CN115803020A - Orally disintegrating tablet containing milobarin besylate - Google Patents

Abstract

The object of the present invention is to provide an orally disintegrating tablet containing milobalin besylate having excellent stability. The embodiment of the present invention is an orally disintegrating tablet containing (A) granules containing milobarin besylate, and (B) drug-free granules containing crystalline cellulose or drug-free mixed powder containing crystalline cellulose.

Description

Orally disintegrating tablet containing milobarin besylate

technical field

The present invention relates to an orally disintegrating tablet containing milobalin besylate having excellent stability.

The orally disintegrating tablet of the present invention is an orally disintegrating tablet that disintegrates rapidly when held in the mouth or placed in water, but has sufficient hardness in normal production, transportation and use.

The invention further relates to a process for its preparation.

Background technique

Tablets, capsules, granules, powders, etc. are known as oral solid dosage forms in the field of pharmaceutical products and food. However, as a dosage form that is more likely to be taken by the elderly, children, and patients who have difficulty swallowing, it is required to develop an orally disintegrating tablet that disintegrates rapidly when held in the mouth or placed in water.

In addition to the performance of rapid disintegration in the oral cavity, like ordinary tablets, orally disintegrating tablets also need to have sufficient hardness to withstand physical impact during production, transportation and use. In addition, in consideration of drug compliance, it is also desirable to suppress unpleasant taste and irritation when contained in the mouth and provide good taste.

Patent Document 1 discloses an orally disintegrating tablet containing a drug, crystalline cellulose having a bulk density of 0.23 g/cm ³ or less, sugar alcohol, and pregelatinized starch. However, this document does not describe orally disintegrating tablets containing milobalin besylate.

Patent Document 2 discloses a medical solid composition, which contains (i) one selected from D-mannitol, lactose, cornstarch, and crystalline cellulose in addition to miloparin besylate, and (ii) ) carmellose calcium. However, this document does not describe orally disintegrating tablets containing milobalin besylate.

Patent Document 3 discloses that stabilization of milobalin besylate can be observed in pharmaceutical solid preparations containing excipients, disintegrants, and specific antioxidants in addition to milopalin besylate . However, this document does not describe orally disintegrating tablets containing milobalin besylate.

Patent Document 4 discloses a pharmaceutical solid composition, which contains (i) one or more selected from D-mannitol, lactose, corn starch and crystalline cellulose in addition to milobarin besylate, (ii) calcium carmellose, and (iii) titanium oxide as a colorant, one or more other colorants. However, this document does not describe orally disintegrating tablets containing milobalin besylate.

Citation list

patent documents

Patent Document 1: US Patent Application No. 2015/0110880A1

Patent Document 2: US Patent Application No. 2015/0079166A1

Patent Document 3: US Patent Application No. 2018/0042878A1

Patent Document 4: US Patent Application No. 2018/0243223A1.

Contents of the invention

technical problem

An object of the present invention is to provide an orally disintegrating tablet containing milobalin besylate having excellent stability.

The orally disintegrating tablet of the present invention is an orally disintegrating tablet that disintegrates rapidly when held in the mouth or placed in water, but has sufficient hardness in normal production, transportation and use.

In addition, the present invention also provides its excellent preparation method.

problem solution

In order to solve the above problems, as a result of diligent research, the present inventors have found that by combining (A) granules containing milobarin besylate and (B) drug-free granules containing crystalline cellulose or non-drug containing crystalline cellulose Drug mixed powder to produce an orally disintegrating tablet having excellent properties solves the above-mentioned problems, thus completing the present invention.

That is, the present invention is as follows.

[1] An orally disintegrating tablet comprising (A) granules containing milobarin besylate and (B) drug-free granules containing crystalline cellulose or drug-free mixed powder containing crystalline cellulose.

[2] The orally disintegrating tablet according to [1], wherein the average particle diameter of miloparin besylate contained in (A) is 60 μm or less, and 100% by weight, its content as milobalin is 0.5-10% by weight.

[3] The orally disintegrating tablet according to [1] or [2], wherein the bulk density of the crystalline cellulose contained in (B) is 0.10 to 0.26 g/cm ³ , and disintegrates relative to the orally 100% by weight of the tablet, its content is 1.0-50% by weight.

[4] The orally disintegrating tablet according to any one of [1] to [3], wherein (A) is a milobarin besylate-containing granule further containing low molecular weight hydroxypropylcellulose.

[5] The orally disintegrating tablet according to [4], wherein the content of the low molecular weight hydroxypropylcellulose contained in (A) is 0.1 to 2.0 with respect to 100% by weight of the orally disintegrating tablet. weight%.

[6] The orally disintegrating tablet according to any one of [1] to [3], wherein (A) is milobarin besylate-containing granules further containing citric acid hydrate and tocopherol.

[7] The orally disintegrating tablet according to [6], wherein the content of citric acid hydrate contained in (A) is 0.2 to 1.0% by weight relative to 100% by weight of the orally disintegrating tablet, And the content of the tocopherol contained in (A) is 0.01-0.4% by weight relative to 100% by weight of the orally disintegrating tablet.

[8] The orally disintegrating tablet according to [3], wherein (A) is a milobalin besylate-containing granule further containing D-mannitol and carmellose.

[9] The orally disintegrating tablet according to any one of [6] to [8], wherein (A) is a milobarin besylate-containing granule further containing hydroxypropylcellulose.

[10] The orally disintegrating tablet according to [9], wherein the content of hydroxypropylcellulose in (A) is 0.1 to 3.0% by weight relative to 100% by weight of the orally disintegrating tablet.

[11] The orally disintegrating tablet according to any one of [6] to [10], wherein (B) is a drug-free granule further containing D-mannitol and pregelatinized starch.

[12] The orally disintegrating tablet according to [11], wherein the content of D-mannitol contained in (B) is 20 to 55% by weight relative to 100% by weight of the orally disintegrating tablet, And the content of the pregelatinized starch contained in (B) is 1.0-10% by weight relative to 100% by weight of the orally disintegrating tablet.

[13] The orally disintegrating tablet according to [4] or [5], wherein (B) is a drug-free mixed powder further containing carmellose and acesulfame potassium.

[14] The orally disintegrating tablet according to [13], wherein the content of carmellose contained in (B) is 2.0 to 20% by weight relative to 100% by weight of the orally disintegrating tablet, And the content of potassium acesulfamate contained in (B) is 1.0 to 5.0% by weight relative to 100% by weight of the orally disintegrating tablet.

[15] A method for preparing orally disintegrating tablets, comprising: mixing miloparin besylate, D-mannitol, and citric acid hydrate and spraying a low-molecular-weight hydroxypropylcellulose binder solution to produce granules the step of mixing granule A, crystalline cellulose, carmellose and acesulfame potassium, then adding magnesium stearate to the mixed powder, followed by mixing to form a mixture for tableting; and using tableting The steps of machine compression.

[16] A method for preparing an orally disintegrating tablet, comprising: a step of mixing tocopherol and crystalline cellulose to produce a tocopherol powder; mixing miloparin besylate, D-mannitol, carmellose , citric acid hydrate, tocopherol powder and aluminum magnesium silicate and spraying hydroxypropyl cellulose binder solution to produce granules; mixing D-mannitol and crystalline cellulose and spraying pregelatinized starch dispersion to produce granules a step of mixing the two granules, crospovidone and acesulfame potassium, and then mixing magnesium stearate to form a mixture for tablet compression; and a step of compressing tablets using a tablet machine.

Advantageous Effects of the Invention

The present invention can provide an orally disintegrating tablet containing milobalin besylate having excellent stability.

Specifically, the orally disintegrating tablet of the present invention is an orally disintegrating tablet having good stability of milobalin besylate by containing citric acid hydrate and tocopherol.

The orally disintegrating tablet of the present invention disintegrates rapidly when held in the mouth or placed in water, exhibits excellent solubility, and has good taste.

The orally disintegrating tablet of the present invention is an orally disintegrating tablet having sufficient hardness in normal production, transportation and use, and excellent storage stability.

The orally disintegrating tablet of the present invention can be prepared by normal compression molding without complicated steps and special equipment.

Description of the implementation

The "orally disintegrating tablet" in the present invention is a molded substance which has rapid disintegration and solubility when contained in the mouth or placed in water. Specifically, it refers to a tablet that, in a disintegration test mainly performed by saliva in the oral cavity or by a disintegration test by a device, exhibits a disintegration in the range of usually 5-180 seconds, preferably 5-60 seconds, more preferably Disintegrates in about 5-40 seconds.

The orally disintegrating tablet of the present invention has sufficient hardness during normal production, transportation and use. For example, in a hardness test, orally disintegrating tablets generally have a hardness of 2 kg or more, preferably 3 kg or more, further preferably 5 kg or more.

The orally disintegrating tablet of the present invention retains leachability suitable for use in pharmaceutical products. For example, in a dissolution test, orally disintegrating tablets generally exhibit an average dissolution rate of 80% or more, preferably 85% or more, at 30 minutes.

The dissolution test is described in 6.10 Dissolution test method in 6. Preparation test methods of the eighteenth revision of the Japanese Pharmacopoeia. This test is performed to determine whether an oral formulation meets dissolution testing criteria, but is also intended to prevent significant bioinequivalence. The sample in this test corresponds to the minimum dose, and for tablets means one tablet, for capsules means one capsule, and for other formulations means the stated amount. Examples of devices to be used in this test include devices of the spinning basket method, devices of the paddle method, and devices of the flow cell method. The details thereof are described in the eighteenth revised edition of the Japanese Pharmacopoeia.

"Milopalin" used in the present invention is a compound represented by the following formula (I):

[Formula 1]

"Milopalin besylate" used in the present invention is a salt of milopalin and benzenesulfonic acid and is represented by the following formula (Ia):

[Formula 2]

Milobalin used in the present invention is considered to exert analgesic effect by inhibiting calcium flow by binding to α2δ subunit which plays an auxiliary role in the function of voltage-dependent calcium channel in the nervous system.

In clinical trials conducted in Japan and overseas, milobarin besylate used in the present invention has been approved for production and sale as a therapeutic agent for peripheral neuropathic pain.

For the treatment of peripheral neuropathic pain, adults typically administer an initial dose of milobarin 5 mg orally twice daily, followed by gradual dose increases of 5 mg at intervals of one week or longer, and each dose is administered orally twice daily 15 mg. The dose is adjusted according to the patient's age and symptoms, ranging from 10 mg to 15 mg, and administered twice daily.

The method of producing the orally disintegrating tablet of the present invention and aspects thereof (aspect A and aspect B) will be described as follows.

Aspect A:

An orally disintegrating tablet comprising drug-free granules containing crystalline cellulose having a bulk density of 0.26 g/ ^cm3 or less, D-mannitol, and pregelatinized starch together with milobarin besylate obtained from particles.

In this regard, the drug-free granules function as the matrix of the formulation, which can impart the desired disintegration and formability to the orally disintegrating tablet. The drug-free granules consist of only the three components of crystalline cellulose, D-mannitol and pregelatinized starch having a bulk density of 0.26 g/cm or ^less (but may contain one or more other additives) to exhibit excellent disintegration and excellent formability.

In addition, the orally disintegrating tablet in this aspect exhibits excellent stability by adding citric acid hydrate and tocopherol to the milobarin besylate-containing granules.

The method for preparing the orally disintegrating tablet of aspect A comprises (1) the step of preparing drug-free granules, (2) the step of preparing milobarin besylate-containing granules, and (3) mixing the drug-free granules 1. The step of said granules containing milobarin besylate and another extragranular mixed powder for compression molding.

(1) Steps for preparing drug-free granules

Drug-free particles can be prepared using the following method 1) or 2).

1) A method of wet granulating a mixture containing crystalline cellulose having a bulk density of 0.26 g/cm ³ or less, D-mannitol, and pregelatinized starch with water.

2) A method of granulating a mixture containing crystalline cellulose and D-mannitol having a bulk density of 0.26 g/cm ³ or less with a liquid (dissolving or dispersing pregelatinized starch in water or the like).

Here, conventionally used extrusion granulation method, mixing stirring granulation method, high-speed stirring granulation method, fluidized bed granulation method, rolling granulation method, etc. may be used for granulation.

Pregelatinized starch exhibits a suitable viscosity for granulation when dissolved or dispersed in a liquid such as water. Examples of granulation methods include a method of mixing pregelatinized starch with other components as they are in powder form, followed by granulation with water, and a method of granulation with a liquid in which pregelatinized starch is dissolved or dispersed in water. Any method can produce tablets with the desired properties, but the latter method is preferred.

In addition, in the case of granulation using a liquid in which pregelatinized starch is dissolved or dispersed, either of the high-speed stirring granulation method and the fluidized bed granulation method can be applied, but in the case of granulation by fluidized bed In the case of preparing granules by the granulation method, an orally disintegrating tablet with more excellent properties can be obtained. In case another additive such as a conventional disintegrant is mixed into the drug-free granules, it can be mixed with the mixture before granulation.

In drug-free granules, the ratio of D-mannitol to crystalline cellulose having a bulk density of 0.26 g/cm or ^less is 1-3 parts by weight of D-mannitol relative to 1 part of crystalline cellulose , preferably 1-2 parts by weight of D-mannitol.

(2) Steps for preparing granules containing milobarin besylate

Milopalin besylate can be mixed with the drug-free granules as such in powder form, or after it has been granulated (if desired). For example, miloparin besylate-containing granules can be produced by the conventionally used extrusion granulation method, mixing stirring granulation method, high-speed stirring granulation method, fluidized bed granulation method or rolling granulation method.

For example, by mixing powdered or granular milobarin besylate, D-mannitol, carmellose, citric acid hydrate, 10% tocopherol with a liquid in which hydroxypropylcellulose is dissolved or dispersed in water Granulation of mixed powder of phenol powder (by mixing tocopherol and crystalline cellulose having a bulk density of 0.26 g/cm ³ or less) and magnesium aluminum silicate can give miloparin besylate-containing granules.

In addition, powdered or granular milobarin besylate, D-mannitol, carmellose, citric acid hydrate, 10% tocopherol powder (by mixing ^tocopherol and The mixed powder granulation of crystalline cellulose with smaller bulk density), aluminum magnesium silicate and hydroxypropyl cellulose can obtain the granules containing medicine.

For example, by granulating a mixed powder of powdery or granulated miloparin besylate, D-mannitol and citric acid hydrate with a liquid in which low molecular weight hydroxypropylcellulose is dissolved or dispersed in water, it can be obtained Granules containing miloparin besylate. In addition, drug-containing granules can be obtained by granulating a mixed powder of powdery or granular milobarin besylate, D-mannitol, citric acid hydrate, and low molecular weight hydroxypropylcellulose with water.

Granules containing milobalin besylate may be masked for unpleasant taste and odor such as bitterness and irritancy, or coated to control leachability. For coating, a coating agent and a plasticizer can be appropriately used. For example, coating using a fluidized bed granulator/coater, a rolling fluidized bed granulator/coater, a centrifugal fluidized granulator/coater or a Worcester-type fluidized bed granulator/coater method.

Where two or more drugs are used, they may be contained in the same granule or in different granules and compression molded, depending on the dosing suitability of the drugs.

(3) The step of mixing drug-free granules, granules containing milobarin besylate and other extragranular mixed powders for compression molding. agent and other additives (if necessary), followed by compression molding to produce orally disintegrating tablets. For example, mixing is performed by using a tumble mixer or a convective mixer.

The compression molding of the orally disintegrating tablet of the present invention can be performed using a common tablet press. The molding pressure of the tablet press can be the same as that of ordinary tablets, but it is preferably 2-20kN, more preferably about 4-14kN, although it also depends on the shape and size of the tablet.

The compounding ratio of drug-free granules may be 30-90% relative to the total weight of tablet components. In case the drug is in powder form, the compounding ratio is 30-80%, preferably 45-70%. In the case of using the drug after granulation, the compounding ratio is 30-80%, preferably 45-70%. Furthermore, in the case of using a drug after granulation, the compounding weight ratio of the drug-free granules is preferably 1.0 to 3.5 with respect to the drug-containing granules.

Aspect B:

An orally disintegrating tablet obtained by mixing a drug-free mixed powder containing crystalline cellulose having a bulk density of 0.26 g/ ^cm3 or less, D-mannitol, and pregelatinized starch, or another extragranular mixed powder It is obtained by compression molding together with granules containing milobarin besylate.

In aspect B, the drug-free admixed powder or the other extragranular admixed powder imparts the desired disintegration and formability properties to an orally disintegrating tablet.

The drug-free mixed powder contains only three components of crystalline cellulose, D-mannitol and pregelatinized starch having a bulk density of 0.26 g/cm or ^less (but may contain one or more of other additives) to exert excellent disintegration and excellent formability.

In addition, the other extragranular mixed powder exhibits excellent disintegration by containing only three components of crystalline cellulose, carmellose, and acesulfame potassium (but may contain one or more other additives if necessary) and excellent formability.

The method for preparing the orally disintegrating tablet of aspect B comprises the steps of preparing granules containing milobarin besylate and mixing the granules containing milobarin besylate and one or more other additives, followed by compression molding ( if necessary). The procedure for preparing the milobarin besylate-containing granules is the same as that in (2) of Aspect A.

In the step of mixing the miloparin besylate-containing granules and one or more other additives, followed by compression molding, the mixing or compression molding process is the same as that in (3) of Aspect A.

The orally disintegrating tablet of the present invention obtained as above has excellent disintegration and excellent solubility when placed in the oral cavity or water, and has excellent physical and chemical stability.

The disintegration or solubility of the orally disintegrating tablet of the present invention refers to the disintegration or dissolution time in the oral cavity (in the oral cavity of a healthy adult male, in the absence of water in the mouth, the tablet completely disintegrates only with saliva solution or dissolution time) is usually 5-180 seconds, preferably 5-60 seconds, more preferably about 5-40 seconds.

The orally disintegrating tablet of the present invention is gradually disintegrated or dissolved by saliva when held in the mouth, but it is Will disintegrate or dissolve in less time. For people with dry mouth or little saliva, it can be disintegrated and dissolved in the mouth with water or hot water, or it can be taken with water as it is with ordinary tablets.

At the same time, the hardness of the orally disintegrating tablet of the present invention is sufficient even after a stability test under certain temperature and humidity conditions (for example, a temperature of 25°C and a humidity of 75% in an open system for one week) .

Therefore, it has hardness that does not collapse during preparation and distribution of formulations, has practical hardness even when stored under constant temperature and humidity conditions, and is excellent in storage stability and disintegration.

The orally disintegrating tablet of the present invention can be used as a preparation that is easy to take even for the elderly, children, and patients who have difficulty swallowing, and as a safe preparation for ordinary adults, for treating diseases.

"Milobalin besylate" used in the present invention suitably has an average particle diameter of 60 μm (further suitably, 40 μm) or less. The "average particle diameter" in the present invention refers to the particle diameter at the 50% integral value in the particle diameter distribution determined by the laser diffraction/light scattering method.

With respect to 100% by weight of the orally disintegrating tablet, the milobarin besylate used in the present invention suitably accounts for 0.5-40% by weight, further suitably accounts for 0.5-25% by weight, especially It suitably accounts for 0.5-10% by weight.

As "D-mannitol" used in the present invention, those conforming to the pharmacopoeias of Japan, Europe and the United States can generally be used. The crystal form, particle size and specific surface area of D-mannitol to be contained are not particularly limited, but the crystal form may be any of α form, β form, δ form and amorphous form, and the particle size is preferably 10 μm or more Large and 250 μm or less, more preferably 20 μm or more and 150 μm or less, specific surface area is preferably 0.1 m ² /g or more and 4 m ² /g or less, more preferably 0.1 m ² /g or more And 2m ² /g or less. For example, crystal form, particle diameter and specific surface area can be measured by X-ray diffraction, laser diffraction particle size measurement method and BET specific surface area measurement method (multi-point method), respectively. Examples of commercially available products include D-mannitol manufactured by Merck KGaA, Roquette Freres, Towa Kasei Co., Ltd., and Kao Corporation.

In the case of using D-mannitol, its content is usually 20-95% by weight, preferably 20-55% by weight, relative to 100% by weight of the orally disintegrating tablet.

D-mannitol may be mixed with other components as a tablet powder as it is in powder form and then subjected to compression molding, or may be granulated with other components using a suitable binder and then subjected to compression molding.

"Carmellose" used in the present invention is usually 1-20% by weight, preferably 2-20% by weight relative to 100% by weight of the orally disintegrating tablet.

The "citric acid hydrate" used in the present invention is citric acid hydrate that can be used as a pharmaceutical additive (for example, a product conforming to the Japanese Pharmacopoeia), and is usually citric acid monohydrate. Alternatively, citric acid anhydride may be used instead of citric acid hydrate.

"Citrate hydrate" and "tocopherol" used in the present invention function as stabilizers. With respect to 100% by weight of the orally disintegrating tablet, the content of the citric acid hydrate of the present invention is suitably 0.01-10 wt%, further suitably 0.1-5.0 wt%, more suitably 0.2-1.0 wt% %.

In addition, relative to 100% by weight of the orally disintegrating tablet, the content of the tocopherol of the present invention is suitably 0.01-10 wt%, further suitably 0.01-1.0 wt%, more suitably 0.01-0.4 wt% %.

"Crystalline cellulose" used in the present invention is generally a grade with a bulk density of 0.10-0.46 g/cm ³ , preferably 0.10-0.42 g/cm ³ , more preferably 0.10-0.26 g/cm ³ . Examples of commercially available products include CEOLUS KG-1000 (with a bulk density of 0.10-0.15 g/ ^cm ), CEOLUS KG-802 (with a bulk density of 0.13-0.23 g/ ^cm ), CEOLUSUF-711 (with Bulk density of 0.20-0.26 g/cm ³ ) (both of which are manufactured by Asahi Kasei Chemicals Corporation). In addition, it is also possible to combine two or more kinds of crystalline cellulose having different bulk densities and adjust them to obtain a desired bulk density.

The content of crystalline cellulose is preferably 1.0 to 50% by weight relative to 100% by weight of the orally disintegrating tablet. When it exceeds 50% by weight, fluidity may deteriorate, and manufacturability may decrease. The content is more preferably 5.0 to 30% by weight.

With respect to 1 part of crystalline cellulose, the ratio of D-mannitol to crystalline cellulose is 1.0-10 parts by weight of D-mannitol, preferably 1.0-8.5 parts by weight, more preferably 1.0-3.0 parts by weight.

The orally disintegrating tablet of the present invention may contain inorganic excipients, and examples of inorganic excipients may include synthetic aluminum magnesium carbonate, precipitated calcium carbonate, hydrous silica, light anhydrous silicic acid, silicon One or a combination of two or more of aluminum magnesium hydroxide and magnesium hydroxide.

"Hydroxypropylcellulose" used in the present invention is not limited as long as it maintains desired properties (disintegration time, hardness and leachability) as an orally disintegrating tablet.

In consideration of formability and disintegration/suspension in water, the content of hydroxypropylcellulose in the orally disintegrating tablet of the present invention is generally preferably 0.1 to 3.0% by weight relative to 100% by weight of the orally disintegrating tablet. weight%. When the content of hydroxypropylcellulose is too large, the time required for suspension is prolonged, and suitability for orally disintegrating tablets decreases.

The "low molecular weight hydroxypropyl cellulose" used in the present invention is hydroxypropyl cellulose having a molecular weight of 140,000 (GPS method) or less. Uncoated tablets containing low-molecular-weight hydroxypropylcellulose were shown to inhibit both the production of similar substances and the prolongation of disintegration time, which are desirable properties for orally disintegrating tablets.

The content of the low molecular weight hydroxypropyl cellulose in the orally disintegrating tablet of the present invention is preferably 0.1-2.0% by weight relative to 100% by weight of the orally disintegrating tablet.

"Analogs" as used in the present invention are lactam compounds of milobalin and other related substances with undetermined structures.

The orally disintegrating tablet in the present invention further contains crospovidone (for example, a product conforming to the Japanese Pharmacopoeia) and pregelatinized starch as a "disintegrant" in addition to the aforementioned components.

Pregelatinized starch is obtained by heating starch to pregelatinize it, and includes partially pregelatinized starch. In addition, those described in Japanese Pharmaceutical Additive Standards can be used as pregelatinized starches. The average degree of pregelatinization is preferably 90% or less, more preferably 70-80%. As a commercially available product, for example, pregelatinized starch SWELSTAR PD-1 (manufactured by Asahi Kasei Chemicals Corporation) can be used.

The content of pregelatinized starch is generally 1.0-15% by weight, preferably 1.0-10% by weight relative to 100% by weight of the orally disintegrating tablet.

The pregelatinized starch may be mixed with other components as a tablet powder in the form of powder as it is and then subjected to compression molding, or may be granulated together with other components and then subjected to compression molding.

In the orally disintegrating tablet of the present invention, pregelatinized starch is used as a disintegrant. Meanwhile, it becomes viscous when it is dissolved or dispersed in a liquid such as water during preparation, and thus when it is sprayed on raw materials in powder form, granulation is performed and granules can be formed. Using this property, by spraying the lysate or dispersion (in which pregelatinized starch is dissolved or dispersed in water) to a powder containing crystalline cellulose and D-mannitol having a bulk density of 0.26 g/ ^cm3 or less Granules are prepared on a mixture (for fluidized bed granulation), and mixed with other components as necessary, followed by compression molding, so that tablets with good formability and desired disintegration in the oral cavity can be obtained. When using conventional disintegrants such as low-substituted hydroxypropyl cellulose or crospovidone, such advantages can hardly be obtained in the preparation, and this is a characteristic property of pregelatinized starch.

The content of crospovidone is usually 0.5-20% by weight, preferably 2.0-20% by weight relative to 100% by weight of the orally disintegrating tablet.

The orally disintegrating tablet of the present invention may contain various "additives" generally used in tablet preparation as long as the effect of the present invention is not hindered.

Examples of additives may include binders, lubricants, coating agents, plasticizers, colorants, flavoring agents, sweeteners, corrective agents, fluidizing agents, foaming agents and surfactants.

Examples of "binders" may include gum arabic, sodium alginate, carboxyvinyl polymer, gelatin, dextrin, pectin, sodium polyacrylate, pullulan, methyl cellulose, hydroxypropyl cellulose One or a combination of two or more of polyvinyl alcohol, hydroxypropyl methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone and polyethylene glycol.

Examples of "lubricant" may include magnesium stearate (for example, products complying with the Japanese Pharmacopoeia), calcium stearate (for example, products complying with the Japanese Pharmacopoeia), sodium stearyl fumarate (for example, products complying with the drug Additive standard product) and talcum powder (for example, a combination of two or more), particularly preferably magnesium stearate.

The content of the lubricant is preferably 0.1-5.0% by weight relative to 100% by weight of the orally disintegrating tablet.

Examples of "coating agents" may include those selected from ethyl cellulose, aminoalkyl methacrylate copolymer E, methacrylic acid copolymer L, dried methacrylic acid copolymer LD, methacrylic acid copolymer LD, Methacrylic acid copolymer S, aminoalkyl methacrylate copolymer RS, aminoalkyl methacrylate copolymer RS, ethyl acrylate-methyl methacrylate copolymer, polyvinyl acetal-diethyl acetate One or a combination of two or more of amino esters and polyvinyl acetate resins is used as a coating agent to coat the surface of powdered drugs (the surface of crystals) or the surface of particles of granulated drugs.

"Plasticizer" is usually used in combination with a coating agent, and examples thereof may include diethyl sebacate, dibutyl sebacate, triethyl citrate, stearic acid, polyethylene glycol, and triacetate One or a combination of two or more of them.

Examples of "colorant" may include one or a combination of two or more selected from: edible pigments such as food yellow No. 5, food red No. 2, and food blue No. 2; food lake pigments, Yellow iron oxide, ferric oxide, titanium oxide, beta-carotene and riboflavin.

Examples of the "flavoring agent" may include one or a combination of two or more selected from orange, lemon, strawberry, mint, menthol, micron menthol, and various spices.

Examples of "sweeteners" may include one or two selected from sodium saccharin, saccharin, aspartame, acesulfame potassium, dipotassium glycyrrhizinate, sucralose, steviol glycosides, and thaumatin. More combinations.

Examples of the "flavoring agent" may include one or a combination of two or more selected from sodium chloride, magnesium chloride, disodium inosinate, monosodium L-glutamate, and honey.

Examples of the "fluidizing agent" may include one or a combination of two or more selected from hydrous silica, light anhydrous silicic acid, and talc.

Examples of "foaming agents" may include tartaric acid.

Examples of "surfactants" may include polyoxyethylene stearate 40, sorbitan fatty acid esters, polyoxyethylene hardened castor oil, polysorbate, glyceryl monostearate and sodium lauryl sulfate one or a combination of two or more.

Example

Hereinafter, the present invention will be described through examples of the present invention.

(Example 1) Molecular Weight of Hydroxypropyl Cellulose and Stability of Preparation

(1) Preparation of Particle A

Milopalin besylate, D-mannitol, and citric acid hydrate were weighed in the proportion shown in Table 1, mixed for 3 minutes using a PE bag, and used Comil (U-10, diameter: 1.143mm, QUADRO) Screened at 1100 rpm to produce a screened powder. The sieved powder was placed in a fluidized bed granulator (FL-labo2L, FREUND), and a low molecular weight hydroxypropyl cellulose binder solution (7 wt/wt%, dissolved in purified water) was prepared in Table 1 The formulations shown were sprayed at about 8 g/min at a supply air temperature of 77°C and then dried to a product temperature of 50°C after spraying was complete.

Screening was performed using Comil (U-10, diameter: 1.143 mm, QUADRO) at 1100 rpm to produce Particle A.

(2) Preparation of granules for tableting

Granules A, crystalline cellulose, carmellose and acesulfame potassium were weighed in the proportions shown in Table 1, and mixed for 10 minutes at a rotation speed of 34 rpm using a V-type mixer (5 L) to produce Mix powder.

Then, magnesium stearate was weighed in the formula shown in Table 1 and added to the mixed powder, followed by mixing for 10 minutes at a rotation speed of 34 rpm using a V-type mixer (5 L) to produce granules for tableting .

(3) Preparation of tablets

Using a tablet press (Virgo0524SS1AX, manufactured by KIKUSUI SEISAKUSHO LTD.), the tablet mass was adjusted to 300 mg, and uncoated tablets (12.1 x 6.4 mm) were obtained by molding at a tablet pressure of 5.5 kN.

(Comparative Example 1) Molecular Weight of Hydroxypropyl Cellulose and Stability of Preparation

(1) Preparation of Particle A

Milopalin besylate, D-mannitol, and citric acid hydrate were weighed in the proportions shown in Table 1, mixed for 3 minutes using a PE bag, and mixed using a Comil (U-10, diameter: 1.143mm, QUADRO) Screened at 1100 rpm to produce a screened powder. The sieved powder was placed in a fluidized bed granulator (FL-labo2L, FREUND), and the hydroxypropyl cellulose binder solution (7 wt/wt%, dissolved in purified water) was prepared in the form shown in Table 1. The formulation was sprayed at about 8 g/min at a supply air temperature of 80°C and then dried to a product temperature of 50°C after spraying had ended.

Screening was performed using Comil (U-10, diameter: 1.143 mm, QUADRO) at 1100 rpm to produce Particle A.

(2) Preparation of granules for tableting

Granule A, crystalline cellulose, carmellose, potassium acesulfamate were weighed in the proportion shown in Table 1, and mixed at a rotation speed of 34 rpm for 10 minutes using a V-type mixer (5 L) to A mixed powder is produced. Then, magnesium stearate was weighed in the formula shown in Table 1 and added to the mixed powder, followed by mixing for 10 minutes at a rotation speed of 34 rpm using a V-type mixer (5 L) to produce granules for tableting .

(3) Preparation of tablets

Using a tablet press (Virgo0524SS1AX, manufactured by KIKUSUI SEISAKUSHO LTD.), the tablet mass was adjusted to 300 mg, and uncoated tablets (12.1 x 6.4 mm) were obtained by molding at a tablet pressure of 6 kN.

(Evaluation method and results) Molecular weight of hydroxypropyl cellulose and stability of preparation

After the uncoated tablets of Example 1 and Comparative Example 1 were left to stand for 1 month in an aluminum bag under the condition of 40°C/75%RH, HPLC (Agilent infinity 1290) was used under the conditions shown in Table 2. The amount of similar substances produced was measured below. In addition, the disintegration test was based on the disintegration test method of the Japanese Pharmacopoeia revised seventeenth, and the initial disintegration after being left in an aluminum bag for 3 months under the condition of 40°C/75%RH was evaluated without a pan. product and uncoated tablets.

Table 3 shows the results for the amount of similar material produced. In uncoated tablets using low-molecular-weight hydroxypropylcellulose (having a molecular weight of 140,000 (GPS method) or less), it was confirmed that the amount of similar material produced was that of normal hydroxypropylcellulose (having a molecular weight of 1,000,000 ( GPS method) or less molecular weight) about 1/2 the amount in uncoated tablets.

Table 4 shows the results of the disintegration test. In uncoated tablets using normal hydroxypropylcellulose (having a molecular weight of 1,000,000 (GPS method) or less), the disintegration time after standing at 40°C/75%RH for 3 months was prolonged by 38 seconds , but in uncoated tablets using low molecular weight hydroxypropylcellulose (having a molecular weight of 140,000 (GPS method) or less), the increase in disintegration time was as small as 12 seconds.

From the foregoing results, it can be seen that the uncoated tablet containing low-molecular-weight hydroxypropylcellulose has the desired properties for an orally disintegrating tablet in terms of suppressing the generation of similar substances and suppressing prolongation of disintegration time.

[Table 1]

[Table 2]

[table 3]

The difference in the amount of similar substances produced

Example 1 Comparative Example 1 0.19% 0.39%

.

[Table 4]

The results of the disintegration test

(Example 2) Content of crystalline cellulose and stability of preparation

(1) Preparation of Particle A

Tocopherol and crystalline cellulose were weighed in the proportion shown in Table 5, and rotated at a blade rotation speed of 180rpm and a shear paddle (chopper) of 3000rpm using a high-speed stirring granulator (VG-50, POWREX) Mix at speed for 15 minutes to produce a 10% tocopherol powder.

Milopalin besylate, D-mannitol, carmellose, citric acid hydrate, 10% tocopherol powder, and magnesium aluminum silicate were weighed in the proportions shown in Table 5, using a V-type mixing (30L) was mixed at a rotation speed of 27rpm for 5 minutes and sieved at 600rpm using Comil (QC-194S, diameter: 1.143mm, QUADRO) to produce a sieved powder. The sieved powder was placed in a fluidized bed granulator (FLO-5), and the hydroxypropyl cellulose binder solution (7 wt/wt%, dissolved in purified water) was formulated in Table 5. Spray at about 40 g/min at a supply air temperature of 80° C., followed by drying to a product temperature of 55° C. after spraying has ended.

Screening was performed using Comil (QC-194S, diameter: 1.143 mm, QUADRO) at 1400 rpm to produce Particle A.

(2) Preparation of Particle B

D-mannitol and crystalline cellulose were weighed with the proportion shown in Table 5 and placed in a fluidized bed granulator (GPCG-15, POWREX), and the pregelatinized starch dispersion (8 wt/wt% , dissolved in purified water) was sprayed at about 140 g/min at a supply air temperature of 85° C. in the proportion shown in Table 5, and then dried to an exhaust gas temperature of 45° C. after the end of spraying.

Screening was performed using Comil (QC-194S, diameter: 1.143 mm, QUADRO) at 600 rpm to produce Particle B.

(3) Preparation of granules for tableting

Granule A, Granule B, Crospovidone and Potassium Acesulfame Potassium were weighed in the proportion shown in Table 5, and were mixed using a V-type mixer (10L) at a rotation speed of 32rpm for 5 minutes to produce a mixed powder. Then, magnesium stearate was weighed in the formula shown in Table 5, added to the mixed powder, and mixed at a rotation speed of 32 rpm for 10 minutes using a V-shaped mixer (10 L) to produce granules for tableting .

(4) Preparation of tablets

Using a tablet press machine (Virgo0524SS1AX, manufactured by KIKUSUI SEISAKUSHO LTD.), the tablet mass was adjusted to 300 mg, and uncoated tablets (φ 10.0 mm) were obtained by molding at a tablet pressure of 8 kN.

(Comparative Example 2) Content of Crystalline Cellulose and Stability of Preparation

(1) Preparation of Particle A

Tocopherol and crystalline cellulose were weighed in the proportion shown in Table 5, and mixed using a high-speed stirring granulator (VG-50, POWREX) at a paddle rotation speed of 180 rpm and a shear paddle rotation speed of 3000 rpm for 15 minutes to produce 10% tocopherol powder.

Milopalin besylate, D-mannitol, carmellose, citric acid hydrate, 10% tocopherol powder, and magnesium aluminum silicate were weighed in the proportions shown in Table 5, using a V-type mixing (30L) was mixed at a rotation speed of 27rpm for 5 minutes and sieved at 600rpm using Comil (QC-194S, diameter: 1.143mm, QUADRO) to produce a sieved powder. The sieved powder was placed in a fluidized bed granulator (FLO-5, FREUND), and the hydroxypropyl cellulose binder solution (7 wt/wt%, dissolved in purified water) was prepared as shown in Table 5. The formulation was sprayed at about 40 g/min at a supply air temperature of 80°C and then dried to a product temperature of 55°C after spraying was complete.

Screening was performed using Comil (QC-194S, diameter: 1.143 mm, QUADRO) at 1400 rpm to produce Particle A.

(2) Preparation of granules for tableting

Granules A, D-mannitol, crospovidone and acesulfame potassium were weighed in the proportion shown in Table 5, and mixed for 5 minutes at a rotation speed of 32 rpm using a V-type mixer (10 L) to A mixed powder is produced. Then, magnesium stearate was weighed in the formula shown in Table 5, added to the mixed powder, and mixed at a rotation speed of 32 rpm for 10 minutes using a V-shaped mixer (10 L) to produce granules for tableting .

(3) Preparation of tablets

Using a tablet press (Vela5, manufactured by KIKUSUI SEISAKUSHO LTD.), the tablet mass was adjusted to 300 mg, and uncoated tablets (φ9.5 mm) were obtained by molding at a tablet pressure of 7 kN.

(Evaluation method and results) Content of crystalline cellulose and stability of preparation

After the uncoated tablets of Example 2 and Comparative Example 2 were left to stand for 6 months in a plastic bottle at 40°C/75%RH, the results shown in Table 2 were obtained using HPLC (Agilent infinity 1290). Measure the amount of similar substances produced under the same conditions.

Table 6 shows the results. It was confirmed that in the uncoated tablet (Example 2) using D-mannitol, crystalline cellulose and pregelatinized starch as granules B, the total amount of similar substances produced was greater than that without using granules B or crystalline cellulose and About 1/3 of the uncoated tablet of pregelatinized starch (comparative example 2).

[table 5]

[Table 6]

Example 2 Comparative Example 2 0.27% 0.74%

.

(Example 3) Content of crystalline cellulose and disintegration time, degree of abrasion and hardness of preparation (1) preparation of tablet

Using a tablet press (Virgo0524SS1AX, manufactured by KIKUSUI SEISAKUSHO LTD.), the quality of the tablet was adjusted to 300 mg, and by compression molding at 6, 8 and 10 kN, the tablet for tableting prepared in Example 2 was Granules were obtained as uncoated tablets (φ10.0 mm).

(Comparative Example 3) Content of crystalline cellulose and disintegration time, degree of abrasion and hardness of preparation (1) Preparation of tablet

Using a tablet press (Vela5, manufactured by KIKUSUI SEISAKUSHO LTD.), the quality of the tablet was adjusted to 300 mg, and by compression molding at 6, 8 and 10 kN, the tablet for tableting prepared in Comparative Example 2 was prepared. granules to give uncoated tablets (9.5 mm).

(Evaluation method and results) Content of crystalline cellulose and disintegration time, degree of abrasion and hardness of the preparation

Tables 7 to 9 show the evaluation results of the prepared uncoated tablets. The hardness of the tablets was measured using a fully automatic tablet measuring device (TypeWHT-2, PHARMA TEST APPRATEBAU GmbH). In addition, the disintegration test was based on the disintegration test method of the Seventeenth Revision of the Japanese Pharmacopoeia, and the evaluation was performed without a disc. The measurement of the abrasion test was performed using a tablet abrasion tester (SZ-03, Rinkan).

Although the hardness of Example 3 was lower than that of Comparative Example 3, the degree of wear was low, and it was shown that a good degree of wear was imparted. In addition, it was confirmed that the disintegration time of Example 3 was shortened by about 1/2 compared with the uncoated tablet of Comparative Example 3 having almost the same hardness.

From the foregoing results, it can be seen that the uncoated tablet containing D-mannitol, crystalline cellulose and pregelatinized starch as B granules has the advantages of both low abrasion degree and short disintegration time for orally disintegrating tablets. expected performance.

[Table 7]

[Table 8]

[Table 9]

(Example 4) Stability of Tocopherol and Preparation

(1) Preparation of Particle A

Tocopherol and crystalline cellulose were weighed in the proportions shown in Table 10, and mixed using a high-speed stirring granulator (VG-50, POWREX) at a blade rotation speed of 180 rpm and a shear paddle rotation speed of 3000 rpm for 15 minutes to produce 10% tocopherol powder.

Milopalin besylate, D-mannitol, carmellose, citric acid hydrate, 10% tocopherol powder, and magnesium aluminum silicate were weighed in the proportions shown in Table 10, using a V-type mixing (2L) was mixed at a rotation speed of 39 rpm for 5 minutes and sieved at 2200 rpm using a Comil (U-10, diameter: 1.143 mm, QUADRO) to produce a sieved powder. The sieved powder was placed in a fluidized bed granulator (FLO-5), and the hydroxypropyl cellulose binder solution (7 wt/wt%, dissolved in purified water) was formulated in Table 10. Spray at about 7 g/min at a supply air temperature of 78°C, followed by drying to a product temperature of 55°C after spraying has ended.

Screening was performed using Comil (U-10, diameter: 1.143 mm, QUADRO) at 2200 rpm to produce Particle A.

(2) Preparation of Particle B

D-mannitol and crystalline cellulose were weighed with the proportion shown in Table 10, and placed in a fluidized bed granulator (NFLO-5, FREUND), and the pregelatinized starch dispersion (8 wt/wt %, dissolved in purified water) was sprayed at a supply air temperature of 85° C. at about 45 g/min in the proportion shown in Table 10, and then dried to an exhaust gas temperature of 45° C. after the spraying was completed.

Screening was performed using Comil (QC-197, diameter: 1.143 mm, QUADRO) at 800 rpm to produce Particle B.

(3) Preparation of granules for tableting

Granules A, Granules B, Crospovidone and Potassium Acesulfame Potassium were weighed in the proportions shown in Table 10, and mixed for 5 minutes at a rotation speed of 39 rpm using a V-type mixer (2L) to produce Mix powder. Then, magnesium stearate was weighed in the formula shown in Table 10, added to the mixed powder, and mixed for 5 minutes at a rotation speed of 39 rpm using a V-type mixer (2 L) to produce granules for tableting .

(4) Preparation of tablets

Using a tablet press (Virgo0524SS1AX, manufactured by KIKUSUI SEISAKUSHO LTD.), the tablet mass was adjusted to 300 mg, and uncoated tablets (12.1 x 6.4 mm) were obtained by molding at a tablet pressure of 6 kN.

(Comparative Example 4) Stability of Tocopherol and Preparation

(1) Preparation of Particle A

Milopalin besylate, D-mannitol, carmellose, citric acid hydrate, and magnesium aluminum silicate were weighed in the proportions shown in Table 10, using a V-type mixer (5 L) at 34 rpm The rotation speed was mixed for 5 minutes and sieved using Comil (QC-197, diameter: 1.143mm, QUADRO) at 2200rpm to produce sieved powder. The sieved powder was placed in a fluidized bed granulator (NFLO-5, FREUND), and the hydroxypropyl cellulose binder solution (7 wt/wt%, dissolved in purified water) was prepared as shown in Table 10 The formulation was sprayed at about 7 g/min at a supply air temperature of 80°C and then dried to a product temperature of 55°C after spraying was complete.

Screening was performed using Comil (QC-197, diameter: 1.143 mm, QUADRO) at 2200 rpm to produce Particle A.

(2) Preparation of Particle B

D-mannitol and crystalline cellulose were weighed with the proportion shown in Table 10, and placed in a fluidized bed granulator (NFLO-5, FREUND), and the pregelatinized starch dispersion (8 wt/wt %, dissolved in purified water) was sprayed at a supply air temperature of 85° C. at about 45 g/min in the proportion shown in Table 1, and then dried to an exhaust gas temperature of 45° C. after the spraying was completed.

Screening was performed using Comil (QC-197, diameter: 1.143 mm, QUADRO) at 800 rpm to produce Particle B.

(3) Preparation of granules for tableting

Granules A, Granules B, Crospovidone and Potassium Acesulfame were weighed in the proportions shown in Table 10, and mixed for 5 minutes at a rotation speed of 34 rpm using a V-type mixer (5 L) to produce Mix powder. Then, magnesium stearate was weighed with the formula shown in Table 10, and added to the mixed powder, followed by using a V-type mixer (5L) at a rotation speed of 34rpm for 10 minutes to produce a mixture for tableting. particles.

(4) Preparation of tablets

Using a tablet press (Virgo0524SS1AX, manufactured by KIKUSUI SEISAKUSHO LTD.), the tablet mass was adjusted to 300 mg, and uncoated tablets (12.1 x 6.4 mm) were obtained by molding at a tablet pressure of 6 kN.

(Evaluation method and results) Stability of tocopherol and preparation

After the uncoated tablets of Example 4 and Comparative Example 4 were left standing without packaging under the conditions of 25°C/75%RH, the resulting amount of similar substances.

Table 11 shows the results. It was confirmed that in the uncoated tablet using tocopherol, the total amount of similar substances produced was about 1/2 of that in the uncoated tablet not using tocopherol.

[Table 10]

[Table 11]

Example 4 Comparative Example 4 25℃/75%RH6 months 0.71% 1.64%

.

Claims (16)

1. An orally disintegrating tablet comprising: (A) granules containing milopalin besylate; and (B) Drug-free granules containing crystalline cellulose or drug-free mixed powder containing crystalline cellulose. 2. The orally disintegrating tablet according to claim 1, wherein The average particle diameter of milobarin besylate contained in (A) is 60 μm or less, and Its content as milobarin is 0.5-10% by weight relative to 100% by weight of the orally disintegrating tablet. 3. The orally disintegrating tablet according to claim 1 or 2, wherein The bulk density of the crystalline cellulose contained in (B) is 0.10-0.26 g/cm ³ , and Its content is 1.0-50% by weight relative to 100% by weight of the orally disintegrating tablet. 4. The orally disintegrating tablet according to any one of claims 1 to 3, wherein (A) is a granule containing miloparin besylate, which further contains low molecular weight hydroxypropylcellulose. 5. The orally disintegrating tablet according to claim 4, wherein The low molecular weight hydroxypropyl cellulose contained in (A) is contained in an amount of 0.1 to 2.0% by weight relative to 100% by weight of the orally disintegrating tablet. 6. The orally disintegrating tablet according to any one of claims 1 to 3, wherein (A) is a granule containing miloparin besylate, which further contains citric acid hydrate and tocopherol. 7. The orally disintegrating tablet according to claim 6, wherein The content of citric acid hydrate contained in (A) is 0.2 to 1.0% by weight relative to 100% by weight of the orally disintegrating tablet, and The content of tocopherol contained in (A) is 0.01-0.4% by weight relative to 100% by weight of the orally disintegrating tablet. 8. The orally disintegrating tablet according to claim 3, wherein (A) is a granule containing miloparin besylate, which further contains D-mannitol and carmellose. 9. The orally disintegrating tablet according to any one of claims 6 to 8, wherein (A) is a granule containing miloparin besylate, which further contains hydroxypropylcellulose. 10. The orally disintegrating tablet according to claim 9, wherein The content of hydroxypropylcellulose in (A) is 0.1-3.0% by weight relative to 100% by weight of the orally disintegrating tablet. 11. The orally disintegrating tablet according to any one of claims 6 to 10, wherein (B) is a drug-free granule which further contains D-mannitol and pregelatinized starch. 12. The orally disintegrating tablet according to claim 11, wherein The content of D-mannitol contained in (B) is 20-55% by weight relative to 100% by weight of the orally disintegrating tablet, and relative to 100% by weight of the orally disintegrating tablet, The content of the pregelatinized starch contained in (B) is 1.0-10 weight%. 13. The orally disintegrating tablet according to claim 4 or 5, wherein (B) is a drug-free mixed powder which further contains carmellose and acesulfame potassium. 14. The orally disintegrating tablet according to claim 13, wherein The content of carmellose contained in (B) is 2.0 to 20% by weight relative to 100% by weight of the orally disintegrating tablet, and The content of acesulfamate potassium contained in (B) is 1.0 to 5.0% by weight relative to 100% by weight of the orally disintegrating tablet. 15. A method for producing an orally disintegrating tablet comprising: a step of mixing miloparin besylate, D-mannitol and citric acid hydrate and spraying a low molecular weight hydroxypropyl cellulose binder solution to produce granules; a step of mixing granule A, crystalline cellulose, carmellose and acesulfame potassium, then adding magnesium stearate to the mixed powder, followed by mixing to form a mixture for tableting; and Steps for compressing tablets using a tablet press. 16. A method for producing an orally disintegrating tablet comprising: the step of mixing tocopherol and crystalline cellulose to produce tocopherol powder; a step of mixing miloparin besylate, D-mannitol, carmellose, citric acid hydrate, tocopherol powder, and magnesium aluminum silicate and spraying the hydroxypropylcellulose binder solution to produce granules; a step of mixing D-mannitol and crystalline cellulose and spraying the pregelatinized starch dispersion to produce granules; the step of mixing the two granules, crospovidone and acesulfame potassium, and then magnesium stearate to form a mixture for tableting; and Steps for compressing tablets using a tablet press.