200906383 九、發明說明： 【發明所屬之技術領域】 本發明係關於一種包含甲福明酸鹽之持續釋放配方。 【先前技術】 作為/α療糖尿病之雙脈樂劑的曱福明（Metf〇rlnin ) ，以氯化氳鹽形式使用之。治療非胰島素依賴型糖尿病之 藥劑的曱福明係被單獨使用於以飲食治療仍不足之病 症，，或與硫醯基尿素類媒介共同使用於無法只以硫醯基尿 素類媒介治療之病症。 甲福明氯化氫鹽及其他甲福明鹽類之物性、化性及其 被揭示於貿〇 99/29314專利案中。在醫藥製i 士=處理甲福明氯化氫鹽。原因係該甲福明氯化氫鹽為 色/、黏性之粉末，其具有相當高的水溶解度（大於300 之溶解度大於23G mg/mi°)需大量持續 f放^水合物以製備持續釋放配方，不僅如此，該曱福明 ίίΐ鹽具有高度吸濕性(於攝氏25度/相對溼度為95% 条件下、6小時吸附20〇/〇，具高度壓密感受性）。因此， :::::氯化氫鹽之物性及化性導致大量持續釋放賦 形月丨之而求，配方之體積變得相當大的問題因而產生。 【發明内容】 性忐ί :二目的係提供一種醫藥組合物，包含-做為活 酸鹽’其可增進病患服用之便利性，並可 曰商亦衣備之便利性’以及透過減小最終配方體積促進 200906383 持續釋放配方之製備。 最終配方之體積可藉由以其他做為活性成分之甲福 明酸鹽取代曱福明氯化氫鹽來減小。原因係前述其他曱福 明酸鹽具有相較於曱福明氯化氫鹽相似之分子量及較低 之水浴解度。據此，當製備配方時可能可使用較少量之持 續釋放賦形劑。 本杳s共一種治療或預防糖尿病及其相關疾病之 組合物，包s-做級性成分之甲福明酸鹽及—持續釋放 賦形劑，進一步包含—醫藥可接受之載體。 本發明之甲福明酸鹽之溶解度不超過甲福明之溶 度23〇mg/ml，較佳的甲福明酸鹽 及曱福明草酸鹽。本發明之包含甲福明丄 受載體的醫藥衫㈣製備接 明之持續釋放配方可同時包含放配方本發 佳妯可戎任八田甘、 他冶療糖尿病之藥劑，較 甲基福明酸鹽及硫酶基尿素類藥物之複合 福明ϊ ί ί 類的甲福明號蘭鹽及〒 明氯;氯:相：:r較:積之福 現顯著的持續釋放型態。據此，^解度，在藥物釋放上呈 方時，其持續釋放劑之用量係少：二，製5甲福明配 控制甲福明的釋放。因此’其係可，、:、乳，氫鹽而容易 病患可輕易服用此藥物，且相較先、^2劑之體積使 明配方，其製料之持轉放的甲福 200906383 【實施方式】 本發明係使用羥丙基曱基纖維素、丙烯酸及其衍生 物、或丙烯酸樹脂s(Eudragits)做為一持續釋放配方之持續 釋放賦形劑。較佳的持續釋放配方之施用方式係口服。錠 劑或膠囊可例示為此類施用之手段。此配方可以混合一活 性成分及一載體，接著將此混合產物製成錠劑。此時，所 使用載體的合適例子可包含一崩散劑如甘醇酸澱粉鈉、交 聯聚維酮、殿粉、葡萄糖及甘露醇；一填充劑及增量劑如 乳糖、磷酸鈣及矽酸衍生物；一黏結劑如聚乙烯吡咯烷 酮、羧曱基纖維素及其他纖維素衍生物及明膠；一潤滑劑 如滑石、硬脂酸鈣、硬脂酸鎂及固態聚乙二醇等等。包含 一活性成分之有或無載體的硬式或軟式明膠膠囊也可以 傳統方法製備。最好每單位劑量之醫藥組合物包含200mg 到lOOOmg之做為活性成分的曱福明酸鹽。 本發明將參考以下實施例進行詳盡描述。然而以下實 施例僅為例示，並非用於偈限本發明之範圍。 甲福明酸鹽之製備 實施例1:曱福明琥珀酸鹽之製備 甲福明氯化氫鹽（l〇.〇g，60.4mmol)及氫氧化納（2.42g, 60.4mmol)加入純水(30ml)中並攪拌30分鐘，該溶液於減 壓及40〜45°C環境中濃縮。接續將產生之產物添加20%的 乙醇（100ml)並溶解於反應裝置中。琥珀酸（7.09g， 200906383 60jmmol)先於另—個反應裝置中溶解於i2_的 接者加入含有甲福明溶液之反應裝置中。產生之溶液 2小+時且溫度不高於1(rc，過濾並以(2〇吨乙醇清洗之， 接著置於60°C的環境中6小時使之乾燥 題化合物。 S扪知 H i>iMR (D20) _ δ 2_28 (s，4H), 2.93 (s，12 H) 實施例2:甲福明草酸鹽之製備 除了以草酸取代琥轴酸外皆根據實施例i之 法，可得到8.2g的標題組合物。 β方 158.52 (C=N), i6〇 1? C NMR (D20): δ 37.57 (methylamine-C), (C=N), 173.46 (carboxyl-C) —甲.福明酸鹽之醫藥組合物砧f備 為了確認本發明中酸鹽類之持續釋放效 施例3及4中製備含有做為持續釋放賦形劑之只 基甲基纖維素(40%〜45〇/0)之甲福明酸鹽之持續釋放=内 組合物 備200906383 IX. DESCRIPTION OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to a sustained release formulation comprising metformin. [Prior Art] Metf〇rlnin, which is a double-pulse agent for the treatment of diabetes, is used in the form of a barium chloride salt. The sulphate system for the treatment of non-insulin-dependent diabetes mellitus is used alone in a disease that is still insufficiently treated by diet, or in combination with a thioglycolide-based medium for a condition that cannot be treated with a thiopurine-based urinary vector. The physical properties and chemical properties of metformin hydrogen chloride and other metformin salts are disclosed in the Trade No. 99/29314 patent case. In the pharmaceutical industry i = treatment of metformin hydrogen chloride. The reason is that the metformin hydrogen chloride salt is a color/viscous powder which has a relatively high water solubility (a solubility greater than 300 is greater than 23 G mg/mi°) requiring a large amount of continuous hydrate to prepare a sustained release formulation. Not only that, the 曱Fuming ίίΐ salt is highly hygroscopic (at a temperature of 25 ° C / 95% relative humidity, adsorption at 20 〇 / 6 for 6 hours, with high pressure sensitivity). Therefore, the physical properties and the chemical properties of the :::::hydrogen chloride salt lead to a large number of sustained release of the shape of the moon, and the problem that the volume of the formulation becomes quite large arises. SUMMARY OF THE INVENTION The present invention provides a pharmaceutical composition comprising - as a live acid salt, which enhances the convenience of taking a patient, and facilitates the convenience of clothing and clothing. The final formulation volume promotes the preparation of the 200,906,383 sustained release formulation. The volume of the final formulation can be reduced by replacing the hydrazine molybdenate with other as the active ingredient of metformin. The reason is that the other hydrazine sulphate described above has a molecular weight similar to that of the hydrazine hydrogen chloride salt and a lower water bath resolution. Accordingly, a smaller amount of the sustained release excipient may be used when preparing the formulation. The present invention relates to a composition for treating or preventing diabetes and related diseases, comprising a s-grade component of metformin and a sustained release excipient, further comprising a pharmaceutically acceptable carrier. The solubility of the formazan acid salt of the present invention does not exceed the solubility of metformin of 23 〇 mg/ml, preferably metformin and guanidine oxalate. The invention discloses a sustained release formula prepared by the invention comprising a medical shirt (4) containing a carrier, which can simultaneously contain a formula, which can be used as an agent for the treatment of diabetes, which is better than methyl fumarate and Sulfuric acid-based urea compound Fuming ϊ ί ί 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲 甲Accordingly, the degree of resolution is less when the drug is released, and the amount of sustained release agent is small: Second, the system 5 is used to control the release of metformin. Therefore, 'the system can be,,:, milk, hydrogen salt and easy to patients can easily take this drug, and compared with the first, ^ 2 agent volume to make the formula, the material is transferred to the Jiafu 200906383 [implementation] Modes: The present invention uses hydroxypropyl decyl cellulose, acrylic acid and its derivatives, or acrylic s (Eudragits) as a sustained release vehicle for a sustained release formulation. A preferred sustained release formulation is administered orally. Tablets or capsules can be exemplified as a means of such administration. This formulation can be combined with an active ingredient and a carrier which is then formulated into a tablet. At this time, suitable examples of the carrier to be used may include a disintegrating agent such as sodium starch glycolate, crospovidone, house powder, glucose, and mannitol; a filler and extenders such as lactose, calcium phosphate, and citric acid. Derivatives; a binder such as polyvinylpyrrolidone, carboxymethylcellulose and other cellulose derivatives and gelatin; a lubricant such as talc, calcium stearate, magnesium stearate and solid polyethylene glycol, and the like. Hard or soft gelatin capsules containing an active ingredient with or without a carrier can also be prepared by conventional methods. Preferably, the pharmaceutical composition per unit dose contains from 200 mg to 1000 mg of the guanidine acid as the active ingredient. The invention will be described in detail with reference to the following examples. However, the following examples are merely illustrative and are not intended to limit the scope of the invention. Preparation of formazanate Example 1: Preparation of indole fumarate succinate Hydrocarbyl hydrogen chloride (1 〇g, 60.4 mmol) and sodium hydroxide (2.42 g, 60.4 mmol) were added to pure water (30 ml) The mixture was stirred for 30 minutes, and the solution was concentrated under reduced pressure at 40 to 45 ° C. The resulting product was added with 20% ethanol (100 ml) and dissolved in the reaction apparatus. Succinic acid (7.09 g, 200906383 60jmmol) was added to the reaction device containing the metformin solution prior to the addition of i2_ to the other reaction unit. The resulting solution was 2 small + and the temperature was not higher than 1 (rc, filtered and washed with 2 ton of ethanol, then placed in an environment of 60 ° C for 6 hours to dry the title compound. S扪 know H i> iMR (D20) _ δ 2_28 (s, 4H), 2.93 (s, 12 H) Example 2: Preparation of metformin oxalate except that oxalic acid was substituted for succinic acid according to the method of Example i 8.2 g of the title composition. β 158.52 (C=N), i6〇1? C NMR (D20): δ 37.57 (methylamine-C), (C=N), 173.46 (carboxyl-C) — A. The pharmaceutical composition of the acid salt is prepared for confirming the sustained release effect of the acid salt in the present invention. The preparation of the methyl methacrylate (40% to 45 做) as a sustained release excipient is prepared in the examples 3 and 4. /0) sustained release of formazan acid salt = internal composition preparation
43〇g :甲福明琥珀酸鹽之琶製 1. 曱福明破拍酸鹽 (390g曱福明的對應量） 2. 羥丙基曱基纖維素i〇〇,〇〇〇cps 3. 乳糖 4.聚乙烯吡咯烷酮K30 3〇g 35g 200906383 5. 硬脂酸鎂 5g 6. 純水_(200g) 曱福明琥珀酸，羥丙基曱基纖維素，乳糖及聚乙烯D比 咯烷酮添加於一混合器中並全部一起混合。之後，添加純 水並混合之。此混合的組合物於流動層乾燥機並以50 mesh的篩網篩選之。硬脂酸鎂添加於其中後，混合並製 成一錠劑（每錠劑1068.5g)。 實施例4 :曱福明草酸鹽之醫藥組合物的製備 組合物 1.曱福明草酸鹽 661.9g (390g曱福明的對應量） 2.羥丙基曱基纖維素100,000cps 430g 3.乳糖 3〇g 4.聚乙烯吡咯烷酮K30 35g 5.硬脂酸鎂 5g 6.純水 (200g) 除了以草酸取代琥珀酸做為活性成分外皆根據實施 例3之相同方法，可製備成一錠劑（每錠劑1161.9mg)。 在實施例5及6中，試圖顯示本發明達成增加基準適 應性，並且如實例1中製備甲基福明酸鹽時，減少做為持 續釋放賦形劑之羥丙基曱基纖維素的量以減少錠劑體 積，達到減低成本的效果。 200906383 實施例5 :曱福明琥珀酸之醫藥組合物讀製備，其中 持續釋放賦形劑的量減少至總重量之30%。 組合物 1.曱福明琥珀酸鹽 568.5g (390g曱福明的對應量） 2.羥丙基甲基纖維素100,000cps 280g 3.乳糖 3〇g 4.聚乙烯吡咯烷酮K30 35g 5.硬脂酸鎂 5g 6.純水 (200g) 依據實施例3相同方法，將做為持續釋放賦形劑之羥 丙基曱基纖維素的量，減少至總重量之30%(約280g)得到 一錠劑(每錠劑918.5mg)。 實施例6 :曱福明琥珀酸之醫藥組合物的製備，其中 持續釋放賦形劑的量減少至總重量之14%。 組合物 1.甲福明琥珀酸鹽 568.5g (390g曱福明的對應量） 2.羥丙基曱基纖維素100,000cps l〇5g 3.乳糖 3〇g 4.聚乙烯吡咯烷酮K30 35g 5.硬脂酸鎂 5g 10 200906383 6.純水 (200g) 依據實施例3相同方法，，將做為持續釋放賦形劑之 沒丙基甲基纖維素的量，減少至總重量之14%(約105g) 得到一錠劑(每錠劑743.5mg)。 實施例7 :結合實施例6組合物與格列美脲 (Glimepiride)^§j組合物的複合持續釋放配方之製備 組合物 1.甲基福明琥珀酸鹽 568.5g (390g曱福明的對應量） 2.輕丙基甲基纖維素i〇〇,〇〇〇CpS l〇5g 3.乳糖 3〇g 4.聚乙烯η比洛烧酮K30 35g 5.硬脂酸鎂 5g 6.純水 (200g) 包衣製備 7.格列美脲(glimepiride) 2.0g 8.座丙基甲基纖維素l〇〇,〇〇〇cps 24.9g 9.聚乙二醇 4.9g 10.二氧化鈦 l-7g 11.十二烷基硫酸鈉 1.5g 將實施例6之醫藥組合物以格列美脲(glimepiride)、 經丙基曱基纖維素、聚乙二醇、二氧化鈦、十二烧基琉酸 11 200906383 納之混合溶液塗覆，得一錠劑（每錠劑778 5mg)。 比較例 劑的甲 比較例1 :含有佔總重量43%之持續釋放賦形 福明氯化氫鹽之醫藥組合物的製備〇 組合物 500.〇g 430g 3〇g 35g 5g (2〇〇g) .甲福明氯化氫鹽 (390g甲福明的對應量） s 2. 羥丙基曱基纖維素i〇〇,〇〇〇cp 3. 乳糖 4. 聚乙稀吡略烧酮K30 5. 硬脂酸鎮 .純水 除了以甲福明氯化氫鹽做為活 例3之相同方法製備醫藥組合物。成刀外白根據貫知 實驗例 福，鹽溶解度之測量 述甲福明:溶解度’我們進行以下所 實施例1、2製備之相試之進行係藉由量測 每個鹽類之溶解声。ϋ先雨鹽類（曱福明氣化氫鹽）中 述實施例製備之;類及=3^中充分地加入利用前 拌之。接著，得到的樣口 ^於至，皿（22±5〇C)攪 僳叩於固疋_間測量其甲福明之 12 200906383 量。結果顯示於表1。 【表1】 攪拌時間 (小時） 甲福明之溶解度（mg/ml如曱福明） 比較例 實施例1 實施例2 0.5 231.8 72.9 136.5 1.0 237.5 74.1 137.2 4.0 243.9 73.8 137.5 如表1所示，本發明中曱福明酸鹽之溶解度顯著低於 曱福明氯鹽 實驗例2:曱福明酸鹽之溶解速率的測量 為了確認水溶性活性成分之連續釋放效率，我們進行 下列敘述之曱福明的溶解測試，該測試之進行係測量實例 3、4與比較例中每一配方之溶解速率。此溶解測試係根 據描述於美國藥典中溶解2之方法，其係於37°C使用 900ml pH值為6.8之模擬漿液狀流體。曱福明之量的量 測係於每個時間點取樣檢查溶解量(η值為6)。結果顯示 於第一圖及表2。 【表2】 溶解時間 (小時） 曱福明之溶解百分比（％) 比較例1 實施例3 實施例4 0.5 18.9 9.9 11.0 13 200906383 1.0 28.0 16.1 17.1 2.0 42.0 25.4 27.1 4.0 59.1 39.1 42.1 8.0 78.3 57.2 62.5 12.0 86.0 71.6 75.6 16.0 92.7 83.0 86.2 20.0 96.2 90.1 91.2 如第一圖及表2所示，即使持續釋放賦形劑之使用含 量相同，實施例3及4中曱基福明酸鹽之溶解度仍明顯低 於比較例。此可見實施例3及4所製備之新穎酸鹽類的效 果。 實驗例3 :根據曱福明酸鹽之持續釋放賦形劑的用量 變化，測量錠劑之溶解速率 為根據持續釋放賦形劑的減用來確認對水溶性活性 成分的連續釋放的影響，我們將後述之曱福明進行一溶解 測試，該測試之進行係測量實施例3、5、6、7及比較例 所製備之每個配方中曱福明之溶解量。此溶解測試係根據 美國藥點中溶解2之方法，其係於37°C使用900ml pH值 為6.8之模擬漿液狀流體。曱福明之量的量測係於每個時 間點取樣檢查溶解量（η值為6)。此結果顯示於第二圖及 表3。 【表3】 14 20090638343〇g: 甲 明 琥珀 succinate 1 1. 1. 曱 明 破 破 ( ( ( ( 390 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. Lactose 4. Polyvinylpyrrolidone K30 3〇g 35g 200906383 5. Magnesium stearate 5g 6. Pure water _(200g) 曱福明 succinic acid, hydroxypropyl decyl cellulose, lactose and polyethylene D pyrrolidone Add in a mixer and mix all together. After that, add pure water and mix it. The combined composition was sieved to a flow layer dryer and screened with a 50 mesh screen. After magnesium stearate was added thereto, it was mixed and made into a tablet (1068.5 g per tablet). Example 4: Preparation of pharmaceutical composition of bismuth oxalate oxalate 1. 曱福明 oxalate 661.9 g (corresponding amount of 390 g 曱福明) 2. Hydroxypropyl decyl cellulose 100,000 cps 430 g 3 Lactose 3〇g 4. Polyvinylpyrrolidone K30 35g 5. Magnesium stearate 5g 6. Pure water (200g) An ingot can be prepared according to the same method as in Example 3 except that oxalic acid is substituted for succinic acid as an active ingredient. Agent (1161.9 mg per tablet). In Examples 5 and 6, an attempt was made to show that the present invention achieves an increased baseline suitability, and when methylprevalinate is prepared as in Example 1, the amount of hydroxypropyl decyl cellulose as a sustained release excipient is reduced. In order to reduce the volume of the tablet, the effect of reducing the cost is achieved. 200906383 Example 5: A pharmaceutical composition of indole succinic acid was read and prepared in which the amount of sustained release excipient was reduced to 30% of the total weight. Composition 1. 曱福明 succinate 568.5 g (corresponding amount of 390 g 曱福明) 2. Hydroxypropyl methylcellulose 100,000 cps 280 g 3. Lactose 3 〇 g 4. Polyvinylpyrrolidone K30 35 g 5. Stearic acid Magnesium 5g 6. Pure water (200 g) According to the same method as in Example 3, the amount of hydroxypropyl decyl cellulose as a sustained release excipient was reduced to 30% (about 280 g) of the total weight to obtain an ingot. Agent (918.5 mg per tablet). Example 6: Preparation of a pharmaceutical composition of sulphate succinic acid wherein the amount of sustained release excipient was reduced to 14% by weight. Composition 1. Mefyfine succinate 568.5 g (corresponding amount of 390 g oxime) 2. Hydroxypropyl decyl cellulose 100,000 cps l 〇 5 g 3. Lactose 3 〇 g 4. Polyvinylpyrrolidone K30 35 g 5. Magnesium stearate 5g 10 200906383 6. Pure water (200g) According to the same method as in Example 3, the amount of propylmethylcellulose which is a sustained release excipient is reduced to 14% of the total weight (about 105 g) A lozenge (743.5 mg per tablet) was obtained. Example 7: Preparation of a composite sustained release formulation of the composition of Example 6 in combination with a Glimepiride composition. 1. Methylfoam succinate 568.5 g (corresponding to 390 g 曱福明) Amount) 2. Light propyl methyl cellulose i 〇〇, 〇〇〇 CpS l 〇 5g 3. Lactose 3 〇 g 4. Polyethylene η than crotonone K30 35g 5. Magnesium stearate 5g 6. Pure water (200g) Coating Preparation 7. Glimepiride 2.0g 8. Propylmethylcellulose l〇〇, 〇〇〇cps 24.9g 9. Polyethylene glycol 4.9g 10. Titanium dioxide l-7g 11. Sodium lauryl sulfate 1.5 g The pharmaceutical composition of Example 6 was treated with glimepiride, propyl decyl cellulose, polyethylene glycol, titanium dioxide, and decyl decanoic acid 11 200906383 The mixed solution was applied to obtain a lozenge (778 mg per tablet 778). Comparative Example A Comparative Example 1 : Preparation of a pharmaceutical composition containing a sustained release of a fumigant hydrogen chloride salt of 43% by weight of total weight 500. 〇g 430g 3〇g 35g 5g (2〇〇g) . Methodamine hydrogen chloride salt (corresponding amount of 390 g of metformin) s 2. Hydroxypropyl decyl cellulose i〇〇, 〇〇〇 cp 3. Lactose 4. Polyethyl pyridine ketone K30 5. Stearic acid Town. Pure water A pharmaceutical composition was prepared in the same manner as in the case of using formazan hydrogen chloride as the living example 3. The outer white of the knife was determined according to the experimental example. The measurement of the solubility of the salt was described as the solubility. The following experiments were carried out in the following Examples 1 and 2 to measure the dissolved sound of each salt. It is prepared in the above-mentioned examples of the salt salt (曱福明 gasification hydrogen salt); the class and the =3^ are fully added to the mixture before use. Next, the obtained sample was obtained, and the dish (22±5〇C) was stirred in the solid state to measure the amount of 12 200906383 of the metformin. The results are shown in Table 1. [Table 1] Stirring time (hours) Solubility of metformin (mg/ml as 曱福明) Comparative Example 1 Example 2 0.5 231.8 72.9 136.5 1.0 237.5 74.1 137.2 4.0 243.9 73.8 137.5 As shown in Table 1, the present invention The solubility of guanidine fumarate is significantly lower than that of ruthenium citrate. Example 2: Measurement of the dissolution rate of bismuth fumarate In order to confirm the continuous release efficiency of the water-soluble active ingredient, we carry out the following description of 曱福明Dissolution test, which was performed to measure the dissolution rate of each of the formulations in Examples 3, 4 and Comparative Examples. This dissolution test was carried out according to the method described in the United States Pharmacopoeia for Dissolution 2 using 900 ml of a simulated slurry fluid having a pH of 6.8 at 37 °C. The amount of 曱福明 is measured at each time point to check the amount of dissolution (η value is 6). The results are shown in the first figure and Table 2. [Table 2] Dissolution time (hours) Percent dissolution (%) of 曱福明 Comparative Example 1 Example 3 Example 1 0.5 18.9 9.9 11.0 13 200906383 1.0 28.0 16.1 17.1 2.0 42.0 25.4 27.1 4.0 59.1 39.1 42.1 8.0 78.3 57.2 62.5 12.0 86.0 71.6 75.6 16.0 92.7 83.0 86.2 20.0 96.2 90.1 91.2 As shown in the first and Table 2, the solubility of the thioglycolate in Examples 3 and 4 was significantly lower than that of the sustained release excipients. example. Thus, the effects of the novel acid salts prepared in Examples 3 and 4 can be seen. Experimental Example 3: The dissolution rate of the tablet was measured according to the amount of the sustained release excipient of the guanidine acid salt, and the effect of the continuous release of the sustained release excipient on the continuous release of the water-soluble active ingredient was confirmed. The dissolution test was carried out by the following method, which was carried out by measuring the dissolution amount of ruthenium in each of the formulations prepared in Examples 3, 5, 6, and 7 and the comparative examples. This dissolution test was carried out according to the method of Dissolving 2 in the U.S. Patent, using 900 ml of a simulated slurry fluid having a pH of 6.8 at 37 °C. The amount of 曱福明 is measured by sampling at each time point to check the amount of dissolution (η value is 6). This result is shown in the second and table 3. [Table 3] 14 200906383
^門比較實施例3、5、6及比較例每個例 :持、1放賦形劑用量之所有溶解速率 ，減 =’於啸例及實_ 6之組合物只含有i4Q^^ 賦形劑’其溶解速率相似。不僅如此，實施例上 ^備之複合持續釋放配方具有和比較例相似的釋放模 式^表示錠劑體積的明顯減小可藉由減少在製備配方時 所使用之持續釋放成分的用量來達成，如實補6及7 所示。 、 實驗例4 :測量大鼠金液中藥物之濃度 為研究水溶性活性成分之藥物動力特性，將6至7 週大之大鼠頸靜脈接管後，對指定數量的大屬分別餵食甲 福明氯化氫鹽及實施例1、6及比較例中製備的醫藥組合 物。接著於 0.25、0.5、0.75、1、1.25、1.5、2、4、6、9 15 200906383 小時取樣檢查0.4ml之血液來量測之活性成分的濃度。所 得結果如第三圖及表四所示。 【表4】 藥物 曱福明氯 化氫鹽 比較例之 組合物 實施例1 之鹽類 實施例6 之組合物 曲線下面積 (Area Under the Curve ; AUC) 29.49 33.13 38.14 46.60 Cmax (β g/ml) 8.63 6.36 45.35 8.49 Tmax(小時） 1.25 2 0.25 4 在第三圖及表4中，我們檢測曱福明氯化氫鹽及實施 例1、6與比較例中水溶性活性成分之藥物特性。我們從 曲線下面積（Area Under the Curve，· AUC)得知，實施例1 及6之組合物的生體利用率較曱福明氯化氫鹽及比較例 之組合物為佳。此事實證明包含新穎之酸鹽類的持續釋放 配方，其生體利用率係非常優異。 16 200906383 【圖式簡單說明】 第一圖係實施例3、4及比較例於pH值6.8時，不同 時間之溶解測試結果(η值為6)。 第二圖係實施例3、5、6、7及比較例於pH值6.8 時，不同時間之溶解測試結果(η值為6)。 第三圖係實施例1、6及比較例於pH值6.8時，不同 時間之藥物於大鼠血漿中濃度(η值為6)。 17^ 门 Comparing Examples 3, 5, 6 and Comparative Examples Each example: holding and discharging all the dissolution rates of the amount of excipients, minus = 'The composition of the whistling case and the real _ 6 only contains i4Q^^ The agent's dissolution rate is similar. Moreover, the composite sustained release formulation of the examples has a release mode similar to that of the comparative example. ^ A significant reduction in the volume of the tablet can be achieved by reducing the amount of sustained release component used in preparing the formulation. Supplements 6 and 7 are shown. Experimental Example 4: Measuring the concentration of the drug in the rat gold solution To study the pharmacokinetic properties of the water-soluble active ingredient, after taking the jugular vein of the rat 6 to 7 weeks old, the specified number of large genus were fed with metformin. Hydrogen chloride salt and the pharmaceutical compositions prepared in Examples 1, 6 and Comparative Examples. Next, a concentration of 0.4 ml of blood was taken at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 4, 6, 9 15 200906383 hours to measure the concentration of the active ingredient. The results obtained are shown in the third and fourth tables. [Table 4] Composition of the drug bismuth hydride hydrogen chloride salt Comparative Example The salt of the composition of Example Example 1 Area Under the Curve (AUC) 29.49 33.13 38.14 46.60 Cmax (β g/ml) 8.63 6.36 45.35 8.49 Tmax (hours) 1.25 2 0.25 4 In the third and fourth tables, we examined the pharmaceutical properties of the hydrazine molybdenum salt and the water-soluble active ingredients of Examples 1, 6 and Comparative Examples. From the area under the curve (AUC), it is known that the compositions of the compositions of Examples 1 and 6 have better bioavailability than the compositions of the Fuming hydrogen chloride and the comparative examples. This fact proves that the sustained release formulation containing the novel acid salt has excellent bioavailability. 16 200906383 [Simplified description of the drawings] The first figure shows the dissolution test results (η value of 6) at different times in the examples 3, 4 and the comparative examples at pH 6.8. The second graph is the dissolution test results (η value of 6) at different times for Examples 3, 5, 6, and 7 and the comparative examples at pH 6.8. The third panel is the concentration of the drug at different times in the plasma of rats in Examples 1, 6 and Comparative Example at pH 6.8 (η value of 6). 17