200835527 九、發明說明： t發明所眉之技術領域3 技術領域 於近來的口服投予劑中，係被期待能有對於吞啤能力 5 低的高齡者或兒童而言亦可輕易服用的製劑，而已開發了 數種可於口腔内迅速崩解，且能在幾乎未感覺到苦味之下 服用的製劑。 於抗精神病藥之領域中，因可以口腔内的唾液來迅速 崩解而不可需水服用的口腔内崩解錠劑、幾乎不會感到苦 10味之苦味抑制製劑等，亦被期待是否能從「服藥遵從性 (compliance)」進一步前進，而與稱為「服藥嚴守性 (adherence)」之患者積極治療參加、提高服藥行為有關。 再者，因亦為對過於興奮或激烈拒絶的急性患者亦可容易 接受的劑型，故亦認為在治療上有極大的價值。 15 本發明係有關於一種已被作為抗精神病藥使用的理思 必妥(risperidone)之口腔内崩解錠劑及苦味抑制製劑。 t先前技術3 背景技術 為確保服藥後的易崩解 於製造口腔内崩解錠劑時， 例如以下所述的文獻。200835527 IX. Description of the invention: Technical field of the invention of the invention 3 In the recent oral administration, it is expected that it can be easily taken for elderly people or children with a low ability to swallow beer, Several formulations have been developed which can be rapidly disintegrated in the oral cavity and can be taken under almost no bitter taste. In the field of antipsychotic drugs, oral disintegrating tablets which can be rapidly disintegrated without the use of saliva in the oral cavity, and bitterness-suppressing preparations which hardly feel bitterness of 10 flavors, are also expected to be able to "Compliance" is further advanced, and it is related to the active treatment and participation of patients who are called "adherence". Furthermore, it is also considered to be of great value in treatment because it is also an easily acceptable dosage form for acute patients who are too excited or strongly rejected. The present invention relates to an oral disintegrating lozenge and a bitter suppressing preparation which have been used as an antipsychotic risperidone. t Prior Art 3 Background Art In order to ensure disintegration after administration of a drug, an intraoral disintegrating tablet is produced, for example, the literature described below.
專利文獻2中，係記載有包含有醫藥成分、d 20性，-般會使用糖類、糖醇及/或崩解劑。教示有包含有 糖類、糖醇、崩解劑等之口腔内崩解旋劑等之文獻，可舉 再者，於 甘露糖醇、 5 200835527 、、截、准素類以及崩解劑之口腔内崩解錠劑。本文獻係揭示有 以平均粒彳：為3〇〜3叫m^D _甘露糖醇為佳之文獻。專 利文獻1及2，係摻合於口腔内崩解鍵劑之處方中最常被使 用來作為添加劑之橋類、糖醇與崩解劑，以加快崩解時間 5 的處方例。 於專利文獻3中，係記載包含有於成形性低的糖類中 將成开；I*生局的糖類作為結合劑而進行喷霧之造粒物的口腔 内崩解鍵劑之製造法。於專利文獻4中，係記載到可藉由 將使無機物”糖類均勻分散的懸浮液進行喷霧乾燥之粉體 10物，與結晶纖維素、崩解劑等共同進行打鍵，而得到口腔 内崩解鍵劑。另-方面，亦記載到將由同様的組成所構成 的單純混合物進行直接打錠的錠劑之硬度會很差。然後， 於專利文獻5中，係記載有於藥效成分中混合輕質無水石夕 酸等之表面處理基劑，並使用高速攪拌造粒機等進行表面 15處理，並於依此得到的表面處理粉體中添加崩解劑且直接 打錠，藉此可得到口腔内崩解錠劑。並記載有崩解劑以部 分^化澱粉以及交聯聚維酮最適合。該等專利文獻3、4及 5之製劑中，為使崩解性以及錠劑的硬度提升，則必須要追 加製劑步驟，而使得生產效率不佳。 於專利文獻6中，係記載有可於包含有水易溶性藥物 之顆粒摻合崩解劑，再添加纖維素粉末及/或無機系添加 物後，進行打錠而得到崩解性良好的錠劑。此專利文獻6， 係衣蜊之崩解時間大大超過3分鐘者，而並無法滿足作為 口腔内崩解錠劑之崩解時間。 6 200835527 再者’非專利文獻1(協和化學工業股份有限公司之小 冊(供直接打錠的賦形劑無水填酸氫詞GS))中，係記載有 摻合有結晶纖維素、無水磷酸氫鈣、羧甲基纖維素、以及 硬脂酸镁1重量％之製劑的資料。本製劑作為潤滑劑的硬 5脂酸鎮之摻合量係丨％，而會有在加溫以及加濕化下減低錠 劑崩解性之虞。 另一方面，係開發有各種抑制苦味的製劑。具體而言， :專引文獻7中，係記載有於溶解有作為疏水性高分子之 乙基纖維素與作為水溶性高分子之經丙基纖維素的乙醇溶 1〇液中添加苦味物質，並將該溶液與賦形劑混合之製劑。再 者，於專利文獻8中，係記載有在錢用疏水性高分子時， 於此合有碳青黴烯系抗生素與乳糖之粉末中，將胃溶性塗 =基劑之乙醇溶液進行噴霧而製造的顆粒劑中，進—步： =礼糖，乙稀t线酮等，並將經丙基纖維素之匕 進订策霧’而抑制了苦味的細粒劑。 夜 於將&水性高分子作為基劑使用的如專 之☆未抑制製劑之情形中，雖可抑制苦味，但會抑^獻7 ^之溶解速度的可能性很高。抑制溶解速度時，二理思 20 為亦會變動’岐思必妥錢亦有㈣之虞 令出行 利文獻7及8任一愔形、 者，於專 抑制苦味的納I 料有贿知容解 ^ 的基J。然而，此時有必要附設機械性 备劑的機器，而亦會對環境產生不良影響。枚有機 —已被作為抗精神病藥使用的理思必妥，係 π的苯并異噚唑衍生物： 式表 7 200835527 【化1】In Patent Document 2, it is described that a pharmaceutical ingredient and a d 20 are contained, and a saccharide, a sugar alcohol, and/or a disintegrating agent are generally used. The literature includes an oral disintegration rotator such as a saccharide, a sugar alcohol, or a disintegrator, and the like, and may be exemplified in the oral cavity of mannitol, 5 200835527, a cut, a quasi-class, and a disintegrating agent. Disintegrating tablets. This document discloses that the average granules are 3 〇 to 3, called m ^ D _ mannitol. Patent Documents 1 and 2 are prescriptions which are most commonly used as an additive bridge, a sugar alcohol and a disintegrant in the case of incorporation into an orally disintegrating agent to accelerate the disintegration time 5. Patent Document 3 describes a method for producing an orally disintegrating agent containing a granulated product which is sprayed into a saccharide having a low formability and which is opened as a binder. Patent Document 4 describes that a powder 10 which can be spray-dried by a suspension in which an inorganic substance "fine sugar is uniformly dispersed" is bonded together with a crystalline cellulose, a disintegrator or the like to obtain an oral cavity collapse. In addition, it is described that the hardness of a tablet which is directly tableted by a simple mixture composed of the same composition is poor. Then, in Patent Document 5, it is described that it is mixed in the medicinal ingredient. a surface treatment base such as light anhydrous arsenoic acid, and surface 15 treatment using a high-speed stirring granulator, and adding a disintegrant to the surface-treated powder thus obtained and directly ingot, thereby obtaining Oral disintegrating lozenge. It is also described that a disintegrant is most suitable for partially-treating starch and crospovidone. In the preparations of Patent Documents 3, 4 and 5, in order to make disintegration and hardness of the tablet In the case of lifting, it is necessary to add a preparation step, which results in poor production efficiency. In Patent Document 6, it is described that a disintegrating agent can be blended in a particle containing a water-soluble drug, and then a cellulose powder and/or an inorganic substance is added. Additive Ingots are obtained by tableting to obtain a tablet having good disintegration properties. In Patent Document 6, the disintegration time of the coat is much longer than 3 minutes, and the disintegration time as an orally disintegrating tablet is not satisfied. 6 200835527 Further, in Non-Patent Document 1 (a booklet of Kyowa Chemical Industry Co., Ltd. (excipients for direct injection of anhydrous hydrogen-filled hydrogen GS)), it is described that crystalline cellulose and anhydrous calcium hydrogen phosphate are blended. , carboxymethyl cellulose, and 1% by weight of magnesium stearate preparations. The amount of hard oleic acid blended as a lubricant in this preparation is 丨%, and there will be heating and humidification On the other hand, various formulations for suppressing bitterness have been developed. Specifically, in the literature 7, it is described that ethylcellulose as a hydrophobic polymer is dissolved in A formulation in which a bitter substance is added to a propylcellulose-soluble ethanol-soluble liquid of a water-soluble polymer, and the solution is mixed with an excipient. Further, in Patent Document 8, it is described that it is hydrophobic in money. In the case of a polymer, there is a carbapenem-resistant antibiotic. In the powder of the pigment and the lactose, the granules prepared by spraying the stomach-soluble coating solution of the base agent are sprayed into the granules, and the following steps are carried out: = sugar, ethylene t-ketone, etc. A fine granule that inhibits the bitterness of the formulation. In the case where the ☆ uninhibited preparation is used as a base, it can suppress bitterness, but it suppresses 7 ^ The possibility of dissolution rate is very high. When suppressing the dissolution rate, Ericsson 20 will also change. The bitter taste of the material I has the basis of bribes to understand the ^. However, at this time it is necessary to attach a mechanical preparation machine, but it will also have an adverse effect on the environment. Organic - has been used as an antipsychotic Sibital, a benzoisoxazole derivative of π: Formula 7 200835527 [Chemical 1]
且作為對多巴胺D2受體以及血清素5 — HT2A受體兩者 展現拮抗作用的非典型抗精神病藥來使用。本劑係對精神 5 分裂症之陽性與陰性任一者的症狀皆展現改善作用，而較 少非典型抗精神病藥之副作用（體重增加），且產生糖尿病的 危險也很低（參照專利文獻9)。 【專利文獻1】特開平10— 182436 【專利文獻2】特開2001 —58944 10 【專利文獻3】W095/20380 【專利文獻4】特開2000—86537 【專利文獻5】WOOO/54752 【專利文獻6】特開2002— 12540 【專利文獻7】特開2002 — 363066 15 【專利文獻8】特開2004—35518 【專利文獻9】特開昭61 — 221186 【非專利文獻1】協和化學工業股份有限公司之小冊（直 接打錠用賦形劑無水磷酸氫鈣GS) 【發明内容】 20 發明内容 發明所欲解決之課題 8 200835527 於理思必妥之錠劑中，提供一種硬度適當，於口腔内 迅速崩解且具有良好服用感，且不需要特殊製劑機械，可 以既存設備生産的口腔内崩解疑劑以及抑制理思必妥的苦 咮之苦味抑制製劑。 $ 解決課題的方法 本發明人發現藉由將包含有理思必妥、結晶纖維素、 無機賦形劑、作為崩解劑的特別是羧甲基纖維素以及每1 疑錠劑0.8重量％以下，較佳為0.5重量％以下，更佳為 〇·1重量％以下的潤滑劑之粉末直接壓縮成形，而可得到展 1〇 現良好的崩解性並確保錠劑硬度之口腔内崩解錠劑。前述 情形中，藉由將作為無機賦形劑之無水碟酸氫約、作為潤 滑劑之硬脂酸金屬鹽之摻合量調整成每1錠錠劑0.8重量 %以下，較佳為0 5重量％以下，更佳為重量％以下， 特別是摻合理思必妥、結晶纖維素、無水麟酸氫舞、叛甲 I5基纖維素以及每1錠錠劑0.1重量％以下之硬脂酸鎂，日 以外部潤滑法壓縮成形，藉此可得到展現良好的崩解性並 確保錠劑硬度之口腔内崩解錠劑。 2〇 冉者，本發明人在全力研究改善如上述苦味抑制 ㈣的製劑，結果發現只要是於純度之液中使理思必二 懸斤’且將依此得到的液體加至賦形劑及/或崩 粒所製侍之粉、粒體製劑(例如散劑 二 衆劑），即可抑制苦味，m 顆叔劑、糖 =中記叙添加物㈣於醫藥品添加物事典年本^ 份有限公司藥事日報公司發行）中所記載者。 年，版 9 200835527 亦即’本發明係有關於以下發明。 ⑴-種纏’其魏在於包含有m妥、結晶纖維素、 無機賦形劑、羧甲基纖維素以及每丨錠錠劑重量％以 下之潤滑劑； m 0 5 (2)如前述（1)所記載之錠劑，其中前述無 酸氫鈣； 機賦形劑係無水磷 ⑶如前述⑴或(2)所記載之錠劑，係含有每ι⑽劑〇 $重 量％以下之潤滑劑； ⑷如前述⑶所記載之錠劑，係含有每丨峰劑G]重 10 以下之潤滑劑； (5)如前述⑴至(4)之任-項中所記載之錠劑，係含有每i鍵 錠劑1〜30重量％之羧甲基纖維素； ⑹如刚述⑴至(5)之任一項中所記載之錠劑，其中前述潤滑 劑係硬脂酸金屬鹽； 15⑺如前述⑹所記載之錠劑，其中前述硬脂酸金屬鹽係硬脂 酸鎂； ⑻士月〕述⑴至⑺之任一項中所記載之錠劑，係含有甜味 劑； ()$述(8)所记載之錠劑，其中前述甜味劑係在將白糖之 2〇甜未田作1時，具有50倍以上甜度之甜味劑； ()而述(9)所記載之錠劑，其中前述甜味劑係醋石黃内酯 鉀或蔗糖素； (11)如刚述⑴至（1Q)之任一項中所記載之鍵劑，其中前述潤 滑劑之添加方法為外部潤滑法； 200835527 (12) 如前述（11)所記載之錠劑，係含有理思必妥、結晶纖維 素、無水磷酸氫鈣、羧甲基纖維素以及每丨錠錠劑01重 量％以下之硬脂酸鎂，且潤滑劑之添加方法為外部潤滑法； (13) 如前述（1)至（12)之任一項中所記載之錠劑，其係口腔内 5 崩解錠劑； (14) 如前述（1)所圮載之錠劑，含有理思必妥、結晶纖維素、 無機賦形劑、羧甲基纖維素以及每丨錠錠劑〇·8重量％以 下之潤滑劑，但不含有糖類以及糖醇類； (15) —種含有理思必妥的粉、粒體製劑之製造方法，係特徵 10 在於含有以下之步驟： 1 )使理思必女懸浮於黏度(2〇。〇為50〜14000mPa · s的液 體中； 1 1 )將於前記1 )步驟中獲得的溶液或懸浮液加至賦形劑 及/或崩解劑中後，進行造粒； Θ I5 (16)如月|^述（15)所記栽之粉、粒體製劑之製造方法，其中气 液體之黏度(2(TC)係1〇〇〜14⑻〇mPa.s; 、 Μ (17)如月述（15)或（ι6)所記載之粉、粒體製劑之製造方法， 其中該液體巾含有㈣基素； 項中 (18)一種粉、粒體製劑，係藉由前述（15)至（17)之任一 2〇所記載之製造方法所獲得者· (19)如前述(18)所記栽II、粒體製劑 ，其係顆粒劑； (=如月述(18)或(19)所記載之粉、粒體製劑，係已抑制苦 (21)種!疋劑之製造方法，其特徵在於將前述㈣中所記栽 11 200835527 之粉、粒體製劑打疑； (22)—種錠劑之製造方法，其特徵在於在前述(2〇)中所記载 之粉、粒體製劑中混合賦形劑、潤滑劑、崩解劑及/或結 合劑並且打疑； 5 (23) —種錠劑，係藉由前述(21)或(22)中所記載之製造方法 而獲得者； (24)如前述(23)所記載之錠劑，其係口腔内崩解錠劑。 發明之效果 本發明之錠劑即使無水亦可輕易服用，且可於口腔内 1〇迅速崩解，又具有適當的硬度，且服用感良好。因此，可 作為口腔内崩解錠劑來使用。此外，該錠劑之製造法相當 簡便。再者，本發明之苦味抑制製劑、係於高黏性的添加 物液中使苦味成分理思必妥懸浮，並將所獲得之液體加至 賦形劑及/或崩解劑中，並進行造粒，藉此達成理思必妥 15之苦味抑制者。本發明之苦味抑制製劑可抑制苦味，而不 會抑制理思必妥之溶解。 C資施方式3 「一種口腔内崩解錠劑，係含有理思必妥、結晶纖維 素、無機賦形劑、羧甲基纖維素以及每丨錠錠劑ga8重量 2。％以下之潤滑劑」係指，藉由包含有理思必妥、結晶纖維 素、無機賦形劑、敌甲基纖維素以及每i鍵鍵劑〇8重量 %以下之潤滑劑，以發揮本糾效果(㈣之良好崩解性以 及適當鍵劑硬度之確⑹的製劑之意。將理思必妥、結晶纖 維素、無機賦形劑、叛甲基纖維素以及每1錠錠劑0.8重 12 200835527 量％以下之潤滑劑作為必須構成成分，而在不影響本發明 效果的範圍内，亦可包含有其他添加劑。 於本發明之錠劑中所含有的藥物理思必妥之含量，係 每1錠錠劑0·1〜6重量％，而以0.125〜4重量％為宜，又 5以〇·25〜2.5重量％更佳。若比此含量更少，含量均一性會 有惡化的可能性，若比此含量更多，會有變得容易感到苦 味的可能性。 於本發明之錠劑中所使用的結晶纖維素，雖只要是於 醫藥領域中所使用者即可，但具體而言可舉例如Ceolus 10 PH101、Ceolus PH102、Ceolus PH301、Ceolus PH302、艾 維素(Avicel) PH — F20JP、Ceolus KG802(旭化成工業（股) 製）、VIVAPUR(等級 105、101、103、301、102、112)、 ARBOCEL(等級 M80、P290、A300)、Prosolv SMCC50、 Prosolv SMCC90(JRS PHARMA公司製）等。該等結晶纖維 15 素雖可單獨使用，但亦可併用二種以上。較佳地，錠劑製 造前的結晶纖維素之平均粒徑為10〜150//m，且以30〜 130//m為宜，特別是以40〜120//m為佳。比該平均粒徑 更大或更小時，會有錠劑之硬度降低、崩解時間延遲的可 能性。具體而言，以Ceolus PH102(旭化成工業（股）製，平 2〇 均粒徑約100//m)為佳。 於本發明之錠劑中所使用的無機賦形劑，雖只要是於 醫藥領域中所使用者即可，但具體而言可舉例如填酸氫 詞、無水碟酸氫約、鎮铭偏石夕酸鹽、合成水滑石、沉殿碳 酸鈣、碳酸鎂，且特別是以無水磷酸氫鈣：無水磷酸氫鈣 13 200835527 GS(協和化學工業股份有限公司製）、叫&仙(富士化學工 業股伤有限公司）、無水填酸氫約輕質（協和化學工業股份有 限公司製）、無水鱗酸氫約重質(協和化學卫業股份有=司 製）等為佳。該等無機賦形劑雖可單獨使用，但亦可併用二 5種以上。錠劑製造前之無機賦形劑的總體密度以山邛〜；!.％ /mL為宜，又以為佳，且特別是以〇 6〜 l.〇g/mL更佳。比此總體密度更低或更高時，會有錠劑之 硬度降低，崩解時間延遲的可能性。具體而言，以無水鱗 酸氫約GS(協和化學工業股份有限公司製、總體密度〇71 10 〜1.0g/mL)為佳。 於本發明之錠劑中’結晶纖維素與無機賦形劑無水磷 酸氫鈣之含量係可輕易決定。舉例而言，將所希望量的結 晶纖維素、無水磷酸氫鈣、羧甲基纖維素與活性成分適當 混合後，進行壓縮成形，並確認硬度與崩解性，藉此輕易 15 地判別其適當與否。 因結晶纖維素與無機賦形劑之含量亦依存於活性成分 之物理性質，故依前述般適當決定為宜。特別是，以使用 相對於錠劑全重量30〜99·9重量％之結晶纖維素以及無機 賦形劑為宜。且特別是，以使用5〇〜99 9重量％之結晶纖 2〇維素以及無機賦形劑為佳。於該等含量中，不易受到活性 成分之物理性質的影響，本發明製劑係展現特別良好的崩 解速度以及錠劑硬度。 再者’結晶纖維素與無水磷酸氫鈣的重量比亦以依前 述般適當決定為宜，且結晶纖維素與無水磷酸氫鈣之重量 14 200835527 比只要在8 : 2〜2 : 8之範圍内即可。於前述範圍内，玎得 到具有良好的崩解速度以及錠劑硬度的口腔内速崩解錠。 若結晶纖維素之重量比比其高則會有因結晶纖維素的粗糙 感而降低口感的可能性，又結晶纖維素之重量比比其低則 5 會有錠劑硬度降低的可能。以將結晶纖維素與無水磷酸氫 #5以重量比5 : 5〜3 : 7之比例含有之錠劑為宜，且以將結 晶纖維素與無水構酸氫妈以重量比約4 : 6之比例含有之|定 劑更佳。 於本發明之錠劑中’結晶纖維素之含量為每1鍵錠劑 10 12〜80重量％，且以12.5〜75重量％為宜，又以15〜7〇 重量％為佳。若比此含量更少，會有錠劑硬度降低的可能 性；若比此含量更多，則會有因結晶纖維素的粗糙感而降 低口感的可能性。 於本發明之錠劑中，無水磷酸氫鈣之摻合量係每丨錠 15旋劑12〜80重量％，而以12·5〜75重量％為佳，且以15 :70重量％更佳。若比此掺合量更少，會有旋劑無法充分 崩解的可能性；若比此摻合量更多，則會有旋劑硬度降低 的可能性。 於本發明之錠劑中所使用的崩解劑以羧曱基纖維素為 20佳。魏曱基纖維素（carmdl〇se)別名為_叫酬㈣ Μ1"1·後甲基纖維素）。魏甲基纖維素只要是於日本藥局 方第14改正準挪之中者即可。具體而言為NS-300(五德 藥品股份有限公司）。 魏甲基纖維素之含量係每1旋錠劑1〜30重量％，且 15 200835527 以5〜25重量％為佳，又以7.5〜20重量％更佳。若比此 含量更少，會有錠劑之崩解時間變長的可能；若比此含量 更多，則會有錠劑之硬度降低的可能性。 於本發明之錠劑中所使用的潤滑劑，雖只要是於醫藥 5 領域中所使用者即可，但具體而言可舉例如蔗糖脂肪酸 酯、滑石、含水二氧化矽、硬脂酸金屬鹽等，並以硬脂酸 金屬鹽為佳。硬脂酸金屬鹽雖可舉例如硬脂酸鎂、硬脂酸 I弓等，但以硬脂酸鎂為佳。 硬脂酸金屬鹽之含量係每1錠錠劑0.8重量％以下， 10 且以0.5重量％以下為宜，又以0.1重量％以下更佳。具體 而言，為0.001〜0.8重量％，以0.001〜0.5重量％為佳， 且以0.001〜0.1重量％更佳。若比此含量更多，會有錠劑 之崩解時間變長的可能性；若比此含量更少，則會有無法 形成錠劑之可能。 15 本發明之錠劑，只要是在不會對崩解性、壓縮成型性 造成影響的範圍内，即可包含有於錠劑製造中一般所使用 的各種添加劑。可舉例如賦形劑、甜味劑、調味劑、香料、 潤滑劑、結合劑、流動化劑、著色劑、塗布劑等。再者， 該等物質係可單獨或以任意比例混合來使用。 20 甜味劑係指糖類以及含有糖醇的糖質以及除此之外的 非糖質。本發明製劑並不含作為賦形劑之糖類以及糖醇， 因此難以使用糖類以及糖醇產生充分的甜味。因此，本發 明之錠劑中，特別是口腔内崩解錠劑中，以與糖類、糖醇 比較起來以少量而能感到較強甜味之物為宜，而以非糖質 16 200835527 之天然甜味料、合成甜味料為宜。具體而言，為將白糖之 甜度當作1時，具有50倍以上之甜度的甜味劑。可舉例如 醋績内酯鉀、阿斯巴甜、糖精或其鹽、甘草酸或其鹽、甜 菊素或其鹽、蔗糖素、索馬甜等。甜味劑之含量係每1錠 5 錠劑10重量％以下，而以0.1〜10重量％為佳，又以0.5 〜7.5重量％更佳。 調味劑可舉例如抗壞血酸及其鹽、甘胺酸、氯化納、 氯化鎂、鹽酸、稀鹽酸、檸檬酸及其鹽、無水擰檬酸、L 一麩醯胺酸及其鹽、琥珀酸及其鹽、醋酸、酒石酸及其鹽、 10 碳酸氫鈉、反丁烯二酸及其鹽、蘋果酸及其鹽、冰醋酸、 肉苷酸二鈉、蜂蜜等。 香料係包含被稱為香味劑者，可舉例如橙香精、橙油、 焦糖、樟腦、桂皮油、綠薄荷油、草莓香精、巧克力香精、 櫻桃調味料、苦橙油、松油、薄荷油、香草調味料、苦味 15 香精、水果調味料、薄荷香精、混合調味料、薄荷調味料、 薄荷腦、檸檬粉、擰檬油、玫瑰油等。 結合劑可舉例如阿拉伯膠、阿拉伯膠粉、部分α化澱 粉、明膠、洋菜、糊精、聚三葡萄糖、聚維酮、聚乙烯醇、 乙基纖維素、羧甲基乙基纖維素、羧甲基纖維素、羧甲基 20 纖維素鈉、羥乙基纖維素、羥乙基甲基纖維素、羥丙基纖 維素、羥丙基甲基纖維素等。 流動化劑可舉例如含水二氧化矽、輕質無水矽酸、重 質無水矽酸、氧化鈦等。 著色劑可舉例如食用紅色3號、食用黃色5號、食用 17 200835527 籃色1號等之食用色素、黄色 三氧化二鐵、三氧化二鐵、 褐色氧化鐵、黑氧化鐵、銅葉綠素、銅葉綠素鈉、核黃素、 抹茶粉等。 塗布劑可舉例如聚乙烯醇、乙基纖維素、羧甲基乙基 5纖維素、叛甲基纖維素、羧甲基纖維素鈉、羥乙基纖維素、 ^乙基甲基纖維素、經丙基纖維素、㈣基甲基纖維素、p VA共聚物、兩烯酸乙酯•甲基丙烯酸甲酯共聚物分散 液、曱基丙烯酸胺烷酯共聚物、歐巴代(〇padry)、棕櫚蠟、 ^乙稀聚合物、乾燥甲基丙烯酸共聚物、甲基丙烯酸二甲 10 $乙S旨•甲基丙稀酸甲醋共聚物、十八醇、蟲膠、十六醇、 @丙基甲基纖維素乙酸g|綱酸_、經丙基甲基纖維素欧 酉文酉曰、反丁締二酸•硬脂酸·聚乙烯縮醛二乙基胺基乙酸 自曰•搜丙基甲基纖維素混合物、聚乙烯祕二乙基胺基乙 H聚乙烯醇、甲基丙烯酸共聚物、丙烯酸2一甲基一5 15 —乙烯吡啶甲酯•甲基丙烯酸共聚物等。 該等成分只要是於本發明之錠劑中不會損及崩解性、 成形性之範圍内，通常可將任意量單獨或是混合來使用。 於作為藥物的包含有理思必妥之錠劑時，較佳的添加劑組 口’係結晶纖維素/無水磷酸氫鈣/羧甲基纖維素/硬脂 酉欠鎂/醋磺内酯鉀、結晶纖維素/無水磷酸氫鈣/羧甲基 纖維素/硬脂酸鎂/醋磺内酯鉀/薄荷油/含水二氧化 石夕、結晶纖維素/無水磷酸氫鈣/羧甲基纖維素/硬脂酸 鎂/蔗糖素、結晶纖維素/無水磷酸氫鈣/羧甲基纖維素 /硬骑酸鎂/蔗糖素/薄荷油/含水二氧化矽之組合。使 18 200835527 用該等組合之添加劑日寸，可製造出錠劑之崩解時間迅速， 錠劑之硬度高，|可抑制苦味之 口腔内崩解旋劑。 於口腔内崩解1疋劑中’ -般而言，係使用作為賦形劑 的糖類、擴醇。另方面，本發明之口腔内崩解疑劑，實 5質上為由理思必妥、結晶纖維素以及無機賦形劑所構成的 口腔内崩解綻劑。亦即，其特徵為實質上不含於口腔内崩 解錠劑中所〆般作為賦形劑使用的糖類。於本發明之口腔 内崩解錠劑中，不將蔗糖、葡萄糖、果糖、糖漿、乳糖等 糖類作為賦形劑使用。使用該等糖類會使錠劑之崩解時間 〇加長。又，於此所述之「糖類」係依營養學上的基準（來昭 例如厚生勞動省之營養表示基準），具體而言係指單糖類以 及雙糖類。 丹有’本發明之口腔内崩解旋劑，特徵為實質上不含 15 腔内崩_劑中所—般作為賦形劑使用的糖醇。於本 二明：口腔内崩解鍵劑中，係不將紅藻糖醇、D-山梨糖 :、木糖醇、D—甘露糖醇、麥芽糖醇等糖醇作為賦形劑。 糖2等糖醇會使崩解時間加長。於此「糖醇」係指還原 ^犬員57子之羰基而得之多價醇。 19 200835527 量％、羧甲基纖維素為2.5〜25重量％以及硬脂酸鎂為ο」 重Ϊ%以下為佳’又以理思必妥為0.5〜4.5重量％、纟士晶 纖維素為20〜70重量％、無水構酸氫躬為2〇〜重量％、 竣甲基纖維素為5〜20重置％以及硬脂酸鎮為〇 1重量％ 5 以下更佳。 另一方面’為了製造理思必妥之苦味抑制製劑而將理 思必妥懸浮之液體，於20°C之液體黏度為5〇〜14〇〇〇mPa • s，且以 100〜14000mPa · s 為佳，又以 250〜i4〇〇〇mPa • s更佳’特別是以500〜14000mPa · s最佳來調整即可。 10若比此黏度更低’會有苦味抑制效果無法充分發揮的可 能；若比此黏度更高，會有於造粒機中無法分散添加物之 摻合液的可能性。此添加物需要溶解及/或懸浮於水中。 於本說明書中，「懸浮」係指於液體中可見到為膠體粒子或 可以顯微鏡看到左右之粒子之固體粒子。 15 前述使理思必妥懸浮之液體，需要添加對水添加之添 加物以調整黏度。添加物（以下亦有稱為「苦味抑制基劑」 之情形。）係只要是溶解及/或懸浮於水，並成為高黏性， 特別是於20°C中液體之黏度為5〇〜i4000mPa · s之液體般 的物質，且於醫藥領域中所被使用者即可。具體而言，係 20羥丙基甲基纖維素、反丁烯二酸•硬脂酸·聚乙烯縮醛二 乙基胺基乙酸酯•羥丙基甲基纖維素混合物、羥丙基纖維 素、甲基纖維素、羥乙基纖維素、羧甲基纖維素鈉、聚乙 烯吼咯啶酮K25、聚乙烯吼洛啶_ K30、聚乙烯吡略唆酮 K90、聚乙烯醇（完全皂化物）、聚乙烯醇(部分皂化物）、阿 20 200835527 拉伯膠、阿拉伯膠粉、褐藻酸鈉、褐藻酸丙，、洋菜、 洋菜末、明膠、純化明膠、黃蓍膠、三仙膠、α化殿粉、 部分α化殿粉、幾甲基殿_、聚三葡萄糖、糊精等。且 以羥丙基甲基纖維♦、巧Τ Ρ ^ 5 10 戰、、隹素反丁細二酸•硬脂酸•聚乙稀縮酸 二乙基胺基乙酸L基甲基纖維素㈣混合物、經丙 基纖維素、聚乙烯料Κ25、聚乙烯料㈣、 聚乙烯t各訓請等為佳。又以㈣基甲基纖維素、或 反丁稀二酸·硬脂酸•聚乙烯祕二乙基胺基乙動旨•声 喊甲基纖維纽合物聽。又，縣加物「溶解以及^ 洋」係指添加物之-部分溶解於水，且其他部分懸浮於水。 舉例而s ’於反丁烯二酸•硬脂酸·聚乙烯縮駿二乙基胺 基乙Μ ·㈣基甲基纖維素混合物之情形，反丁晞二酸 •硬脂酸·聚乙烯祕二乙基胺基乙_係懸浮於水，經 丙基甲基纖維素則溶解於水。 於本發明中，特佳的苦味抑制基劑經丙基甲基纖維素 只要是於醫藥領域中所使用者即可。具體而言，於日本藥 局方所收錄記載之羥丙基甲基纖維素22〇8、羥丙基甲基纖 維素2906、羥丙基甲基纖維素291〇，又特別是以羥丙基甲 基纖維素2910為佳。羥丙基甲基纖維素291〇係纖維素之 2〇甲基以及羥丙基之混合酯，於乾燥時定量時，為含有曱氧 基28.0〜30.0%以及羥丙氧基7.〇〜12〇%者。羥丙基甲基 纖維素2910，更具體而吕為Tc — 5E(信越化學工業股份有 限公司製）、Methocel E(陶氏化學日本）、Marp〇l〇se(松本油 脂製藥）。 21 200835527 特別是，苦味抑制基劑為羥丙基甲基纖維素時，具體 而言，使用為羥丙基甲基纖維素2910之1種的TC—5E(信 越化學工業股份有限公司製）時，液中含量（以下有時將「重 量％」記載成「w/w%」）為6〜35w/w%，且以6.5〜32.5w 5 /w%為佳，又以7〜30w/w%更佳。 苦味抑制基劑羥丙基甲基纖維素相對於製劑全量之重 量為0.001〜50w/w%，且以0.01〜30w/w%為宜，又以 0.1〜25w/w%為佳。若比此含量更少，會有無法充分發揮 苦味抑制效果的可能性；若比此含量更多，則會有製劑崩 10 解延遲的可能性。 理思必妥係可單獨使用或作為與其他藥物之合劑使 用。再者，理思必妥係因應患者之疾病、年齡等適當地投 予所定之習知適當量。 苦味抑制基劑羥丙基甲基纖維素液中之理思必妥含量 15 係0.001〜40w/w%，且以1〜30w/w%為佳，又以2〜 20w/w%更佳。若比此含量更多，會有無法抑制理思必妥 苦味的可能性。 苦味抑制基劑羥丙基甲基纖維素與理思必妥之重量比 係 1000 : 1 〜0.5 ·· 1，而以 100 ·· 1 〜0.75 ·· 1 為佳，又以 10 ·· 20 1〜1 : 1更佳。若羥丙基甲基纖維素之比例相較於羥丙基甲 基纖維素與理思必妥之重量比1000 : 1還更多的話，會有 理思必妥之溶解延遲的可能。另一方面，若理思必妥之比 例相較於羥丙基曱基纖維素與理思必妥之重量比0.5 : 1還 更多的話，則會有無法抑制理思必妥之苦味的可能。 22 200835527 理思必妥懸浮液之製備方法並無特別限定。例如，於 將規定量的羥丙基甲基纖維素溶解及/或懸浮於水中之液 體中，使規定量的理思必妥懸浮之方法，或是將規定量的 理思必妥懸浮於水，並將羥丙基甲基纖維素溶解及/或懸 5 浮於該液中之方法。 於本發明之苦味抑制製劑中，所使用的賦形劑只要是 於醫藥領域中所使用者即可。具體而言，可使用水溶性賦 形劑、水不溶性賦形劑任一者。更具體的賦形劑，係葡萄 糖、果糖、乳糖、蔗糖、D —甘露糖醇、紅藻糖醇、麥芽 10 糖醇、海藻糖、山梨糖醇、玉米澱粉、馬鈴薯澱粉、小麥 殿粉、米殿粉、結晶纖維素、無水石夕酸、無水填酸氫妈、 磷酸氫鈣，碳酸鈣、沉澱碳酸鈣、矽酸鈣、含水二氧化矽 等。且以結晶纖維素、碳酸鈣、沉澱碳酸鈣、無水磷酸氫 鈣、磷酸氫鈣等之水不溶性賦形劑為佳。 15 於本發明之苦味抑制製劑中賦形劑之含量，相對於製 劑全量為0〜99.9w/w%，且以5〜90w/w%為佳，又以 30〜70w/w%更佳。若比此摻合量更少，會有無法形成 粉、粒體製劑的可能性。 於本發明之苦味抑制製劑中亦可使用崩解劑。特別是 20 在攪拌造粒的情形中崩解劑係必要。所使用的崩解劑只要 是於醫藥領域中所使用者即可。具體而言，崩解劑具體而 言為低取代度羥丙基纖維素、羧甲基纖維素、羧甲基纖維 素鈣、羧甲基澱粉鈉、交聯羧甲基纖維素鈉、交聯聚維酮、 玉米澱粉、α化澱粉，洋菜末等。且以交聯聚維酮為佳。 23 200835527 本發明之苦味抑制製劑的崩解劑之含量，相對於製劑 全量為0〜99.9w/w%，且以5〜90w/w%為佳，又以10 〜70w/w%更佳。若比此摻合量少，會有崩解性降低的可 能性。 5 於本發明之苦味抑制製劑中亦可使用結合劑。所使用 的結合劑，只要是於醫藥領域中所使用者即可。具體而言 係羥丙基曱基纖維素、反丁烯二酸•硬脂酸•聚乙烯縮醛 二乙基胺基乙酸酯•羥丙基甲基纖維素混合物、羥丙基纖 維素、羧甲基纖維素、羧甲基纖維素鈉、羧甲基澱粉鈉、 10 交聯羧甲基纖維素鈉、交聯聚維酮、羥乙基甲基纖維素、 羥丙基澱粉、羥乙基纖維素等。且以羥丙基甲基纖維素或 反丁烯二酸·硬脂酸•聚乙烯縮醛二乙基胺基乙酸酯•羥 丙基甲基纖維素混合物為佳。 本發明之苦味抑制製劑之結合劑之含量，相對於製劑 15 全量為0〜20w/w%。若比此換合量更多，會有崩解延遲 的可能性。 於本發明之苦味抑制製劑，為了減輕苦味亦可使用調 味劑。具體而言，如薄荷油、擰檬酸。 於本發明之苦味抑制製劑中，最適合的苦味抑制基劑 20 之一的羥丙基甲基纖維素以及理思必妥之液中含量，於使 用羥丙基曱基纖維素2910之1種的TC—5E(信越化學工業 股份有限公司製）時，係經丙基甲基纖維素為6〜35w/w %、理思必妥為0.001〜40w/w%，且以經丙基甲基纖維 素為6.5〜32.5w/w%、理思必妥為1〜30w/w%為佳， 24 200835527 又以罗！丙基甲基纖維素為7〜3Gw/w%、理思必妥為2〜 20w/w% 更佳。 丄 >於本發明之苦味抑制製劑中的粉、粒體製劑，具體而 。係导曰日本藥局方第14改正所記載之製劑總則中的散劑、 顆粒刮、糖漿劑。特》沒，本發明的製造方法係對顆粒劑， =別疋古味經抑制之顆粒劑的製造最適合的製造方法。 實施發明的最佳形態 以下記載本發明之口腔内崩麟卿製造法。 1〇 7具體的製造方法，可舉例如量取活性成分與製劑原 並將以V型、混合機等之適當的混合機混合的錠劑用混 4 ’使用後述的打錠機進行直接賴打錠而製造的方法 等°具 、。冉者，為了得到錠劑用混合粉，亦可使用藉由攪拌造 粒機進仃強力混合的方法、藉由粉碎機進行混合粉碎的方 ls法、错由乾式造粒機進行壓縮造粒的方法、因應需要而使 ^ β或溶解有結合劑之水、丙酮、乙醇、丙醇或該等混 ° 2並進㈣式造粒的方法、或進一步分成2個以上的群 7來1造!定劑用混合粉的方法。於製造錠_混合粉時可 口應而要混合結合劑、調味劑、流動化劑、潤滑劑、香料、 甜味劑、著色劑等。 2〇 ^ 、 ，關於壓縮成形，若為本發明之處方，即使潤滑 』為）ΐ(每1旋旋劑〇·8重量％以下，且以〇 $重量％以 、 Λ u.i重量％以下更佳），仍可使用一般的打錠 法(:部混合法）或使潤滑劑附著於打錠機之白杵上的外部 /閑'月去。（股）菊水製作所製造的ELSP卜TYPEIII等可作為 25 200835527 進行外部潤滑法的裝置。 使潤滑劑之含量減少時，可加快崩解速度’且提升錠 劑硬度，並提高藥物的穩定性。將潤滑劑混合於錠劑用混 合粉之一般方法，對於處方中10〇mg之錠劑雖需要有1〜 5 3mg之潤滑劑，但於本發明處方中則可以每1錠錠劑0.8 重量％以下，且以0.5重量％以下為佳，又以〇·1重量％以 下更佳的少量潤滑劑來進行打錠。特別是，若摻合活性成 分、結晶纖維素、無水磷酸氫鈣、羧甲基纖維素以及每i 錠錠劑0.1重量％以下之硬脂酸鎂，且潤滑劑之添加方法 10 為外部潤滑法則更佳。 前述内容中，特別是以將實質上包含有活性成分、結 晶纖維素 '無水罐酸氫約、羧甲基纖維素(添加甜味劑時為 醋確内醋鉀或蔗糖*。添加香料時為薄荷的粉末以内部 混合法、外部潤滑法成形為佳。又，於本發明中活性成; 15 以及添加物的粒徑係無特別限定。 ，此而得的_用混合⑽例如使用進行外部肝 打鍵的裝置、單發打鍵機、旋轉打在定機等，以打旋壓: ^〜⑽kg壓縮細彡。若比其壓力更低，_硬度 足而然法確保操作上充分的硬度； 又㈢ 右1刀更高，則 20 會延遲而不佳。 、】口朋解 關於本發明口腔内速崩解錠之成形， 可，例如圓形、楕圓形、球形，㈣、㈣任何形狀皆 亦可為積層竣、有賊等，且亦可進_仲长形之形狀以及 再者，亦可附加為了提升識別度的 4㈣而覆膜。 又子荨之刻印及 26 200835527 分割用之割線。 本發明之键劑作為口腔内崩解錠劑係十分有用，辑由 垂液可於口腔内迅速地崩解，且可不會殘留粗糙感而滑川頁 地服用。本發明之口腔内崩解錠劑之口中溶解通常為1〜恥 5移’且以1〜40秒為佳，又以1〜30秒左右更佳。 再者，雖已知硬度（以錠劑硬度計測得之測量値)通常u 2疋3〇〜7〇N&右即為無問題的數値，但本發明之口胺内 崩解敲劑為10〜2〇〇n，且以30〜150N左右為佳。 又，此製劑亦可不於口腔内崩解來服用或與水— 10用。 取服 15 、於本發明中的苦味抑制製劑的粉、粒體製劑之製' 宜雖只要是製劑學上可使用者即可，但以濕式造粒法為 =且以流動層造粒法、攪拌造粒法或壓出造粒法、轉動 為佳，又以擾拌造粒法更佳。流動層造粒法係如 方夺結合劑對被流動化的粉體進行喷霧而得到造粒 。搜拌造粒法係指藉由將結合液添加至裝人槽 質中，並使作成各種形狀的授拌葉旋轉，以給予、 法t厂《作用等而得到目的之造粒物的方法。壓出造板 20 出而得到造粒物的方法。=塊強制地遷 的轉 ’、、'再者，轉動造粒法係指藉由旋轉 鏠之離心力，而使接近於外壁部之原料粉體藉由從狹 到t欠的空氣而轉動，並於此時將結合劑進行噴霧而得 製2物㈣法。又，藉由«絲法之製造時間比前述 〜更長，會更難以抑制理思必妥之苦味。 27 200835527 於藉由流動層造麵 溶解或懸浮有理思必妥衣造本發明之製_，製備預 液，並-邊於㈣制基劑的溶解及/或懸= 將前述液體進行噴或崩_流動’一邊 於藉由攪拌造粒法 m^^ ^ ^ 本發明之製劑時，製備預先洛 ;于!妥之苦味抑制基劑的溶解"或懸浮 :，亚:邊於攪拌造教機 拌賦形一 劑，一邊添加前述•以造粒。 10 於藉由壓出造教法製造本發明之製劑時，製備預先溶 解或懸浮有理思必要之苦味抑制基劑的溶解及/或懸浮 ;，並將該液混合、料於_劑及/«_，且將此 授和物壓出且以处機造粒。 、；藉由轉動製造本發明之製劑時，製備預先溶 η解或有理思必妥之苦味抑制基劑的溶解及/或懸浮 /夜’亚-邊於離心轉動造粒裝置之槽内使賦形劑及/或崩 解劑轉動，並添加前述液體以造粒。 本發明之粉、粒體製劑可以依原樣，例如作為苦味經 抑制的顆粒劑或是細粒劑來使用。此時，認定理思必妥之 血中動態並不特別遜色。 20 再者’可將竦形劑、崩解劑、結合劑、潤滑劑與本發 月之粉、粒體製劑一起混合、打錠而成形為錠劑。賦形劑、 朋解劑、結合劑可使用前述之物。再者，潤滑劑為硬脂酸 鎂、蔗糖脂肪酸酯、碳酸鎂等。 再者’亦可藉由將賦形劑、崩解劑、結合劑與本發明 28 200835527 之籾粒體製劑一起混合，並於打 量潤滑劑，將^人 機之白、杵上附著少 键齊卜該打錢、二 之外部调滑打趁法，亦可製造 ， Η丁釦去糸可以少量的潤滑劑 5 10 15 20 見讀:變質的理思必妥而言為有用的打旋法。對 内瞬間:::劑之外’將本發明粉、粒體製劑摻合於口腔 瞬門山紐口腔内崩解錠劑中’可製造錠劑會 ㈣之新型態·於口腔内辦 述般的添加劑=者潤滑劑可使用如前 添加例如薄荷油、«酸般的調2良好，亦可於鍵劑中 先^知理思必妥會呈現極苦的味道。如前述般，製造預 參=有ί思必妥之本發明苦味經抑制的粉、粒體(例如， 南Ic/述實加例1之1})後，若將該粉、粒體製劑包含於鍵 可製造古味經抑制的錠劑。再者，若將前述苦味經 /制的粉、粒體包含於前述口腔内崩解旋劑中，可製造苦 味經抑制的口腔内崩解錠劑。 田又，本發明之口腔内崩解錠劑之血中動態與習知的理 ，必妥錠劑相較之下並無任何遜色。 貫施例 卜以下，雖舉出實施例與比較例詳細說明本發明，但其 等當不限定本發明。 以實施例得到的錠劑係藉由下列試驗法來測量錠劑 又以及崩解時間，並進行苦味之官能試驗。 (1)硬度試驗 使用硬度測定專用機(ERWEKA International AG製）進 29 200835527 行測量。試驗係以10錠進行，並顯示其平均値。（將30N 以上作為基準） (2) 崩解試驗 以第十四改正曰本藥局方崩解試驗法為準，測量6錠 5 之崩解時間，顯示其最大値。（將20秒以内作為基準） (3) 苦味之官能試驗 將所製造的製劑含於健康成人5名之口腔内，於舌上 進行約5秒之官能試驗。 實施例1 10 理思必妥口腔内崩解錠劑之製備（其1，外部潤滑法） 【表1】 成 分 理思必妥口腔内崩解錠劑 0.5 mg 錠 1 mg錠 2 mg !定 3 mg錠 顆粒内處方 理思必妥 0.5 1 2 3 經丙基甲基 1.5 r 〇 纖維素2910 5 0 y 無水填酸氳妈 5 10 20 30 羧曱基纖維素鈣 5 10 20 30 顆粒外處方 結晶纖維素 無水構酸氳1弓 適量（13) 19.2 適量 (26) 38.4 適量 (27) 39.94 適量 (40.5) 59.91 醋石黃内S旨1甲 0.7 1.4 1.8 2.7 羧甲基纖維素 5 10 13 19.5 薄荷油 含水二氧化矽 微量 微量 微量 微量 (0.05) 0.1 (0.1) 0.2 (0.13) 0.26 (0.195) 0.39 硬脂酸鎂 微量 微量 微量 微量 全量(mg) 50 100 130 195 30 200835527 1)包含有理思必妥的苦味抑制製劑(顆粒)之製造 依表1記載之量，以1萬鍵之規模，使經丙基甲 維素291G畴於純水後，使理思必妥料，料到造^織 又，於20C之造粒液的黏度係1〇〇〜14〇〇〇mPa . $夜 將無水雜氫触”基_钱投人第 、 拌機之中並混合。接荽、真、，i 巧迷攪 T匕〇接者一邊注加前述造粒液一邊造极 得到造粒物。 >'’而 將所得到的造粒物以流動層造粒機乾燥， 10 得到乾燥顆粒。將乾燥難以P_3型P_ mill進杆:' 而得到理思必妥顆粒。 丁麵 又，針對該顆粒實施苦味之官能試驗，並不會感到苦 2) 薄荷油粉之製造 15 依表1記載之摻合量，以10萬錠之規模，將薄荷油添 二:K烯蛵袋中的含水二氧化矽中，混合聚烯烴袋而得到 卷將混合粉以金網進行手篩，混合聚烯烴袋，而得 到薄荷油粉。 3) 口腔内崩解錠劑之製造 20鈣依表1記载之摻合量，以50錠之規模，將無水磷酸氫 月11述之理思必妥顆粒、醋磺内酯鉀、薄荷油粉以及結 晶纖維♦、'm u 代/、羧甲基纖維素投入聚烯烴袋中，並混合聚烯烴 合粉。將此混合粉以金網進行手筛，並混合聚 歸烴袋， ^曰 而得到製錠粉。以綿棒使硬脂酸鎂以鍵劑質量之 〇·ι %以下之旦务 里附者於杵臼（使用杵：0.5 mg錠φ =5.0 mm、 31 200835527 1 mg !定 φ =6.5 mm、2 mg !定 φ =7 mm、3 mg 鍵 φ =8.0 mm) 上，並將所得到的製錠粉以靜壓縮試驗機進行打錠而得到 理思必妥口腔内崩解錠劑。 (錠劑硬度、崩解時間以及苦味之官能試驗） 5 藉由前述方法，試驗所得到的理思必妥口腔内崩解錠 劑之硬度與崩解時間。將結果示於表2。又，於苦味之官能 試驗中，任一製劑皆不會感到苦味。 【表2】 口腔内崩解錠劑 錠劑硬度(N) 崩解時間（秒） 0.5 mg 錠 42 9 lmg錠 58.4 13 2mg錠 42.5 16 3mg錠 72 23 10 僅止於參考，而於以下表示以目前市售的理思必妥之 錠劑（lmg)的硬度以及崩解時間的測量結果。 【表3】 質量 (mg) 錠劑厚度 (mm) 錠劑硬度(N) 崩解時間 (秒） 1 102.2 3.21 45 — 2 102.6 3.21 46 — 3 104.7 3.28 45 — 4 103.4 3.25 — 373 5 102.3 3.24 — 306 平均 103.0 3.24 45.3 340 實施例2 15 理思必妥口腔内崩解錠劑之製備（其2，内部混合法) (錠劑之製造方法） 32 200835527 依表4記載之摻合量量取以實施例1製造的理思必妥 顆粒、羧甲基纖維素、結晶纖維素、無水磷酸氫鈣、醋磺 内酯鉀，並以聚烯烴袋混合，且添加硬脂酸鎂再混合後， 得到製錠粉。將所得到的製錠粉以靜壓縮試驗機(使用杵： 5 φ =6.5 mm)進行打錠而得到理思必妥口腔内崩解錠劑。 【表4】 成分 實施例2 理思必妥 1 羥丙基甲基纖維素2910 3 無水磷酸氫鈣輕質 10 羧甲基纖維素妈 10 結晶纖維素 適量(26) 無水填酸氫妈GS 37.8 醋石黃内S旨鉀 1.4 羧甲基纖維素 10 硬脂酸鎂 0.8 全量(mg) 100 (錠劑硬度、崩解時間以及苦味之官能試驗） 藉由前述方法試驗所得到的理思必妥口腔内崩解錠劑 10 之硬度與崩解時間。將結果示於表5。又，於苦味之官能試 驗中，並不會感到苦味。 【表5】 口腔内崩解錠劑 錠劑硬度(N) 崩解時間（秒） 實施例2 59.4 16 實施例3 15 理思必妥口腔内崩解錠劑之製備（其3，外部潤滑法) (錠劑之製造方法） 33 200835527 依表5記載之摻合量量取理思必妥、羧甲基纖維素、 結晶纖維素、無水磷酸氫鈣、醋磺内酯鉀，並以聚烯烴袋 混合’而得到製錠粉。以綿棒使硬脂酸鎂以錠劑質量之0.1% 以下之量附著於杵臼（使用杵：p=6.5 mnl)上，並將所得到 的衣旋物以靜壓縮試驗機打旋而得到理思必妥口腔内崩解 錠劑。 【表6】Further, it is used as an atypical antipsychotic drug which exhibits antagonism against both the dopamine D2 receptor and the serotonin 5-HT2A receptor. This agent exhibits an improvement in the symptoms of either positive or negative psycho5 schizophrenia, and less side effects (weight gain) of atypical antipsychotic drugs, and the risk of developing diabetes is also low (refer to Patent Document 9). ). [Patent Document 1] Japanese Laid-Open Patent Publication No. Hei No. 2001-58944 [Patent Document 3] Patent Publication No. 2001-58944 [Patent Document 3] JP-A-2000-86537 [Patent Document 5] WOOO/54752 [Patent Literature] 6: JP-A-2002- 12 540 [Patent Document 7] JP-A-2002-356066 15 [Patent Document 8] JP-A-2004-35518 [Patent Document 9] JP-A-61-221186 [Non-Patent Document 1] Concord Chemical Industry Co., Ltd. The company's booklet (excipients for the direct ingots, anhydrous calcium hydrogen phosphate GS) [Summary of the Invention] 20 SUMMARY OF THE INVENTION The problem to be solved by the invention 8 200835527 A suitable hardness in the oral cavity is provided in the oral cavity. It disintegrates rapidly and has a good feeling of ingestion, and does not require special preparation machinery. It can store the oral disintegration agent produced by the equipment and the bitterness-suppressing preparation which inhibits the bitterness of Risperid. $ Method for solving the problem The present inventors have found that by containing Ristolide, crystalline cellulose, inorganic excipients, as a disintegrant, especially carboxymethylcellulose and each of the suspected tablets. 8 wt% or less, preferably 0. The powder of the lubricant of 5% by weight or less, more preferably 〇·1% by weight or less, is directly compression-molded, and an orally disintegrating tablet which exhibits good disintegratability and ensures the hardness of the tablet can be obtained. In the above case, the blending amount of the anhydrous sodium hydrogen hydride as an inorganic excipient as a lubricating agent is adjusted to 0 per one tablet. 8 wt% or less, preferably 0.5 wt% or less, more preferably less than wt%, especially mixed with spirulina, crystalline cellulose, anhydrous lithopic hydrogen dance, rebel I5-based cellulose, and each ingot Agent 0. Magnesium stearate of 1% by weight or less is compression molded by an external lubrication method, whereby an orally disintegrating tablet which exhibits good disintegratability and ensures the hardness of the tablet can be obtained. In the second inventors, the inventors of the present invention have made every effort to improve the preparation of the above-mentioned bitterness suppression (IV), and as a result, it has been found that as long as it is in a liquid of purity, the liquid obtained by the method is added to the excipient and / or the powder prepared by the granules, the granule preparation (for example, the powder two-agent), can suppress the bitterness, the m-distance agent, the sugar = the medium-speaking additive (4) in the pharmaceutical supplements Those recorded in the company's Pharmaceutical Affairs Daily. Year, Edition 9 200835527 That is, the present invention relates to the following invention. (1) - a kind of wrap" is a lubricant containing m, crystalline cellulose, inorganic excipients, carboxymethyl cellulose, and less than or equal to the weight of each of the ingots; m 0 5 (2) as described above (1) And the lozenge of the above-mentioned (1) or (2), which is a lubricant containing 〇% by weight or less per 1 (10) dose; (4) The tablet according to the above (3) is a lubricant containing a weight of 10 or less per peak of the peak agent G; (5) The tablet according to any one of the above items (1) to (4), which contains an i bond. (1) The tablet according to any one of (1) to (5), wherein the lubricant is a metal stearate; 15 (7) is as described in the above (6) The tablet according to any one of (1) to (7), wherein the tablet is a sweetener; () $ (8) In the above-mentioned tableting agent, the sweetener is a sweetener having a sweetness of 50 times or more when the sweetness of the white sugar is 2, and the sweetener having the sweetness of 50 times or more; Preceded The key agent as described in any one of (1) to (1Q), wherein the lubricant is added by an external lubrication method; 200835527 (12) The tablet according to the above (11), which comprises Risperidone, crystalline cellulose, anhydrous calcium hydrogen phosphate, carboxymethylcellulose, and magnesium stearate in an amount of 01% by weight or less per tablet. And a lozenge according to any one of the above (1) to (12), which is an intraoral 5 disintegrating tablet; (14) as described above (1) The lozenge contained therein contains Risperidone, crystalline cellulose, inorganic excipients, carboxymethylcellulose, and a lubricant of less than 8% by weight per ingot, but does not contain sugars. And a sugar alcohol; (15) A method for producing a powder or granule preparation containing Risperidine, characterized in that the method comprises the following steps: 1) suspending the physiophyte in a viscosity (2 〇. 50~14000 mPa · s of liquid; 1 1 ) Adding the solution or suspension obtained in the step 1) to the excipient and/or disintegrant After the middle, the granulation is carried out; Θ I5 (16), as described in (15), the method of manufacturing the powder and granule preparation, wherein the viscosity of the gas liquid (2(TC) is 1〇〇~14(8)〇mPa . s; Μ (17) A method for producing a powder or granule preparation as described in (15) or (1), wherein the liquid towel contains (iv) a base; (18) a powder or granule preparation, According to the production method described in any one of the above (15) to (17), (19) as described in the above (18), the granule preparation is a granule; (= as described in the month The powder or granule preparation according to (18) or (19), which is a method for producing a sputum-inhibiting agent, which is characterized in that the powder or granule preparation of the plant of the above-mentioned (4) (22) A method for producing a tablet, characterized in that an excipient, a lubricant, a disintegrant, and/or a binder are mixed in the powder or granule preparation described in the above (2) 5 (23) A lozenge obtained by the production method according to the above (21) or (22); (24) The lozenge according to the above (23), which is an oral cavity The effect of the invention is that the tablet of the present invention can be easily taken even if it is anhydrous, and can be rapidly disintegrated in the oral cavity, has appropriate hardness, and has a good feeling of ingestion. It is used for the disintegration tablet in the oral cavity. In addition, the method for producing the tablet is relatively simple. Further, the bitterness-suppressing preparation of the present invention is contained in a highly viscous additive liquid to suspend the bitter component. The obtained liquid is added to an excipient and/or a disintegrating agent, and granulated, thereby achieving a bitterness suppressant of Risperto 15 . The bitterness-suppressing preparation of the present invention can suppress bitterness without Inhibition of the dissolution of Risper. C. Application 3 "An oral disintegrating lozenge containing Risperidone, crystalline cellulose, inorganic excipients, carboxymethylcellulose, and bismuth tablets per ingot. "Lubricant of less than 2.% by weight" means a lubricant containing arsenic, crystalline cellulose, inorganic excipients, dimethicone, and 8% by weight or less per ton of bonding agent The purpose of this corrective effect ((4) is good disintegration and the hardness of the appropriate bond is correct (6). Will be Risperto, crystalline cellulose, inorganic excipients, m-cellulosic cellulose and each lozenge 0. 8 weight 12 200835527 The lubricant in an amount of less than % by weight is an essential component, and other additives may be contained insofar as the effects of the present invention are not impaired. The content of the physical property of the drug contained in the tablet of the present invention is 0. 1 to 6 wt% per one tablet, and is 0. 125~4% by weight is suitable, and 5 is 〇·25~2. More preferably 5 wt%. If it is less than this content, the content uniformity may be deteriorated, and if it is more than this content, there is a possibility that it becomes easy to feel bitterness. The crystalline cellulose used in the tablet of the present invention may be any one as long as it is used in the medical field, but specifically, for example, Ceolus 10 PH101, Ceolus PH102, Ceolus PH301, Ceolus PH302, Avicel (Avicel) PH — F20JP, Ceolus KG802 (Asahi Kasei Industrial Co., Ltd.), VIVAPUR (grades 105, 101, 103, 301, 102, 112), ARBOCEL (grade M80, P290, A300), Prosolv SMCC50, Prosolv SMCC90 ( JRS PHARMA company) and so on. These crystal fibers may be used singly or in combination of two or more. Preferably, the crystalline cellulose before the tablet preparation has an average particle diameter of 10 to 150 / / m, preferably 30 to 130 / / m, particularly preferably 40 to 120 / / m. When the average particle diameter is larger or smaller, there is a possibility that the hardness of the tablet is lowered and the disintegration time is delayed. Specifically, Ceolus PH102 (manufactured by Asahi Kasei Kogyo Co., Ltd., having a uniform particle size of about 100/m) is preferred. The inorganic excipient used in the tablet of the present invention may be any one as long as it is used in the medical field, but specifically, for example, an acid-filled hydrogen word, anhydrous hydrogen-dissolved acid, and a rock of the town An acid salt, a synthetic hydrotalcite, a calcium carbonate, a magnesium carbonate, and especially an anhydrous calcium hydrogen phosphate: anhydrous calcium hydrogen phosphate 13 200835527 GS (made by Kyowa Chemical Industry Co., Ltd.), called & Xian (Fuji Chemical Industry) Shares Injury Co., Ltd.), anhydrous hydrogen-filled hydrogen is about light (made by Xiehe Chemical Industry Co., Ltd.), and anhydrous sulphuric acid is about heavy (Xiehe Chemical Weishi Co., Ltd. = system). These inorganic excipients may be used singly or in combination of two or more. The overall density of the inorganic excipients before the manufacture of the tablet is in the form of hawthorn ~;!. % /mL is appropriate, and it is better, and especially 〇 6~ l. 〇g/mL is better. When the overall density is lower or higher, there is a possibility that the hardness of the tablet is lowered and the disintegration time is delayed. Specifically, anhydrous sulphuric acid is about GS (made by Kyowa Chemical Industry Co., Ltd., and the overall density is 71 10 〜1. 0 g/mL) is preferred. The content of the crystalline cellulose and the inorganic excipient anhydrous calcium hydrogen phosphate in the tablet of the present invention can be easily determined. For example, a desired amount of crystalline cellulose, anhydrous calcium hydrogen phosphate, carboxymethyl cellulose and an active ingredient are appropriately mixed, and then compression-molded, and hardness and disintegration property are confirmed, thereby easily discriminating the appropriate amount. Whether or not. Since the content of the crystalline cellulose and the inorganic excipient also depends on the physical properties of the active ingredient, it is preferably determined as described above. In particular, it is preferred to use crystalline cellulose and an inorganic excipient in an amount of from 30 to 99.9% by weight based on the total weight of the tablet. In particular, it is preferred to use from 5 〇 to 99 9% by weight of the crystalline cellulose oxime and an inorganic excipient. Among these contents, the formulation of the present invention exhibits particularly good disintegration speed and tablet hardness, which are not easily affected by the physical properties of the active ingredient. Further, the weight ratio of the crystalline cellulose to the anhydrous calcium hydrogen phosphate is preferably determined as described above, and the weight of the crystalline cellulose and the anhydrous calcium hydrogen phosphate 14 200835527 is only in the range of 8:2 to 2:8. Just fine. Within the foregoing range, an orally disintegrating ingot having a good disintegration speed and tablet hardness is obtained. If the weight ratio of the crystalline cellulose is higher than this, there is a possibility that the texture is lowered due to the rough feeling of the crystalline cellulose, and if the weight ratio of the crystalline cellulose is lower than 5, the hardness of the tablet may be lowered. Preferably, the crystalline cellulose and the anhydrous hydrogen phosphate #5 are contained in a ratio of 5:5 to 3:7 by weight, and the weight ratio of the crystalline cellulose to the anhydrous acid hydrogen is about 4:6. The ratio contains a better fixer. The content of the crystalline cellulose in the tablet of the present invention is 10 12 to 80% by weight per 1 bond, and is 12. 5 to 75% by weight is preferred, and 15 to 7 % by weight is preferred. If it is less than this content, there is a possibility that the hardness of the tablet is lowered; if it is more than this, there is a possibility that the texture of the crystalline cellulose is lowered to lower the texture. In the tablet of the present invention, the blending amount of anhydrous calcium hydrogen phosphate is 12 to 80% by weight per 15 ingots, preferably 12 to 55% by weight, and more preferably 15:70% by weight. . If it is less than this, there is a possibility that the spinning agent cannot be sufficiently disintegrated; if it is more than this, there is a possibility that the hardness of the spinning agent is lowered. The disintegrant used in the tablet of the present invention is preferably carboxymethyl cellulose. The name "Carmdl〇se" is _calling (four) Μ1"1·post methylcellulose). Wei methyl cellulose can be as long as it is corrected by the Japanese Pharmacopoeia. Specifically, it is NS-300 (Wude Pharmaceutical Co., Ltd.). The content of Wei methyl cellulose is 1 to 30% by weight per 1 spindle, and 15 200835527 is preferably 5 to 25% by weight, and is further 7. 5 to 20% by weight is more preferable. If it is less than this content, there is a possibility that the disintegration time of the tablet becomes long; if it is more than this content, there is a possibility that the hardness of the tablet is lowered. The lubricant to be used in the tablet of the present invention may be any one as long as it is used in the field of medicine, and specific examples thereof include sucrose fatty acid ester, talc, aqueous cerium oxide, and metal stearate. Salt, etc., and preferably a metal stearate. The stearic acid metal salt may, for example, be magnesium stearate or stearic acid I, but magnesium stearate is preferred. The content of stearic acid metal salt is 0 per 1 tablet. 8 wt% or less, 10 and 0. 5 wt% or less is appropriate, and 0. More preferably 1% by weight or less. Specifically, it is 0. 001~0. 8 wt%, to 0. 001~0. 5 wt% is preferred, and is 0. 001~0. 1% by weight is more preferable. If it is more than this content, there is a possibility that the disintegration time of the tablet becomes long; if it is less than this, there is a possibility that the tablet cannot be formed. The tablet of the present invention may contain various additives generally used in the production of tablets, as long as they do not affect the disintegratability and compression moldability. For example, an excipient, a sweetener, a flavoring agent, a fragrance, a lubricant, a binder, a fluidizer, a coloring agent, a coating agent, etc. are mentioned. Further, the materials may be used singly or in any ratio. 20 Sweeteners refer to sugars and sugars containing sugar alcohols and other non-saccharides. The preparation of the present invention does not contain sugars and sugar alcohols as excipients, and thus it is difficult to produce sufficient sweetness using sugars and sugar alcohols. Therefore, in the tablet of the present invention, particularly in the orally disintegrating tablet, it is preferred to use a small amount of sugar and sugar alcohol to induce a strong sweetness, and the non-saccharin 16 200835527 is natural. Sweeteners and synthetic sweeteners are preferred. Specifically, in order to treat the sweetness of white sugar as 1, a sweetener having a sweetness of 50 times or more is used. For example, potassium acetophenone, aspartame, saccharin or a salt thereof, glycyrrhizic acid or a salt thereof, stevioside or a salt thereof, sucralose, thaumatin or the like can be mentioned. The content of the sweetener is 10% by weight or less per 5 tablets, and is 0. 1 to 10% by weight is preferred, and 0. 5 ~ 7. More preferably 5 wt%. Examples of the flavoring agent include ascorbic acid and salts thereof, glycine, sodium chloride, magnesium chloride, hydrochloric acid, dilute hydrochloric acid, citric acid and salts thereof, anhydrous citric acid, L-glutamic acid and salts thereof, succinic acid and Salt, acetic acid, tartaric acid and its salts, 10 sodium hydrogencarbonate, fumaric acid and its salts, malic acid and its salts, glacial acetic acid, disodium sarcosylate, honey, and the like. Flavors include those known as fragrances, such as orange essence, orange oil, caramel, camphor, cinnamon oil, spearmint oil, strawberry flavor, chocolate flavor, cherry seasoning, bitter orange oil, pine oil, peppermint oil. , vanilla seasoning, bitter 15 flavor, fruit seasoning, mint flavor, mixed seasoning, mint seasoning, menthol, lemon powder, lemon oil, rose oil, etc. The binding agent may, for example, be gum arabic, gum arabic powder, partially gelatinized starch, gelatin, agar, dextrin, polytriglucose, povidone, polyvinyl alcohol, ethyl cellulose, carboxymethyl ethyl cellulose, Carboxymethylcellulose, sodium carboxymethyl 20 cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and the like. The fluidizing agent may, for example, be aqueous cerium oxide, light anhydrous citric acid, heavy anhydrous citric acid, titanium oxide or the like. Examples of the coloring agent include food coloring such as edible red No. 3, edible yellow No. 5, edible 17 200835527 basket color No. 1, yellow ferric oxide, ferric oxide, brown iron oxide, black iron oxide, copper chlorophyll, copper. Chlorophyll sodium, riboflavin, matcha powder, etc. The coating agent may, for example, be polyvinyl alcohol, ethyl cellulose, carboxymethylethyl 5 cellulose, m-methyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl cellulose, ethyl ethyl cellulose, Propylcellulose, (tetra)methylcellulose, p VA copolymer, ethyl enoate/methyl methacrylate copolymer dispersion, amidinoyl methacrylate copolymer, 〇padry , palm wax, ^ ethylene polymer, dry methacrylic acid copolymer, dimethyl methacrylate 10 $ B S · methyl methacrylate copolymer, octadecyl alcohol, shellac, cetyl alcohol, @ Propylmethylcellulose acetic acid g||acid _, propyl methylcellulose 酉 酉 酉曰 反, counter-butanedioic acid · stearic acid · polyvinyl acetal diethyl acetoxy acetic acid 曰 搜 搜Methylcellulose mixture, polyethylene, diethylaminoethylethylene H polyvinyl alcohol, methacrylic acid copolymer, 2-methyl-5 5 -vinylpyridine methyl acrylate/methacrylic acid copolymer, and the like. These components are usually used alone or in combination in any amount as long as they do not impair the disintegratability and formability in the tablet of the present invention. In the case of a medicinal lozenge containing a rationale, the preferred additive group is crystalline cellulose/anhydrous dibasic calcium phosphate/carboxymethylcellulose/stearin, magnesium sulphate, crystallization. Cellulose / anhydrous calcium hydrogen phosphate / carboxymethyl cellulose / magnesium stearate / acesulfame potassium / peppermint oil / aqueous dioxide, crystallization, crystalline cellulose / anhydrous calcium hydrogen phosphate / carboxymethyl cellulose / hard A combination of magnesium sucrose/sucralose, crystalline cellulose/anhydrous calcium hydrogen phosphate/carboxymethyl cellulose/hard acid magnesium citrate/sucralose/menthol oil/aqueous cerium oxide. 18 200835527 With the combination of these additives, it is possible to produce a rapid disintegration time of the tablet, a high hardness of the tablet, and an intraoral disintegration agent which can suppress bitterness. In the case of disintegration in the oral cavity, the saccharide and the alcohol are used as excipients. On the other hand, the orally disintegrating agent of the present invention is an oral cavity disintegrating agent composed of Risperidone, crystalline cellulose and an inorganic excipient. That is, it is characterized in that it is substantially free of sugars used as excipients in the orally disintegrating tablets. In the orally disintegrating tablet of the present invention, sugars such as sucrose, glucose, fructose, syrup, and lactose are not used as excipients. The use of these sugars will lengthen the disintegration time of the tablet. In addition, the term "sugar" as used herein refers to a nutritional standard (see, for example, the nutrition index of the Ministry of Health, Labour and Welfare), and specifically refers to a monosaccharide and a disaccharide. Dan has the orally disintegrating rotatory agent of the present invention, which is characterized by being substantially free of the sugar alcohol used as an excipient in a 15-cavity internal disintegration agent. Yu Benming: In the orally disintegrating agent, sugar alcohols such as erythritol, D-sorbose, xylitol, D-mannitol, and maltitol are not used as excipients. Sugar alcohols such as sugar 2 can lengthen the disintegration time. Here, "sugar alcohol" means a polyvalent alcohol obtained by reducing the carbonyl group of the dog. 19 200835527 %, carboxymethyl cellulose is 2. 5 to 25% by weight and magnesium stearate are ο"% 以下% or less is good. 5~4. 5% by weight, strontium cellulose is 20 to 70% by weight, anhydrous hydrazine hydrochloride is 2 〇% by weight, 竣methyl cellulose is 5 to 20% by weight, and stearic acid is 〇1% by weight. 5 is better. On the other hand, 'the liquid which is suspended in order to make the bitterness-suppressing inhibitor of Risperdo, the liquid viscosity at 20 ° C is 5 〇 14 14 mPa · s, and 100 to 14000 mPa · s For better, it is better to use 250~i4〇〇〇mPa • s, especially for 500~14000mPa·s. If it is lower than this viscosity, there is a possibility that the bitterness suppressing effect cannot be fully exerted; if it is higher than this, there is a possibility that the blending liquid of the additive cannot be dispersed in the granulator. This additive needs to be dissolved and/or suspended in water. In the present specification, "suspended" means solid particles which are visible as colloidal particles in a liquid or which can be seen by a microscope. 15 For the above-mentioned liquids that have been suspended, it is necessary to add an additive to the water to adjust the viscosity. Additives (hereinafter also referred to as "bitter suppressing base") are as long as they are dissolved and/or suspended in water and become highly viscous, especially at 20 ° C, the viscosity of the liquid is 5 〇 to i 4000 mPa. · s liquid-like substance, and can be used by users in the medical field. Specifically, it is 20 hydroxypropyl methylcellulose, fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, hydroxypropyl methylcellulose mixture, hydroxypropyl fiber. , methylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone K25, polyvinylpyrrolidine _ K30, polyvinylpyrrolidone K90, polyvinyl alcohol (complete saponification) ), polyvinyl alcohol (partially saponified), A 20 200835527 Labo gum, gum arabic powder, sodium alginate, sodium alginate, amaranth, amaranth, gelatin, purified gelatin, tragacanth, three cents Glue, alpha-dose powder, some alpha-dose powder, several methyl temples, polytriglucose, dextrin, etc. And hydroxypropyl methylcellulose ♦, Qiao Τ 5 ^ 5 10 battle, 隹素 counter-butylic acid • stearic acid • polyglycolic acid diethylaminoacetic acid L-methyl cellulose (four) mixture It is better to use propyl cellulose, polyethylene material Κ25, polyethylene material (four), and polyethylene t. In addition, (4)-based methyl cellulose, or anti-succinic acid, stearic acid, polyethylene, and diethylamine-based ethylene are used to listen to methyl fiber conjugates. In addition, the county additive "dissolving and ^yang" means that the additive is partially dissolved in water and the other part is suspended in water. For example, in the case of a mixture of fumaric acid, stearic acid, polyethylene, diethylaminodiethylamine, (tetra)methylcellulose, antibutyric acid, stearic acid, and polystyrene The diethylaminoethyl group is suspended in water and dissolved in water by propylmethylcellulose. In the present invention, a particularly preferred bitter suppressing base is propylmethylcellulose as long as it is a user in the medical field. Specifically, hydroxypropylmethylcellulose 22〇8, hydroxypropylmethylcellulose 2906, hydroxypropylmethylcellulose 291〇, and especially hydroxypropyl group are listed in the Japanese Pharmacopoeia. Methylcellulose 2910 is preferred. Hydroxypropyl methylcellulose 291 纤维素 cellulose 2 〇 methyl and hydroxypropyl mixed ester, when quenched when dry, contains oxime oxygen 28. 0~30. 0% and hydroxypropoxy group 7. 〇~12〇%. Hydroxypropyl methylcellulose 2910, more specifically, Tc-5E (manufactured by Shin-Etsu Chemical Co., Ltd.), Methocel E (Dow Chemical Japan), Marp〇l〇se (Matsumoto Oil Pharmaceutical Co., Ltd.). 21 200835527 In particular, when the bitterness-suppressing base is hydroxypropylmethylcellulose, specifically, TC-5E (manufactured by Shin-Etsu Chemical Co., Ltd.) which is one of hydroxypropylmethylcellulose 2910 is used. The liquid content (hereinafter, "% by weight" is described as "w/w%") is 6 to 35 w/w%, and is 6. 5~32. 5w 5 /w% is better, and 7~30w/w% is better. The weight of the bitterness-suppressing base hydroxypropylmethylcellulose relative to the total amount of the preparation is 0. 001~50w/w%, and 0. 01~30w/w% is appropriate, and 0. 1 to 25 w/w% is preferred. If it is less than this content, there is a possibility that the bitterness suppressing effect cannot be sufficiently exerted; if it is more than this content, there is a possibility that the formulation collapses. Risperidin can be used alone or as a mixture with other drugs. Furthermore, it is appropriate to administer the appropriate amount according to the disease, age, etc. of the patient. The content of the Risperidin in the bitterness-suppressing base hydroxypropyl methylcellulose solution is 15 series 0. 001 to 40w/w%, and preferably 1 to 30 w/w%, and more preferably 2 to 20 w/w%. If it is more than this content, there is a possibility that it will not inhibit the bitter taste of the mind. The weight ratio of the bitterness-suppressing base hydroxypropylmethylcellulose to Risperid is 1000 : 1 ~0. 5 ·· 1, and 100 ·· 1 ~0. 75 ·· 1 is better, and 10 ·· 20 1~1 : 1 is better. If the ratio of hydroxypropyl methylcellulose is more than the weight ratio of hydroxypropylmethylcellulose to Risperidone of 1000:1, there will be a possibility of dissolution delay. On the other hand, if the ratio of rationality is compared with the weight ratio of hydroxypropyl fluorenyl cellulose to Ristox 0. 5 : 1 If you have more, there will be a possibility that you can't suppress the bitter taste of the mind. 22 200835527 The preparation method of the Risperid suspension is not particularly limited. For example, in a method in which a predetermined amount of hydroxypropylmethylcellulose is dissolved and/or suspended in a liquid in water, a predetermined amount of the method is suspended, or a prescribed amount of Lisquito is suspended in water. And a method of dissolving and/or suspending hydroxypropyl methylcellulose in the liquid. In the bitterness-suppressing preparation of the present invention, the excipient to be used may be any one as long as it is used in the medical field. Specifically, any of a water-soluble excipient and a water-insoluble excipient can be used. More specific excipients are glucose, fructose, lactose, sucrose, D-mannitol, erythritol, maltitol, trehalose, sorbitol, corn starch, potato starch, wheat flour, Rice powder, crystalline cellulose, anhydrous oxalic acid, anhydrous hydrogen peroxide, calcium hydrogen phosphate, calcium carbonate, precipitated calcium carbonate, calcium citrate, aqueous cerium oxide, and the like. Further, a water-insoluble excipient such as crystalline cellulose, calcium carbonate, precipitated calcium carbonate, anhydrous calcium hydrogen phosphate or calcium hydrogen phosphate is preferred. 15 The content of the excipient in the bitterness-suppressing preparation of the present invention is 0 to 99 with respect to the total amount of the preparation. 9w/w%, and preferably 5 to 90 w/w%, and more preferably 30 to 70 w/w%. If the amount is less than this, there is a possibility that a powder or granule preparation cannot be formed. A disintegrating agent can also be used in the bitterness-suppressing preparation of the present invention. In particular, 20 is necessary in the case of agitation granulation. The disintegrant to be used may be any one as long as it is used in the medical field. Specifically, the disintegrant is specifically low-substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, sodium carboxymethyl starch, croscarmellose sodium, cross-linking Povidone, corn starch, alpha-starch, and amaranth. It is preferred to use crospovidone. 23 200835527 The content of the disintegrant of the bitterness-suppressing preparation of the present invention is 0 to 99 with respect to the total amount of the preparation. 9w/w%, and preferably 5 to 90 w/w%, and more preferably 10 to 70 w/w%. If it is less than this, the possibility of disintegration is lowered. 5 A binding agent can also be used in the bitterness-suppressing preparation of the present invention. The binder to be used may be any one as long as it is used in the medical field. Specifically, it is hydroxypropyl decyl cellulose, fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, hydroxypropyl methylcellulose mixture, hydroxypropyl cellulose, Carboxymethylcellulose, sodium carboxymethylcellulose, sodium carboxymethyl starch, 10 croscarmellose sodium, crospovidone, hydroxyethyl methylcellulose, hydroxypropyl starch, hydroxyethyl Cellulose and the like. Further, a mixture of hydroxypropylmethylcellulose or fumaric acid·stearic acid·polyvinylacetal diethylaminoacetate•hydroxypropylmethylcellulose is preferred. The content of the binding agent of the bitterness-suppressing preparation of the present invention is 0 to 20 w/w% based on the total amount of the preparation 15. If there is more than this swap, there is a possibility of a disintegration delay. In the bitterness-suppressing preparation of the present invention, a flavoring agent can also be used in order to reduce bitterness. Specifically, it is peppermint oil and citric acid. In the bitterness-suppressing preparation of the present invention, the most suitable bitterness-suppressing base 20 is hydroxypropylmethylcellulose and the content of the liquid of Ristolide, which is one of hydroxypropylmethylcellulose 2910. TC-5E (manufactured by Shin-Etsu Chemical Co., Ltd.) is 6~35w/w% with propylmethylcellulose and 0. 001~40w/w%, and propylmethylcellulose is 6. 5~32. 5w/w%, Lisi must be 1~30w/w% is better, 24 200835527 and Luo! The propylmethylcellulose is 7 to 3 Gw/w%, and the Risperid is 2 to 20 w/w%.丄 > A powder or granule preparation in the bitterness-suppressing preparation of the present invention, specifically. The system guides the powder, granule scraping and syrup in the general preparations described in the 14th revision of the Japanese Pharmacopoeia. In particular, the manufacturing method of the present invention is the most suitable manufacturing method for the manufacture of granules, granules which are not inhibited by ancient odor. BEST MODE FOR CARRYING OUT THE INVENTION The oral cavity collapse manufacturing method of the present invention is described below. In the specific production method, for example, the amount of the active ingredient and the original preparation is mixed, and the tablet is mixed with a suitable mixer such as a V-type or a mixer, and the mixture is directly used. A method of manufacturing an ingot, etc. In order to obtain a mixed powder for tablets, it is also possible to use a method of intensively mixing by a stirring granulator, a method of mixing and pulverizing by a pulverizer, and a granulation by a dry granulator. The method and the method of granulating water, acetone, ethanol, propanol or the like, or the method of granulating the mixture according to the need, or further dividing into two or more groups 7 The method of mixing powder with the agent. In the manufacture of ingot-mixed powders, it is possible to mix binders, flavoring agents, fluidizers, lubricants, perfumes, sweeteners, colorants and the like. 2〇 ^ , , Regarding compression molding, if it is the point of the invention, even if the lubrication is ΐ (1% by weight or less per rpm, and 重量 $% by weight, Λ u. i is more preferably less than or equal to the weight percent), and it is still possible to use a general tableting method (part mixing method) or to attach the lubricant to the outer/free month of the whitehead of the tableting machine. (E) ELSP TYPE III manufactured by Kikusui Seisakusho Co., Ltd. can be used as an apparatus for external lubrication by 25 200835527. When the content of the lubricant is reduced, the disintegration speed is accelerated and the hardness of the tablet is increased, and the stability of the drug is improved. The general method of mixing the lubricant into the mixed powder for tablets may require 1 to 5 mg of the lubricant for the 10 mM tablet in the formulation, but may be 0 per liter of the tablet in the formulation of the present invention. 8% by weight or less, and 0. Preferably, 5% by weight or less is used, and further, a small amount of lubricant is preferably used in an amount of less than 1% by weight. In particular, if the active ingredient is blended, crystalline cellulose, anhydrous calcium hydrogen phosphate, carboxymethyl cellulose, and each of the ingots. Magnesium stearate of 1% by weight or less, and the method of adding the lubricant 10 is more preferable for the external lubrication method. In the above, in particular, the active ingredient, crystalline cellulose 'anhydrous pot acid hydrogen, carboxymethyl cellulose is substantially contained (when the sweetener is added, the vinegar is vinegar or sucrose*. The mint powder is preferably formed by an internal mixing method or an external lubrication method. Further, it is active in the present invention; 15 and the particle diameter of the additive is not particularly limited. The resulting mixture (10) is used, for example, for external liver. Key-operated device, single-shot keying machine, rotary hitting in fixed machine, etc., to make spinning pressure: ^~(10)kg compression fine 彡. If it is lower than its pressure, _hardness is enough to ensure sufficient hardness in operation; If the right knife is higher, then 20 will be delayed. _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ It can be a layer of enamel, a thief, etc., and can also enter the shape of the _ secary shape and, in addition, it can also be coated with 4 (4) to enhance the recognition. The marking of the 荨 及 and 26 200835527 secant for division. Inventive bond agent as oral disintegration tablet system Usefully, the drip liquid can be rapidly disintegrated in the oral cavity, and can be taken without slipperiness. The dissolution of the mouth of the orally disintegrating tablet of the present invention is usually 1 to shame 5 and is 1 ~40 seconds is better, and it is preferably about 1 to 30 seconds. Further, although the hardness (measured by the tablet hardness tester) is usually u 2 疋 3 〇 ~ 7 〇 N & right is no problem. However, the oral amine disintegrating and knocking agent of the present invention is 10 to 2 〇〇n, and preferably about 30 to 150 N. Further, the preparation may not be taken orally disintegrated in the oral cavity or with water - 10 The method for obtaining the powder or granule preparation of the bitterness-suppressing preparation of the present invention is preferably as long as it is pharmaceutically acceptable, but it is made by a wet granulation method and is made of a fluidized layer. The granulation method, the stirring granulation method or the extrusion granulation method, the rotation is preferred, and the granulation method is better. The fluidized layer granulation method such as the granule bonding agent sprays the fluidized powder. The granulation method is obtained by adding the binding liquid to the loading tank and rotating the mixing leaves of various shapes to give, The method of obtaining the desired granules by the action of the plant, etc. The method of extruding the slabs 20 and obtaining the granulated material is carried out. = The block is forced to move, and the rotatory granulation method is borrowed. By rotating the centrifugal force of the crucible, the raw material powder close to the outer wall portion is rotated by the air owed from the narrow to the t, and the bonding agent is sprayed at this time to obtain the two (four) method. The manufacturing time of the silk method is longer than the above-mentioned ~, and it is more difficult to suppress the bitterness of the rationale. 27 200835527 The preparation of the pre-liquid is prepared by dissolving or suspending the surface of the invention by a fluidized layer. And - in the dissolution and/or suspension of the base material (4), the liquid is sprayed or collapsed and flowed while preparing the preparation of the present invention by agitation granulation method, and prepared in advance; The bitter taste inhibits the dissolution of the base " or suspension: ya: Add the above-mentioned granules while mixing the ingredients. 10 in the preparation of the preparation of the present invention by the extrusion teaching method, preparing a dissolution and/or suspension of a bitterness-suppressing base which is pre-dissolved or suspended in a rational manner; and mixing the liquid with the _ agent and /« _, and the contents were pressed out and granulated by machine. When preparing the preparation of the present invention by rotation, preparing a pre-dissolved η solution or a rationally prepared bitterness-suppressing base for dissolution and/or suspension/night's sub-edge in a tank of a centrifugal rotating granulation device The agent and/or disintegrant is rotated, and the aforementioned liquid is added to granulate. The powder or granule preparation of the present invention can be used as it is, for example, as a bitter-suppressed granule or a fine granule. At this point, it is not particularly inferior to determine the dynamics of the blood. 20 Further, a flaky agent, a disintegrating agent, a binder, and a lubricant may be mixed with a powder of the present invention and a granule preparation to form a tablet. The foregoing can be used as an excipient, a detoxifying agent, and a binding agent. Further, the lubricant is magnesium stearate, sucrose fatty acid ester, magnesium carbonate or the like. Furthermore, it is also possible to mix the excipient, the disintegrant, and the binding agent with the granule preparation of the present invention 28 200835527, and to measure the lubricant, and attach the lesser key to the white and the enamel of the human machine. If you want to play money, the second is to adjust the slippery snoring method, you can also make it. You can use a small amount of lubricant when you pull it out. 5 10 15 20 See: Deterioration is a useful method of spinning. Intra-instantaneous::: In addition to the agent, the powder and granule preparation of the present invention are blended into the oral cavity disintegrating lozenge of the instant instant scent of the mouth, and the novel state of the tablet can be produced (4). The additive = the lubricant can be used as before, for example, peppermint oil, "acid-like adjustment 2" is good, or in the key agent, the first thing is to have a very bitter taste. As described above, after the preparation of the powder and the granules (for example, the South Ic/the actual addition example 1) of the present invention, the powder or granule preparation is contained. Yuyou can manufacture ancient flavor-suppressed tablets. Further, when the bitter taste-containing powder or granules are contained in the orally disintegrating rotatory agent, an orally disintegrating tablet having a suppressed bitterness can be produced. Tian, the blood dynamics of the orally disintegrating tablet of the present invention is not inferior to the conventional one. BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail by way of examples and comparative examples, but the present invention is not limited thereto. The tablet obtained in the examples was subjected to the following test method to measure the tablet and the disintegration time, and subjected to a bitterness functional test. (1) Hardness test The measurement was performed using a special machine for hardness measurement (manufactured by ERWEKA International AG). The test was carried out in 10 spindles and the average enthalpy was shown. (Based on 30N or more as a basis) (2) Disintegration test The 14th correction time of the 6-ingot 5 is measured according to the fourteenth correction of the local disintegration test method, and the maximum flaw is shown. (Based on less than 20 seconds) (3) Functional test of bitterness The prepared preparation was contained in the oral cavity of 5 healthy adults, and a functional test was performed on the tongue for about 5 seconds. Example 1 10 Preparation of Risperid Oral Disintegrating Lozenge (1, External Lubrication Method) [Table 1] Ingredients Risebital Oral Disintegrating Tablets 0. 5 mg ingot 1 mg ingot 2 mg! fixed 3 mg ingots granules prescription Lisibituo 0. 5 1 2 3 propylmethyl group 1. 5 r 纤维素 Cellulose 2910 5 0 y Anhydrous acid-filled aunt 5 10 20 30 Carboxymethyl cellulose calcium 5 10 20 30 Extragranular prescription Crystalline cellulose Anhydrous acid 氲1 bow Appropriate amount (13) 19. 2 Appropriate amount (26) 38. 4 Appropriate amount (27) 39. 94 moderation (40. 5) 59. 91 vinegar yellow inside S purpose 1 A 0. 7 1. 4 1. 8 2. 7 Carboxymethylcellulose 5 10 13 19. 5 peppermint oil aqueous cerium oxide micro trace micro trace (0. 05) 0. 1 (0. 1) 0. 2 (0. 13) 0. 26 (0. 195) 0. 39 Magnesium stearate A trace amount of trace amount (mg) 50 100 130 195 30 200835527 1) The manufacture of the bitterness-suppressing preparation (granules) containing Risperidin is based on the amount shown in Table 1, on the scale of 10,000 bonds. After the propyl acetaminophen 291G domain is in pure water, the rationale is expected to be prepared, and the viscosity of the granulating liquid at 20C is 1〇〇14〇〇〇mPa. $Night will be anhydrous hydrogen-free "base" _ money investment in the first, mixing machine and mix. After picking up, true, i cleverly stir the T splicer while adding the granulation liquid while making the granulation >''The obtained granules are dried by a fluidized bed granulator, 10 to obtain dry granules. It is difficult to dry P_3 type P_mill into the rod: 'and get the Risto granules. The functional test of bitterness on the granules does not feel bitter. 2) Manufacture of peppermint oil powder 15 According to the blending amount described in Table 1, the peppermint oil is added in a scale of 100,000 spindles: In the aqueous cerium oxide, the polyolefin bag is mixed to obtain a roll, and the mixed powder is hand-sifted with a gold mesh, and the polyolefin bag is mixed to obtain peppermint oil powder. 3) Production of an orally disintegrating tablet 20 Calcium according to Table 1 The amount of blending, on the scale of 50 ingots, the anhydrous hydrogen phosphate moon 11 said Risperid granules, potassium acesulfame lactone, peppermint oil powder and crystalline fiber ♦, 'mu generation /, carboxymethyl cellulose input In the polyolefin bag, and mix the polyolefin powder. The mixed powder is hand-sifted with gold mesh and mixed into the hydrocarbon bag. ^ Said ingot powder to obtain cotton stick to the mass of the magnesium stearate-linking agents square denier · ι% or less of traffic in a mortar and pestle is attached to a person (using pestle: 0. 5 mg ingot φ = 5. 0 mm, 31 200835527 1 mg ! 定 φ = 6. 5 mm, 2 mg ! φ = 7 mm, 3 mg key φ = 8. On the 0 mm), the obtained ingot powder was tableted by a static compression tester to obtain a Risperous Oral Disintegrating Lozenge. (Functional test of tablet hardness, disintegration time, and bitterness) 5 The hardness and disintegration time of the Risperid's orally disintegrating tablet obtained by the above method were tested. The results are shown in Table 2. Moreover, in the bitterness-featured test, neither of the preparations felt bitter. [Table 2] Oral disintegrating tablets Lozenge hardness (N) Disintegration time (seconds) 0. 5 mg ingot 42 9 lmg ingot 58. 4 13 2mg ingots 42. 5 16 3 mg ingot 72 23 10 is only for reference, and the results of the measurement of the hardness and disintegration time of the currently commercially available tablets of risbital (1 mg) are shown below. [Table 3] Mass (mg) Lozenge Thickness (mm) Lozenge Hardness (N) Disintegration Time (seconds) 1 102. twenty three. 21 45 — 2 102. 6 3. 21 46 — 3 104. 7 3. 28 45 — 4 103. 4 3. 25 — 373 5 102. 3 3. 24 — 306 Average 103. 0 3. 24 45. 3 340 Example 2 15 Preparation of Risperid Oral Disintegrating Lozenge (2, Internal Mixing Method) (Manufacturing Method of Lozenge) 32 200835527 The amount of blending according to Table 4 was measured and produced in Example 1. The risperidone granules, carboxymethyl cellulose, crystalline cellulose, anhydrous calcium hydrogen phosphate, potassium acesulfame lactone, and mixed in a polyolefin bag, and added with magnesium stearate, are mixed to obtain a tablet powder. The obtained ingot powder was subjected to a static compression tester (using 杵: 5 φ = 6. 5 mm) Ingots were obtained by injecting tablets. [Table 4] Ingredient Example 2 Risperid 1 Hydroxypropylmethylcellulose 2910 3 Anhydrous dicalcium phosphate light 10 Carboxymethylcellulose Ma 10 Crystalline amount (26) Anhydrous hydrogen peroxide GS 37 . 8 vinegar yellow inside S means potassium 1. 4 Carboxymethylcellulose 10 Magnesium stearate 0. 8 Total amount (mg) 100 (Functional test of tablet hardness, disintegration time, and bitterness) The hardness and disintegration time of the Risperid oral disintegrating tablet 10 obtained by the above method were tested. The results are shown in Table 5. Also, in the bitter taste test, it does not feel bitter. [Table 5] Oral disintegrating tablet Lozenge hardness (N) Disintegration time (seconds) Example 2 59. 4 16 Example 3 15 Preparation of Risperid Oral Disintegrating Lozenge (3, External Lubrication Method) (Manufacturing Method of Lozenges) 33 200835527 The amount of blending according to Table 5 is taken as a Carboxymethylcellulose, crystalline cellulose, anhydrous calcium hydrogen phosphate, potassium acesulfame, and mixed in a polyolefin bag to obtain a tablet powder. Using magnesium rods to make magnesium stearate the mass of the lozenge. The amount below 1% is attached to 杵臼 (using 杵: p=6. On 5 mnl), the obtained spirulina was swirled by a static compression tester to obtain a Risperous Oral Disintegration Lozenge. [Table 6]
1〇 ( 更度、崩解時間以及苦味之官能試驗） 藉由别述方法試驗所得到的理思必妥口腔内崩解疑劑 之硬度與崩解相。將結㈣於表7。又，於苦味之官能試 ’中雖曰感到少許苦味，但其為可服用的水準。 【表7】 ~_ggjZTi [I ^ 15產業上的可利用性 存時之2之叙裔1其製造步驟容易’且兼備製造時以及保 又，此外長期間保存穩定性極優。再者，因於口 34 200835527 腔内會迅速崩解，而對非常興奮或激烈拒絶的急性患者而 言亦為容易接受的劑型，因此被認定在治療上有極大的價 值。再者，本發明僅以溶解或懸浮於水中的基劑即可抑制 苦味，且僅只使用水作為溶劑，因此實用性極高。再者， 5 本發明製劑亦可摻合於口腔内崩解錠劑中，而可製造可瞬 間於口腔内崩解，且同時可抑制苦味的錠劑。 t圖式簡單說明3 無 【主要元件符號說明】 無 351 〇 (more sensitivities, disintegration time, and bitterness sensitization test) The hardness and disintegration phase of the Risperid's oral disintegration agent obtained by the method described elsewhere. Will be knotted (four) in Table 7. In addition, although it is slightly bitter in the bitter taste functional test, it is a level that can be taken. [Table 7] ~_ggjZTi [I^15 Industrial Applicability] The narration of the time 2 is easy to manufacture, and it has both manufacturing and maintenance, and excellent storage stability over a long period of time. Furthermore, because the oral cavity 34 200835527 will rapidly disintegrate in the cavity, and it is also an easily accepted dosage form for acute patients who are very excited or strongly rejected, it is considered to be of great value in treatment. Further, the present invention can suppress bitterness only by a base dissolved or suspended in water, and only water is used as a solvent, so that the utility is extremely high. Further, the preparation of the present invention can also be incorporated into an orally disintegrating tablet, and a tablet which can be disintegrated in the oral cavity instantaneously and which can suppress bitterness can be produced. t Schematic description 3 None [Main component symbol description] None 35