Magnesium oxide tablets

Abstract

To provide tablets whose main component is magnesium oxide particles that can achieve both a reduction in abrasion and a reduction in the rate of capping. [Solution] A tablet comprising granules containing magnesium oxide particles and an internal additive, and an external additive, wherein the internal and external additives contain at least cellulose and / or cellulose derivatives, and the mass ratio of [cellulose and / or cellulose derivative contained as internal additive]:[cellulose and / or cellulose derivative contained as external additive] is in the range of 75:25 to 10:90.

Description

Technical Field

[0001] The present invention relates to tablets containing magnesium oxide particles as a main component.

Background Art

[0002] Tablets containing magnesium oxide particles as a main component are known and widely used as tablets for various purposes such as antacid, laxative, magnesium supplementation, and anti-hypomagnesemia. However, since magnesium oxide tablets have poor formability, they have a high wear rate, and chipping and capping during transportation and handling are problematic. Due to the occurrence of wear and capping, chipping of the tablets during manufacturing, transportation, and dispensing becomes a problem. In order to obtain tablets with high hardness, low wear rate, and good formability, it is common to compress a mixed powder with a low bulk density. However, on the other hand, by entrapping air inside the tablets during compression, capping is likely to occur. Therefore, it has been an issue to achieve both reduction of wear rate and reduction of capping occurrence rate.

[0003] Here, various attempts have been made to reduce capping. For example, in Patent Document 1, by blending a binder and a disintegrant during dry granulation, wear of the mortar during tableting is suppressed, and an example of dealing with capping caused by abrasion of the mortar is shown. In Patent Document 2, a device is devised to suppress capping caused by the inability of air to escape completely during compression by making the shape of the pestle such that air can easily escape.

[0004] In the case of magnesium oxide tablets, cellulose or cellulose derivatives are sometimes added as additives that are highly compressible and have high plastic deformability. However, due to concerns about reduced fluidity, delayed disintegration time due to aggregation of magnesium oxide particles, reduced tube passability, and increased capping, it is common technical knowledge in this field that they are sometimes added before granulation but not after. Nevertheless, Patent Document 2 describes a formulation using two types of disintegrants and two types of binders (crystalline cellulose), and attempts to improve the long-term persistence of short-term disintegration and strength by adding them both before and after granulation. However, the improvement in the capping rate is mainly achieved by modifying the shape. [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] Japanese Patent Publication No. 2003-146889 [Patent Document 2] Special Publication No. 2011-030659 [Overview of the project] [Problems that the invention aims to solve]

[0006] The object of the present invention is to provide a magnesium oxide tablet that can achieve both a reduction in abrasion and a reduction in the rate of capping. [Means for solving the problem]

[0007] The inventors diligently studied how to achieve both a reduction in abrasion and a reduction in the rate of capping of tablets mainly composed of magnesium oxide particles. As a result, they unexpectedly came to the novel discovery that by optimizing the blending of cellulose and / or cellulose derivatives contained in the internal and external additives, tablets with reduced abrasion and capping rates can be obtained. They then found the appropriate blending ratio and completed the present invention.

[0008] In other words, the present invention provides, for example, the following embodiments. [1] A tablet containing magnesium oxide as the active ingredient, The tablet comprises granules containing magnesium oxide particles and an internal additive, and an external additive, and contains at least cellulose and / or a cellulose derivative as the internal and external additives. Tablets in which the mass ratio of [cellulose and / or cellulose derivatives contained as internal additives] to [cellulose and / or cellulose derivatives contained as external additives] is within the range of 75:25 to 10:90. [2] The tablet according to [1], wherein the cellulose and / or cellulose derivative is at least one selected from the group consisting of crystalline cellulose, microcrystalline cellulose, powdered cellulose, methylcellulose, ethylcellulose, carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and low-substituted hydroxypropylcellulose. [3] A tablet according to [1] or [2], wherein the magnesium oxide particles content is 80-90% by mass relative to the entire tablet. [4] The tablet according to any one of [1] to [3], wherein the granules contain at least one selected from the group including croscarmellose sodium, corn starch, carmellose calcium, crospovidone, and carboxystarch sodium in an amount of 1 to 3.5% by mass relative to the total weight of the tablet. [5] A method for manufacturing tablets containing magnesium oxide as an active ingredient, Mixing magnesium oxide particles with an internal additive containing cellulose and / or a cellulose derivative; Granulating the aforementioned mixture to form granules; The process involves adding an external additive containing cellulose and / or a cellulose derivative to the granules and then compressing them into tablets; A manufacturing method in which the mass ratio of [cellulose and / or cellulose derivatives contained as internal additives] to [cellulose and / or cellulose derivatives contained as external additives] is within the range of 75:25 to 10:90. [6] The method according to [5], characterized in that the cellulose and / or cellulose derivative is at least one selected from the group consisting of crystalline cellulose, microcrystalline cellulose, powdered cellulose, methylcellulose, ethylcellulose, carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and low-substituted hydroxypropylcellulose. [7] Tablets manufactured by the method described in [5] or [6]. [Effects of the Invention]

[0009] According to the present invention, by adjusting the ratio of cellulose and / or cellulose derivatives contained in the internal and external additives, it is possible to simultaneously reduce the degree of wear and the rate of capping of tablets mainly composed of magnesium oxide particles. When both the degree of wear and the rate of capping are reduced, it is possible to suppress cracking and chipping during manufacturing, transportation, and dispensing. [Modes for carrying out the invention]

[0010] The present invention will be described below based on specific embodiments, but the present invention is not limited to these forms, and can be implemented with any modifications as long as they do not depart from its spirit.

[0011] [overview] As described above, magnesium oxide tablets have poor formability, resulting in high abrasion and capping problems. However, if the hardness is increased to reduce the abrasion, although the formability improves, the incidence of capping increases due to entrained air during compression. Therefore, the problem is to achieve both a reduction in abrasion and a reduction in the incidence of capping. In Patent Document 2, two types of disintegrants and two types of binders (crystalline cellulose) were added before and after granulation, and various studies were conducted, but it was not possible to conceive of achieving both a reduction in abrasion and a reduction in the incidence of capping by adjusting the ratio of cellulose and / or cellulose derivatives contained in the internal and external additives.

[0012] The inventors of the present invention conducted intensive studies to achieve both a reduction in abrasion and a reduction in the incidence of capping. Surprisingly, not only were cellulose and / or cellulose derivatives added before and after granulation, but also by optimizing the ratio of cellulose and / or cellulose derivatives contained in the internal additives added before granulation and the external additives added after granulation, the inventors conceived of achieving both a reduction in abrasion and a reduction in the incidence of capping. The present invention is based on such unexpected findings of the inventors.

[0013] [Abrasion level] In the present invention, the "abrasion" is an index of the abrasion and brittleness of tablets against impact and can be measured by the method described in the "Seventeenth Revised Japanese Pharmacopoeia, Reference Information - Tablet Abrasion Test Method". Specifically, for the number of tablets close to 6.5 g, using a tablet abrasion meter (manufactured by Toyama Sangyo Co., Ltd., tablet abrasion tester TFT-1200), abrasion of 100 rotations (24 - 26 rotations / min) is applied to the test tablets, the initial mass of the tablets before abrasion and the mass of the tablets after abrasion are measured, and the abrasion can be obtained by calculating the abrasion according to the following formula 1.

Equation

[0014] When using the above measurement method, the wear degree range of the tablets of the present invention may be less than 0.40% as the upper limit, preferably less than 0.35%, and more preferably less than 0.30%. On the other hand, since it is desirable that the wear degree is lower, no lower limit is particularly provided.

[0015] [Capping] In the present invention, "capping" refers to the peeling of the upper or lower surface portion of a tablet as a cross-sectional piece, which is caused by impacts during tableting, transportation, packaging, etc. in the tablet manufacturing process. The capping occurrence rate can be determined by a cassette rotor test. Specifically, tablets are discharged from a cassette rotor (manufactured by TOSHO, for 500 mg Magmit tablets) set at a height of 2 m, and the number of capping tablets is counted from the dropped tablets. A sufficient number, for example, 100 test tablets are tested, and the number of tablets in which capping has occurred is counted, and the ratio can be determined by calculating according to the following formula 2. As the floor material specification used at that time, a concrete trowel + epoxy-based coated floor material + paste method (thickness 2 mm) (ABC Chamber of Commerce) Chemicrete E or its equivalent specification can be adopted.

Number

[0016] When using the above measurement method, the range of the capping occurrence rate of the tablets of the present invention is preferably less than 12%, preferably less than 11%, and more preferably less than 10%. On the other hand, since it is desirable that the capping occurrence rate is lower, no lower limit is particularly provided.

[0017] [hardness] In this invention, "hardness" is an indicator of the hardness of a tablet and can be measured with a commercially available tablet hardness tester. Specifically, it can be determined by measuring the tablet hardness in the diametrical direction using a tablet hardness tester such as the DC-50 (Okada Seikou Co., Ltd.). From the viewpoint of achieving the effects of this invention, if the hardness is too low, the degree of abrasion will increase, so a lower limit of 30N or higher is preferable, more preferably 40N or higher, and even more preferably 50N or higher. On the other hand, since higher hardness is desirable, no upper limit is set.

[0018] [Collapse Time] In this invention, "disintegration time" is an indicator of how easily a tablet disintegrates in a solution. Disintegration time can be measured according to the disintegration test method in the general test methods of the 17th edition of the Japanese Pharmacopoeia. Specifically, it can be determined by using a disintegration tester (disintegration tester NT-20HS, manufactured by Toyama Sangyo Co., Ltd.) and measuring the disintegration time of an appropriate number of test tablets, for example, 6 tablets, in a test solution, for example, water. An appropriate disintegration time is preferable because it allows for the provision of easy-to-swallow tablets that disintegrate quickly in the oral cavity after administration. The upper limit of an appropriate disintegration time is preferably 20 seconds or less, more preferably 15 seconds or less, and even more preferably 11 seconds or less. The lower limit is not particularly limited, but is usually 5 seconds or more, or 1 second or more.

[0019] [Cellulose and / or cellulose derivatives] In this invention, "cellulose" means β-glucose Molecules glycosidic bond By doing so, in a linear chain polymerization (C6H) 10 O5) nThis refers to a linear polymer represented by , for example, crystalline cellulose, microcrystalline cellulose, powdered cellulose, etc. "Cellulose derivative" refers to a cellulose molecule in which different substituents have been introduced to the hydroxyl group by an ether bond or an ester bond, for example, methylcellulose, ethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, low-substituted hydroxypropylcellulose, etc. In this invention, "cellulose and / or cellulose derivative" refers to at least one selected from the above-mentioned "cellulose" and "cellulose derivative". Low-substituted hydroxypropylcellulose refers to cellulose in which a very small amount of hydroxypropoxy group has been introduced to the glucose ring, that is, cellulose with a molar substitution degree of 0.2 to 0.4 that has been O-(2-hydroxypropyl) at a low level. The form of such cellulose derivatives may be, for example, powder, particulate, or fine particles.

[0020] Cellulose and / or cellulose derivatives may be synthesized or commercially available. Commercially available options include various grades of Ceolus® from Asahi Kasei Corporation, such as Ceolus® PH-101, UF-711, PH-102, PH-200, PH-301, PH-302, PH-20JP, UF-702, KG-802, and KG-1000, which are crystalline celluloses.

[0021] [Magnesium oxide particles] The magnesium oxide particles used in this invention are magnesium oxide (MgO) particles. These magnesium oxide particles can be obtained by calcining magnesium hydroxide particles. For example, they can be obtained by calcining magnesium hydroxide with an average particle size of 1 to 10 μm, as determined by laser diffraction scattering, at 600 to 1000°C. Magnesium oxide particles may be synthesized or commercially available. Examples include heavy grade from Kyowa Chemical Industry Co., Ltd., powder grade from Kamishima Chemical Industry Co., Ltd., or light grade and heavy grade magnesium oxide from Tomita Pharmaceutical Co., Ltd. (Japanese Pharmacopoeia).

[0022] The magnesium oxide particles used in this invention may be in powder or granular form, but the granular form offers superior wear prevention for the tablet press and allows for the production of high-content tablets with better shape retention stability.

[0023] The magnesium oxide particles used in this invention are not limited, but it is preferable that they have a predetermined particle size. For example, the upper limit of the average particle size of magnesium oxide particles measured by laser diffraction scattering can be, for example, 40 μm or less, 20 μm or less, or 10 μm or less. By setting the average particle size of the magnesium oxide particles to or below the above upper limit, the size of suspended particles when the tablet disintegrates becomes smaller, which can result in a tablet that feels less gritty in the mouth. On the other hand, the lower limit of the average particle size is not limited, but depending on manufacturing limitations and cost-effectiveness, it can be, for example, 0.25 μm or more, 0.5 μm or more, or 1 μm or more.

[0024] The laser diffraction scattering method used to determine the average particle size and average particle diameter of magnesium oxide particles and magnesium hydroxide particles, which are the raw materials for the present invention, can be achieved using commonly used equipment, such as a particle size distribution analyzer (Microtrac Bell Co., Ltd. MT3300EX2).

[0025] In this invention, the bulk density of magnesium oxide particles can be set to an upper limit of 0.8 g / mL or 0.7 g / mL or less, as excessively high bulk density may cause a decrease in hardness. On the other hand, excessively low bulk density may cause capping and lamination, so the lower limit can be set to 0.1 g / mL or more, or 0.2 g / mL or more. Bulk density can be measured, for example, using a 100 mL stainless steel cup (measured mass value (g) / 100 (mL)).

[0026] In this invention, the angle of repose of magnesium oxide particles can be set to an upper limit of 50° or 48° or less, as a larger angle of repose may lead to poor fluidity and variations in tablet mass during tableting. On the other hand, a lower angle of repose is desirable, so no lower limit is set. The angle of repose can be measured, for example, using a multi-tester MT-1 manufactured by Seishin Corporation.

[0027] [tablet] One aspect of the present invention relates to a tablet containing magnesium oxide as an active ingredient, comprising granules containing magnesium oxide particles and an internal additive, and an external additive, wherein the internal and external additives contain at least cellulose and / or a cellulose derivative, and the mass ratio of [cellulose and / or cellulose derivative contained as internal additive]:[cellulose and / or cellulose derivative contained as external additive] is within a certain range.

[0028] From the viewpoint of achieving the effects of the present invention, magnesium oxide particles are preferably included in the granules together with the internal additives. The content of magnesium oxide particles can be set to, for example, 90% by mass or less, or 88% by mass or less, relative to the total tablet, as too high a content may result in insufficient moldability. On the other hand, if the content is too low, it is possible to incorporate additives with high compressibility and plastic deformability, resulting in a tablet with high moldability, but the cost per tablet will increase. Therefore, it is preferable to set the content to, for example, 80% by mass or more, or 85% by mass or more, relative to the total tablet.

[0029] The tablets of the present invention have a certain mass ratio of [cellulose and / or cellulose derivatives contained as internal additives]:[cellulose and / or cellulose derivatives contained as external additives]. Increasing the proportion of external additives can be expected to increase hardness and reduce abrasion, but if it increases too much, it can lead to an increase in the rate of capping and a decrease in tube passability. Therefore, when the total mass of cellulose and / or cellulose derivatives contained in the tablet is set to 100, the upper limit of the mass ratio of external additives is preferably 90 or less, for example, 88 or less, 85 or less, 80 or less, or 75 or less, and the lower limit is preferably greater than 20, for example, 21 or more, 22 or more, 23 or more, 24 or more, or 25 or more. On the one hand, if the proportion of internal additives is too small, densification will be insufficient, resulting in the generation of many fine particles that easily trap air. This can lead to capped tablets because the air is not completely removed during subsequent tableting. Therefore, a certain amount is necessary. Conversely, if the proportion of internal additives is too large, granules that have been densified by granulation will be obtained. Further densification during tableting will make the granules less susceptible to damage, leading to a decrease in moldability and an increase in abrasion. Therefore, the mass ratio of internal additives should preferably have an upper limit of less than 80, for example, 79 or less, 78 or less, 77 or less, 76 or less, or 75 or less, and a lower limit of 10 or more, for example, 12 or more, 15 or more, 20 or more, or 25 or more.

[0030] Furthermore, the content of cellulose and / or cellulose derivatives relative to the whole tablet can be set to 20% by mass or less, 15% by mass or less, or 12% by mass or less, because too much would increase the cost per tablet. On the other hand, if the amount is too little, the effects of the present invention may not be achieved, so it can be set to 5% by mass or more, 7% by mass or more, or 9% by mass or more, relative to the whole tablet.

[0031] In the tablets of the present invention, the cellulose and / or cellulose derivatives defined above are preferably used as excipients or binders in both the internal and external additives. Furthermore, the cellulose and / or cellulose derivatives contained in the internal and external additives may be the same or different.

[0032] In the present invention, internal additives refer to additives containing one or more substances that are added to and mixed with the active ingredient before the granulation process in the manufacture of tablets. In addition to the cellulose and / or cellulose derivatives defined above, other additives may be added as internal additives. In particular, in order to adjust to the preferred disintegration time as described above, it is preferable to add disintegrants such as croscarmellose sodium, corn starch, carmellose calcium, crospovidone, and carboxystarch sodium as internal additives, in addition to the cellulose and / or cellulose derivatives contained in the internal and external additives in the specific ratios defined above. Disintegrants may be synthesized or commercially available. Commercially available products such as Kikkolate® ND-2HS manufactured by Nichirin Chemical Industry Co., Ltd. can be used. As it may be difficult to form the tablets, the upper limit can be, for example, 5% by mass or 3.5% by mass or less of the total tablet weight. On the other hand, if it is too little, it may be difficult to disintegrate, so the lower limit can be, for example, 1% by mass or more, or 2% by mass or more of the total tablet weight.

[0033] In the present invention, external additives refer to additives containing one or more substances that are added to granules produced after the granulation process in the manufacture of tablets and compressed together with the granules. In addition to cellulose and / or cellulose derivatives contained in the internal and external additives in the specific ratios defined above, other additives may also be added as external additives. In particular, it is preferable to add a lubricant from the viewpoint of achieving the desired effect of the present invention. Examples of lubricants include stearic acid and its salts (Mg,Ca salts), with stearate salts being preferred, and magnesium stearate and calcium stearate being preferred among them. Lubricants may be synthesized or commercially available. Too much lubricant may lead to delayed disintegration, so the upper limit can be, for example, 2% by mass or less, 1.5% by mass or less, or 1.0% by mass or less, relative to the total weight of the tablet. On the other hand, too little lubricant may cause it to adhere to the pestle and mortar, so the lower limit of the amount of lubricant added relative to the total weight of the tablet can be, for example, 0.2% by mass or more, 0.5% by mass or more, or 0.9% by mass or more.

[0034] The shape of the tablets of the present invention is not particularly limited, taking into consideration the effectiveness of the present invention and ease of swallowing as an oral preparation. For example, the upper limit of the diameter can be 14 mm or less, or 10 mm or less, and the lower limit can be 5 mm or more, or 6 mm or more. Similarly, the upper limit of the thickness is not particularly limited, but it can be 8 mm or less, or 7 mm or less, and the lower limit can be 3 mm or more, or 4 mm or more. In addition, for example, a shape such as that shown in Patent Document 2 may be used to further suppress capping.

[0035] The mass of the tablets of the present invention is not particularly limited as long as it is within the range of oral preparations commonly used as tablets containing magnesium oxide as an active ingredient. For example, the upper limit per tablet may be 1000 mg or less, or 800 mg or less, or 600 mg or less, and the lower limit may be 10 mg or more, or 50 mg or more, or 100 mg or more.

[0036] The tablets of the present invention are administered orally as pharmaceuticals for humans or animals for purposes such as antacid, laxative, and prevention of the formation of calcium oxalate stones in the urinary tract. They can also be used as supplements for humans or animals for purposes such as magnesium supplementation and anti-hypomasemia. The dosage depends on the use, purpose, or medical condition. For example, when used as an antacid, the usual dose for an adult is 0.5 to 1.0 g per day in magnesium oxide equivalent, administered orally in several divided doses. When used as a laxative, the usual dose for an adult is 2 g per day in magnesium oxide equivalent, administered orally in three divided doses before or after meals, or once before bedtime. When used to prevent the formation of calcium oxalate stones in the urinary tract, the usual dose for an adult is 0.2 to 0.6 g per day in magnesium oxide equivalent, administered orally with a large amount of water. For other uses, the intake is usually within the tolerable upper intake level for magnesium. For example, regarding intake from sources other than normal foods, the U.S. Dietary Reference Intakes are set at 350 mg per day for healthy adults and 5 mg per kg of body weight per day for healthy children (Institute of Medicine (IOM). Food and Nutrition Board). Dietary Reference Intakes: Calcium, Phosphorus, Magnesium, Vitamin D and Fluoride” Washington, DC: National Academy Press, 1997).

[0037] The pharmaceutical product of the present invention is approved in Japan for use as a desired antacid, laxative, and preventative agent for the formation of urinary tract calcium oxalate stones due to its active ingredient. The internal and / or external additives may contain one or more other optional components, provided that they do not substantially hinder the expected effects in each application, as well as the reduction of abrasion and the reduction of capping incidence. Such other components are not limited to, but include, various pharmaceutically acceptable pharmaceutical additives, such as colorants and flavorings. These components may be used individually or in any combination and ratio of two or more.

[0038] [Method of manufacturing tablets] Another aspect of the present invention is a method for producing tablets containing magnesium oxide as an active ingredient, Mixing magnesium oxide particles with an internal additive containing cellulose and / or a cellulose derivative; Granulating the aforementioned mixture to form granules; The process involves adding an external additive containing cellulose and / or a cellulose derivative to the granules and then compressing them into tablets; This invention relates to a manufacturing method in which the mass ratio of [cellulose and / or cellulose derivatives contained as internal additives] to [cellulose and / or cellulose derivatives contained as external additives] is within the range of 75:25 to 10:90.

[0039] First, an internal additive containing magnesium oxide particles, cellulose and / or cellulose derivatives, and optionally one or more other components is mixed according to a known method.

[0040] Subsequently, the resulting mixture is granulated into granules. Considering the components of the tablets of the present invention, granulation by dry granulation is preferable. For example, granules can be produced by using a commercially available dry granulator (Freund Industrial Co., Ltd. dry granulator RC-156) and performing granulation under normal granulation conditions.

[0041] The granules produced in this manner are then combined with an external additive containing cellulose and / or cellulose derivatives and optionally one or more other components, and then compressed into tablets. Any method is used to add the external additive, as long as it allows the external additive to be added around the granules. The compression pressure is the punch pressure per tablet, and for example, the upper limit can be 20kN or less, or 18kN or less, or 16kN or less, and the lower limit can be 2kN or more, or 3kN or more, or 4kN or more. The shape of the punch can be standard R, or two-stage R, sugar-coated R, corner R, corner flat, rounded flat, etc.

[0042] Although various aspects of the present invention have been described above, the present invention is not limited to these aspects. As will be apparent to those skilled in the art, it is also possible to extract any other aspects of the present invention from the above detailed description and the examples described below. [Examples]

[0043] The present invention will be described in more detail below with reference to examples, but these examples are merely illustrative examples for explanatory purposes, and the present invention is not limited in any sense to these examples.

[0044] [Prescription] The tablets were manufactured using the formulations shown in the table below. [Table 1] [Table 2] The details of the raw materials used in each of the above examples and comparative examples are as follows. Magnesium Oxide: Manufactured by Kyowa Chemical Industry Co., Ltd. Japanese Pharmacopoeia Magnesium Oxide (Heavy Grade) Crystalline cellulose: Ceolus PH-101 (Examples 1-4, Comparative Examples 1-3), Ceolus UF-711 (Examples 5-8, Comparative Examples 4-6), manufactured by Asahi Kasei Corporation. Croscarmellose sodium: Manufactured by Nichirin Chemical Industries Co., Ltd., Kikkolate ND-2HS Calcium stearate: Manufactured by Taihei Chemical Industry Co., Ltd. Calcium stearate (plant-derived) The physical properties of the magnesium oxide used in this example were measured and found to be as follows. • Average particle size: 7.691 μm (measured by laser diffraction scattering method using Microtrac Bell Co., Ltd. MT3300 EX2) • Bulk density: 0.249 g / mL (measured using a 100 mL stainless steel cup (actual mass value (g) / 100 (mL))) • Angle of repose: 41.7° (measured using a multi-tester MT-1 manufactured by Seishin Corporation)

[0045] [Manufacturing method] According to the above formulation, each ingredient was weighed using an electronic balance (Mettler Toledo, 5kg capacity, PB5001-S / FACT) on a 15,000-tablet scale.

[0046] 1.Mixing The weighed magnesium oxide and internal additive raw materials were placed in a polyethylene bag (1100mm x 600mm) and the bag was shaken 30 times from side to side to mix. After the mixing process, the bulk density was measured using a 100mL stainless steel cup (measured mass value (g) / 100 (mL)).

[0047] 2. Granulation The obtained mixture was granulated using a dry granulator (Freund Industrial Co., Ltd., dry granulator RC-156) under the following granulation conditions to produce granules. [Table 3]

[0048] After granulation, the following evaluation items were performed. • Flake ratio: The mass of the 1-minute processed product (A) and the 1-minute processed product (A) sieved through a 1000 μm sieve (B) are measured and calculated using the following formula 3.

number

[0049] 3. Addition of external additives The granules and the weighed raw materials for the external additive were placed in a polyethylene bag (1100mm x 600mm) and the bag was shaken 30 times from side to side to mix them. After mixing, the following evaluation items were performed. • Bulk density: Measured using a 100mL stainless steel cup (actual mass value (g) / 100 (mL)). • Angle of repose: Measured using the MT-1 multi-tester manufactured by Seishin Corporation.

[0050] 4.Tablet compression The mixed granules and external additives were compressed into tablets using a tablet press (VIRG, a small, high-speed rotary tablet press manufactured by Kikusui Seisakusho Co., Ltd.) under the following conditions. [Table 4]

[0051] After tableting, the following evaluation items were performed. • Mass: (Number of test tablets: 10 tablets) • Thickness: (Number of test tablets: 5), using a Peacock thickness gauge. • Hardness: (Number of test tablets: 10 tablets), using a DC-50 load cell type bench hardness tester manufactured by Okada Seikou Co., Ltd. • Abrasion resistance test: Conducted using a tablet abrasion resistance tester TFT-1200 manufactured by Toyama Sangyo Co., Ltd., with 100 rotations (number of test tablets: as close as possible to 6.5g). • Disintegration time: (Number of test tablets: 6 tablets), in accordance with the 17th edition of the Japanese Pharmacopoeia, general test methods, disintegration test method. The disintegration time of the test tablets in water was measured using a disintegration tester (Toyama Sangyo Co., Ltd., Disintegration Tester NT-20HS). • Tableting status: Visually check the tableting pressure and whether there are any tableting defects. • Suspended particle size D50 (μm): (Number of test tablets: 1 tablet), the suspended particle size was measured when the test tablet was suspended in water using the LMS-2000e laser diffraction scattering particle size analyzer manufactured by Seishin Corporation. • Tube purging ability 5Fr: The plunger of a catheter syringe (Nipro Corporation, Enteral Nutrition Infusion Set Syringe DS 20mL Catheter Yellow) was removed, one tablet was placed inside the outer barrel, the plunger was returned, 20mL of 55°C warm water was drawn in, the end of the barrel was capped and left to stand for 5 minutes. After 5 minutes, the catheter syringe was manually rotated 90 degrees 15 times, then an enteral nutrition tube (Atom Medical, Atom Nutrition Catheter T; diameter 5Fr, length 120cm) was connected, and 20mL of the internal suspension and ion-exchanged water for washing were injected to check whether the tube was blocked. This test was performed three times, and it was evaluated as "suitable" if the tube was not blocked and "unsuitable" if it was blocked. • Calculation of compression ratio in the tableting process: Let the filling depth be (a) and the final compression thickness be (b), and calculate using the following formula 4.

number

[0052] [result] The table below shows the measurement results of the bulk density of the resulting product (mixture) after mixing. [Table 5] [Table 6] The bulk density of the mixed product was within the range of 0.20 to 0.25 (g / mL) for both the examples and comparative examples, and no significant differences were observed.

[0053] The measurement results for each item of the granules (granulated product) after granulation are shown in the table below. [Table 7] [Table 8]

[0054] Regarding granulation properties, the higher the amount of crystalline cellulose included as an internal additive, the better the processing capacity, flake rate, and the higher the bulk density of the granulated product. Therefore, it is preferable to include a certain amount of crystalline cellulose as an internal additive.

[0055] The measurement results after the addition of external additives are shown in the table below. [Table 9] [Table 10]

[0056] When comparing the particle size after the addition of the external additive in Comparative Examples 1 and 4, which did not contain crystalline cellulose as an external additive, with that of Comparative Examples 3 and 6, which contained 100% crystalline cellulose as an external additive, an increase of 150 μm Pass was observed in Comparative Examples 3 and 6. However, since the angle of repose was within the range of 40° to 44° in all cases, there was not much difference, and therefore it is considered that there was no difference in fluidity.

[0057] The measurement results for each item after tableting are shown in the table below. [Table 11] [Table 12]

[0058] As the mass ratio of crystalline cellulose contained as an external additive to the crystalline cellulose contained as an internal additive increased (Comparative Example 1 → Comparative Example 3, Comparative Example 4 → Comparative Example 6), hardness increased and abrasion decreased, but an increase in the rate of capping and aggregation of suspended particles were observed. It is thought that as the mass ratio of crystalline cellulose contained as an external additive to the crystalline cellulose contained as an internal additive increased, the proportion of uncompressed crystalline cellulose that could contribute to tablet formation increased, and the compression ratio during tableting increased, leading to increased hardness and decreased abrasion. On the other hand, it is thought that the insufficient compaction during granulation made it easier for fine particles that did not become flakes to trap air, and the overall bulk density of the granules to be tableted also decreased due to the influence of the uncompressed crystalline cellulose added later, resulting in insufficient degassing during compression and trapping air, which is the cause of the increased rate of capping. In addition, in Comparative Example 3, where the entire amount of crystalline cellulose was contained as an external additive, clogging was also observed in the tube passability test. Therefore, in order to reduce the degree of abrasion, the mass ratio of crystalline cellulose contained as an external additive is preferably approximately 25 or more, and is considered appropriate to be approximately 90 or less, when the total mass of cellulose and / or cellulose derivatives contained in the tablet is set to 100.

[0059] The tablet thickness after compression was within the range of 5.3 to 5.5 mm in all cases, with no significant differences observed. The disintegration time was within an appropriate range for both the examples and the comparative examples.

[0060] From the above results, it was found that by adjusting the mass ratio of [cellulose and / or cellulose derivatives contained as internal additives]:[cellulose and / or cellulose derivatives contained as external additives] to within the range of 75:25 to 10:90, for example, within the range of 75:25 to 20:80, and especially within the range of 75:25 to 25:75, magnesium oxide tablets that can simultaneously reduce abrasion and capping can be efficiently manufactured. Furthermore, with such a ratio, it is possible to achieve both a reduction in abrasion and a reduction in capping while ensuring the physical properties required during tablet manufacturing, such as moldability, granulation, tabletability, flowability, and tube passage, as well as the physical properties required for magnesium oxide tablets, such as disintegration. [Industrial applicability]

[0061] This invention has extremely high applicability in industrial fields, particularly in the fields of pharmaceutical manufacturing and distribution, where there is a need to achieve both a reduction in the degree of wear and a reduction in the rate of capping of tablets mainly composed of magnesium oxide particles.

Claims

1. A tablet containing magnesium oxide as the active ingredient, The tablet comprises granules containing magnesium oxide particles and an internal additive, and an external additive, and contains at least cellulose and / or a cellulose derivative as the internal and external additives. Tablets in which the mass ratio of [cellulose and / or cellulose derivatives contained as internal additives] to [cellulose and / or cellulose derivatives contained as external additives] is within the range of 75:25 to 10:

90.

2. The tablet according to claim 1, wherein the cellulose and / or cellulose derivative is at least one selected from the group consisting of crystalline cellulose, microcrystalline cellulose, powdered cellulose, methylcellulose, ethylcellulose, carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and low-substituted hydroxypropylcellulose.

3. The tablet according to claim 1 or 2, wherein the proportion of magnesium oxide particles in the total tablet is 80 to 90% by mass.

4. The tablet according to any one of claims 1 to 3, wherein the granules contain at least one selected from the group including croscarmellose sodium, corn starch, carmellose calcium, crospovidone, and carboxystarch sodium in an amount of 1 to 3.5% by mass relative to the total weight of the tablet.

5. A method for manufacturing tablets containing magnesium oxide as an active ingredient, Mixing magnesium oxide particles with an internal additive containing cellulose and / or a cellulose derivative; Granulating the aforementioned mixture to form granules; The process involves adding an external additive containing cellulose and / or a cellulose derivative to the granules and then compressing them into tablets; A method for manufacturing in which the mass ratio of [cellulose and / or cellulose derivatives contained as internal additives] to [cellulose and / or cellulose derivatives contained as external additives] is within the range of 75:25 to 10:

90.

6. The method according to 5, characterized in that the cellulose and / or cellulose derivative is at least one selected from the group consisting of crystalline cellulose, microcrystalline cellulose, powdered cellulose, methylcellulose, ethylcellulose, carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and low-substituted hydroxypropylcellulose.

7. A tablet manufactured by the method described in claim 5 or 6.

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