570797 Α7 Β7 五、發明説明（ 、十發明相關於-種組成物，特別是相關於—種醫藥用 組成物，及相’轉纟且成物於醫藥上之職，相關於該 等組成物之製法以及有胁該等方法巾之組成物。 歐洲專利申請案’公開號〇,3〇6,228相關於揭示具有 低血糖和低血齡性之特定錢射二晴生物。揭示於 EP 0306228中特別的四氫嘍唾二酮為5_[4_[2_(n_甲基善 〇吼咬基)胺基)乙氧基]+基]四氫嗔嗤_2,4_二酉同（以下作 為“化合物⑴”）。國際專利申請案公開號WO 94/565S ，示化合物⑴之特定鹽類，包括該等於實 來酸鹽。 ~ /外地’現已指化合物(I)分開和特定之每曰劑量 =提供特定有利之作用於血糖的控制，並因此而特別有用 j糖尿病，尤其U Η型糖尿病以及與糖尿_關 之治療。 物，因ί發明最初之方面係在提供—種醫藥用組成 物人=於早位劑型，其包含化合物(D，特徵為該組成 需i人有ί」2毫克w藥上可接受形式之化合物⑴，且視 而要3有4樂上可接受之載體。 接為適宜之化合物⑴之㈣上可接如斌絲括醫藥上可 醫ίίΐϊ形式以及醫藥上可接受之溶劑合物形式，包括 -樂上可接受鹽類之溶劑合物形式。 適係含有 2、3、4、5、6、7、8、9、1〇、 或丨2毫克醫藥上可接受形式之化合物⑴。 特別的組成物係含有2至4毫克醫藥上可接受形式之 本紙張尺度埏 用屮國 _ 標，一(Τ^Τ^Τ^^ΓΓ 570797 五、發明説明（ 化合物(I) 〇 化合:;的組成物係含有4至8毫克醫藥上可接断 之化組成物係含有8至12毫切藥上可接受形式 —種含有2毫克醫藥上可接受形式之化合物(1)。 物(I) 較佳的組成物係含有4毫克醫藥上可接受形式之化合 〇 較佳的組成物係含有8毫克醫藥上可接受形式之化人 物(I) 〇 口 適宜化合物(I)之醫藥上可接受鹽類形式，係包括彼等 於ΕΡ 0306228和W0 94/05659令所述者。較佳之醫藥上 可接受鹽為馬來酸鹽。 μ 適宜化合物(I)之醫藥上可接受溶劑合物形式，係包括 彼等於ΕΡ 0306228和WO 94/05659中所述者，特別是水 合物。570797 Α7 Β7 V. Description of the invention (), (10) inventions are related to a kind of composition, especially to a kind of medicinal composition, and the position of “transformation and formed in medicine”, related to the composition Manufacturing method and composition threatening these methods. European Patent Application 'Publication No. 0,306,228 is related to the disclosure of specific money-eating organisms with hypoglycemia and low blood age. It is disclosed in EP 0306228. Tetrahydrosialedione is 5_ [4_ [2_ (n_methylshenyl) amino) ethoxy] + yl] tetrahydrostilbene_2,4_dihydrazone (hereinafter referred to as "compound ⑴ "). International Patent Application Publication No. WO 94 / 565S shows specific salts of compound VII, including the same as the acid salt. ~ / Field 'now refers to compound (I) separately and specific dosages = providing specific beneficial effects on blood glucose control and is therefore particularly useful. J Diabetes, especially U-type diabetes and treatment with diabetes. Since the original aspect of the invention is to provide a medical composition human = in the early dosage form, it contains a compound (D, characterized in that the composition requires 2 mg of the compound in a pharmaceutically acceptable form). ⑴, and if necessary, there are 3 and 4 pharmaceutically acceptable carriers. The appropriate compounds are ⑴ 接 可 接 接 接 如 括 括 括 括 括 括 and pharmaceutically acceptable solvate forms, and pharmaceutically acceptable solvate forms, including- The solvate form of pharmaceutically acceptable salts. Suitable for compounds containing 2, 3, 4, 5, 6, 7, 8, 9, 10, or 2 mg of pharmaceutically acceptable form of the compound ⑴. Special composition The system contains 2 to 4 milligrams of this paper in a pharmaceutically acceptable form. This paper uses the national standard, one (T ^ Τ ^ Τ ^^ Γ 570797 V. Description of the invention (Compound (I)) Contains 4 to 8 milligrams of pharmaceutically acceptable chemical composition. Contains 8 to 12 milligrams of pharmaceutically acceptable form—a compound (1) containing 2 milligrams of pharmaceutically acceptable form. The composition contains 4 mg of the compound in a pharmaceutically acceptable form. The preferred composition contains 8 mg of the compound Persons in the acceptable form (I) 〇 The pharmaceutically acceptable salt forms of the suitable compound (I) include those described in EP 0306228 and WO 94/05659. The preferred pharmaceutically acceptable salts are Maleate. Μ Suitable pharmaceutically acceptable solvate forms of compound (I) include those described in EP 0306228 and WO 94/05659, especially hydrates.
化合物⑴，或其醫藥上可接受鹽，或其醫藥上可接受 溶劑合物，係可使用已知方法，例如ΕΡ 0306228和WO 94/05659中所揭示者而製備得。ΕΡ 0306228和WO 94/05659中所揭示者，係併入本文作為參考文獻。 化合物(I)可以數種互變異構形式中之一種存在，所有 互變異構形式，係包含於“化合物(1)”此項措詞中，作為 各別互變異構形式或其混合物。 化合物⑴包含一個不對稱碳原子，並因此可有至多兩 本紙張尺度询州中國1¾家標CNS ) Λ4規格（210X 297公釐） 570797 A7 B7 五Compound VII, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof can be prepared using known methods such as those disclosed in EP 0306228 and WO 94/05659. The disclosures in EP 0306228 and WO 94/05659 are incorporated herein by reference. Compound (I) may exist in one of several tautomeric forms, and all tautomeric forms are included in the term "compound (1)" as individual tautomeric forms or mixtures thereof. The compound ⑴ contains an asymmetric carbon atom, and therefore can have up to two paper sizes. Inquiry China 1¾ family standard CNS) Λ4 size (210X 297 mm) 570797 A7 B7 5
、發明説明I 經濟部中央標準局員工消費合作社印製 種立體異構形式存在，措詞化合物⑴，係包含所有該等 異構形式’無論其為各別異構物或是該等異構物之混合 物，包括消旋物。 文中所使用措詞“與糖尿病相關之狀況，，，係包括該 等與糖尿病前期相關之狀況、與糖尿病本身相關之狀況、 以及與糖尿病相關之併發症。 文中所使用措詞“與糖尿病前期相關之狀況”，係包 =該等狀況，例如胰島素抗性，包含遺傳性胰島素抗性， 損害性葡萄糖耐受性以及高胰島素血症。 文中所使用措詞“與糖尿病本身相關之狀況”，係包 括高血糖症、胰島素抗性，包括後天性胰島素抗性和肥胖。 而進一步與糖尿病本身相關之情況還可包括高血壓 、心血 f疾病’尤其是動脈舰魏，特定飲食失轉礙，特別 是該等需要食肺攝食_者，例如減食低下相關之障 礙，如神經性食慾缺乏，以及過度飲食相關之障礙，如肥 胖和暴食症。 “與糖尿射目社·症，，，係包姆赫，尤直是 相關於第π型糖尿病之腎疾病，包括糖尿病性神經病、 絲球體性腎炎、腎小球魏症、腎雜候群、冑血紐 硬化以及腎疾病末期。 2中所使用“醫藥上可接受，，措詞，係涵蓋人類和 獸醫方面之用途.例如“醫藥上可接受” 醫上可接冑德合物。 錄 本文中所使用針對於醫藥上可接受形式之化合物⑴， (請先閱讀背面之注意事項 本貢) .裝· 、1Τ 線 • n n n · 本紙張尺度適财關家鰣（CNS 21()x29：^ 570797 五、發明説明^ 經 濟 部 中 標 準 局 員 工 消 f 合 作 社 印 % j %藥上可接受形式之化合物⑺之比例含量， 其係大於存於給藥組成物中者。①㊁=文中所提作為參考之標量’包括“化合物 較形式”之毫克含量及％重量含量，該提 及之知置係相關於化合物①本身：例如2毫克化合 之馬來酸鹽形式’係指含有2毫克化合物(I)之馬來酸鹽。 糖尿病較佳為第II型糖尿病。 另+—方面，本發明提供一種瑁於製備含有2至12毫 式之化合物⑴之醫藥組成物，以及為 丹之，樂上可接受載體之方法，此方法包含將2至12毫 克醫藥上可接受形式之化合物(1)與醫藥上可接受載體混 並視需要於®後將所製備得之組成物調配成給藥形 如上所述，本發明亦提供一種用於製備含有醫藥上可 接受形式之化合_之糾方法，其制適合於製備一 定範圍之化合物(I)之單位劑型。因此，本發明另可提供 - 於藥上可接受形式之化合物⑴之醫藥組成 物，以及為其之醫藥上可接受紐之方法，此方法包含： (1)製備最初組成物，其係含有醫藥上可接受形式之化合 物(I)以及最初醫藥上可接受之载體； ⑻將最她成物與第二醫藥上可接受之賴混合，以提 供所需之化合物(I) ’並視需要於爾後將所製備得之组 成物調配成給藥形式。 ’ 較佳化合物⑴之醫藥組成物為單位劑量紐成物。 項 頁 訂 線 6 570797 A7 -----—_______B7 五、發明説明< ) 經濟部中央標準局員工消費合作社印製 除非另有說明，適宜之單位劑量係包含最多12毫克， 例如1至12毫克M上可接受形叙化合物(1)。其他單位劑量係包括彼等於之前所述者。 上述最後方法令之關鍵成分為最初組成物。因此，本發明亦提供-種可麟作為最她成物於製鮮位劑量醫 藥上可接受形式化合物①之組成物。 本發明亦提供-種包含醫藥上可接受形式之化合物⑴ 之組成物，以及視需要之醫藥上可接受之載體，其特徵在 於該組成物為醫藥上可接受之預先給藥組成物。適宜之醫藥上可接受之預先給藥組成物為濃縮物，較 佳為-種醫藥上可接受形式德合_之齡濃縮物。此顆粒濃縮物特別適合於稀釋，以提供用於給藥之組成 物，較佳為錠劑。 於另一方面，本發明提供一種包含醫藥上可接受形式 之化合物(I)及醫藥上可接受之載體之組成物，其特徵在 於該組成物為醫藥上可接受形式之化合物①之^ 其適合於稀釋，以提供用於給藥之組成物。 適宜地，最初組成物，預先給藥組成物或可稀釋組成 物（此後為方便起見指稱為“最初組合物”），按重量計， 其可含最多50%，例如醫藥上可接受形式之化合物⑴， 按重量計，含量為2至50%。 較佳地，最初組成物含有醫藥上可接受形式之化合物 ⑴含量範圍，按重量計，係自5至20%，特別是按重量 計為5%、10%或15%，例如按重量計ι〇〇/〇。 (請先閲讀背面之注意事項►本頁} —^i i *ϋι · •裝* -訂 -線 7 ( CNS ) ( 210X297^ ) 570797 、發明説明& 經濟部中央榡準局員工消費合作社印製 經腸ίΓΓ法可提供任何習用給藥形式，包括口服或非 適入於i借形式之醫藥用化合物(1)之組成物。彼等特別 (1):鍵=服形式’尤其是醫藥塊^ 接爲=醫藥上可接受之載體可包含任何制之醫藥上可 包iit，其係包含制醫藥上可接受之_劑，彼等係以等揭示於底下所提參考教科書中者。然而，最初醫 =上可接，之載體為給藥形式是非必要的，其並不需要含 僅與給藥相關之賦形劑。例如最初醫藥上可接受之載體 並不需要含有潤滑劑。 第二醫藥上可接受之載體係包括任何習用醫荦上可接 劑之任何習用醫藥上可接受之載體，包括崩解劑、 =釋劑、以及麟劑’包括鱗揭示於底下所提 書中者。 人一種特別的最初組成物係包括醫藥上可接受形式之化 合物①、崩解劑、結合劑以及稀釋劑。 適宜之崩解劑為澱粉羥基乙酸鈉。 適且之結合劑為甲基纖維素結合劑，例如輕 纖維素2910。 適宜之稀釋劑包括纖維素，例如微晶纖維素、以及乳 糖單水合物。 適宜之潤滑劑為硬脂酸鎂。 吾4已發現’特別有利之最初組成物係包含醫藥上可 接又形式之化合物⑴、殿粉羥基乙酸納、經丙基甲基纖 CNS ) (請先閲讀背面之注意事項 本頁) .裝· 570797 A7 B7 五、發明説明{ leu m · 經濟部中央標準局員工消費合作社印製 維素2910、微晶纖維素、以及乳糖單水合物，特別是顆 粒形式。該等顆粒形式現已發現特別安定。 當袁初組成物含有按重量計為10%之醫藥上可接受 形式之化合物(I)時，其可迅速稀釋而獲得單位劑量組成 物，其係含有介於2至12毫克範圍，特別是2至8毫克、 2至4毫克、4至8毫克、以及8至12毫克醫藥上可接受 形式之化合物⑴。 最初組成物之製備係使用任何適合於該最初組成物本 質之方法而完成，例如溼式製粒法，以提供顆粒形式之最 初組成物。 將本發明組成物調配成給藥形式之方法係包括習用之 調劑方法，如揭示於本文所引用參考教科書中者，包括製 键法。 本發明之給藥組成物較佳係適合於口服。然而，彼等 亦可適合於其他的給藥模式，例如非經腸道給藥、舌下或 經皮給藥。 給藥組成物可為錠劑、膠囊劑、散劑、顆粒劑、含片、 栓劑、可重組散劑、或液體製劑，例如口服或滅菌之腸道 外溶液劑或懸浮劑形式。 為使給藥獲得一致，本發明組成物較佳係以單位劑量 形式給藥。 口服給藥時之單位劑量形式可為錠劑和膠囊劑，並可 含有習用賦形劑，例如結合劑，如糖漿、阿拉伯膠、山梨 醇、黃耆膠、或聚乙烯吡咯烷填充劑，如乳糖、糠、 (請先閲讀背面之注意事項) 裝- 訂 線 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 570797 A7I. Description of the invention I The stereocomeric forms printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economy exist, and the wording compound ⑴ contains all such isomeric forms' whether it is an individual isomer or such isomer Mixtures, including racemates. The wording "conditions related to diabetes mellitus" used in the text includes such conditions related to pre-diabetes, conditions related to diabetes itself, and complications related to diabetes. The wording used in the text "related to pre-diabetes "Conditions" = systemic conditions, such as insulin resistance, including hereditary insulin resistance, impaired glucose tolerance, and hyperinsulinemia. The wording "conditions related to diabetes itself" is used Including hyperglycemia, insulin resistance, including acquired insulin resistance and obesity. Further conditions related to diabetes itself can also include hypertension, heart disease, especially arterial disease, specific dietary disorders, especially Those who need lung and food intake, such as reduced diet-related disorders, such as anorexia nervosa, and disorders related to overeating, such as obesity and binge eating disorder. "" Is especially related to kidney disease of type π diabetes, including diabetic neuropathy, filamentous nephritis, renal ministry Wei disease, kidney waiting miscellaneous group, helmet and hardening of blood York stage renal disease. The term "pharmaceutically acceptable," as used in 2, covers human and veterinary uses. For example, "pharmaceutically acceptable" is a medically acceptable compound. Records used in this article are intended to be medically acceptable. Form of compound ⑴, (please read the precautions on the back of this article first). Packing ·, 1T line · nnn · This paper size is suitable for financial affairs (CNS 21 () x29: ^ 570797 V. Explanation of the invention ^ Ministry of Economic Affairs The staff of the Bureau of Standards Bureau Cooperative Association printed% j% The proportion of compound ⑺ in a medicinally acceptable form is greater than those stored in the administration composition. ① 之 = scalar referenced in the text 'includes "compound comparative forms" The content of milligrams and% by weight is related to the compound ① itself: for example, 2 milligrams of the combined maleate salt form means that it contains 2 milligrams of the compound (I). Diabetes is preferred It is type II diabetes. In another plus aspect, the present invention provides a method for preparing a pharmaceutical composition containing 2 to 12 milligrams of the compound ⑴, and a method for danzhi, an acceptable carrier, which method comprises 2 to 12 mg of the compound (1) in a pharmaceutically acceptable form is mixed with a pharmaceutically acceptable carrier, and if necessary, the prepared composition is formulated into a dosage form as described above, and the present invention also provides a A method for preparing a compound containing a pharmaceutically acceptable form, which is suitable for preparing a unit dosage form of a certain range of the compound (I). Therefore, the present invention may further provide-a pharmaceutical composition of the compound ⑴ in a pharmaceutically acceptable form And a method for the pharmaceutically acceptable button thereof, the method comprising: (1) preparing an initial composition containing the compound (I) in a pharmaceutically acceptable form and an initially pharmaceutically acceptable carrier; ⑻ Mix the final product with a second pharmaceutically acceptable ingredient to provide the desired compound (I) 'and, if necessary, later formulate the prepared composition into a form for administration.' Preferred compound ⑴ 之The pharmaceutical composition is a unit dosage unit. Item line 6 570797 A7 -----_______ B7 V. Description of the invention <) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs unless otherwise stated, it is appropriate Dosage doses contain up to 12 mg, such as 1 to 12 mg of the acceptable compound (1) in M. Other unit doses include those described previously. The key ingredient of the last method described above is the initial composition. Therefore, The present invention also provides a composition which can be used as the most effective ingredient in a pharmaceutically acceptable form of the compound ①. The present invention also provides a composition comprising the compound ⑴ in a pharmaceutically acceptable form, and The required pharmaceutically acceptable carrier is characterized in that the composition is a pharmaceutically acceptable pre-administration composition. A suitable pharmaceutically acceptable pre-administration composition is a concentrate, preferably a kind of medicament An acceptable form of Dehe ageing concentrate. This granular concentrate is particularly suitable for dilution to provide a composition for administration, preferably a lozenge. In another aspect, the present invention provides a composition comprising a compound (I) in a pharmaceutically acceptable form and a pharmaceutically acceptable carrier, characterized in that the composition is a compound in a pharmaceutically acceptable form It is diluted to provide a composition for administration. Suitably, the initial composition, the pre-administration composition or the dilutable composition (hereinafter referred to as "the initial composition" for convenience) may contain up to 50% by weight, for example, in a pharmaceutically acceptable form. Compound IX is present in an amount of 2 to 50% by weight. Preferably, the initial composition contains a compound in a pharmaceutically acceptable form in a content range of from 5 to 20% by weight, in particular 5%, 10% or 15% by weight, for example by weight. 〇〇 / 〇. (Please read the notes on the back ►This page} — ^ ii * ϋι • • Packing *-Order-Line 7 (CNS) (210X297 ^) 570797 、 Invention & Printed by the Central Consumers Bureau of the Ministry of Economic Affairs Consumer Cooperatives The enteral ΓΓΓ method can provide any conventional form of administration, including oral or non-suitable forms of medicinal compounds (1). They are special (1): bond = service form 'especially pharmaceutical blocks ^ It follows that the pharmaceutically acceptable carrier may include any system of pharmaceutically acceptable package, which includes the system of pharmaceutically acceptable agents, which are disclosed in the reference textbooks mentioned below. However, initially It is not necessary that the carrier is in the form of administration, it does not need to contain excipients related to administration only. For example, the carrier that was originally pharmaceutically acceptable does not need to contain a lubricant. Acceptable carriers include any conventionally pharmaceutically acceptable carriers that are accessible on any conventional medicine, including disintegrants, release agents, and linal agents, including those disclosed in the books mentioned below. Special initial composition includes medical Acceptable forms of compounds ①, disintegrants, binders, and diluents. Suitable disintegrants are sodium starch glycolate. Suitable binders are methyl cellulose binders, such as light cellulose 2910. Suitable diluents Includes cellulose, such as microcrystalline cellulose, and lactose monohydrate. A suitable lubricant is magnesium stearate. We have found that 'the particularly advantageous initial composition is that it contains pharmaceutically acceptable compounds, Powder sodium glycolate, via propyl methyl cellulose CNS) (Please read the precautions on the back page first). Equipment · 570797 A7 B7 V. Description of the invention {leu m · Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 2910, microcrystalline cellulose, and lactose monohydrate, especially in granular form. These granular forms have now been found to be particularly stable. When the composition of Yuan Chu contains 10% by weight of compound (I) in a pharmaceutically acceptable form, it can be quickly diluted to obtain a unit dose composition, which contains a range of 2 to 12 mg, especially 2 To 8 mg, 2 to 4 mg, 4 to 8 mg, and 8 to 12 mg of compound IX in a pharmaceutically acceptable form. The initial composition is prepared using any method suitable for the nature of the initial composition, such as wet granulation, to provide the initial composition in the form of granules. The method of formulating the composition of the present invention into an administration form includes the conventional method of dispensing, as disclosed in the reference textbooks cited herein, including the bond method. The administration composition of the present invention is preferably suitable for oral administration. However, they may also be suitable for other modes of administration, such as parenteral, sublingual or transdermal administration. The administration composition may be in the form of a tablet, capsule, powder, granule, lozenge, suppository, reconstitutable powder, or liquid preparation, such as an oral or sterilized parenteral solution or suspension. In order to achieve uniform administration, the composition of the present invention is preferably administered in a unit dosage form. Unit dosage forms for oral administration may be lozenges and capsules, and may contain conventional excipients, such as binding agents such as syrup, acacia, sorbitol, tragacanth, or polyvinylpyrrolidine fillers, such as Lactose, bran, (please read the precautions on the back first) Binding-Bookmark This paper size applies to China National Standard (CNS) A4 (210X297 mm) 570797 A7
570797 A7 B7 五、發明説明（) 經濟部中央標準局員工消費合作社印製 經腸迢組成物’係包含活性化合物和誠雜，且視所使 用濃度而定’可财於或絲於载體中。韻用於非經腸 道給樂之溶液劑時’可將本化合物溶解在水中以便注射， 並且在填充人適合之管瓶或安赠，經過濾顧且密封。 有利地’可將佐劑’如局部麻醉劑、防腐劑和緩衝劑溶解 於載體中。為增強安紐，本組成物可於填充人管瓶後冷 凍，並將水於真空下移除。除將化合物①懸浮於載體而 非溶解’以及滅菌不能伴隨過濾完成外，非經腸道懸浮劑， 本質上係以姻方式製備得。本化合物可在麟於滅菌載 體前，經由暴露於環氧乙烧而滅g。有利地，可將界面活 性劑或凓潤劑包含於本組成物中，以利化合物均勻分布。 除非另有說明，本發明組成抝按重量計含有活性化合 物自0.1%至99% ’較佳為按重量計，自i請％，端視給 藥方法而定。 組成物，若需要，可為附有書寫或打印使用說明書之 包裝形式。 )★本發明組成物可根據習用方法製備及調配而得，例如 諸等揭示於標準參考教科書，如英國和美國藥典、雷明頓 氏醫藥科學（馬克出版公司）、馬丁代爾補充藥典（偷敦， 普藥出版社）以及哈里氏化妝品學（倫納德希爾圖書）。 本發明亦提供一種f藥組成物，其包含2至12毫克 化合物⑴，以及為此之醫藥上可接受載體，用以作為有 效治療物質。 特別是本發明提供一種用於糖尿病，特別是第II型570797 A7 B7 V. Description of the invention () Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, the composition of the intestinal tincture 'contains active compounds and sincere impurities, and depends on the concentration used' can be in or in the carrier . When used in parenteral solution, the compound can be dissolved in water for injection, and filled in a suitable vial or gift, filtered and sealed. Advantageously, " adjuvants " such as a local anesthetic, preservative and buffering agent can be dissolved in the carrier. To strengthen Anu, this composition can be frozen after filling in a human vial, and water can be removed under vacuum. Except for suspending compound ① in the carrier without dissolving it 'and sterilization cannot be completed with filtration, parenteral suspensions are essentially prepared by marriage. This compound can be destroyed by exposure to ethylene oxide before being exposed to a sterilized carrier. Advantageously, a surfactant or humectant may be included in the composition to facilitate uniform distribution of the compound. Unless otherwise stated, the composition of the present invention contains from 0.1% to 99% by weight of the active compound, preferably from weight to%, depending on the method of administration. The composition, if required, may be in the form of a package with written or printed instruction manuals. ) ★ The composition of the present invention can be prepared and formulated according to conventional methods, such as those disclosed in standard reference textbooks, such as the British and American Pharmacopoeia, Remington's Medical Science (Mark Publishing Company), Martindale Supplementary Pharmacopoeia (Stolen , General Medicine Press) and Harry's Cosmetics (Leonard Hill Books). The present invention also provides a f drug composition comprising 2 to 12 mg of compound IX, and a pharmaceutically acceptable carrier therefor for use as an effective therapeutic substance. In particular, the present invention provides a method for use in diabetes, particularly type II
(請先閱讀背面之注意事項 本買) -裝. 訂 線 570797 A7 B7 五、發明説明Q ) 經濟部中央標隼局員工消費合作社印裂 糖尿病，以及與糖尿病相關狀況治療之醫藥組成物，其包 含2至12毫克醫藥上可接受形式之化合物①。 本發明組成物可每日給藥自i至6次，但最佳為每曰 1或2次。 因此，另一方面本發明提供一種用於哺乳動物，如人 類中糖尿病，特別是第π型糖尿病，以及與糖尿病相關 狀況治療之方法，該方法包含對所需哺乳動物每日給藥2 至12耄克醫藥上可接受形式之化合物①。 特別地，本方法包括給藥2至4、4至8、或8至12 毫克醫藥上可接受形式之化合物(1)。 特別地，本方法包括給藥2至4毫克醫藥上可 形 式之化合物(I)。 特別地，本方法包括給藥4至8毫克醫藥上可接受形 式之化合物(I)。 特別地，本方法包括給藥8至12毫克醫藥上可接典 形式之化合物(I)。 又 特別地，本方法包括給藥2毫克醫藥上可接受 化合物(I)。 特別地，本方法包括給藥4毫克醫藥上可接 化合物(I)。 特別地，本方法包括給藥8毫克醫藥上可 化合物(I)。 y式之 2至4毫克範圍係包括2·1至4、2.2至4、2 3至4、 2.4 至 4、2.5 至 4、2.6 至 4、2.7 至 4、2,8 至 4、2 9 至 4 (請先閲讀背面之注意事項 — I裝| 本頁 訂 線· 12 本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ297公釐） 570797 Α7 Β7 五、發明説明) 或3至4毫克範圍。 4至8毫克範圍係包括4〗至§、4.2至8、4.3至8、 4.4 至 8、4.5 至 8、4.6 至 8、4·7 至 8、4.8 至 8、4.9 至 8、 5至8、6至8、或7至8毫克範圍。 8至12毫克範圍係包括8丨至12、8 2至12、8 3至 12、8·4 至 12、8.5 至 12、8.6 至 12、8.7 至 12、8.8 至 12、 8.9至12、9至12、10至12、或Π至12毫克範圍。 於上述劑量範圍内，本發明組成物或方法並未形成不 良的毒性效應。 底下實施例係用作說明，絕非對其多作限制。 請先閲讀背面之注事項本頁 裝· 、1Τ 經濟部中央標準局員工消費合作社印製(Please read the precautions on the back first to buy)-Packing. 570797 A7 B7 V. Description of the invention Q) Employees of the Central Bureau of Standards of the Ministry of Economy, Consumer Cooperatives, Diabetes Mellitus, and Pharmaceutical Compositions for the Treatment of Diabetes-related Conditions. Contains 2 to 12 mg of the compound in a pharmaceutically acceptable form. The composition of the present invention can be administered from i to 6 times per day, but is preferably 1 or 2 times per day. Therefore, in another aspect, the present invention provides a method for the treatment of diabetes in mammals, such as humans, especially type π diabetes, and conditions associated with diabetes, the method comprising administering 2 to 12% daily to a desired mammal G. Compounds in a pharmaceutically acceptable form①. In particular, the method comprises administering 2 to 4, 4 to 8, or 8 to 12 mg of the compound (1) in a pharmaceutically acceptable form. Specifically, the method includes administering 2 to 4 mg of a compound (I) in a pharmaceutically acceptable form. Specifically, the method includes administering 4 to 8 mg of Compound (I) in a pharmaceutically acceptable form. In particular, the method comprises administering 8 to 12 mg of Compound (I) in a pharmaceutically acceptable form. Still more particularly, the method comprises administering 2 mg of a pharmaceutically acceptable compound (I). Specifically, the method includes administering 4 mg of a pharmaceutically acceptable compound (I). Specifically, the method includes administering 8 mg of a pharmaceutically acceptable compound (I). The range of 2 to 4 mg of y formula includes 2.1 to 4, 2.2 to 4, 2 3 to 4, 2.4 to 4, 2.5 to 4, 2.6 to 4, 2.7 to 4, 2, 8 to 4, 2 9 to 4 (Please read the precautions on the back — I pack | Binding on this page · 12 This paper size applies to Chinese National Standard (CNS) A4 specification (210 × 297 mm) 570797 Α7 Β7 V. Description of the invention) or 3 to 4 mg range . The 4 to 8 mg range includes 4 to §, 4.2 to 8, 4.3 to 8, 4.4 to 8, 4.5 to 8, 4.6 to 8, 4.7 to 8, 4.8 to 8, 4.9 to 8, 5 to 8, 6 to 8, or 7 to 8 mg range. The range of 8 to 12 mg includes 8 丨 to 12, 8 2 to 12, 8 3 to 12, 8 · 4 to 12, 8.5 to 12, 8.6 to 12, 8.7 to 12, 8.8 to 12, 8.9 to 12, 9 to 12, 10 to 12, or Π to 12 mg range. Within the above-mentioned dosage range, the composition or method of the present invention does not form an adverse toxic effect. The following examples are provided for illustration and are not intended to limit them in any way. Please read the notes on the back page first, printed by 1T, printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs
3 IX 本紙張尺度適用?( CNS ) Μ祕（210X297公釐〉 570797 ^_I______ 經濟部中央標準局員工消費合作社印製 A7 ______B7 發明説明P ) 實施例丨：濃縮製劑 將大約二分之一的乳糖單水合物通過適當之篩，並與 經輾壓過之化合物(I)之馬來酸鹽摻和。將澱粉羥基乙酸 納、經丙基甲基纖維素、微晶纖維素以及剩餘之乳糖通過 適當之篩，並加入該混合物中。然後持續摻和。之後，將 結果混合物與純水進行溼製粒。然後將溼顆篩選出，於 流化床乾燥器上乾燥，並將乾燥顆粒通過另外之筛，並於 最後勻化。 粒狀濃縮物之組成％ 成分 含量(％) 輾壓化合物(I)成馬來酸鹽 13.25 (純馬來酸鹽） 澱粉羥基乙酸鈉 5‘0〇 羥丙基甲基纖維素2910 5.00 微晶纖維素 20.0 乳糖單水合物，標準級 至100 純水 氺 *加工期間移除。 實施例2 :調製濃縮物成錠劑 將從實施例1中所得之顆粒置於滾筒摻和機中。將大 約三分之二的乳糖單水合物通過適當之筛，並加至該摻和 機内。將微晶纖維素、澱粉羥基乙酸鈉、硬脂酸鎂以及剩 餘之乳糖通過適當之篩，並加至該摻和機中一併摻和此浪 合物。然後將結果混合物，於旋轉式壓片機中壓縮成用於 14 本紙張尺度適用中國國家標準（CNS >A4規格（210x297公釐） 570797 A7 B7 五、發明説明 請 先 閱 讀 背 面 之 注 1、2和4毫克錠劑中之150毫克靶重，以及用於8毫克 錠劑中之300毫克革巴重。 然後，將錠劑核心轉移至錠劑塗層機中，以暖空氣（大 約65°C )預熱，並塗膜至該錠劑重量增加2.0%至3.5%。 含量（每錠劑毫克數） 錠劑強度 1 Π惠古· 2.0亳克 4.G毫克 毫克 活性成分： 化合物(I)馬來酸鹽》展縮狗顆粒 10.00 20.00 40.00 80.00 其他成分： 澱粉羥基乙酸鈉 6.96 6.46 5.46 10.92 微晶纖維素 27.85 25.85 21.85 43.70 乳糖單水合物 104.44 96.94 81.94 163.88 硬脂酸鎂 0.75 0.75 0.75 1.50 4vjT «·> 150.0 150.0 150.0 300.0 水性塗膜物質 4.5 4.5 4.5 9.0 被娱楚#總重 154.5 154.5 154.5 309.0 項 經濟部中央標準局員工消費合作社印製 15 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）3 IX This paper size is applicable? (CNS) M secret (210X297 mm> 570797 ^ _I ______ Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 ______B7 Invention Description P) Example 丨: The concentrated preparation will be about one half of lactose The monohydrate is passed through a suitable sieve and blended with the maleate salt of the rolled compound (I). Sodium starch glycolate, passed through propylmethyl cellulose, microcrystalline cellulose, and the remaining lactose were passed through a suitable sieve and added to the mixture. Then continue blending. Thereafter, the resulting mixture was subjected to wet granulation with pure water. The wet granules are then sieved out, dried on a fluid bed dryer, and the dried granules are passed through another sieve, and finally homogenized. Composition% of granular concentrate Ingredient content (%) Rolled compound (I) into maleate 13.25 (pure maleate) Starch sodium glycolate 5'0〇hydroxypropylmethyl cellulose 2910 5.00 Microcrystalline Cellulose 20.0 Lactose monohydrate, standard grade to 100 pure water 氺 Removed during processing. Example 2: Preparation of Concentrates into Lozenges The granules obtained from Example 1 were placed in a roller blender. About two-thirds of the lactose monohydrate was passed through a suitable sieve and added to the blender. Microcrystalline cellulose, sodium starch glycolate, magnesium stearate, and the remaining lactose were passed through a suitable sieve, and added to the blender to blend the prodrug. The resulting mixture is then compressed in a rotary tablet press for use in 14 paper sizes that comply with Chinese national standards (CNS > A4 size (210x297 mm) 570797 A7 B7. V. Description of the invention Please read Note 1 on the back first. 150 mg target weight in 2 and 4 mg tablets, and 300 mg gaba weight for 8 mg tablets. Then transfer the tablet cores to the tablet coating machine with warm air (approximately 65 ° C) Preheating and coating until the weight of the lozenge is increased by 2.0% to 3.5%. Content (mg per lozenge) Strength of lozenge 1 Π Huigu · 2.0 g 4.G mg mg Active ingredient: Compound (I ) Maleate ”Expanded Dog Granules 10.00 20.00 40.00 80.00 Other Ingredients: Sodium Starch Glycolate 6.96 6.46 5.46 10.92 Microcrystalline Cellulose 27.85 25.85 21.85 43.70 Lactose Monohydrate 104.44 96.94 81.94 163.88 Magnesium Stearate 0.75 0.75 0.75 1.50 4vjT «· ≫ 150.0 150.0 150.0 300.0 Water-based coating material 4.5 4.5 4.5 9.0 Being entertainment Chu #Total weight 154.5 154.5 154.5 309.0 Items 15 paper rulers printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Degree applies to Chinese National Standard (CNS) A4 specification (210X297 mm)