TW201249440A

TW201249440A - Doxylamine resinate complex

Info

Publication number: TW201249440A
Application number: TW101109375A
Authority: TW
Inventors: Cot Jordi Font; Aldea Albert Falivene; Ranzani Luis Soler; Pujals Gemma Casadevall
Original assignee: Esteve Labor Dr
Priority date: 2011-03-18
Filing date: 2012-03-19
Publication date: 2012-12-16

Abstract

The invention refers to a new doxylamine resinate complex comprising doxylamine bound to a weakly acidic synthetic cation exchange resin, such as a copolymer of methacrylic acid and divinylbenzene The invention discloses a process for its preparation which comprises contacting a weakly acidic synthetic cation exchange resin with doxylamine or a pharmaceutically acceptable salt thereof and its use for the preparation of pharmaceutical compositions, such as chewable tablets or oral disintegrating tablets of immediate release. Further the invention refers to the doxylamine resinate complex for use as a medicament, preferably as a medicament for use in the treatment of occasional insomnia.

Description

201249440 六、發明說明：【發明所屬之技術領域】本發明係關於在杜西拉明與合成弱酸性陽離子交換樹脂之間形成的杜西拉明樹脂酸鹽複合物、其製備方法及其作為治療偶爾失眠之藥劑的用途。本發明亦係關於包含該杜西拉明樹脂酸鹽複合物之醫藥調配物，例如口服醫藥調配物p 【先前技術】杜西拉明係基於乙醇胺之抗組胺劑，其用於管理失眠且與鎮咳劑及減充血劑組合用於緩解咳嗽及感冒症狀。其亦與止痛劑撲熱息痛（paracetamol)(乙酿胺紛）及可待因 (codeine)作為止痛劑/鎮痛劑製劑組合使用，且指定與維生素Be (吡哆醇）組合以預防孕婦晨吐。杜西拉明之化學名稱為（凡二甲基_2_(丨-苯基_丨_(吡咬-2-基）乙氧基）乙胺，其具有下式：201249440 VI. Description of the Invention: [Technical Field] The present invention relates to a dusimamine resin salt complex formed between ducisamine and a synthetic weakly acidic cation exchange resin, a preparation method thereof and a treatment thereof The use of occasional insomnia medications. The present invention is also directed to a pharmaceutical formulation comprising the duzolamamine resinate complex, such as an oral pharmaceutical formulation p. [Prior Art] Duzolamamine is an ethanolamine-based antihistamine for managing insomnia and Used in combination with antitussive and decongestants to relieve cough and cold symptoms. It is also used in combination with the analgesic paracetamol (paracetamol) and codeine as an analgesic/analgesic formulation, and is specified in combination with vitamin Be (pyridoxine) to prevent morning sickness in pregnant women. The chemical name of Dusilamin is (where dimethyl 2-(?-phenyl-indole-(pyridin-2-yl)ethoxy)ethylamine has the formula:

杜西拉明杜西拉明可作為生理上可接夸上# a A上王工接又之鹽、尤其作為琥珀酸鹽自市售購得。杜西拉明琥酸鹽之一個問Bg # > _ ^個問碭其尚吸濕性（易潮解），此 I63202.doc 201249440 可導致需要特別製造條件或難以長時間保持劑型之性質。杜西拉明琥拍酸鹽亦具有與—些醫藥賦形劑（例如阿斯巴甜（aspartame))之不相容性的缺點，此會導致含有其之醫藥製劑之降格及雜質增加。杜西拉明琥珀酸鹽固有地具有苦味，且此構成又一缺點，尤其在調配某些類型之口服製劑時。就此而言，眾所周知，若給患者所開處方的口服味道尤其令人不快則患者可能完不成必需療程。苦味可藉助使用甜味劑及/或矯味劑或脂質包衣來遮蔽，但其並不令人滿意，且不令人不快之後味仍可維持於口内。出於該等原因，杜西拉明琥珀酸鹽之口服調配物目前並不完全令人滿意。已闡述遮蔽與原料藥相關之苦味的各種方法，包括使用離子交換樹脂。亦已揭示離子交換樹脂作為手段用於提供具有受控或持續釋放性質之口服調配物。就此而言，w〇 92/u〇38 (Richarson-Vicks公司）揭示口服醫藥製劑，其包含結合至陽離子交換樹脂之藥理學活性多胺藥物，以提供藥物含量大於每當量陽離子交換能力1當量胺之藥物_樹脂複合物，該複合物在胃腸道中遇到之條件下提供藥物之可控釋放 (所結合超過1當量之多胺藥物之立即釋放及剩餘多胺藥物之較緩慢釋放）。所用陽離子交換樹脂安伯萊特 69(Amberlite IRP 69)係源自苯乙烯與二乙烯基苯之磺化共聚物的強酸性陽離子樹脂。【發明内容】 163202.doc 201249440 根據上文所述，欲藉由本發明解決之問題係提供杜西拉明之克服上述缺點中之至少一部分的新穎藥物形式。因此，將期望發現杜西拉明之與賦形劑更相容且可口的新賴藥物形式，其亦可較便利地用於在水性環境中較快或 , 立即釋放之醫藥調配物。因此，本發明之目標之一係藉由 - 提供杜西拉明之新穎藥物形式來改良杜西拉明之釋放速率，該等形式可快速遞送杜西拉明且產生較快速治療起始本發明之另一目標係提供杜西拉明之具有較小吸濕性的新穎藥物形式。就此而言，本發明者現已發現，可在杜西拉明與合成弱酸性陽離子交換樹脂之間形成複合物，以提供杜西拉明樹脂酸鹽複合物。與杜西拉明琥珀酸鹽相比，杜西拉明樹脂酸鹽複合物在與一些醫藥上可接受之賦形劑組合時令人驚奇地呈現降低之吸濕性及改良之穩定性，此因此會產生杜西拉明之更穩定之藥物形式。此外，樹脂酸鹽複合物呈現更易於經口投與之優點，此乃因其實質上不含與杜西拉明琥珀酸鹽相關之苦味。 , 【實施方式】在第一態樣中’本發明係關於杜西拉明樹脂酸鹽複合 * ’物’下文稱為本發明之樹脂酸鹽複合物，其包含結合至弱酸性合成陽離子交換樹脂之杜西拉明。原則上’可使用呈現羧基之任何弱酸性合成陽離子交換樹脂來製備杜西拉明樹脂酸鹽複合物，只要其係醫藥可接受的°較佳弱酸性合成陽離子交換樹脂係聚丙烯酸系共聚 I63202.doc 201249440 物及曱基丙烯酸與二乙烯基苯之共聚物，其中後者較佳，其可根據業内習知方法合成或自市面購得^適用於本發明樹脂酸鹽複合物之樹脂的實例係安伯萊特IRp64、安伯萊特IRP88、安伯萊特IRC86及安伯萊特IR(：76 (R〇hm及Dusilamin Dusitamine can be used as a physiologically acceptable salt on the # a A, especially as succinate. One of the sirolimus succinates is Bg # > _ ^ 砀砀尚尚尚尚尚 I I I I I I I I I I I I I I I I I I 494 494 494 494 494 494 494 494 494 494 494 494 494 494 494 494 494 494 494 Duzolamidine has also been disadvantageous in incompatibility with some pharmaceutical excipients such as aspartame, which results in an increase in the deterioration and impurities of the pharmaceutical preparations containing it. Duzolam succinate inherently has a bitter taste and this constitutes a further disadvantage, especially when formulating certain types of oral formulations. In this regard, it is well known that if the oral taste prescribed to a patient is particularly unpleasant, the patient may not be able to complete the necessary course of treatment. Bitterness can be masked by the use of sweeteners and/or flavoring agents or lipid coatings, but it is not satisfactory and can be maintained in the mouth without undue delay. For these reasons, oral formulations of duxiramin succinate are not currently fully satisfactory. Various methods of masking the bitterness associated with the drug substance have been described, including the use of ion exchange resins. Ion exchange resins have also been disclosed as a means for providing oral formulations having controlled or sustained release properties. In this regard, w〇92/u〇38 (Richarson-Vicks) discloses an oral pharmaceutical preparation comprising a pharmacologically active polyamine drug bound to a cation exchange resin to provide a drug content greater than one equivalent of amine per equivalent of cation exchange capacity The drug-resin complex provides controlled release of the drug under conditions encountered in the gastrointestinal tract (immediate release of more than one equivalent of the polyamine drug combined with slower release of the remaining polyamine drug). The cation exchange resin used, Amberlite IRP 69, is a strongly acidic cationic resin derived from a sulfonated copolymer of styrene and divinylbenzene. SUMMARY OF THE INVENTION According to the above, the problem to be solved by the present invention is to provide a novel pharmaceutical form of Dusitamine that overcomes at least some of the above disadvantages. Accordingly, it would be desirable to find a new form of the drug that is more compatible and palatable with excipients, which may also be conveniently used for faster or immediate release pharmaceutical formulations in aqueous environments. Accordingly, one of the objects of the present invention is to improve the release rate of duzolamamine by providing a novel pharmaceutical form of dexiramide, which can rapidly deliver ducisamine and produce a faster therapeutic initiation of the present invention. One goal is to provide a novel drug form of dusiramidine with less hygroscopicity. In this regard, the inventors have now discovered that a complex can be formed between dusiramamine and a synthetic weakly acidic cation exchange resin to provide a dusiramamine resinate complex. The dusilamamine resinate complex surprisingly exhibits reduced hygroscopicity and improved stability when combined with some pharmaceutically acceptable excipients compared to dexsamine succinate. This will result in a more stable form of the drug of dusimamine. In addition, the resinate complex exhibits the advantage of being more easily orally administered because it is substantially free of the bitter taste associated with duzolam succinate. [Embodiment] In the first aspect, the present invention relates to a dexlamethamine resinate composite*'s hereinafter referred to as a resinate complex of the present invention, which comprises binding to a weakly acidic synthetic cation exchange resin. Dusitamine. In principle, a weakly acidic synthetic cation exchange resin exhibiting a carboxyl group can be used to prepare a dusimamine resin salt complex, as long as it is pharmaceutically acceptable, preferably a weakly acidic synthetic cation exchange resin-based polyacrylic copolymer I63202. Doc 201249440 and a copolymer of methacrylic acid and divinylbenzene, wherein the latter is preferred, which can be synthesized according to conventional methods in the art or commercially available as an example of a resin suitable for use in the resinate complex of the present invention. Amber Wright IRp64, Amber Wright IRP88, Amber Wright IRC86 and Amber Wright IR (:76 (R〇hm and

Haas)。下文亦稱為波拉克磷樹脂（polacrilex)之安伯萊特 IRP64係較佳樹脂，其呈現以下化學結構：Haas). Also known as the Amberlite IRP64 based resin of polacrilex, which exhibits the following chemical structure:

已確定本發明樹脂酸鹽複合物中存在之杜西拉明含量且其相對於杜西拉明樹脂酸鹽複合物之總重量佔介於1〇重量 %與55重量。/。之間、較佳介於15重量％與3〇重量％之間。已將杜西拉明複合效率確定為佔介於80。/。與95%之間。在另一態樣中’本發明提供製備本發明之杜西拉明樹脂酸鹽複合物的方法。該方法包含使如上文所揭示之弱酸性合成陽離子交換樹脂與杜西拉明或與其醫藥上可接受之鹽接觸。可根據熟習此項技術者已知之方法（例如分批法或官柱法）來實施結合。在特定實施例中，樹脂酸鹽複合物係藉由分批法製備，該方法包含使先前在水性緩衝溶液中 I63202.doc 201249440 水合之樹脂與杜西拉明或杜西拉明之醫藥上可接受之蹄接觸的步驟。攪拌並維持所得懸浮液直至達成複合平衡。然後將形成之樹脂酸鹽複合物過濾且用蒸餾水洗滌以確保消除未結合之杜西拉明且視情況乾燥，以獲得微細白色粉末。該方法可在25。(：至6(TC之溫度範圍下實施。較佳地，該溫度包含介於4(TC與5(TC之間。結合步驟係在弱酸性合成陽離子交換樹脂之叛基係呈離子形式且杜西拉明經質子化的pH值下實施。因此，在每一情形下，熟習此項技術者可容易地確定pH值。通常’ PH值等於或高於4。樹脂中之流動可交換陽離子可係氫離子（H+)或陽離子，例如鈉 (Na+)、鉀(K+)或銨(NH4+)。在本發明方法之特定實施例中，杜西拉明係以杜西拉明之醫藥上可接受之鹽形式、更特定而言以杜西拉明琥珀酸鹽形式使用。當使用杜西拉明琥珀酸鹽時，杜西拉明號雖酸鹽與弱酸性合成陽離子交換樹脂之所用重量比在1 :丨至 1:5之範圍内。根據USP ΧΧΙΠ槳板法使用usp溶解測試裝置2 (槳板）在 37C及50 rpm下在900 mL 0，1 N HC1中在30分鐘期間確定杜西拉明自添加至釋放介質中之杜西拉明樹脂酸鹽複合物的釋放。杜西拉明自杜西拉明樹脂酸鹽複合物之溶解型態顯示快速釋放，例如，在上述條件下釋放> 85%杜西拉明。杜西拉明自杜西拉明樹脂酸鹽複合物之釋放與杜西拉明琥珀酸鹽之釋放類似，此意味著該樹脂酸鹽複合物提供杜西拉明之立即釋放。 163202.doc 201249440 尤其期望此快速釋放來獲得呈（例如）口服可分散旋劑 (ODT)形式之立即釋放調配物。該等固體劑型係在無水之口中於60秒或更短時間内崩解並溶解之形式。因此，杜西拉明樹脂酸鹽複合物之藥物釋放速率與單獨杜西拉明號王白酸鹽之藥物釋放速率相比可用作是否可製得具有甚至較快釋放型態之藥物調配物之指示，且因此可用於製備有益醫藥產物（參見實例8)。已It由雷射繞射分析儀（Malvern Mastersizer 2000)藉由濕式量測模式來測定杜西拉明樹脂酸鹽複合物之粒徑分佈。根據較佳實施例，定義為體積加權平均值D[4,3]之杜西拉明樹脂酸鹽複合物之粒徑包含介於2〇 μηι與3〇〇 ^爪之間 '較佳介於30 μιη與100 μιη之間。在醫藥組合物之製備中使用本發明之樹脂酸鹽複合物。其係比杜西拉明琥珀酸鹽更穩定之杜西拉明的藥物形式，該杜西拉明琥珀酸鹽係市面上可獲得之杜西拉明之生理上可接受的鹽。本發明之樹脂酸鹽複合物之吸濕性較低且與 -些常見醫藥上可接受之載劑、佐劑或媒劑(通常亦稱為賦形劑）較相容。該等賦形劑之實例係硬脂酸鎮、硬脂酸、聚維酮Κ90、乳糖及阿斯巴甜。因此’在又一態樣中，本發明提供包含本發明樹脂酸鹽複合物之醫藥組合物’下文稱為本發明組合物。本發明組合物進一步包含至少一種醫藥上可接受之賦形劑。本發明醫藥組合物可呈適於藉由任何投與途徑施加或投與人類及/或動物、較佳人類（包括嬰兒 '兒童及成人）的任 I63202.doc 201249440 何形式。該組合物可呈任何劑型且可端視投與途徑而變化貫例尤其包括固體形式（如粉末 '疑劑、丸劑、膠囊等）或液體形式（例如滴劑、溶液、懸浮液、乳液等），其用於口服或局部投與。本發明樹脂酸鹽複合物實質上不含不適口之苦味，且因此其尤其適用於製備用於經口投與之醫藥組合物，此投與途徑通常對於患者之便利性較佳。此外，杜西拉明自如上文所述本發明樹脂酸鹽複合物之快速溶解型態使其適於其在口服立即釋放醫藥調配物中之用途。、本發明組合物可呈經口可投與之含有一或多種生理上相容之賦形劑之組合物形式，其呈固體或液體形式。該組合物可呈任何便利形式，例如口服醫藥劑型’如錠劑、膠囊、菱形錠劑、顆粒、可填充於藥囊或棒狀包裝中之粉末、可0且嚼旋劑、口服可分散錠劑（ODT)或口香糖。該等組合物可含有習用賦形劑，例如結合劑、填充劑、潤滑劑，且亦可含有其他賦形劑（添加劑）叫列#甜味劑、橋味劑及防腐劑。較佳醫藥組合物係口服劑型，更佳為可咀嚼錠劑、口服可分散錠劑(ODT)及填充於藥囊中之粉末。對於多數有鍵劑吞°燕困難之患者（即兒童及老年人）而言，該等醫藥^ 物係便利劑型。在下文中，除非另有明確說明，否則百八比係以相對於醫藥組合物之總重量之重量計。刀在特定實施例中’本發明醫藥組合物包含如上文所定之杜西拉明樹脂酸鹽複合物，其量包含介於1〇重量％至5〇 163202.doc 201249440 重量。/。、較佳ίο重量％至40重量％、最佳1〇重量％至3〇 %之間。本發明醫藥組合物可進一步含有可係業内已知之任何藥理學上可接受之成份的填充劑、崩解劑、結合劑、潤滑劑、甜味劑及矯味劑。填充劑較佳係選自糖醇，如甘露醇、木糖醇、異麥芽酮糖醇（isomalt)、山梨醇、赤藻糖醇 '蔗糖、果糖、右旋糖、海藻糖（trehalose)及磷酸鈣，且更佳係異麥芽酮糖醇或甘露醇亦及來自乳糖家族之填充劑。特定而言，本發明醫藥組合物包含30重量％至80重量。/❶填充劑、較佳4〇重量 %至80重量％填充劑。朋解劑較佳係選自父聯聚維酮（Cr〇SSp〇vid〇ne)、經基乙酸澱粉鈉' 交聯羧曱基纖維素鈉、波拉克林鉀（poucrilin potassium)、預膠凝澱粉、低取代羥基丙基纖維素（L Hpc) 及其混合物。特定而言，本發明醫藥組合物包含3重量％至20重量％崩解劑、較佳4重量％至丨5重量％崩解劑。結合劑較佳係選自微晶纖維素、玉米殿粉、聚乙二醇、經基丙基纖維素（HPC)、羥基丙基曱基纖維素（Hpmc)、聚乙烯基》比洛咬酮、偏矽酸鎂鋁、曱基纖維素及其混合物。特定而言’本發明醫藥組合物包含5重量。/。至5 〇重量％結合劑、較佳7重量％至20重量°/〇結合劑。潤滑劑較佳係選自硬脂基富馬酸鈉、硬脂酸鎖、硬脂酸鈣、滑石粉、親水性發煙二氧化矽 '二山籥酸甘油酯、二硬脂酸甘油酯、山S&基-聚烴氧甘油酯及其混合物。特 163202.doc 201249440 定而言，本發明醫藥組合劑、較佳1重一量二°。·1重量㈣甜味劑較佳係選自阿斯巴糖、斧撼冬資兄拉美（cyclamate)、蔗橄庶糖素、糖精鈉及其混合中品士，〇 ^•敢佳為阿斯巴甜。特 5 ’本發明醫藥組合物包含〇1重量％至5重量❶/〇甜味 W、較佳〇 5重量％至4重量％甜味劑。 ^特定實施例中’本發明醫藥組合物包含如上文所定義 :杜西拉明樹脂酸鹽複合物及至少一種填充劑。特定而 …亥等醫藥組合物包含1〇重量％至5〇重量％杜西拉明樹㈣鹽複合物 '較佳1G重量％至4()重量％杜西拉明樹脂酸 -複口物、最佳10重1%至3〇重量％杜西拉明樹脂酸鹽複 Ml於本發明醫藥組合物中之填充劑之量係介於30重里/〇與80重里。/。之間、較佳介於4〇重量％與重量％之間。在本發明之另一態樣中，醫藥組合物包含10重量％至50 重里/〇杜西拉明樹脂酸鹽複合物、至少3〇%至8〇%之填充劑、3%至20%之至少一種崩解劑、5%至5〇%之至少一種結口劑、0.1%至6%之至少一種潤滑劑、〇 1%至5%之至少— 種甜味劑及0.1%至5%之至少一種矯味劑。水分可影響在最終劑型製造期間粉末之流動及壓縮。亦可影響杜西拉明之最終劑型可咀嚼或〇DT錠劑之儲存及穩定性。為防止與吸濕性原料藥杜西拉明琥珀酸鹽有關之問題’重要的是’具有杜西拉明之新穎藥物形式以保護其免受濕度影響，從而改良杜西拉明醫藥劑型之最終穩定性。由於杜西拉明之新穎藥物形式在與一些常見的醫藥上可 163202.doc 11 201249440 接受之賦形劑組合時，吸濕性較低且更穩定，因此可有利地製造具有簡化包《需要之包含本發明樹脂酸鹽複合物的醫藥劑型。另外，本發明樹脂酸鹽複合物能夠遮蔽與杜西拉明琥珀酸鹽相關之苦味，此在製造口服醫藥劑型、尤其本發明較佳醫藥組合物方面係又一優點。此外，已知濕度可促進某些醫藥活性成份（API)(例如杜西拉明琥珀酸鹽）之結晶形式之變化。結晶形式之變化之此效應可產生不同溶解型態及/或較低穩定性，此進而影響活性成份生物利用度。本發明之樹脂酸鹽複合物可避免杜西拉明琥珀酸鹽之結晶形式之此變化。在另一態樣中，本發明提供製備本發明醫藥組合物之方法。該等組合物可藉由彼等熟習此項技術者已知之習用標準程序（例如彼等於歐洲或美國藥典或類似參考文本中所述者）來製備。本發明錠劑之製備可根據習用製錠技術（例如乾式造粒或濕式造粒及直接壓製）來達成^ 〇DT之製造涉及直接屋製技術。在特定實施例中，製備本發明醫藥組合物之方法包含使用如上文所定義之杜西拉明樹脂酸鹽複合物，其量包含介於10重量°/〇至50重量％、較佳10重量❹/。至40重量❶/。、最佳1〇重量％至30重量。/。之間。在本發明之另一態樣中，製備本發明醫藥組合物之方法包含使用如上文所定義之杜西拉明樹脂酸鹽複合物及至少一種填充劑’該複合物之量包含介於10重量％至5〇重量 163202.doc 12 201249440 /。、較佳ίο重量％至40重量％、最佳ι〇重量％至㈣量％之間。本發明醫藥組合物中與杜西拉明樹脂酸鹽複合物摻和之填充劑的量係介於3()重量％與8〇重量％之間、較佳介於 4〇重量％與80重量％之間。根據特定實施例，將1〇%至5〇%杜西拉明樹脂酸鹽複合物與以下掺和：至少3G%至8。％之填充劑、3%至鳩之至少一種崩解劑、5%至观之至少—種結合劑、q隐㈣之至少-種潤滑劑' 〇.1%至5%之至少一種甜味劑及〇】% 至5%之至少一種矯味劑。在摻和後，壓製摻和產物以達成錠劑。根據本發明之特定實施例，醫藥組合物係呈用於治療偶爾失眠之劑型形式’其包含治療有效量之杜西拉明樹脂酸皿複&物在本發明上下文中，治療有效量應理解為在所 /口療的偶爾失眠之患者中達成益處所必需之量”台療有效量將取决於若干因t ’例如患者之重量及性別、偶爾失眠之厫重程度等。然而，本發明之樹脂酸鹽複合物通常會一天投與一次或多次’其中典型劑量在〇 1 mg/kg/天至2 5 mg/kg/天之範圍内。在另態樣中，本發明提供用作藥劑之本發明杜西拉明樹脂酸鹽複合物。在較佳實施例中，該藥劑係用於治療偶爾失眠。本發明者已實施若干實驗且已證明藉由本發明達成之改良。在一個實驗（參見實例5)中，比較本發明樹脂酸鹽複合 163202.doc •13· 201249440 物（試樣2)之吸濕度與杜西拉明琥珀酸鹽（試樣”之吸濕度》將試樣1與2二者暴露於濕度條件下24小時且質量增加 %之結果顯示於實例5之表2中。可發現，在試樣丨之情形下，吸收足量水而形成液體，而在試樣2中，在實驗後觀察到相同固態外觀。根據實例5中之所述標度，杜西拉明琥珀酸鹽將易潮解，而將杜西拉明波拉克磷樹脂複合物視為具有吸濕性。因此，可推斷，本發明之樹脂酸鹽複合物與杜西拉明琥珀酸鹽相比呈現降低之吸濕性。實施又一實驗以評價與杜西拉明破珀酸鹽相比本發明之樹脂酸鹽複合物相容性（參見實例6)。特定而言，比較杜西拉明波拉克磷樹脂複合物與阿斯巴甜（欲用於口服調配物中之潛在甜味劑賦形劑）之相容性及杜西拉明琥珀酸鹽與相同賦形劑之相容性《藥物·賦形劑相容性研究提供與潛在調配物賦形劑與活性醫藥成份（API)之間之真正且可能之相互作用有關的資訊。製備以下試樣：試樣 ~ 杜西拉明琥珀酸鹽杜西拉明波拉克破樹脂複合物阿斯巴甜杜西拉明琥珀酸鹽:阿斯巴甜(1:1) 杜西拉明波拉克填樹脂複合物:阿斯巴甜(i: i) 且使該等試樣經受不同條件（參見實例6之表2)，其中初始係指實驗開始時試樣之初始狀態或外觀。條件係：在 I63202.doc -14.rs 201249440 40°C下15天，相對濕度為75% ;在5〇°c下15天，在4〇»c下 30天，相對濕度為75% ;及在501下30天。試樣之外觀結果匯總於表3中。可發現，在研究期間在任何條件之後，以下試樣之「白色粉末」之初始外觀不會改變：杜西拉明波拉克磷樹脂複合物、阿斯巴甜及二元混合物杜西拉明波拉克磷樹脂複合物：阿斯巴甜。然而，在 40°C/75% RH下15天後，以及在4(TC/75% RH下30天後，初始外觀為「白色粉末」之試樣杜西拉明琥珀酸鹽及二元混合物杜西拉明琥珀酸鹽：阿斯巴甜變成附著至小瓶之發白濕團塊。然而’在5 (TC下15天或3 0天後，杜西拉明破j白酸鹽之外觀不會改變，且二元混合物杜西拉明琥珀酸鹽：阿斯巴甜略有改變。亦使試樣在初始狀態下及在其經受不同條件後經受超高效液相層析（UPLC)分析。每一試樣之比較層析圖之結果顯不於表4、表5、表6、表7及表8中且對應比較層析圖顯示於圖1至圖5中。關於超高效液相層析（UPLC)分析，有關物質i係在初始產物中業已觀察到之物質’且其量在任一條件下研究之任一試樣的研究期間不會增加（個別阿斯巴甜除外，其不顯示此雜質）。個別杜西拉明琥珀酸鹽（表4)在4〇〇c /75% RH下30天後顯不一定降格，而其他個別試樣，即杜西拉明波拉克磷樹脂複合物及阿斯巴甜，在研究期間不顯示任何降格。容易識別本發明樹脂酸鹽複合物之改良穩定性。 I63202.doc 201249440 關於一元混合物杜西拉明琥珀酸鹽：阿斯巴甜及杜西拉明波拉克墙樹脂複合物：阿斯巴甜，觀察到以下情形。在40°c/75% RH下15天及30天後，杜西拉明琥珀酸鹽：阿斯巴甜（1:1)(表7)顯示杜西拉明琥珀酸鹽組份之一定降格 (參見有關物質2、3、4及5之存在）。亦可觀察到，在 40 C/75% RH下15天及30天後，阿斯巴甜（物質6至9之外觀）可能因平衡而在兩性離子形式與部分離子化形式之間發生轉化。在50°C下15天或30天之研究條件下，杜西拉明琥珀酸鹽：阿斯巴甜（1:1)在研究期間不顯示大的變化。相反，對於二元混合物杜西拉明波拉克磷樹脂複合物：阿斯巴甜（1:1)(表8)而言，在使此試樣經受暴露條件後在研究期間完全未觀察到顯著變化。根據所觀察之結果可推斷，當使試樣暴露於4〇<t /75% RH時，在杜西拉明琥珀酸鹽：阿斯巴甜（1:1)之二元混合物中觀察到賴相互作用，而尤其在杜西拉明波拉克碟樹脂複合物··阿斯巴甜(1:1)之二元混合物中，在賦形劑與本發明之樹脂酸鹽複合物之間未檢測到相互作用。因此，本發明之樹脂酸鹽複合物顯示與一些賦形劑（例如阿斯巴甜）之增加之相容性。因此’本發明之又一態樣提供杜西拉明樹脂酸鹽複合物用於增加杜西拉明之賦形劑相容性的用途。在特定實施例中’賦形劑係選自硬脂酸鎖、硬脂酸、聚維酮K90、乳糖 163202.doc -16- 201249440 及阿斯巴甜。在較佳實施例中，賦形劑係阿斯巴甜。在又一態樣中，本發明提供杜西拉明樹脂酸鹽複合物用於降低杜西拉明之吸濕性的用途。上文用於說明本發明。然而，本發明並不限於以下本文所述之具體實施例，而是涵蓋屬於下文申請專利範圍之範圍内之所有等效修改。實例 t蝌w杜西拉明·波拉克磷樹脂複合物之製備· 使8.72 Kg安伯萊特IRP64在預先加熱至45_5〇〇C2216 [ pH 8磷酸鹽緩衝液中水合45分鐘。將3 49 Kg杜西拉明琥珀酸鹽添加m中且在仏抓τ維持授掉5小時以達成複合平衡（藥物：樹脂比係1:2 5)。藉助離心機過濾懸浮液。用1〇 L蒸餾水洗滌餅狀物且在旋轉乾燥器中在60°C下乾燥。獲得微細白色粉末狀複合物安伯萊特IRpM_杜西拉明’ 其含有1 8·7%杜西拉明游離驗。所得杜西拉明複合效率係90.3%。實例2 .杜西拉明_波拉克磷樹脂口服可分散錠劑. 藉由直接壓製技術來製備含有杜西拉明_安伯萊特lRp64 複。物之口服崩解錠劑。將杜西拉明·安伯萊特irp料複合物與甘露醇、交聯聚維_(或羥基乙酸澱粉鈉)、微晶纖維素、硬脂基富馬St鈉、阿斯巴甜及續味劑摻和在一起。 I63202.doc 201249440 壓製經摻和產物以達成具有以下組成之錠劑。 % (w/w) 杜西拉明-波拉克磷樹脂複合物 25.0 甘露醇 50.0 微晶纖維素 14.5 交聯聚維酮 7.0 硬脂基富馬酸鈉 1.5 阿斯巴甜 1.0 橋味劑 1.0 實例3 :杜西拉明-波拉克磷樹脂口服可分散錠劑· 藉由直接壓製技術來製備含有杜西拉明-安伯萊特IRP64 複合物之口服崩解錠劑。將杜西拉明-安伯萊特IRP64複合物與甘露醇、交聯聚維酮（或羥基乙酸澱粉鈉）、檸檬酸單水合物、硬脂基富馬酸鈉、氧化鐵（III)、阿斯巴甜及矯味劑摻和在一起。壓製經摻和產物以達成具有以下組成之錠劑。 % (w/w) 杜西拉明-波拉克磷樹脂複合物 14.47 甘露醇 74.98 交聯聚維酮 6.0 轉檬酸單水合物 0.5 硬脂基富馬酸鈉 2.0 氧化鐵(III) 0.15 阿斯巴甜 1.0 端味劑 0.9 163202.doc -18- rs 201249440 實例4.杜西拉明_波拉克鱗樹脂複合物可吸嚼鍵劑. 藉由直接壓製技術來製備含有杜西拉明·安伯萊特IRp64 複合物之可咀嚼錠劑。將杜西拉明-安伯萊特IRP64複合物與可溶性異麥芽酮糖醇、聚乙二醇、硬脂基富馬酸鈉、阿斯巴甜及矯味劑摻和在一起。壓製經摻和產物以達成錠劑0 壓製經摻和產物以達成具有以下組成之錠劑： % (w/w) 杜西拉明-波拉克磷樹脂複合物 25.0 異麥芽_糖酵 63.5 聚乙二醇 8.0 硬脂基富馬酸鈉 1.5 阿斯巴甜 1.0 矯味劑 1.0 實例S:本發明之杜西拉明琥珀酸鹽及杜西拉明波拉克磷樹脂複合物之吸濕度的測定：該實驗之目標係量測杜西拉明波拉克磷樹脂複合物之吸濕度並比較其與杜西拉明琥珀酸鹽中之一者。計算質量增加百分比以評價試樣中水之吸附。根據歐洲藥典 6.0 中之「5.11 Characters section in monographs」，基於在80士2%相對濕度及25：U°C下暴露24 小時後物質之質量增加百分比來界定物質之吸濕度。結果解釋如下： 163202.doc 201249440 表1.有關吸濕性之物質之分類質量增加百分比吸濕度 △<0.2% 不吸濕 0.2%<Δ<2% 微吸濕 2%<Δ<15°/〇吸濕 15%<Δ 極吸濕溶於水中易潮解材料及方法：動態蒸氣吸附（DVS)分析係經專門設計用於提供與相對濕度及T°C變化之材料反應有關之資訊的技術。使用來自 TA Instruments之Q5000 SADVS設備來運行實驗。程式經組態以在25°C及80%RH下將分析運行24 h。使先前程式在60°C下運行直至達成試樣之恆定重量以開始用乾燥試樣進行分析。所分析試樣係· 試樣1 :杜西拉明琥珀酸鹽粉末（藥物）試樣2 :杜西拉明波拉克磷樹脂複合物粉末（藥物：樹脂複合物）結果：控制重量之變異且計算以下百分比： Δ重量 ο/ο^Ρη-ΡΟ/ΡγΙΟΟ 其中：Pi係初始重量，Ρη係針對試樣所量測之重量。所得結果匯總於下表中： 163202.doc -20- rs 201249440 表2 :質量增加％之結果試樣 △ 24 1|重量％試樣1 29-30% 試樣2 10.0-15.0% 在試樣1之情形下，吸收足量水而形成液體。在試樣2 中，在實驗後觀察到相同固態外觀。根據上述標度，杜西拉明琥珀酸鹽將易潮解，而將杜西拉明波拉克磷樹脂複合物視為吸濕。實例6:藥物-賦形劑相容性研究該研究之目標係量測杜西拉明波拉克磷樹脂複合物與阿斯巴甜（欲用於口服調配物卡之潛在甜味劑賦形劑）之相容性並比較其與杜西拉明琥珀酸鹽與相同賦形劑之相容性。藥物-賦形劑相容性研究提供與潛在調配物賦形劑與API 之間之真正且可能之相互作用有關的資訊。材料及方法：試樣在合適小瓶（每一試樣，5個小瓶）中準確地稱量足量個別物質及二元混合物。所製備之試樣列示於下表中：表1.所製備用於藥物：賦形劑相容性研究之試樣試樣量ΛΙ、瓶杜西拉明琥珀酸鹽 50 mg 杜西拉明波拉克磷樹脂複合物 180 mg* 阿斯巴甜 50 mg 杜西拉明琥珀酸鹽:阿斯巴甜(1:1) 50+50 mg 杜西拉明波拉克磷樹脂複合物：阿斯巴甜(1:1) 180*+180 mg I63202.doc 21 201249440 存在於18 0 m g杜西拉明波拉克攝樹脂複合物之活性物質的量約等效於存在於50 mg杜西拉明琥珀酸鹽中之活性物質的量。儲存及分析使用該等小瓶中之一者進行初始分析，將2個封口小瓶置於50°C烘箱中且將其他2個（開口小瓶，以使濕度之效應最大化）置於4(TC/75% RH之人工氣候室中。在研究期間測試外觀、活性物質分析及有關物質（UPLC)。儲存及分析頻率匯總於下表中：表2.儲存及分析頻率The dusilamamine content present in the resinate complex of the present invention has been determined to be between 1% by weight and 55 parts by weight based on the total weight of the duzolamin resinate complex. /. Between, preferably between 15% by weight and 3% by weight. Dusamine's composite efficiency has been determined to be between 80. /. Between 95%. In another aspect, the invention provides a method of preparing a duxramine resin complex of the invention. The method comprises contacting a weakly acidic synthetic cation exchange resin as disclosed above with dusimamine or a pharmaceutically acceptable salt thereof. The binding can be carried out according to methods known to those skilled in the art, such as batch or column methods. In a particular embodiment, the resinate complex is prepared by a batch process comprising pharmaceutically acceptable hydration of the resin previously hydrated with I63202.doc 201249440 in an aqueous buffer solution with duzolam or durazine. The steps of the hoof contact. The resulting suspension was stirred and maintained until a complex equilibrium was achieved. The formed resinate complex is then filtered and washed with distilled water to ensure elimination of unbound dusimamine and, if appropriate, drying to obtain a fine white powder. The method can be at 25. (: to 6 (the temperature range of TC is implemented. Preferably, the temperature is comprised between 4 (TC and 5 (TC). The bonding step is in the ionic form of the weakly acidic synthetic cation exchange resin. Simalamin is carried out at a protonated pH. Thus, in each case, the pH can be readily determined by those skilled in the art. Typically, the pH is equal to or higher than 4. The flowable exchangeable cations in the resin can be Hydrogen ion (H+) or cation, such as sodium (Na+), potassium (K+) or ammonium (NH4+). In a particular embodiment of the method of the invention, the exoramamine is pharmaceutically acceptable as dusilamamine. The salt form, more specifically in the form of dusiramamine succinate, when using dusiramidine succinate, the weight ratio of the excipitin and the weakly acidic synthetic cation exchange resin is 1 : 丨 to 1:5. According to USP ΧΧΙΠ paddle method using usp dissolution test device 2 (paddle plate) at 37C and 50 rpm in 900 mL 0,1 N HC1 during 30 minutes to determine dusiramamine Release from the dusiuramin resinate complex added to the release medium. Dusila The dissolution profile from the exomethamine resinate complex shows rapid release, for example, release under the above conditions > 85% dusilamamine. Release of dusilamamine from dusiramamine resinate complex Similar to the release of duzolam succinate, this means that the resinate complex provides immediate release of duzolam. 163202.doc 201249440 This rapid release is particularly desirable to obtain, for example, an orally dispersible rotatory agent ( An immediate release formulation in the form of ODT). These solid dosage forms are in the form of a disintegration and dissolution in a mouth of no water in 60 seconds or less. Therefore, the drug release rate of the dusiramamine resinate complex is separate The drug release rate of Dusilamin will be compared to an indication of whether a pharmaceutical formulation with even a faster release profile can be made, and thus can be used to prepare a beneficial pharmaceutical product (see Example 8). It has been determined by a laser diffraction analyzer (Malvern Mastersizer 2000) by means of a wet measurement mode to determine the particle size distribution of the dusimamine resin salt complex. According to a preferred embodiment, it is defined as volume weighting. The particle size of the Dusilamin resinate complex of the mean D[4,3] is comprised between 2〇μηι and 3〇〇^ claws, preferably between 30 μηη and 100 μηη. The resinate complex of the present invention is used in the preparation. It is a more stable form of the drug of duxiramin than the simiramine succinate, which is commercially available on the market. A physiologically acceptable salt of lamamine. The resinate complex of the present invention has a low hygroscopicity and is compatible with some commonly pharmaceutically acceptable carriers, adjuvants or vehicles (also commonly referred to as excipients). More compatible. Examples of such excipients are stearic acid, stearic acid, povidone 90, lactose and aspartame. Thus, in yet another aspect, the present invention provides a pharmaceutical composition comprising a resinate complex of the present invention hereinafter hereinafter referred to as a composition of the present invention. The compositions of the present invention further comprise at least one pharmaceutically acceptable excipient. The pharmaceutical composition of the present invention may be in any form suitable for application or administration to humans and/or animals, preferably humans (including infants 'children and adults') by any route of administration, in the form of I63202.doc 201249440. The composition may be in any dosage form and may vary depending on the route of administration, including in solid form (eg, powder 'suspect, pill, capsule, etc.) or liquid form (eg, drops, solutions, suspensions, emulsions, etc.). It is used for oral or topical administration. The resinate complex of the present invention is substantially free of unpleasant bitterness and is therefore particularly suitable for the preparation of pharmaceutical compositions for oral administration, which is generally preferred for patient convenience. Furthermore, the rapid dissolution profile of the sirolimus of the present invention from the above-described resinate complexes makes it suitable for its use in oral immediate release pharmaceutical formulations. The compositions of the present invention may be in the form of a composition which is orally administered with one or more physiologically compatible excipients, either in solid or liquid form. The composition may be in any convenient form, such as an oral pharmaceutical dosage form such as a troche, a capsule, a lozenge, a granule, a powder that can be filled in a sachet or a stick package, a 0 and a chewable, an orally dispersible ingot. Agent (ODT) or chewing gum. These compositions may contain conventional excipients such as binders, fillers, lubricants, and may also contain other excipients (additives) such as #甜甜剂, bridge flavor, and preservative. The preferred pharmaceutical composition is an oral dosage form, more preferably a chewable tablet, an orally dispersible tablet (ODT), and a powder filled in a sachet. For most patients (ie children and the elderly) who have difficulty in swallowing, these medicines are convenient dosage forms. In the following, the octave ratio is based on the total weight of the pharmaceutical composition, unless otherwise specifically stated. Knife In a particular embodiment, the pharmaceutical composition of the present invention comprises a dusiramamine resinate complex as defined above in an amount comprised between 1% by weight and 5〇 163202.doc 201249440 by weight. /. Preferably, it is between 5% by weight and 40% by weight, preferably between 3% and 3% by weight. The pharmaceutical compositions of the present invention may further comprise fillers, disintegrating agents, binding agents, lubricating agents, sweetening agents and flavoring agents which may be any of the pharmaceutically acceptable ingredients known in the art. Preferably, the filler is selected from the group consisting of sugar alcohols such as mannitol, xylitol, isomalt, sorbitol, erythritol 'sucrose, fructose, dextrose, trehalose and Calcium phosphate, and more preferably isomalt or mannitol, is also a filler from the lactose family. In particular, the pharmaceutical composition of the present invention comprises from 30% by weight to 80% by weight. / ❶ filler, preferably 4% by weight to 80% by weight of filler. Preferably, the phlegm agent is selected from the group consisting of crospovidone (Cr〇SSp〇vid〇ne), sodium starch acetate, croscarmellose sodium, poucrilin potassium, pregelatinization. Starch, low substituted hydroxypropyl cellulose (L Hpc) and mixtures thereof. In particular, the pharmaceutical composition of the present invention comprises from 3% by weight to 20% by weight of a disintegrant, preferably from 4% by weight to 5% by weight of a disintegrant. Preferably, the binding agent is selected from the group consisting of microcrystalline cellulose, corn powder, polyethylene glycol, propyl propyl cellulose (HPC), hydroxypropyl fluorenyl cellulose (Hpmc), polyvinyl bisperrone , magnesium bismuth citrate, sulfhydryl cellulose and mixtures thereof. Specifically, the pharmaceutical composition of the present invention contains 5 parts by weight. /. Up to 5 % by weight of binder, preferably 7 % by weight to 20 % by weight of binder. The lubricant is preferably selected from the group consisting of sodium stearyl fumarate, stearic acid lock, calcium stearate, talc, hydrophilic fuming cerium dimercapto glyceride, glyceryl distearate, Mountain S& base-polyoxyl glycerides and mixtures thereof. 163202.doc 201249440 In general, the pharmaceutical composition of the present invention preferably has a weight of two. · 1 weight (4) Sweetener is preferably selected from the group consisting of aspartame, axe, cyclamate, sugar cane, sodium saccharin, and their blends. 〇^•敢佳为阿斯巴sweet. The pharmaceutical composition of the present invention comprises from 1% by weight to 5% by weight of ❶/〇 sweetness W, preferably from 5% by weight to 4% by weight of a sweetener. In a particular embodiment, the pharmaceutical composition of the invention comprises as defined above: a dusimamine resinate complex and at least one filler. Specifically, the pharmaceutical composition such as hai contains 1% by weight to 5% by weight of the cecilamine tree (tetra) salt complex' preferably 1G% by weight to 4% by weight of cecilramin resin-partition, most Preferably, the amount of the filler in the pharmaceutical composition of the present invention is between 30% by weight and 3% by weight. /. Between, preferably between 4% by weight and between% by weight. In another aspect of the present invention, the pharmaceutical composition comprises 10% by weight to 50% by weight of hydrazolamine resinate complex, at least 3% to 8% by weight of filler, and 3% to 20% by weight. At least one disintegrant, 5% to 5% by weight of at least one mouthing agent, 0.1% to 6% of at least one lubricant, 〇1% to 5% of at least one sweetener, and 0.1% to 5% At least one flavoring agent. Moisture can affect the flow and compression of the powder during the manufacture of the final dosage form. It can also affect the storage and stability of the final dosage form of dusiramamine for chewable or 〇DT tablets. In order to prevent the problems associated with the hygroscopic drug durazine succinate, it is important to have a novel pharmaceutical form of dusiramamine to protect it from humidity, thereby improving the ultimate stability of the pharmaceutical dosage form of dusiramidine. Sex. Since the novel pharmaceutical form of duzolamin is less hygroscopic and more stable when combined with excipients accepted in some common medicines, 163202.doc 11 201249440, it can be advantageously manufactured with a simplified package. A pharmaceutical dosage form of the resinate complex of the present invention. Further, the resinate complex of the present invention is capable of masking the bitter taste associated with dusiramin succinate, which is a further advantage in the manufacture of oral pharmaceutical dosage forms, especially the preferred pharmaceutical compositions of the present invention. In addition, it is known that humidity promotes changes in the crystalline form of certain pharmaceutically active ingredients (APIs) such as duzolam succinate. This effect of a change in the crystalline form can result in different dissolution patterns and/or lower stability, which in turn affects the bioavailability of the active ingredient. The resinate complex of the present invention avoids this change in the crystalline form of duxylamine succinate. In another aspect, the invention provides a method of preparing a pharmaceutical composition of the invention. Such compositions may be prepared by conventional standard procedures known to those skilled in the art (e.g., as described in the European or U.S. Pharmacopoeia or similar reference text). The preparation of the tablet of the present invention can be carried out according to conventional tableting techniques (e.g., dry granulation or wet granulation and direct compression). The manufacture of 〇DT involves direct housekeeping techniques. In a particular embodiment, a method of preparing a pharmaceutical composition of the invention comprises using a dusimamine resinate complex as defined above, in an amount comprising from 10 weight percent to about 50 weight percent, preferably 10 weight percent ❹/. Up to 40 weights /. , preferably 1% by weight to 30% by weight. /. between. In another aspect of the invention, a method of preparing a pharmaceutical composition of the invention comprises the use of a dusimamine resinate complex as defined above and at least one filler 'the amount of the complex comprising between 10 and 10 weights % to 5〇 weight 163202.doc 12 201249440 /. Preferably, it is between 5% by weight and 40% by weight, preferably between 5% by weight and (%) by weight. The amount of the filler blended with the duzolamin resinate complex in the pharmaceutical composition of the present invention is between 3 ()% by weight and 8% by weight, preferably between 4% by weight and 80% by weight. between. According to a particular embodiment, from 1% to 5% by weight of the cecilramin resinate complex is blended with at least 3G% to 8. % filler, 3% to at least one disintegrant, 5% to at least one binder, q hidden (four) at least one lubricant '〇. 1% to 5% of at least one sweetener And 〇] from at least 5% of at least one flavoring agent. After blending, the blended product is compressed to form a tablet. According to a particular embodiment of the invention, the pharmaceutical composition is in the form of a dosage form for the treatment of occasional insomnia, which comprises a therapeutically effective amount of dusilamamine resin, an acid & medicinal compound, in the context of the present invention, the therapeutically effective amount is understood The amount necessary for achieving a benefit in a patient who is occasionally insomnia in the oral/oral treatment will depend on a number of factors such as the weight and sex of the patient, the severity of the occasional insomnia, etc. However, the present invention The resinate complex is typically administered one or more times a day, where typical dosages are in the range of from 1 mg/kg/day to 25 mg/kg/day. In other aspects, the invention provides for use as a medicament The present invention is a simiramine resin complex. In a preferred embodiment, the agent is used to treat occasional insomnia. The inventors have performed several experiments and have demonstrated improvements achieved by the present invention. Referring to Example 5), comparing the moisture absorption of the resinate composite 163202.doc •13·201249440 (sample 2) of the present invention with the moisture absorption of the exoramamine succinate (sample), sample 1 and 2 both exposed to wet The results of 24 hours and % mass increase are shown in Table 2 of Example 5. It can be found that in the case of the sample, a sufficient amount of water is absorbed to form a liquid, and in the sample 2, it is observed after the experiment. To the same solid appearance. According to the scale described in Example 5, the simiramine succinate will be deliquescent, and the Dusilaramopol resin complex is considered to be hygroscopic. Therefore, it can be inferred that The resinate complex of the present invention exhibits reduced hygroscopicity compared to duramin succinate. A further experiment was performed to evaluate the resinate complex of the present invention compared to the cecilamine chopped acid salt. Compatibility (see Example 6). In particular, compare the compatibility of Dusilamin Polak Phosphate Resin Complex with Aspartame (a potential sweetener excipient to be used in oral formulations) And the compatibility of dusiramidine succinate with the same excipients. The Drugs/Excipient Compatibility Study provides a real and possible mutual interaction with potential formulation excipients and active pharmaceutical ingredients (APIs). Information about the role. Prepare the following sample: Sample ~ Dusilamin Persalamine borax broken resin complex Aspartame Dusilamin succinate: Aspartame (1:1) Dusilamin Polak filled resin complex: Aspartame ( i: i) and subject the samples to different conditions (see Table 2 of Example 6), where the initial means the initial state or appearance of the sample at the beginning of the experiment. Conditions are: I63202.doc -14.rs 201249440 40 At 15 °C for 15 days, the relative humidity is 75%; at 15 °C for 15 days, 30 days at 4〇»c, the relative humidity is 75%; and at 501 for 30 days. The appearance of the sample is summarized in In Table 3, it can be found that the initial appearance of the "white powder" of the following samples does not change after any conditions during the study period: Dusilamin Pollack Phosphorus Resin Complex, Aspartame and Binary Mixture Syramine Polak Phosphate Complex: Aspartame. However, after 15 days at 40 ° C / 75% RH, and after 4 days at TC / 75% RH, the sample with the initial appearance of "white powder" was dusiram succinate and a binary mixture. Dusilamin succinate: Aspartame becomes a white wet mass attached to the vial. However, after 15 days or 30 days under TC, the appearance of Dusilamin breaks the white acid salt. Will change, and the binary mixture of dusiramin succinate: a slight change in aspartame. The sample was also subjected to ultra-high performance liquid chromatography (UPLC) analysis in the initial state and after it was subjected to different conditions. The results of the comparative chromatogram of each sample are not shown in Table 4, Table 5, Table 6, Table 7, and Table 8 and the corresponding comparative chromatograms are shown in Figures 1 to 5. About the ultra-high performance liquid layer Analysis (UPLC) analysis, the substance i is the substance that has been observed in the initial product' and its amount does not increase during the study period of any of the samples studied under any of the conditions (except for individual aspartame, which does not show This impurity). Individual dusiramidine succinate (Table 4) does not necessarily degrade after 30 days at 4〇〇c /75% RH, while other individual samples That is, Dusilalam Pollack Phosphorus Resin Complex and Aspartame did not show any degradation during the study. It is easy to identify the improved stability of the resinate complex of the present invention. I63202.doc 201249440 About the one-component mixture Dusimamin Succinate: Aspartame and Dusilamin Polak Wall Resin Complex: Aspartame, observed as follows. After 10 and 30 days at 40 ° C / 75% RH, Dusimamin Succinate: Aspartame (1:1) (Table 7) shows a certain degradation of the sirolimus succinate component (see the presence of substances 2, 3, 4 and 5). It can also be observed that After 15 days and 30 days at 40 C/75% RH, aspartame (the appearance of substances 6 to 9) may be converted between zwitterionic form and partially ionized form due to equilibrium. At 50 ° C Under the 15-day or 30-day study conditions, dusiramidine succinate: aspartame (1:1) did not show large changes during the study. Conversely, for the binary mixture Dusimalam Polak phosphor Complex: Aspartame (1:1) (Table 8), completely exposed to exposure conditions during the study period Significant changes were observed. Based on the observed results, it can be inferred that when the sample is exposed to 4 〇 < t /75% RH, in the case of duzamine succinate: aspartame (1:1) The iridium interaction was observed in the meta-mixture, especially in the binary mixture of Dusitamine-Poblac resin complex · Aspartame (1:1), in the excipients and the resinate of the invention No interaction was detected between the complexes. Thus, the resinate complex of the present invention showed increased compatibility with some excipients such as aspartame. Thus, yet another aspect of the present invention provides The use of duzolamin resinate complex for increasing the compatibility of excipients of duzolam. In a particular embodiment the 'excipient is selected from the group consisting of stearic acid lock, stearic acid, povidone K90, lactose 163202.doc -16-201249440 and aspartame. In a preferred embodiment, the excipient is aspartame. In still another aspect, the present invention provides the use of a dusimamine resinate complex for reducing the hygroscopicity of duzolam. The above is used to illustrate the invention. However, the invention is not limited to the specific embodiments described herein, but all equivalent modifications within the scope of the following claims. EXAMPLES Preparation of t蝌w Dusimamin Pollack Phosphorus Resin Composite 8. 8.72 Kg of Amberlite IRP64 was hydrated for 45 minutes in a pH 8 phosphate buffer before preheating to 45_5 〇〇 C2216. 3 49 Kg of dexlamethamine succinate was added to m and the iodine was maintained for 5 hours to achieve a complex balance (drug: resin ratio 1:25). The suspension was filtered by means of a centrifuge. The cake was washed with 1 L of distilled water and dried at 60 ° C in a rotary drier. A fine white powdery complex was obtained from Amber Wright IRpM_Dusilamin' which contained 18.7% dexramethamine free test. The resulting duximamine composite efficiency was 90.3%. Example 2. Dusilamin _ Polak Phosphate Oral Dispersible Lozenge. Prepared by direct compression technique to contain dexilamine-Amberlite lRp64 complex. Oral disintegrating tablet. Dusilamin Amberlite irp complex with mannitol, cross-linked poly- _ (or sodium starch glycolate), microcrystalline cellulose, stearyl fumar S, aspartame and continued flavor The agents are blended together. I63202.doc 201249440 The blended product is compressed to achieve a tablet having the following composition. % (w/w) Dusilamin-Polac Phosphate Complex 25.0 Mannitol 50.0 Microcrystalline Cellulose 14.5 Cross-linked Povidone 7.0 Sodium Stearyl Fumarate 1.5 Aspartame 1.0 Bridge Flavor 1.0 Example 3: Dusilamin-Polac Phosphate Orally Dispersible Lozenges • An orally disintegrating tablet containing a Dusilamin-Amberlite IRP64 complex was prepared by a direct compression technique. Adding citrusol-Amberlite IRP64 complex with mannitol, crospovidone (or sodium starch glycolate), citric acid monohydrate, sodium stearyl fumarate, iron (III) oxide, The spartan and flavoring agents are blended together. The blended product is compressed to achieve a tablet having the following composition. % (w/w) Dusilamin-Polac Phosphate Complex 14.47 Mannitol 74.98 Cross-linked Povidone 6.0 Citric Acid Monohydrate 0.5 Stearyl Fumarate 2.0 Iron Oxide (III) 0.15 Aspen Batian 1.0 Terminal Flavor 0.9 163202.doc -18- rs 201249440 Example 4. Dusimamin _ Polak scale resin composite chewable bond. Preparation by the direct compression technique containing Dusilamin Amber A chewable lozenge of Wright IRp64 Complex. The Dusilamin-Amberlite IRP64 complex is blended with soluble isomalt, polyethylene glycol, sodium stearyl fumarate, aspartame and flavoring agents. The blended product is compressed to achieve tablet 0. The blended product is compressed to achieve a tablet having the following composition: % (w/w) Dusilamin-Polac Phosphate Complex 25.0 Isomalt-Brucrose 63.5 Poly Ethylene glycol 8.0 sodium stearyl fumarate 1.5 Aspartame 1.0 Flavoring agent 1.0 Example S: Determination of moisture absorption of the sirolimus succinate and Dusilamin Polak phosphor resin complex of the present invention: The objective of this experiment was to measure the moisture absorption of the Dusimalam Pollack Phosphorus Resin Complex and compare it to one of the simiramine succinates. The mass increase percentage was calculated to evaluate the adsorption of water in the sample. According to "5.11 Characters section in monographs" in the European Pharmacopoeia 6.0, the moisture absorption of a substance is defined based on the percentage increase in mass of the substance after exposure to 80 ° 2% relative humidity and 25: U ° C for 24 hours. The results are explained as follows: 163202.doc 201249440 Table 1. Classification of substances related to hygroscopicity. Mass increase percentage moisture absorption Δ < 0.2% non-hygroscopic 0.2% < Δ < 2% micro moisture absorption 2% < Δ < 15 °/〇Hydraulic 15%<Δ Moisture Soluble Materials Decomposed in Water and Methods: Dynamic Vapor Sorption (DVS) analysis is designed to provide information on material reactions that are subject to changes in relative humidity and T°C. Technology. The experiment was run using a Q5000 SADVS device from TA Instruments. The program was configured to run the analysis for 24 h at 25 ° C and 80% RH. The previous program was run at 60 ° C until a constant weight of the sample was reached to begin the analysis with the dried sample. Analytical sample system · Sample 1: Dusilamin succinate powder (drug) Sample 2: Dusilamin Polak phosphor resin composite powder (drug: resin composite) Result: Control the variation of weight and Calculate the following percentages: Δweight ο/ο^Ρη-ΡΟ/ΡγΙΟΟ where: Pi is the initial weight and Ρη is the weight measured for the sample. The results obtained are summarized in the following table: 163202.doc -20- rs 201249440 Table 2: Results of % increase in mass Δ 24 1|% by weight Sample 1 29-30% Sample 2 10.0-15.0% In sample 1 In this case, a sufficient amount of water is absorbed to form a liquid. In Sample 2, the same solid appearance was observed after the experiment. According to the above scale, the simiramine succinate will be deliquescent and the Dusilamin Polak phosphor resin complex will be considered to be hygroscopic. Example 6: Drug-Excipient Compatibility Study The objective of this study was to measure the excipients of Dusimalam Polak Phosphorus Resin and Aspartame (potential sweetener excipients intended for oral formulation cards) Compatibility and comparison of its compatibility with dusimamine succinate with the same excipients. Drug-excipient compatibility studies provide information on the true and possible interactions between potential formulation excipients and API. Materials and Methods: Specimens Accurately weigh enough individual substances and binary mixtures in suitable vials (each sample, 5 vials). The prepared samples are listed in the following table: Table 1. Samples prepared for drug: excipient compatibility study. Samples of sputum, bottle of dusiramamine succinate 50 mg of cecilamine Pollack Phosphate Complex 180 mg* Aspartame 50 mg Duzolam succinate: Aspartame (1:1) 50+50 mg Dusilamin Polak Phosphate Complex: Asparta Sweet (1:1) 180*+180 mg I63202.doc 21 201249440 The amount of active substance present in the 180 mg of Dusimalam Polak resin composite is approximately equivalent to the presence of 50 mg of dusimamine succinic acid. The amount of active substance in the salt. Storage and Analysis Initial analysis was performed using one of the vials, placing 2 sealed vials in a 50 °C oven and placing the other 2 (open vials to maximize the effect of humidity) at 4 (TC/ In the artificial climate chamber of 75% RH. Appearance, active substance analysis and related substances (UPLC) were tested during the study. The storage and analysis frequencies are summarized in the following table: Table 2. Storage and analysis frequency

天數存儲、\^^ 條件初始 15天 30天 50°C烘箱 40〇C/75% RH 結果外觀最初觀察到所有研究試樣均為白色粉末。在研究期間試樣之外觀匯總於下表中： 163202.doc -22- rs 201249440 表3.外觀結果試樣初始 15天 15天 30天 30天 40〇C/75% RH 50°C 40〇C/75% RH 50°C 杜西拉明琥珀白色附著至小瓶之白色附著至小瓶之白色酸鹽粉末發白團塊粉末無色團塊粉末杜西拉明波白色白色白色白色白色拉克磷樹脂複合物粉末粉末粉末粉末粉末阿斯巴甜白色白色白色白色白色粉末粉末粉末粉末粉末杜西拉明琥珀白色粉末附著至小瓶之輕微附附著至小瓶之輕微附酸鹽：阿斯巴發白團塊及一著之白發白團塊及一著之白甜(1:1) 些白色粉末色粉末些白色粉末色粉末杜西拉明波拉克磷樹脂複合白色白色白色白色白色物：阿斯巴甜 (1:1) 粉末粉末粉末粉末粉末分析及有關產物（UPLC) 層析圖中出現之峰（拒絕匹配空白溶液之峰）係藉由面積 %來量化。所得結果匯總於下表中：表4.杜西拉明琥珀酸鹽之比較層析圖面積％值初始 15 天 40°C/75% RH 15 天 50°G 30天40°C/75% RH 30天 50°C 300241 99.70 99.67 99.72 99.53 99.67 有關物質1 0.30 0.33 0.28 0.30 0.30 有關物質2 - _ _· 0.02 __ 有關物質3 攀· 一- 0.09 0.02 有關物質4 一 —— —— 0.06 0.01 163202.doc •23· 201249440 表5‘ 杜西拉明波拉克磷; 封脂複合物之比較層析圖面積％值初ώ T5^m ： .... 30 夭 40eC/75% RH 30 夫 50t 300241 ; ' .'K_. 99.82 99.82 99.82 99.82 99.84 有關杨f i 0.18 0.18 0.18 0.18 0.16 表6.阿斯巴甜之比較層析圖面積％值初始 15 天40eC：775%‘ICH ...' · 15夫知°έ 30夫40°C/75%RH 30 天 50°C 阿斯巴甜 95.26 100.00 100.00 100.00 98.52 有關物質6 4.74 — — — 1.48 奏7.杜西拉明琴珀酸鹽：阿斯巴甜（1:1)之比較層析圖Days Storage, \^^ Conditions Initial 15 Days 30 Days 50°C Oven 40〇C/75% RH Results Appearance All study samples were initially observed as white powder. The appearance of the samples during the study is summarized in the following table: 163202.doc -22- rs 201249440 Table 3. Appearance Results Initial 15 Days 15 Days 30 Days 30 Days 40〇C/75% RH 50°C 40〇C /75% RH 50°C DuSilamin Amber White Attached to Vial White Attached to Vial White Salt Powder White Bulk Powder Colorless Agglomerate Powder Dusilamin Wave White White White White White Lac Phosphate Resin Composite Powder powder powder powder Aspartame white white white white powder powder powder powder powder Dusilamin amber white powder adhered to the vial slightly attached to the vial of slight acid salt: Asparta white agglomerate and one White hair white block and white sweetness (1:1) Some white powder color powder White powder color powder Dusilamin Polak phosphor resin compound white white white white white substance: Aspartame (1 :1) Powder powder powder powder analysis and peaks appearing in the product (UPLC) chromatogram (rejection of the peak matching the blank solution) are quantified by area %. The results obtained are summarized in the following table: Table 4. Comparative chromatogram area of dusimamine succinate % value initial 15 days 40 ° C / 75% RH 15 days 50 ° G 30 days 40 ° C / 75% RH 30 days 50°C 300241 99.70 99.67 99.72 99.53 99.67 Related substances 1 0.30 0.33 0.28 0.30 0.30 Related substances 2 - _ _· 0.02 __ Related substances 3 Climbing · One - 0.09 0.02 Relevant substances 4 One - —— 0.06 0.01 163202.doc •23· 201249440 Table 5' Dusilamin Polak phosphorus; Comparative comparison of the chromatographic area of the lipid-seal complex. Initial value T5^m : .... 30 夭40eC/75% RH 30 Fu 50t 300241 ; .'K_. 99.82 99.82 99.82 99.82 99.84 About Yang fi 0.18 0.18 0.18 0.18 0.16 Table 6. Comparative chromatogram area of Aspartame % value Initial 15 days 40eC: 775% 'ICH ...' · 15 Fuzhi ° έ 30 ° 40 ° C / 75% RH 30 days 50 ° C Aspartame 95.26 100.00 100.00 100.00 98.52 Related substances 6 4.74 — — — 1.48 Playing 7. Dusilamin Cinnamate: Aspartame (1 :1) Comparative chromatogram

I I . νί· -ί,ν：·· I. ·· s - — · 1. ./ -·- - - . :- -/ I 面積°/。值初 15*l〇fc:/75々^Si '' V1. . . i.'.VW . .15 夫 50°c ./ ..'· . .： y . 3〇X40〇C/75%RH 30 天 50〇C 300241 'V:化:. 96.16 94.73 96.34 95.30 96.75 有關gii 0.30 0.26 0.28 0.29 0.29 有關_楚2 • .·· ··,,· *. .**·.·' — 0.05 — 0.08 — 有關擔寶3 — 0.25 — 0.18 — 有關 -- 0.16 — 0.36 0.04 有關寶5 — 1.09 — U6 — 阿斯色甜 3.54 0.14 3.29 0.65 2.59 有闞A質:6 丨..V.. -- 2.94 0.09 1.67 0.32 - - ；' s # 有闢辦7 .Π'；.ν5,：. - . ] -1 ' \ -- 0.22 — 0.18 — 有1_8 — 0.10 — 0.13 — 有關物#9 -- 0.05 — — — 163202.doc •24- rs 201249440 表8.杜西拉明波拉克磷樹脂複合物：阿斯巴甜之比較層析圖面積％值初始 Ϊ5 夫4〇fc/75%RH 4夫解 3〇天 4〇°C/7§¥rH 3b 夫 50t 300241 86.53 89.28 89.14 89.25 89.16 有關物質1 0,15 0.16 0.17 0.16 0.16 阿斯巴甜 13.17 10.40 10.45 10.42 10.51 有關杨質6 0.15 0.15 0.24 0.18 0.17 分析試樣在研究之不同時間點下之層析圖顯示於下圖1 至5中。根據所觀察之結果可推斷，當使試樣暴露於4〇〇c /75〇/〇 RH時，在杜西拉明琥珀酸鹽：阿斯巴甜（1:1)之二元混合物中觀察到明顯相互作用，而尤其在杜西拉明波拉克磷樹脂複合物：阿斯巴甜（1:1)之二元混合物中，在賦形劑與本發明之樹脂酸鹽複合物之間未檢測到相互作用。因此，本發明之樹脂酸鹽複合物顯示與一些賦形劑（例如阿斯巴甜）之增加之相容性。實例7 :粉末X射線繞射（PXRD):(參見圖6、7及8) · 使用兩種聚乙酸酯镇在標準試樣架中製備約2〇爪§試樣。在D8 Advance系列2Θ/Θ粉末繞射系統上使用cuKal_輻射以透射幾何學獲得粉末繞射圖案。該系統配備有 VANTEC-1單光子計數PSD、鍺單色儀、9〇位自動變換器試樣台、固定發散狹縫及徑向索勒（radial s〇1丨er)狹縫。所用程式用 DIFFRAC plus XRD Commander V.2.4.1 收集數 I63202.doc -25· 201249440 據且用EVA V· 12.0評價。在4。至40。之範圍内之2Θ内以20 min掃描量測試樣（參見圆6、7及8)。收集杜西拉明琥珀酸鹽、樹脂安伯萊特IRP64及杜西拉明樹脂酸鹽複合物之 PXRD圖案。表9 :藉由杜西拉明琥珀酸鹽之粉末X射線繞射獲得之所選峰的列表（參見圖6)。 d-值(人）角度2Θ1 相對強度 % d-值(A) 角度2Θ1 相對強度 % 8.18 10.80 8.30 3.82 23.28 7.50 7.98 11.08 51.10 3.79 23.47 9.90 7.70 11.48 21.00 3.77 23.60 11.50 7.44 11.89 14.40 3.76 23.67 9.90 7.06 12.53 18.30 3.70 24.00 9.00 6.99 12.65 28.40 3.68 24.19 22.20 6.81 13.00 6.40 3.65 24.38 25.80 6.73 13.14 9.40 3.61 24.67 11.00 6.68 13.25 8.70 3.48 25.60 16.50 6.60 13.40 5.50 3.46 25.71 8.60 6.30 14.05 8.00 3.44 25.88 8.10 6.11 14.47 5.70 ] 3.40 26.16 7.00 5.97 14.82 12.80 3.37 26.44 4.60 5.86 15.10 4.90 3.32 26.83 9.30 5.62 15.77 4.10 3.28 27.17 10.10 5.44 16.29 4.20 3.24 27.53 6.40 5.29 16.76 31.60 3.18 28.05 5.10 5.14 17.23 17.50 3.10 28.73 4.40 5.11 17.34 49.80 2.99 29.88 12.60 163202.doc • 26· 201249440 5.03 17.63 10.90 2.93 30.44 6.40~~~~ 4.96 17.85 18.20 2.84 31.43 5.50 4.82 — 18.40 32.80 2.83 31.64 4.20~~~~ 4.78 18.53 46.00 2.80 31.96 5.40 4.54 19.53 28.40 2.77 32.25 8.00~~~ 4.52 19.64 39.60 2.76 32.43 2.76— 4.41 20.13 25.30 2.72 32.88 • 1--- 2.72 4.34 20.44 43.20 2.71 33.07 2.71 〜 4.32 20.53 100.00 2.66 33.65 2.66 ~~~ 4.18 21.24 18.70 2.63 34.01 2.63〜 4.14 21.47 25.30 2.61 34.31 2.61 4.11 21.61 34.80 2.60 34.52 2.60 —~ 3.99 22.25 22.50 2.58 34.79 2.58— 3.96 22.41 19.60 2.52 35.54 2.5ΪΓ~~ 3.91 22.74 6.60 2.46 36.53 5.10— 藉由PXRD研究提供複合物形成之證據。杜西拉明琥轴酸鹽、樹脂安伯萊特IRP64及杜西拉明樹脂酸鹽複合物之 PXRD圖案呈現於圖6、7及8中。杜西拉明琥珀酸鹽之繞射展現 11.08 度、16.76 度、17.34 度、18.40 度、18.53 度、 19.64度、20.44度、20.53度、21.61度之2Θ下之一系列強烈峰以及其他峰。在杜西拉明琥珀酸鹽存在此等尖銳峰指示其結晶特性（圖6)。在樹脂安伯萊特IRP64i情形下，不存在此等峰，從而指示此離子交換樹脂之非晶形特徵（圖7)。實例1之杜西拉明之樹脂酸鹽複合物顯示複合物結晶度之降低（圖8)。該等結果可能歸因於杜西拉明與離子交換樹脂之間的相互作用’從而表明存在結晶度低於游離藥物及樹 163202.doc -27- 201249440 脂的新固相。實例8:藥物釋放溶解型態 a) 0.1 N HC1 根據USP XXIII紫板法使用USP溶解測試裝置2 (槳板）在 37°C及50 rpm下在900 mL 〇_1 N HC1中在30分鐘期間確定杜西拉明自添加至釋放介質中之杜西拉明樹脂酸鹽複合物的釋放。圖9顯示杜西拉明之溶解型態之結果，該杜西拉明係來自實例1 (杜西拉明-波拉克磷樹脂複合物）、實例2 及3 (杜西拉明-波拉克磷樹脂口服可分散錠劑）、實例* (杜西拉明-波拉克磷樹脂可咀嚼鍵劑）之杜西拉明樹脂酸鹽複合物及來自市售杜西拉明琥珀酸鹽調配物實例2及3之藥物釋放速率顯示比杜西拉明琥珀酸鹽市售IR錠劑更快速之釋放，例如在上述條件下在5 min内釋放> 90%杜西拉明。表11· 0·1 N HC1之藥物釋放時間(分鐘）溶解％介質：HC10.1N 0 5 10 15 20 30 45 60 杜西拉明琥珀酸鹽市售 100. IR鍵劑 0.0 36.0 71.9 96.3 98.2 99.0 99.3 0 杜西拉明樹脂酸鹽複合物實例1 0.0 84.8 91.0 92.9 93.7 95.0 96.2 97.1 杜西拉明樹脂酸鹽可咀 101. 101. 101. 101. 102. 嚼錠劑實例4 0.0 70.9 94.8 5 7 8 9 0 杜西拉明樹脂酸鹽ODT 100. 100. 100. 100. 100. 錠劑實例2 0.0 99.9 99.9 0 0 1 3 2 杜西拉明樹脂酸鹽ODT 100. 100. 101. 100. 101. 101. 101. 艘劑實例3 0.0 5 8 1 9 0 3 1 163202.doc -28- 201249440 b) 0.01 N HC1 根據USP XXIII紫板法使用uSP溶解測試裝置2 (柴板）在 37°C及50 rpm下在900 mL 0.01 N HC]中在3〇分鐘期間確定杜西拉明自添加至釋放介質中之杜西.拉明樹脂酸鹽複合物的釋放H0顯示來自實例i (杜西拉明·波拉克錢脂複合物）之杜西拉明樹脂酸鹽複合物之杜西拉明之溶解型態的結果。實例1之藥物釋放速率顯示自分析開始在2分鐘時段内超過90%之杜西拉明。表12· 〇,〇1 N HC1下之藥物釋放時間(分鐘）溶解％介質：HC10.01M 0 2 4 6 8 10 12 15 杜西拉明樹脂酸鹽複4物 0.0 99.8 103.4 103.2 103.0 102.9 102.8 102.8 【圖式簡單說明】圖1 ·杜西拉明琥珀酸鹽之比較層析圖圖2.杜西拉明波拉克磷樹脂複合物之比較層析圖圖3.阿斯巴甜之比較層析圖圖4.杜西拉明琥珀酸鹽··阿斯巴甜（1:1)之比較層析圖圖5.杜西拉明波拉克填樹脂複合物：阿斯巴甜（丨：1)之比較層析圖圖6.杜西拉明琥珀酸鹽之PXRD (粉末X射線繞射）圖案。圓7.樹脂安伯萊特IRP64之PXRD (粉末X射線繞射）圖案。 163202.doc • 29- 201249440 圓8.杜西拉明與安伯萊特IRP64之樹脂酸鹽複合物的 PXRD (粉末X射線繞射）圖案。I I . νί· -ί,ν:·· I. ·· s - — · 1. ./ -·- - - . :- -/ I Area °/. Initial value 15*l〇fc:/75々^Si '' V1. . . i.'.VW . .15 husband 50°c ./ ..'· . .: y . 3〇X40〇C/75% RH 30 days 50〇C 300241 'V:化:. 96.16 94.73 96.34 95.30 96.75 About gii 0.30 0.26 0.28 0.29 0.29 About _楚 2 • .·· ···,·· *. .**···' — 0.05 — 0.08 — About Zhanbao 3 — 0.25 — 0.18 — Related -- 0.16 — 0.36 0.04 About Bao 5 — 1.09 — U6 — Aspen Sweet 3.54 0.14 3.29 0.65 2.59 阚 A Quality: 6 丨..V.. -- 2.94 0.09 1.67 0.32 - - ;' s #有有办7 .Π';.ν5,:. - . ] -1 ' \ -- 0.22 — 0.18 — with 1_8 — 0.10 — 0.13 — related object #9 -- 0.05 — — — 163202.doc •24- rs 201249440 Table 8. Dusilamin Polak Phosphate Resin Complex: Aspartame Comparative Chromatogram Area % Value Initial Ϊ 5 Fu 4〇fc/75%RH 4 Fu Jie 3 〇天4〇°C/7§¥rH 3b Fu 50t 300241 86.53 89.28 89.14 89.25 89.16 Related substances 1 0,15 0.16 0.17 0.16 0.16 Aspartame 13.17 10.40 10.45 10.42 10.51 About poplar 6 0.15 0.15 0.24 0.18 0.17 Analytical test Chromatography at different time points of the study It is shown in FIGS. 15 to. Based on the observed results, it can be inferred that when the sample is exposed to 4〇〇c /75〇/〇RH, it is observed in a binary mixture of duxamine succinate: aspartame (1:1). To a significant interaction, especially in a binary mixture of Dusitamine Polaco Phosphate Complex: Aspartame (1:1), between the excipient and the resinate complex of the present invention An interaction was detected. Thus, the resinate complex of the present invention exhibits increased compatibility with some excipients such as aspartame. Example 7: Powder X-ray diffraction (PXRD): (See Figures 6, 7 and 8) • Approximately 2 paws § samples were prepared in a standard sample holder using two polyacetate towns. The powder diffraction pattern was obtained in transmission geometry using cuKal_radiation on a D8 Advance Series 2 Θ/Θ powder diffraction system. The system is equipped with a VANTEC-1 single photon counting PSD, a helium monochromator, a 9-position automatic transducer sample stage, a fixed divergence slit, and a radial s〇1丨er slit. The program used is DIFFRAC plus XRD Commander V.2.4.1. The number of I63202.doc -25· 201249440 is evaluated according to EVA V·12.0. In; 4. To 40. Within 20 之 of the range, the test sample is scanned in 20 min (see circles 6, 7 and 8). The PXRD pattern of dusiramin succinate, resin Amberlite IRP64 and dusiramin resinate complex was collected. Table 9: List of selected peaks obtained by powder X-ray diffraction of duzolam succinate (see Figure 6). D-value (person) Angle 2Θ1 Relative strength % d-value (A) Angle 2Θ1 Relative strength % 8.18 10.80 8.30 3.82 23.28 7.50 7.98 11.08 51.10 3.79 23.47 9.90 7.70 11.48 21.00 3.77 23.60 11.50 7.44 11.89 14.40 3.76 23.67 9.90 7.06 12.53 18.30 3.70 24.00 9.00 6.99 12.65 28.40 3.68 24.19 22.20 6.81 13.00 6.40 3.65 24.38 25.80 6.73 13.14 9.40 3.61 24.67 11.00 6.68 13.25 8.70 3.48 25.60 16.50 6.60 13.40 5.50 3.46 25.71 8.60 6.30 14.05 8.00 3.44 25.88 8.10 6.11 14.47 5.70 ] 3.40 26.16 7.00 5.97 14.82 12.80 3.37 26.44 4.60 5.86 15.10 4.90 3.32 26.83 9.30 5.62 15.77 4.10 3.28 27.17 10.24 5.43 6.40 5.29 16.76 31.60 3.18 28.05 5.10 5.14 17.23 17.50 3.10 28.73 4.40 5.11 17.34 49.80 2.99 29.88 12.60 163202.doc • 26·201249440 5.03 17.63 10.90 2.93 30.44 6.40 ~~~~ 4.96 17.85 18.20 2.84 31.43 5.50 4.82 — 18.40 32.80 2.83 31.64 4.20~~~~ 4.78 18.53 46.00 2.80 31.96 5.40 4.54 19.53 28.40 2.77 32.25 8.00~~~ 4.52 19.64 39.60 2.76 32.43 2.76- 4.4 1 20.13 25.30 2.72 32.88 • 1--- 2.72 4.34 20.44 43.20 2.71 33.07 2.71 to 4.32 20.53 100.00 2.66 33.65 2.66 ~~~ 4.18 21.24 18.70 2.63 34.01 2.63~ 4.14 21.47 25.30 2.61 34.31 2.61 4.11 21.61 34.80 2.60 34.52 2.60 —~ 3.99 22.25 22.50 2.58 34.79 2.58— 3.96 22.41 19.60 2.52 35.54 2.5ΪΓ~~ 3.91 22.74 6.60 2.46 36.53 5.10—Proof of complex formation is provided by PXRD studies. The PXRD patterns of duzolam succinate, resin Amberlite IRP64 and Dusilamin resinate complex are presented in Figures 6, 7 and 8. Dusturamin succinate diffraction exhibits a strong series of peaks and other peaks at 11.08 degrees, 16.76 degrees, 17.34 degrees, 18.40 degrees, 18.53 degrees, 19.64 degrees, 20.44 degrees, 20.53 degrees, and 21.61 degrees. The presence of these sharp peaks in the simiramine succinate indicates its crystalline nature (Figure 6). In the case of the resin Amberlite IRP64i, there are no such peaks indicating the amorphous character of the ion exchange resin (Fig. 7). The resin salt complex of Dusimamin of Example 1 showed a decrease in the crystallinity of the composite (Fig. 8). These results may be attributed to the interaction between duxiramin and the ion exchange resin, indicating the presence of a new solid phase with lower crystallinity than the free drug and tree 163202.doc -27-201249440 lipid. Example 8: Drug release dissolved form a) 0.1 N HC1 USP dissolution test device 2 (paddle plate) according to USP XXIII purple plate method at 37 ° C and 50 rpm in 900 mL 〇 1 N HC1 during 30 minutes The release of the exosimamine resinate complex added to the release medium was determined. Figure 9 shows the results of the dissolution profile of Dusilamin from Example 1 (Dusilamin-Polac Phosphate Complex), Examples 2 and 3 (Dusilamin-Polac Phosphate) Oral dispersible tablet), Example* (duxilamin-polak phosphoric acid chewable bond), dirsalamine resinate complex and example 2 from commercially available dusimamine succinate formulations The drug release rate of 3 showed a faster release than the commercially available IR lozenge of duxiramin succinate, for example, releasing > 90% duxamine in 5 min under the above conditions. Table 11·0·1 N Drug release time of HC1 (minutes) Dissolution % Medium: HC10.1N 0 5 10 15 20 30 45 60 Duzolam succinate is commercially available 100. IR bond 0.0 36.0 71.9 96.3 98.2 99.0 99.3 0 Duzolamin resinate complex Example 1 0.0 84.8 91.0 92.9 93.7 95.0 96.2 97.1 Duzolamamine resinate can be 101. 101. 101. 101. 102. Chewable tablet example 4 0.0 70.9 94.8 5 7 8 9 0 Duzolamin resinate ODT 100. 100. 100. 100. 100. Tablets example 2 0.0 99.9 99.9 0 0 1 3 2 Duzolamamine resinate ODT 100. 100. 101. 100. 101 101. 101. Example of the agent 3 0.0 5 8 1 9 0 3 1 163202.doc -28- 201249440 b) 0.01 N HC1 According to USP XXIII purple plate method using uSP dissolution test device 2 (wood board) at 37 ° C and The release of duxilamamine resinate from the addition of duxiramin to the release medium was determined during 30 minutes at 900 rpm in 900 mL of 0.01 N HC] at 50 rpm from Example i (Dusilamin) The results of the dissolved form of dusilamamine in the sirolimus resin complex of Pollack's lipid complex. The drug release rate of Example 1 showed more than 90% of dexmedamin over the 2 minute period from the start of the analysis. Table 12· 〇, 〇1 N Drug release time under HC1 (minutes) Dissolution % Medium: HC10.01M 0 2 4 6 8 10 12 15 Dusilamin Resin Complex 4 0.0 99.8 103.4 103.2 103.0 102.9 102.8 102.8 [Simple diagram of the diagram] Figure 1. Comparative chromatogram of sirolimus succinateFig. 2. Comparative chromatogram of dusiramaminepol resin complex. Figure 3. Comparative chromatography of aspartame Figure 4. Comparative chromatogram of Dusilamin succinate· Aspartame (1:1) Figure 5. Dusilamin Polak filled resin complex: Aspartame (丨: 1) Comparative Chromatogram Figure 6. PXRD (Powder X-Ray Diffraction) pattern of Dusilamin succinate. Round 7. Resin Amberlite IRP64 PXRD (Powder X-Ray Diffraction) pattern. 163202.doc • 29- 201249440 Round 8. PXRD (Powder X-Ray Diffraction) pattern of the resinate complex of Dusitamine and Amberlite IRP64.

圖9.比較溶解型態-HC1 0.1 N 圖10.杜西拉明樹脂酸鹽複合物-HC1 0.01 N之藥物釋放溶解型態。 163202.doc -30- rsFigure 9. Comparison of dissolved forms - HC1 0.1 N Figure 10. Drug release of dusiramamine resinate complex - HC1 0.01 N. 163202.doc -30- rs

Claims

201249440 VII. Patent application scope: 1 · A doxylamine resinate complex comprising dusimamine conjugated to a weakly acidic synthetic cation exchange resin. 2. The dusiramamine resinate complex as claimed in claim 1, wherein the weakly acidic s is a cation exchange resin-based copolymer of methacrylic acid and diethylbenzene. 3. The dusiramamine resinate complex of claim 1, wherein the amount of the dusilamamine is between 10% and 5% and 55% by weight relative to the total weight of the dexilamine resinate complex. Between, preferably between Η% by weight and 3% by weight. 4. A method of preparing a dusiuramin resinate complex according to any one of claims 3 to 3, which comprises weakly acidic synthesis The cation exchange resin is contacted with dusimamine or a pharmaceutically acceptable salt thereof. 5. The method of claim 4, wherein the dexiramine used is in the form of a pharmaceutically acceptable salt of dusiramamine, i.e., dusiramamine. 6. The method of claim 4 or 5, wherein the weight ratio of the exoramamine succinate to the weakly acidic synthetic cation exchange resin is in the range of from 1:1 to 1:5. 7. The dosilamine resin salt complex according to any one of items 1 to 3, which is used as a medicament. 〃 8. For example, the dusiramamine resinate complex of Item 7 is used for the treatment of insomnia. 9. A medicinal composition comprising <RTI ID=0.0>>>>><>> 10. The pharmaceutical composition according to claim 9, 11. The immediate release of the pharmaceutical composition of claim 1 . It is used for oral administration. Wherein the pharmaceutical composition provides Duxi 12. The pharmaceutical composition of claim 1 or η, wherein the pharmaceutical composition is an oral dispersible agent. And chew the key or the powder stored in the sachet. 13. A pharmaceutical composition according to any one of claims 9 to 11 for use in the treatment of occasional insomnia, the composition comprising an effective amount of a duramine resin complex. 14. Use of a dusimamine resin salt complex according to any one of claims 1 to 3 which is for increasing the excipient compatibility of duzolam. The use of the sirolimus resinate complex according to any one of claims 1 to 3, which is for reducing the hygroscopicity of dusimamine. 163202.doc