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TWI883230B - Orally disintegrating tablet containing mirogabalin besylate - Google Patents

Orally disintegrating tablet containing mirogabalin besylate Download PDF

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Publication number
TWI883230B
TWI883230B TW110127306A TW110127306A TWI883230B TW I883230 B TWI883230 B TW I883230B TW 110127306 A TW110127306 A TW 110127306A TW 110127306 A TW110127306 A TW 110127306A TW I883230 B TWI883230 B TW I883230B
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orally disintegrating
disintegrating tablet
weight
granules
mirobalin
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TW110127306A
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Chinese (zh)
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TW202220643A (en
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吉永真治
中橋俊之
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日商第一三共股份有限公司
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    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
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    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
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Abstract

本發明之課題為提供一種含有米羅巴林苯磺酸鹽之安定性優良的口腔內崩散錠。 本發明之解決手段為一種口腔內崩散錠，其含有：(A)含米羅巴林苯磺酸鹽之顆粒；(B)含有結晶纖維素的不含藥物之顆粒、或含有結晶纖維素的不含藥物之混合粉末。 The subject of the present invention is to provide an orally disintegrating tablet containing mirobalin benzenesulfonate with excellent stability. The solution of the present invention is an orally disintegrating tablet containing: (A) granules containing mirobalin benzenesulfonate; (B) drug-free granules containing crystalline cellulose, or drug-free mixed powder containing crystalline cellulose.

Description

含有米羅巴林苯磺酸鹽之口腔內崩散錠Orally disintegrating tablets containing mirobalin besylate

本發明係關於含有米羅巴林苯磺酸鹽(mirogabalin besylate)之安定性優良的口腔內崩散錠。 本發明之口腔內崩散錠，為含在口中時、或放入水中時會快速地崩散，但於通常之製造、輸送、使用時具有充分之硬度的口腔內崩散錠。 又，本發明係關於其製造方法。 The present invention relates to an orally disintegrating tablet containing mirogabalin besylate and having excellent stability. The orally disintegrating tablet of the present invention is an orally disintegrating tablet that rapidly disintegrates when held in the mouth or placed in water, but has sufficient hardness for normal manufacturing, transportation, and use. In addition, the present invention relates to a method for manufacturing the same.

就醫藥品、食品領域中的經口用固體製劑之劑型而言，已知有錠劑、膠囊劑、顆粒劑、散劑等，然而就老人、兒童或吞嚥困難患者較易服用的劑型而言，期待開發在含於口中時、或放入水中時會快速地崩散的口腔內崩散錠。As for the dosage forms of oral solid preparations in the field of pharmaceuticals and foods, tablets, capsules, granules, powders, etc. are known. However, as for dosage forms that are easier for the elderly, children, or patients with difficulty swallowing to take, it is desired to develop orally disintegrating tablets that quickly disintegrate when held in the mouth or when placed in water.

口腔內崩散錠被認為除了在口腔內會快速地崩散之特性以外，與通常之錠劑同樣地，在製造、輸送、使用時，必須兼具能耐受物理性衝撃的充分硬度。又，在服藥順從性方面，亦期望含於口中時，不愉快之味道或刺激被抑制，且具有良好之口感。Orally disintegrating tablets are considered to have the property of disintegrating quickly in the mouth and, like ordinary tablets, must have sufficient hardness to withstand physical impact during production, transportation, and use. In terms of medication compliance, it is also expected that when held in the mouth, unpleasant taste or irritation is suppressed and the mouthfeel is good.

關於口腔內崩散錠，係在專利文獻1中記載含有藥物、容積密度(bulk density)為0.23g/cm 3以下之結晶纖維素、糖醇及α化澱粉的口腔內崩散錠。然而，在該文獻中並無關於含有米羅巴林苯磺酸鹽之口腔內崩散錠的記載。 Regarding orally disintegrating tablets, Patent Document 1 describes orally disintegrating tablets containing a drug, crystalline cellulose having a bulk density of 0.23 g/cm 3 or less, sugar alcohol, and alpha-starch. However, the document does not describe orally disintegrating tablets containing mirogabalin besylate.

在專利文獻2中，記載含有米羅巴林苯磺酸鹽、(i)選自包含D-甘露醇、乳糖、玉米澱粉、及結晶纖維素之群組的1種、以及(ii)羧甲基纖維素鈣的醫藥用固體組成物。然而，在該文獻中，並無關於含有米羅巴林苯磺酸鹽之口腔內崩散錠的記載。Patent Document 2 describes a pharmaceutical solid composition containing mirobalin benzenesulfonate, (i) one selected from the group consisting of D-mannitol, lactose, corn starch, and crystalline cellulose, and (ii) calcium carboxymethylcellulose. However, this document does not describe an orally disintegrating tablet containing mirobalin benzenesulfonate.

在專利文獻3中，記載使米羅巴林苯磺酸鹽含有賦形劑、崩散劑及特定之抗氧化劑而成的醫藥用固體製劑中，可見到米羅巴林苯磺酸鹽之安定化。然而，在該文獻中，並無關於含有米羅巴林苯磺酸鹽之口腔內崩散錠的記載。Patent document 3 describes that mirobaline besylate is stabilized in a pharmaceutical solid preparation containing a formulator, a disintegrating agent, and a specific antioxidant. However, the document does not describe an orally disintegrating tablet containing mirobaline besylate.

專利文獻4中，記載在米羅巴林苯磺酸鹽中，含有(i)選自包含D-甘露醇、乳糖、玉米澱粉、及結晶纖維素之群組中的1種或2種以上、(ii)羧甲基纖維素鈣、及(iii)作為著色劑之氧化鈦及1種或2種以上其他著色劑的醫藥用固體組成物。然而，在該文獻中並無關於含有米羅巴林苯磺酸鹽之口腔內崩散錠的記載。 [先前技術文獻] [專利文獻] Patent document 4 describes a pharmaceutical solid composition containing (i) one or more selected from the group consisting of D-mannitol, lactose, corn starch, and crystalline cellulose, (ii) calcium carboxymethylcellulose, and (iii) titanium oxide as a coloring agent and one or more other coloring agents in mirobalin benzenesulfonate. However, the document does not describe an orally disintegrating tablet containing mirobalin benzenesulfonate. [Prior art document] [Patent document]

[專利文獻1] US2015/0110880A1 [專利文獻2] US2015/0079166A1 [專利文獻3] US2018/0042878A1 [專利文獻4] US2018/0243223A1 [Patent Document 1] US2015/0110880A1 [Patent Document 2] US2015/0079166A1 [Patent Document 3] US2018/0042878A1 [Patent Document 4] US2018/0243223A1

[發明欲解決之課題][Problems to be solved by the invention]

本發明之課題為提供一種含有米羅巴林苯磺酸鹽之安定性優良的口腔內崩散錠。 本發明之口腔內崩散錠，係在含於口中時、或放入水中時會快速地崩散，但在通常之製造、輸送、使用時具有充分之硬度的口腔內崩散錠。 又，本發明係其製造方法亦優良。 [用以解決課題之手段] The subject of the present invention is to provide an orally disintegrating tablet containing mirobalin benzenesulfonate with excellent stability. The orally disintegrating tablet of the present invention will disintegrate quickly when held in the mouth or placed in water, but has sufficient hardness during normal manufacturing, transportation, and use. In addition, the present invention is also excellent in its manufacturing method. [Means for solving the subject]

本發明人等為解決上述課題而專心致力研討之結果，發現藉由組合(A)含米羅巴林苯磺酸鹽之顆粒、與(B)含有結晶纖維素的不含藥物之顆粒或含有結晶纖維素的不含藥物之混合粉末，而製造具有優良性質的口腔內崩散錠，解決上述課題，使本發明完成。As a result of intensive research to solve the above-mentioned problems, the inventors of the present invention have found that by combining (A) granules containing mirobalin benzenesulfonate and (B) drug-free granules containing crystalline cellulose or drug-free mixed powder containing crystalline cellulose, an orally disintegrating tablet with excellent properties can be produced, thereby solving the above-mentioned problems and completing the present invention.

亦即，本發明為以下所記載之發明。That is, the present invention is the invention described below.

[1] 一種口腔內崩散錠，其含有：(A)含米羅巴林苯磺酸鹽之顆粒；及(B)含有結晶纖維素的不含藥物之顆粒、或含有結晶纖維素的不含藥物之混合粉末。 [2] 如[1]記載之口腔內崩散錠，其中(A)所含有的米羅巴林苯磺酸鹽之平均粒徑為60μm以下，其含量以米羅巴林計，為每100重量%口腔內崩散錠中0.5～10重量%。 [3] 如[1]或[2]記載之口腔內崩散錠，其中(B)所含有的結晶纖維素之容積密度為0.10～0.26g/cm 3，其含量為每100重量%口腔內崩散錠中1.0～50重量%。 [4] 如[1]至[3]中任一項記載之口腔內崩散錠，其中(A)為進一步含有小分子羥丙基纖維素的含米羅巴林苯磺酸鹽之顆粒。 [5] 如[4]記載之口腔內崩散錠，其中(A)所含有的小分子羥丙基纖維素之含量，為每100重量%口腔內崩散錠中0.1～2.0重量%。 [6] 如[1]至[3]中任一項記載之口腔內崩散錠，其中(A)為進一步含有檸檬酸水合物及生育酚的含米羅巴林苯磺酸鹽之顆粒。 [7] 如[6]記載之口腔內崩散錠，其中(A)所含有的檸檬酸水合物之含量，為每100重量%口腔內崩散錠中0.2～1.0重量%，(A)所含有的生育酚之含量，為每100重量%口腔內崩散錠中0.01～0.4重量%。 [8] 如[3]記載之口腔內崩散錠，其中(A)為進一步含有D-甘露醇及羧甲基纖維素的含米羅巴林苯磺酸鹽之顆粒。 [9] 如[6]至[8]中任一項記載之口腔內崩散錠，其中(A)為進一步含有羥丙基纖維素的含米羅巴林苯磺酸鹽之顆粒。 [10] 如[9]記載之口腔內崩散錠，其中(A)所含有的羥丙基纖維素之含量，為每100重量%口腔內崩散錠中0.1～3.0重量%。 [11] 如[6]至[10]中任一項記載之口腔內崩散錠，其中(B)為進一步含有D-甘露醇及α化澱粉的不含藥物之顆粒。 [12] 如[11]記載之口腔內崩散錠，其中(B)所含有的D-甘露醇之含量，為每100重量%口腔內崩散錠中20～55重量%，(B)所含有的α化澱粉之含量，為每100重量%口腔內崩散錠中1.0～10重量%。 [13] 如[4]或[5]記載之口腔內崩散錠，其中(B)為進一步含有羧甲基纖維素及乙醯磺胺酸鉀(acesulfame potassium)的不含藥物之混合粉末。 [14] 如[13]記載之口腔內崩散錠，其中(B)所含有的羧甲基纖維素之含量，為每100重量%口腔內崩散錠中2.0～20重量%，(B)所含有的乙醯磺胺酸鉀之含量，為每100重量%口腔內崩散錠中1.0～5.0重量%。 [15] 一種口腔內崩散錠之製造方法，其包含：將米羅巴林苯磺酸鹽、D-甘露醇、檸檬酸水合物混合，以小分子羥丙基纖維素結合液進行噴霧，製造顆粒的步驟； 將A顆粒、結晶纖維素、羧甲基纖維素、乙醯磺胺酸鉀混合，繼而，將硬脂酸鎂加入混合粉末中混合，作成打錠用混合物的步驟； 使用打錠機而得到錠劑的步驟。 [16] 一種口腔內崩散錠之製造方法，其包含：將生育酚及結晶纖維素混合，作成生育酚倍散的步驟； 將米羅巴林苯磺酸鹽、D-甘露醇、羧甲基纖維素、檸檬酸水合物、生育酚倍散、及偏矽酸鋁酸鎂混合，以羥丙基纖維素結合液進行噴霧，製造顆粒的步驟； 將D-甘露醇及結晶纖維素混合，以α化澱粉分散液進行噴霧，製造顆粒的步驟； 將上述2種顆粒、交聯聚維酮(crospovidone)、及乙醯磺胺酸鉀混合，繼而混合硬脂酸鎂，作成打錠用混合物的步驟； 使用打錠機而得到錠劑的步驟。 [發明之效果] [1] An orally disintegrating tablet comprising: (A) granules containing mirobalin benzenesulfonate; and (B) granules containing crystalline cellulose and containing no drug, or a mixed powder containing crystalline cellulose and containing no drug. [2] The orally disintegrating tablet as described in [1], wherein the average particle size of mirobalin benzenesulfonate contained in (A) is 60 μm or less, and its content, calculated as mirobalin, is 0.5 to 10% by weight per 100% by weight of the orally disintegrating tablet. [3] The orally disintegrating tablet as described in [1] or [2], wherein the bulk density of the crystalline cellulose contained in (B) is 0.10 to 0.26 g/cm 3 , and its content is 1.0 to 50% by weight per 100% by weight of the orally disintegrating tablet. [4] The orally disintegrating tablet as described in any one of [1] to [3], wherein (A) is a granule containing mirobalin benzenesulfonate further comprising low-molecular weight hydroxypropyl cellulose. [5] The orally disintegrating tablet as described in [4], wherein the content of low-molecular weight hydroxypropyl cellulose contained in (A) is 0.1 to 2.0 wt. % per 100 wt. % of the orally disintegrating tablet. [6] The orally disintegrating tablet as described in any one of [1] to [3], wherein (A) is a granule containing mirobalin benzenesulfonate further comprising citric acid hydrate and tocopherol. [7] The orally disintegrating tablet as described in [6], wherein the content of citric acid hydrate contained in (A) is 0.2-1.0 wt% per 100 wt% of the orally disintegrating tablet, and the content of tocopherol contained in (A) is 0.01-0.4 wt% per 100 wt% of the orally disintegrating tablet. [8] The orally disintegrating tablet as described in [3], wherein (A) is a granule containing mirobalin benzenesulfonate further containing D-mannitol and carboxymethyl cellulose. [9] The orally disintegrating tablet as described in any one of [6] to [8], wherein (A) is a granule containing mirobalin benzenesulfonate further containing hydroxypropyl cellulose. [10] The orally disintegrating tablet according to [9], wherein the content of hydroxypropyl cellulose contained in (A) is 0.1 to 3.0% by weight per 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 comprising D-mannitol and alpha-starch. [12] The orally disintegrating tablet according to [11], wherein the content of D-mannitol contained in (B) is 20 to 55% by weight per 100% by weight of the orally disintegrating tablet, and the content of alpha-starch contained in (B) is 1.0 to 10% by weight per 100% by weight of the orally disintegrating tablet. [13] The orally disintegrating tablet as described in [4] or [5], wherein (B) is a drug-free mixed powder further comprising carboxymethylcellulose and acesulfame potassium. [14] The orally disintegrating tablet as described in [13], wherein the content of carboxymethylcellulose contained in (B) is 2.0 to 20% by weight per 100% by weight of the orally disintegrating tablet, and the content of acesulfame potassium contained in (B) is 1.0 to 5.0% by weight per 100% by weight of the orally disintegrating tablet. [15] A method for producing orally disintegrating tablets, comprising: mixing mirobalin benzenesulfonate, D-mannitol and citric acid hydrate, and spraying with a small molecule hydroxypropyl cellulose binding liquid to produce granules; mixing granules A, crystalline cellulose, carboxymethyl cellulose and acesulfame potassium, and then adding magnesium stearate to the mixed powder to prepare a mixture for tableting; and using a tableting machine to obtain tablets. [16] A method for producing an orally disintegrating tablet, comprising: mixing tocopherol and crystalline cellulose to prepare a tocopherol dispersion; mixing mirobalin benzenesulfonate, D-mannitol, carboxymethyl cellulose, citric acid hydrate, tocopherol dispersion, and magnesium aluminum metasilicate, and spraying the mixture with a hydroxypropyl cellulose binder to produce granules; mixing D-mannitol and crystalline cellulose, and spraying the mixture with an alpha starch dispersion to produce granules; mixing the above two granules, crospovidone, and potassium acesulfame, and then mixing with magnesium stearate to produce a mixture for tableting; The step of using a tablet machine to obtain tablets. [Effect of the invention]

可藉由本發明而提供一種含有米羅巴林苯磺酸鹽之安定性優良的口腔內崩散錠。 本發明之口腔內崩散錠，係特別為藉由含有檸檬酸水合物及生育酚，而米羅巴林苯磺酸鹽之安定性良好的口腔內崩散錠。 本發明之口腔內崩散錠，在含於口中時、或放入水中時會快速地崩散，顯示優良的溶解性，且口感良好。 本發明之口腔內崩散錠，係在通常之製造、輸送、使用時具有充分之硬度，且保存安定性優良的口腔內崩散錠。 本發明之口腔內崩散錠，可不需要複雜的步驟或特殊設備，而藉由通常之壓縮成形製造。 The present invention can provide an orally disintegrating tablet containing mirobalin benzenesulfonate with good stability. The orally disintegrating tablet of the present invention is an orally disintegrating tablet with good stability of mirobalin benzenesulfonate, especially containing citric acid hydrate and tocopherol. The orally disintegrating tablet of the present invention will disintegrate quickly when contained in the mouth or put into water, showing good solubility and good taste. The orally disintegrating tablet of the present invention has sufficient hardness during normal manufacturing, transportation and use, and has good storage stability. The orally disintegrating tablet of the present invention can be manufactured by normal compression molding without complicated steps or special equipment.

[用以實施發明的形態][Form used to implement the invention]

在本發明中「口腔內崩散錠」，係在含於口中時、或放入水中時，具有快速之崩散性、溶解性的壓縮成形物。具體而言，意指在口腔內之主要藉由唾液的崩散試驗、或藉由裝置的崩散試驗等中，通常在5～180秒、較佳為在5～60秒、進一步更佳在為5～40秒左右崩散的錠劑。In the present invention, "orally disintegrating tablets" are compressed products that have rapid disintegration and solubility when held in the mouth or placed in water. Specifically, it means tablets that usually disintegrate in 5 to 180 seconds, preferably in 5 to 60 seconds, and more preferably in 5 to 40 seconds in a disintegration test mainly by saliva in the oral cavity or a disintegration test by a device.

本發明之口腔內崩散錠，在通常之製造、輸送、使用之過程中具有充分的硬度。例如，在硬度試驗中，係通常具有硬度2kg以上的口腔內崩散錠，較佳為具有3kg以上、進一步更佳為具有5kg以上之硬度的口腔內崩散錠。The orally disintegrating tablet of the present invention has sufficient hardness in the usual manufacturing, transportation and use processes. For example, in a hardness test, the orally disintegrating tablet generally has a hardness of 2 kg or more, preferably 3 kg or more, and more preferably 5 kg or more.

本發明之口腔內崩散錠，係保持適於醫藥品的溶出性。例如，在溶出試驗中，係通常於30分鐘之時點顯示80%以上之平均溶出率，且較佳為顯示85%以上之溶出率的口腔內崩散錠。 溶出試驗，係在日本藥典第十八次修訂版之6.製劑試驗法6.10溶出試驗法中記載的溶出試驗。本試驗係為了針對經口製劑判定是否符合溶出試驗規格而進行者，但同時以防止顯著的非生體相等為目的。本試驗中之試料，意指相當於最小投與量者，就錠劑而言為1錠，就膠囊劑而言為1膠囊，就其他之製劑而言為所規定之量。就使用於本試驗之裝置而言，有旋轉籃法之裝置、槳法之裝置、流通池(flow through cell)法之裝置。關於其詳細情形，於日本藥典第十八次修訂版有記載。 The orally disintegrating tablet of the present invention maintains dissolution properties suitable for pharmaceutical products. For example, in the dissolution test, the orally disintegrating tablet usually shows an average dissolution rate of more than 80% at the 30-minute point, and preferably shows a dissolution rate of more than 85%. The dissolution test is a dissolution test described in 6. Preparation test method 6.10 Dissolution test method of the 18th revised edition of the Japanese Pharmacopoeia. This test is conducted to determine whether the oral preparation meets the dissolution test specifications, but at the same time, it is intended to prevent significant non-biological equivalence. The sample in this test means the equivalent of the minimum dosage, which is 1 tablet for tablets, 1 capsule for capsules, and the specified amount for other preparations. The devices used in this test include the rotating basket method, the paddle method, and the flow through cell method. Details are described in the 18th revised edition of the Japanese Pharmacopoeia.

本發明中所用的「米羅巴林(miragabalin)」，係下述式(I)所示的化合物：The "miragabalin" used in the present invention is a compound represented by the following formula (I):

。 .

本發明中所用的「米羅巴林苯磺酸鹽」，係包含米羅巴林及苯磺酸之鹽，以下述式(Ia)表示The "mirobaline benzenesulfonate" used in the present invention comprises a salt of mirobaline and benzenesulfonic acid, and is represented by the following formula (Ia):

。 .

本發明中所用的米羅巴林，被認為是在神經系統中透過與對於電位依存性鈣通道功能擔任輔助性角色的α2δ次單元之結合，而抑制鈣電流，藉以發揮鎮痛作用。Mirobalan used in the present invention is believed to exert analgesic effect by binding to α2δ subunits that play an auxiliary role in the function of potential-dependent calcium channels in the nervous system, thereby inhibiting calcium currents.

本發明中所用的米羅巴林苯磺酸鹽，係藉由於國內外實施之臨床試驗，而作為末梢性神經障礙性疼痛治療劑取得製造販賣認可，並販賣。Mirobalan benzylsulfonate used in the present invention has obtained manufacturing and sales approval as a therapeutic agent for peripheral neuropathy pain through clinical trials conducted domestically and overseas, and is sold.

末梢性神經障礙性疼痛之治療中，通常對成人，係以米羅巴林計，將初期用量1次5mg進行1日2次經口投與，然後拉開1週間以上的間隔而各漸增5mg作為1次用量，將1次15mg進行1日2次經口投與。再者，依據年齡、症狀而在1次10mg至15mg之範圍適宜增減，進行1日2次投與。In the treatment of peripheral neuropathy pain, for adults, the initial dose is 5 mg per oral administration twice a day, and then the dose is gradually increased by 5 mg at intervals of more than one week, and 15 mg is administered orally twice a day. Furthermore, the dose can be appropriately increased or decreased within the range of 10 mg to 15 mg per oral administration according to age and symptoms, and administered twice a day.

關於本發明之口腔內崩散錠的製造方法，於以下與其態樣(態樣A、及態樣B)一起說明。The method for producing the orally disintegrating tablet of the present invention is described below together with its embodiments (Aspect A and Aspect B).

態樣A： 將含有容積密度為0.26g/cm 3以下之結晶纖維素、D-甘露醇及α化澱粉的不含藥物之顆粒、與含米羅巴林苯磺酸鹽之顆粒壓縮成形所得到的口腔內崩散錠。 在本態樣中，不含藥物之顆粒，係作為可賦予口腔內崩散錠所期望之崩散性及成形性之製劑的骨骼而發揮功能。不含藥物之顆粒，即使只摻合容積密度為0.26g/cm 3以下之結晶纖維素、D-甘露醇、及α化澱粉的3種成分，亦可發揮優良的崩散性及成形性，但亦可視需要而摻合其他添加劑。 又，本態樣中的口腔內崩散錠，係藉由在含米羅巴林苯磺酸鹽之顆粒中添加檸檬酸水合物、及生育酚，而發揮優良的安定性。 態樣A之口腔內崩散錠的製造方法係包含：(1)製造不含藥物之顆粒的步驟，(2)製造含米羅巴林苯磺酸鹽之顆粒的步驟，及(3)將不含藥物之顆粒、含米羅巴林苯磺酸鹽之顆粒、及其他顆粒以外的混合粉末混合，並壓縮成形的步驟。 Aspect A: Orally disintegrating tablets obtained by compressing and molding drug-free granules containing crystalline cellulose with a bulk density of less than 0.26 g/cm 3 , D-mannitol, and alpha starch, and granules containing mirobalin benzenesulfonate. In this aspect, the drug-free granules function as the skeleton of the preparation that can give the orally disintegrating tablets the desired disintegration and formability. The drug-free granules can exhibit excellent disintegration and formability even if only three components of crystalline cellulose with a bulk density of less than 0.26 g/cm 3 , D-mannitol, and alpha starch are blended, but other additives can also be blended as needed. In addition, the orally disintegrating tablets in this embodiment have excellent stability by adding citric acid hydrate and tocopherol to the granules containing mirobalin benzenesulfonate. The method for manufacturing the orally disintegrating tablets of embodiment A comprises: (1) a step of manufacturing granules not containing a drug, (2) a step of manufacturing granules containing mirobalin benzenesulfonate, and (3) a step of mixing the granules not containing a drug, the granules containing mirobalin benzenesulfonate, and a mixed powder other than other granules, and compressing and molding.

(1)製造不含藥物之顆粒的步驟 採用以下之1)、或2)的方法，可製造不含藥物之顆粒。 1)將包含容積密度為0.26g/cm 3以下之結晶纖維素、D-甘露醇、及α化澱粉的混合物，藉由水而進行濕式造粒的方法。 2)將包含容積密度為0.26g/cm 3以下之結晶纖維素、及D-甘露醇的混合物，藉由使α化澱粉溶解或分散於水等中而成之液體而進行造粒的方法。 此處，於造粒可使用慣用之押出造粒法、混合攪拌造粒法、高速攪拌造粒法、流動層造粒法、或轉動造粒法等。 α化澱粉若溶解或分散於液體、例如水中，則會顯示適於造粒的黏性。進行造粒的方法中，有將α化澱粉以粉末狀態原樣與其他成分混合，藉由水而進行造粒的方法；以及藉由使α化澱粉溶解或分散於水中而成之液體而進行造粒的方法。任何方法皆可提供具有期望之性質的錠劑，然而較佳可舉出後者之方法。 又，使用使α化澱粉溶解或分散而成之液體進行造粒的情況，亦可採用高速攪拌造粒法及流動層造粒法之任一種方法，但在以流動層造粒法製造顆粒的情況，可得到更優良之口腔內崩散錠。在不含藥物之顆粒中摻合有慣用之崩散劑等其他添加劑的情況，可將其摻合在造粒前的混合物中。 不含藥物之顆粒中之容積密度為0.26g/cm 3以下之結晶纖維素與D-甘露醇的摻合比率，係相對於1重量份之結晶纖維素，D-甘露醇為1～3重量份，較佳為1～2重量份。 (1) Step of producing drug-free granules Drug-free granules can be produced by using the following method 1) or 2). 1) A method of wet granulating a mixture of crystalline cellulose having a bulk density of 0.26 g/ cm3 or less, D-mannitol, and alpha-starch with water. 2 ) A method of granulating a mixture of crystalline cellulose having a bulk density of 0.26 g/cm3 or less and D-mannitol with a liquid prepared by dissolving or dispersing alpha-starch in water or the like. Here, conventional extrusion granulation, mixing and stirring granulation, high-speed stirring granulation, fluidized bed granulation, or tumbling granulation can be used for granulation. If alpha starch is dissolved or dispersed in a liquid such as water, it will show a viscosity suitable for granulation. Among the methods of granulation, there are a method of mixing alpha starch in a powder state with other ingredients and granulating with water; and a method of granulating with a liquid obtained by dissolving or dispersing alpha starch in water. Any method can provide tablets with the desired properties, but the latter method is preferred. In addition, when granulating with a liquid obtained by dissolving or dispersing alpha starch, either a high-speed stirring granulation method or a fluidized layer granulation method can be used, but when granules are produced by the fluidized layer granulation method, better orally disintegrating tablets can be obtained. When other additives such as conventional disintegrating agents are mixed in the drug-free granules, they can be mixed in the mixture before granulation. The mixing ratio of crystalline cellulose and D-mannitol in the drug-free granules with a bulk density of 0.26 g /cm3 or less is 1 to 3 parts by weight of D-mannitol per 1 part by weight of crystalline cellulose, preferably 1 to 2 parts by weight.

(2)製造含米羅巴林苯磺酸鹽之顆粒的步驟 米羅巴林苯磺酸鹽可以粉末狀原樣、或視需要作成顆粒狀後，與不含藥物之顆粒混合。含米羅巴林苯磺酸鹽之顆粒，例如，可藉由慣用之押出造粒法、混合攪拌造粒法、高速攪拌造粒法、流動層造粒法、或轉動造粒法製造。 例如，亦可將粉末狀、或顆粒狀之米羅巴林苯磺酸鹽、D-甘露醇、羧甲基纖維素、檸檬酸水合物、生育酚10倍散(將生育酚與容積密度為0.26g/cm 3以下之結晶纖維素混合)、及偏矽酸鋁酸鎂的混合粉末，藉由使羥丙基纖維素溶解、或分散於水中而成之液體而進行造粒，而作成含米羅巴林苯磺酸鹽之顆粒。 又，亦可將粉末狀、或顆粒狀之米羅巴林苯磺酸鹽、D-甘露醇、羧甲基纖維素、檸檬酸水合物、生育酚10倍散(將生育酚與容積密度為0.26g/cm 3以下之結晶纖維素混合)、偏矽酸鋁酸鎂、及羥丙基纖維素的混合粉末，藉由水而進行造粒，而作成含藥物之顆粒。 例如，亦可將粉末狀、或顆粒狀之米羅巴林苯磺酸鹽、D-甘露醇、及檸檬酸水合物的混合粉末，藉由使小分子羥丙基纖維素溶解、或分散於水中而成之液體而進行造粒，而作成含米羅巴林苯磺酸鹽之顆粒。又，亦可將粉末狀、或顆粒狀之米羅巴林苯磺酸鹽、D-甘露醇、檸檬酸水合物、及小分子羥丙基纖維素的混合粉末，藉由水而進行造粒，作成含藥物之顆粒。 含米羅巴林苯磺酸鹽之顆粒，亦可為了苦味或刺激性等不快味道或氣味之遮蔽、或溶出性的控制，而施行塗覆。於塗覆，可適宜使用塗覆劑、及可塑劑。塗覆方法，係藉由使用例如流動層造粒・塗覆機、轉動流動層造粒・塗覆機、離心流動型造粒・塗覆機、沃斯特(Wurster)型流動層造粒・塗覆機而進行。 在使用2種以上之藥物的情況，可依據藥物彼此之摻合適性，而於同一顆粒內含有，或於不同顆粒中分別含有，而供予壓縮成形。 (2) Step of producing granules containing miropalin benzenesulfonate Miropalin benzenesulfonate can be prepared in a powdered form or in a granulated form as required, and then mixed with granules not containing a drug. Granules containing miropalin benzenesulfonate can be produced, for example, by conventional extrusion granulation, mixing and stirring granulation, high-speed stirring granulation, fluidized layer granulation, or tumbling granulation. For example, a mixed powder of powdered or granular mirobalin benzenesulfonate, D-mannitol, carboxymethyl cellulose, citric acid hydrate, 10-fold tocopherol powder (mixed with crystalline cellulose having a bulk density of 0.26 g/ cm3 or less), and magnesium aluminum metasilicate can be granulated with a liquid prepared by dissolving or dispersing hydroxypropyl cellulose in water to prepare granules containing mirobalin benzenesulfonate. In addition, a mixed powder of powdered or granular mirobalin benzenesulfonate, D-mannitol, carboxymethyl cellulose, citric acid hydrate, tocopherol 10 times powder (mixed with crystalline cellulose having a bulk density of 0.26 g/ cm3 or less), magnesium aluminum metasilicate, and hydroxypropyl cellulose can be granulated with water to prepare drug-containing granules. For example, a mixed powder of powdered or granular mirobalin benzenesulfonate, D-mannitol, and citric acid hydrate can be granulated with a liquid prepared by dissolving or dispersing small molecular weight hydroxypropyl cellulose in water to prepare granules containing mirobalin benzenesulfonate. In addition, a mixed powder of powdered or granular mirobalin benzenesulfonate, D-mannitol, citric acid hydrate, and small molecular weight hydroxypropyl cellulose can be granulated with water to prepare drug-containing granules. Granules containing mirobalin benzenesulfonate can also be coated to mask unpleasant tastes or odors such as bitterness or irritation, or to control solubility. For coating, a coating agent and a plasticizer can be appropriately used. The coating method is carried out by using, for example, a fluidized layer granulator/coater, a rotary fluidized layer granulator/coater, a centrifugal fluidized type granulator/coater, or a Wurster type fluidized layer granulator/coater. When two or more drugs are used, they can be contained in the same granule or in different granules according to their compatibility with each other and then subjected to compression molding.

(3)將不含藥物之顆粒、含米羅巴林苯磺酸鹽之顆粒、及其他顆粒外混合粉末混合，進行壓縮成形的步驟 將不含藥物之顆粒、含米羅巴林苯磺酸鹽之顆粒、及視需要之崩散劑、潤滑劑、其他添加劑混合，進行壓縮成形，而作成口腔內崩散錠。混合係藉由使用例如滾筒混合機(tumble mixer)、對流式混合機而進行。 本發明之口腔內崩散錠的壓縮成形，可使用通常之打錠機進行。來自打錠機的成形壓力，可為與通常之錠劑相同程度，雖隨錠劑之形狀、大小而異，但較佳為2～20kN、更佳為約4～14kN左右。 (3) A step of mixing the drug-free granules, the granules containing mirobalin benzenesulfonate, and other granular mixed powders and performing compression molding The drug-free granules, the granules containing mirobalin benzenesulfonate, and the disintegrant, lubricant, and other additives as required are mixed and compressed to form an orally disintegrating tablet. The mixing is performed by using, for example, a tumble mixer or a convection mixer. The compression molding of the orally disintegrating tablet of the present invention can be performed using a conventional tablet press. The forming pressure from the tablet press can be the same as that of ordinary tablets. Although it varies with the shape and size of the tablet, it is preferably 2 to 20 kN, and more preferably about 4 to 14 kN.

不含藥物之顆粒對錠劑成分總重量的摻合比率，若為30～90%即可。在藥物為粉末狀之情況，該摻合比率為30～80%，較佳為45～70%。在將藥物造粒而使用的情況，該摻合比率為30～80%，較佳為45～70%。又，在將藥物造粒而使用的情況，不含藥物之顆粒與含藥物之顆粒的摻合重量比，係以相對於含有藥物之顆粒1份，而不含藥物之顆粒1.0～3.5份為較佳。The blending ratio of the non-drug-containing granules to the total weight of the tablet ingredients is preferably 30 to 90%. When the drug is in powder form, the blending ratio is 30 to 80%, preferably 45 to 70%. When the drug is granulated and used, the blending ratio is 30 to 80%, preferably 45 to 70%. Furthermore, when the drug is granulated and used, the blending weight ratio of the non-drug-containing granules to the drug-containing granules is preferably 1.0 to 3.5 parts of the non-drug-containing granules to 1 part of the drug-containing granules.

態樣B： 將含有容積密度為0.26g/cm 3以下之結晶纖維素、D-甘露醇及α化澱粉的不含藥物之混合粉末、或其他顆粒之外的混合粉末、與含米羅巴林苯磺酸鹽之顆粒，進行壓縮成形而得到的口腔內崩散錠。 Sample B: An orally disintegrating tablet obtained by compressing a drug-free mixed powder containing crystalline cellulose with a bulk density of 0.26 g/cm 3 or less, D-mannitol and alpha-starch, or a mixed powder other than other granules, and granules containing miropalanine benzenesulfonate.

在態樣B中，不含藥物之混合粉末、或其他顆粒之外的混合粉末，係賦予作為口腔內崩散錠所期望的崩散性及成形性。 不含藥物之混合粉末，即使只摻合容積密度為0.26g/cm 3以下之結晶纖維素、D-甘露醇、及α化澱粉的3種成分，亦可發揮優良的崩散性及成形性，但亦可視需要而摻合其他添加劑。 又，其他顆粒之外的混合粉末，即使只摻合結晶纖維素、羧甲基纖維素、及乙醯磺胺酸鉀的3種成分，亦可發揮優良的崩散性及成形性，但亦可視需要而摻合其他添加劑。 In aspect B, the mixed powder without the drug or the mixed powder other than other granules is endowed with the desired disintegration and formability as an orally disintegrating tablet. The mixed powder without the drug can exhibit excellent disintegration and formability even if it is mixed with only three components of crystalline cellulose, D-mannitol, and alpha-starch having a bulk density of 0.26 g/cm 3 or less, but other additives can also be mixed as needed. In addition, the mixed powder other than other granules can exhibit excellent disintegration and formability even if it is mixed with only three components of crystalline cellulose, carboxymethyl cellulose, and acesulfame potassium, but other additives can also be mixed as needed.

態樣B之口腔內崩散錠的製造方法，係視需要而包含製造含米羅巴林苯磺酸鹽之顆粒的步驟；將含米羅巴林苯磺酸鹽之顆粒、及其他添加劑混合，進行壓縮成形的步驟。製造含米羅巴林苯磺酸鹽之顆粒的步驟，係與態樣A之(2)相同。The method for producing orally disintegrating tablets of aspect B comprises, as necessary, the steps of producing granules containing mirobalin benzenesulfonate; and the steps of mixing the granules containing mirobalin benzenesulfonate and other additives and compressing and forming the granules. The step of producing granules containing mirobalin benzenesulfonate is the same as (2) of aspect A.

在將含米羅巴林苯磺酸鹽之顆粒、及其他添加劑混合，進行壓縮成形的步驟中，混合或壓縮成形的步驟係與態樣A之(3)相同。In the step of mixing the granules containing mirobalin benzenesulfonate and other additives and compressing and molding, the mixing or compressing step is the same as that of (3) of aspect A.

如上述地得到的本發明之口腔內崩散錠，係於口腔內或放入水中時崩散性、溶解性優良，且物理上、化學上之安定性優良。The orally disintegrating tablet of the present invention obtained as described above has excellent disintegration and solubility in the oral cavity or in water, and has excellent physical and chemical stability.

本發明之口腔內崩散錠的崩散性或溶解性，係在口腔內之崩散、溶解時間(在健康成人男子之口腔內，口中不含水分，至錠劑僅藉由唾液而完全崩散或溶解為止的時間)，通常為在5～180秒、較佳為在5～60秒、進一步更佳為在5～40秒左右。 本發明之口腔內崩散錠，係含於口中時藉由唾液逐漸地崩散或溶解者，但藉由口腔內之壓迫，亦即利用上額及舌之壓力、或利用舌之摩擦，亦即“舔”之動作等，而於更短時間內崩散或溶解。口腔內乾燥之人、或唾液少之人，亦可使用水或熱水，而於口腔內崩散、溶解，或者與通常之錠劑同樣地，直接與水一起服用，亦無任何不可。 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, the time from when the tablet is completely disintegrated or dissolved by saliva alone without moisture in the mouth), which is usually 5 to 180 seconds, preferably 5 to 60 seconds, and more preferably about 5 to 40 seconds. The orally disintegrating tablet of the present invention gradually disintegrates or dissolves by saliva when contained in the mouth, but disintegrates or dissolves in a shorter time by pressure in the oral cavity, i.e., by using the pressure of the forehead and tongue, or by using the friction of the tongue, i.e., by the action of "licking", etc. People with dry mouth or little saliva can also use water or hot water to disintegrate and dissolve in the mouth, or take it directly with water like a normal tablet.

另一方面，本發明之口腔內崩散錠的硬度，在一定之溫度、濕度條件下(例如，溫度25℃、濕度75%、開放系、1週)的安定性試驗後，仍具有充分硬度。 因此，在製劑之製造步驟及配送過程中具有不崩散的硬度，在一定之溫度、濕度條件下的保存中亦具有實用之硬度，保存安定性、崩散性亦優良。 On the other hand, the hardness of the orally disintegrating tablet of the present invention still has sufficient hardness after the stability test under certain temperature and humidity conditions (for example, temperature 25°C, humidity 75%, open system, 1 week). Therefore, it has a hardness that does not disintegrate during the preparation manufacturing steps and distribution process, and also has a practical hardness during storage under certain temperature and humidity conditions, and the storage stability and disintegration are also excellent.

本發明之口腔內崩散錠，係可作為即使是老年者、兒童或吞嚥困難之患者亦容易服用之製劑，又可作為一般成人用之安全製劑，而使用於疾病之治療。The orally disintegrating tablet of the present invention can be used as a preparation that is easy to take even for the elderly, children or patients with difficulty swallowing, and can also be used as a safe preparation for general adults to treat diseases.

在本發明中所使用的「米羅巴林苯磺酸鹽」，較佳為其平均粒徑為60μm(更佳為40μm)以下。再者，本發明之「平均粒徑」，意指在藉由雷射繞射・散射法所求得的粒度分布中之累積值50%之粒徑。 在本發明中所使用的米羅巴林苯磺酸鹽，係以米羅巴林計，而每100重量%口腔內崩散錠中，較佳為0.5～40重量%，更佳為0.5～25重量%，特佳為0.5～10重量%。 The "mirobalin benzenesulfonate" used in the present invention preferably has an average particle size of 60 μm (more preferably 40 μm) or less. Furthermore, the "average particle size" of the present invention means the particle size of the cumulative value of 50% in the particle size distribution obtained by the laser diffraction and scattering method. The mirobalin benzenesulfonate used in the present invention is preferably 0.5 to 40% by weight, more preferably 0.5 to 25% by weight, and particularly preferably 0.5 to 10% by weight per 100% by weight of the orally disintegrating tablet, based on mirobalin.

在本發明中所使用的「D-甘露醇」，通常可使用符合日本、歐洲及美國之藥典者。摻合之D-甘露醇的結晶形、粒徑及比表面積並無特別限定，但結晶形可為α型、β型、δ型、非晶質之任一者，粒徑以10μm以上250μm以下為較佳，更佳為20μm以上150μm以下，比表面積以0.1m 2/g以上4m 2/g以下為較佳，更佳為0.1m 2/g以上2m 2/g以下，結晶形、粒徑及比表面積可分別藉由例如X射線繞射法、雷射繞射式粒度測定法、BET式比表面積測定法(多點法)而測定。就市售者而言，可舉出例如Merk公司、Roquette公司、東和化成公司、花王公司等之D-甘露醇。 The "D-mannitol" used in the present invention can generally be used in accordance with the pharmacopoeias of Japan, Europe and the United States. The crystal form, particle size and specific surface area of the blended D-mannitol are not particularly limited, but the crystal form can be any of α-type, β-type, δ-type and amorphous. The particle size is preferably 10 μm to 250 μm, more preferably 20 μm to 150 μm, and the specific surface area is preferably 0.1 m 2 /g to 4 m 2 /g, more preferably 0.1 m 2 /g to 2 m 2 /g. The crystal form, particle size and specific surface area can be measured by, for example, X-ray diffraction method, laser diffraction particle size measurement method, BET specific surface area measurement method (multi-point method), respectively. Commercially available products include D-mannitol from Merck, Roquette, Towa Chemical, and Kao Corporation.

使用D-甘露醇的情況，係每100重量%口腔內崩散錠中，通常為20～95重量%，較佳為20～55重量%。When D-mannitol is used, the content is usually 20 to 95% by weight, preferably 20 to 55% by weight, per 100% by weight of the orally disintegrating tablet.

D-甘露醇可以粉末原樣與其他成分混合而作成打錠粉末，進行壓縮成形，又，亦可使用適當之結合劑進行造粒後供予壓縮成形。D-mannitol can be mixed with other ingredients in powder form to form a tablet powder, which can then be compressed. Alternatively, it can be granulated with an appropriate binder and then compressed.

在本發明中所使用的「羧甲基纖維素」，係每100重量%口腔內崩散錠中，通常為1～20重量%，較佳為2～20重量%。The "carboxymethyl cellulose" used in the present invention is usually 1 to 20% by weight, preferably 2 to 20% by weight, per 100% by weight of the orally disintegrating tablet.

在本發明中所使用的「檸檬酸水合物」，係可作為醫藥品添加物而使用的檸檬酸水合物(例如，日本藥典合格品)，通常為檸檬酸一水合物。又，亦可使用檸檬酸酐代替檸檬酸水合物。The "citric acid hydrate" used in the present invention is a citric acid hydrate that can be used as a pharmaceutical additive (for example, a product that is qualified in the Japanese Pharmacopoeia), usually citric acid monohydrate. In addition, citric anhydride can also be used instead of citric acid hydrate.

在本發明中所使用的「檸檬酸水合物」及「生育酚」，係具有安定化劑之功能。本發明之檸檬酸水合物的含量，係每100重量%口腔內崩散錠中，較佳為0.01～10重量%，更佳為0.1～5.0重量%，進一步更佳為0.2～1.0重量%。 又，本發明之生育酚的含量，係每100重量%口腔內崩散錠中，較佳為0.01～10重量%，更佳為0.01～1.0重量%，進一步更佳為0.01～0.4重量%。 The "citric acid hydrate" and "tocopherol" used in the present invention have the function of stabilizers. The content of citric acid hydrate in the present invention is preferably 0.01 to 10% by weight, more preferably 0.1 to 5.0% by weight, and further preferably 0.2 to 1.0% by weight per 100% by weight of the orally disintegrating tablet. In addition, the content of tocopherol in the present invention is preferably 0.01 to 10% by weight, more preferably 0.01 to 1.0% by weight, and further preferably 0.01 to 0.4% by weight per 100% by weight of the orally disintegrating tablet.

在本發明中所使用的「結晶纖維素」，通常為容積密度0.10～0.46g/cm 3之等級，較佳為0.10～0.42g/cm 3，進一步更佳為0.10～0.26g/cm 3。就市售者而言，可舉出例如Ceolus KG-1000(容積密度0.10～0.15g/cm 3)、Ceolus KG-802(容積密度0.13～0.23g/cm 3)、Ceolus UF-711(容積密度0.20～0.26g/cm 3)(以上，旭化成Chmicals製)。又，亦可使用將容積密度相異的2種以上之結晶纖維素組合，而調整成為期望之容積密度者。 The "crystalline cellulose" used in the present invention generally has a bulk density of 0.10 to 0.46 g/cm 3 , preferably 0.10 to 0.42 g/cm 3 , and more preferably 0.10 to 0.26 g/cm 3 . Examples of commercially available cellulose include Ceolus KG-1000 (bulk density 0.10 to 0.15 g/cm 3 ), Ceolus KG-802 (bulk density 0.13 to 0.23 g/cm 3 ), and Ceolus UF-711 (bulk density 0.20 to 0.26 g/cm 3 ) (all manufactured by Asahi Kasei Chemicals). Furthermore, a combination of two or more types of crystalline cellulose having different bulk densities may be used to adjust the bulk density to a desired value.

上述結晶纖維素之摻合量，係每100重量%口腔內崩散錠中，以1.0～50重量%為較佳。若超過50重量%，則流動性惡化，有製造性降低的可能性。更佳之摻合量為5.0～30重量%。The blending amount of the above-mentioned crystalline cellulose is preferably 1.0 to 50 weight % per 100 weight % of the orally disintegrating tablet. If it exceeds 50 weight %, the fluidity may deteriorate and the manufacturability may be reduced. A more preferred blending amount is 5.0 to 30 weight %.

上述結晶纖維素與D-甘露醇之摻合比率，係相對於之結晶纖維素1重量份，D-甘露醇為1.0～10重量份，較佳為1.0～8.5重量份，更佳為1.0～3.0重量份。The blending ratio of the crystalline cellulose and D-mannitol is 1.0 to 10 parts by weight of D-mannitol per 1 part by weight of the crystalline cellulose, preferably 1.0 to 8.5 parts by weight, and more preferably 1.0 to 3.0 parts by weight.

本發明之口腔內崩散錠中，可含有無機賦形劑，就該無機賦形劑而言，可舉出選自合成水滑石、沉降碳酸鈣、含水二氧化矽、輕質無水矽酸、矽酸鋁酸鎂及氫氧化鎂的1種或2種以上之組合。The orally disintegrating tablet of the present invention may contain an inorganic filler, and the inorganic filler may be one or a combination of two or more selected from synthetic hydrotalcite, precipitated calcium carbonate, hydrous silica, light anhydrous silicic acid, magnesium aluminum silicate and magnesium hydroxide.

在本發明中所使用的「羥丙基纖維素」，只要維持作為口腔內崩散錠之期望的性質(崩散時間、硬度、溶出性)，則不被限定。The "hydroxypropyl cellulose" used in the present invention is not limited as long as it maintains the desired properties (disintegration time, hardness, solubility) as an orally disintegrating tablet.

本發明之口腔內崩散錠中的羥丙基纖維素之含量，係從成形性及對水之崩散性・懸浮性的觀點，而通常每100重量%口腔內崩散錠中，較佳為0.1～3.0重量%。在羥丙基纖維素之含量過多的情況，懸浮所需要之時間延長，作為口腔內崩散錠的適合性降低。The content of hydroxypropyl cellulose in the orally disintegrating tablet of the present invention is preferably 0.1 to 3.0% by weight per 100% by weight of the orally disintegrating tablet from the viewpoint of formability, disintegration in water, and suspension. If the content of hydroxypropyl cellulose is too high, the time required for suspension is prolonged, and the suitability as an orally disintegrating tablet is reduced.

在本發明中所使用的「小分子羥丙基纖維素」，為分子量140,000(GPS法)以下之羥丙基纖維素。含有小分子羥丙基纖維素之素錠，係具有兼具類緣物質生成抑制及崩散時間延長抑制之對口腔內崩散錠而言期望的性質。 本發明之口腔內崩散錠中之小分子羥丙基纖維素的含量，係每100重量%口腔內崩散錠中，較佳為0.1～2.0重量%。 The "small molecule hydroxypropyl cellulose" used in the present invention is hydroxypropyl cellulose with a molecular weight of 140,000 or less (GPS method). The tablet containing small molecule hydroxypropyl cellulose has the desired properties for orally disintegrating tablets, which is to inhibit the generation of quasi-substances and inhibit the extension of disintegration time. The content of small molecule hydroxypropyl cellulose in the orally disintegrating tablet of the present invention is preferably 0.1 to 2.0 weight % per 100 weight % of the orally disintegrating tablet.

在本發明中所使用的「類緣物質」，意指米羅巴林之內醯胺化物、及其他結構未確定的關連物質。The "related substances" used in the present invention refer to the lactamized form of miropalanine and other related substances whose structures are not determined.

本發明中之口腔內崩散錠，係除了上述成分以外，進一步含有交聯聚維酮(例如，日本藥典合格品)、及α化澱粉作為「崩散劑」。The orally disintegrating tablet of the present invention further contains crosslinked polyvidone (for example, a product qualified in the Japanese Pharmacopoeia) and alpha-starch as "disintegrating agents" in addition to the above ingredients.

上述α化澱粉係指將澱粉加熱處理而進行α化者，亦包含部分α化澱粉。又，就上述α化澱粉而言，可使用日本醫藥品添加物規格中所記載者。平均α化度以90%以下為較佳，更佳為70～80%。就市售者而言，例如，可使用α化澱粉SWELSTAR PD-1(旭化成Chemicals製)。The above-mentioned alpha starch refers to starch that is alpha-treated by heat treatment, and also includes partially alpha-treated starch. In addition, as for the above-mentioned alpha-treated starch, those listed in the Japanese Pharmaceutical Additives Standard can be used. The average alpha degree is preferably 90% or less, and more preferably 70 to 80%. As for commercially available ones, for example, alpha-treated starch SWELSTAR PD-1 (manufactured by Asahi Kasei Chemicals) can be used.

上述α化澱粉之摻合量，係每100重量%口腔內崩散錠中，通常為1.0～15重量%，較佳為1.0～10重量%。The blending amount of the above-mentioned alpha-starch is usually 1.0 to 15% by weight, preferably 1.0 to 10% by weight, per 100% by weight of the orally disintegrating tablet.

α化澱粉可以粉末原樣與其他成分混合而作成打錠粉末，進行壓縮成形，又，亦可與其他成分一起造粒後供予壓縮成形。The alpha starch can be mixed with other ingredients as a powder to make a tablet powder and then compressed. Alternatively, it can be granulated with other ingredients and then compressed.

在本發明之口腔內崩散錠中，α化澱粉係扮演作為崩散劑的角色，但在另一方面，於製造時，由於若溶解或分散於液體、例如水中，則會顯示黏性，故若對粉末狀態之原料進行噴霧，則造粒就進行，可作成顆粒。可利用此性質，對包含容積密度為0.26g/cm 3以下之結晶纖維素及D-甘露醇之粉末狀的混合物，噴霧將α化澱粉溶解或分散於水中而成之溶解液或分散液，進行流動層造粒法，藉此而製造顆粒，且藉由將其與視需要添加之其他成分混合，進行壓縮成形，而得到具有良好成形性及期望之口腔內崩散性的錠劑。此種製造上之優點，係在使用為慣用崩散劑之低置換度羥丙基纖維素、交聯聚維酮等的情況幾乎無法得到之α化澱粉特有的性質。 In the orally disintegrating tablet of the present invention, alpha starch plays a role as a disintegrating agent, but on the other hand, when it is manufactured, if it is dissolved or dispersed in a liquid such as water, it will show viscosity, so if the raw material in a powdered state is sprayed, granulation is performed and granules can be made. This property can be utilized to spray a solution or dispersion obtained by dissolving or dispersing alpha starch in water on a powdered mixture containing crystalline cellulose with a bulk density of 0.26 g/ cm3 or less and to perform a fluidized layer granulation method to manufacture granules, and by mixing it with other ingredients added as needed and performing compression molding, a tablet having good moldability and desired orally disintegrating properties can be obtained. The advantage of this manufacturing process is that it has the unique properties of alpha-starch, which is almost impossible to obtain when using low-substitution hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, etc., which are commonly used disintegrating agents.

上述交聯聚維酮之摻合量，係每100重量%口腔內崩散錠中，通常為0.5～20重量%，較佳為2.0～20重量%。The blending amount of the crosslinked polyvidone is usually 0.5 to 20 wt %, preferably 2.0 to 20 wt %, per 100 wt % of the orally disintegrating tablet.

本發明之口腔內崩散錠，只要不妨礙發明之效果，則可包含錠劑之製造一般所用的各種「添加劑」。The orally disintegrating tablet of the present invention may contain various "additives" generally used in the manufacture of tablets as long as they do not hinder the effects of the present invention.

就添加劑而言，可舉出例如結合劑、潤滑劑、塗覆劑、可塑劑、著色劑、著香劑、甜味劑、矯味劑、流動化劑、發泡劑及界面活性劑等。As additives, for example, binders, lubricants, coating agents, plasticizers, colorants, flavoring agents, sweeteners, flavor correctors, fluidizers, foaming agents, and surfactants may be cited.

就「結合劑」而言，可舉出例如選自阿拉伯膠、海藻酸鈉、羧基乙烯基聚合物、明膠、糊精、果膠、聚丙烯酸鈉、聚三葡萄糖(pullulan)、甲基纖維素、羥丙基纖維素、羥丙基甲基纖維素、聚乙烯基醇、聚乙烯基吡咯啶酮及聚乙二醇(Macrogol)的1種或2種以上之組合。As for the “binder”, for example, one or a combination of two or more selected from gum arabic, sodium alginate, carboxyvinyl polymer, gelatin, dextrin, pectin, sodium polyacrylate, pullulan, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone and polyethylene glycol (Macrogol) can be cited.

就「潤滑劑」而言，可舉出選自硬脂酸鎂(例如，日本藥典合格品)、硬脂酸鈣(例如，日本藥典合格品)、富馬酸硬脂酯鈉(例如，醫藥品添加物規格合格品)及滑石(例如，日本藥典合格品)的1種或2種以上之組合，特佳為硬脂酸鎂。 潤滑劑之摻合量，係每100重量%口腔內崩散錠中，較佳為0.1～5.0重量%。 As for the "lubricant", one or a combination of two or more selected from magnesium stearate (e.g., a product qualified in the Japanese Pharmacopoeia), calcium stearate (e.g., a product qualified in the Japanese Pharmacopoeia), sodium stearyl fumarate (e.g., a product qualified in the pharmaceutical additive specification) and talc (e.g., a product qualified in the Japanese Pharmacopoeia) can be cited, and magnesium stearate is particularly preferred. The blending amount of the lubricant is preferably 0.1 to 5.0 weight % per 100 weight % of the orally disintegrating tablet.

就「塗覆劑」而言，作為被覆粉末狀藥物之表面(結晶之表面)或造粒之藥物顆粒表面的塗覆劑，而可舉出選自乙基纖維素、甲基丙烯酸胺基烷酯共聚合物E、甲基丙烯酸共聚合物L、乾燥甲基丙烯酸共聚合物LD、甲基丙烯酸共聚合物LD、甲基丙烯酸共聚合物S、甲基丙烯酸胺基烷酯共聚合物RS、甲基丙烯酸胺基烷酯共聚合物RS、丙烯酸乙酯・甲基丙烯酸甲酯共聚合物、聚乙烯縮醛・二乙基胺基乙酸酯及聚乙酸乙烯酯樹脂的1種或2種以上之組合。As for the "coating agent", as a coating agent for coating the surface of a powdered drug (crystallized surface) or the surface of granulated drug particles, one or a combination of two or more 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-diethylaminoacetate and polyvinyl acetate resin can be cited.

就「可塑劑」而言，通常為與塗覆劑組合而使用者，可舉出選自癸二酸二乙酯、癸二酸二丁酯、檸檬酸三乙酯、硬脂酸、聚乙二醇及三乙醯甘油(triacetin)的1種或2種以上之組合。As for the "plasticizer", it is usually used in combination with a coating agent, and one or a combination of two or more selected from diethyl sebacate, dibutyl sebacate, triethyl citrate, stearic acid, polyethylene glycol and triacetin can be cited.

就「著色劑」而言，可舉出選自食用黃色5號、食用紅色2號、食用藍色2號等食用色素；食用色澱(lake)色素、黃色三氧化二鐵、三氧化二鐵、氧化鈦、β-胡蘿蔔素及核黃素的1種或2種以上之組合。As for the "coloring agent", there may be cited food coloring selected from food yellow No. 5, food red No. 2, food blue No. 2, etc.; food coloring (lake) coloring, yellow ferric oxide, ferric oxide, titanium oxide, β-carotene and riboflavin, one or a combination of two or more thereof.

就「著香劑」而言，可舉出選自橙橘、檸檬、草莓、薄荷、薄荷醇、薄荷醇微米(menthol micron)及各種香料的1種或2種以上之組合。As for the “fragrance”, one or a combination of two or more selected from orange, lemon, strawberry, mint, menthol, menthol micron and various flavors may be cited.

就「甜味劑」而言，可舉出選自糖精鈉、糖精(saccharin)、阿斯巴甜(aspartame)、乙醯磺胺酸鉀、甘草酸二鉀、蔗糖素(sucralose)、甜菊(stevia)及索馬甜(thaumatin)的1種或2種以上之組合。As for the “sweetener”, one or a combination of two or more selected from sodium saccharin, saccharin, aspartame, acesulfame potassium, dipotassium glycyrrhizinate, sucralose, stevia and thaumatin may be cited.

就「矯味劑」而言，可舉出選自氯化鈉、氯化鎂、肌苷酸二鈉、L-麩胺酸鈉及蜜糖的1種或2種以上之組合。As the “flavor corrector”, one or a combination of two or more selected from sodium chloride, magnesium chloride, disodium inosinate, sodium L-glutamate and honey can be cited.

就「流動化劑」而言，可舉出選自含水二氧化矽、輕質無水矽酸及滑石的1種或2種以上之組合。As the “fluidizing agent”, one or a combination of two or more selected from hydrous silica, light anhydrous silicic acid and talc can be cited.

就「發泡劑」而言，可舉出酒石酸等。As for the "foaming agent", tartaric acid and the like can be cited.

就「界面活性劑」而言，可舉出選自硬脂酸Polyoxyl 40、山梨醇酐脂肪酸酯、聚氧伸乙基硬化蓖麻油、聚山梨糖醇酯(Polysorbate)、單硬脂酸甘油及月桂基硫酸鈉的1種或2種以上之組合。 [實施例] As for the "surfactant", one or a combination of two or more selected from Polyoxyl 40 stearate, sorbitan fatty acid ester, polyoxyethylated castor oil, polysorbate, glyceryl monostearate and sodium lauryl sulfate can be cited. [Example]

以下，記載本發明之實施例，將本發明加以說明。 (實施例1)羥丙基纖維素之分子量及製劑之安定性 (1)A顆粒之調製 以表1所示的摻合比率量取米羅巴林苯磺酸鹽、D-甘露醇、檸檬酸水合物，使用PE袋，混合3分鐘，使用Comil整粒機(U-10，Φ1.143mm，QUADRO)，以1100 rpm篩分，得到過篩粉末。將過篩粉末投入流動層造粒機(FL-labo2L，FREUND)，在給氣溫度77℃下，以成為表1所示之摻合比率的方式，將小分子羥丙基纖維素結合液(7 wt/wt%，以精製水溶解)以約8 g/min進行噴霧，噴霧終了後，乾燥至製品溫度成為50℃。 使用Comil整粒機(U-10，Φ1.143mm，QUADRO)，以1100 rpm整粒，作成A顆粒。 (2)打錠用顆粒之調製 以表1所示之摻合比率量取A顆粒、結晶纖維素、羧甲基纖維素、乙醯磺胺酸鉀，使用V型混合機(5L)，以旋轉數34 rpm混合10分鐘，作成混合粉末。 繼而，以表1所示之摻合比率量取硬脂酸鎂，添加於混合粉末，使用V型混合機(5L)，以旋轉數34 rpm混合10分鐘，作成打錠用顆粒。 (3)錠劑之調製 使用打錠機(Virgo0524SS1AX，菊水製作所)，使錠劑質量為300 mg，以打錠壓力5.5 kN成形，得到素錠(12.1×6.4 mm)。 The following describes the examples of the present invention to illustrate the present invention. (Example 1) Molecular weight of hydroxypropyl cellulose and stability of preparation (1) Preparation of granules A Mirobalin benzenesulfonate, D-mannitol, and citric acid hydrate were weighed at the blending ratio shown in Table 1, mixed for 3 minutes using a PE bag, and sieved at 1100 rpm using a Comil granulator (U-10, Φ1.143 mm, QUADRO) to obtain a sieved powder. The sieved powder was put into a fluidized bed granulator (FL-labo2L, FREUND), and the small molecule hydroxypropyl cellulose binding liquid (7 wt/wt%, dissolved in purified water) was sprayed at about 8 g/min at an air supply temperature of 77°C in a manner to achieve the blending ratio shown in Table 1. After the spraying was completed, it was dried until the product temperature reached 50°C. Use a Comil granulator (U-10, Φ1.143mm, QUADRO) to granulate at 1100 rpm to produce A granules. (2) Preparation of granules for tableting Particle A, crystalline cellulose, carboxymethyl cellulose, and acesulfame potassium were weighed at the blending ratio shown in Table 1, and mixed at 34 rpm for 10 minutes using a V-type mixer (5 L) to prepare a mixed powder. Next, magnesium stearate was weighed at the blending ratio shown in Table 1, added to the mixed powder, and mixed at 34 rpm for 10 minutes using a V-type mixer (5 L) to prepare granules for tableting. (3) Preparation of tablets A tablet press (Virgo0524SS1AX, Kikusui Seisakusho) was used to prepare tablets with a mass of 300 mg, and the tablets were formed at a tableting pressure of 5.5 kN to obtain plain tablets (12.1×6.4 mm).

(比較例1)羥丙基纖維素之分子量與製劑之安定性 (1)A顆粒之調製 以表1所示之摻合比率量取米羅巴林苯磺酸鹽、D-甘露醇、檸檬酸水合物，使用PE袋，混合3分鐘，使用Comil整粒機(U-10，Φ1.143mm，QUADRO)，以1100 rpm篩分，作成過篩粉末。將過篩粉末投入流動層造粒機(FL-labo2L，FREUND)，在給氣溫度80℃下，以成為表1所示之摻合比率的條件方式，將羥丙基纖維素結合液(7 wt/wt%，以精製水溶解)以約8 g/min進行噴霧，噴霧終了後，乾燥至製品溫度成為50℃。 使用Comil整粒機(U-10，Φ1.143mm，QUADRO)，以1100 rpm整粒，作成A顆粒。 (2)打錠用顆粒之調製 以表1所示之摻合比率量取A顆粒、結晶纖維素、羧甲基纖維素、乙醯磺胺酸鉀，使用V型混合機(5L)，以旋轉數34 rpm混合10分鐘，作成混合粉末。繼而，以表1所示之摻合比率量取硬脂酸鎂，添加於混合粉末，使用V型混合機(5L)，以旋轉數34 rpm混合10分鐘，作成打錠用顆粒。 (3)錠劑之調製 使用打錠機(Virgo0524SS1AX，菊水製作所)，使錠劑質量為300 mg，以打錠壓力6 kN成形，得到素錠(12.1×6.4 mm)。 (Comparative Example 1) Molecular weight of hydroxypropyl cellulose and stability of preparation (1) Preparation of granules A Mirobalin benzenesulfonate, D-mannitol, and citric acid hydrate were weighed in the blending ratio shown in Table 1, mixed for 3 minutes using a PE bag, and sieved at 1100 rpm using a Comil granulator (U-10, Φ1.143 mm, QUADRO) to prepare a sieved powder. The sieved powder was put into a fluidized bed granulator (FL-labo2L, FREUND), and the hydroxypropyl cellulose binding liquid (7 wt/wt%, dissolved in purified water) was sprayed at about 8 g/min at an air supply temperature of 80°C to obtain the blending ratio shown in Table 1. After the spraying was completed, it was dried until the product temperature reached 50°C. Using a Comil granulator (U-10, Φ1.143mm, QUADRO), the granules were granulated at 1100 rpm to produce A granules. (2) Preparation of granules for tableting Particle A, crystalline cellulose, carboxymethyl cellulose, and potassium acesulfame were weighed at the blending ratio shown in Table 1, and mixed at 34 rpm for 10 minutes using a V-type mixer (5 L) to prepare a mixed powder. Next, magnesium stearate was weighed at the blending ratio shown in Table 1, added to the mixed powder, and mixed at 34 rpm for 10 minutes using a V-type mixer (5 L) to prepare granules for tableting. (3) Preparation of tablets A tablet press (Virgo0524SS1AX, Kikusui Seisakusho) was used to prepare tablets with a mass of 300 mg. The tablets were formed at a tableting pressure of 6 kN to obtain plain tablets (12.1×6.4 mm).

(評價方法及結果)羥丙基纖維素之分子量及製劑之安定性 將實施例1及比較例1之素錠，以40℃/75%RH之條件，於鋁袋中放置1個月後，使用HPLC(Agilent infinity 1290)，以表2所示之條件，測定類緣物質之生成量。又，崩散試驗係以日本藥典第17次修訂版之崩散試驗法為基準，於無輔助盤的情況下，評價初期品、及以40℃/75%RH之條件在鋁袋中放置3個月後之素錠。 將類緣物質之生成量的結果示於表3。得知：在使用小分子羥丙基纖維素(分子量140,000(GPS法)以下)之素錠，與使用通常的羥丙基纖維素(分子量1,000,000(GPS法)以下)之素錠相比，類緣物質之生成量成為約1/2。 將崩散試驗之結果示於表4。使用通常的羥丙基纖維素(分子量1,000,000(GPS法)以下)之素錠，雖於40℃/75%RH放置3個月後之崩散時間延長38秒，但是使用小分子羥丙基纖維素(分子量140,000(GPS法)以下)的素錠，崩散時間之延長少至12秒。 從以上之結果，顯示含有小分子羥丙基纖維素的素錠，具有兼具類緣物質生成抑制及崩散時間延長抑制之對口腔內崩散錠而言期望的性質。 [表1] 含有成分 組成(mg/錠) 實施例1 比較例1 A顆粒 米羅巴林苯磺酸鹽 26.34 26.34 D-甘露醇 (Pearlitol50C，Roquette) 49.64 51.06 檸檬酸水合物(Merck) 2.997 2.997 小分子羥丙基纖維素 (HPC-L(分子量140,000(GPS法)以下)、日本曹達股份有限公司) 2.205 - 羥丙基纖維素 (HPC-H(分子量1,000,000(GPS法)以下)、日本曹達股份有限公司) - 0.6075 結晶纖維素 (UF702，旭化成Chemicals股份有限公司) 180 180 羧甲基纖維素 (NS-300，五徳藥品股份有限公司) 30 30 乙醯磺胺酸鉀 (Sunett Pharma Grade D，丸善製藥) 3 3 硬脂酸鎂 (HyQual Code5712，Mallinckrodt) 6 6 合計 300 300 [表2] 測定波長 215 nm 管柱 Sunshell C18(2.1 mmID×100 nm、2.6 μm，ChromaNik製) 保護管柱 SecurityGuard ULTRA C18(2.1 mmID，Phenomenex製) 淨化管柱 Ghost Trap DS(7.6 mmID×30 mm，島津製) 管柱溫度 45℃ 移動層A 0.01 mol/L磷酸氫二銨緩衝液(pH 6.2) 移動層B 甲醇/乙腈/0.01 mol/L磷酸氫二銨緩衝液(pH 6.2)混液(9: 3: 4) 分析時間 35分鐘 注入量 3 μL 樣本冷卻器溫度 6℃附近之一定溫度 [表3] 類緣物質之生成量的差異 實施例1 比較例1 0.19% 0.39% [表4] 崩散試驗之結果   實施例1 比較例1 製造時 21秒 21秒 40℃/75%RH 3個月 33秒 59秒 (實施例2)結晶纖維素之摻合量及製劑之安定性 (1)A顆粒之調製 以表5所示之摻合比率量取生育酚及結晶纖維素，使用高速攪拌造粒機(VG-50，POWREX)，以刀片旋轉數180 rpm，切斷器旋轉數3000 rpm混合15分鐘，作成生育酚10倍散。 以表5所示之摻合比率量取米羅巴林苯磺酸鹽、D-甘露醇、羧甲基纖維素、檸檬酸水合物、生育酚10倍散、偏矽酸鋁酸鎂，使用V型混合機(30L)，以旋轉數27 rpm混合5分鐘，使用Comil整粒機(QC-194S，Φ1.143mm，QUADRO)，以600 rpm篩分，得到過篩粉末。將過篩粉末投入流動層造粒機(FLO-5)，在給氣溫度80℃下，以成為表5所示之摻合比率的方式，將羥丙基纖維素結合液(7 wt/wt%，以精製水溶解)以約40 g/min進行噴霧，噴霧終了後，乾燥至製品溫度成為55℃。 使用Comil整粒機(QC-194S，Φ1.143mm，QUADRO)，以1400 rpm整粒，作成A顆粒。 (2)B顆粒之調製 以表5所示之摻合比率量取D-甘露醇及結晶纖維素，投入流動層造粒機(GPCG-15，POWREX)，在給氣溫度85℃下，以成為表5所示之摻合比率的方式，將α化澱粉分散液(8 wt/wt%，以精製水溶解)以約140 g/min進行噴霧，噴霧終了後，乾燥至排氣溫度成為45℃。 使用Comil整粒機(QC-194S，Φ1.143mm，QUADRO)，以600 rpm整粒，得到B顆粒。 (3)打錠用顆粒之調製 以表5所示之摻合比率量取A顆粒、B顆粒、交聯聚維酮、乙醯磺胺酸鉀，使用V型混合機(10L)，以旋轉數32 rpm混合5分鐘，作成混合粉末。繼而，以表5所示之摻合比率量取硬脂酸鎂，添加於混合粉末，使用V型混合機(10L)，以旋轉數32 rpm混合10分鐘，作成打錠用顆粒。 (4)錠劑之調製 使用打錠機(Virgo0524SS1AX，菊水製作所)，使錠劑質量為300 mg，以打錠壓力8 kN成形，得到素錠(φ10.0 mm)。 (Evaluation method and results) Molecular weight of hydroxypropyl cellulose and stability of preparation The tablets of Example 1 and Comparative Example 1 were placed in aluminum bags at 40°C/75%RH for 1 month, and the amount of generated related substances was determined using HPLC (Agilent infinity 1290) under the conditions shown in Table 2. In addition, the disintegration test was based on the disintegration test method of the 17th revised edition of the Japanese Pharmacopoeia, and the initial product and the tablets placed in aluminum bags at 40°C/75%RH for 3 months were evaluated without an auxiliary plate. The results of the amount of generated related substances are shown in Table 3. It was found that the amount of hydroxypropyl cellulose produced in the tablets using small molecule hydroxypropyl cellulose (molecular weight 140,000 (GPS method) or less) was about 1/2 of that in the tablets using normal hydroxypropyl cellulose (molecular weight 1,000,000 (GPS method) or less). The results of the disintegration test are shown in Table 4. Although the disintegration time of the tablets using normal hydroxypropyl cellulose (molecular weight 1,000,000 (GPS method) or less) was extended by 38 seconds after being placed at 40°C/75%RH for 3 months, the extension of the disintegration time of the tablets using small molecule hydroxypropyl cellulose (molecular weight 140,000 (GPS method) or less) was as short as 12 seconds. The above results show that the tablets containing small molecule hydroxypropyl cellulose have the desired properties for orally disintegrating tablets, namely, inhibition of the production of quasi-substances and inhibition of the prolonged disintegration time. [Table 1] Contains ingredients Composition (mg/tablet) Embodiment 1 Comparative example 1 A granules Mirobalin benzenesulfonate 26.34 26.34 D-Mannitol (Pearlitol 50C, Roquette) 49.64 51.06 Citric acid hydrate (Merck) 2.997 2.997 Small molecule hydroxypropyl cellulose (HPC-L (molecular weight 140,000 (GPS method) or less), Japan Soda Co., Ltd.) 2.205 - Hydroxypropyl cellulose (HPC-H (molecular weight 1,000,000 (GPS method) or less), Nippon Soda Co., Ltd.) - 0.6075 Crystalline cellulose (UF702, Asahi Kasei Chemicals Co., Ltd.) 180 180 Carboxymethylcellulose (NS-300, Wude Pharmaceutical Co., Ltd.) 30 30 Acesulfame potassium (Sunett Pharma Grade D, Maruzen Pharmaceutical) 3 3 Magnesium stearate (HyQual Code5712, Mallinckrodt) 6 6 total 300 300 [Table 2] Measurement wavelength 215 nm String Sunshell C18 (2.1 mmID×100 nm, 2.6 μm, manufactured by ChromaNik) Protective column SecurityGuard ULTRA C18 (2.1 mmID, made by Phenomenex) Purification column Ghost Trap DS (7.6 mmID×30 mm, made by Shimadzu) Column temperature 45℃ Mobile Layer A 0.01 mol/L diammonium hydrogen phosphate buffer (pH 6.2) Mobile layer B Methanol/acetonitrile/0.01 mol/L diammonium hydrogen phosphate buffer (pH 6.2) mixture (9: 3: 4) Analysis time 35 minutes Injection volume 3 μL Sample cooler temperature A certain temperature around 6℃ [Table 3] Differences in the amount of generated substances Embodiment 1 Comparative example 1 0.19% 0.39% [Table 4] Results of the collapse test Embodiment 1 Comparative example 1 During manufacturing 21 seconds 21 seconds 40℃/75%RH 3 months 33 seconds 59 seconds (Example 2) Blending amount of crystalline cellulose and stability of preparation (1) Preparation of granules A Tocopherol and crystalline cellulose were measured at the blending ratio shown in Table 5 and mixed for 15 minutes using a high-speed stirring granulator (VG-50, POWREX) at a blade rotation speed of 180 rpm and a chopper rotation speed of 3000 rpm to prepare a tocopherol 10-fold powder. Mirobalin benzenesulfonate, D-mannitol, carboxymethyl cellulose, citric acid hydrate, tocopherol 10 times powder, and magnesium aluminum metasilicate were weighed in the blending ratio shown in Table 5, mixed at 27 rpm for 5 minutes using a V-type mixer (30L), and sieved at 600 rpm using a Comil granulator (QC-194S, Φ1.143 mm, QUADRO) to obtain a sieved powder. The sieved powder was put into a fluidized bed granulator (FLO-5), and a hydroxypropyl cellulose binding liquid (7 wt/wt%, dissolved in purified water) was sprayed at about 40 g/min at an air supply temperature of 80°C to obtain the blending ratio shown in Table 5. After the spraying was completed, the powder was dried until the product temperature reached 55°C. A Comil granulator (QC-194S, Φ1.143 mm, QUADRO) was used to granulate at 1400 rpm to obtain A granules. (2) Preparation of Granule B D-mannitol and crystalline cellulose were weighed at the blending ratio shown in Table 5 and put into a fluidized bed granulator (GPCG-15, POWREX). At a supply air temperature of 85°C, a dispersion of alpha starch (8 wt/wt%, dissolved in purified water) was sprayed at a rate of about 140 g/min to obtain the blending ratio shown in Table 5. After the spraying was completed, the mixture was dried until the exhaust air temperature reached 45°C. Granule B was obtained by using a Comil granulator (QC-194S, Φ1.143 mm, QUADRO) at 600 rpm. (3) Preparation of granules for tableting Granules A, Granules B, crosslinked povidone, and potassium acesulfame were weighed at the blending ratio shown in Table 5, and mixed at 32 rpm for 5 minutes using a V-type mixer (10 L) to prepare a mixed powder. Then, magnesium stearate was weighed at the blending ratio shown in Table 5, added to the mixed powder, and mixed at 32 rpm for 10 minutes using a V-type mixer (10 L) to prepare granules for tableting. (4) Preparation of tablets A tablet press (Virgo0524SS1AX, Kikusui Seisakusho) was used to prepare tablets with a mass of 300 mg, and the tablets were formed at a tableting pressure of 8 kN to obtain plain tablets (φ10.0 mm).

(比較例2)結晶纖維素之摻合量及製劑之安定性 (1)A顆粒之調製 以表5所示之摻合比率量取生育酚及結晶纖維素，使用高速攪拌造粒機(VG-50，POWREX)，以刀片旋轉數180 rpm、切斷器旋轉數3000 rpm混合15分鐘，作成生育酚10倍散。 以表5所示之摻合比率量取米羅巴林苯磺酸鹽、D-甘露醇、羧甲基纖維素、檸檬酸水合物、生育酚10倍散、偏矽酸鋁酸鎂，使用V型混合機(30L)，以旋轉數27 rpm混合5分鐘，使用Comil整粒機(QC-194S，Φ1.143mm，QUADRO)，以600 rpm篩分，得到過篩粉末。將過篩粉末投入流動層造粒機(FLO-5、FREUND)，在給氣溫度80℃下，以成為表5所示之摻合比率的方式，將羥丙基纖維素結合液(7 wt/wt%，以精製水溶解)以約40 g/min進行噴霧，噴霧終了後，乾燥至製品溫度成為55℃。 使用Comil整粒機(QC-194S，Φ1.143mm，QUADRO)，以1400 rpm整粒，作成A顆粒。 (2)打錠用顆粒之調製 以表5所示之摻合比率量取A顆粒、D-甘露醇、交聯聚維酮、乙醯磺胺酸鉀，使用V型混合機(10L)，以旋轉數32 rpm混合5分鐘，作成混合粉末。繼而，以表5所示之摻合比率量取硬脂酸鎂，添加於混合粉末，使用V型混合機(10L)，以旋轉數32 rpm混合10分鐘，作成打錠用顆粒。 (3)錠劑之調製 使用打錠機(Vela5，菊水製作所)，使錠劑質量為300 mg，以打錠壓力7 kN成形，得到素錠(φ9.5 mm)。 (Comparative Example 2) Blending amount of crystalline cellulose and stability of preparation (1) Preparation of granules A Tocopherol and crystalline cellulose were weighed at the blending ratio shown in Table 5 and mixed for 15 minutes using a high-speed stirring granulator (VG-50, POWREX) at a blade rotation speed of 180 rpm and a chopper rotation speed of 3000 rpm to prepare a 10-fold tocopherol powder. Mirobalin benzenesulfonate, D-mannitol, carboxymethyl cellulose, citric acid hydrate, tocopherol 10 times powder, and magnesium aluminum metasilicate were weighed in the blending ratio shown in Table 5, mixed at 27 rpm for 5 minutes using a V-type mixer (30L), and sieved at 600 rpm using a Comil granulator (QC-194S, Φ1.143 mm, QUADRO) to obtain a sieved powder. The sieved powder was put into a fluidized bed granulator (FLO-5, FREUND), and the hydroxypropyl cellulose binding liquid (7 wt/wt%, dissolved in purified water) was sprayed at about 40 g/min at an air supply temperature of 80°C in a manner to obtain the blending ratio shown in Table 5. After the spraying was completed, it was dried until the product temperature reached 55°C. Using a Comil granulator (QC-194S, Φ1.143mm, QUADRO), the granules were granulated at 1400 rpm to produce A granules. (2) Preparation of granules for tableting Granules A, D-mannitol, cross-linked povidone, and potassium acesulfame were weighed at the blending ratio shown in Table 5, and mixed at 32 rpm for 5 minutes using a V-type mixer (10 L) to prepare a mixed powder. Next, magnesium stearate was weighed at the blending ratio shown in Table 5, added to the mixed powder, and mixed at 32 rpm for 10 minutes using a V-type mixer (10 L) to prepare granules for tableting. (3) Preparation of tablets A tablet press (Vela5, Kikusui Seisakusho) was used to prepare tablets with a mass of 300 mg, and the tablets were formed at a tableting pressure of 7 kN to obtain plain tablets (φ9.5 mm).

(評價方法及結果)結晶纖維素之摻合量及製劑之安定性 將實施例2及比較例2之素錠以40℃/75%RH之條件，放置塑膠瓶中6個月後，使用HPLC(Agilent infinity 1290)，以表2所示之條件測定類緣物質的生成量。 將其結果示於表6。得知：在使用D-甘露醇、結晶纖維素及α化澱粉作為B顆粒之素錠(實施例2)，與不使用B顆粒且不使用結晶纖維素及α化澱粉的素錠(比較例2)相比，總類緣物質之生成量成為約1/3。 [表5] 含有成分 組成(mg/錠) 實施例2 比較例2 A顆粒 米羅巴林苯磺酸鹽 26.34 26.34 D-甘露醇 (Pearlitol50C，Roquette) 73.08 73.08 羧甲基纖維素 (NS-300，五徳藥品股份有限公司) 15 15 檸檬酸水合物(Merck) 1.5 1.5 生育酚(三菱化學食品) 0.21 0.21 結晶纖維素 (UF702，旭化成Chemicals股份有限公司) 0.189 0.189 偏矽酸鋁酸鎂 (UFL2，富士化學工業股份有限公司) 1.5 1.5 羥丙基纖維素 (HPC-H，日本曹達股份有限公司) 3.69 3.69 B顆粒 D-甘露醇 (Pearlitol50C，Roquette) 90 - 結晶纖維素 (KG802，旭化成Chemicals股份有限公司) 51 - α化澱粉 (SWELSTAR PD-1，旭化成Chemicals股份有限公司) 9 - D-甘露醇(Mannogem EZ，SPI pharma) - 150 交聯聚維酮 (Kollidon CL-F，BASF) 15 15 乙醯磺胺酸鉀 (Sunett Pharma Grade D，丸善製藥) 6 6 硬脂酸鎂 (HyQual Code5712，Mallinckrodt) 6 6 合計 300 300 [表6] 實施例2 比較例2 0.27% 0.74% (實施例3)結晶纖維素之摻合量及製劑之崩散時間、磨損度、及硬度 (1)錠劑之調製 使用實施例2所調製的打錠用顆粒，藉由打錠機(Virgo0524SS1AX，菊水製作所)，使錠劑質量為300 mg，以打錠壓力6、8、10 kN成形，得到素錠(φ10.0 mm)。 (Evaluation method and results) Blending amount of crystalline cellulose and stability of preparation The tablets of Example 2 and Comparative Example 2 were placed in plastic bottles at 40°C/75%RH for 6 months, and then the amount of generated related substances was measured using HPLC (Agilent infinity 1290) under the conditions shown in Table 2. The results are shown in Table 6. It was found that the amount of total related substances generated in the tablets using D-mannitol, crystalline cellulose and α-starch as B particles (Example 2) was about 1/3 of that in the tablets not using B particles and not using crystalline cellulose and α-starch (Comparative Example 2). [Table 5] Contains ingredients Composition (mg/tablet) Embodiment 2 Comparative example 2 A granules Mirobalin benzenesulfonate 26.34 26.34 D-Mannitol (Pearlitol 50C, Roquette) 73.08 73.08 Carboxymethylcellulose (NS-300, Wude Pharmaceutical Co., Ltd.) 15 15 Citric acid hydrate (Merck) 1.5 1.5 Tocopherol (Mitsubishi Chemical Foods) 0.21 0.21 Crystalline cellulose (UF702, Asahi Kasei Chemicals Co., Ltd.) 0.189 0.189 Magnesium aluminum metasilicate (UFL2, Fuji Chemical Industries, Ltd.) 1.5 1.5 Hydroxypropyl cellulose (HPC-H, Nippon Soda Co., Ltd.) 3.69 3.69 B granules D-Mannitol (Pearlitol 50C, Roquette) 90 - Crystalline cellulose (KG802, Asahi Kasei Chemicals Co., Ltd.) 51 - Alpha starch (SWELSTAR PD-1, Asahi Kasei Chemicals Co., Ltd.) 9 - D-Mannitol (Mannogem EZ, SPI pharma) - 150 Crosslinked polyvinylpyrrolidone (Kollidon CL-F, BASF) 15 15 Acesulfame potassium (Sunett Pharma Grade D, Maruzen Pharmaceutical) 6 6 Magnesium stearate (HyQual Code5712, Mallinckrodt) 6 6 total 300 300 [Table 6] Embodiment 2 Comparative example 2 0.27% 0.74% (Example 3) Blending amount of crystalline cellulose and disintegration time, abrasion resistance, and hardness of the preparation (1) Preparation of tablets The granules prepared in Example 2 were used to prepare tablets with a mass of 300 mg. The tablets were formed at tableting pressures of 6, 8, and 10 kN to obtain plain tablets (φ10.0 mm).

(比較例3)結晶纖維素之摻合量及製劑之崩散時間、磨損度、及硬度 (1)錠劑之調製 使用比較例2所調製的打錠用顆粒，藉由打錠機(Vela5，菊水製作所)，使錠劑質量為300 mg，以打錠壓力6、8、10 kN成形，得到素錠(9.5 mm)。 (Comparative Example 3) Blending amount of crystalline cellulose and disintegration time, abrasion resistance, and hardness of the preparation (1) Preparation of tablets Using the tablet granules prepared in Comparative Example 2, the tablet mass was adjusted to 300 mg by a tablet press (Vela5, Kikusui Seisakusho), and the tablets were formed at tableting pressures of 6, 8, and 10 kN to obtain plain tablets (9.5 mm).

(評價方法及結果)結晶纖維素之摻合量及製劑之崩散時間、磨損度、及硬度 將製造之素錠的評價結果示於表7~9。錠劑之硬度係使用全自動錠劑測定裝置(Type WHT-2，PHARMA TEST APPRATEBAU GmbH)測定。又，崩散試驗係以日本藥典第17次修訂版之崩散試驗法為基準，於無輔助盤的情況下進行評價。磨損度試驗係使用錠劑磨損度試驗機(SZ-03，林間工業)測定。 儘管實施例3與比較例3相比而硬度低，但顯示磨損度變低，被賦予良好的磨損度。再者，得知：實施例3以約略相同硬度之素錠，而與比較例3相比，崩散時間縮短至約1/2。 從以上之結果，顯示含有D-甘露醇、結晶纖維素及α化澱粉作為B顆粒的素錠，具有兼具低磨損度及短崩散時間之對口腔內崩散錠而言期望之性質。 [表7] 打錠壓 實施例3 比較例3 硬度 6 kN 2.8 kg 4.1 kg 8 kN 4.3 kg 5.5 kg 10 kN 5.7 kg 7.5 kg [表8] 打錠壓 實施例3 比較例3 磨損度 6 kN 2.2% 2.0% 8 kN 0.7% 1.3% 10 kN 0.4% 1.0% [表9] 打錠壓 實施例3 比較例3 崩散時間 6 kN 21秒 40秒 8 kN 26秒 49秒 10 kN 31秒 65秒 (實施例4)生育酚及製劑之安定性 (1)A顆粒之調製 以表10所示之摻合比率量取生育酚及結晶纖維素，使用高速攪拌造粒機(VG-50、POWREX)，以刀片旋轉數180 rpm、切斷器旋轉數3000 rpm混合15分鐘，作成生育酚10倍散。 以表10所示之摻合比率量取米羅巴林苯磺酸鹽、D-甘露醇、羧甲基纖維素、檸檬酸水合物、生育酚10倍散、偏矽酸鋁酸鎂，使用V型混合機(2L)，以旋轉數39 rpm，混合5分鐘，使用Comil整粒機(U-10，Φ1.143mm，QUADRO)，以2200 rpm篩分，得到過篩粉末。將過篩粉末投入流動層造粒機(FLO-5)，在給氣溫度78℃下，以成為表10所示之摻合比率的方式，將羥丙基纖維素結合液(7 wt/wt%，以精製水溶解)以約7 g/min進行噴霧，噴霧終了後，乾燥至製品溫度成為55℃。 使用Comil整粒機(U-10，Φ1.143mm，QUADRO)，以2200 rpm整粒，作成A顆粒。 (2)B顆粒之調製 以表10所示之摻合比率量取D-甘露醇及結晶纖維素，投入流動層造粒機(NFLO-5，FREUND)，在給氣溫度85℃下，以成為表10所示之摻合比率的方式，將α化澱粉分散液(8 wt/wt%，以精製水溶解)以約45 g/min進行噴霧，噴霧終了後，乾燥至排氣溫度成為45℃。 使用Comil整粒機(QC-197，Φ1.143mm，QUADRO)，以800 rpm整粒，作成B顆粒。 (3)打錠用顆粒之調製 以表10所示之摻合比率量取A顆粒、B顆粒、交聯聚維酮、乙醯磺胺酸鉀，使用V型混合機(2L)，以旋轉數39 rpm混合5分鐘，作成混合粉末。繼而，以表10所示之摻合比率量取硬脂酸鎂，添加於混合粉末中，使用V型混合機(2L)，以旋轉數39 rpm混合5分鐘，作成打錠用顆粒。 (4)錠劑之調製 使用打錠機(Virgo0524SS1AX，菊水製作所)，使錠劑質量為300 mg，以打錠壓力6 kN成形，得到素錠(12.1×6.4 mm)。 (Evaluation method and results) The evaluation results of the prepared plain tablets, the amount of crystalline cellulose blended, and the disintegration time, abrasion, and hardness of the preparation are shown in Tables 7 to 9. The hardness of the tablets was measured using a fully automatic tablet measuring device (Type WHT-2, PHARMA TEST APPRATEBAU GmbH). In addition, the disintegration test was based on the disintegration test method of the 17th revised edition of the Japanese Pharmacopoeia, and the evaluation was performed without an auxiliary disk. The abrasion test was measured using a tablet abrasion tester (SZ-03, Linjian Industry). Although Example 3 has a lower hardness than Comparative Example 3, it shows a lower abrasion and is given good abrasion. Furthermore, it is known that the disintegration time of Example 3 is shortened to about 1/2 compared with that of Comparative Example 3 with a plain tablet of approximately the same hardness. The above results show that the plain tablet containing D-mannitol, crystalline cellulose and alpha-starch as B particles has the desired properties for an orally disintegrating tablet, namely, low abrasiveness and short disintegration time. [Table 7] Tablet pressure Embodiment 3 Comparative example 3 hardness 6 kN 2.8 kg 4.1 kg 8 kN 4.3 kg 5.5 kg 10 kN 5.7 kg 7.5 kg [Table 8] Tablet pressure Embodiment 3 Comparative example 3 Wear 6 kN 2.2% 2.0% 8 kN 0.7% 1.3% 10 kN 0.4% 1.0% [Table 9] Tablet pressure Embodiment 3 Comparative example 3 disintegration time 6 kN 21 seconds 40 seconds 8 kN 26 seconds 49 seconds 10 kN 31 seconds 65 seconds (Example 4) Stability of tocopherol and preparation (1) Preparation of A granules Tocopherol and crystalline cellulose were measured at the blending ratio shown in Table 10 and mixed for 15 minutes using a high-speed stirring granulator (VG-50, POWREX) at a blade rotation speed of 180 rpm and a chopper rotation speed of 3000 rpm to prepare a tocopherol 10-fold powder. Mirobalin benzenesulfonate, D-mannitol, carboxymethyl cellulose, citric acid hydrate, tocopherol 10 times powder, and magnesium aluminum metasilicate were weighed in the blending ratio shown in Table 10, mixed for 5 minutes at a rotation speed of 39 rpm using a V-type mixer (2L), and sieved at 2200 rpm using a Comil granulator (U-10, Φ1.143 mm, QUADRO) to obtain a sieved powder. The sieved powder was put into a fluidized bed granulator (FLO-5), and a hydroxypropyl cellulose binding liquid (7 wt/wt%, dissolved in purified water) was sprayed at about 7 g/min at an air supply temperature of 78°C in a manner to obtain the blending ratio shown in Table 10. After the spraying was completed, it was dried until the product temperature reached 55°C. A Comil granulator (U-10, Φ1.143 mm, QUADRO) was used to granulate at 2200 rpm to produce A granules. (2) Preparation of B granules D-mannitol and crystalline cellulose were weighed at the blending ratio shown in Table 10 and placed in a fluidized bed granulator (NFLO-5, FREUND). At a supply air temperature of 85°C, a dispersion of alpha starch (8 wt/wt%, dissolved in purified water) was sprayed at a rate of about 45 g/min to obtain the blending ratio shown in Table 10. After the spraying was completed, the mixture was dried until the exhaust air temperature reached 45°C. A Comil granulator (QC-197, Φ1.143 mm, QUADRO) was used to granulate at 800 rpm to obtain B granules. (3) Preparation of granules for tableting Granules A, Granules B, crosslinked povidone, and potassium acesulfame were weighed at the blending ratio shown in Table 10, and mixed at a rotation speed of 39 rpm for 5 minutes using a V-type mixer (2 L) to prepare a mixed powder. Then, magnesium stearate was weighed at the blending ratio shown in Table 10, added to the mixed powder, and mixed at a rotation speed of 39 rpm for 5 minutes using a V-type mixer (2 L) to prepare granules for tableting. (4) Preparation of tablets A tablet press (Virgo0524SS1AX, Kikusui Seisakusho) was used to prepare tablets with a mass of 300 mg, and the tablets were formed at a tableting pressure of 6 kN to obtain plain tablets (12.1×6.4 mm).

(比較例4)生育酚及製劑之安定性 (1)A顆粒之調製 以表10所示之摻合比率量取米羅巴林苯磺酸鹽、D-甘露醇、羧甲基纖維素、檸檬酸水合物、偏矽酸鋁酸鎂，使用V型混合機(5L)，以旋轉數34 rpm混合5分鐘，使用Comil整粒機(QC-197，Φ1.143mm，QUADRO)，以2200 rpm篩分，作成過篩粉末。將過篩粉末投入流動層造粒機(NFLO-5，FREUND)，在給氣溫度80℃下，以成為表10所示之摻合比率的方式，將羥丙基纖維素結合液(7 wt/wt%，以精製水溶解)以約7 g/min進行噴霧，噴霧終了後，乾燥至製品溫度成為55℃。 使用Comil整粒機(QC-197，Φ1.143mm，QUADRO)，以2200 rpm整粒，作成A顆粒。 (2)B顆粒之調製 以表10所示之摻合比率量取D-甘露醇及結晶纖維素，投入流動層造粒機(NFLO-5，FREUND)，在給氣溫度85℃下，以成為表1所示之摻合比率的方式，將α化澱粉分散液(8 wt/wt%，以精製水溶解)以約45 g/min進行噴霧，噴霧終了後，乾燥至排氣溫度成為45℃。 使用Comil整粒機(QC-197，Φ1.143mm，QUADRO)，以800 rpm整粒，作成B顆粒。 (3)打錠用顆粒之調製 以表10所示之摻合比率量取A顆粒、B顆粒、交聯聚維酮、乙醯磺胺酸鉀，使用V型混合機(5L)，以旋轉數34 rpm混合5分鐘，作成混合粉末。繼而，以表10所示之摻合比率量取硬脂酸鎂，添加於混合粉末中，使用V型混合機(5L)，以旋轉數34 rpm混合10分鐘，作成打錠用顆粒。 (4)錠劑之調製 使用打錠機(Virgo0524SS1AX，菊水製作所)，使錠劑質量為300 mg，以打錠壓力6 kN成形，得到素錠(12.1×6.4 mm)。 (Comparative Example 4) Stability of tocopherol and preparations (1) Preparation of Granule A Mirobalin benzenesulfonate, D-mannitol, carboxymethyl cellulose, citric acid hydrate, and magnesium aluminum metasilicate were weighed in the blending ratio shown in Table 10, mixed at 34 rpm for 5 minutes using a V-type mixer (5L), and sieved at 2200 rpm using a Comil granulator (QC-197, Φ1.143 mm, QUADRO) to prepare a sieved powder. The sieved powder was put into a fluidized bed granulator (NFLO-5, FREUND), and the hydroxypropyl cellulose binding liquid (7 wt/wt%, dissolved in purified water) was sprayed at about 7 g/min at an air supply temperature of 80°C in a manner to obtain the blending ratio shown in Table 10. After the spraying was completed, it was dried until the product temperature reached 55°C. A Comil granulator (QC-197, Φ1.143mm, QUADRO) was used to granulate at 2200 rpm to produce A granules. (2) Preparation of B granules D-mannitol and crystalline cellulose were weighed at the blending ratio shown in Table 10 and put into a fluidized bed granulator (NFLO-5, FREUND). At a supply air temperature of 85°C, a dispersion of alpha starch (8 wt/wt%, dissolved in purified water) was sprayed at a rate of about 45 g/min to obtain the blending ratio shown in Table 1. After the spraying was completed, the mixture was dried until the exhaust air temperature reached 45°C. Use a Comil granulator (QC-197, Φ1.143 mm, QUADRO) to granulate at 800 rpm to obtain B granules. (3) Preparation of granules for tableting Particle A, particle B, crosslinked povidone, and potassium acesulfame were weighed at the blending ratio shown in Table 10, and mixed at 34 rpm for 5 minutes using a V-type mixer (5L) to prepare a mixed powder. Then, magnesium stearate was weighed at the blending ratio shown in Table 10, added to the mixed powder, and mixed at 34 rpm for 10 minutes using a V-type mixer (5L) to prepare granules for tableting. (4) Preparation of tablets A tablet press (Virgo0524SS1AX, Kikusui Seisakusho) was used to prepare tablets with a mass of 300 mg. The tablets were formed at a tableting pressure of 6 kN to obtain plain tablets (12.1×6.4 mm).

(評價方法及結果)生育酚及製劑之安定性 將實施例4及比較例4之素錠以25℃/75%RH之條件，以無包裝條件放置後，使用HPLC(Agilent infinity 1290)，以表2所示之條件測定類緣物質的生成量。 將其結果示於表11。得知：在使用生育酚之素錠，與未使用生育酚之素錠相比，總類緣物質的生成量成為約1/2。 [表10] 含有成分 組成(mg/錠) 實施例4 比較例4 A顆粒 米羅巴林苯磺酸鹽 26.34 26.34 D-甘露醇 (Pearlitol50C，Roquette) 73.76 74.96 羧甲基纖維素 (NS-300，五徳藥品股份有限公司) 15 15 檸檬酸水合物(Merck) 1.5 1.5 生育酚(三菱化學食品) 0.12 - 結晶纖維素 (UF702，旭化成Chemicals股份有限公司) 1.08 - 偏矽酸鋁酸鎂 (UFL2，富士化學工業股份有限公司) 1.5 1.5 羥丙基纖維素 (HPC-H，日本曹達股份有限公司) 3.69 3.69 B顆粒 D-甘露醇 (Pearlitol50C，Roquette) 90 90 結晶纖維素 (KG802，旭化成Chemicals股份有限公司) 51 51 α化澱粉 (SWELSTAR PD-1，旭化成Chemicals股份有限公司) 9 9 交聯聚維酮 (Kollidon CL-F，BASF) 15 15 乙醯磺胺酸鉀 (Sunett Pharma Grade D，丸善製藥) 6 6 硬脂酸鎂 (HyQual Code5712，Mallinckrodt) 6 6 合計 300 300 [表11]   實施例4 比較例4 25℃/75%RH 6個月 0.71% 1.64% (Evaluation method and results) Stability of tocopherol and preparations The tablets of Example 4 and Comparative Example 4 were placed without packaging at 25°C/75%RH, and then the amount of generated substances was measured using HPLC (Agilent infinity 1290) under the conditions shown in Table 2. The results are shown in Table 11. It was found that the amount of total generated substances in the tablets using tocopherol was about 1/2 of that in the tablets not using tocopherol. [Table 10] Contains ingredients Composition (mg/tablet) Embodiment 4 Comparative example 4 A granules Mirobalin benzenesulfonate 26.34 26.34 D-Mannitol (Pearlitol 50C, Roquette) 73.76 74.96 Carboxymethylcellulose (NS-300, Wude Pharmaceutical Co., Ltd.) 15 15 Citric acid hydrate (Merck) 1.5 1.5 Tocopherol (Mitsubishi Chemical Foods) 0.12 - Crystalline cellulose (UF702, Asahi Kasei Chemicals Co., Ltd.) 1.08 - Magnesium aluminum metasilicate (UFL2, Fuji Chemical Industries, Ltd.) 1.5 1.5 Hydroxypropyl cellulose (HPC-H, Nippon Soda Co., Ltd.) 3.69 3.69 B granules D-Mannitol (Pearlitol 50C, Roquette) 90 90 Crystalline cellulose (KG802, Asahi Kasei Chemicals Co., Ltd.) 51 51 Alpha starch (SWELSTAR PD-1, Asahi Kasei Chemicals Co., Ltd.) 9 9 Crosslinked polyvinylpyrrolidone (Kollidon CL-F, BASF) 15 15 Acesulfame potassium (Sunett Pharma Grade D, Maruzen Pharmaceutical) 6 6 Magnesium stearate (HyQual Code5712, Mallinckrodt) 6 6 total 300 300 [Table 11] Embodiment 4 Comparative example 4 25℃/75%RH 6 months 0.71% 1.64%

無。without.

無。without.

無。without.

Claims (14)

一種口腔內崩散錠，其含有：(A)含米羅巴林苯磺酸鹽之顆粒；及(B)含有結晶纖維素的不含藥物之顆粒、或含有結晶纖維素的不含藥物之混合粉末；其中(B)進一步含有D-甘露醇及α化澱粉。 An orally disintegrating tablet comprising: (A) granules containing mirobalin benzenesulfonate; and (B) drug-free granules containing crystalline cellulose, or drug-free mixed powder containing crystalline cellulose; wherein (B) further contains D-mannitol and alpha-starch. 如請求項1之口腔內崩散錠，其中(A)所含有的米羅巴林苯磺酸鹽之平均粒徑為60μm以下，其含量以米羅巴林計，為每100重量%口腔內崩散錠中0.5~10重量%。 For example, in the orally disintegrating tablet of claim 1, the average particle size of mirobalin benzenesulfonate contained in (A) is less than 60 μm, and its content, calculated as mirobalin, is 0.5 to 10% by weight per 100% by weight of the orally disintegrating tablet. 如請求項1或2之口腔內崩散錠，其中(B)所含有的結晶纖維素之容積密度為0.10~0.26g/cm3，其含量為每100重量%口腔內崩散錠中1.0~50重量%。 The orally disintegrating tablet of claim 1 or 2, wherein the crystalline cellulose contained in (B) has a bulk density of 0.10-0.26 g/cm 3 and is contained in an amount of 1.0-50 wt % per 100 wt % of the orally disintegrating tablet. 如請求項1或2之口腔內崩散錠，其中(A)為進一步含有小分子羥丙基纖維素的含米羅巴林苯磺酸鹽之顆粒。 For orally disintegrating tablets as claimed in claim 1 or 2, wherein (A) is granules containing mirobalin benzenesulfonate further containing low-molecule hydroxypropyl cellulose. 如請求項4之口腔內崩散錠，其中(A)所含有的小分子羥丙基纖維素之含量，為每100重量%口腔內崩散錠中0.1~2.0重量%。 For example, in the orally disintegrating tablet of claim 4, the content of small molecule hydroxypropyl cellulose contained in (A) is 0.1-2.0% by weight per 100% by weight of the orally disintegrating tablet. 如請求項1或2之口腔內崩散錠，其中(A)為進一步含有檸檬酸水合物及生育酚的含米羅巴林苯磺酸鹽之顆粒。 The orally disintegrating tablet of claim 1 or 2, wherein (A) is a granule containing mirobalin benzenesulfonate further containing citric acid hydrate and tocopherol. 如請求項6之口腔內崩散錠，其中(A)所含有的檸檬酸水合物之含量，為每100重量%口腔內崩散錠中0.2~1.0重量%，(A)所含有的生育酚之含量，為每100重量%口腔內崩散錠中0.01~0.4重量%。 For example, the orally disintegrating tablet of claim 6, wherein the content of citric acid hydrate contained in (A) is 0.2-1.0% by weight per 100% by weight of the orally disintegrating tablet, and the content of tocopherol contained in (A) is 0.01-0.4% by weight per 100% by weight of the orally disintegrating tablet. 如請求項3之口腔內崩散錠，其中(A)為進一步含有D-甘露醇及羧甲基纖維素的含米羅巴林苯磺酸鹽之顆粒。 The orally disintegrating tablets as claimed in claim 3, wherein (A) is granules containing mirobalin benzenesulfonate further containing D-mannitol and carboxymethyl cellulose. 如請求項6之口腔內崩散錠，其中(A)為進一步含有羥丙基纖維素的含米羅巴林苯磺酸鹽之顆粒。 The orally disintegrating tablet of claim 6, wherein (A) is granules containing mirobalin benzenesulfonate further containing hydroxypropyl cellulose. 如請求項9之口腔內崩散錠，其中(A)所含有的羥丙基纖維素之含量，為每100重量%口腔內崩散錠中0.1~3.0重量%。 For example, in the orally disintegrating tablet of claim 9, the content of hydroxypropyl cellulose contained in (A) is 0.1-3.0 weight % per 100 weight % of the orally disintegrating tablet. 如請求項6之口腔內崩散錠，其中(B)為不含藥物之顆粒。 For orally disintegrating tablets as in claim 6, (B) is a granule containing no drug. 如請求項11之口腔內崩散錠，其中(B)所含有的D-甘露醇之含量，為每100重量%口腔內崩散錠中20~55重量%，(B)所含有的α化澱粉之含量，為每100重量%口腔內崩散錠中1.0~10重量%。 For example, the orally disintegrating tablet of claim 11, wherein the content of D-mannitol contained in (B) is 20-55% by weight per 100% by weight of the orally disintegrating tablet, and the content of alpha-starch contained in (B) is 1.0-10% by weight per 100% by weight of the orally disintegrating tablet. 如請求項4之口腔內崩散錠，其中(B)為進一步含有羧甲基纖維素及乙醯磺胺酸鉀的不含藥物之混合粉末。 The orally disintegrating tablets as claimed in claim 4, wherein (B) is a drug-free mixed powder further containing carboxymethylcellulose and acesulfame potassium. 如請求項13之口腔內崩散錠，其中(B)所含有的羧甲基纖維素之含量，為每100重量%口腔內崩散錠中2.0~20重量%，(B)所含有的乙醯磺胺酸鉀之含量，為每100重量%口腔內崩散錠中1.0~5.0重量%。 For example, the orally disintegrating tablet of claim 13, wherein the content of carboxymethyl cellulose contained in (B) is 2.0-20% by weight per 100% by weight of the orally disintegrating tablet, and the content of acesulfame potassium contained in (B) is 1.0-5.0% by weight per 100% by weight of the orally disintegrating tablet.
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