JP7795705B2 - Powder mixture for compression molding and compression molded product - Google Patents

Description

The present invention relates to a powder mixture for compression molding that does not cause molding problems during compression molding, and a compression molded product obtained by compression molding the mixture that has excellent disintegration properties and sustained release properties.

Generally, there is no legal definition of health foods, and they broadly refer to any food sold or used as a food that contributes to maintaining and improving health. With the rise in awareness of health promotion following the Tokyo Olympics and growing recognition of the importance of health management following the spread of the new coronavirus infection, interest in health is on the rise, and demand for health foods will continue to grow.

Health foods come in a variety of forms, including hard capsules, soft capsules, granules, drinks, and jellies, in addition to tablets. Tablets were originally a form of pharmaceuticals, but following the 2001 revision of the "Standards Concerning the Scope of Pharmaceuticals," they rapidly became popular as food forms, along with hard and soft capsules. Because tablets are easier for consumers to handle, they are more widely used than granules or capsules and are one of the most important forms. Tablets are made by compressing powders. In addition to the active ingredient, various additives such as excipients, lubricants, and disintegrants are used as ingredients for tableting. Compared to active ingredients in pharmaceuticals, active ingredients in foods are often consumed in larger amounts to exert their physiological functions. Therefore, increasing the active ingredient content inevitably reduces the amount of additives that can be used. Furthermore, because the additives available for food products are more limited than those available for pharmaceuticals, the design hurdles are high, and the challenge is to balance the high active ingredient content in the tablet with the quality of compression moldability.

As the lineup of health food products expands, consumers are demanding health foods with higher functionality. Companies are now required to differentiate their products through higher functionality. Key points of differentiation include not only blending active ingredients with high physiological effects, but also products that are easy to swallow and contain a high amount of active ingredients that allow for the intake of a small number of pills. However, how efficiently the active ingredients are delivered to the body is also becoming an important point of differentiation.
Specific examples include the function of delivering live bacteria such as lactic acid bacteria to the intestines alive, and making the bioabsorption of active ingredients more efficient.
Bioabsorbability is an important quality that must be evaluated in pharmaceuticals, but in the technological development of health foods, which require differentiated functionality, pharmaceutical-level quality is now required.

For active ingredients to be properly absorbed, tablets must disintegrate appropriately within the digestive tract after ingestion. Traditionally, disintegration time standards for pharmaceuticals have been established based on disintegration tests specified in the Japanese Pharmacopoeia. Accordingly, on August 2, 2019, the Japan Health and Nutrition Food Association, an industry association, made disintegration tests mandatory for GMP-certified factories for health foods. Thus, industry associations place great importance on bioabsorbability, citing disintegration as one of the evaluation criteria. Health foods are increasingly being required to be formulated in a manner similar to pharmaceuticals, and formulations that take bioabsorbability, including disintegration, into account are more important than ever before.
If the compressed product disintegrates downstream of the absorption site in the digestive tract or is released from the body without disintegrating, the active ingredient will not be absorbed by the body, so it is important that it disintegrates appropriately.

Another factor that improves the bioavailability of active ingredients in health foods is sustained-release. Water-soluble active ingredients such as water-soluble vitamins have an upper limit to the amount absorbed from the digestive tract, and even if they are absorbed, if their internal concentration exceeds this limit, they may be excreted from the body before being metabolized or utilized in the body. Therefore, even if a large amount is ingested all at once, bioavailability decreases once a certain amount is reached. On the other hand, consumers want to minimize the frequency of intake, so there is a need to formulate high-concentration active ingredients into tablets, increase the amount ingested at one time, and maintain physiological effects for a long period of time. In such cases, one method of improving bioavailability is to slow down bioabsorption. Specific methods include slowing the release of active ingredients by making the tablet itself less likely to disintegrate, or applying a film or sugar coating to the tablet itself to provide sustained release.

Various efforts have been made to provide tablets with good disintegration and sustained-release properties. For example, a method of imparting sustained-release properties by coating the entire surface of a compressed product with a water-insoluble substance is known. However, while this method can increase the bioavailability of the water-soluble active ingredient, it also slows the disintegration of the compressed product, thereby reducing the bioavailability of ingredients other than the water-soluble active ingredient.
In addition, in some cases, particles of water-soluble active ingredients are coated to impart sustained release properties in order to mask unpleasant tastes such as bitterness, but this often affects the disintegration properties, making them difficult to disintegrate or making it difficult to form a compression-molded product.

Patent Document 1 discloses a technique relating to a disintegration-delay inhibiting coated powder.
Patent Document 2 discloses a technique relating to a sustained-release preparation of lacosamide, a pharmaceutical ingredient.
Non-Patent Document 1 discloses a technology relating to a "food delivery system" that controls sustained release by combining a specific coating agent and a gelling agent.

Japanese Patent Application Laid-Open No. 2019-119675 Japanese Patent Application Laid-Open No. 2017-31206

Functionality research report on "B-ReC Tablets," a formulation aiming to maximize food functionality, FOODSTYLE 21 (Food Chemistry Newspaper Co.), 23, 27-29 (2019)

Both disintegration and sustained release are processing technologies for increasing bioavailability, but achieving both is not easy. This is particularly true for foods, where high concentrations of active ingredients are required and there are limitations on the amount and types of additives that can be added.
As described above, there has been a demand for a tablet product that has good disintegrability but is endowed with sustained release properties for an active ingredient whose bioavailability is insufficient when ingested in large amounts all at once.

The present invention aims to provide a powder mixture for compression molding that does not cause molding problems and a compression molded product obtained by compression molding the mixture that has excellent disintegration and sustained release properties, particularly a powder mixture for compression molding for food use and a compression molded product obtained by compression molding the mixture.

In view of the above-mentioned problems, the inventors conducted extensive research and found that a powder mixture for compression molding containing double-coated particles having a specific coating structure in specific raw materials and in specific ratios, and a specific carbohydrate, can solve the above-mentioned problems, and thus completed the present invention.
That is, the present invention provides the following [1] to [3].

[1] A powder mixture for compression molding comprising double-coated particles and a carbohydrate (D),
The double-coated particles comprise a core material (A), a primary coating material (B) that coats the powder surface of the core material (A), and a secondary coating material (C) that coats the surface of the primary coating material (B),
(A) is a powder of a water-soluble substance,
(B) is a poorly water-soluble substance,
(C) is an edible fat or oil having a melting point of 40°C to 90°C, and
the carbohydrate (D) is one or more carbohydrates selected from the group consisting of sugar alcohols, carbohydrates in which three or more monosaccharides are bonded, and dietary fiber;
A powder mixture for compression molding, characterized in that
[2] The powder mixture for compression molding according to [1], further comprising a functional component.
[3] A compression-molded product obtained by compression-molding the powder mixture for compression molding according to [1] or [2].

This document relates to a powder mixture for compression molding that does not cause molding problems and a compression molded product obtained by compression molding the mixture, which has excellent disintegration and sustained-release properties, particularly a powder mixture for compression molding for food use and a compression molded product obtained by compression molding the mixture.

<Powder mixture for compression molding>
The powder mixture for compression molding of the present invention comprises the following double-coated particles and a carbohydrate (D):
The double-coated particles comprise a core material (A), a primary coating material (B) that coats the powder surface of the core material (A), and a secondary coating material (C) that coats the surface of the primary coating material (B),
(A) is a powder of a water-soluble substance,
(B) is a poorly water-soluble substance, and (C) is an edible oil or fat having a melting point of 40°C to 90°C.
The carbohydrate (D) is one or more carbohydrates selected from the group consisting of sugar alcohols, carbohydrates in which three or more monosaccharides are bonded, and dietary fiber.
The use of the powder mixture for compression molding of the present invention is not particularly limited, and examples thereof include foods (health foods, tablet candy), pharmaceuticals, feed, etc. Particularly preferred uses include foods with a high content of the core substance (A).

When preferred numerical ranges (e.g., mass %) are described in stages in this specification, the respective lower and upper limits can be independently combined. For example, in the description "preferably 10 or more, more preferably 20 or more, and preferably 100 or less, more preferably 90 or less," the "preferable lower limit: 10" and the "more preferred upper limit: 90" can be combined to form "10 or more and 90 or less." Similarly, in the description "preferably 10 to 100, more preferably 20 to 90," the range can be similarly changed to "10 to 90."

<Compression molded product>
The compression-molded product of the present invention can be obtained by compression-molding the powder mixture for compression molding of the present invention. The compression-molded product of the present invention corresponds to typical forms of health foods in the food field, such as tablets, tablet confectionery such as Ramune, and block-type soups and powdered milk.
The use of the compression molded product of the present invention is not particularly limited, and examples thereof include foods (health foods, tablet candy), pharmaceuticals, feed, etc. Particularly preferred uses include foods having a high content of the core substance (A).
The tablet hardness of the compression-molded product of the present invention when made into a tablet is not particularly limited as long as the effects of the present invention can be achieved, but can be, for example, in the range of 95 to 104 N.

<Core substance (A) of double-coated particles>
The core substance (A) of the double-coated particles of the present invention is not particularly limited as long as it is a water-soluble powder having a solubility in water at 20° C. of 0.01 g/100 g or more.
The types of water-soluble substances can include the following within the scope of the present invention.
Ascorbic acid, ascorbate, or water-soluble derivatives, commonly known as vitamin C; B vitamins such as thiamine hydrochloride, thiamine nitrate, thiamine cetyl sulfate, thiamine thiocyanate, thiamine naphthalene-1,5-disulfonate, thiamine lauryl sulfate, dibenzoylthiamine, dibenzoylthiamine hydrochloride, bisbentiamine, riboflavin, riboflavin butyrate, riboflavin 5'-phosphate sodium, nicotinic acid, nicotinamide, pyridoxine hydrochloride, cyanocobalamin, folic acid, biotin, calcium pantothenate, sodium pantothenate, and other vitamin-like substances such as inositol and hesperidin derivatives.
The amino acids arginine, lysine, histidine, phenylalanine, tyrosine, leucine, isoleucine, methionine, valine, alanine, glycine, proline, glutamic acid, glutamine, serine, threonine, aspartic acid, asparagine, tryptophan, and cystine.
Microbial powder containing water-soluble minerals such as ferric chloride, sodium ferrous citrate, iron citrate, ammonium ferrous citrate, iron lactate, ferrous sulfate, calcium ascorbate, calcium lactate, calcium gluconate, calcium sulfate, calcium chloride, zinc gluconate, zinc sulfate, magnesium chloride, magnesium carbonate, copper gluconate, copper sulfate, and other minerals.
In order to adjust the content of these water-soluble substances, a powder mixture with an excipient may be used as the core substance (A). Examples of the excipient include powders of lactose, starch, sucrose, maltitol, sorbitol, dextrin, crystalline cellulose, etc.

When the core substance (A) in the double-coated particles of the present invention is 50% by mass to 95% by mass, the effects of the present invention are more easily achieved. When it is more than 50% by mass, the amount of the active ingredient in the compression-molded product can be increased. When it is less than 95% by mass, the coating of the core substance (A) can be made more effective, making it easier to achieve sustained release.
The content of (A) in the double-coated particles is 50% by mass to 95% by mass, preferably 60% by mass to 90% by mass, and more preferably 65% by mass to 85% by mass. In particular, such a content by mass is preferably the value at the time of production of the double-coated particles, the powder mixture for compression molding, or the compression molded product.

<Primary coating material (B) of double-coated particles>
The primary coating material (B) of the double-coated particles of the present invention is not particularly limited as long as it is a poorly water-soluble substance having a solubility in water at 20°C of 0.1 g/100 g or less and a solubility in an 80% ethanol-containing aqueous solution at 20°C of 0.1 g/100 g or more.
The types of poorly water-soluble substances can be listed below, provided that they do not deviate from the scope of the present invention.
Prolamins such as zein, gliadin, hordein, avenin, and secalin.
Resinous substances such as shellac.
Zein, also known as zein, is a corn-derived protein that is soluble in aqueous alcohol and is generally extracted by mixing corn gluten meal with an aqueous solution containing 60 to 95% by mass of alcohol, acetone, etc. These aqueous alcohol-soluble proteins are called prolamins and are rich in hydrophobic amino acids such as proline.
Shellac, also known as shellac, is a resinous substance secreted by the lac scale insect after sucking the sap from certain trees. Generally, refined shellac, which has had impurities removed, is used.

When the primary coating material (B) of the double-coated particles of the present invention is 3% to 45% by mass, the effects of the present invention are more easily achieved. When it is greater than 3% by mass, sustained release is more easily achieved, while when it is less than 45% by mass, the amount of core substance (A), the active ingredient in the compression-molded product, can be increased. The content of (B) in the double-coated particles is 3% to 45% by mass, more preferably 5% to 35% by mass, and most preferably 10% to 27% by mass. In particular, these mass % contents are preferably values at the time of production of the double-coated particles, powder mixture for compression molding, or compression-molded product.

<Secondary coating material (C) of double-coated particles>
The secondary coating material (C) of the double-coated particles of the present invention is not particularly limited as long as it is an edible oil or fat having a melting point of 40°C to 90°C.
The type of edible fat or oil having a melting point of 40° C. to 90° C. can be, for example, fatty acid esters, higher alcohols, waxes, etc., as long as it does not deviate from the scope of the present invention.
Triglycerides, which are fatty acid esters, have a structure in which three fatty acid molecules are ester-bonded to glycerin, and are derived from, for example, soybean oil, rapeseed oil, cottonseed oil, rice oil, corn oil, sesame oil, peanut oil, sunflower oil, safflower oil, camellia oil, olive oil, coconut oil, palm oil, palm kernel oil, cacao butter, perilla oil, shiso oil, lard, beef tallow, chicken oil, whale oil, and fish oil. The melting point is adjusted by hydrogenation or the like.
Other fatty acid esters also include emulsifiers, such as glycerin fatty acid esters, sorbitan fatty acid esters, propylene glycol fatty acid esters, sucrose fatty acid esters, and lecithin.
Higher alcohols include linear or branched alcohols having 20 to 36 carbon atoms, and specific examples thereof include eicosanol (20 carbon atoms), docosanol (26 carbon atoms), octacosanol (28 carbon atoms), triacontanol (=myricyl alcohol, 30 carbon atoms), and hexatriacontanol (36 carbon atoms).
Waxes include carnauba wax, candelilla wax, rice wax, and the like.
The melting point of edible fats and oils can be measured in accordance with Standard Fats and Oils Analysis Test Method "2.2.4.2 Melting Point (Slip Melting Point)." The melting point of edible fats and oils is preferably 50°C to 80°C, more preferably 50°C to 70°C.

The secondary coating material (C) of the double-coated particles of the present invention is preferably a triglyceride or a glycerin fatty acid ester as a type of emulsifier. For triglycerides, using extremely hydrogenated oils in which the double bonds in the constituent fatty acids are nearly saturated by hydrogenation produces a good coating, which is preferable for imparting good disintegrability to the compression-molded product. As glycerin fatty acid esters, extremely hydrogenated rapeseed oil and extremely hydrogenated palm oil are preferred, and as glycerin fatty acid esters as emulsifiers, monoglycerin monostearate ester, monoglycerin monopalmitate ester, monoglycerin distearate ester, monoglycerin dipalmitate ester, and monoglycerin monostearate monopalmitate ester are preferred.

When the content of (C) in the double-coated particles is 2% by mass to 40% by mass, the effects of the present invention are more easily achieved. When it is more than 2% by mass, sustained release properties are preferably obtained. When it is less than 40% by mass, the amount of the core substance (A), which is the active ingredient in the compression-molded product, can be increased, and water penetration into the compression-molded product can be promoted, resulting in preferable disintegration properties.
The content of (C) in the double-coated particles is 2% by mass to 40% by mass, preferably 2% by mass to 30% by mass, and most preferably 2% by mass to 20% by mass. In particular, such a content by mass is preferably the value at the time of production of the double-coated particles, the powder mixture for compression molding, or the compression molded product.

<Structure of double-coated particles>
The structure of the double-coated particles includes a core material (A), a primary coating material (B) that coats the core material (A), and a secondary coating material (C) that coats the surface of the primary coating material (B).
The core material (A) in the primary coated particle may be either a single particle or multiple particles, and it is important that the particle surface of the core material (A) is covered with the primary coating material (B).
Although it is important that the particle surface of the primary coating material (B) is covered with the secondary coating material (C), it is preferable that the primary coated particle within the double-coated particle is a single particle. The presence of a single primary coated particle within the double-coated particle makes the double-coated particle less likely to crumble under the pressure during compression molding, and by maintaining a good coating state even within the compression-molded product, sustained release properties are more effectively exhibited.
Furthermore, the average particle size of the primary coated particles is preferably 5 to 2000 μm, more preferably 10 to 1000 μm, and most preferably 100 to 500 μm. When the average particle size of the primary coated particles is 5 to 2000 μm, secondary coating can be carried out efficiently, and sustained release properties can be easily obtained.

In order to achieve sustained release of the core substance (A), it is important to coat the core substance (A). However, simply coating the core substance (A) may make it difficult to perform compression molding, or even if compression molding is possible, the core substance may not disintegrate properly.
Although the primary coating material (B) of the present invention has excellent coating performance, compression molding using only the primary coating is difficult due to the physical properties of the primary coating material (B).
The secondary coating material (C) of the present invention is a material suitable for coating the core substance (A), but if the core substance is coated only with the secondary coating material (C) without the primary coating material, sufficient sustained release properties will not be obtained or the compression-molded product will not disintegrate properly.
Therefore, it is important that the double-coated particles of the present invention are coated with the primary coating material (B) and then double-coated with the secondary coating material (C).

<Mass Ratio of (B) and (C)>
The mass ratio of the primary coating material (B) to the secondary coating material (C) of the present invention is preferably 1:3 to 9:1. This range makes it easier to obtain both sustained release and disintegration properties. It also makes it less likely that molding defects, such as scratches on the sides of the compression-molded product, known as binding, will occur during compression molding.
The mass ratio of the primary coating material (B) to the secondary coating material (C) is 1:3 to 9:1, more preferably 1:2 to 9:1, and most preferably 1:1 to 9:1. In particular, such a mass ratio is preferably the value at the time of producing the double-coated particles, the powder mixture for compression molding, or the compression molded product.

<Mass ratio of double-coated particles in powder mixture for compression molding>
The mass proportion of the double-coated particles in the powder mixture for compression molding of the present invention is preferably 1% by mass to 60% by mass. By increasing it to more than 1% by mass, the amount of active ingredient in the compression-molded product can be increased. By decreasing it to less than 60% by mass, good disintegrability can be achieved.
The mass proportion of the double-coated particles in the powder mixture for compression molding is 1% by mass to 60% by mass, more preferably 10% by mass to 40% by mass, and most preferably 10% by mass to 30% by mass. In particular, such a mass % content is preferably the value at the time of production of the double-coated particles, the powder mixture for compression molding, or the compression molded product.

<Mass Proportion of Secondary Coating Material (C) in Powder Mixture for Compression Molding>
The mass proportion of the secondary coating material (C) in the powder mixture for compression molding of the present invention is preferably 0.02% by mass to 10% by mass. By increasing the mass proportion to more than 0.02% by mass, sufficient sustained release properties can be obtained and molding problems such as scratches on the sides of the compression molded product, known as binding, during compression molding can be prevented. By reducing the mass proportion to less than 10% by mass, the disintegration properties of the compression molded product can be improved. The mass proportion of the secondary coating material (C) in the powder mixture for compression molding is preferably 0.02% by mass to 10% by mass, more preferably 0.02% by mass to 5% by mass, and most preferably 0.02% by mass to 2.5% by mass. In particular, these mass percentage contents are preferably values at the time of production of the double-coated particles, the powder mixture for compression molding, or the compression molded product.

<Carbohydrates>
The carbohydrate (D) of the present invention is not particularly limited as long as it is one or more carbohydrates selected from the group consisting of sugar alcohols, carbohydrates consisting of three or more monosaccharides bonded together, and dietary fiber. The carbohydrate (D) is called an excipient or disintegrant in the formulation of tablets and compressed products.
Examples of sugar alcohols include maltitol, erythritol, lactitol, xylitol, mannitol, and sorbitol.
Examples of carbohydrates in which three or more monosaccharides are bonded include starch, chitin, dextrin, cyclodextrin, glycogen, curdlan, paramylon, pectin, xyloglucan, arabinogalactan, xylan, glucomannan, raffinose, stachyose, and verbascose.
Examples of dietary fiber include indigestible dextrin, polydextrose, cellulose, hemicellulose, pectin, inulin, β-glucan, and citrus fiber containing multiple other components.
Among the above, carbohydrates with five or more monosaccharides bonded together and dietary fiber are preferred, as the use of these carbohydrates not only facilitates compression molding, but also ensures that the compression molded product disintegrates properly.
The reason for this is that the surface of the double-coated particles of the present invention is made of edible oils and fats, which are the secondary coating material (C), making the surface and interior of the compression-molded product hydrophobic, making it difficult for water to penetrate into the interior of the compression-molded product, and as a result, making the compression-molded product less likely to disintegrate in the digestive tract. The presence of carbohydrates (D) in the compression-molded product promotes water conduction into the interior of the compression-molded product and promotes appropriate disintegration. Furthermore, carbohydrates and dietary fiber having five or more monosaccharides bonded together not only facilitate water penetration into the interior of the compression-molded product, but also swell and increase in volume by absorbing water, further promoting the disintegration properties of the compression-molded product.

<Other ingredients>
The powder mixture for compression molding of the present invention may contain other ingredients as long as the effects of the present invention are not exceeded. Examples of such ingredients include the same substance as the core substance (A), a functional ingredient that is desired to be rapidly dissolved without sustained release, a lubricant that prevents powder from adhering to the compression molding machine during compression and smooths the surface of the compression molded product, a fruit juice powder that imparts a flavor, and a powdered flavoring agent that imparts a flavor. Examples of lubricants include calcium stearate, magnesium stearate, and sucrose fatty acid esters.
The functional component is a component intended to be absorbed in the body, and is not particularly limited, and may be the same substance as the core substance (A).
By applying the effects of the present invention, a functional component to be provided with sustained release properties and a functional component to be rapidly released without sustained release properties can be blended in the same compression molded product. In other words, by not including the functional component to be rapidly released without sustained release properties in the double-coated particles, a compression molded product can be obtained in which the release behavior of each component is intentionally controlled to be different.
More specifically, the powder mixture for compression molding of the present invention is a powder mixture for compression molding containing double-coated particles, a functional component (particularly a functional component that is desired to be rapidly dissolved without being given sustained release properties), and a carbohydrate (D), and the double-coated particles are composed of a core substance (A), a primary coating material (B) coating the powder surface of the core substance (A), and a secondary coating material (C) coating the surface of the primary coating material (B).
Furthermore, by simultaneously incorporating the same functional component into the double-coated particles as a core material (A) and as another component outside the double-coated particles in the same compression-molded product, a time-release compression-molded product can be obtained in which the dissolution of the functional component begins quickly and continues for a long period of time.
More specifically, the powder mixture for compression molding of the present invention is a powder mixture for compression molding containing double-coated particles and, as other components, a core substance (A) and a carbohydrate (D), and the double-coated particles are composed of a core substance (A), a primary coating material (B) coating the powder surface of the core substance (A), and a secondary coating material (C) coating the surface of the primary coating material (B).
The mass proportion of other components in the powder mixture for compression molding of the present invention is 0.1 mass % to 30 mass %.

<Method of manufacturing double-coated particles>
In the present invention, the method for producing double-coated particles is not particularly limited as long as it is a method that can coat primary granulated coated particles, in which a core substance (A) is coated with a primary coating material (B), with a secondary coating material (C) of the double-coated particles.
Examples of methods for coating the core substance (A) with the primary coating material (B) include a method in which a spray liquid prepared by dissolving the primary coating material (B) in a solvent such as an aqueous ethanol solution is sprayed onto the surface of the core substance (A) using a fluidized bed granulator to coat it, a method in which the same coating is performed using an agitation granulator, and other granulation methods using a tumbling granulator, a spouted bed granulator, a fluidized bed granulator with a tumbling disc, etc.
Furthermore, examples of methods for coating the primary granulated coated particles with the secondary coating material (C) include a method in which the secondary coating material (C) is melted and sprayed onto the primary granulated coated particles, and a method in which a powdered secondary coating material (C) is mixed in a mixer and brought into contact with or collided with the surfaces of the primary granulated coated particles.

<Method of manufacturing powder mixture for compression molding>
In the present invention, the method for producing the powder mixture for compression molding is not particularly limited as long as it is a method that can uniformly mix the respective powders. For example, a method in which the double-coated particles, the carbohydrate (D), and other ingredients, as needed, are charged into a V-type mixer and mixed therein can be mentioned. Other examples include mixing methods using a tumbler mixer, a double cone mixer, a container mixer, a ribbon mixer, etc.

<Method of manufacturing a compression molded product>
In the present invention, the method for producing the compression-molded product is not particularly limited. For example, a method in which the powder mixture for compression molding is tableted using a continuous rotary tablet press can be mentioned. In addition to the continuous type, a single-shot tablet press can also be used. Furthermore, the shape of the compression-molded product is not particularly limited. The weight and the size of the mortar and pestle can be set according to the purpose and use, and compression molding can be performed.

The present invention will be explained in more detail below using examples and comparative examples, but the present invention is not limited to these examples. The copolymers used in the examples and comparative examples are as follows:

<Method for evaluating disintegrability>
The disintegrability of the present invention refers to the property of the compression-molded product to disintegrate appropriately in the digestive tract when swallowed orally by a living body in its original form. The disintegrability was evaluated as follows.
The compression-molded product was placed in water and stirred, and the disintegration time until disintegration was evaluated by a disintegration test.
The disintegration test was carried out using a disintegration tester TMB-81 manufactured by Toyama Sangyo Co., Ltd., in accordance with the measurement method prescribed in the 17th edition of the Japanese Pharmacopoeia. Specifically, purified water adjusted to 37±2°C was used as the test liquid, and each tablet (compression molded product) was placed in a glass tube, which was then vibrated up and down in the tester 30 times per minute with an amplitude of 55 mm. The time until the compression molded product disintegrated and no residue of the compression molded product remained in the glass tube was measured.
[Criteria for disintegration: ◎: Less than 20 minutes, ◯: 20 minutes or more but less than 25 minutes, △: 25 minutes or more but less than 30 minutes, ×: 30 minutes or more]

<Method for evaluating sustained release>
The sustained release property of the present invention refers to the property that the active ingredient contained in the compression molded product is gradually released in the digestive tract of the living body over a longer period of time than under normal conditions. The sustained release property was evaluated as follows.
The dissolution time was measured by measuring the amount of core substance (A) dissolved into water when the compression-molded product was placed in water and stirred. The dissolution test was performed using a dissolution tester NTR-6600A manufactured by Toyama Sangyo Co., Ltd., in accordance with the measurement method (paddle method) in accordance with the 17th edition of the Japanese Pharmacopoeia. Specifically, 900 ml of purified water adjusted to 37±0.5°C was filled into a vessel, and the amount of core substance (A) dissolved after 60 minutes was measured when the paddle was rotated at 100 rpm with the compression-molded product inside.
[Criteria for sustained release: ◎: Less than 40%, ○: 40% or more but less than 45%, △: 45% or more but less than 50%, ×: 50% or more]

<Method for evaluating suitability for compression molding>
Tableting suitability was evaluated visually to see whether three main tableting problems occurred: sticking, capping, and binding. Sticking refers to a condition in which the surface of a compression-molded product is uneven or the center is depressed, capping refers to a condition in which the top or bottom surface of a compression-molded product peels off like a cap, and binding refers to a condition in which the tablet raw materials are adsorbed to the die and vertical scratches are left on the side of the tablet when it is discharged. The evaluation was performed as follows.
◯: No tableting problems occurred in any of the 10 compressed products. △: Tableting problems occurred in 1 or 2 of the 10 compressed products. ×: Tableting problems occurred in 5 or more of the 10 compressed products.

Example 1
<Method for producing core substance (A) of double-coated particles>
19.0% by mass of vitamin B2 (Riboflavin Universal: manufactured by DSM Co., Ltd.) and 81.0% by mass of dextrin (Pineflow: manufactured by Matsutani Chemical Industry Co., Ltd.) were mixed to obtain a total amount of 500 g of diluted riboflavin powder, which was used as the core material (A) of the double-coated particles.

<Method of manufacturing double-coated particles>
A shellac-ethanol solution (FSP. No. 232, manufactured by Koyo Chemical Co., Ltd.) containing 32% by mass of shellac and 68% by mass of ethanol as the primary coating material (B), 99% ethanol (99% ethanol, first-class, manufactured by Imazu Pharmaceutical Co., Ltd.), and water were used to prepare 500 mL of a 75% aqueous ethanol solution containing 15.0 g/100 mL of shellac, which was used as a spray liquid. Using a fluidized bed granulator (Flow Coater, manufactured by Freund Corporation), 416.2 mL of the spray liquid was sprayed onto 500 g of the riboflavin diluted powder as the core material (A), and the resulting mixture was dried to obtain primary granulated coated particles containing 88.9% by mass of the riboflavin diluted powder as the core material (A) and 11.1% by mass of shellac.
450 g of the obtained primary granulated coated particles and 50 g of extremely hardened rapeseed oil (manufactured by NOF Corporation, melting point 67°C) as secondary coating material (C) were mixed in a mixer (VG-05, manufactured by Powrex Corporation) to obtain 500 g of secondary coated particles (core substance (A): 80 mass%, primary coating material (B): 10 mass%, secondary coating material (C): 10 mass%).

<Method of manufacturing powder mixture for compression molding>
150 g of the obtained secondary coated particles were mixed with 830 g of starch (Lonfood OWP: manufactured by Nippon Starch Chemical Co., Ltd.) as carbohydrate (D) and 20 g of calcium stearate (calcium stearate: manufactured by Taihei Chemical Industry Co., Ltd.) as other component to obtain a powder mixture for compression molding.

<Method of manufacturing a compression molded product>
The obtained powder mixture for compression molding was tableted in an amount of 500 g using a rotary tablet press (product name "VELA5", manufactured by Kikusui Seisakusho Co., Ltd.) to obtain tablets with a hardness of 95 to 104 N. The tableting conditions were a mortar and pestle of 9.0 mm, R7.5, a weight of 350 mg/particle, a turret rotation speed of 20 rpm, and a tableting pressure of 5 to 20 kN.
The sustained release properties of the compression molded product were evaluated by measuring the absorbance at 275 nm, where riboflavin was the target ingredient, and the absorption maximum was measured.

(Examples 2, 3, 5 to 18, Comparative Examples 1 to 4, 6, 7)
Based on the table, production was carried out in the same manner as in Example 1. The raw materials used in the examples and comparative examples are as follows.
Cellulose (Ceolas UF-F711: manufactured by Asahi Kasei Corporation)
Maltitol (Amalty MR50: manufactured by Mitsubishi Corporation Life Sciences Co., Ltd.)
Lactose (SuperTab 11SD: manufactured by DMV Fonterra Exipients Co., Ltd.)
Zein (Kobayashi Zein DP-N: manufactured by Kobayashi Perfume Co., Ltd.)
Hardened palm oil (NOF Corporation, melting point 60°C)
Carnauba wax (manufactured by Toa Kasei Co., Ltd., melting point 85°C)
Hardened palm kernel oil (NOF Corporation, melting point 34°C)

Example 4
A compression molded product was obtained in the same manner as in Example 1, except that L-ascorbic acid (Vitamin C Type S: manufactured by Fuso Chemical Co., Ltd.) was used as the core material (A) of the double-coated particles.
The sustained release properties of the compression molded product were evaluated by measuring the absorbance at 265 nm, where the absorption maximum is found, using ascorbic acid as the target ingredient.

Example 19
In Example 2, a compression molded product was obtained in the same manner as in Example 2, except that 830 g of starch (Lonfood OWP: manufactured by Nippon Starch Chemical Co., Ltd.) was used as carbohydrate (D) but reduced to 760 g, and 70 g of L-ascorbic acid was added as another ingredient (a functional ingredient that is desired to be rapidly released without being given sustained release properties).

(Comparative Example 5)
In the method for producing double-coated particles, 450 g of primary coated particles were prepared by coating the surfaces of 88.9 mass % of core material (A) with 11.1 mass % of coating material (C). 500 g of secondary coated particles were prepared by coating the surfaces of 90.0 mass % of these primary coated particles with 10.0 mass % of coating material (B), and a compression-molded product was obtained in the same manner as in Example 1, except that the order of the coating materials was reversed.

The results of the above Examples and Comparative Examples are shown in Tables 2 and 3.
From the results of Examples 1 to 19, it was confirmed that the compression molded product of the present invention did not suffer from tableting problems such as sticking, capping, or binding during compression molding, disintegrated within 25 minutes, and the dissolution rate after 60 minutes was 45% or less, and therefore had excellent disintegrability and sustained release properties.
The results of Examples 1 to 3 confirmed that starch is the most preferable carbohydrate (D), and cellulose is the most preferable.
The results of Examples 1 and 4 confirmed that diluted riboflavin powder was preferable as the core substance (A).
The results of Examples 1 and 5 confirmed that shellac is preferable as the primary coating material (B).
The results of Examples 1, 6 and 7 confirmed that the most preferable secondary coating material (C) was the highly hydrogenated rapeseed oil, and the most preferable was the highly hydrogenated palm oil.
The results of Examples 1 and 8 to 18 confirmed that the effects of the present invention are easily achieved when the double-coated particles contain 50 to 95% by mass of (A). Furthermore, it was determined that the content of (A) in the double-coated particles is preferably 60 to 90% by mass, and more preferably 65 to 85% by mass.
The results of Examples 1 and 8 to 18 confirmed that the effects of the present invention are easily achieved when the double-coated particles contain (B) in an amount of 3 to 45% by mass. Furthermore, it was determined that the content of (B) in the double-coated particles is preferably 5 to 35% by mass, and more preferably 10 to 27% by mass.
The results of Examples 1 and 8 to 18 confirmed that the effects of the present invention are easily achieved when the double-coated particles contain (C) in an amount of 2 to 40% by mass. Furthermore, it was determined that the content of (C) in the double-coated particles is preferably 2 to 30% by mass, and more preferably 2 to 20% by mass.
From the results of Examples 1, 8 to 18, it was confirmed that the mass ratio of (B) to (C) in the double-coated particles is preferably 1:3 to 9:1, more preferably 1:2 to 9:1, and most preferably 1:1 to 9:1.
From the results of Examples 1 to 18, it was determined that the mass ratio of the double-coated particles in the powder mixture for compression molding is preferably 1 mass% to 60 mass%, more preferably 10 mass% to 40 mass%, and most preferably 10 mass% to 30 mass%.
From the results of Examples 1 to 18, it was determined that the mass proportion of (C) in the powder mixture for compression molding is preferably 0.02 mass% to 10 mass%, more preferably 0.02 mass% to 5 mass%, and most preferably 0.02 mass% to 2.5 mass%.
In the results of Example 19, the dissolution rate of ascorbic acid, a functional ingredient that is desired to be rapidly released without sustained release properties, after 5 minutes was 100%, and the dissolution rate of riboflavin, the core substance (A), after 60 minutes was 38%. This enabled the functional ingredient (riboflavin) to be sustained-released and the functional ingredient (ascorbic acid) to be rapidly released without sustained-release properties to be blended in the same compression-molded product.

In Comparative Examples 1 and 2, the secondary coating material (C) of the double-coated particles was not blended, and therefore binding occurred due to the frictional force of the primary coating material (B), which forms the outermost layer of the double-coated particles during compression molding, resulting in poor suitability for compression molding.
Regarding Comparative Example 1, the evaluation of the compression molding suitability was x due to binding, so other evaluations were not carried out.
In Comparative Example 2, when the amount of the primary coating material (B) was reduced, binding was alleviated, but the dissolution rate also increased, and sustained release was not achieved.
In Comparative Example 3, the primary coating material (B) of the double-coated particles was not blended, resulting in weak coating performance, and the dissolution rate after 60 minutes was 95%, indicating insufficient sustained release.
In Comparative Example 4, the primary coating material (B) of the double-coated particles was not blended, and although sustained release properties could be obtained by increasing the amount of secondary coating material (C), the disintegration time was prolonged and appropriate disintegration properties were not obtained.
In Comparative Example 5, the coating order of the double-coated particles with the primary coating material (B) and the secondary coating material (C) was reversed, and therefore binding occurred due to the frictional force of the primary coating material (B), which forms the outermost layer of the double-coated particles, during compression molding, resulting in poor suitability for compression molding, just as in Comparative Example 2. Because the compression molding suitability was rated as × due to binding, no other evaluations were made.
In Comparative Example 6, the carbohydrate (D) was lactose, a disaccharide, and therefore the binding power of the carbohydrate was strong, the disintegration time was long, and the disintegration properties were poor.
In Comparative Example 7, the melting point of the secondary coating material (C) of the double-coated particles was lower than 40°C, so the secondary coating material gradually melted due to the heat during tableting, causing sticking and peeling of the coating layer of the double-coated particles, resulting in poor sustained release properties.

Until now, there has been no tablet product that has good disintegrability but is endowed with sustained-release properties for an active ingredient that has the property of being insufficiently bioavailable when taken in large amounts all at once.
However, from the above results, it can be seen that the powder mixture for compression molding containing the double-coated particles and carbohydrates of the present invention does not cause tableting problems such as sticking, capping, or binding during compression molding, disintegrates within 30 minutes (particularly within 25 minutes), and has a dissolution rate of 50% or less (particularly 45% or less) after 60 minutes, making it possible to provide a compression molded product with excellent disintegrability and sustained release properties.

We provide a powder mixture for compression molding that does not cause molding problems, and a compression molded product obtained by compression molding the mixture that has excellent disintegration and sustained release properties.

Claims (3)

A powder mixture for compression molding comprising double-coated particles and a carbohydrate (D),
The double-coated particles comprise a core material (A), a primary coating material (B) that coats the powder surface of the core material (A), and a secondary coating material (C) that coats the surface of the primary coating material (B),
(A) is a powder of a water-soluble substance,
(B) is a poorly water-soluble substance, wherein the poorly water-soluble substance has a solubility in water at 20°C of 0.1 g/100 g or less and a solubility in an 80% ethanol-containing aqueous solution at 20°C of 0.1 g/100 g or more, and is selected from zein, gliadin, hordein, avenin, secalin, and shellac;
(C) is an edible fat or oil having a melting point of 60°C to 85°C ,
the carbohydrate (D) is one or more carbohydrates selected from the group consisting of sugar alcohols, carbohydrates in which three or more monosaccharides are bonded, and dietary fiber;
the mass ratio of the primary coating material (B) to the secondary coating material (C) is 1:1 to 9:1;
The content of the double-coated particles in the powder mixture for compression molding is 10% to 40% by mass, and
The content of the secondary coating material (C) in the powder mixture for compression molding is 0.8% by mass to 1.5% by mass.
A powder mixture for compression molding, characterized in that
The powder mixture for compression molding according to claim 1, further comprising a functional ingredient.
A compression-molded product obtained by compression-molding the powder mixture for compression molding according to claim 1 or 2.