules of glucose are linked with α1-4 bonds, and is obtained by enzymatically decomposing starch.

The core of the tablet of the present invention preferably further contains at least one component selected from (D) vitamins, polyphenols, amino acids, peptides, lactic acid bacteria, charcoal, and fragrances as a component for sustained release. , more preferably two or more types of components, and even more preferably three or more types of components. As component (D), vitamins, polyphenols, lactic acid bacteria, and fragrances are preferable, and fragrances are particularly preferable. Note that the component for sustained release is not limited to the component (D) exemplified above.

Each component of component (D) will be explained below. Commercially available products can be used for each component. Furthermore, two or more of each component may be used in combination.

Vitamins include water-soluble vitamins (vitamin B1, B2, B3, B5, B6, B12, B13, B15, B17, biotin, choline, folic acid, inositol, PABA, vitamin C, vitamin P), oil-soluble vitamins (vitamin A , D, E, K) and the like. As the vitamin, vitamin B2, vitamin C, and vitamin E are preferred, and vitamin B2 and vitamin E are particularly preferred.

Polyphenols include catechol, catechin, epicatechin, gallocatechin, epigallocatechin, gallocatechin gallate, epigallocatechin gallate, tannic acid (m-galloyl gallic acid), hamamelitannin (1,5-digalloyl hamame loose), anthocyanins, proanthocyanidins, resveratrol, caffeic acid derivatives, gallic acid, pyrogallol tannins, catechol tannins, and the like. As the polyphenol, catechin, anthocyanin, and proanthocyanidin are preferable, and proanthocyanidin is particularly preferable.

As the polyphenol, synthesized polyphenols, extracts or extraction residues of plants containing polyphenols, dried powders of plants containing polyphenols, and the like can be used. When using plant-derived polyphenols, the type of plant is not particularly limited, but for example, plants such as Pinaceae, Camellia, Rubiaceae, Vitaceae, and Convolvulaceae can be used. When using a plant extract containing polyphenols, extraction methods include, for example, hot water extraction fraction, solvent extraction fraction with organic solvents such as alcohol, ethyl acetate, and petroleum ether, steam distillation fraction, press fraction, Examples include fat and oil adsorption fraction, liquefied gas extraction fraction, supercritical extraction fraction, and dry distillation fraction. Moreover, when using a plant extract, pine bark extract, tea extract, and coffee extract are preferable, and pine bark extract is particularly preferable.

Examples of amino acids include alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, proline, serine, tyrosine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine, and histidine. As the amino acid, alanine, glycine, and tyrosine are preferred, and alanine is particularly preferred.

Examples of peptides include decomposition products of animal proteins and vegetable proteins. Examples of animal proteins include livestock meat such as cows, pigs, and chickens; collagen derived from fish and eggs; elastin; and glycoproteins such as chondroitin protein complexes. Examples of vegetable proteins include soybeans, wheat, corn, and peas. As the peptide, milk-derived peptides, soybean-derived peptides, and collagen peptides are preferred, and collagen peptides are particularly preferred.

Lactic acid bacteria are not particularly limited as long as they produce lactic acid as a metabolite, and include those that are conventionally ingested orally by animals such as humans, and may be live or dead bacteria. . Specific examples include bacteria of the genus Bifidobacterium, Lactbacillus, Enterococcus, Leuconostoc, Pediococcus, Staphylococcus, Tetragenococcus, and Bacillus. As the lactic acid bacteria, lactic acid bacteria of the genus Lactbacillus, Enterococcus, and Bacillus are preferred, and lactic acid bacteria of the genus Lactbacillus and Enterococcus are particularly preferred.

The genus Bifidobacterium includes Bifidobacterium bifidum, Bifidobacterium breve, Bifidobacterium infantis, Bifidobacterium lactis, Bifidobacterium longum, Bifidobacterium adolescentis, and Bifidobacterium mongoliense. The genus Lactbacillus includes Lactobacillus brevis, Lactobacillus gasseri, Lactobacillus acidophilus, Lactobacillus buchneri, Lactobacillus bulgaricus, Lactobacillus delburvecki, Lactobacillus casei, Lactobacillus crispatus, Lactobacillus curvatus, Lactobacillus halivaticus, Lactobacillus pentosus, Lactobacillus plantarum, Lactobacillus paracasei, Lactobacillus rhamnosus, Lactobacillus salivarius, Examples include Lactobacillus sporogenes, Lactobacillus sakei, Lactobacillus fructivorans, Lactobacillus hilgardii, Lactobacillus reuteri, and Lactobacillus fermentum.

The Enterococcus genus includes Enterococcus faecalis (sometimes called Streptococcus faecalis), Enterococcus faesium (sometimes called Streptococcus faesium), Streptococcus thermophilus, and Lactococcus lactis (sometimes called Streptococcus lactis). Can be mentioned. The genus Leuconostoc includes Leuconostoc mesenteroides and Leuconostoc oenos. Pediococcus genus includes Pediococcus acidilactici and Pediococcus pentosaceus. The genus Staphylococcus includes Staphylococcus carnosus and Staphylococcus xylosus. The genus Tetragenococcus includes Tetragenococcus halophilus. The genus Bacillus includes Bacillus coagulans and Bacillus mesentericus.

The charcoal is not particularly limited as long as it is edible, and examples include charcoal, bamboo charcoal, pure charcoal, and the like. These charcoals can be obtained, for example, by burning, carbonizing, and pulverizing trees, bamboo, cellulose extracted from these, and synthesized cellulose. As the charcoal, charcoal and bamboo charcoal are preferred, and bamboo charcoal is particularly preferred.

The fragrance can be appropriately selected from natural fragrances obtained from animals and plants by physical means such as extraction, compression, distillation, or enzyme treatment, and synthetic fragrances. Specifically, for example, peppermint oil, spearmint oil, anise oil, eucalyptus oil, wintergreen oil, cassia oil, clove oil, thyme oil, sage oil, lemon oil, orange oil, peppermint oil, cardamom oil, coriander oil, mandarin oil. Oil, lime oil, lavender oil, rosemary oil, laurel oil, chamomile oil, caraway oil, marjoram oil, bay oil, lemongrass oil, origanum oil, pine needle oil, neroli oil, rose oil, jasmine oil, grapefruit oil , sweetie oil, yuzu oil, iris concrete, absolute peppermint, absolute rose, orange flower, tea-derived fragrances such as green tea, oolong tea, and black tea, and coffee-derived fragrances, as well as the processing of these natural fragrances (pre-distillation). Examples include perfumes that have been made (partial cut, post-reservoir cut, fractional distillation, liquid-liquid extraction, essence, powder perfume, etc.). In addition, menthol, carvone, anethole, cineole, methyl salicylate, cinnamic aldehyde, eugenol, 3-1-menthoxypropane-1,2-diol, thymol, linalool, linaryl acetate, limonene, menthone, menthyl acetate, N- Substituted-paramenthane-3-carboxamide, pinene, octylaldehyde, citral, pulegone, carbyl acetate, anisaldehyde, ethyl acetate, ethyl butyrate, allyl cyclohexane propionate, methyl anthranilate, ethyl methyl phenyl glycidate, vanillin, Single fragrances such as undecalactone, hexanal, butanol, isoamyl alcohol, hexenol, dimethyl sulfide, cyclotene, furfural, trimethylpyrazine, ethyl lactate, and ethyl thioacetate can be mentioned. Further examples include mixed flavors such as mint flavor, strawberry flavor, apple flavor, banana flavor, pineapple flavor, grape flavor, mango flavor, butter flavor, milk flavor, mixed fruit flavor, and tropical fruit flavor. As the fragrance, a menthol fragrance and a mint-scented fragrance are preferable, and a mint-scented fragrance is particularly preferable.

The total amount of components (A) to (C) in the tablet core of the present invention is not particularly limited, but is preferably 30 to 100% by mass, and 50 to 99% by mass of the entire tablet core. The content is more preferably 70 to 95% by mass.

Further, the total blending amount of component (A) and component (B) is not particularly limited, but is preferably 1 to 50% by mass, and 3 to 30% by mass based on the total of components (A) to (C). %, and even more preferably 5 to 20% by mass.

Furthermore, from the viewpoint of sustained release effects, it is preferable that the amount of hydroxypropyl methyl cellulose as component (A) is greater than the amount of hydroxypropyl cellulose as component (B). It is more preferable to contain 1.6 parts by mass or more of component (A), even more preferably 2 parts by mass or more, and particularly preferably 3 parts by mass or more of component (A) per 1 part by mass of component (B). In addition, from the viewpoint of tablet manufacturability, it is preferable that component (A) is contained in 20 parts by mass or less, more preferably 15 parts by mass or less, and 10 parts by mass or less per 1 part by mass of component (B). It is even more preferable.

The amount of component (A) to be blended per 1 part by mass of component (C) is not particularly limited, but from the viewpoint of sustained release and manufacturability, it is preferably 0.01 to 1.5 parts by mass, and 0.01 to 1.5 parts by mass. The amount is more preferably 0.05 to 1 part by weight, even more preferably 0.1 to 1 part by weight, and particularly preferably 0.15 to 0.5 part by weight.

The amount of component (B) to be blended per 1 part by mass of component (C) is not particularly limited, but from the viewpoint of sustained release and manufacturability, it is preferably 0.001 to 0.3 parts by mass, and 0.001 to 0.3 parts by mass. The amount is more preferably 0.05 to 0.2 parts by weight, even more preferably 0.01 to 0.15 parts by weight, and particularly preferably 0.03 to 0.12 parts by weight.

The blending amount of component (D) in the tablet core of the tablet of the present invention is not particularly limited, but it is preferably 0.1 to 50% by mass, and preferably 0.5 to 40% by mass of the entire tablet core. The content is more preferably 1 to 30% by mass, even more preferably 5 to 20% by mass.

The amount of component (D) to be blended per 1 part by mass of component (A) is not particularly limited, but from the viewpoint of slowly releasing component (D), it is preferably 0.01 to 10 parts by mass, and 0.01 to 10 parts by mass. The amount is more preferably 0.5 to 5 parts by weight, even more preferably 0.1 to 3 parts by weight, and particularly preferably 0.5 to 2 parts by weight.

The tablets of the present invention can be used, for example, in so-called health foods such as foods for specified health uses, foods with nutritional function claims, functional foods whose efficacy has been approved by designated organizations such as foods with nutritional function claims, general foods, and pharmaceuticals ( (including quasi-drugs), feed, etc.

The tablet of the present invention has excellent sustained release properties as described above, and is preferably used as a sustained release tablet. Most conventional sustained-release tablets were developed for pharmaceutical use, whereas the sustained-release tablets of the present invention were developed for food use, and can be sustained-release without containing pharmaceutical additives. It is characterized by the ability to fully demonstrate one's sexuality. Therefore, the sustained-release tablet of the present invention is suitable for use in foods such as so-called health foods such as functional foods and general foods. A sustained-release tablet is not particularly limited as long as it can be distinguished from other products in that the ingredient intended for sustained release is gradually released (slowly dissolves). For example, the scope of the present invention includes products that indicate that the ingredients are gradually released (slowly melting) on the main body, packaging, instruction manual, or promotional material of the product according to the present invention. Specifically, sustained-release tablets include those labeled with "sustained type," "slow release," "slow dissolving," "slow absorption," "sustained absorption," etc.

Further, the tablet of the present invention may be a white tablet, but may be a colored tablet since color is difficult to adhere to the outside (color transfer is difficult) when wet. That is, in the tablet of the present invention, colored components can be easily blended without worrying about color transfer.

Although the method for manufacturing the tablet core of the tablet of the present invention may be a method in which each component is granulated and then tableted, from the viewpoint of reducing the number of manufacturing steps, each component is not granulated and each component is A method of compressing a mixed powder into tablets (direct tableting method) is preferred. Tableting can be carried out by a known method using a device such as a rotary tabletting machine, for example. In the present invention, since components (A) to (C) are included as components of the tablet core, it is easy to manufacture, and sustained-release tablets can also be obtained by direct compression. In addition, in the production of the tablet core, in addition to the above components (A) to (C), binders, excipients, disintegrants, lubricants, fluidizers, etc. may be added.

Examples of the lubricant include, but are not limited to, calcium stearate, magnesium stearate, stearic acid, sucrose fatty acid ester, talc, glycerin fatty acid ester, and the like. As the lubricant, from the viewpoint of sustained release properties, calcium stearate, sucrose fatty acid ester, and glycerin fatty acid ester are preferred, and calcium stearate is particularly preferred.

Examples of the fluidizing agent include, but are not limited to, silicon dioxide, magnesium oxide, magnesium silicate, calcium silicate, and the like. From the viewpoint of sustained release, silicon dioxide is particularly preferred as the fluidizing agent.

As mentioned above, the tablet of the present invention can be made into a tablet as is from the manufactured tablet core, or can be made into a coated tablet by providing a coating layer on the surface of the tablet core.

Hereinafter, the present invention will be explained based on examples.
<Manufacture of tablets>
200 mg of powder having the composition shown in Table 1 below was weighed using a medicine paper. Tablets were molded using a tabletop tablet molding machine (HANDTAB-200/manufactured by Ichihashi Seiki Co., Ltd.). Using a mortar with a diameter of 8 mm and a radius of curvature of 10 mm, a tablet was molded by applying pressure until the impact force reached 3 kN.

<Tablet evaluation>
1. Evaluation of disintegration time The disintegration time was measured according to the method described in item "6.09""Disintegration test method" in the 15th edition of the Japanese Pharmacopoeia. Specifically, it is as follows.

First, a tablet was placed in a glass tube of a disintegration tester having a glass tube. Note that each glass tube has an open upper and lower surface, and a stainless steel mesh with a mesh opening of 1.8 mm to 2.2 mm is attached to the lower surface of the glass tube.
The glass tube containing the tablet was placed in water at 37±2°C, and the disintegration tester was activated. The glass tube in the disintegration tester was observed, and when it was confirmed that the tablet was about to disintegrate, the glass tube was pulled up and the disintegration of the tablet was observed. This operation was repeated and observed until the tablet completely disintegrated. The time from when the disintegration tester was activated to when the tablet disintegrated was measured, and the measured time was defined as the disintegration time. Note that the tablet was considered to have disintegrated if no tablet residue was found in the glass tube, or if it was found, it was a soft substance that clearly did not retain its original shape.
The results are shown in Table 2.

As shown in Table 2, the tablets of Examples had a disintegration time of over 20 minutes, indicating that they had excellent sustained release properties. Among these, the tablets of Examples 1, 3, 5, 6, and 7 containing two or more types of component (C) had a disintegration time of more than 30 minutes and were excellent in sustained release properties. In particular, the tablet of Example 7 containing maltose, starch, and reduced maltose as component (C) had a disintegration time of more than 70 minutes, and had particularly excellent sustained release properties.

2. Evaluation of dissolution: Riboflavin is water-soluble and exhibits a yellow color when dissolved in water. Therefore, by placing tablets containing riboflavin in water and evaluating the degree of coloration of the solution, riboflavin (the ingredient intended for sustained release) was eluted. The degree can be evaluated. The dissolution of the component targeted for sustained release (riboflavin) was evaluated according to the following procedure.

[procedure]
30 mL of pure water was placed in a beaker, and two tablets were added. Thereafter, it was stirred every 2 minutes (3 rotations/3 seconds). After 10 minutes had passed since the tablets were added (the number of stirring was 5 times in total), the tablets were removed, and the brightness of the pure and 2-fold diluted solutions was compared according to the following criteria.
The results are shown in Table 3.

[Evaluation criteria]
2: The color is obviously lighter than Comparative Example 1. 1: The color is a little lighter than Comparative Example 1. 0: The same level as Comparative Example 1. -1: The color is a little darker than Comparative Example 1. -2: The color is a little darker than Comparative Example 1. is also clearly darker in color

As shown in Table 3, it can be seen that the tablets of Examples 1 to 7 have slower elution of riboflavin and superior sustained release properties than Comparative Example 1 which does not contain component (C).

3. Evaluation of color transfer The tablets of Examples and Comparative Examples are colored tablets because they contain riboflavin (orange-yellow color). The degree to which color adhered to the outside of the colored tablet (color transfer) when the tablet got wet was evaluated according to the following procedure.
The results are shown in Table 4.

[procedure]
One tablet was placed on cotton (5.5 cm x 7 cm) on which 1000 μL of pure water had been dropped, and then 1000 μL of pure water was added dropwise. After 5 minutes, the tablet was turned over and an additional 1000 μL of water was added dropwise. After another 5 minutes, the tablets were removed and the color of the cotton (yellow because the color of ribofuvin transfers to the cotton) was compared.

[Evaluation criteria]
2: The color is obviously lighter than Comparative Example 1. 1: The color is a little lighter than Comparative Example 1. 0: The same level as Comparative Example 1. -1: The color is a little darker than Comparative Example 1. -2: The color is a little darker than Comparative Example 1. is also clearly darker in color

As shown in Table 4, it can be seen that the tablets of Examples 1, 3, and 4 are less susceptible to color transfer than Comparative Example 1, which does not contain component (C).

<Prescription example>
Tablets were manufactured by direct compression using the following formulation containing components (A), (B), and (C).

The tablets produced according to the above formulation had excellent sustained release properties.

The tablet of the present invention has excellent sustained release properties and is suitable for supplements and the like, and is therefore industrially useful.

Claims (1)

A sustained-release tablet comprising a tablet core containing the following components (A), (B), and (C).
(A) Hydroxypropyl methylcellulose (B) Hydroxypropylcellulose (C) Reduced maltose, starch and maltose