TW200938233A - Oral dispersable tablet - Google Patents

Abstract

The present invention is directed to an oral disintegratable tablet which exhibits oral disintegratability of not more than 60 seconds. The tablet for oral administration, comprises an effective amount of at least one active agent, an amount of at least 50% (w/w) of a water insoluble parts, a surfactant and a disintegrant, such that said tablet is orally disintegretable or dispersable.

Description

200938233 六、發明說明： 【發明所屬之技術領域】 5 Ο 10 15 Ο 20 本發明係專注於一種口服可崩解鍵劑，其呈現不超過 之口服可崩解性。經口投藥之該淀劑，其包含：-有 ^里^至少-種活性劑、—至少5G%(Ww)量之水不溶性部 : 界面活性劑及一崩散劑，致使該錠劑為口服可崩散 或可分散。 【先前技術】 口服可分散的錠劑原則上與一般立即釋放(IR)錠劑沒 六，，之4 4等應為物理上穩^，在工業上操作期間可 t許Z理且可由患者或消費者自行處理者。該等在有水環 士兄之崩解時間應為迅速及完全。在釋出情況下之軟化處 理’以便微弱的物理性壓力足以完成分散，為*人可接受 的。 為改良朋解性質，有共通的一些原則^例如錠劑包括 發’包混合物，其為至少一種酸組成份（有例如檸檬酸)與至少 一種驗組成份而為碳酸鹽或氫碳酸鹽之形式。這樣的口服 可分散性用鍵劑已揭示於例如US 2002/0110578。另一種— 般的方法為使用可迅速溶解的錠劑賦形劑，有例如糖醇類 (甘露醇、山梨糖醇、木糖醇、丁四醇等）、糖類或這些專門 的形式’如？1^11131)1«^1^或F—MeltTM。迅速崩解為這此 賦形劑溶解的結果。 對錠劑而言，用在口腔中崩解，有需要某些附加的性 3 200938233 ι〇 15 2〇 質。在錠劑崩解後生成的溶液或分散液應可易於吞服，味 道上與口感為可接受的。因此對活性組成份或組成份(如微 裂膠囊:包膜、鹽形成、酉旨形成等)之味道遮蔽效果有需要 鍊常進仃額外的測量。再者，香料及/或增甜職用以改良 氺;^與患者可接焚度。有時候所用的賦形劑也有令人愉快 的冰道(糖類、糖醇類)且以此性質來改良患者可接受度。 口腔中迅速㈣另1難之處在於畴在液體之有限 黉〜、水比較’口腔内之液體為高黏性。液體之量與其黏 捧#互定'。依照：天中不同時間、所消耗液體之量(飲 辦批食物等使得在不同的被實驗者之間且甚至 在:㈣變動。高度的多賊劑構造，液體可容 !而亦為在口服可分散之錠劑領域為常見。 第製造技術可確保高度的多孔錠劑構造。錠劑之 響崩解時間。對液體渗入之較短途徑:較 #。此^要條件亦會影響錠劑形狀與幾何學。所需最理想 的幾何子亦需考量物理上穩定性，如已敘述者。 。二亦對口服可分散之錠劑，成本 择為重要2造成本應盡量越低越好。可轉 的耩準技術並保持製造過程盡可能精簡而；以最佳U 遠成。任何額外的製造步驟將會增加成本並應 工 署賦形劑之使料傾向於增加成本樣 彬劑費用更昂貴。 银《比橾旱賦 在服用口服可分散錠劑的目標群可 者或在正常陳服用時，水並非立 ❹ Ο 4 200938233 組。在某些市場不喝水服用錠劑之便利性為最優先。就一 切情況而論’錠劑崩解時間應予以縮短且患者/消費者應有 印象錠劑在他/她的口中會發生什麼事。此種崩解作用之感 知可幫助患者/消費者預期對他/她的身體狀況或健康之一 種或多種活性主成分會有正面的影響。 JP 9071523揭示口服可分散錠劑之配製物❶其揭示微 晶纖維素(MCC)與低取代羥丙基纖維素(l - HPC)組合之用 途。該兩種賦形劑之某些比率被認為可產生所需的錠劑性 10200938233 VI. Description of the invention: [Technical field to which the invention pertains] 5 Ο 10 15 Ο 20 The present invention is directed to an orally disintegrable bond which exhibits no more than oral disintegratability. The orally administered dosage agent comprises: - having at least one active agent, at least 5 G% (Ww) of a water-insoluble portion: a surfactant and a disintegrating agent, so that the tablet is orally available Disintegrated or dispersible. [Prior Art] Orally dispersible lozenges are in principle not in general with general immediate release (IR) lozenges, and 4, 4, etc. should be physically stable, and can be used during industrial operations and can be Consumers are their own processors. The disintegration time of those who have a water ring should be prompt and complete. Softening treatment in the case of release so that weak physical pressure is sufficient to complete the dispersion, which is acceptable to * people. In order to improve the nature of the disintegration, there are some common principles. For example, a tablet comprises a 'package mixture, which is in the form of at least one acid component (having, for example, citric acid) and at least one component, in the form of a carbonate or a hydrogen carbonate. . Such a key for oral dispersibility has been disclosed, for example, in US 2002/0110578. Another common method is to use a fast-dissolving tablet excipient such as sugar alcohols (mannitol, sorbitol, xylitol, butyltetraol, etc.), sugars or these specialized forms. 1^11131) 1«^1^ or F-MeltTM. Rapid disintegration is the result of dissolution of this excipient. For tablets, for disintegration in the mouth, some additional properties are required 3 200938233 ι〇 15 2〇. The solution or dispersion formed after the disintegration of the tablet should be easily swallowed, and the taste and mouthfeel are acceptable. Therefore, there is a need for an additional measurement of the taste masking effect of the active component or component (e.g., microcapsule: envelope, salt formation, formation, etc.). In addition, the fragrance and/or sweetening position is used to improve the sputum; ^ and the patient can be incinerated. Sometimes the excipients used also have pleasant ice channels (sugars, sugar alcohols) and are used to improve patient acceptability. Rapid in the mouth (4) Another difficulty is that the domain is limited in liquid 、~, water comparison The liquid in the mouth is highly viscous. The amount of liquid and its adhesion # mutually set '. According to: the amount of liquid consumed at different times in the day (drinking food, etc., so that it can be changed between different subjects and even in: (4). The height of the multi-thief structure, the liquid can be accommodated! The field of dispersible tablets is common. The first manufacturing technology ensures a high degree of porous tablet construction. The disintegration time of the tablet. The shorter way to infiltrate the liquid: compared to #. This condition also affects the shape of the tablet. And geometry. The ideal geometry required also needs to consider physical stability, as already described. 2. Also for oral dispersible tablets, the cost is important 2, which should be as low as possible. Transfer the quasi-technique and keep the manufacturing process as lean as possible; to achieve the best U. Any additional manufacturing steps will increase the cost and the cost of the excipients of the Agency will increase the cost. Silver "Compared with the target group of oral dispersible tablets or when taken in normal aging, the water is not standing ❹ 4 200938233. In some markets, the convenience of taking tablets is the most convenient. Priority. In all cases The 'disintegration time of the tablet should be shortened and the patient/consumer should have an impression of what happens to the lozenge in his/her mouth. The perception of this disintegration can help the patient/consumer anticipate his/her One or more active principal components of physical condition or health may have a positive effect. JP 9071523 discloses formulations of orally dispersible troches which reveal microcrystalline cellulose (MCC) with low substituted hydroxypropyl cellulose (l - HPC) The use of the combination. Certain ratios of the two excipients are believed to produce the desired lozenge 10

20 W02004091585揭示用於口服可分散錠劑的配製物 Prosolv® (經石夕化結晶微晶纖維素）之用途。係一種 賦形劑的商標名，且進一步在US6471994揭示作為新穎錠 劑賦形劑，亦可與口服可分散之錠劑一起使用。 、 在開始著手於口服可分散之錠劑的新穎配製物之發展 方面，吾人已研究界面活性劑之使用。界面活性劑與親水 性、加濕聚合物，如普羅沙姆(p〇1〇xamer)，可择 等溶解度而被用於協助活性組成份（―種或㈣^該 的濕^，或增加該等生物利用率。在口服可分散質) 領域界面活性劑可使用以減少口腔内水性介質之黏性： 性物質之濕潤性_立性。藉由㈣-種或多種20 W02004091585 discloses the use of a formulation for oral dispersible tablets, Prosolv® (through Shihua crystallized microcrystalline cellulose). It is a trade name for an excipient and is further disclosed as a novel tablet excipient in US Pat. No. 647,1994, and may also be used with an orally dispersible lozenge. In the development of novel formulations that have begun to work on orally dispersible tablets, we have investigated the use of surfactants. The surfactant and the hydrophilic, humidifying polymer, such as prosham (p〇1〇xamer), may be used to assist the active component ("seed" or "four" Such as bioavailability. In the field of oral dispersibles, surfactants can be used to reduce the viscosity of aqueous media in the oral cavity: the wettability of sexual substances - standing. By (4) - one or more

於配此等效果。鹽⑽卬、酸組成份或= 味成刀可，、有相似功效且亦可減少 J 性。該等組合可強效果。 ㈣μ"質之黏 吾人發現迅速的錠㈣解可被減到最小量之更少的疏 5 200938233 水I·生，π劑所促進，而最普遍使用之硬脂酸鎂傾向於 有:效的錠劑崩散劑在配製物内與其他不溶物質 【發明内容】 本發明係專注於經口投藥用 效量的至少一種爷枓麻丨 〇匕3 .有 八、-反而、、 至少5〇%(W/W)量之水不溶性部With this effect. Salt (10) bismuth, acid component or = can be used as a knife, has similar effects and can also reduce J. These combinations can have a strong effect. (4) μ" viscous viscous people find that the rapid ingot (four) solution can be reduced to a minimum amount of less 5 200938233 water I · raw, π agent promoted, and the most commonly used magnesium stearate tends to have effect Tablets disintegrating agent in the formulation and other insoluble substances [Summary of the Invention] The present invention is directed to at least one kind of medicinal efficacy of at least one kind of ramie 丨〇匕 3. There are eight, - instead, at least 〇 ( ( W/W) water insoluble part

\ I '舌性劑與一崩散劑，致使該錠劑為口服可崩I 10 15\ I 'tongue agent and a disintegration agent, causing the tablet to be orally disintegratable I 10 15

在⑽現衝崩解性= /以、…超呈現口服可崩解性。更佳為錠劑 1秒内呈現口服可崩解性。最佳是鍵劑在不超過2 秒内呈現口服可崩解性。 錢4]中水不洛性載體係選自纖維素、微晶纖維素或經 石夕化微晶纖維素或其混合物之組群。㈣化微晶纖維素係 包括於2G%至90%範_，較佳為在25%至帆範圍内。In (10), the current disintegration = / /, ... super-present oral disintegration. More preferably, the tablet exhibits oral disintegratability within 1 second. Preferably, the key exhibits oral disintegration in less than 2 seconds. The water-insoluble carrier is selected from the group consisting of cellulose, microcrystalline cellulose or smectic microcrystalline cellulose or a mixture thereof. (4) The microcrystalline cellulose system is included in the range of 2G% to 90%, preferably in the range of 25% to the sail.

該經石夕化微晶纖維素包括〗至5%二氧化♦。錠劑經石夕 化微晶纖維素錠有平均粒子大小在2()•獅阿範圍内。 鍵劑中之崩散劑係選自低取代經丙基纖維素、叛甲基 纖維素、父聯甲基緩纖維素鈉、交聯普威隆（交聯聚乙稀啦 洛咬酮）、殿祕基醋酸鈉、澱粉及其組合。較佳之崩散劑 為低取代羥丙基纖維素或交聯普威隆（交聯聚乙烯吼咯啶 嗣）或其組合。朋散劑包括於鏡劑之量為〇5%至50%。 錠劑中界面活性劑係選自十二烷基硫酸鈉、聚氧乙烯 山梨糖醇酐脂肪酸酯（Tweens)、聚氧乙烯硬脂酸酯、山梨糖 20 200938233 醇軒脂肪酸酯（Spans)之組群。 本發明之錠劑係一種具有抗拉強度3〇〇至2〇〇〇 kN/m2 (以抗拉強度=2*破壞負載/(直徑*厚度*冗）計算;所觀察到 的經測量的錠劑拉力破壞）。 5 ❹ 10 15 ❹ 20 本發明之錠劑具有低於1%之易碎性。本發明之錠劑並 不包括水可溶性黏著劑。 根據本發明之錠劑可進而包括至少一種添加之賦形 劑，其係選自味道遮蔽劑、增甜劑、潤滑劑、安定劑、防 腐劑與pH調節劑所成群。根據本發明錠劑中之活性劑，係 選自藥學活性劑、營養劑、營養醫學品及化妝品所成群。 活性劑可為一種或多種維生素。活性劑可為一種或多種藥 學上的活性劑。 該藥學活性劑可以包括該藥學活性劑的包膜粒子之形 式存在。包膜可為延長釋放或腸溶衣。 根據本發明之錠劑，其中該藥學活性劑係選自抗炎性 劑、抗風濕劑、止吐劑、止痛劑、抗癲癇劑、抗精神病劑、 抗抑鬱劑、安眠劑、抗潰癌劑(antiuicerics)、促腸胃襟動劑、 抗氣喘劑、抗帕金森病劑、心血管劑、血管擴張劑、泌尿 科學劑、降血脂劑、抗糖尿病劑及抗組織胺劑所成群。 該藥學活性劑可選自伊布落芬(ibuprofen)、乙酿胺基酴 (acetominophen)、匹若卡（piroxicam)、雅努麻键 (leflunomide)、恩丹西 _ (ondansetron)、格拉司 ί复 (granisetron)、乙醯胺苯酚（paracetamol)、顛妥鍵 (carbamazepin)、樂命達(lamotrigine)、氣氮平(clozapine)、 7 200938233 奥氮平（olanzapine)、理思必妥（risperidone)、赛達樂 (citalopram)、帕羅西汀(paroxetine)、抗憂服(sertraline)、百 憂解(fluoxetine)、樂得腸(fluvoxamine)、宜眠安(zopiclon)、 使蒂諾斯（zolpidem)、西咪替丁（cimetidine)、善胃得 5 (ranitidine)、奥美拉坐（omeprazole)、美多科拉酿胺 (metoclopramide)、希塞菩(cisapride)、通平(domperidon)、 雅樂得（zafirlukast)、欣流（montelukast)、樂伯克 (prarnipexol)、迪普寧（selegiline)、使蒂諾斯(zolpidem)、口坐 〇 匹可隆（zopiclon)、多薩坐辛（doxazosin)、服脈錠 ίο (terazosin)、阿替洛爾（atenolol)、必落瑞（bisoprolol)、安洛 待平（amlodipine)、硝苯地平（nifedipine)、地爾硫卓 (diltiazem)、伊那拉普利（enalapril)、卡托普利（captopril)、 心達舒石疋（ramipril)、洛沙東（losartan)、***油（glycerol trinitrate)、扎特（alfuzosin)、柔沛（finasteride)、普伐他丁 15 (Pravastatin)、阿多路巴史達丁（atorvastatin)、辛伐他汀 (simvastatin)、洛脂(gemfibrozil)、二曱雙脈(metf〇rmin)、特 芬那定（terfenadine)、樂雷塔定（1〇ratadine)、希樂操〇 (celecoxib)、偉克適(dfecoxib)、及憶思能(rivastigmine)所成 群，以及該活性劑之藥學上可接受的鹽、酯、水合物或溶 20 劑化物。 根據本發明，藥學上口服可崩解之非泡騰鍵劑係一種 ^本上由20%至9〇%财化微晶纖維素或纖維素微晶纖維 素、G%至20%低取代㈣基纖維素、㈣至篇交聯聚 鱗咬嗣、潤滑劑、界面活性劑與有效量的藥學活性劑所 200938233 1至 見 =試管内崩解試驗測試時，該錠劑在 包括香料、色料或兩者。 5 ❹ 10 15 ❹ 20 服可崩解的非泡騰活性劑之用途’用以製造口 程，一種自固體鍵劑可迅速釋放活性劑之過 崩散；劑於有水環境，如上述方式使鍵劑 男八每垅為口腔或充水容器。 錠劑混合物不溶部分百分率應高 來源(如鹽類:例如•二= 鎂碳馱鈣、矽酸鹽類、氧化物如二氧化 化鎮或該等各自的水合物及域同素異、 ==物類:例如纖維素、纖維 曱成素、4Τ聚糖、殿粉、澱粉__類，藻酸鹽、人 成聚合物：例如聚乙烯、聚丙烯、聚氯乙烯、；二The crystallization of the microcrystalline cellulose comprises from 5% to 5%. The tablet has a mean particle size in the range of 2 () • Lion A. The disintegrating agent in the key is selected from the group consisting of low-substituted propyl cellulose, m-methyl cellulose, parent-linked methyl slow-sodium cellulose, cross-linked Pwesome (cross-linked polyethylene lycopene), and temple Sodium acetate, starch and combinations thereof. Preferred disintegrating agents are low substituted hydroxypropyl cellulose or crosslinked Pvillon (crosslinked polyethylene pyrrolidine) or a combination thereof. The amount of the agent is included in the amount of 镜 5% to 50%. The surfactant in the tablet is selected from the group consisting of sodium lauryl sulfate, polyoxyethylene sorbitan fatty acid ester (Tweens), polyoxyethylene stearate, sorbose 20 200938233 Alcohol fatty acid ester (Spans) Group of groups. The tablet of the present invention is a tensile strength of 3 〇〇 to 2 〇〇〇 kN/m 2 (calculated as tensile strength = 2 * breaking load / (diameter * thickness * redundancy); observed ingots are observed) Agent pull damage). 5 ❹ 10 15 ❹ 20 The tablet of the present invention has a friability of less than 1%. The lozenge of the present invention does not include a water-soluble adhesive. The tablet according to the present invention may further comprise at least one added excipient selected from the group consisting of a taste masking agent, a sweetener, a lubricant, a stabilizer, a preservative, and a pH adjusting agent. The active agent in the tablet according to the present invention is selected from the group consisting of pharmaceutically active agents, nutraceuticals, nutraceuticals, and cosmetics. The active agent can be one or more vitamins. The active agent can be one or more pharmaceutically active agents. The pharmaceutically active agent may be in the form of a coated particle comprising the pharmaceutically active agent. The envelope may be an extended release or an enteric coating. The tablet according to the present invention, wherein the pharmaceutically active agent is selected from the group consisting of an anti-inflammatory agent, an anti-rheumatic agent, an anti-emetic agent, an analgesic agent, an anti-epileptic agent, an antipsychotic agent, an antidepressant, a hypnotic agent, and an anti-cancer agent. (antiuicerics), gastrointestinal motility agents, anti-asthmatic agents, anti-Parkinson's agents, cardiovascular agents, vasodilators, urological agents, hypolipidemic agents, anti-diabetic agents and antihistamines. The pharmaceutically active agent may be selected from the group consisting of ibuprofen, acetominophen, piroxicam, leflunomide, ondansetron, glas Granisetron, paracetamol, carbamazepin, lamotrigine, clozapine, 7 200938233 olanzapine, risperidone , citalopram, paroxetine, sertraline, fluoxetine, fluvoxamine, zopiclon, zolpidem, west Cimetidine, ranitidine, omeprazole, metoclopramide, cisapride, domperidon, jafirlukast ), montelukast, prarnipexol, selegiline, zolpidem, zopiclon, doxazosin, orthodontic ingot Ίο (terazosin), atenolol, bisoprolol, ang Amlodipine, nifedipine, diltiazem, enalapril, captopril, ramipril, losartan, Glycerol trinitrate, alfuzosin, finasteride, Pravastatin, atorvastatin, simvastatin, gemfibrozil ), metf〇rmin, terfenadine, 1〇ratadine, celecoxib, dfecoxib, and memory The rivastigmine is a group, and a pharmaceutically acceptable salt, ester, hydrate or solvate of the active agent. According to the present invention, a pharmaceutically acceptable orally disintegrable non-effervescent agent is one of 20% to 9% by weight of microcrystalline cellulose or cellulose microcrystalline cellulose, G% to 20% low substitution (4) Cellulose, (4) to cross-linked polyscale bitumen, lubricant, surfactant and effective amount of pharmaceutically active agent 200938233 1 to see = in-tube disintegration test test, the tablet contains spices, colorants Or both. 5 ❹ 10 15 ❹ 20 The use of a disintegrable non-effervescent active agent is used to make a mouth, a self-solids agent that rapidly releases the active agent over collapse; the agent is in an aqueous environment, as described above The key agent male is used for oral or water-filled containers. The percentage of the insoluble portion of the tablet mixture should be high (such as salts: for example • two = magnesium strontium calcium, strontium salts, oxides such as dioxide towns or the respective hydrates and domains are the same, == Species: for example, cellulose, fiber sputum, 4 Τ glycan, house powder, starch __, alginate, human polymer: such as polyethylene, polypropylene, polyvinyl chloride;

酸醋）。若雜域分（―種錢數種）為不溶或其ς解度 低’其亦會作用為不溶部分。 X 在這方面之適當的崩散劑有例如可膨脹聚合物類、麫 交聯之可膨脹聚合物類、親水性聚合物類或其他物質，2 可吸收水且藉此可使體積增加。藥學上—般常見者為交、 曱基羧纖維素、交聯聚乙烯吡咯啶酮’ L-HPC或澱粉_臬 醋酸鈉。其他可溶解的贼形劑’可使用諸如糖類（乳糖、^ 糖(saccharose)、葡萄糠、果糠、麥芽糖）、糖醇類(甘露醇 山梨糖醇、木糖醇、丁四醇）或可溶性活性物質，只要該等 9 200938233 比率不致過尚且其平均粒子大小維持於5〇μιη之上。此可溶 性賦形劑之使用在口服可分散錠劑之領域亦為常見。 對於可溶性活性物質之結合，吾人發現該等粒子大小 對錠劑崩解具有-定程度之影響。在此情況使粒子不致過 5 小為有利的。粒子大小大於50叫（分佈之平均值)被認為會 產生所需錠劑性質。若-種或多種活性物質溶解度高時， 或者溶解之時間短時，大小以比平均粒子大為佳，粒子大 小之增加方式並不重要。大型結晶就跟以造粒方法（可使用 濕或乾造粒方法)所製造之黏聚物—樣的好。 〇 10 為了製造上述配製物、可使用一種直接壓製紫造、、* 程。因而製造成本低且可使用標準技術，而接其=茲 本。 所需的錠劑性質有：足夠的物理上穩定性（以抗拉強度 與易碎〖生表示）、迅速崩解性（以使用揭示於歐洲血 15 藥，，第五版2007 (5.8)方法2.9」，在3n：使用水與圓盤） 之崩解時間來表示）、可接受的口感與味道。 以上述之配製物主成分，不同溶解度的藥學上活性物❹ 質（藥物物質）可以調配出。藥物物質不是為可溶（有例如口 服抗糖尿病劑醣祿錠或米格列醇(Miglit〇1))或不溶(例如硝 20 苯地平）。在可溶藥物物質之情況，對於崩解時間、内容物 均勻性與錠劑硬度，粒子大小之特殊定義（級分)極為有利。 藥學上活性物質之粒子可為結晶或黏聚物。藥學上活性物 質之粒子大小可為5〇μιη— ΙΟΟΟμιη、較佳為1〇〇μιη_ 800μηι、更佳為 125μιη—630μιη、且最佳為 125μπι-800μιη。 200938233 在此粒子大小尤其疋特別可用者為藥學活性物質醣祿錠、 米格列醇及伏格列波糖。 【實施方式】 5 實施例： 藉由混合已知組成份（除了潤滑劑硬脂醯基反丁烯二 酸鈉之外）於適當的混合装置（例如三維混合機（Turbula® mixer)或滾動撲拌器）、經W分鐘可獲得旋劑。其後添加潤 11 滑劑並多混合5分鐘。 10 歧合物係使用衝壓器之9毫米平端面斜稜組，其後 壓製成錠劑以生成已知質量之錠劑。對於雙劑量錠劑則使 用13毫米平端面斜稜衝壓器並壓製成已知質量之雙倍。键 劑應配合已知的抗拉強度範圍（破壞負載在20至60N之 間）。 15 在使醣祿錠作為活性物質之情況，醣祿錠預先與0.5% (w/w)硬脂醯基反丁稀二酸鈉混合並予以緻密化。使緻密體 ❹ 破裂並篩分（進行乾燥造粒或以輥機壓實）。在篩分之後使用 德份 125μιη-800μΓη。 使用上述的歐洲擦典方法，使錠劑在5至10秒内崩解 20 實施例1 物質 一 總量[毫克/敍 質量[%1 活性物質*) _ I-**·*" 50,25 30,15% Prosolv (SMMC 90) _ — -------—" 101,00 60,61% 11 200938233 L-HPCB1 型 13,3〇 7,98% 十二烷基硫酸鈉 0,42 0,25% 氣化納 0,50 0,30% 糖精鈉 硬脂酿基反丁稀二酸納 0,17 0,10% 1,00 0,60% 鍵劑 166,64 100,00% *)用做99,5°/〇 (m/m)醣祿錠及0.5% (m/m)硬脂醯基反丁烯二酸鈉(Sodium stearyl flimerat)或米格列醇Sour vinegar). If the miscellaneous domain ("the kind of money" is insoluble or its degree of decompression is low", it will also act as an insoluble part. Suitable disintegrating agents in this regard are, for example, swellable polymers, fluorinated cross-linked swellable polymers, hydrophilic polymers or other materials, 2 which absorb water and thereby increase the volume. In pharmacy, it is common to be conjugated, mercapto carboxycellulose, crosslinked polyvinylpyrrolidone 'L-HPC or starch 臬 醋酸 sodium acetate. Other soluble thief-shaped agents can be used such as sugars (lactose, saccharose, grape vine, candied fruit, maltose), sugar alcohols (mannitol sorbitol, xylitol, butyl alcohol) or soluble The active material, as long as the ratio of 9 200938233 is not excessive and its average particle size is maintained above 5 〇 μιη. The use of such soluble excipients is also common in the field of oral dispersible tablets. For the combination of soluble active substances, we have found that the particle size has a certain degree of influence on the disintegration of the tablet. In this case, it is advantageous to make the particles less than 5 small. Particle sizes greater than 50 (average of distribution) are believed to produce the desired lozenge properties. If the solubility of the active substance or substances is high, or when the dissolution time is short, the size is preferably larger than the average particle, and the manner in which the particle size is increased is not important. Large crystals are better than those made by granulation methods (wet or dry granulation methods). 〇 10 In order to manufacture the above formulation, a direct compression purple, * process can be used. Therefore, the manufacturing cost is low and standard techniques can be used, and then it can be used. The properties of the lozenges required are: sufficient physical stability (in terms of tensile strength and brittleness), rapid disintegration (using the method disclosed in European Blood 15th, Fifth Edition 2007 (5.8)) 2.9", expressed in 3n: using the disintegration time of water and disc), acceptable mouthfeel and taste. The pharmaceutically active substance (drug substance) having different solubility can be formulated with the above-mentioned main components of the formulation. The drug substance is not soluble (for example, the oral antidiabetic agent or the miglitol (Miglit(R) 1) or insoluble (e.g., nitrobenzoate). In the case of soluble drug substances, the specific definition (fraction) of particle size is extremely advantageous for disintegration time, content uniformity and tablet hardness. The particles of the pharmaceutically active substance may be crystalline or agglomerated. The particle size of the pharmaceutically active substance may be 5 〇 μηη - ΙΟΟΟμιη, preferably 1 〇〇 μιη _ 800 μηι, more preferably 125 μηη - 630 μηη, and most preferably 125 μπι - 800 μιη. 200938233 In this particle size, especially those which are particularly useful are the pharmaceutically active substances, lycopene, miglitol and voglibose. [Embodiment] 5 Example: By mixing a known component (except the lubricant stearyl sulfoxylate) in a suitable mixing device (for example, a three-dimensional mixer (Turbula® mixer) or a rolling flap Mixer), can be obtained in W minutes. Thereafter, the lubricant was added and mixed for 5 minutes. The 10 conjugate is a 9 mm flat end bevel set of a stamper which is then pressed into a tablet to produce a tablet of known quality. For double dose tablets, a 13 mm flat end bevel punch is used and doubled to a known mass. The bond should be compatible with the known tensile strength range (breaking load between 20 and 60 N). 15 In the case where the sugar lozenge is used as an active material, the sugar lozenge is previously mixed with 0.5% (w/w) stearyl-based sodium butadisulfate and densified. The dense body 破裂 is broken and sieved (dried granulation or compacted by a roller machine). After the sieving, the use of 125 μιη - 800 μΓη was used. Using the above-mentioned European method, the tablet is disintegrated in 5 to 10 seconds. 20 The total amount of the substance of Example 1 [mg/synthesis mass [%1 active substance*) _ I-**·*" 50, 25 30,15% Prosolv (SMMC 90) _ — -------—" 101,00 60,61% 11 200938233 L-HPCB1 type 13,3〇7,98% sodium lauryl sulfate 0 , 42 0,25% gasification nano 0,50 0,30% saccharin sodium stearin brewing base anti-succinic acid sodium 0,17 0,10% 1,00 0,60% bond agent 166,64 100,00 % *) used as 99,5 ° / 〇 (m / m) sugar Lu and 0.5% (m / m) Sodium stearyl flimerat or miglitol

實施例2 物質 總量[毫克/鍵] 質量[%] 活性物質*) 50,25 30,15% Prosolv (SMMC 90) 75,00 45,01% Avicel PH200 26,08 15,65% L-HPCB1 型 13,3〇 7,98% 十二烷基硫酸鈉 0,42 0,25% 氣化納 0,50 0,30% 糖精鈉 0,09 0,05% 硬脂醯基反丁烯二酸鈉 1,00 0,60% 錠劑 166,64 100,00% *)用做99.5% (m/m)醣祿錠及0.5% (m/m)硬脂醯基反丁烯二酸鈉或米格列 醇 實施例3 物質 總量[毫克/錠] 質量「％] 活性物質*) 50,25 30,21% Prosolv (SMMC 90) 45,00 27,05% 12 200938233Example 2 Total amount of substance [mg/bond] Mass [%] Active substance*) 50,25 30,15% Prosolv (SMMC 90) 75,00 45,01% Avicel PH200 26,08 15,65% L-HPCB1 Type 13,3〇7,98% sodium lauryl sulfate 0,42 0,25% gasification nano 0,50 0,30% sodium saccharin 0,09 0,05% stearyl thioglycolic acid Sodium 1,00 0,60% Lozenges 166,64 100,00% *) Used as 99.5% (m/m) sugar sulphate and 0.5% (m/m) sodium stearyl sulphate or Miglitol Example 3 Total amount of substance [mg/ingot] Quality "%] Active substance*) 50,25 30,21% Prosolv (SMMC 90) 45,00 27,05% 12 200938233

Avicel PH200 26,08 ______ 15,68% Arbocel P290 25,00 L-HPCB1 型 18,00 10,82% 十二烷基硫酸鈉 0,42 0,25% 一一_^ 氯化鈉 0,50 0,30% _- 糖精鈉 0,09 0,05%___- 硬脂醯基反丁烯二酸鈉 1,00 0,60%__一 鍵劑 166,34 100,00%__ *)用做99.5% (m/m)餹祿錠及0.5% (m/m)硬脂醯基反丁烯二酸納或米格列 醇 實施例4 5 物質 總量[毫克/鍵] 質量[%] 活性物質*) 50,25 30,21% Prosolv (SMMC 90) 45,00 27,05% Arbocel 290 20,00 12,02% Kollidon CL 49,08 29,51% 十二烷基硫酸鈉 0,42 0,25% 氣化鈉 0,50 0,30% 糖精鈉 0,09 0,05% 硬脂醯基反丁烯二酸納 1,00 0,60% 錠劑 166,34 100,00% ---~~~_ *) 1做99.5% (m/m)醣祿錠及0.5% (m/m)硬脂醯基反丁烯二酸鈉或米袼列 實施例5 物質 總量[毫克/錠] 質量[%] 13 10 200938233Avicel PH200 26,08 ______ 15,68% Arbocel P290 25,00 L-HPCB1 type 18,00 10,82% sodium lauryl sulfate 0,42 0,25% one__ sodium chloride 0,50 0 ,30% _- Sodium saccharin 0,09 0,05%___- Sodium stearyl succinimide 1,00 0,60%__One bond agent 166,34 100,00%__ *) 99.5% (m/m) 餹Lu ingot and 0.5% (m/m) stearyl succinimide or miglitol. Example 4 5 Total amount of substance [mg/bond] Mass [%] Activity Substance*) 50,25 30,21% Prosolv (SMMC 90) 45,00 27,05% Arbocel 290 20,00 12,02% Kollidon CL 49,08 29,51% Sodium lauryl sulfate 0,42 0 , 25% sodium gas 0,50 0,30% sodium saccharin 0,09 0,05% sodium stearyl sulfonate 1,00 0,60% tablets 166,34 100,00% -- -~~~_ *) 1 Do 99.5% (m/m) sugar sulphate and 0.5% (m/m) stearyl succinate or sodium glutamate. Example 5 Total amount of substance [mg/ Ingot] quality [%] 13 10 200938233

活性物質*) 50,25 30,21% Prosolv (SMMC 90) 45,00 27,05% Arbocel 290 30,00 18,04% Kollidon CL 39,08 23,49% 十二烷基硫酸鈉 0,42 0,25% 氯化納 0,50 0,30% 糖精鈉 0,09 0,05% 硬脂醯基反丁烯二酸鈉 1,00 0,60% 錠劑 166,34 100,00% *)用做99.5% (m/m)醣祿錠及0.5% (m/m)硬脂醯基反丁烯二酸納或米格列 醇 實施例6 物質 總量[毫克/錠1 質量[%] 活性物質*) 50,25 30,21% Prosolv (SMMC 90) 45,00 27,05% Aqualon EC T10 38,00 22,84% Kollidon CL 15,08 9,07% L-HPCB1 型 16,00 9,62% 十二烷基硫酸鈉 0,42 0,25% 氣化納 0,50 0,30% 糖精一納 0,09 0,05% 鈉一硬脂醯基一反丁烯二 酸鹽 1,00 0,60% 錠劑 166,34 100,00% *)用做99.5% (m/m)醣祿錠及0.5% (m/m)硬脂醯基反丁烯二酸鈉或米格列 醇 14 200938233 【圖式簡單說明】 無 【主要元件符號說明】 無 5Active substance*) 50,25 30,21% Prosolv (SMMC 90) 45,00 27,05% Arbocel 290 30,00 18,04% Kollidon CL 39,08 23,49% sodium lauryl sulfate 0,42 0,25% sodium chloride 0,50 0,30% sodium saccharin 0,09 0,05% sodium stearyl sulfonate 1,00 0,60% tablets 166,34 100,00% * ) used as 99.5% (m / m) sugar sulphate and 0.5% (m / m) stearyl sulfonate sodium or miglitol Example 6 total amount of substance [mg / ingot 1 mass [% Active substance*) 50,25 30,21% Prosolv (SMMC 90) 45,00 27,05% Aqualon EC T10 38,00 22,84% Kollidon CL 15,08 9,07% L-HPCB1 type 16,00 9,62% sodium lauryl sulfate 0,42 0,25% gasification nano 0,50 0,30% saccharin-nano 0,09 0,05% sodium-stearyl sulfonyl-fumarate 1,00 0,60% lozenges 166,34 100,00% *) used as 99.5% (m/m) sugar sulphate and 0.5% (m/m) stearyl sulphate sodium or rice Glycerol 14 200938233 [Simple description of the diagram] No [Main component symbol description] None 5

Claims (1)

200938233 七、申請專利範圍： . 1. 一種用於口服之非泡騰錠劑，其包含一有效量之至少一 種活性劑、至少50%(w/w)的量之水不溶部分、一界面活 性劑及一崩散劑，致使該錠劑為口服可崩散或可分散。 5 2.如申請專利範圍第1項之鍵劑，其中該錠劑於不超過60 秒内呈現口服可崩解性。 3.如申請專利範圍第1或2項之鍵劑，其中該水不溶性載 . 體係選自纖維素、微晶纖維素或經石夕化微晶纖維素或其 混合物之組群。 〇 10 4.如申請專利範圍第6項之錠劑，其中該經矽化微晶纖維 素包括於20%至90%範圍内之量。 5·如申請專利範圍第6至9項之錠劑，其中該經矽化微晶 纖維素具有在20 — 300μιη範圍内的平均粒子大小。 6_如申請專利範圍第1至5項之錠劑’其中該崩散劑係選 15 自低取代羥丙基纖維素、羧甲基纖維素、交聯曱基叛纖 維素鈉（crosscarmelose sodium)、交聯普威隆 (crosspovidone，交聯聚乙烯吼咯咬酮）、經基醋酸澱粉〇 納、澱粉及其組合所組成之組群。 7.如申請專利範圍第1至6項之錠劑，其中該界面活性劑 20 係選自十二烧基硫酸鈉、聚氧乙稀山梨糖醇野脂肪酸醋 (Tweens)、聚氧乙烯硬脂酸酯、山梨糖醇酐脂肪酸醋 (Spans)所組成之組群。 16 200938233 8·如申請專利範圍第1至7項之錠劑，其中該活性劑係選 自藥學活性劑、營養劑、營養醫學品(nutriceuticals)及化 妝品所組成之組群。 5 Ο 10 15 ❹ 20 9. 如申請專利範圍第1至8項之錠劑，其中該藥學活性劑 係選自抗炎性劑、抗風濕劑、止吐劑.、止痛劑、抗癲癇 劑、抑精神病劑、抗抑鬱劑、安眠劑、抗潰瘍劑、促腸 胃螺動劑（prokinetic)、抗氣喘劑、抗帕金森病劑 (parkinsonics)、心血管劑、血管擴張劑、泌尿科學劑 (urologies)、降血脂劑、抗糖尿病劑、及抗組織胺劑所組 成之組群。 10, 如申請專利範圍第1至8項之錠劑，其中該藥學活性劑 係選自伊布落芬（ibUprofen)、乙醢胺基盼 (acetominophen)、匹若卡（pir0Xicam)、雅努麻錠 (leflunomide)、恩丹西 _ (ondansetron)、格拉司瓊 (granisetron)、乙醯胺苯紛（paracet；amol)、顛妥鍵 (carbamazepin)、樂命達（lamotrigine)、氣氮平 (clozapine)、奥氮平（olanzapine)、理思必妥(risperidone)、 赛達樂（citalopram)、帕羅西汀（paroxetine)、抗憂服 (sertraline)、百憂解(fluoxetine)、樂得腸（fluvoxamine)、 宜眠安（zopiclon)、使蒂諾斯（zolpidem)、西p米替丁 (cimetidine)、善胃得(ranitidine)、奥美拉坐(omeprazole)、 美多科拉酿胺(metoclopramide)、希塞菩（cisapride)、通平 (domperidon)、雅樂得(zafirlukast)、欣流(montelukast)、 樂伯克（prarnipexol)、迪普寧（selegiline)、使蒂諾斯 17 200938233 (zolpidem)、峻匹可隆(zopicl〇n)、多薩坐辛（d〇xaz〇sin)、 服脈錠（terazosin)、阿替洛爾（aten〇i〇1)、必落瑞 (bisoprolol)、安洛待平（amlodipine)、硝苯地平 (nifedipine)、地爾硫卓（diltiazem)、伊那拉普利 5 (enalaPril)、卡托普利（captopril)、心達舒碇(ramiprii)、洛 沙東（losartan)、***油（glycerol trinitrate)、扎特 (alfuzosin)、柔沛（finasteride)、普伐他丁（pravastatin)、阿 多路巴史達汀（atorvastatin)、辛伐他汀（simvastatin)、洛 脂（gemfibrozil)、二曱雙胍（metformin)、特芬那定 ίο (terfenadine)、樂雷塔定(loratadine)、希樂撰（celecoxib)、 偉克適（rifecoxib)、及憶思能（rivastigmine)所組成之組 群’以及該活性劑之藥學上可接受的鹽、酯、水合物或 溶劑化物。 11. 一種界面活性劑供製造口服可崩解非泡騰的藥學錠劑之 15 用途。200938233 VII. Patent application scope: 1. A non-effervescent tablet for oral administration, comprising an effective amount of at least one active agent, at least 50% (w/w) of water-insoluble portion, and an interfacial activity The agent and a disintegrating agent cause the tablet to be orally disintegratable or dispersible. 5 2. The bonding agent of claim 1, wherein the tablet exhibits oral disintegratability in less than 60 seconds. 3. The bonding agent according to claim 1 or 2, wherein the water insoluble carrier system is selected from the group consisting of cellulose, microcrystalline cellulose or sillimanite microcrystalline cellulose or a mixture thereof.锭 10 4. The tablet of claim 6, wherein the deuterated microcrystalline cellulose is included in an amount ranging from 20% to 90%. 5. The tablet of claim 6 to 9, wherein the deuterated microcrystalline cellulose has an average particle size in the range of from 20 to 300 μm. 6_such as the tablet of claim 1 to 5, wherein the disintegrating agent is selected from the group consisting of low-substituted hydroxypropylcellulose, carboxymethylcellulose, crosscarmelose sodium, A group consisting of cross-povidone (cross-linked polyvinyl ketone), transamidyl acetate, canine, starch, and combinations thereof. 7. The tablet of claim 1 to 6, wherein the surfactant 20 is selected from the group consisting of sodium lauryl sulfate, Tweens, and polyoxyethylene stearin. a group consisting of acid esters and sorbitan fatty acid vinegars (Spans). The tablet of claim 1 to 7, wherein the active agent is selected from the group consisting of pharmaceutically active agents, nutrients, nutriceuticals, and cosmetics. 5 Ο 10 15 ❹ 20 9. The tablet of claim 1 to 8, wherein the pharmaceutically active agent is selected from the group consisting of an anti-inflammatory agent, an anti-rheumatic agent, an anti-emetic agent, an analgesic agent, an anti-epileptic agent, Psychotropic agents, antidepressants, hypnotics, antiulcer agents, prokinetic agents, anti-asthmatic agents, anti-Parkinsonics, cardiovascular agents, vasodilators, urology agents (urologies) a group of hypolipidemic agents, anti-diabetic agents, and antihistamines. 10. The tablet of claim 1 to 8, wherein the pharmaceutically active agent is selected from the group consisting of ibUprofen, acetominophen, piroxine, yanoxi Influx (leflunomide), ondansetron _ (ondansetron), granisetron (granisetron), acetaminophen (paracet; amol), carbamazepin, lamorrigine, nitrozapine (clozapine) ), olanzapine, risperidone, citalopram, paroxetine, sertraline, fluoxetine, fluvoxamine, Zopiclon, zolpidem, cimetidine, ranitidine, omeprazole, metoclopramide, 希Cisapride, domperidon, zafirlukast, montelukast, prarnipexol, selegiline, tyros 17 200938233 (zolpidem), piri隆 (zopicl〇n), 达萨坐辛 (d〇xaz〇sin), serving veins (terazosin), Atenolol (aten〇i〇1), bisoprolol, amlodipine, nifedipine, diltiazem, enalapril, cato Captopril, ramiprii, losartan, glycerol trinitrate, alfuzosin, finasteride, pravastatin, ado Atorvastatin, simvastatin, gemfibrozil, metformin, terfenadine, loratadine, celecoxib , a group consisting of rifecoxib, and rivastigmine', and a pharmaceutically acceptable salt, ester, hydrate or solvate of the active agent. 11. A surfactant for the manufacture of an orally disintegrable non-effervescent pharmaceutical lozenge. 18 200938233 四、指定代表圖： (一) 本案指定代表圖為：第（無）圖。 (二) 本代表圖之元件符號簡單說明： 無 五、本案若有化學式時，請揭示最能顯示發明特徵的化學式： 益18 200938233 IV. Designation of Representative Representatives: (1) The representative representative of the case is: (No). (2) A brief description of the symbol of the representative figure: None 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: