TWI263508B - Composition for a modified-release oral tablet and method for manufacturing of the composition - Google Patents

Abstract

The present invention relates to a composition for a modified-release oral tablet, characterized in that comprising: a micronized active ingredient for lowering the blood glucose level and a modified-release agent for controlling the release of the active ingredient, and a method for manufacturing of the composition.

Description

I263508 性疾病 成視網 r u 1 〇 s c 發症， 37人竄 與第二 為幼年 性酮酸 稱作成 抗性和 域】 種口服延遲釋放（〇1〇(|丨£丨6(1-^16836) 關於一種至少包含醫藥上有效量之微 與以親水性聚合物組成之延遲釋放 口服延遲釋放錠劑組成物的製法。 ，是由許多 膜病變（ret 1 e r 〇 s i s )和 為台灣十大 升到1 9 9 9年 型，第一型 型糖尿病， 中毒；第二 年型糖尿病 冷細胞功能 案號 93103500 發明說明（1) 【發明所屬之技術領 本發明係關於一 贫劑組成物，特別是 米化降血糖活性成分 劑’以及關於該新穎 【先前技術】 糖尿病是一種慢 向血糖現象，其會造 脈血管球硬化（g 1 〇 m e 血管方面的病變或併 Ugo年每萬人中有〇. 尿病主要分為第一型 尿病（IDDM)，早期稱 狀況下，容易陷入急 素依賴型糖尿病，又 礙造成，即胰島素之 服降血糖藥物來治療 修正 不同原因所造成的 inopathy)、腎小動 其他腎臟、神經及 死因之第五位，從 母萬人有4·1人。糖 為胰島素依賴型糖 在不注射胰島素之 型糖尿病為非胰島 ，因為代謝機能障 的缺4貝所致，需口， 一般而言 口服 類（sulfonylurea)、 (thiazolidinedione inhibitor)。績醯尿 血糖藥物，主要用於 作用為刺激胰臟分泌 粒發生脫顆粒作用， 胰島素在肝臟的代謝 ί,糖藥物可分為四，，為續醯尿素 雙胍類（biguanides )〇J π坐燒二§同 、 )及α-配糖_抑制劑（二二sid_ 素類是一類主治成年型糖尿病之口 非肥胖型且万細胞尚有功能之患者& 胰島素，使点細胞中含有胰島;^之 放出顆粒中的胰島素，此外，可減少 ’促使胰島素之受體數目增加。其副I263508 sexually transmitted diseases ru1 〇sc disease, 37 people with sputum and the second is juvenile ketoacid called resistance and domain] oral delayed release (〇1〇(|丨£丨6(1-^16836) a method for the preparation of a delayed release oral delayed release tablet comprising at least a pharmaceutically effective amount and a hydrophilic polymer. It is composed of a plurality of membrane lesions (ret 1 er 〇 sis ) and is a Taiwanese ten liter To the type of 1989, type 1 diabetes, poisoning; second year type diabetes cold cell function case number 93103500 invention description (1) [Technical Field of the Invention] The present invention relates to a composition of a poor agent, in particular Rice hypoglycemic active ingredient' and about the novel [previous technique] Diabetes is a slow-glyphemia phenomenon, which can cause vascular sclerosis (g 1 〇me vascular lesions or Ugo years per 10,000 people Urinary diseases are mainly classified into type 1 urinary disease (IDDM). In the early stage, it is easy to fall into acute-dependent diabetes, and it is caused by the use of insulin-lowering blood sugar drugs to treat different causes. Inopathy), the fifth place of other kidneys, nerves and causes of death in the kidneys, and 4.1 people from the mothers. Sugar is an insulin-dependent type of sugar. Non-insulin is not a type of insulin, because of the lack of metabolic dysfunction. 4 shells, need mouth, generally oral (sulfonylurea), (thiazolidinedione inhibitor). Performance urinary blood glucose drugs, mainly used to stimulate the secretion of granules in the pancreas, insulin metabolism in the liver, Sugar drugs can be divided into four, for the continuous sputum urea biguanides (biguanides) 〇J π sit burn two § with, and α-glycoside inhibitors (two or two sid_ genus is a class of primary diabetes mellitus Obese and 10,000-cell functional patients & insulin, so that the cells contain islets; the release of insulin from the particles, in addition, can reduce the number of receptors that promote insulin.

1263508 修正 案號 93103500 五、發明說明（2) 作用較少，多半是抑制碘離子進入甲狀腺利用，過量會導 致低血糖，引起噁心、嘔吐、皮膚發癢。目前台灣醫院多 為使用第二代之磺醯尿素類藥物，像是葛立克拉 _ (Gliclazide)、格力匹來（Glipizide)與格力本 ’ (G1 i bene 1 amide)等；而雙胍類藥物不會刺激胰島素分泌， 故造成低血糖之危險性較績醯尿素類為低，為肥胖型病患 首選用藥；鹰唑烷二酮類之作用機轉主要在於降低肌肉與 脂肪組織對胰島素的阻抗而減少内生性葡萄糖製造；α-配 糖 抑制劑作用為抑制腸絨毛邊上的α -配糖g|，而抑制瘢 粉與雙糖類之吸收，減少飯後血糖值的上升，也常與其他 口服降血糖藥併用。 使用控制釋放降血糖藥物以達成平穩持續的治療效果 對糖尿病患者之疾病管理來說，是非常重要的，尤其是糖 尿病患必須長期服用藥物以控制病情，在不得不服用藥物^ 之情形下，必須開發儘量可使患者得到最佳治療之藥物， 並避免因服用這些藥物所帶來之負面影響；對於延遲釋放 型之藥物來說，因為可以延長藥物在血液中之有效量的維 持，而讓藥效持續，故有減少服藥次數，進而使釋放速度 與方式更為貼近生理與慢性治療的優點；也因藥效較為平 穩持續，因此也不需使用較高劑量作為達成較持久藥效的 手段，可能產生之副作用或是抗性機率因而降低；例如， 微米化葛立克拉（Gliclazide)80毫克一天兩次（bid)，在臨 床使用上，未微米化成分因溶解度不佳，無法完全釋放， 因此無法達到臨床有效治療效果。如美國專利第6，4 5 1，3 3 9 號與6，5 3 7，5 7 8號等即屬針對控制釋放藥劑的目的所進行之1263508 Amendment Case No. 93103500 V. Description of invention (2) Less effect, most of which inhibits the use of iodide ions into the thyroid gland. Excessive amounts may cause hypoglycemia, causing nausea, vomiting, and itchy skin. At present, Taiwanese hospitals mostly use the second-generation sulfonamides, such as Gliclazide, Glipizide, and G1 i bene 1 amide. It will stimulate insulin secretion, so the risk of hypoglycemia is lower than that of urea. It is the first choice for obese patients; the role of thiazolidinediones is mainly to reduce the impedance of muscle and adipose tissue to insulin. Reduce endogenous glucose production; α-glycoside inhibitors act to inhibit α-glycoside g| on the edge of the villi, while inhibiting the absorption of sputum and disaccharides, reducing the rise in blood glucose after meals, often with other oral Hypoglycemic agents are used together. The use of controlled release of hypoglycemic drugs to achieve a smooth and continuous therapeutic effect is very important for the management of diseases in diabetic patients, especially in patients with diabetes who must take drugs for a long time to control the disease. Develop drugs that maximize the patient's treatment and avoid the negative effects of taking these drugs; for delayed-release drugs, because they can prolong the effective amount of the drug in the blood, let the drug The effect is sustained, so the number of medications is reduced, and the release rate and mode are closer to the advantages of physiological and chronic treatment; and because the efficacy is relatively stable and continuous, it is not necessary to use higher doses as a means to achieve longer-lasting efficacy. Possible side effects or reduced resistance are reduced; for example, micronized Gliclazide 80 mg twice a day (bid), in clinical use, the unmicronized component cannot be completely released due to poor solubility, so Unable to achieve clinically effective treatment. For example, U.S. Patent Nos. 6, 4 5 1, 3 3 9 and 6, 5 3 7, 5 7 8 are for the purpose of controlled release agents.

第6頁 1263508 案號 93103500 Λ_η 曰 修正 五、發明說明（3) 製劑製作。本發明則是主要針對糖尿病患者，期望利用藥, 物溶出控制等手段，達成符合上述目的之口服延遲釋放錠 劑，進而使藥物達成更佳之安全性與療效。 【發明内容】 本發明之一目的係關於一種口服延遲釋放（modified -r e 1 e a s e )錠劑組成物，其特徵為至少由有一微米化之降血, 糖活性成分及一控制活性成分釋放之延遲釋放劑所組成者 之降血糖活 未使用微米 〇 放錠劑組成 :S 5微米 %)佔總體積之 體積百分比 )活性成分之 以上，接 遲釋放劑加 形劑後進行 口服延遲释 有較佳之吸 主成份微米 可達到現有 經過一定時間之溶離測試下，經過微米化 性成分在與延遲釋放劑共同形成組成物下，比 化降血糖活性成分之組成物具有更佳之溶出率 本發明之另一目的係關於上述口服延遲釋 物之製法，其係先將降血糖活性成分微米化為 (// m )活性成分之粒子累積體積百分比（V ο 1 u m e 5 0 %以上、S 1 5微米（// m )活性成分之粒子累積 (V ο 1 u m e % )佔總體積之9 0 %以上與$ 2 5微米（// m 粒子累積體積百分比（Volume%)佔總體積之9 5 % 著，接著，將已微米化之降血糖活性成分與延 以混合、造粒、乾燥及整粒等；最後再加入賦 打錠，以製成硬度4至8公斤間之錠劑。 本發明之再一目的係在提供一種微米化之 放錠劑組成物及其製法，使製作出之組成物具 收穩定性。 本發明之又一目的係在採用微米化技術將 化之後，使其在臨床使用上使用較少之劑量即Page 6 1263508 Case No. 93103500 Λ_η 曰 Correction V. Description of the invention (3) Preparation of the preparation. The present invention is mainly directed to diabetic patients, and it is desired to use drugs, substance dissolution control and the like to achieve an oral delayed release tablet which meets the above objectives, thereby achieving better safety and efficacy of the drug. SUMMARY OF THE INVENTION One object of the present invention is directed to a modified-re 1 ease tablet composition characterized by a delay of release of at least a micronized blood drop, a sugar active ingredient, and a controlled active ingredient. The hypoglycemic activity of the composition of the release agent is not composed of micron barium tableting agent: S 5 micron%) by volume of the total volume of the active ingredient or more, and the delayed release of the delayed release agent is preferably followed by oral delayed release. The micron absorption component can reach the existing dissolution test after a certain period of time, and the micronized component forms a composition with the delayed release agent, and has a better dissolution rate than the composition of the hypoglycemic active ingredient. The invention relates to the method for preparing the above-mentioned oral delayed release, which firstly micronizes the hypoglycemic active ingredient into (//m) the cumulative volume percentage of the active ingredient (V ο 1 ume 5 0 % or more, S 1 5 μm (/ / m ) Particle accumulation of the active ingredient (V ο 1 ume % ) accounts for more than 90% of the total volume and $ 2 5 μm (// m % cumulative volume percentage (Volume%) of the total volume 95%, then, the micronized hypoglycemic active ingredient is mixed with, granulated, dried and granulated; finally, the ingot is added to prepare a tablet having a hardness of 4 to 8 kg. A further object of the present invention is to provide a micronized tableting agent composition and a process for the same, which provide a stable stability of the composition. Another object of the present invention is to use micronization technology to To make it use less doses in clinical use.

第7頁 1263508 年 月 修正· 曰 Ι 號 93103500 五、發明說明（4) 治療劑量效果。 【實施方式】 本發明係關於一種新穎之口服延遲釋放錠劑組成物，-主要所含成分為經過微米化之降血糖活性成分，以及含有 親水性的聚合物作為延遲釋放劑，以達成控制降血糖活性 成分之延遲釋放效果。 降血糖活性成分可以是已知之任何降血糖藥物中所採 用之活性成分’較佳為以磺醯尿素類作為本發明降血糖活 性成分’若有需要並可運用組合二種以上活性成分以達成 較佳之治療效果’如選自葛立克拉（G1 iclazide)、格力匹 來（Glipizide)與格力本（Glibencl amide)、格力奎東寧 (Gliquidonem)、格力美保來（Glimepiride)及其組合。在 組成物中之含量範圍以葛立克拉為例則較佳是在3 〇毫克至 6 0毫克。該活性成分之特徵為經過微米化之處理，較佳能 達到如下之粒子大小範圍： (1 ) S5微米（# m)活性成分之粒子累積體積百分比（Volume% 佔總體積之5 0 %以上； (2 ) S 1 5微米（// m)活性成分之粒子累積體積百分比 (Volume%)佔總體積之90%以上；且 (3 ) S 2 5微米（// m)活性成分之粒子累積體積百分比 (Volume%)佔總體積之95%以上。 本發明所選用之延遲釋放劑則較佳選自下述物質：羥 丙基甲基纖維素、曱基纖維素、聚乙烯咯酮、羥丙基纖 維素、乙烯基醋酸酯共聚物、聚乙烯氧化物及其組合，且 較佳具有黏度從4000cps至100，000cps，因此熟於此技藝者Page 7 1263508 Rev. 曰 93 93103500 V. Description of invention (4) Therapeutic dose effect. [Embodiment] The present invention relates to a novel oral delayed release tablet composition, which comprises a micronized hypoglycemic active ingredient and a hydrophilic polymer as a delayed release agent to achieve controlled release. Delayed release of glycemic active ingredients. The hypoglycemic active ingredient may be any active ingredient used in any hypoglycemic drug known. 'Preferably sulfonium urea as the hypoglycemic active ingredient of the present invention'. If necessary, a combination of two or more active ingredients may be used to achieve Good therapeutic effects are selected from the group consisting of G1 iclazide, Glipizide and Glibencl amide, Gliquidonem, Glimepiride and combinations thereof. The content in the composition is preferably in the range of 3 〇 to 60 mg in the case of gricla. The active ingredient is characterized by micronization, preferably to achieve the following particle size range: (1) S5 micron (#m) active ingredient particle cumulative volume percentage (Volume% accounted for more than 50% of the total volume; 2) The cumulative volume percentage (Volume%) of the S 1 5 micron (//m) active ingredient is more than 90% of the total volume; and (3) S 2 5 micrometers (// m) of the cumulative volume percentage of the active ingredient particles (Volume%) accounts for more than 95% of the total volume. The delayed release agent selected for use in the present invention is preferably selected from the group consisting of hydroxypropylmethylcellulose, mercaptocellulose, polyvinyl ketone, hydroxypropyl Cellulose, vinyl acetate copolymer, polyethylene oxide, and combinations thereof, and preferably have a viscosity of from 4,000 cps to 100,000 cps, so those skilled in the art are familiar with

1263508 _案號93103500_年月日 修正、_ 五、發明說明（5) 可根據所選用之降血糖活性物質，調整延遲釋放劑之成分' ，以使延遲釋放效果達到最佳化。延遲釋放劑則約佔錠劑 組成物之1 0 %至4 0 %。 在本發明錠劑之製造上可於合適之時機加入醫藥上可 接受且與降血糖活性成分不易產生反應之各種賦形劑，如 增量劑、稀釋劑、潤滑劑、矯味劑、崩散劑、黏合劑或著' 色劑、甜味劑等而製成錠劑，例如乳糖、二氧化鈦 '微晶 纖維素、山梨糖醇、硬脂酸鎂與滑石等；像是可於打錠步 驟前加入或是在微米化降血糖活性成分與延遲釋放劑混合 時便加入。打錠後之硬度則大約在4 - 8公斤左右較佳。 本發明之錠劑建議使用方式為每天口服一次，一次使 用1至2顆，並預期但不限於用於治療糖尿病之用途上。 實施例1 : 準備含有降血糖藥物葛立克拉之口服錠劑組成物成分 如 下 所 述 ·· 微 米 化 之 葛 立 克 拉 30 毫 克 乳 糖 30 毫 克 二 氧 化 矽 1 . 6 毫 克 羥 丙 基 曱 基 纖 維 素 84 毫 克 聚 乙 稀 吡 咯 酮 8 毫 克 油 酸 聚 醇 山 梨 醇 3. 2 毫 克 硬 脂 酸 鎭 1 . 6 毫 克 滑 石 粉 1. 6 毫 克1263508 _ Case No. 93103500_年月日日 Amendment, _ V. Description of invention (5) The composition of the delayed release agent can be adjusted according to the selected hypoglycemic active substance to optimize the delayed release effect. The delayed release agent is about 10% to 40% of the tablet composition. In the manufacture of the tablet of the present invention, various excipients, such as extenders, diluents, lubricants, flavoring agents, disintegrating agents, which are pharmaceutically acceptable and which do not readily react with the hypoglycemic active ingredient, may be added at an appropriate timing. a binder or a coloring agent, a sweetener, etc., such as lactose, titanium dioxide 'microcrystalline cellulose, sorbitol, magnesium stearate and talc; as it can be added before the ingot tableting step or It is added when the micronized hypoglycemic active ingredient is mixed with a delayed release agent. The hardness after ingoting is preferably about 4-8 kg. The tablet of the present invention is preferably administered orally once a day, once or twice, and is expected, but not limited to, for the purpose of treating diabetes. Example 1: Preparation of an oral lozenge composition containing a hypoglycemic drug Glycara The composition is as follows: • Micronized Glica 30 mg Lactose 30 mg Ceria 1. 6 mg Hydroxypropyl fluorenyl cellulose 84千千的的 乙 吡 咯 毫克 毫克 毫克 毫克 3 3 3 3 3 3 3 3 3 3 3 3 6 6 6 6 6 6 6 6 6 6 6 6 6 6

第9頁 1263508 _案號 93103500 五、發明說明（6) 總計 年 月 曰 修正 160 毫克 將上述組成物成分進行以下之步驟得到本發明之錠 ， 劑： (1 )將微米化的葛立克拉、乳糖、二氧化矽、羥丙基甲基纖 維素、聚乙烯I咯酮相混合。 (2 )將油酸聚醇山梨醇溶於酒***溶液中。 (3 )將前述（2 )之溶液倒入前述（1 )之混合粉末中，所得濕潤 團塊再製成顆粒，乾燥後再整粒（# 2 0 m e s h )。 (4 )將步驟（3 )得之顆粒，再和硬脂酸鎂、滑石粉相混合。 (5)採用迴轉式打錠機打錠，其硬度大約在4〜8 kg之間。 實施例2 : 含 有 降 血 糖 藥物 葛立克 所 述 • 微 米 化 之 葛 立 克 拉 60 乳 糖 60 二 氧 化 矽 3.2 羥 丙 基 甲 基 纖 維 素 168 聚 乙 稀 〇tL 咯 酮 16 油 酸 聚 醇 山 梨 醇 6.4 硬 脂 酸 Μ 3. 2 滑 石 粉 3.2 拉之口服錠劑組成物成分如下 毫克 毫克 毫克 毫克 毫克 毫克 毫克 毫克 總計 3 2 0 毫克 1263508 案號 93103500 A_η 年 曰 修正 五、發明說明（7) 實施例3 : ^ 含有降血糖藥物葛立克拉之口服錠劑組成物成分如下 所述： 微米化之葛立克拉 30 毫克 甘露糖醇 90 毫克 二氧化矽 1. 6 毫克 曱基纖維素 25. 6 毫克 聚乙烯此咯酮 6. 4 毫克 十二烧基硫酸鈉 3. 2 毫克 硬脂酸鎂 1 . 6 毫克 滑石粉 1. 6 毫克 總計 160 毫克 實施例4 含 有降 血 糖 藥物 葛 立克拉 之 π 所 述 • 微 米 化 之葛 立 克 拉 60 毫 克 甘 露 糖 醇 180 毫 克 二 氧 化 矽 3. 2 毫 克 曱 基 纖 維素 51.2 毫 克 聚 乙 晞此略 酮 12.8 毫 克 十 -— 烷 基硫 酸 納 6. 4 毫 克 硬 脂 酸 鎮 3. 2 毫 克 滑 石 粉 3. 2 毫 克Page 9 1263508 _ Case No. 93103500 V. Description of Invention (6) Total Years and Months Correction 160 mg The above composition components are subjected to the following steps to obtain the ingot of the present invention: (1) Micronized Gelikra, Lactose, cerium oxide, hydroxypropyl methylcellulose, and polyethylene I ketone are mixed. (2) Dissolving oleic acid sorbitol in an aqueous alcohol solution. (3) The solution of the above (2) is poured into the mixed powder of the above (1), and the resulting wet mass is further granulated, and after drying, it is granulated (#20 m e s h ). (4) The granule obtained in the step (3) is mixed with magnesium stearate and talc. (5) The spindle is made by a rotary tableting machine with a hardness of about 4 to 8 kg. Example 2: Containing hypoglycemic drug Glick® • Micronized Glycar 60 Lactose 60 Ceria 3.2 Hydroxypropyl methylcellulose 168 Polyethyl hydrazine tL rosin 16 Oleic acid sorbitol 6.4 Stearic acid Acid Μ 3. 2 talcum powder 3.2 The oral tablet composition is as follows: mg mg mg mg mg mg mg mg mg total 3 2 0 mg 1263508 case number 93103500 A_η year correction 5, invention description (7) Example 3 : ^ The composition of the oral lozenge containing the hypoglycemic drug Gelikra is as follows: micronized glicera 30 mg mannitol 90 mg cerium oxide 1. 6 mg thiol cellulose 25. 6 mg polyethylene Ketone 6.4 mg of sodium dodecyl sulfate 3. 2 mg of magnesium stearate 1. 6 mg of talc 1. 6 mg total 160 mg Example 4 Containing hypoglycemic drug Glycra π described • Micronized Ge Likla 60 mg mannitol 180 mg dioxide Yue-yl 3.2 mg 51.2 mg of cellulose acetate, polyethylene Xi this skip-one 12.8 mg of TEN - alkyl sulfuric acid, sodium stearate 6.4 mg 3.2 mg town acids talc powder 3.2 mg

第11頁 1263508 _案號 93103500_± 五、發明說明（8) 月 曰 修正 總計 3 2 0 毫克 實施例5 : 含有降血糖藥物葛立克拉之口服錠劑組成物成分如下 所 述 • 微 米 化 之 葛 立 克 拉 30 毫 克 微 晶 纖 維 素 60 毫 克 乳 糖 30 毫 克 •—^ 氧 化 矽 1 . 6 毫 克 羥 丙 基 甲 基 纖 維 素 24 毫 克 聚 乙 稀 也咯 酉同 4. 8 毫 克 油 酸 聚 醇 山 梨 醇 6. 4 毫 克 硬 脂 酸 鎂 1 . 6 毫 克 滑 石 粉 1. 6 毫 克 總 計 160 毫 克 實 施 例6 含 有 降 血 糖 藥 物 葛 立克拉之口 服 鍵劑組成物成分如下所Page 11 1263508 _ Case No. 93103500_± V. Description of Invention (8) Monthly Amendment Total 3 2 0 mg Example 5: The composition of the oral lozenge containing the hypoglycemic drug Gelikra is as follows: • Micronized Likla 30 mg microcrystalline cellulose 60 mg lactose 30 mg•—^ cerium oxide 1. 6 mg hydroxypropyl methylcellulose 24 mg polyethylene is also the same as 4. 8 mg oleic acid polyol sorbitol 6. 4 mg of magnesium stearate 1. 6 mg of talc 1. 6 mg total 160 mg Example 6 Oral key composition containing hypoglycemic agent Glycara

60 毫克 1 20 毫克 60 毫克 3. 2毫克 48 毫克 9. 6 毫克60 mg 1 20 mg 60 mg 3. 2 mg 48 mg 9. 6 mg

微米化之葛立克拉 微晶纖維素 乳糖 二氧化矽 羥丙基甲基纖維素 聚乙烯咯酮Micronized glitica microcrystalline cellulose lactose ceria hydroxypropyl methylcellulose polyvinyl ketone

第12頁 1263508 修正 案號 93103500Page 12 1263508 Amendment Case No. 93103500

五、發明說明（9) 油 酸 聚醇 山 梨 醇 12.8 毫 克 硬 脂 酸錢 3. 2 毫 克 滑 石 粉 3. 2 毫 克 總 計 320 毫 克 實 施 例7 含有 降 血 糖 藥 物 葛 立克拉 之 α 所 述 ； 微 米 化之 葛 立 克 拉 30 毫 克 乳 糖 90 毫 克 二 氧 化矽 1 . 6 毫 克 羥 丙 基甲 基 纖 維 素 24 毫 克 聚 乙 稀C咯 酮 8 毫 克 油 酸 聚醇 山 梨 醇 3. 2 毫 克 硬 脂 酸鎂 1 . 6 毫 克 滑 石 粉 1 . 6 毫 克 總 計 160 毫 克 實 施 例8 : 含有 降 血 糖 藥 物 葛 立克拉 之 V 所 述 • 微 米 化之 葛 立 克 拉 60 毫 克 乳 糖 180 毫 克 第13頁 1263508 案號 93103500 曰 修正 五、發明說明（10) 二 氧 化 矽 3. 2 毫 克 羥 丙 基 甲 基 纖 維 素 48 毫 克 聚 乙 稀 DtL 咯 酮 16 毫 克 油 酸 聚 醇 山 梨 醇 6. 4 毫 克 硬 脂 酸 鎂 3. 2 毫 克 滑 石 粉 3. 2 毫 克 總 計 320 毫 克 本 發 明 之 a 服 錠劑組成物 之 體 外 試 驗 -溶離測試 以 微 米 化 之 葛 立 克 拉 作 為 口服錠劑之 活 性 成 分 j 使實施例1 所 製 之 藥 錠 在 轉 速 為1 00 rpm之USP第 一 型 藥 籃 裝 置中於37 °C下900 毫 升 之 純 水 中 進 行 溶離測試， 所 得 結 果 如 表一及第1 圖 所V. Description of the invention (9) Oleic acid polyol sorbitol 12.8 mg stearic acid money 3. 2 mg talc powder 3. 2 mg total 320 mg Example 7 Containing hypoglycemic drug Glycarat α; Micronized Ge Likla 30 mg lactose 90 mg cerium oxide 1. 6 mg hydroxypropyl methylcellulose 24 mg polyethyl carbitol 8 mg oleic acid sorbitol 3. 2 mg magnesium stearate 1. 6 mg Talc 1. 6 mg in total 160 mg Example 8: Containing hypoglycemic drug Glylaca V • Micronized Glycar 60 mg Lactose 180 mg Page 13 1263508 Case No. 93103500 曰 Amendment 5, Invention Description ( 10 二2. 2 mg hydroxypropyl methylcellulose 48 mg polyethylene DtL ketone 16 mg oleic acid polyol sorbitol 6. 4 mil Mg gram magnesium stearate 3. 2 mg talc powder 3. 2 mg total 320 mg In vitro test of the composition of the present invention as a lozenge composition - dissolution test using micronized gelipram as an active ingredient of an oral lozenge The ingot prepared in Example 1 was subjected to a dissolution test in 900 ml of pure water at 37 ° C in a USP Type 1 basket device rotating at 100 rpm. The results are shown in Table 1 and Figure 1.

第14頁 1263508 案號 93103500 曰 修正 五、發明說明（11) 5 10. 0 10. 5 11.0 11.5 12. 0 克拉 八小 已有 未經 離測 為口 第一 試， 由上可 釋出， 時後約 大於8 5 本發明 微米化 試分別 服錠劑 型藥籃 所得結 知， 在四 有50 %之 之口 之口 以微 之活 裝置 果如 35. 6 40.8 46. 2 51.5 56.6 【 61.4 66. 5 71.5 76. 0 80. 6 85.2 89. 3 93. 0 96. 5 100.1 在溶離測試兩小時後約有5〜1 5 % 的葛立 小時後約有1 5〜35 %的葛立克拉釋出，在 〜8 0 %的葛立克拉釋出而在1 2小時的時候 葛立克拉釋出。 服錠劑組成物（實驗組）與降血糖活性成分 服錠劑組成物（對照組）相較之體外試驗-溶 米化（實施例1 )與未經微米化之葛立克拉作 性成分並製作錠劑，在轉速為1 0 0 r p m之U S P ，於3 7 °C下9 0 0毫升之純水中進行溶離測 第2圖所示。菱形（♦)代表活性成分微米化Page 14 1263508 Case No. 93103500 曰 Amendment 5, Invention Description (11) 5 10. 0 10. 5 11.0 11.5 12. 0 Carat Eight has been tested for the first time without being tested, and can be released from the time. After the invention is more than 8 5, the micronized test of the present invention is obtained by separately taking the lozenge type medicine basket, and the mouth of the mouth is 50% of the mouth, such as 35. 6 40.8 46. 2 51.5 56.6 [61.4 66. 5 71.5 76. 0 80. 6 85.2 89. 3 93. 0 96. 5 100.1 After about 5 to 15% of the germination hour after two hours of the dissolution test, about 15 to 35 % of the gerapella is released. At the release of ~80% of Glicla and release it at 12 hours. The ingot test composition (experimental group) and the hypoglycemic active ingredient serving tablet composition (control group) were compared in vitro test-dissolved (Example 1) with the unmicronized Geli carrageen component. The tablet was prepared and subjected to dissolution measurement in USP at 100 rpm and in 90 ml of pure water at 37 °C. Diamond (♦) represents the active ingredient micronization

第15頁 1263508 _案號93103500_年月日_iMz_ 五、發明說明（12) 所製成之錠劑，而正方形（)代表活性分未經微米化所製 成之旋劑，而結果顯示本發明之旋劑可以在較長時間之溶 離測試下比未經微米化之葛立克拉所製成之錠劑具有較佳’ 之溶出率，且未經微米化之劑型係無法達到完全釋放。 此外，在本發明中，此口服延遲釋放錠劑組成物在血 ‘中濃度與時間之關係請參閱第3圖所示，其係選擇符合試驗 ^ 要求之健康受試者，服用本發明之微米化製程所製造之降 血糖藥物，服用方式為每日定時服用一次並連續服用六氐 ，並設計採血點檢測藥物血中濃度；由圖可知，降血糖藥 物在血中釋放之劑量係隨著長時間變化而持續釋放，故可 達到控制降血糖活性成分之延遲釋放效果。 於此所引用之文件併入為參考資料。每一資料皆可作 為本說明書揭示之一部分。熟於此技藝者將可從本發明之 具體例例示而運用改良之而不偏離本發明之應用性及原則 。也就是，本發明雖然藉由特定較佳具體例來敘述，但對 熟於此技藝者為明顯可知之其他具體例改良也落於本發明 之範圍内。Page 15 1263508 _ Case No. 93103500_Year of the month _iMz_ V. Description of the invention (12) The tablet made, and the square () represents the spinning agent prepared by the micronization of the active component, and the result shows The spinner of the invention can have a better dissolution rate of the tablet made from the unmicronized gelerak in the long-term dissolution test, and the unmicronized dosage form cannot achieve complete release. Further, in the present invention, the relationship between the concentration of the oral delayed release tablet composition in blood and time is shown in Fig. 3, which is selected from the healthy subjects meeting the requirements of the test, and the micron of the present invention is administered. The blood glucose lowering medicine manufactured by the chemical process is taken once a day and continuously taken six times, and the blood concentration is designed to detect the blood concentration; as shown in the figure, the dose of the blood sugar lowering drug released in the blood is long The time is changed and sustained release, so that the delayed release effect of controlling the hypoglycemic active ingredient can be achieved. The documents cited herein are incorporated by reference. Each material can be used as part of this manual. Modifications may be made by those skilled in the art without departing from the invention. That is, the present invention has been described with reference to specific preferred embodiments, but other specific examples that are apparent to those skilled in the art are also within the scope of the invention.

第16頁 1263508 修正 案號 93103500 圖式簡單說明 圖式說明： 第1圖為本發明之含微米化降血糖活性成分葛立克拉之口服 錠劑組成物在純水中隨著時間所顯示之溶離曲線圖。 第2圖為口服錠劑組成物中，含有微米化降血糖活性成分葛 立克拉（菱形）與含有未經微米化降血糖活性成分葛立克， 拉（正方形）之錠劑相比在純水中隨著時間所顯示之溶離 曲線圖。 第3圖為本發明之血中濃度隨時間的曲線圖。Page 16 1263508 Amendment No. 93103500 Brief Description of the Drawings: Figure 1 is a diagram showing the dissolution of the composition of the oral lozenge containing the micronized hypoglycemic active ingredient of the present invention in pure water over time. Graph. Figure 2 is a composition of an oral lozenge containing a micronized hypoglycemic active ingredient, genica (diamond), in a pure water compared with a tablet containing a micronized hypoglycemic active ingredient, gelik, pull (square). The dissolution profile shown by time. Figure 3 is a graph of blood concentration versus time for the present invention.

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Claims (1)

1263508 案號 93103500 _η 曰 95. i 修正 六、申請專利範圍 其 1、 一種口服延遲釋放（modified-release)錄：劑組成物 特徵為至少包含： 一微米化之降血糖活性成分，其微米化之大小與比例 為： (1 ) $ 5微米（/z m)活性成分之粒子累積體積百分比 (V ο 1 u m e % )佔總體積之5 0 %以上； (2 ) $ 1 5微米（// m)活性成分之粒子累積體積百分比 (Volume%)佔總體積之90%以上；及 (3 ) S 2 5微米（// m)活性成分之粒子累積體積百分比 (Volume%)佔總體積之95%以上；以及 一控制活性成份釋放之延遲釋放劑 2、 如申請專利範圍第1項所述之口服延遲釋放錠劑組成 物，其中該微米化之降血糖活性成分係選自磺醯尿素類、‘ 葛立克拉（Gliclazide)、格力匹來（Glipizide)、格力本 (Glibenclamide)、格力奎東寧（Gliquidonem)及格力美保 來（Glimepiride)及其組合。 3、 如申請專利範圍第1項所述之口服延遲釋放錠劑組成 物，其中該延遲釋放劑係選自羥丙基甲基纖維素、甲基纖 維素、聚乙烯 咯酮、羥丙基纖維素、乙烯基醋酸酯共聚 物、聚乙稀氧化物及其組合。 4、 如申請專利範圍第1項所述之口服延遲釋放錠劑組成 物，其中該延遲釋放劑佔錠劑組成物之1 0 %至4 0 %。 5、 如申請專利範圍第1項所述之口服延遲釋放錠劑組成 物，其中該微米化之降血糖活性成分葛立克拉1263508 Case No. 93103500 _η 曰95. i Amendment 6. Patent Application Area 1. An oral modified-release recording: The composition of the agent is characterized by at least: a micronized hypoglycemic active ingredient, which is micronized The size and proportion are: (1) The cumulative volume percentage of particles of the active ingredient of 5 μm (/zm) (V ο 1 ume % ) accounts for more than 50% of the total volume; (2) $ 1 5 μm (// m) The cumulative volume percentage of the active ingredient (Volume%) is more than 90% of the total volume; and (3) the cumulative volume percentage of the active ingredient of the S 2 5 micron (//m) is more than 95% of the total volume. And a delayed release agent composition according to claim 1, wherein the micronized hypoglycemic active ingredient is selected from the group consisting of sulfonium urea, 'Ge Gliclazide, Glipizide, Glibenclamide, Gliquidonem, and Glimepiride, and combinations thereof. 3. The oral delayed release tablet composition of claim 1, wherein the delayed release agent is selected from the group consisting of hydroxypropyl methylcellulose, methylcellulose, polyvinyl ketone, and hydroxypropyl fiber. , vinyl acetate copolymer, polyethylene oxide, and combinations thereof. 4. The oral delayed release tablet composition of claim 1, wherein the delayed release agent comprises from 10% to 40% of the tablet composition. 5. The composition of the oral delayed release lozenge according to claim 1, wherein the micronized hypoglycemic active ingredient Ge Likla 第18頁 1263508 修正 案號 93103500 六、申請專利範圍 * (Gliclazide)之重量係界於30毫克至60毫克之間。 6、 如申請專利範圍第5項所述之口服延遲釋放錠劑組成 物，其係經溶離測試兩小時後約有5〜1 5 % 的該微米化降 血糖活性成分釋出，在四小時後約有1 5〜3 5 %釋出，在八 小時後師釋出約5 0〜8 0 %，而在1 2小時的時候已有8 5 %以 上之成份釋出。 7、 如申請專利範圍第5項所述之口服延遲釋放錠劑組成 物，係以每天口服一次，一次服用1至2錠。 8、 如申請專利範圍第1項所述之口服延遲釋放錠劑組成 物，其組成包含微米化之葛立克拉（Gliclazide)、經丙基 甲基纖維素、聚乙烯咯酮、乳糖、二氧化矽、油酸聚醇 山梨醇、硬脂酸鎂及滑石粉。 9、 如申請專利範圍第3項所述之口服延遲釋放錠劑組成 物，其中該延遲釋放劑具有黏度從4 0 0 0 cps至1 0 0,0 0 0 c p S ° 1 1 0、一種口服延遲釋放録：劑組成物的製法，至少包含： 將降血糖活性成分微米化為： (1 )‘ 5微米m)活性成分之粒子累積體積百分比 (Volume%)佔總體積之50%以上； (2 ) $ 1 5微米（// m)活性成分之粒子累積體積百分比 1 (Volume%)佔總體積之90%以上；及 (3 ) S 2 5微米（// m)活性成分之粒子累積體積百分比 (Volume%)佔總體積之95%以上； 將微米化之該降血糖活性成分與延遲釋放劑加以混合、Page 18 1263508 Amendment Case No. 93103500 VI. Scope of Application * The weight of (Gliclazide) is between 30 mg and 60 mg. 6. The oral delayed release tablet composition of claim 5, wherein about 5 to 15% of the micronized hypoglycemic active ingredient is released two hours after the dissolution test, after four hours About 15 to 35% were released, and after about eight hours, the teacher released about 50 to 80%, and at 12 hours, more than 85% of the ingredients were released. 7. The composition of the oral delayed release tablet according to claim 5, which is administered orally once a day, once or twice a day. 8. The oral delayed release tablet composition according to claim 1, wherein the composition comprises micronized Gliclazide, propylmethylcellulose, polyvinyl ketone, lactose, dioxide Bismuth, oleic acid sorbitol, magnesium stearate and talc. 9. The oral delayed release tablet composition of claim 3, wherein the delayed release agent has a viscosity of from 4,000 cps to 1,0 0 cp S ° 1 1 0, an oral dose. The method for preparing a delayed release composition comprises at least: micronizing the hypoglycemic active ingredient to: (1) '5 micrometers m) a cumulative volume percentage of the active ingredient (Volume%) of 50% or more of the total volume; 2) $1 5 micrometers (//m) of active ingredient particles cumulative volume percentage 1 (Volume%) accounted for more than 90% of the total volume; and (3) S 2 5 micron (/ / m) active ingredient particle cumulative volume Percentage (% by volume) of more than 95% of the total volume; mixing the micronized hypoglycemic active ingredient with a delayed release agent, 第19頁 1263508Page 19 1263508 第20頁 1263508 案號93103500 年 月 日 修正Page 20 1263508 Case No. 93103500 Year Month Correction 第3頁Page 3