Magnesium oxide tablet

Abstract

This invention provides a tablet primarily composed of magnesium oxide particles that can reduce both wear and the incidence of tip cracking. The tablet comprises granules containing magnesium oxide particles and internal additives, as well as external additives, and contains at least cellulose and / or cellulose derivatives as both internal and external additives, wherein the mass ratio of [cellulose and / or cellulose derivatives contained as internal additives] to [cellulose and / or cellulose derivatives contained as external additives] is in the range of 75:25 to 10:90.

Description

Technical Field

[0001] This invention relates to an ingot containing magnesium oxide particles as the main component. Prior Technology

[0002] Magnesium oxide tablets are widely used in various applications such as antacids, laxatives, magnesium supplements, and treatments for hypomagnesemia. However, due to their poor formability and high abrasion rate, magnesium oxide tablets are prone to breakage and capping during transportation / handling. These abrasion and capping issues contribute to tablet breakage during manufacturing, transportation, and dispensing. To obtain tablets with high hardness, low abrasion rate, and good formability, a low-density mixed powder is typically compressed. However, this compression can trap air within the tablets, easily causing capping. Therefore, reducing both abrasion rate and capping incidence has become a research topic.

[0003] Various attempts have been made to reduce top cracking. For example, Patent Document 1 discloses an example of suppressing the wear of the pestle and mortar during pelletizing by adjusting the binder and disintegrant during dry granulation, thus addressing top cracking caused by pestle and mortar scraping. Patent Document 2 describes a method to suppress top cracking caused by failure to remove air during compression by shaping the pestle to facilitate air removal.

[0004] In the case of magnesium oxide tablets, although cellulose and cellulose derivatives are added as additives with high compressibility and plasticity, concerns about reduced fluidity, delayed disintegration time due to magnesium oxide particle agglomeration, reduced channel penetration, and increased incidence of top cracking have led to the common practice in the art that they are not added after granulation, even if they are added before granulation. Nevertheless, in Patent Document 2, a formulation using two disintegrants and two binders (crystalline cellulose) was studied, with these added both before and after granulation, in an attempt to improve the persistence and strength of short-term disintegration. However, the improvement in the incidence of top cracking was achieved solely by designing its shape.

[0005] [Previous Technical Documents]

[0006] [Patent Literature]

[0007]

[0008] [Patent Document 1] Japanese Patent Publication No. 2003-146889

[0009] [Patent Document 2] Japanese Patent Publication No. 2011-030659 Summary of the Invention Problems to be Solved by the Invention

[0010] The problem of the present invention is to provide magnesium oxide tablets that can simultaneously reduce the wear rate and the incidence of top cracking. Means for Solving the Problems

[0011] As a result of intensive studies by the present inventors to make tablets mainly composed of magnesium oxide particles have both a reduced wear rate and a reduced incidence of top cracking, it was unexpectedly found that by optimizing the formulation of cellulose and / or cellulose derivatives contained in the internal additive and the external additive, a new finding was obtained that tablets with simultaneously reduced wear rate and incidence of top cracking could be obtained, and further, an appropriate formulation ratio was found, thus completing the present invention.

[0012] That is, the present invention provides, for example, the following aspects.

[0013] [1] A tablet containing magnesium oxide as an active ingredient;

[0014] The aforementioned tablet includes granules containing magnesium oxide particles and an internal additive and an external additive, and contains at least cellulose and / or cellulose derivatives as the internal additive and the external additive;

[0015] Among them, the mass ratio of [cellulose and / or cellulose derivatives contained as the internal additive]: [cellulose and / or cellulose derivatives contained as the external additive] is within the range of 75:25 to 10:90.

[0016] [2] The tablet according to [1], wherein the aforementioned cellulose and / or cellulose derivatives are at least one selected from the group consisting of crystalline cellulose, microcrystalline cellulose, powdered cellulose, methyl cellulose, ethyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and low-substituted hydroxypropyl cellulose.

[0017] [3] The tablet according to [1] or [2], wherein the content ratio of magnesium oxide particles relative to the whole tablet is 80 to 90% by mass.

[0018] [4] The tablet according to any one of [1] to [3], wherein in the aforementioned granules, at least one selected from the group consisting of croscarmellose sodium, corn starch, calcium carboxymethylcellulose, crospovidone, and sodium carboxymethyl starch is contained at 1 to 3.5% by mass based on the whole tablet.

[0019] [5] A method for manufacturing a tablet, which manufactures a tablet having magnesium oxide as an active ingredient, the manufacturing method including: mixing magnesium oxide particles and an internal additive containing cellulose and / or a cellulose derivative;

[0020] granulating the aforementioned mixture to form granules; and

[0021] adding an external additive containing cellulose and / or a cellulose derivative to the aforementioned granules and tableting;

[0022] wherein, the mass ratio of [cellulose and / or cellulose derivative contained as an internal additive]:[cellulose and / or cellulose derivative contained as an external additive] is within the range of 75:25 to 10:90.

[0023] [6] The manufacturing method according to [5], wherein the aforementioned cellulose and / or cellulose derivative is at least one selected from the group consisting of crystalline cellulose, microcrystalline cellulose, powdered cellulose, methyl cellulose, ethyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and low-substituted hydroxypropyl cellulose.

[0024] [7] A tablet manufactured by the manufacturing method according to [5] or [6]. Effects of the Invention

[0025] According to the present invention, by adjusting the ratio of cellulose and / or cellulose derivative contained in the internal additive and the external additive, it is possible to simultaneously reduce the abrasion degree and the incidence of top-cracking of the tablet mainly composed of magnesium oxide particles. If both the abrasion degree and the incidence of top-cracking are reduced, breakage and defect during the manufacturing process / transportation process / dispensing can be suppressed. Embodiments

[0026] The present invention will now be described with reference to specific embodiments, but the present invention is not limited to these embodiments and any variations may be added without departing from its spirit.

[0027] [summary]

[0028] As mentioned above, magnesium oxide ingots lack formability, have high abrasion rates, and are prone to cracking. While increasing hardness to reduce abrasion improves formability, air entrainment during compression increases the cracking rate. Therefore, reducing both abrasion rate and cracking rate is a challenge. Patent Document 2 conducted various studies by adding two disintegrants and two binders (crystalline cellulose) before and after granulation, but it was not found that adjusting the ratio of cellulose and / or cellulose derivatives in the internal and external additives could achieve both abrasion rate and cracking rate reduction.

[0029] In their in-depth research to achieve both reduced wear and reduced cracking rate, the inventors unexpectedly discovered that by not only adding cellulose and / or cellulose derivatives 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, both reduced wear and reduced cracking rate can be achieved. This invention is based on this unexpected insight of the inventors.

[0030] [Wear]

[0031] In this invention, the term "wear degree" refers to an index of the abrasiveness and brittleness of a tablet under impact, and can be measured using the method described in "Japanese Pharmacopoeia Amendment 17, Reference Information / Test Method for Tablet Wear Degree". Specifically, for a tablet quantity of approximately 6.5g, a tablet wear degree tester (Toyama Sangyo Co., Ltd., Tablet Wear Degree Tester TFT-1200) is used to apply 100 revolutions (24 to 26 revolutions / minute) of abrasion to the test tablet, and the initial mass of the tablet before abrasion and the mass of the tablet after abrasion are measured, and the result is calculated according to the following formula 1.

[0032]

[0033] The wear rate of the tablets of the present invention, when using the above-described measurement method, has an upper limit of less than 0.40%, more preferably less than 0.35%, and even more preferably less than 0.30%. On the other hand, lower wear rate is desirable, so no lower limit is specifically set.

[0034] [Top Crack]

[0035] In this invention, "top cracking" refers to the situation where the top or bottom portion of the tablet becomes a flaked section, occurring during the tablet manufacturing process due to impacts during tablet making, transportation, packaging, etc. The top cracking rate can be obtained using a cassette rotor test. Specifically, tablets are discharged from a cassette rotor (manufactured by TOSOH, for 500mg magnesium oxide tablets) positioned at a height of 2m. The number of tablets with top cracking is counted from the falling tablets. A sufficient number (e.g., 100 tablets) of test tablets are tested, and the number of tablets with top cracking is counted. The ratio can be calculated using Equation 2 below. The flooring specifications used in this case can be concrete plastering + epoxy coating material + paste application method (2mm thickness) (ABC Chamber of Commerce) chemical plywood E or equivalent products.

[0036]

[0037] When using the above-described measurement method, the upper limit of the cracking rate of the tablets of the present invention can be less than 12%, more preferably less than 11%, and even more preferably less than 10%. On the other hand, it is desirable for the cracking rate to be as low as possible, so no lower limit is specifically set.

[0038] [hardness]

[0039] In this invention, "hardness" refers to the hardness of the tablet, which can be measured using a commercially available tablet hardness tester. Specifically, it is obtained by measuring the tablet hardness in the diameter direction using a tablet hardness tester such as DC-50 (Okada Seiko Co., Ltd.). From the viewpoint of achieving the effect of this invention, wear will increase if the hardness is too low, so the lower limit is preferably 30N or higher, more preferably 40N or higher, and even more preferably 50N or higher. On the other hand, higher hardness is desirable, so no upper limit is specifically set.

[0040] [Disintegration Time]

[0041] In this invention, "disintegration time" is an indicator of the ease with which a tablet disintegrates in solution. Disintegration time can be measured according to the 17th Amendment Japanese Pharmacopoeia, General Test Method / Disintegration Test Method. Specifically, it is obtained by measuring the disintegration time of an appropriate number (e.g., 6 tablets) of test tablets in a test solution (e.g., water) using a disintegration tester (Toyama Sangyo Co., Ltd., Disintegration Tester NT-20HS). If the disintegration time is appropriate, it provides an easily ingestible tablet that disintegrates quickly in the mouth upon ingestion, which is ideal. The upper limit of an appropriate disintegration time is preferably less than 20 seconds, more preferably less than 15 seconds, and even more preferably less than 11 seconds. The lower limit is not particularly limited, but is usually more than 5 seconds or more, or more than 1 second.

[0042] [Cellulose and / or cellulose derivatives]

[0043] In this invention, "cellulose" refers to [β-glucose molecules] through [glycosidic bond] linear [Polymerization] refers to linear polymers represented by (C6H10O5)n, such as crystalline cellulose, microcrystalline cellulose, and powdered cellulose. The term "cellulose derivative" refers to cellulose molecules in which hydroxyl groups are introduced with different substituents via ether or ester bonds, such as methylcellulose, ethylcellulose, carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and low-substituted hydroxypropylcellulose. In this invention, "cellulose and / or cellulose derivatives" refers to at least one selected from the above-mentioned "cellulose" and "cellulose derivatives". Low-substituted hydroxypropylcellulose refers to cellulose with a very small amount of hydroxypropoxy group incorporated into the glucose ring, i.e., cellulose with a molar substitution degree of 0.2 to 0.4 after low-degree O-(2-hydroxypropyl)ation. Such cellulose derivatives can be in the form of powder, granules, microparticles, etc.

[0044] Cellulose and / or cellulose derivatives may be synthesized or commercially available products may be used. Commercially available products may include various grades of CEOLUS (registered trademark) from companies such as Asahi Kasei Corporation, such as CEOLUS (registered trademark) PH-101, UF-711, PH-102, PH-200, PH-301, PH-302, PH-20JP, UF-702, KG-802, and KG-1000 crystalline cellulose.

[0045] [Magnesium oxide particles]

[0046] The magnesium oxide particles used in this invention are particles of magnesium oxide (MgO). 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 measured by laser diffraction, at 600 to 1000 °C. The magnesium oxide particles can be synthesized or commercially available products can be used. Examples of suitable products include heavy-weight magnesium oxide manufactured by Kyowa Chemical Industry Co., Ltd., powdered magnesium oxide manufactured by Shinjima Chemical Industry Co., Ltd., and lightweight and heavy-weight magnesium oxide manufactured by Tomita Pharmaceutical Co., Ltd., as well as magnesium oxide from the Japanese Pharmacopoeia.

[0047] The magnesium oxide particles used in this invention can be either powder or granules. Granular particles have an excellent effect on preventing wear on the ingot making machine and can produce ingots with high content and excellent shape stability.

[0048] The magnesium oxide particles used in this invention are not limited, but sometimes it is preferable to have a predetermined particle size. For example, the upper limit of the average particle size of magnesium oxide particles measured by laser diffraction scattering is typically 40 μm or less, or 20 μm or less, or 10 μm or less. By setting the average particle size of magnesium oxide particles below the aforementioned upper limit, the suspended particle size during tablet disintegration is reduced, resulting in tablets with low roughness in the oral cavity. On the other hand, while there is no limitation on the lower limit of the average particle size, from the perspective of manufacturing limitations and cost-effectiveness, it is typically 0.25 μm or more, or 0.5 μm or more, or 1 μm or more.

[0049] The measurement of the average particle size of the magnesium oxide particles of the present invention and the magnesium hydroxide particles used as raw materials, by means of laser diffraction scattering, can be achieved by using a commonly used machine such as a particle size distribution measuring instrument (Micro Track Bell MT3300EX2).

[0050] When the bulk density of the magnesium oxide particles used in this invention is too high, it can cause a decrease in hardness; therefore, its upper limit can be 0.8 g / mL or below 0.7 g / mL. On the other hand, when the bulk density is too low, it can cause cracking and delamination; its lower limit can be above 0.1 g / mL or above 0.2 g / mL. The bulk density can be measured, for example, using a 100 mL stainless steel cup (measured mass value (g) / 100 (mL)).

[0051] When the settling angle of the magnesium oxide particles used in this invention is too large, it can lead to uneven ingot quality during ingot making due to poor flowability. Therefore, its upper limit can be below 50° or 48°. On the other hand, a smaller settling angle is desirable, so no lower limit is specifically set. The settling angle can be measured, for example, using the MT-1 multi-functional tester manufactured by Seishin Corporation.

[0052] [Tablets]

[0053] One aspect of the present invention relates to an ingot containing magnesium oxide as an active ingredient. The ingot comprises granules containing magnesium oxide particles and internal additives, as well as external additives, and contains at least cellulose and / or cellulose derivatives as internal and external additives; wherein 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 a certain range.

[0054] From the viewpoint of achieving the effects of the present invention, magnesium oxide particles are preferably included in the particles together with internal additives. If the content of magnesium oxide particles is too high, insufficient formability may occur; therefore, relative to the overall ingot, it can be, for example, 90% by mass or less, or 88% by mass or less. On the other hand, if it is too low, a corresponding amount of additives with high compressibility and high plasticity can be added, thus obtaining an ingot with high formability, but the cost per ingot increases. Therefore, relative to the overall ingot, it is preferably, for example, 80% by mass or more, or 85% by mass or more.

[0055] The mass ratio of [cellulose and / or cellulose derivatives contained as internal additives] to [cellulose and / or cellulose derivatives contained as external additives] in the tablets of the present invention is within a certain range. Increasing the proportion contained as external additives can be expected to improve hardness and reduce abrasion, but excessive increases can lead to increased top cracking and reduced tube penetration. Therefore, the mass ratio of external additives, when the total mass of cellulose and / or cellulose derivatives contained in the tablets is 100, preferably has an upper limit of 90 or less, for example, 88 or less, 85 or less, 80 or less, or 75 or less, and a lower limit of more than 20, for example, 21 or more, 22 or more, 23 or more, 24 or more, or 25 or more. On the other hand, if the proportion of internal additives is too low, insufficient compaction will result in many fine particles that easily trap air. This air cannot be completely expelled during subsequent billet making, potentially leading to billet cracking. Therefore, a certain amount must be adjusted. Conversely, if the proportion of internal additives is too high, compacted particles can be obtained through granulation. Further compaction during billet making makes the particles less prone to breakage, leading to reduced formability and increased wear. Therefore, the mass ratio of internal additives, when the total mass of cellulose and / or cellulose derivatives in the billet is 100%, is preferably below 80 (e.g., 79, 78, 77, 76, 75) and above 10 (e.g., 12, 15, 20, 25).

[0056] Furthermore, if the content of cellulose and / or cellulose derivatives is too high relative to the total amount of tablets, the cost per tablet increases. Therefore, the content can be 20% by mass or less, or 15% by mass or less, or 12% by mass or less relative to the total amount of tablets. On the other hand, if the content is too low, the effects of the present invention cannot be achieved. Therefore, the content can be 5% by mass or more, or 7% by mass or more, or 9% by mass or more relative to the total amount of tablets.

[0057] In the tablets of the present invention, the cellulose and / or cellulose derivatives as 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.

[0058] In this invention, the term "internal additive" refers to an additive containing one or more substances, added to the active ingredient and mixed with it before the granulation step in the manufacture of the tablets. Besides cellulose and / or cellulose derivatives as defined above, other additives may also be added as internal additives. In particular, to adjust for the preferred disintegration time as described above, it is preferable to add, in addition to the cellulose and / or cellulose derivatives contained in the internal and external additives at the specific ratio defined above, disintegrants such as croscarmellose sodium, corn starch, calcium carboxymethyl cellulose, croscarmellose, and sodium carboxystarch as internal additives. The disintegrant can be synthesized or commercially available products can be used. Commercially available products may include KICCOLATE (registered trademark) ND-2HS, etc., manufactured by Nichirin Chemical Industry Co., Ltd. Since some tablets are difficult to form, the upper limit relative to the total tablet content may be, for example, 5% by mass or less, or 3.5% by mass or less. On the other hand, if too little is used, disintegration may be difficult; therefore, the lower limit relative to the total tablet content may be, for example, 1% by mass or more, or 2% by mass or more.

[0059] In this invention, the term "external additive" refers to an additive containing one or more substances that is added to the granules produced after the granulation step during the manufacture of the tablets and is used to form tablets together with the granules. Besides the internal additives and cellulose and / or cellulose derivatives contained in the external additives in the specific ratios defined above, other additives may also be added. Particularly from the viewpoint of the effects of this invention, the addition of a lubricant is preferred. Lubricants include, for example, stearic acid and its salts (Mg, Ca salts), preferably stearates, and more preferably magnesium stearate and calcium stearate. The lubricant can be synthesized or commercially available products can be used. Too much lubricant can lead to delayed disintegration; therefore, its upper limit relative to the total tablet amount may be, for example, less than 2% by mass, less than 1.5% by mass, or less than 1.0% by mass. On the other hand, too little lubricant can cause adhesion to the pestle and mortar; therefore, the lower limit of the amount of lubricant added to the total tablet amount may be, for example, more than 0.2% by mass, more than 0.5% by mass, or more than 0.9% by mass.

[0060] The shape of the tablets of the present invention is not particularly limited in consideration of achieving the effects of the present invention and ease of administration as an oral dosage form. For example, the upper limit of the diameter may be 14 mm or less, or 10 mm or less, and the lower limit may be 5 mm or more, or 6 mm or more. Similarly, the upper limit of the thickness is not particularly limited, and may be 8 mm or less, or 7 mm or less, and the lower limit may be 3 mm or more, or 4 mm or more. Moreover, for example, for the purpose of further suppressing top cracking, the shape shown in Patent Document 2 may be used.

[0061] The quality of the tablets of the present invention is not particularly limited if it is within the range of oral tablets that typically use magnesium oxide as the active ingredient. For example, the upper limit for each tablet may be less than 1000 mg, or less than 800 mg, or less than 600 mg, and the lower limit may be more than 10 mg, or more than 50 mg, or more than 100 mg.

[0062] The tablets of this invention are intended as a medicine for human or animal use, administered orally for antacid, laxative, and prevention of urinary tract calcium oxalate stones. They can also be used as a magnesium supplement or to treat hypomagnesemia in humans or animals. The dosage depends on the intended use, purpose, or medical condition. For example, when used as an antacid, the usual adult dose is 0.5 to 1.0 g per day, divided into several oral doses, in magnesium oxide form. When used as a laxative, the usual adult dose is 2 g per day, divided into three oral doses before or after meals, or once at bedtime, in magnesium oxide form. When used to prevent urinary tract calcium oxalate stones, the usual adult dose is 0.2 to 0.6 g per day, taken orally with plenty of water, in magnesium oxide form. For other uses, intake is generally within the tolerable upper limit of magnesium. For example, if obtained from sources other than regular food, the equivalent magnesium oxide intake for a healthy adult is 350 mg per day, and for a healthy child it is 5 mg per kilogram of body weight per day. This is the dietary intake standard set for the United States (Institute of Medicine (IOM) Food Grade Nutrition Committee, "Dietary Reference Intakes: Calcium, Phosphorus, Magnesium, Vitamin D and Fluoride", Washington, D.C., National Academy of Sciences Press, 1997).

[0063] The medicine of the present invention is approved for use in Japan as an antacid, laxative, and preventive of urinary tract calcium oxalate stones, utilizing the desired active ingredient. Provided that it does not substantially impair the desired effects for each use, or reduce wear and tear and the incidence of rupture, the internal and / or external additives may further contain one or more other arbitrary ingredients. Such other ingredients are not particularly limited, and may include various pharmaceutical excipients permissible in various pharmaceuticals, such as colorants, flavorings, etc. Any one of these ingredients may be used alone, or in any combination and ratio, using any two or more together.

[0064] [Method for manufacturing tablets]

[0065] Another aspect of the present invention relates to a method for manufacturing an ingot with magnesium oxide as the active ingredient, the method comprising:

[0066] Mixed magnesium oxide particles and internal additives containing cellulose and / or cellulose derivatives;

[0067] The aforementioned mixture is granulated to form particles; and

[0068] External additives containing cellulose and / or cellulose derivatives are added to the aforementioned granules, and then the mixture is granulated.

[0069] The mass ratio of [cellulose and / or cellulose derivatives contained as internal additives] to [cellulose and / or cellulose derivatives contained as external additives] is in the range of 75:25 to 10:90.

[0070] First, magnesium oxide particles and internal additives containing cellulose and / or cellulose derivatives and any one or more other components are mixed according to a known method.

[0071] The resulting mixture is then granulated to form granules. Considering the composition of the tablets of the present invention, granulation is preferably performed by dry granulation. For example, granules can be produced by using a commercially available dry granulator (Freund Industries, Ltd., Dry Granulator RC-156) under normal granulation conditions.

[0072] In this process, external additives comprising cellulose and / or cellulose derivatives and any one or more other components are added to the granules, and then the mixture is pounded. The external additives can be added using any method that allows them to be applied around the granules. The pounding pressure, taking the stamping pressure of each granule as an example, can have an upper limit of less than 20 kN, or less than 18 kN, or less than 16 kN, and a lower limit of more than 2 kN, or more than 3 kN, or more than 4 kN. The shape of the pestle, in addition to the standard radius (R-face), can also be a two-section radius (R-face), a sugar-coated radius (R-face), a corner radius (R-face), a corner plane, a rounded corner plane, etc.

[0073] The foregoing has described various aspects of the present invention, but the present invention is not limited to these aspects. Those skilled in the art will readily recognize other arbitrary aspects of the present invention from the above detailed description and the embodiments described below.

[0074] [Example]

[0075] The present invention will now be described in more detail with reference to the embodiments, but these embodiments are merely examples for ease of explanation and the present invention is not limited to these embodiments in any way.

[0076] [formula]

[0077] Use the formula shown in the table below to manufacture the tablets.

[0078]

[0079]

[0080] The details of the raw materials used in the above embodiments and comparative examples are as follows.

[0081] Magnesium oxide: Magnesium oxide (heavyweight grade) manufactured by Kyowa Chemical Industry Co., Ltd. (Japanese Pharmacopoeia)

[0082] Crystalline cellulose: Asahi Kasei Corporation's CEOLUS PH-101 (Examples 1-4, Comparative Examples 1-3) and CEOLUS F-711 (Examples 5-8, Comparative Examples 4-6)

[0083] Crosslinked carboxymethyl cellulose sodium: KICCOLATE ND-2HS manufactured by Nichirin Chemical Industry Co., Ltd.

[0084] Calcium stearate: Vegetable-based calcium stearate produced by Taiping Chemical Industry (Stock) Co., Ltd.

[0085] The physical properties of the magnesium oxide used in this embodiment were measured as follows.

[0086] • Average particle size: 7.691 μm (measured using laser diffraction scattering method with Micro Track Bell MT3300 EX2)

[0087] • Bulk density: 0.249 g / mL (measured using a 100 mL stainless steel cup (actual mass value (g) / 100 (mL)))

[0088] • Angle of rest: 41.7° (measured using a Seishin MT-1 multi-function tester)

[0089] [Manufacturing Method]

[0090] According to the above formula, each raw material was weighed using an electronic balance (Mettler Toledo, 5kg weighing PB5001-S / FACT) in quantities of 15,000 ingots.

[0091] 1. Mixing

[0092] Weigh out the magnesium oxide and internal additives and place them into a polyethylene bag (1100mm×600mm). Shake the bag left and right 30 times to mix. After mixing, measure the bulk density using a 100mL stainless steel cup (actual mass value (g) / 100 (mL)).

[0093] 2. Granulation

[0094] The resulting mixture was granulated using a dry granulator (Freund Industrial Co., Ltd., RC-156 dry granulator) under the following granulation conditions to produce granules.

[0095]

[0096] After granulation, the following evaluation items are evaluated.

[0097] • Flake rate: The mass of the processed product (A) after 1 minute of granulation and the product (B) obtained by sieving the processed product (A) through a 100μm sieve are measured and calculated according to the following formula 3.

[0098]

[0099] • Bulk density: Measured using a 100mL stainless steel cup (actual mass value (g) / 100 (mL)).

[0100] • Particle size distribution: Measured using a particle size distribution measuring instrument (Seishin Corporation, LMS-2000e, laser diffraction scattering method).

[0101] 3. Addition of external additives

[0102] Place the above-mentioned granules and weighed external additives into a polyethylene bag (1100mm×600mm), and shake the bag left and right 30 times to mix them.

[0103] After mixing, evaluate the following evaluation items.

[0104] • Bulk density: Measured using a 100mL stainless steel cup (actual mass value (g) / 100 (mL)).

[0105] • Angle of rest: Measured using the MT-1 multi-functional tester manufactured by Seishin Enterprises.

[0106] 4. Making ingots

[0107] The mixed granules and external additives are granulated using a tablet granulator (VIRG, a small high-speed rotary tablet granulator manufactured by Kikusui Seisakusho Co., Ltd.) under the following conditions.

[0108]

[0109] After the ingot is produced, the following evaluation items will be evaluated.

[0110] • Quality: (Number of test spindles: 10 spindles)

[0111] • Thickness: (Number of test spindles: 5 spindles), using a thickness gauge manufactured by Peacock.

[0112] • Hardness: (Number of test spindles: 10 spindles), using Okada Seiko DC-50 benchtop hardness tester.

[0113] • Wear test: The wear test was conducted using the Toyama Sangyo Co., Ltd. TFT-1200 tablet wear tester at 100 revolutions (number of tablets tested: the closest tablet to 6.5g).

[0114] • Disintegration Time: (Number of tablets tested: 6 tablets) According to the 17th Amendment to the Japanese Pharmacopoeia, General Test Method / Disintegration Test Method. The disintegration time of the water-based test tablets was measured using a disintegration tester (NT-20HS, Toyama Sangyo Co., Ltd.).

[0115] • Stamping status: Visually check the stamping pressure / whether there is any obstruction to the stamping process.

[0116] • Suspended particle size D50 (μm): (Number of test tablets: 1 tablet) The suspended particle size of the test tablets was measured in water using a Seishin LMS-2000e laser diffraction particle size distribution meter.

[0117] • Tube Penetration Test (5Fr): Remove the plunger from the syringe (NIPRO Corporation DS20mL yellow enteral nutrition delivery syringe), place one tablet into the outer tube, replace the plunger, draw 20mL of 55°C warm water, cover the front end of the tube, and let stand for 5 minutes. After 5 minutes, manually rotate the aforementioned syringe 90 degrees 15 times, then connect the nutrition delivery tubing (ATOM Nutrition Catheter T; 5Fr thickness, 120cm length), and inject the internal suspension and 20mL of ion-exchange water for cleaning. Check for tubing blockage. This test is performed 3 times. A non-blocked tubing is considered suitable, while a blocked tubing is considered unsuitable.

[0118] • Calculation of compression ratio in the ingot-making process: Filling depth (a) and main pressure compression thickness (b) are calculated using the following formula 4.

[0119]

[0120] [result]

[0121] The measurement results of the bulk density of the resulting mixture are shown in the table below.

[0122]

[0123]

[0124] The bulk density of the mixture was in the range of 0.20 to 0.25 (g / mL) in both the examples and comparative examples, with no particularly large differences observed.

[0125] The measurement results of each item of the granulated granules (granulated products) are shown in the following table.

[0126]

[0127]

[0128] Regarding granulation properties, the higher the crystalline cellulose content of the internal additive, the better the processing capacity and flake yield, and the higher the bulk density of the granulated product. Therefore, it can be deduced that the internal additive containing a certain degree of crystalline cellulose is preferable.

[0129] The measurement results after the addition of external additives are shown in the table below.

[0130]

[0131]

[0132] Comparative Examples 1 and 4, which do not contain crystalline cellulose in the external additive, compared with Comparative Examples 3 and 6, which contain 100% crystalline cellulose in the external additive, showed an increase of 150 μm Pass in Comparative Examples 3 and 6. The stationary angle was in the range of 40° to 44°, and no significant difference was observed. Therefore, it was considered that there was no difference in flowability.

[0133] The measurement results of each item after the ingot is shown in the following table.

[0134]

[0135]

[0136] Compared to the crystalline cellulose contained as an internal additive, a higher mass ratio of crystalline cellulose contained as an external additive (Comparative Example 1 → Comparative Example 3, Comparative Example 4 → Comparative Example 6) resulted in increased hardness and decreased wear, but an increased incidence of top cracking and agglomeration of suspended particles were observed. A higher mass ratio of crystalline cellulose contained as an external additive compared to the crystalline cellulose contained as an internal additive resulted in a higher proportion of uncompressed crystalline cellulose contributing to tablet formation, leading to an increased compression rate during tablet forming. Therefore, the increased hardness was attributed to the decreased wear. On the other hand, insufficient compaction during granulation prevented the complete formation of sheet-like microparticles, easily trapping air. Influenced by the subsequently added uncompressed crystalline cellulose, the overall bulk density of the tablet particles decreased, resulting in insufficient degassing and air trapping during compression, which was considered the cause of the increased top cracking rate. Furthermore, in Comparative Example 3, where the entire amount of crystalline cellulose was contained as an external additive, blockage was observed in the pipe penetration test. Therefore, in order to reduce wear, it is considered that the mass ratio of crystalline cellulose contained as an external additive is preferably about 25 or more, and appropriately about 90 or less, when the mass of cellulose and / or cellulose derivatives contained in the whole tablet is 100.

[0137] The thickness of the tablets after disintegration was within the range of 5.3 to 5.5 mm, with no significant difference. The disintegration time was within the appropriate range in both the examples and comparative examples.

[0138] The results above show that, in particular, by adjusting the mass ratio of [cellulose and / or cellulose derivatives contained as internal additives] to [cellulose and / or cellulose derivatives contained as external additives] to a range of 75:25 to 10:90, for example, a range of 75:25 to 20:80, and especially a range of 75:25 to 25:75, magnesium oxide ingots with reduced abrasion and cracking rates can be manufactured efficiently. Furthermore, with such a ratio, the physical properties required for ingot manufacturing, such as formability, granulation, doping properties, flowability, and channel penetration, as well as the physical properties required for magnesium oxide ingots, such as disintegration, can be ensured, achieving both reduced abrasion and cracking rates.

[0139] [Industrial Applicability]

[0140] This invention has extremely high applicability in industries that require tablets with magnesium oxide particles as the main component to have both reduced wear and reduced cracking rate, especially in the fields of pharmaceutical manufacturing and distribution.

Claims

1. A tablet, wherein magnesium oxide is the active ingredient; the tablet comprises granules containing magnesium oxide particles and internal additives, and external additives, and contains at least cellulose and / or cellulose derivatives as both internal and external additives; wherein, The mass ratio of [cellulose and / or cellulose derivatives contained as internal additives] to [cellulose and / or cellulose derivatives contained as external additives] is in the range of 75:25 to 10:90, wherein the aforementioned cellulose and / or cellulose derivatives are selected from at least one of the group consisting of crystalline cellulose, methylcellulose, ethylcellulose, carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and low-substituted hydroxypropylcellulose.

2. The tablets as described in claim 1, wherein, The aforementioned cellulose content relative to the total amount of the tablets is 5 to 20% by mass.

3. The tablets as described in claim 1 or 2, wherein, The content of magnesium oxide particles relative to the total ingot is 80 to 90% by mass.

4. The tablets as described in claim 1 or 2, wherein, The aforementioned internal additives further contain a disintegrant, which contains at least one of the following in a weight percentage of 1 to 3.5% relative to the total amount of the tablets: a disintegrant selected from the group consisting of sodium croscarmellose, corn starch, calcium carboxymethyl cellulose, croscarmellose and sodium carboxy starch.

5. A method for manufacturing an tablet, comprising manufacturing a tablet with magnesium oxide as the active ingredient, the method comprising: Mixed magnesium oxide particles and internal additives containing cellulose and / or cellulose derivatives; The aforementioned mixture is granulated to form particles; The aforementioned granules are then mixed with an external additive containing cellulose and / or cellulose derivatives, and then formed into pellets; wherein the mass ratio of [cellulose and / or cellulose derivatives contained as internal additives] to [cellulose and / or cellulose derivatives contained as external additives] is in the range of 75:25 to 10:90, wherein the cellulose and / or cellulose derivatives are selected from at least one of the group consisting of crystalline cellulose, methylcellulose, ethylcellulose, carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and low-substituted hydroxypropylcellulose.

6. The manufacturing method as described in claim 5, wherein, The aforementioned particles are formed by dry granulation of the aforementioned mixture.

7. The manufacturing method as described in claim 5 or 6, wherein, The bulk density of the aforementioned magnesium oxide particles was measured using a 100 mL stainless steel cup, and the aforementioned bulk density (measured mass value (g) / 100 (mL)) was above 0.1 g / mL and below 0.8 g / mL.

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