A binder for granular excipients, an excipient and a tablet using the same, and a method for increasing disintegration properties.

Abstract

To provide a binder for granular excipients that can produce a tablet having higher hardness and disintegrability compared to a tablet produced from an excipient granulated using hydroxypropylcellulose as a binder.SOLUTION: An excipient is granulated using a binder for granular excipients that contains an aqueous solution of a starch hydrolysate with a monosaccharide, disaccharide, trisaccharide content of 50 mass% or less and a DE of 41 or less or a hydride thereof, with a result that a granular excipient having high disintegrability to water can be obtained, which is processed into a tablet having high hardness and disintegrability.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a binder for granular excipients, a granular excipient and a tablet using the same, and a method for increasing the disintegration property of the granular excipient and the hardness and disintegration property of the tablet.

Background Art

[0002] In the fields of pharmaceuticals and health foods, tablets are widely used as dosage forms. When manufacturing tablets, in order to improve the workability during tableting and obtain tablets with high hardness, granulation of excipient particles etc. is often performed before tableting. However, when the hardness increases, the disintegration property in the body after ingestion may decrease, and by remaining in the body while maintaining the dosage form for a long time, the elution of the active ingredient from the tablet may be delayed.

[0003] For example, during granulation, hydroxypropyl cellulose is used as a binder, and tablets with high hardness are obtained, but the disintegration property cannot be said to be sufficient. Examples of granulating excipient particles include, for example, Japanese Patent Application Laid-Open No. 2014-156435 etc.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0005] Conventionally, tablets with high hardness have not had sufficient disintegration properties. An object of the present invention is to provide tablets with high hardness and disintegration properties, a granular excipient with high solubility and disintegration properties for obtaining the tablets, and a binder for obtaining the granular excipient.

Means for Solving the Problems

[0006] <As a result of their research to solve the above problems, the present inventors have found that by granulating excipient particles, etc., using a starch hydrolysate or its hydrogenated product, reduced starch saccharified, having a specific component composition, as a binder, it is possible to produce a granular excipient with good disintegration properties, and by compressing this into tablets, it is possible to obtain tablets that have sufficient hardness as tablets and disintegrate well in the body, thus completing the present invention.

[0007] In other words, the present invention is, firstly, a binder for granular excipients containing a starch hydrolysate or its hydrogenated product having a DE of 41 or less. Secondly, the binder for granular excipients described in first above contains a starch hydrolysate or its hydrogenated product having a monosaccharide, disaccharide, or trisaccharide content of 50% by mass or less. Thirdly, a granular excipient manufactured using the granular excipient binder described in the first or second above. Fourthly, the granular excipient described in third above is a carbohydrate. Fifth, a tablet manufactured using the granular excipient described in third or fourth above. Sixth, there is a method for increasing the disintegration properties of a granular excipient by using the binder for granular excipients described in the first or second above. Seventh, a method for manufacturing tablets using the granular excipient described in the third or fourth above, thereby increasing the hardness and disintegrability of the tablets.

[0008] The excipients used in this invention are not particularly limited to those that can be used for food or pharmaceutical purposes, but it is preferable to use carbohydrates. In this invention, carbohydrates refer to monosaccharides or their derivatives, and substances obtained by polymerizing them, i.e., carbohydrates. Examples of monosaccharide derivatives include deoxy sugars, sulfates, amino sugars, uronic acid, aldonic acid, aldanoic acid, and sugar alcohols.

[0009] In the present invention, examples of excipient powders include sugar alcohols such as erythritol, xylitol, mannitol, sorbitol, maltitol, reduced isomaltulose, maltotriitol, and reduced starch hydrolysates; glucose polymers such as glucose, maltose, maltotriose, starch hydrolysates, starch, crystalline cellulose, and trehalose; and lactose, sucrose, nystose, kestose, and raffinose, which are formed by the combination of different monosaccharides.

[0010] Excipients can be used individually or in combination as an excipient mixture. Additives and various active ingredient powders can also be used in conjunction with the excipients. These may be granulated together with the excipient and binder, or mixed with the granulated granular excipient. Granular excipients have high disintegration properties in water and can be used as is. Alternatively, by compressing granular excipients with these properties into tablets, tablets with high hardness and high disintegration properties can be obtained.

[0011] Examples of additives used in the present invention include fumed silica, potassium hydrogen phosphate, hypromellose, hydroxypropyl cellulose, methylcellulose, povidone, ethylcellulose, polyvinyl alcohol, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, and polyethylene glycol, hydroxypropyl cellulose, carmellose, carmellose calcium, carmellose sodium, carboxymethyl starch sodium, croscarmellose sodium, crospovidone, sodium starch glycolate, and light anhydrous silicic acid, low-substituted hydroxypropyl cellulose, and polyvinylpyrrolidone.

[0012] The active ingredients used in this invention are not particularly limited as long as they are active ingredients of food supplements such as nutritional supplements, or active ingredients of health functional foods such as Foods for Specified Health Uses and Foods with Nutritional Function Claims. Examples include various vitamins such as ascorbic acid, folic acid, carnitine, and hesperidin; various amino acids such as glutamine, ornithine, and 5-aminolevulinic acid; various amino sugars such as glucosamine and N-acetylglucosamine; various proteins such as collagen and elastin; mucopolysaccharides such as chondroitin; and DNA. Examples of beneficial substances include various nucleic acids, minerals, catechins, various flavonoids such as polyphenols, various carotenoids such as astaxanthin, lycopene, and lycopene, various phospholipids such as phosphatidylserine and phosphatidylcholine, various fatty acids such as EPA and DHA, ubiquinones such as coenzyme Q10, various enzymes, dietary fiber, herbs, fruits and plants and their extracts, fish oil, probiotics such as lactic acid bacteria, and yeast extracts such as cysteine ​​peptide-containing yeast extract.

[0013] Furthermore, the pharmaceutical ingredients used as active ingredients in this invention are not particularly limited and can be used in any way, such as tonics and health supplements, antipyretic, analgesic and anti-inflammatory drugs, psychotropic drugs, anxiolytics, antidepressants, hypnotics and sedatives, antispasmodics, central nervous system agents, cerebral metabolism improvers, cerebral circulation improvers, antiepileptics, sympathomimetic agents, gastrointestinal drugs, antacids, anti-ulcer agents, antitussives and expectorants, antiemetics, respiratory stimulants, bronchodilators, antiallergic drugs, dental and oral drugs, antihistamines, cardiac stimulants, antiarrhythmics, diuretics, antihypertensives, vasoconstrictors, coronary vasodilators, peripheral vasodilators, hyperlipidemia agents, choleretics, antibiotics, and chemotherapy drugs. One or more components selected from drugs, antidiabetic drugs, osteoporosis drugs, antirheumatic drugs, skeletal muscle relaxants, antispasmodics, hormones, alkaloid narcotics, sulfonamides, gout treatment drugs, anticoagulants, anticancer drugs, Alzheimer's disease treatment drugs, etc. are used, and in particular, tonics and health supplements, antipyretic analgesics and anti-inflammatory drugs, hypnotics and sedatives, central nervous system agents, gastrointestinal drugs, anti-ulcer agents, antitussives and expectorants, anti-allergic drugs, antiarrhythmic drugs, diuretics, antihypertensives, vasoconstrictors, coronary vasodilators, antihyperlipidemics, antidiabetic drugs, osteoporosis drugs, skeletal muscle relaxants, and antiseptics are preferably used.

[0014] In the present invention, a water-soluble starch hydrolysate or its hydrogenated form, reduced starch syrup, having a specific component composition, is used as a binder. Starch hydrolysates are substances obtained by chemically or enzymatically partially hydrolyzing starch to reduce its molecular weight, and contain substances with various degrees of polymerization as components. Substances having a structure in which the formyl group of the starch hydrolysate is hydrogenated are called reduced starch syrup, reduced corn syrup, etc. From the viewpoint of the storage stability of the tablets, reduced starch syrup is preferably used as a binder in the present invention. Substances having a structure in which the formyl group or carbonyl group of the carbohydrate is hydrogenated are called sugar alcohols, polyols, etc. In the present invention, commercially available reduced starch syrup may be used, or it may be produced from starch hydrolysate by known methods. Alternatively, reduced starch syrups having different sugar compositions may be mixed to create a composition with any sugar composition.

[0015] In this invention, sugar composition refers to the percentage of the mass of each sugar relative to the total mass of sugars. Sugar composition can be confirmed by high-performance liquid chromatography (HPLC). An aqueous solution of sugars is used as a sample, and HPLC is performed to obtain a chromatogram. The sum of the peak areas of the obtained chromatogram corresponds to the total mass of sugars, and each peak area corresponds to the mass of each sugar, allowing the percentage of each sugar's mass to be determined. The HPLC conditions can be set as appropriate.

[0016] In the present invention, the content of monosaccharides, disaccharides, and trisaccharides as components of the starch hydrolysate or its hydrogenated product is 50 parts by mass or less, preferably 45 parts by mass or less, and more preferably 40 parts by mass or less, per 100 parts by mass of the starch hydrolysate or its hydrogenated product. More preferably, in addition to the above composition, a starch hydrolysate or its hydrogenated product having a content of monosaccharides, disaccharides, trisaccharides, and tetrasaccharides of 50 parts by mass or less can be used as a binder.

[0017] Dextrose equivalent (DE) is an index of the average molecular weight of starch hydrolysates, that is, an index of the degree of hydrolysis in starch hydrolysates, and is a relative scale when the reducing power of D-glucose is set to 100. The closer the value is to 0, the lower the degree of hydrolysis and the larger the average molecular weight, and the closer the value is to 100, the higher the degree of hydrolysis and the smaller the average molecular weight. In the present invention, starch hydrolysates or their hydrogenated products with a DE of 41 or less, preferably DE of 39 or less, can be used as a binder. However, from the viewpoint of ease of handling during granulation, the DE of the starch hydrolysate is preferably 5 or more, and more preferably 10 or more. The binder is used in granulation in an amount of 1 to 10 parts by mass, preferably 1 to 5 parts by mass, and more preferably 2 to 4 parts by mass, per 100 parts by mass of the other components of the granular excipient.

[0018] In the present invention, granulation is the operation of processing particles such as single-component or multi-component excipients into larger granules using a binder or the like. The present invention can be used regardless of the granulation method, but it is preferable to use wet granulation, in which water or a binder solution is dropped or sprayed onto the excipient powder to wet it, and then the moisture is dried during granulation. There are no particular restrictions on the method of adding water or a binder solution in wet granulation; for example, agitated granulation, in which a solution is dropped onto the excipient powder while stirring, and fluidized bed granulation, in which a solution is sprayed onto the excipient powder while it is fluidized in a fluidized bed, can be used, but in the present invention, it is preferable to use fluidized bed granulation from the viewpoint of ease of operation.

[0019] There are no particular limitations on the method for producing tablets from the granular excipient of the present invention, and it can be appropriately selected according to the purpose, and commonly used mixers and tablet presses can be used.

[0020] In the present invention, an increase in hardness means that the hardness of the tablet under certain conditions is higher than that of a system without using the binder of the present invention. Tablet hardness refers to the force immediately before the tablet is broken by sandwiching the tablet between two pressure plates in the circular diameter direction and moving one of the pressure plates at a constant speed. A commercially available measuring device can be used for the measurement.

[0021] In the present invention, an increase in disintegrability means that the disintegration time of the tablet under certain conditions is shorter than that of a system without using the binder of the present invention. The disintegration time can be measured using the apparatus described in the disintegration test method described in the Seventeenth Revision of the Japanese Pharmacopoeia. Additionally, as an auxiliary measure, the time taken for actual disintegration in the human oral cavity may also be measured. Further, in the present invention, for the granular excipient before forming into a tablet, solubility is used as an index of disintegrability. An increase in the solubility (disintegrability) of the granular excipient means that the dissolution time under certain conditions is shorter than that of a system without using the binder of the present invention. The dissolution time refers to the time required from the addition of 5 g of the granular excipient while taking 100 mL of pure water in a 200 mL volumetric beaker, maintaining it at 25°C, and stirring with a stirrer at 400 rpm until dissolution.

Advantages of the Invention

[0022] By adopting the configuration of the present invention, a granular excipient with good solubility and disintegrability can be obtained. Further, by tableting this, a tablet having sufficient hardness and high disintegrability can be obtained.

Brief Description of the Drawings

[0024] The following describes embodiments of the present invention, but the present invention is not limited in any way to these embodiments.

[0025] (Binder) The binders used are shown in Table 1. The values ​​for monosaccharides, disaccharides, trisaccharides, and tetrasaccharides represent parts by mass when the total amount of carbohydrates used as a binder is set to 100 parts by mass. Hydroxypropyl cellulose (HPC-SSL, manufactured by Nippon Soda Co., Ltd.) was used as a control binder.

[0026] [Table 1]

[0027] (Excipient powder) The following excipient powders were used. Crystalline maltitol (Recis fine powder, manufactured by Mitsubishi Corporation Life Sciences Co., Ltd.) Maltitol powder (Amalti MR-50, manufactured by Mitsubishi Corporation Life Sciences Co., Ltd.) Trehalose (Trehalose powder, manufactured by Hayashibara Co., Ltd.) Erythritol (Erythritol T fine powder, manufactured by Mitsubishi Chemical Corporation) Lactose (Pharmatose 200M, manufactured by DFE Pharma) Xylitol (Xylitol fine powder, manufactured by Mitsubishi Corporation Life Sciences Co., Ltd.) Crystalline cellulose (Ceolus PH-101, manufactured by Asahi Kasei Corporation) Starch (corn starch W, manufactured by Nippon Shokuhin Kako Co., Ltd.)

[0028] <Manufacturing of granular excipients> The granular excipients used in the examples, comparative examples, and control examples of the present invention were prepared by the following method. 495 g of excipient powder or a mixture of excipient powders and 5 g of hydrophilic fumed silica (Aerosil 200, manufactured by Nippon Aerosil Co., Ltd.) were placed in a granulator (FD-MP-01: manufactured by Powrec Co., Ltd.), and 150 g of a 10% aqueous solution of the binder was sprayed on to granulate. Granulation was carried out at a product temperature of 40°C, dried at a product temperature of 60°C for 10 minutes, left overnight at room temperature, and sieved through an 850 μm sieve to obtain the granular excipient.

[0029] <Evaluation of granular excipients> As an indicator of the disintegration properties of the granular excipient, the dissolution time was measured. 100 mL of pure water was placed in a 200 mL beaker, maintained at 25°C, and 5 g of the granular excipient was added while stirring at 400 rpm using a stirring bar. The time required from addition to dissolution was measured.

[0030] Granular excipients were prepared and evaluated using crystalline maltitol and powdered maltitol, employing reduced starch saccharifieds with different sugar compositions and DE values ​​as binders. The results are shown in Tables 2-3.

[0031] [Table 2]

[0032] [Table 3]

[0033] The granular excipient (test product) prepared by granulating reduced starch saccharides 1 and 2 according to the present invention as binders showed a shorter dissolution time than the granular excipient (control product) prepared by granulating hydroxypropyl cellulose as a binder, confirming an increase in the disintegration properties of the granular excipient.

[0034] <Tablet manufacturing> Each granular product (100 parts by mass) was mixed with 1 part by mass of magnesium stearate until uniform, and tablets were compressed using a single-shot tablet press (NS-T100: manufactured by NanoSeeds Co., Ltd.) at the molding loads shown in the table below, to produce flat tablets with a diameter of φ8 mm and a mass of 180 mg.

[0035] <Evaluation of tablets> The hardness of tablets obtained from granules was measured using a hardness tester (TH-303MP: Toyama Sangyo Co., Ltd.) on 5 tablets obtained by compression, and the average value was adopted. Disintegration time was measured using a disintegration tester (NT-2H: Toyama Sangyo Co., Ltd.) on 3 tablets in accordance with the method described in the 17th edition of the Japanese Pharmacopoeia, and the average value was adopted. In the oral disintegration test, the time it took for the granules constituting the tablet to disintegrate in the oral cavity was measured.

[0036] (Evaluation of binders) Granulation was performed using crystalline maltitol with reduced starch saccharified products having different sugar compositions and DE values ​​as binders, according to the method described above. The resulting granular granules were compressed into tablets under molding loads of 8kN and 12kN. The relationship between molding load and tablet hardness is shown in Table 4 and Figure 1, and the relationship between tablet hardness and disintegration time (pharmacopoeia, oral) is shown in Figures 2 and 3.

[0037] [Table 4]

[0038] Tablets obtained by compressing granules granulated with reduced starch hydrolysates 1, 2, and 3, and starch hydrolysate 1 as binders, showed higher hardness and shorter disintegration time compared to tablets obtained from the control granules, indicating improved hardness and disintegration. Furthermore, the tablets exhibited good workability during compression. On the other hand, tablets obtained by compressing granules granulated with reduced maltose syrup as a binder showed lower hardness than tablets obtained from the granules in both the examples and the control.

[0039] (Granulation of various excipient powders) Granulation was carried out using the method described above with various excipient powders, reduced starch hydrolysates 1 and 2, reduced maltose syrup, and hydroxypropyl cellulose. The resulting granular material was compressed into tablets under molding loads of 8 kN and 12 kN.

[0040] Table 5 and Figure 4 show the molding load and tablet hardness when the excipient powder is powdered maltitol, and Figures 5 and 6 show the relationship between tablet hardness and disintegration time (pharmacopoeia, oral).

[0041] [Table 5]

[0042] Table 6 and Figure 7 show the molding load and tablet hardness when the excipient powder is erythritol, and Figures 8 and 9 show the relationship between tablet hardness and disintegration time (pharmacopoeia, oral).

[0043] [Table 6]

[0044] Table 7 and Figure 10 show the molding load and tablet hardness when the excipient powder is trehalose, and Figures 11 and 12 show the relationship between tablet hardness and disintegration time (pharmacopoeia, intraoral).

[0045] [Table 7]

[0046] Table 8 and Figure 13 show the molding load and tablet hardness when the excipient powder is lactose, and Figures 14 and 15 show the relationship between tablet hardness and disintegration time (pharmacopoeia, oral).

[0047] [Table 8]

[0048] Table 9 and Figure 16 show the molding load and tablet hardness when the excipient powder is xylitol, and Figures 17 and 18 show the relationship between tablet hardness and disintegration time (pharmacopoeia, oral).

[0049] [Table 9]

[0050] Table 10 and Figure 19 show the relationship between the molding load and tablet hardness when the excipient powder is starch, and Figures 20 and 21 show the relationship between tablet hardness and disintegration time (pharmacopoeia, intraoral).

[0051] [Table 10]

[0052] Table 11 and Figure 22 show the molding load and tablet hardness when the excipient powder mixture is crystalline maltitol / starch = 7 / 3, and Figures 23 and 24 show the relationship between tablet hardness and disintegration time (pharmacopoeia, oral).

[0053] [Table 11]

[0054] In the systems using reduced starch saccharides 1 and 2, tablets with higher hardness and shorter disintegration time than the control example were obtained regardless of which carbohydrate excipient powder was used. In other words, tablets with improved hardness and disintegration properties were obtained. Furthermore, the workability during tableting was also good.

Claims

1. A binder for granular excipients containing a hydrogenated starch hydrolysate having a DE of 41 or less.

2. A binder for granular excipients according to claim 1, comprising a hydride of starch hydrolysate in which the content of each of the hydrides of monosaccharides, disaccharides, and trisaccharides is 50% by mass or less.

3. A granular excipient manufactured using the binder for granular excipients described in claim 1 or 2.

4. The granular excipient according to claim 3, wherein the excipient is a carbohydrate.

5. A tablet manufactured using the granular excipient described in claim 3 or 4.

6. A method for increasing the disintegration properties of a granular excipient using the binder for granular excipients described in claim 1 or 2.

7. A method for manufacturing tablets using the granular excipient described in claim 3 or 4, thereby increasing the hardness and disintegrability of the tablets.

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