JP2017186271A - Compact hydrotalcite tablet with rapid oral disintegration properties - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a compact tablet which rapidly disintegrates in the oral cavity with hydrotalcite particles as an active ingredient.SOLUTION: A compact tablet with rapid oral disintegration properties comprises hydrotalcite with an apparent specific volume of 1.2 to 2.0 mL as a raw material, with the compact tablet having a diameter of not more than 10 mm and a thickness of not more than 6 mm, and the weight of the hydrotalcite being 88 to 100 wt.% relative to the total weight of the tablet.SELECTED DRAWING: None

Description

  The present invention relates to an orally rapidly disintegrating small tablet containing hydrotalcite as an active ingredient. More specifically, the present invention has an excellent ulcer treatment effect and has a disintegration time of 30 seconds or less in the oral cavity. A small tablet having a thickness of 10 mm or less and a thickness of 6 mm or less is provided.

2. Description of the Related Art In recent years, in the treatment of illnesses, formulation development with pharmacological ingenuity has been actively conducted for the purpose of improving the quality of life of patients. For example, it has been practiced to provide a preparation that is reduced in size and easy to take without lowering its medicinal effect. This is because the ease of swallowing, such as the dosage form and the size of the drug product, is an important factor for ensuring that the patient takes the medicine as prescribed. Moreover, if the drug is not given as prescribed, it may lead to a reduction in therapeutic effect and an increased risk of resistant bacteria. Seems to be an effective means.
In addition, development of solid tablets that rapidly disintegrate and dissolve in the oral cavity is underway. Orally disintegrating tablets are easy to take because they disintegrate instantaneously even with a small amount of saliva in the oral cavity, and ordinary tablets are optimal preparations for patients, elderly people or children who have difficulty swallowing drugs. Moreover, since it can be taken without water, it has the advantage that the place and time for taking are not limited.
Under such circumstances, the development of technology capable of reducing the size and disintegrating of tablets independently or simultaneously has been made.

The following can be mentioned as an example of such a pharmaceutical device.
Examples of improving tablet disintegration include: low-substituted hydroxypropylcellulose as a disintegrating agent, crystalline cellulose as an excipient, lubricant in a tablet composition that disintegrates rapidly in saliva (a small amount of water) in the oral cavity. Is a rapidly disintegrating tablet characterized in that the mixing ratio of low-substituted propylcellulose and crystalline cellulose is from 1: 2.3 to 1: 9, and disintegrates in a disintegration test using a small petri dish Examples include a tablet (Patent Document 1) that can provide a tablet that has a time of 70 seconds or less and rapidly disintegrates in a few tens of seconds by saliva (a small amount of water) in the oral cavity.

  As an example of downsizing of tablets, for the purpose of providing a preparation for oral administration of sarpogrelate hydrochloride that is easy to take by downsizing, the content of sarpogrelate hydrochloride per preparation is set to 40% or more as an additive that promotes disintegration , Cellulose derivatives, chemically modified starches or chemically modified cellulose derivatives, or crospovidone show good manufacturability with reduced tableting troubles, etc. There is a miniaturized sarpogrelate hydrochloride oral administration preparation (Patent Document 2) which has a high elution rate of sarpogrelate hydrochloride and exhibits good storage stability.

As an example of simultaneously achieving miniaturization and improvement of disintegration of tablets, a miniaturized oral cavity containing L-carbocysteine that can be produced with high productivity in a general production facility, has high hardness, and has a short disintegration time. For the purpose of providing a disintegrating tablet, it contains (A), (B) and (C), the content of (A) is 70% by mass or more in the tablet, and the content of (C) is in the tablet An orally disintegrating tablet is 5% by mass or more and 30% by mass or less.
(A) L-carbocysteine or a salt thereof, (B) a water-soluble binder having a viscosity of 10 mPa · s or less at 25 ° C. in a 2 mass% aqueous solution, (C) a disintegrant (Patent Document 3), In order to produce an orally disintegrating tablet containing L-carbocysteine with high productivity in a general production facility, it contains carbocysteine, isomalt and a disintegrant, and the carbocysteine content is 75% by mass in the tablet. An orally disintegrating tablet (Patent Document 4) is mentioned above.

As described above, the same improvement has been attempted with respect to tablets related to hydrotalcite, while miniaturization of tablets and improvement of disintegration in the oral cavity are being attempted.
Hydrotalcite particles are blended in general analgesics and antacids by utilizing excellent properties such as strong neutralizing power against gastric acid, pH 3-5 retention, and anti-pepsin action. However, since the hydrotalcite simple tablets are large in size and high in hardness, they are difficult to take for children and elderly patients who have difficulty swallowing. Therefore, an attempt has been made to provide an intraoral rapidly disintegrating small tablet which is an oral preparation that disintegrates in the oral cavity immediately after taking.
For example, the total disintegrating spherical particle composition contains 10 to 90% by weight of inorganic particles and 1 to 50% by weight of a disintegrant, has a sphericity of 0.8 to 1, and a particle strength of 100 to 2000 g / mm 2. The average particle size is 10 to 500 μm, the static specific volume is 1.5 to 5.0 mL / g, the specific surface area is 0.15 to 500 m ² / g, and the disintegration time when in contact with water is 10 minutes or less. The main component is a collapsible spherical particle composition (Patent Document 5) using hydrotalcite as inorganic particles, or hydrotalcite particles having a low mass and capable of obtaining small tablets when compressed. A tablet having a spherical shape under microscope observation and having synthetic hydrotalcite particles represented by the following formula (1) as a main component for the purpose of providing a tablet.
Mg _x Al ₂ (OH) _{2 (xy + 3)} (CO ₃ ) _y · mH ₂ O (1)
(Wherein x, y, and m are values satisfying 5.2 ≦ x ≦ 6.3, 1 ≦ y ≦ 2.0, and 3 ≦ m ≦ 8) (Patent Document 6).

Patent Literature 1: Japanese Patent Laid-Open No. 9-71523 Patent Literature 2: Japanese Patent Laid-Open No. 2007-56011 Patent Literature 3: Japanese Patent Laid-Open No. 2015-182991 Patent Literature 4: Japanese Patent Laid-Open No. 2014-70034 Patent Literature 5: Japanese Patent Laid-Open No. 2004-70034 JP 2011-157348 A Patent Document 6: JP 2013-129595 A

However, studies on the strength of solid preparations and disintegration properties in the oral cavity are not sufficient. An object of the present invention is to provide a hydrotalcite orally rapidly disintegrating small tablet that rapidly disintegrates in the oral cavity, has a simple manufacturing process, and has strength during manufacturing and storage.
Miniaturizing the tablet means reducing the additive. In particular, in order to develop a tablet with a high content of active ingredients while downsizing, there are restrictions on the amount and type of additives that are important in molding a tablet. Problems such as a decrease in formulation function such as disintegration property and dissolution property of the obtained tablets are likely to occur, and formulation is often difficult. The present invention solves these problems, and an object of the present invention is to provide a small tablet comprising a composition of hydrotalcite particles alone or an excipient.
That is, an object of the present invention is to provide a novel small tablet that has a hydrotalcite simple substance as an active ingredient, has a small tablet size, is excellent in disintegration, and has good dosage. The purpose is to provide tablets that are easy to take for children and elderly patients who have difficulty swallowing.

The gist of the present invention is the following intraorally rapidly disintegrating small tablets (1) to (12).
(1) A small tablet having a diameter of 10 mm or less and a thickness of 6 mm or less using hydrotalcite having an apparent specific volume of 1.2 to 2.0 mL as a raw material, and having a hydrotalcite weight relative to the total weight of the tablet. An orally rapidly disintegrating mini-tablet comprising 88 to 100% by weight.
(2) The intraoral rapidly disintegrating small tablet according to (1) above, wherein the hydrotalcite of the raw material has an integrated 50% particle size of 20 to 100 μm.
(3) The intraoral rapidly disintegrating small tablet according to (1) or (2) above, wherein the raw material hydrotalcite is composed of a granular material.
(4) The intraoral quick disintegrating small tablet according to any one of (1) to (3) above, wherein the raw material hydrotalcite is a spherical hydrotalcite.
(5) The hydrotalcite of the raw material has an integrated 10% particle size of 1, an integrated 50% particle size of 1.2 to 2.0, an integrated 90% particle size of 2.0 to 8.0, The intraoral rapidly disintegrating small tablet according to any one of (1) to (4) above, wherein the average particle size is 10 to 100 μm.
(6) The hydrotalcite of the raw material has an integrated 10% particle size of 10 to 70 μm, an integrated 50% particle size of 20 to 100 μm, and an integrated 90% particle size of 90 to 200 μm. ) To (5) orally fast disintegrating small tablets.
(7) Any of (1) to (6) above, wherein the hydrotalcite of the raw material has a cumulative 50% particle size and a cumulative 10% particle size of 1.5 to 1.7. Orally rapidly disintegrating small tablet according to crab.
(8) The intraoral fast disintegrating small tablet according to any one of (1) to (7), wherein the disintegration time in the oral cavity is 30 seconds or less.
(9) The material according to any one of (1) to (8) above, wherein the raw material comprises one or more pharmaceutically acceptable excipients suitable for tablet production. Orally fast disintegrating small tablets.
(10) The intraoral quick disintegrating property according to (9) above, wherein the excipient comprises one or more selected from a disintegrant, a binder, a disintegrant, a lubricant, and a glidant. Small tablets.
(11) The orally rapidly disintegrating small tablet according to (9), wherein the disintegrant comprises one or more selected from crystalline cellulose and low-substituted hydroxypropylcellulose.
(12) The intraoral rapidly disintegrating small tablet according to (9) above, wherein the lubricant comprises magnesium stearate.

INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide a hydrotalcite orally rapidly disintegrating small tablet that rapidly disintegrates in the oral cavity, has a simple manufacturing process, and has strength during manufacturing and storage. The present inventors have found a preparation comprising a hydrotalcite particle simple substance having a small tablet size, excellent disintegration, and good dosage as an active ingredient. That is, it is a small tablet having a tablet diameter of 10 mm or less and a thickness of 6 mm or less and a disintegration time of 30 seconds or less. Conventional hydrotalcite particles have a high bulk density and are difficult to fill, and have a large plastic deformability. When they are tableted, they are hardened into a super-cement state, so it is necessary to increase the blending ratio of the hydrophilic excipient. Therefore, it could inevitably be formed only into large tablets.
It is important that the accumulated 50% particle size is smaller than the accumulated 90% particle size of the hydrotalcite raw material. Under these conditions, a granular material having a low porosity, that is, a low apparent specific volume can be obtained. As a result, improvement in moldability is achieved, and a large amount of powder can be stored in the mold, so that a compact small tablet can be formed with a low tableting pressure. The preferred hydrotalcite used in the present invention has a particle size distribution and a particle size within a specific range, and the particle size is spherical, that is, the ratio of the minor axis / major axis is 0.7 to 1.0, and the apparent ratio The volume is 1.2 to 2.0 mL / g and the powder has good filling properties. In the apparent specific volume, since the value of the example shows a considerably small value, it can be seen that densely packed particles are formed. In addition, when looking at the particle size distribution, the accumulated 10% particle size is 1, and the accumulated 50% particle size is 1.2 to 2.0, and in the examples, 1.5 to 1.7 is low. It is characteristic. It can be seen that the hydrotalcite of the example has a major axis / minor axis close to 1 and is in a spherical state. Further improvement is achieved by using such hydrotalcite as a raw material. Although the formed tablet has a small thickness and a high density, the tablet hardness is low and the disintegration is good.

  As a result of investigating orally disintegrating tablets that can be produced industrially with general equipment without requiring special formulation technology, it is possible to make tablets with the active ingredient hydrotalcite alone. However, as the excipient, one or more selected from binders, disintegrants, lubricants, glidants, or other medicinal ingredients may be used. It was found that by combining a disintegrant, an orally disintegrating tablet having a hardness that is practically satisfactory even with a low dry compression pressure and having no problems in rapid disintegration and manufacturability was obtained. Spherical hydrotalcite particles are heavy, and compaction during compression molding is moderate and can maintain an appropriate hardness. The ratio of the excipient can be reduced, and as a result, the downsizing of the tablet can be smoothly achieved.

MgO / Al ₂ O ₃ molar ratio, liquidity (pH), antacid power, BET specific surface area, apparent specific volume, particle size distribution, X-ray diffraction diagram of hydrotalcite of Examples 1 to 4 and Comparative Example 1, And an optical micrograph of the fluid.

The present invention relates to a small tablet comprising a pharmacologically effective amount of hydrotalcite having a diameter of 10 mm or less and a thickness of 6 mm or less, wherein the active part weight is 88 to 100% by weight relative to the total weight of the tablet. The present invention relates to a small tablet having improved tablet size and good disintegration in the oral cavity. In addition, the present invention has been able to further improve the miniaturization and disintegration of tablets by specifying the particle size of the hydrotalcite granules that are the raw materials of the tablets.
Below, the small tablet of this invention is demonstrated in detail.

[Tablet size]
The small tablet of the present invention has a diameter of 10 mm or less and a thickness of 6 mm or less, and its shape is not particularly limited, but is preferably a tablet. This small tablet preferably has a tablet hardness in the range of 40 to 250 N, and can be swallowed by being disintegrated within 30 seconds in the oral cavity.

[Hydrotalcite]
Hydrotalcite is one of various compounds represented by the structural formula [M ²⁺ _1-x M ³⁺ _x (OH) ₂ ] [A ⁿ⁻ _{x / n} · mH ₂ O] Excellent performance as an antacid to prevent mucosal destruction. For example, the gastric juice is excellent in the buffering effect of adjusting the pH at a pH of about 4 for a long time, and almost 70% of patients are recovered in a case where a duodenal ulcer is prescribed a Mg—Al—CO ₃ hydrotalcite compound. It is an excellent antacid as reported to have no side effects seen with magnesium hydroxide or aluminum hydroxide. The X-ray analysis pattern confirms the hydrotalcite.

  The preferred hydrotalcite used in the present invention has a particle size distribution and a particle size within a specific range, and the particle size is spherical, that is, the ratio of the minor axis / major axis is 0.7 to 1.0, and the apparent ratio The volume is 1.2 to 2.0 mL / g and the powder has good filling properties.

The spherical hydrotalcite particles used as the drug substance (raw material) in the present invention have a molar ratio of MgO / A1 ₂ 0 ₃ of 6.0 soil 1.0, preferably 5.8 ± 0.5. Is because of the reason. The average secondary particle diameter is 10 to 100 μm, preferably 15 to 70 μm, and more preferably 20 to 50 μm. Further, the antacid power is 240 mL or more, preferably 260 mL or more.

[Particle size and shape of hydrotalcite granules]
The hydrotalcite granules used as a raw material for producing the small tablet of the present invention have an integrated 10% particle size of 1, and an integrated 50% particle size of 1.2 to 2.0, preferably 1.4 to 1. .8, 90% cumulative particle size is 2.0 to 8.0, preferably 2.2 to 8.0.
The particle size distribution of hydrotalcite granules is an important condition for making tablets that are small and have good disintegration. In particular, it is important that the accumulated 50% particle size is lower than the accumulated 10% particle size and the accumulated 90% particle size. Under these conditions, a granular material having a low porosity, that is, an apparent specific volume can be obtained. Then, since a large amount of powder can be stored in the mold, a dense small tablet can be formed with a low tableting pressure. It is shown in Table 1 that the formed tablet has a low tablet hardness and a good disintegrating property despite its small thickness and high density.

Moreover, it is preferable that the average particle diameter of a hydrotalcite granule is 10-100 micrometers.
Furthermore, the particle size range in each section of the hydrotalcite particles is as follows: hydrotalcite particles having an integrated 10% particle size of 10 to 70 μm, an integrated 50% particle size of 20 to 100 μm, and an integrated 90% particle size of 90 to 200 μm. It is preferable to use the body as a raw material.
The shape of each particle constituting the hydrotalcite granule is preferably spherical. Due to the spherical shape, it is possible to more closely pack particles having large and small particle sizes, and the apparent specific volume is lowered. The shape of each particle is preferably a sphere whose ratio of major axis to minor axis is closer to 1 than 0.8.

[Excipients, binders, disintegrants, lubricants, and glidants]
Further, in order to mold the small tablet of the present invention, one or more kinds selected roughly such as a binder, a disintegrant, a lubricant, a glidant, or other medicinal ingredients may be used as an excipient. However, it is possible to make tablets with a simple hydrotalcite.

The tablet of the present invention may contain a disintegrant. The disintegrant is a component that swells with water or a component that collapses with water. Disintegrants include lactose hydrate, anhydrous lactose, sucrose, purified sucrose, fructose, glucose, glucose hydrate, sugars such as trehalose, sugar alcohols such as mannitol, sorbitol, xylitol, erythritol, maltitol, isomalt, Examples include crospovidone, carmellose calcium, carmellose, croscarmellose sodium, crystalline cellulose, and low-substituted hydroxypropylcellulose. Crystalline cellulose, low-substituted hydroxypropyl cellulose, mannitol, and the like are preferable in that the granulated product can be rapidly disintegrated in the oral cavity.
The content of the disintegrant is preferably about 0.01% by weight or more, more preferably about 0.1% by weight or more, and still more preferably about 1% by weight or more based on the total amount of the tablet. A disintegrating agent may be used individually by 1 type, and may use 2 or more types. Moreover, about 30 weight% or less is preferable with respect to the whole quantity of a tablet, About 20 weight% or less is more preferable, About 10 weight% or less is further more preferable. If it is the said range, practically sufficient moldability and disintegration can be obtained.

The tablet of the present invention can also contain a binder. The binder has an action of binding the granulated materials to each other during compression. Examples of the binder include magnesium aluminate metasilicate, synthetic aluminum silicate, light anhydrous silicic acid, calcium silicate, crystalline cellulose, powdered cellulose, low-substituted hydroxypropylcellulose, and the like. Of these, crystalline cellulose and low-substituted hydroxypropylcellulose are preferable.
The content of the binder is preferably about 0.01% by weight or more, more preferably about 0.1% by weight or more, and still more preferably about 1% by weight or more based on the total amount of the tablet. Moreover, about 30 weight% or less is preferable with respect to the whole quantity of a tablet, About 20 weight% or less is more preferable, About 10 weight% or less is further more preferable. If it is the said range, practically sufficient moldability and disintegration can be obtained.
A binder may be used individually by 1 type and may use 2 or more types.

  Moreover, the tablet of this invention can contain a lubricant. As the lubricant, magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, sodium stearyl fumarate and the like are used, and magnesium stearate is preferable.

  Moreover, the tablet of this invention can contain a glidant. As the glidant, magnesium stearate and silicon dioxide (for example, Syloid (registered trademark), Aerosil (registered trademark)) are preferable.

In addition, the tablet of the present invention can contain an appropriate amount of additives generally used in pharmaceuticals such as a coloring agent, a corrigent, a sweetener, a fragrance, and a preservative. One additive may be used alone, or two or more additives may be used. Examples of the colorant include foods, pharmaceuticals, and cosmetics such as iron oxide (FD & Colors).
Examples of the corrigent include citric acid hydrate, tartaric acid, malic acid, ascorbic acid and the like.
Examples of the sweetening agent include aspartame, acesulfame potassium, saccharin, sodium saccharin, dipotassium glycyrrhizinate, stevia, thaumatin, sucralose and the like.
Examples of the fragrances include fennel oil, orange oil, chamomile oil, spearmint oil, cinnamon oil, clove oil, mint oil, bergamot oil, eucalyptus oil, lavender oil, lemon oil, rose oil, roman chamomile oil, menthol and the like.
Examples of preservatives include benzoic acid, sodium benzoate, benzyl benzoate, isobutyl paraoxybenzoate, isopropyl paraoxybenzoate, ethyl paraoxybenzoate, butyl paraoxybenzoate, propyl paraoxybenzoate, sodium propyl paraoxybenzoate, paraoxybenzoic acid Examples thereof include methyl and methyl sodium paraoxybenzoate.
An additive may be used individually by 1 type and may use 2 or more types.

[Manufacture of hydrotalcite]
The method for producing spherical hydrotalcite particles used in the present invention comprises reacting spherical magnesium carbonate with aluminum hydroxide gel under caustic. Washing, dehydration, drying and sieving were performed to obtain spherical hydrotalcite particles. Tablets are made using this spherical hydrotalcite as the drug substance.

[Making tablets]
For making small tablets, for example, 88-100% by weight of spherical hydrotalcite particle drug substance, 0-20% by weight of disintegrant and 0-1% by weight of lubricant are mixed and mixed Was used as a tableting sample. This sample was tableted using a TYPE-M type compressor manufactured by Maekawa Test Co., Ltd. Tableting pressure is preferably 0.26~1.5tf / cm ^2, more preferably 0.5~1.0tf / cm ^2.

[Method for measuring characteristics of small tablets and hydrotalcite granules]
Various physical properties of the hydrotalcite particles produced or used in the examples were measured by the following measuring methods.
(A) MgO / Al ₂ O ₃ molar ratio of hydrotalcite particles Measurement was performed according to the quantitative method of Japanese Pharmacopoeia Standards for Pharmaceuticals 2002: “Synthetic Hydrotalcite”, and the molar ratio was calculated.
(B) Average secondary particle size of hydrotalcite particles Determined by measurement using a MICROTRAC particle size distribution analyzer SPA type (manufactured by LEEDS & NORTHRUUP INSTRUMENTS).
700 mg of the sample powder was added to 70 ml of water, and after 3 minutes of dispersion treatment with ultrasonic waves (manufactured by NISSEI, MODEL US-300, current 300 μA), 2-4 ml of the dispersion was taken and 250 ml of degassed water In addition to the sample chamber of the particle size distribution meter containing the sample, the analyzer is operated and the suspension is circulated for 8 minutes, and then the particle size distribution is measured. The measurement is performed twice in total, and the arithmetic average value of the 50% cumulative secondary particle diameter obtained for each measurement is calculated to obtain the average secondary particle diameter of the sample.
(C) BET specific surface area of hydrotalcite particles The hydrotalcite particles were measured by the liquid nitrogen adsorption method.
(D) Liquidity Sample powder 2.0g was measured to a 100 mL beaker, 50 mL of water was added, it stirred for 3 minutes, and it measured with the pH meter.
(E) Apparent specific volume The sample was gently poured into a 20 mL measuring cup, and the surface was flattened using a glass rod. After reading the volume to the unit of 0.5 mL, the sample weight of the contents was weighed to the unit of 0.01 g and displayed in mL / g.

(D) Tablet hardness It was measured with Freund Sangyo Co., Ltd. Table Tester 8M.
(E) Tablet thickness Measured with a vernier caliper 65 manufactured by MITSUTOYO.
(F) Antacid power 0.2 g of a sample was accurately weighed and placed in a 200 mL Erlenmeyer flask, 100 mL of 0.1N HCl was added accurately, sealed, and shaken at 37 ± 2 ° C. for 1 hour, Filter. 50 mL of the filtrate was accurately weighed, and excess hydrochloric acid was titrated with 0.1N sodium hydroxide solution until the pH reached 3.5.
(G) Disintegration test 50 mL of water was put into a 100 mL beaker, one tablet was added, and the change with time was observed.
(H) Stability test Prepared in a glass bottle sealed at 40 ° C and 75% RH (accelerated test) and in open storage, and examined the tablet hardness and disintegration time after various accelerated conditions and storage periods. Measurements were made, and changes in tablet weight and tablet thickness were examined. The results are shown in Table 1.

[Manufacture of hydrotalcite 1]
(1) 591.6 g (2.4 mol) of pulverized magnesium sulfate and 267.1 g (2.52 mol) of sodium carbonate are mixed in a bag (Na ₂ CO ₃ /MgO=1.05).
(2) 5 L of tap water was charged into a 10 L stainless steel reaction vessel, heated to 70 ° C., and then the mixture obtained in (1) was charged over 120 seconds while stirring.
(The container is a 10L stainless steel tank, the heater is an electric stove made by Toshiba Corporation, the stirrer is a B-100 manufactured by Tokyo Rika Kikai Co., Ltd., and a three-blade screw with a radius of 6 cm is rotated at 120 rpm.)
(3) After the addition, the mixture was stirred for 30 seconds, and then the stirring was stopped.
(4) In a state where stirring was stopped, the mixture was cooled at 70 ° C. for 4 hours and then cooled.
(PH of reaction solution after cooling: 8.4)
(5) Suction filtration was carried out using a Buchner funnel (filter paper diameter: 21 cm), washed with 3.0 L of deionized water, and dehydrated.
(6) The dehydrated product was dried at 100 ° C. for 16 hours with a blast constant temperature dryer to obtain about 201 g of a dried product (spherical basic magnesium tannate).
(7) 1200 mL of deionized water was placed in a 3 L beaker, and 150 g (1,582 mol) of the spherical magnesium carbonate obtained above was added with stirring. (The stirrer was B-100 manufactured by Tokyo Rika Kikai Co., Ltd., and a three-blade screw with a radius of 4.5 cm was rotated at 120 rpm.)
(8) Subsequently, 50.52 g (0.264 mol) of dry aluminum hydroxide gel (brand name S-100 manufactured by Kyowa Chemical Industry Co., Ltd.) was added and mixed well (MgO / Al ₂ O ₃ = 5.99). ).
(PH of suspension: 8.87)
(9) A 720 mL of 3.3 mol / L sodium hydroxide solution was weighed into a graduated cylinder and added (NaOH / Al ₂ O ₃ = 9.0).
(10) The temperature of the reaction solution is raised to 90 ° C. (temperature increase rate: 1 ° C./min, the heater is a Toshiba cooking heater), and after stirring for 3 hours (rotation number: 196 rpm), cooling is performed. PH of the reaction solution: 12.72)
(11) The solution was suction filtered using a Buchner funnel (diameter: 12.5 cm), washed with 4.0 L of deionized water, and dehydrated.
(12) The dehydrated product was dried at 100 ° C. for 14 hours with an air-cooled constant temperature dryer to obtain about 158 g of dried product (spherical hydrotalcite particles). X-ray diffraction results showed hydrotalcite. The physical properties of the spherical hydrotalcite are shown in FIG.

[Manufacture of hydrotalcite 2]
Except for dissolving 591.6 g (2.4 mol) of magnesium sulfate in 6 L of water, raising the temperature to 60 ° C., and then adding 267.1 g (2.52 mol) of sodium carbonate over 60 seconds with stirring. Spherical hydrotalcite particles were obtained by the method 1. Analysis results by X-ray showed hydrotalcite. The physical properties of the spherical hydrotalcite are shown in FIG.

[Manufacture of hydrotalcite 3]
Examples All except that 267.1 g (2.52 mol) of sodium carbonate was dissolved in 6 L of water, heated to 60 ° C., and then 591.6 g (2.4 mol) of magnesium sulfate was added over 60 seconds with stirring. 1 to obtain spherical hydrotalcite particles. The analysis result by X 綜 showed hydrotalcite. The physical properties of the spherical hydrotalcite are shown in FIG.

[Manufacture of hydrotalcite 4]
(1) A sodium carbonate aqueous solution (500 mL) having a concentration of 1.0 mol / l and a magnesium sulfate aqueous solution (500 mL) having a concentration of 1.0 mol / L were temperature-controlled at 60 ° C.
(2) The sodium carbonate aqueous solution was placed in a 2 L baffled reaction vessel, and the magnesium sulfate aqueous solution was added at a rate of 1000 mL / min under stirring. The ratio S / V between the addition rate S (L / min) and the reaction volume V (L) at this time is 1. Further, the reaction molar ratio (Na ₂ CO ₃ / MgO) at this time is 1.0. (The container used was a 2 L baffled reaction tank, and a thermostatic bath was used for temperature control by rotating a 7 cm diameter turbine screw at 720 rpm).
(3) After the addition, the mixture was stirred for 30 seconds, and then the combination was stopped.
(4) With stirring stopped, the mixture was maintained at 60 ° C. for 2 hours and then cooled (pH of the reaction solution after cooling: 8.3).
(5) Suction was filtered using a Buchner funnel (filter paper diameter 11 cm) and washed with 0,7 L of deionized water.
(6) The operations from (1) to (5) were repeated 7 times to obtain about 173 g of solid content (spherical basic magnesium carbonate).
(7) Thereafter, the same as in Example 1.
Analysis results by X-ray showed hydrotalcite. The physical properties of the spherical hydrotalcite are shown in FIG.

MgO / Al ₂ O ₃ molar ratio, liquidity (pH), antacid power, BET specific surface area, apparent specific volume, particle size distribution, X-ray diffraction pattern of hydrotalcite of Examples 1 to 4 and Comparative Example 1 , And an optical micrograph of the fluid is shown in FIG. The hydrotalcite particles of the present invention are in the same range as the examples and comparative examples with respect to the measured values of MgO / Al ₂ O ₃ molar ratio, liquidity (pH), antacid power, and BET specific surface area, Productivity shows the same value.
However, in the apparent specific volume, the value of the example shows a considerably small value, so that it is understood that densely packed particles are formed. In addition, looking at the particle size distribution, it is characteristic that the 50% cumulative particle size and the 10% cumulative particle size show 1.5 to 1.7 lower values in the examples.
From the X-ray diffraction, it can be seen that both the examples and comparative examples are hydrotalcite, but from the optical micrographs, it can be seen that the hydrotalcite of the example has a major axis / minor axis close to 1 and is in a spherical state. On the other hand, the particles of the comparative example have an irregular shape.

[Manufacture of hydrotalcite tablets]
Tablets were prepared using the spherical hydrotalcite obtained in Examples 2 and 4 as the drug substance. As a comparative example, hydrotalcite (brand name: Alkamak) manufactured by Kyowa Chemical Industry Co., Ltd. was used. Each hydrotalcite 500 mg is used as the drug substance, and as a disintegrant, Shin-Etsu Chemical Co., Ltd. Nippon Pharmacopoeia, L-HPC “NBD-02 1”, or Asahi Kasei Chemicals Co., Ltd. Cellulose “Theolas 101”, or Freund Sangyo Co., Ltd. D-mannitol “SmartEx QD-100”, containing 0.5-1 wt% magnesium stearate as a lubricant, and shaking 30 times alternately from right and left in a polyethylene bag. Mix. This mixture was used as a tableting sample, and compression molded with a TYPE-M type static compressor manufactured by Maekawa Tester. Moreover, the tablet which consists only of hydrotalcite which does not contain said disintegrating agent and lubricant was compression-molded. Samples for compression molding were filled in 500 to 600 mg in a 10 mm diameter mortar and molded at compression pressures of 0.25, 0.5, and 1.0 tf / cm ² to form tablets. The evaluation of the tablets is shown in Table 1.

Using the spherical hydrotalcite obtained in Example 2 as the drug substance, a tablet was prepared with the following composition and subjected to a stability test. As a comparative example, hydrotalcite (brand name: Alkamak SH) manufactured by Kyowa Chemical Industry Co., Ltd. was used as the drug substance. The results showed that the tablet using the spherical hydrotalcite of the present invention as the drug substance is excellent in stability. The results are shown in Table 2.
(1 tablet)
Hydrotalcite 500mg
Disintegrant / Binder 75mg
Sweetener 10mg
Flavoring 5mg
Lubricant 0.5-1mg

Comparative Example 1

  Tablets were prepared using the hydrotalcite (brand name: Alkamak SH) manufactured by Kyowa Chemical Industry Co., Ltd. under the same conditions as in the Examples, and the characteristics were measured and shown in Table 1.

The present invention relates to an orally rapidly disintegrating small tablet having hydrotalcite having an excellent ulcer treatment effect and an oral disintegration time of 30 seconds or less as an active ingredient. It is possible to provide an optimal formulation for patients, elderly people or children who have difficulty swallowing, and can be taken without water, so that the place and time of taking are not limited.

Claims (12)

  A small tablet having a diameter of 10 mm or less and a thickness of 6 mm or less, using hydrotalcite having an apparent specific volume of 1.2 to 2.0 mL as a raw material, and having a hydrotalcite weight of 88 to 100 based on the total weight of the tablet Orally rapidly disintegrating mini-tablet comprising% by weight.   The intraoral rapidly disintegrating small tablet according to claim 1, wherein the hydrotalcite of the raw material has an integrated 50% particle size of 20 to 100 µm.   The intraoral rapidly disintegrating small tablet according to claim 1 or 2, wherein the raw hydrotalcite is made of a granular material.   The intraoral quick disintegrating small tablet according to any one of claims 1 to 3, wherein the hydrotalcite of the raw material is a spherical hydrotalcite.   The hydrotalcite of the raw material has an integrated 10% particle size of 1, an integrated 50% particle size of 1.2 to 2.0, an integrated 90% particle size of 2.0 to 8.0, and an average particle size The oral cavity rapidly disintegrating small tablet according to any one of claims 1 to 4, characterized in that is composed of 10 to 100 µm.   The hydrotalcite of the raw material has an integrated 10% particle size of 10 to 70 µm, an integrated 50% particle size of 20 to 100 µm, and an integrated 90% particle size of 90 to 200 µm. An orally rapidly disintegrating small tablet according to any one of the above. The hydrotalcite of the raw material has a cumulative 50% particle size and a cumulative 10% particle size of 1.5 to 1.7, according to any one of claims 1 to 6, Oral fast disintegrating small tablet. The intraoral quick disintegrating small tablet according to any one of claims 1 to 7, wherein the disintegration time in the oral cavity is 30 seconds or less.   9. The intraoral rapidly disintegrating property according to any one of claims 1 to 8, wherein the raw material comprises one or more pharmaceutically acceptable excipients suitable for tablet production. Small tablets.   The intraoral rapidly disintegrating small tablet according to claim 9, wherein the excipient comprises one or more selected from a disintegrant, a binder, a disintegrant, a lubricant, and a glidant. The rapidly disintegrating buccal tablet according to claim 9, wherein the disintegrant comprises one or more selected from crystalline cellulose and low-substituted hydroxypropylcellulose. 10. The intraoral rapidly disintegrating mini-tablet according to claim 9, wherein the lubricant comprises magnesium stearate.