TW200522946A - Emulsifying systems containing azetidine derivatives - Google Patents
Emulsifying systems containing azetidine derivatives Download PDFInfo
- Publication number
- TW200522946A TW200522946A TW093121230A TW93121230A TW200522946A TW 200522946 A TW200522946 A TW 200522946A TW 093121230 A TW093121230 A TW 093121230A TW 93121230 A TW93121230 A TW 93121230A TW 200522946 A TW200522946 A TW 200522946A
- Authority
- TW
- Taiwan
- Prior art keywords
- scope
- derivative
- patent application
- active ingredient
- azetidine
- Prior art date
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- 230000001804 emulsifying effect Effects 0.000 title abstract description 3
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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Landscapes
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Description
200522946 九、發明說明: 【發明所屬之技術領域】 本發明關於吖丁啶衍生物之安定調配物。 用於根據本發明醫藥組成物之吖丁啶衍生物可由以下 通式(la)或(lb)表示:
烷基、鹵素、N02、CN、 其中Ar為芳族或雜芳族基團,視情況以一或多個(q C4) (Cl-C4)烷氧基或0H基團取代。 於以上<丁唆街生物之定義中,應瞭解芳族基團代表 尤其為苯基或萘基基®,雜耗基㈣表㈣基、咬喊基、 嗔嗯基m料基或料基基團,且鹵素代表氟、 氯、溴及埃。 以下之化合物(Ic)係為通式(Ia)吖丁啶之特例:
【先前技術J 200522946 於專利申請案 WO 00/15609、WO 01/64633、WO 0064634 及WO 99/01451中,已揭示通式(ia)或(ib)之v丫丁咬衍生 物以及其應用。特別地’此等Τί丫丁咬衍生物因其對於*** 驗受體(尤其CB1型受體)之高親和力而特別有利。 遺憾地,吖丁啶衍生物係為僅具極微弱水溶性之產 αα。远今,可想像於含有尤其纖維素、乳糖及其他賦形劑 之調配物中,特別地透過口服途徑施用藥片形式的通式(Ia) 或(lb)之吖丁啶衍生物。然而,由於極低的生物可利用率, 此等調配物並非總是充分適用於此等微水溶性產品。 許多文件揭示適用於溶解及/或提升疏水性活性成分 的生物可利用率之系統。然而,所測試的系統迄今證實對 於製備含有以上定義的吖丁啶衍生物之醫藥組成物(係安 定且生物可利用的,且其中吖丁啶衍生物係以有效濃度溶 解)是無效的。 特別地,J· Pharm Sciences,89(8),967 (2000)及
Pharmaceutical Technology Europe ,第 20 頁(2000 年 9 月)提到微溶於水的活性成分於中鏈三酸甘油酯中之調配 物。然而’以Miglyol®為基底之調配物所進行之嘗試已得 到不適合的結果(基於其生物可利用率之觀點)。 再者,國際申請案W0 95/24893揭示含有易消化油脂、 親脂性表面活性劑及親水性表面活性劑之組成物,係意欲 調配疏水性活性成分及提升其生物可利用率。國際專利申 明案PCT/FR02/04514解釋’以上的”丫丁咬衍生物在此類型 調配物中具有太弱的生物可利用率。特別地,基於藥物動 200522946 力觀點,此等0丫丁咬衍生物於Migly〇l®/Capryol®/ Cremophor®系統中之調配物在活體中是不適合的。 【發明内容】 此刻頃發現(且其為構成本發明主題者),有可能製備 含有通式(la)或(lb)衍生物之化學上及物理上安定的醫藥 組成物,視情況合併其他於含有以下成分之系統中能賦予 通式(la)或(lb)吖丁啶衍生物效力之活性成分: (i) 溶解於液態溶劑中之麟脂,或 (ii) Miglyol、Capryol 及 Cremophor 之組合。 確切地,頃發現化合物(la)或(lb)與磷脂之調配物容 許獲致意外的極佳活體中藥物動力量變曲線(此涉及AUC、 Cmax及Cmax變異性)。依相同方式且相反於早於 PCT/FR02/04514所宣稱者,針對三隻受評估的狗之一,已 觀察到化合物(la)或(lb)與透過合併Migly〇l、Capryol及 Cremophor得到之微乳液的調配物容許獲致極佳的活體中 藥物動力量變曲線(此涉及AUC及Cmax)。所觀察到的嘔吐 可能為其他二隻狗中之失敗結果的理由之一。 較佳的調配物含有化合物(Ic)。 就每克而言,醫藥調配物較佳含有至多2〇〇毫克吖丁 啶衍生物。 醫藥組成物可進一步包含額外的添加劑,係選自安定 劑、防腐劑、使其可調整黏度之藥劑或可修飾例如感官性 質之藥劑。 200522946 就某些治療而言,例如肥胖症,與*** (sibutramine)同時施用通式(ia)或(ib)之吖丁啶衍生物 可能是有利的,此造成減少食物消耗之增效效果。 ***(sibutramine)及其效果已揭示於以下參考 文獻中· W0 90/061110,D· H· RYAN 等人,Obesity Research,3 (4),553 (1995) ; Η· C· JACKSON 等人,British Journal Pharmacology,121,1758 (1997) ; G· FANGHANEL 等人,Inter· J· Obes·,24(2),144 (2000) ; G· A· BRAY 等人,Obes· Res·,7(2),189 (1999)。 再者’就其他治療(例如精神***症)或神經失調(例如 柏金森氏病)之治療而言,與一或多種活化腦中多巴胺神經 傳遞之藥劑同時施用通式(la)或(Ib)吖丁啶衍生物可能是 有利的。此等組合使得賦予單一治療(左旋多巴、多巴胺促 動劑及酵素的抑制劑)效力成為可能,並且使得降低副作用 (例如運動困難)成為可能。 於多巴胺促動劑中,尤其可提到以下產品:溴隱亭 (bromocriptine,Novartis)、卡麥角林(cabergoline, Pharmacia Corp·)、亞佐戈來(adrogolide , Abbott Laboratories) 、 BAM-1110 (Maruko Seiyaku Co Ltd)、 Duodopa® (Neopharma)、L-多巴、多巴劑(dopadose, Neopharma) 、 CHF1512 (Chiesi) 、 NeuroCel卜PD (Diacrin Inc)、PNU-95666 (Pharmacia & Upjohn)、羅匹尼羅 (ropinirole,GlaxoSmithKline Beecham)、普拉克索 (pramipexole , Boehringer Ingelheim)、羅替戈汀 200522946 (rotigotine , Discovery Therapeutics, Lohmann Therapie System)、斯伐拉胺(spheramine,Titan Pharmaceuticals) 、 TV1203 (Teva Pharmaceutical)、尿 甘(uridine , Polifarma) 〇 應瞭解含有除通式(la)或(lb)吖丁啶衍生物外之活性 成分且能賦予其效力之組成物可含有於以上段落中所定義 之產品’並且該產品係落於本發明之範圍内。 衍生自吖丁啶之活性成分較佳存在量為總組成物之 〇· 01至70%重量。 根據另一態樣,本發明係關於一種製備含有根據本發 明第一態樣吖丁啶之組成物的方法,其中適當地製備主要 賦形劑(於固體或半固體賦形劑之情形中,必要時,於加熱 後)之混合物,接著必要時製備具額外添加劑之混合物,接 著添加式(la)或(lb)吖丁啶衍生物,且適當地添加如申請 專利範圍第1項能賦予通式(la)或(lb)吖丁啶衍生物效力 之活性成分,並且維持攪拌,俾獲致均勻的混合物。 根據又一態樣,本發明係關於含有如上述定義之組成 物之套組,以及含有能賦予通式(la)或(lb)吖丁啶衍生物 效力之活性成分的組成物。 能賦予吖丁啶衍生物效力之表現套組的活性成分較佳 為***(sibutramine)。 根據最後態樣,本發明係關於一種製備含有根據本發 明第一態樣之組成物的表現套組,以及關於含有活化腦中 多巴胺神經傳遞之藥劑的組成物。 200522946 於鼠中進行之第一臨床4研究中,口服施用式(i)藥物 於0· 5/甲基纖維素/〇· 2% tween 8〇中之水性懸浮液(以1〇 毫克/公斤之劑量)導致極低的生物可利用率(3%)。第一調 配方式係使用25毫克/毫升⑽於Migly〇1隨中之溶 液,其係因為在油性成分中具較高物質溶解度而選用(於
Miglyo1812中為35·9毫克/毫升)。再者,此賦形劑(中 鍵三酸甘㈣)係因其消化性及管理 曉。此調配物已用於進一步的臨床 楼又性而被知 藥物於鼠中之提高的生物可利用率C造成式(1C) 克/公斤劑量分別為13及37%)。然而克/公斤及10毫 可觀察到重要的食物影響及個體間變於人類研丸中, 最大财受劑量為約⑽毫克(健、=禁食條件下之 食條件下,最大耐受劑量騎以在進 30%)。 νΊ固體間變異降低至 下:以所有此等結果為基準,發展新_㈣物之需求如 替代㈣㈣度之㈣物U 1D毫克/克 2·提南生物可利用率 3·降低個體間變異 4.降低食物效應(禁食/進食條件) 使用能提高活性成分 調配物之發展。 解度之_,,造成非標準 200522946 因此’已研究其他脂類賦形劑以供進一步調配,目標 在於增進藥物溶解/吸收步驟。由於賦形劑之表面活性性 質’故努力集中於能原位形成均勻及微細乳液或微乳液或 膠微粒溶液之”脂肪基底的調配物,,。確切地,Miglyol展現 乳化性質’但當其與水性媒介物接觸時,形成不均勻及粗 製的乳液(巨觀上可見的大油滴),此可解釋活體中的結 果。’’脂肪基底的調配物”之範圍係從純油脂至含有大量表 面活性劑及共溶劑(較高極性)摻合物。首先決定化合物(Ic) 於一詳盡系列的脂肪及其他醫藥共溶劑中之溶解度。 就化合物(Ic)調配物而言,可確認及選擇三種賦形劑: •施用為溶液之兩性賦形劑(Phosal 50PG, Labrasol),一旦與生理媒介物接觸時,其能夠自身乳化(微 滴尺寸為1-10微米)。 •施用為半固體基質之兩性賦形劑(Gelucire 44/14,維生素E TPGS),係透過膠微粒作用而供藥物溶解 (微滴尺寸<20毫微米)。 •脂類賦形劑(Miglyol 812N)摻合表面活性劑 (Cremophor RH40 或 EL)及共溶劑(Capryol 90)之混合物: 此混合物能夠與腸胃流體原位地自身乳化(微滴尺寸<20毫 微米)。 所有選用的賦形劑之化學組成以及其物化性質及其他 主要特徵將進一步說明如下。 於本案中,於稀釋及以受刺激的腸胃流體培養後,評 估所有確認的調配物原型之活體中性能。研究以下參數: 200522946 所得到之微粒分散液的微觀/巨觀態樣、測定藥物於調配物 培養前後之溶解分率(於腸酵素存在或不存在下)、評估分 散液於培養後之膠態安定性。 所得到的結果容許初步篩選,以確認潛在令人感興趣 於活體中研究之調配物原型。 【實施方式】 $型之^配物| 前言··賦形劑之說明 (i) 維生素 E TPGS (Eastman Chemicals) ·· 維生素E TPGS (d-a-生育紛聚乙二醇1000號ίό酸酯) 係為非動物源之天然來源維生素的水溶性衍生物。 (ii) Phosal 50PG (Aventis Nattermann)
Phosal 50PG係為一種具有至少50% PC及丙二醇之璘 脂醯膽鹼濃縮物。 組成:磷脂醯膽鹼約56.8% 丙二醇:約38% 葵花單/二酸甘油酯:約3% 大豆脂肪酸:約2% 抗壞血酸棕櫚酸酯:約0.2% 乙醇:加至100% 其係自大豆卵磷脂開始合成,純化為磷脂’且接著溶 解於液態載體系統中。 200522946
Nattermann Phospholipid GmbH亦出售其他以不同带 式溶解之磷脂。例如Phosal® 53MCT,其係為由溶解於‘ 有辛酸/癸酸三酸甘油脂、醇、硬脂酸甘油酯、油酸及抗壞 血酸棕櫚酸酯之載體系統中之磷脂醯膽鹼所組成的形式。 磷脂醯膽鹼含量為約56±3%。 (iii) Labrasol (Gattefosse)
Labrasol® (癸醯基己醯基Macrogo卜8甘油酯)係為 一種由單酸甘油酯、二酸甘油酯及三酸甘油酯與聚乙二醇 (PEG)的單脂肪酸及二脂肪酸所組成之飽和聚二醇化的甘 油醋。 得自植物及石化來源之此兩性油脂可溶於水中。 (iv) Labrafi1 (Gattefosse)
Labrafil® M 1944 CS(油酸 Macrogo卜6 甘油酯),係 為一種衍生自選用的高純植物油之可分散於水中的兩性油 脂(HLB 4)。此賦形劑容許提高調配物原型之親脂性,其目 襟為透過微細分散液之形成來改良活性成分於腸胃流體中 的溶解度。此外,此種可與膽固醇及磷脂混溶之材料可經 由非主動機制(被動擴散)通過薄膜。 (v) Gelucire (Gattefosse)
Gelucire® 44/14 (月桂醯基 Macrogol-32 甘油醋)係 為一種由單酸甘油酯、二酸甘油酯及三酸甘油酯與聚乙二 200522946 醇(PEG)的單脂肪酸及二脂肺酸所組成之飽和聚二醇化的 甘油醋。
Gelucire® 44/14係得自氫化的棕櫚核油與pEG 15〇〇 之反應。 (vi) Miglyol 812被描述為透過水解、分餾所得到的脂肪 酸以及重新酯化,而自可可椰子(Coco nucifera L.)胚乳 的硬質乾燥部分萃取之固定性油脂。其係由脂肪酸之完全 短鏈及中鏈三酸甘油酯之混合物所組成,其中不少於95% 為飽和酸辛(caprylic)酸及癸(capric)酸。 其為無色至猶淺黃色油性液體,實際上是無氣味且無 味道的。 (vii) Cremophor RH40 為 Polyoxy 40 氫化的蓖麻油。此 材料係經由使環氧乙烷與氫化的蓖麻油反應而得。其係以 在30°C下液化之白色半固體糊漿出現。其具有極微弱的特 徵氣味及稍許味道(於水溶液中)。 (viii) Cremophor EL為Polyoxy 35蓖麻油(聚氧基伸乙 基甘油三篦麻油酸酯,甘油-聚乙二醇篦麻油酸酯)。此材 料係經由使環氧乙烷與蓖麻油(德國藥物品質)反應而得。 Cremophor EL係為淺黃色的油性液體(於25°C之黏度: 700-850 cP),其在T>26°C為透明的。其僅稍具特徵氣味, 並且可藉加熱至26°C而完全地液化。 200522946 (ix) Capryol 90丙二醇單辛酸酯 此材料係得自植物及石化來源,其不溶於水中。 液體。 第-步驟為決定化合物(lc)於一詳盡系列的脂肪 他醫樂共溶劑(包含植物油、脂類成分、表面活性劑水 性成分及鱗脂)中之溶解度。溶解度測量之規_報告㈣ 件中。 表1 一溶解度數據 商品名 化學說明 植物油 大豆油 花生油 "----- ,« —-----—--- 脂類成分 Imwitor 988 ^-—-----—. 單-二辛酸甘油酯 Imwitor 742 " 一 ——-'1 —-. 單-二辛酸/1酸甘油酯 Miglyol 812 辛酸/癸酸三酸甘油酯 Labrafil M1944 CS 油基macr〇g〇卜6-甘油崎 表面活性劑
31.8 41·2
30· 3 200522946
Tween 80 POE單油酸醋 50.6 Cremophor RH40 POE氮化的蓖麻油 80.6 Span 20 山梨聚糖單月桂酯 31.6 Span 85 山梨聚糖三油酸酯 92· 0 親水性成分 PEG 400 聚乙二醇400 78· 1 其他 乙醇 5.8 HP β環狀糊精 0.05 Transcutol 一縮二乙二醇單乙基醚 89.8 表2—補充溶解度數據 商品名 化學說明 溶解度 (毫克/毫升) 植物油 椰子油 18· 6 蓖麻油 16· 1 葵花油 14· 8 芝麻油 10.9 橄欖油 10· 9 脂類成分 Crossential 094 油酸 19.6 Crossential LN 75 亞麻油酸 45.4 Edenor C8 98-100 辛酸 75.5 16 200522946
Myvacet 9-45 蒸顧的乙酿化單甘油酯 54.8 Neobee Μ 20 PG二辛酸醋/二癸酸酯 47· 7 Lauroglycol PG單月桂酸酯 28· 5 Caproyl 90 聚乙二醇單辛酸酯 56· 6 表面活性劑 Myrj 45 P0E硬脂酸酯 86· 9 Brij 96 PE0油基醚 85· 7 Labrasol 癸醢基己醯基Macrogol-8 甘油酯 111· 8 親水性成分 PEG 1500 聚乙二醇1500 <10 Gelucire 44/14 月桂酿基Macrogol-32甘油 酯 90· 1 Gelucire 50/13 硬脂醯基Macrogol-32甘油 酯 78· 5 磷脂 Phospholipon 90 磷脂醯膽鹼93% 40 Phosal 40 MD 磷脂醯膽鹼38±1, 5%(於硬脂 酸甘油醋、大豆油及亞麻油 酸乙基酯中) 12.5 Phosal 75 SA 磷脂醯膽鹼75土3%(於醇、葵 花油、硬脂酸甘油酯、椰子 油及抗壞血酸棕櫊酸酯中) <10 Phosal 50PG 磷脂醯膽鹼>50%(於丙二醇 11.7 200522946 中) _— Phosal 53 MCT (不飽和賦形劑,不 建議,請看次頁) 填脂醯膽鹼56土3%(於辛酸/ 癸酸三酸甘油酯、醇、硬脂 酸甘油醋、油酸及抗壞血酸 棕櫚酸酯中) 25.8 於測定溶解度後,考量活性成分的溶解度、其可註冊 性以及其提高藥物的生物可利用率之能力(經由溶解改良 或吸收增強),本案之目的為選擇一些賦形劑。 關於第三準則,接著採以下基準來選擇賦形劑·· 1·其能夠溶解親脂性活性成分且能分散或溶解於腸胃 流體中之兩性特質(HLB>l〇)(Labrasol、Gelucire 44/14、 Phosal 50PG、維生素 E TPGS) 2·於以腸胃流體稀釋後,經由充分結合油脂、親水性 表面活性劑(HLB>10)及親油性共表面活性劑(HLBC10),其 於混合物中原位形成微乳液之能力(Migly〇1 812/Cremophor RH40/Capryol 90) 關於Phosal 53MCT,對於賦形劑的物理安定性之主要 爭議導致選擇Phosal 50PG為替代物。確切地,所觀察到 之賦形劑的相分離不僅涉及在Avenfis貯存之批料,也涉 及在Nattermarm貯存之批料。ph〇sal 5〇pG展現極佳的物 理安定性。於下表中描述所選用之賦形劑的主要特性: 200522946 表3—選用之賦形劑的主要择杻 商品名 — 化學說明 特性 溶解度 能形成與生理流體接 膠粒溶液之賦彬_ Labrasol® 癸醯基己醯基 液體/HLB 13 111.8 (Gattefosse) Macrogol-8甘油西与 DMF/歐洲專題論令 Labrafil Μ 1944 CS 油基macrogol〜6甘 液體/HLB 4 30.3 (Gattefosse) 油醋 DMF/歐洲專題論文 Phosal® 50PG 磷脂醯膽& 黏性液體/兩性性 11.7 (Nattermann) >50%(於丙二醇中) 質 GRAS狀態 Gelucire® 44/14 月桂醯基 蠟質固體/熔點44 90.1 (Gattefosse) Macrogol-32 甘油 酯 °C/HLB 14 GRAS狀態/歐洲專 題論文 維生素E TPGS 維生素E d-α-生育 蠟質固體/熔點38 100 (Eastman) 酚聚乙二醇1000琥 珀酸酯 °C/HLB 13 GRAS狀態/USP專題 論文 與生理流體接觸時能自身微乳化之賦形劑的混合物 Miglyol 812 辛酸/癸酸三酸甘 油性相/脂肪酸:C8 37.4 (Condea) 油酯 及C10 GRAS狀態/歐洲專 題論文 200522946
Caproyl® 90 (Gattefosse) 聚乙二醇單辛酸酯 共表面活性劑/液 體/HLB 6 食品添加劑狀態 56· 6 Cremophor RH 40 (BASF) Polyoxy 40氫化的 蓖麻油 表面活性劑/半固 體/液體(於30°〇 HLB 14-16 FDA惰性成分/ USP 專題論文 80.6 " - · 暴型之說明 固體基質(二元及三元混合物j 表1 一選用的原型之說明 □原型1 成分 化學說明 數量 化合物(Ic) 100毫克 Gelucire 44/14 月桂酿基macrogol甘油醋 10克 □原型2 成分 化學說明 數量 化合物(Ic) 100毫克 Labrasol 癸醯基己醯基macrogol甘 油酯 6克
TP 200522946
Labrafil 1944 CS 油基macrogol甘油酯 4克 □原型3 成分 化學說明 數量 化合物(Ic) 100毫克 Phosal 50PG 磷脂與丙二醇之混合物 10克 □原型4 成分 化學說明 數量 化合物(Ic) 100毫克 維生素E TPGS d-a_生育酚聚乙二醇1〇〇〇 琥珀酸酯 10克 就Labrasol原型而言,欲包含於原型中之Labrasol的 最大量為60%(重量/重量)’因為在較高含量下,與膠囊外 殼之明膠不相容的風險增強。可採用非由明膠製成之具較 高含量Labrasol的調配物。為了完成此調配物之大部分組 成,決定使用Labrafil Μ 1944 CS( —種親脂性成分(HLB 4),於40%(重量/重量))。 自身微乳化系統:油脂/表面活性劑/共表面活性劑(假三元 混合物) — -- —— _ 含有兩性表面活性劑/共表面活性劑對之任一種調配 200522946 物導致若干微膠粒態之形成。本案之目標係發展能自發地 與生理流體形成微乳液之調配物原型。可將微乳液定義為 透明、各向同性、熱動力安定的液體。因此,可無限地稀 釋微乳液。透明性係為由尺寸<100毫微米之微滴所組成的 微結構之結果。 醫藥利益之主要性質為:高的藥物溶解能力、稀釋容 量(將分子原位地留在微膠粒溶液中)以及分散容量(採用 容許較易吸收之微滴尺寸)。
賦形劑之選擇 以文獻及以針對微乳液調配物所述之賦形劑所得的溶 解度結果為基礎,選用以下成分,目標為發展一種微乳液 原型:
-油性相:Miglyol 812 -表面活性劑:Cremophor RH40 -共表面活性劑:Capryol 90 -水性相:生理流體 假三元圖 此圖之設計容許測定能提供微乳液區之賦形劑比例。 由於微乳液為四級系統’故其圖形表述需要三維表述。然 而,為了簡化表述,故使用假三元圓。 假定微乳液為以下成分之假三元混合物: 1·水 η 200522946 2·油性相(Miglyol 812N) 3·表面活性劑/共表面活性劑(Cremophor RH40/Capryol 90) 規範: 首先界定比例S/CoS:測試4種不同的比例(1 : 1 ; 2: 1 ; 3 : 1及4 : 1) 〇 就每一比例而言,經由設定以下參數來設計假三元圖: •油性相之百分率(20%、40%、60%及80%) · • S/CoS對之百分率(100%減去油脂百分比) 接著,逐滴地添加水相。因而在每次添加水後修飾每 一”成分”之百分率。 視覺方面的修飾(自渾濁至半透明,且相反地)顯示微 乳液區之邊界。此外,於無限稀釋前後之微滴尺寸測量 (Coulter Nanosizer N4+)容許確定微乳液之形成。 無活性成分而得到假三元圖,並且再度地以活性成分 進行。 ⑩ 結果: •以S/CoS比例3 : 1及4 :卜觀察到微乳液區域。(請 看圖式。)於此區域中,微滴尺寸為約25毫微米。 。 無論S/CoS比例為何(3: 1及4: 1)且具高水含量(從55% 至86W,針對低初百分率之油脂相(2〇%)而言,可得到微乳° 23 200522946 組成為: 比例3 : 1 ---- -— 比例4 : 1 Miglyol 812 , ............_ _— 〜 20% —— —--- 20% Capryol 90 〜 20% —:--——-- 16% Cremophor RH40 __ 60% 64% -- ------ •當含或^含活性成分時(濃度:10毫克/克),微乳液 區域相同。微滴尺寸是相同的,約25毫微米。 nuc)之乳化系統的初組成為: 化合物Ic 比例3 : 1 比例4 : 1 ___ l°/〇 ——.— 1% Miglyol 812 、_ 20% --- —-- 20% Capryol 90 〜 20% 16% Cremophor RH40 1 ----- 、_ 59% —----—·—.. 63% —----—-- 經由各向同#_徵化確認微乳液之形成。 顆粒大小 為了確認微乳液之形成,於在侵襲性條件下貯存後且 於在水中或生理流體中稀釋後,查驗其熱動力安定性。 測試以下樣品: • S/CoS比例 3 ·· 1: 86%水、3%油性相、⑽ cremophor RH40 及3% Capryol 90 24 200522946 • S/CoS比例4:1 ·· 86%水、3%油性相、9% Cremophor RH40 及2% Capryol 90 經由測量於在侵襲性條件下貯存後且於在水中或生理 流體中稀釋後之微滴尺寸,查驗微乳液的安定性。以裝置
Coulter Nanosizer N4+進行分析(準彈性光散射)。 於侵襲性條件下貯存 使樣品受到侵襲性條件··於5〇。(:下,2週,介於-15t 與+50°C間之溫度循環達24小時 針對在50°C下貯存2週後得到之微濟尺寸(以毫微米表 示)合併多分散性指數的結果如下: TO 於1週後 於2週後 比例3 : 1 24 (0.255) 23 (0.255) 25 (0.244) 比例4 : 1 22 (0.278) 22 (0.219) 23 (0.233) 針對在溫度循環後得到之微滴尺寸(以毫微米表示)合 之前 之後 比例3 : 1 24 (0.255) 23 (0.227) 比例4 ·· 1 22 (0.276) 23 (0.254) 以應用的處理未觀察到微滴尺寸之變化:微乳液的結 構對高溫或對熱衝擊不敏感。 200522946 具Cremophor EL之最終調配物
Miglyol 812(液體)、Cremophor RH40(於室溫下為半 固體,固化點28。〇及Capryol 90(液體)混合物之製備必須 在60°C下加熱混合物,以得到均勻的溶液。此外,混合物 之加熱可能對於化合物Ic之化學安定性有影響。考量此二 問題,建議以Cremophor EL(來自相同化學族)替代 Cremophor RH40 。
Cremophor EL(聚氧基35蓖麻油)係為液體表面活性 劑:製造期間不需加熱。 進行二試驗,以評估Cremophor EL相較於Cremophor RH40之利益:針對表面活性劑/共表面活性劑比例3 : 1設計 假三元圖以及測試無限稀釋度。 針對選用的原型之試驗工作 ϋ之製備 石合物(Ic)溶液之製備(10毫克/克) • Miglyol 812N (Condea, Batch 508) • PEG 400-Batch 5056 • Phosal 50PG (Aventis Nattermann,Batch 228188) •Labrafil 1944CS (Gattefoss6, Batch 15195) • Labrasol (Gattefoss6, Batch 22478) • Gelucire 44/14 (Gattefoss6, Batch 14236) •微乳液(Cremophor RH40或EL、Capryol 90、Miglyol 812N) 200522946 將已秤重的藥物(50毫克)分散於賦形劑(至多5克) 中’並且接著維持於機械擾拌下,直到溶解為止。由於欲 得到,溶液濃度⑽毫克/克)與化合物⑽於Phosal 50PG 中的最大溶解度(115毫克/克)間之微小差異,故藥物於 Phosal 50PG中之溶解作用係為關鍵步驟(5h)。 固體基質^¥¥Πο毫克/克)| •化合物Ic φ •維生素 E TPGS (Eastman Chemicals,Batch 90001000) 將已秤重的藥物(50毫克)分散於熔化的賦形劑(5克) 中,並且接著維持於50—6〇〇c之機械攪拌下,直到溶解為 止。將整塊倒入栓劑模具中,並且保持冷藏過夜。就安定 性研究而言,將熔化的整塊倒入硬質明膠膠囊(尺寸丨),並 且保持冷藏過夜。接著去除明膠外殼。 _ 體之活體外性能 媒介物之組成 選擇以下受刺激的媒介物用於本試驗·· •胃媒介物USP,pH 1,2 •禁食的腸媒介物,pH 6, 8 (參照Dressman等人,Pharm. Res·, 1998) 27 200522946 •進食的腸媒介物,pH 5 (參照Dressman等人,Pharm· Res·, 1998) 表2—受刺激的腸-胃媒介物之組成 胃媒介物(G) 氣化鉀 2克 氣化氫1N 100毫升 去礦物質水 qsp 1000毫升 進食的腸媒介物(IFed) 針對500毫升 磷酸氫鉀 0.029 Μ 1·97 克 氫氧化鈉 qs pH 6. 8 qs pH 6. 8 牛膽酸鈉 5 mM 1.34 克 卵磷脂 1.5 mM 0·58 克 氣化鉀 0.22 M 8·2克 含或不含胰酵素 10克或0 5克或0 去礦物質水 qsp 11 qsp 500毫升 禁食的腸媒介物(IFast) 針對500毫升 醋酸 氫氧化納 qs pH 5 qs pH 5 牛膽酸鈉 15 mM 4·03 克 卵磷脂 4 mM 1·55 克 氯化鉀 0· 19 M 7·08 克 200522946 含或不含胰酵素 10克或0 5克或0 去礦物質水 qsp 11 qsp 500毫升 試驗條件及結果 將所有化合物(Ic)調配物(400毫克),於胃媒介物、禁 食的腸媒介物或進食的腸媒介物中(2〇毫升),以1 ·· 50稀 釋,接著在機械攪拌下(300 rpm),於37t培養2小時。於 過濾(0.2或2微米)之前及之後,藉HPLC測定藥物濃度。 膠態安定性及自身乳化性質之測定 本研究之目標係評估(Ic)調配物的乳液/微乳液/微膠 粒溶液於在GI媒介物中培養後之膠態安定性及自身乳化性 質。因此,將樣品過濾為2微米(能保留油脂微滴>2微米以 及藥物晶體>2微米)’接著透過hplc配藥。於以不同攄器尺 寸(〇· 45、2及5微米)針對藥物水溶液測試之篩選後,選擇 濾器尺寸(2微米)者。確切地,如圖1所示,於任一濾器尺 寸下(0.45、2及5微米),可觀察到高的藥物保留率(暗示晶 體>5微米之存在)。濾器尺寸(於研究範圍内)不會影響保留 分率,而媒介物之組成卻徹底地會。簡言之,過濾的分率, 於胃媒介物為約1%,於禁食的腸媒介物為2%,於進食的腸 媒介物為4. 5-5.5%。 於下表中報告及以下圖式中呈現之數據顯示,相較於 參考品(Miglyol 812N及PEG 400),任一受測調配物展現改 良的性能,因而確認選擇的賦形劑於GI流體存在下自身乳 200522946 化之能力。微乳液(3 : 1及4 : 1),以Vit E TPGS得到之微 膠粒溶液及以Phosal 50PG得到之乳液,係為在任一媒介物 中最均勻及安定的系統。毫微級晶體在腸媒介物中是安定 的,而”凝聚作用”出現於胃媒介物中,故造成藥物完全保 留於濾器中。以Labrafil/Labrasol及Gelucire44/14得到 之乳液,於過濾後,展現藥物濃度範圍為20-60% (Labrafil/Labrasol)及40-90% (Gelucire 44/14)。就所 有新穎的調配物而言,除Labrafil/Labrasol外,未觀察到 進食條件(pH、卵磷脂及膽鹽的濃度)之影響。 表3—於以GI媒介物預先培養及於過濾(2微米)後回收之化 M(Ic)(微克/毫升)(請亦看圖1)_ —----- ^mv// "/媒條 ——- 藥物 PEG 400 Gelucir e 44/14 Labrafil/ Labrasol Miglyol Phosal 50PG 微乳液 Cremophor/ Capryol 3/1 微乳液 Cremophor/ Capryol 4/1 度 200微克/毫升 L9 58.3 182.2 84.1 0 188.0 188.3 189.3 $食的腸 _PH^5 8· 8 20.5 90 123· 6 2.3 177.0 187.1 194.2 禁食的腸 _PH^8 4.2 14.5 118.4 39.1 0.6 175.7 198.8 195.6 針對GI流體之活體外效能之結論 200522946 就有關於調配的藥物之自身乳化性質及膠態安定性之 大體結論而言,相較於參考品(Migly〇l 812N及PEG 400), 所有受測的調配物展現改良的性能,因而確認選擇的賦形 劑於GI流體存在下自身乳化之能力。微乳液(3: 1及4: 1), 以Phosal 50PG得到之乳液及以Vit E TPGS得到之微膠粒溶 液,係為在任一媒介物中最均勻及安定的系統。就所有新 穎的調配物而言,除Labrafil/Labrasol外,未觀察到進食 /禁食條件對膠態安定性之影響,其中被過濾之藥物分率於 禁食的腸媒介物中從60降至20%。 於人類中,應暸解為了選擇最適當的每曰劑量,應考 量患者的重量、其一般健康狀態、其年齡及所有可能影響 治療效力之因素。組成物較佳製備為使得單位藥劑含有〇 ^ 至50毫克活性產物。 於通式(la)或(lb)之吖丁啶衍生物中,以下產物為更 特隹者: • 1-[雙(4-氣苯基)甲基]- 3 -[(3, 5-二氟苯基 砜基)亞甲基]吖丁啶 j • N- {1 -[雙(4-氣苯基)甲基]吖丁啶-3-基卜 - 3-基甲基確醯胺 • N-{1-[雙(4-氣苯基)甲基]吖丁啶-3-基卜5 二氟苯基)甲基磺醯胺 ’ 應瞭解根據本發明含有此等產物之組成物為特佳。 於另一方式中(其中引入第二活性成分),於相關產物 200522946 為***(sibutramine)之例子中,組成物可含有〇2至 50毫克。然而’此用量可視情況降低,且可改為〇 2至1〇 毫克。 於相關產物為L-多巴之例子中,組成物可含有刪至 300毫克之此第二活性成分,較佳為25〇毫克。 舉例來說,安定劑可為例如尤其選自α_生育醇、抗壞 血酸棕搁酸酯、ΒΗΤ(丁基羥基甲苯)、ΒΗΑ(丁基羥基茴香 醚)、沒食子酸丙酯或蘋果酸之抗氧化劑。 防腐劑(透過實例)可選自偏亞硫酸鈉、丙二醇、乙醇 或甘油。 於可調整黏度之藥劑中,可提及者為例如卵磷脂、磷 脂、磷脂、丙二醇藻酸酯、藻酸鈉或甘油。 可修飾組成物的感官性質之藥劑(透過實例)為蘋果 酸、反丁稀一*酸、甘油、香草路或甲醇。 當使用此等添加劑時,後者可含有總組成物之〇· 至5%重量。 根據本發明’藉適當地混合主要賦形劑(於固體或半固 體賦形劑之情形中,必要時,於加熱後),接著必要時混合 額外添加劑,接著添加通式(la)或(lb)吖丁咬衍生物,且 適當地添加能賦予通式(la)或(lb)吖丁咬街生物效力之活 性成分,並且維持攪拌,以獲致均勻的混合物,可製得醫 藥組成物。 此使用方法係更詳細地說明於以下實施例中。 可以液體、固體或半糊漿狀態提供根據本發明之組成 200522946 物。 其特別適合以硬質明膠膠囊或軟質明膠膠囊形式,或 以口服液形式呈現。 ^ 根據本發明之組成物,因其良好的安定性(同時兼具物 理上及化學上)及當口服施用通式(la)或(lb)吖丁 σ定衍生 物時所提供之生物可利用性提升,而特別有利。 根據本發明另一替代方式’如上述含有至少一種通式 (la)或(lb)活性成分之較佳組成物可於施用能賦予通式 (la)或(lb)吖丁啶衍生物效力之活性成分之前、同時地或 之後施用。 應瞭解’表現組套(就一方面而言,含有根據本發明如 上述之較佳組成物,以及就另一方面而言,含有具有能賦 予通式(la)或(IbV丫丁咬衍生物效力之活性成分之組成物) 亦落在本發明之範圍内。亦應暸解表現組套可含有具西布 曲明(sibutramine)或具活化腦中多巴胺神經傳遞藥劑之 組成物,作為能賦予通式(la)或(lb)吖丁啶衍生物效力之 組成物。 【圖式簡單說明】 圖1—化合物(Ic)水溶液:濾器尺寸對於回收的化合物 (Ic)分率之影響。 圖2—化合物(Ic)脂類溶液:於在37°C攪拌2小時及 過濾(2微米)後,媒介物對於化合物(ic)濃度之影響。 圖3—於3隻不同的小獵犬中之微乳液調配物中的化合 200522946 物(Ic)PK量變曲線。 圖4—於3隻不同的小獵犬中之Phosal 50PG調配物中 的化合物(Ic)PK量變曲線。 圖5—於3隻不同的小撒犬中之Labrafil/Labrasol調 配物中的化合物(Ic)PK量變曲線。 圖6—於3隻不同的小獵犬中之Miglyol 812N調配物 中的化合物(Ic)PK量變曲線。 【主要元件符號說明】
Claims (1)
- 200522946 十、申請專利範圍: 1. 一種安定的醫藥組成物,其含有至少一種以下通式之吖 丁啶衍生物:其中Ar為芳族或雜芳族基團,視情況以一或多個(a-C4) 烷基、鹵素、N02、CN、(C1-C4)烷氧基或0H基團取代, 視情況合併其他於含有以下成分之系統中能賦予通式 (la)或(lb)吖丁啶衍生物效力之活性成分: (i) 填脂,或 (ii) Miglyol、Capryol 及 Cremophor 之組合。 2.如申請專利範圍第1項之醫藥組成物,其中該至少一種 吖丁啶衍生物為3.如申請專利範圍第1項之醫藥組成物,其中每克調配物 含有至多200毫克之p丫丁咬衍生物。 200522946 4·如申請專利範圍第1至3項中之一項之醫藥組成物,其 進一步包含額外添加劑,係選自安定劑、防腐劑、使其 可調整黏度之樂劑或可修飾例如感官性質之藥劑。 5·如申請專利範圍第i項之醫藥組成物,其中衍生自吖丁 咬之該活性成分係以總組成物之0·01至70%重量之含 量存在。 6· —種製備如申請專利範圍第1至5項中之一項之組成物 的方法,其中適當地製備主要賦形劑(於固體或半固體 賦形劑之情形中,必要時,於加熱後)之混合物,接著 必要時製備具額外添加劑之混合物,接著添加式(1約 或(lb)吖丁啶衍生物,且適當地添加如申請專利範圍第 1項能賦予通式(la)或(lb)吖丁啶衍生物效力之活性成 分,並且維持攪拌,俾獲致均勻的混合物。 7.—種表現套組,其含有如申請專利範圍第丨或2項的組 成物以及具有能賦予如申請專利範圍第丨項所界定A 吖丁啶衍生物效力之活性成分的組成物。 疋之 8·如申請專利範圍第7項之表現套組,其中能賦予v丁咬 衍生物效力之活性成分為***(sibutramine)。 9·一種表現套組,其含有如申請專利範圍第丨或2項的組 成物以及具有活化腦中多巴胺神經傳遞藥劑的組成 物0 ^6
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US6355631B1 (en) * | 2000-03-03 | 2002-03-12 | Aventis Pharma S.A. | Pharmaceutical compositions containing azetidine derivatives, novel azetidine derivatives and their preparation |
FR2814678B1 (fr) * | 2000-10-04 | 2002-12-20 | Aventis Pharma Sa | Association d'un antagoniste du recepteur cb1 et de sibutramine, les compositions pharmaceutiques les contenant et leur utilisation pour la traitement de l'obesite |
FR2829027A1 (fr) * | 2001-08-29 | 2003-03-07 | Aventis Pharma Sa | Association avec un antagoniste du recepteur cb1, les compositions pharmaceutiques les contenant et leur utilisation pour le traitement de la maladie de parkinson |
FR2833842B1 (fr) * | 2001-12-21 | 2004-02-13 | Aventis Pharma Sa | Compositions pharmaceutiques a base de derives d'azetidine |
-
2003
- 2003-07-18 EP EP03291797A patent/EP1498123A1/en not_active Withdrawn
-
2004
- 2004-07-01 PE PE2004000633A patent/PE20050699A1/es not_active Application Discontinuation
- 2004-07-08 AU AU2004262497A patent/AU2004262497A1/en not_active Abandoned
- 2004-07-08 BR BRPI0412239-9A patent/BRPI0412239A/pt not_active IP Right Cessation
- 2004-07-08 OA OA1200600017A patent/OA13190A/en unknown
- 2004-07-08 JP JP2006519900A patent/JP2009513559A/ja active Pending
- 2004-07-08 KR KR1020067001146A patent/KR20060040690A/ko not_active Application Discontinuation
- 2004-07-08 CA CA002532668A patent/CA2532668A1/en not_active Abandoned
- 2004-07-08 RS YUP-2005/0971A patent/RS20050971A/sr unknown
- 2004-07-08 MX MXPA06000478A patent/MXPA06000478A/es not_active Application Discontinuation
- 2004-07-08 NZ NZ544707A patent/NZ544707A/en unknown
- 2004-07-08 WO PCT/EP2004/008552 patent/WO2005013972A1/en active Application Filing
- 2004-07-08 RU RU2006105000/04A patent/RU2348615C2/ru not_active IP Right Cessation
- 2004-07-08 EP EP04741332A patent/EP1648441A1/en not_active Withdrawn
- 2004-07-08 CN CNA2004800206437A patent/CN1822830A/zh active Pending
- 2004-07-08 SG SG200804302-8A patent/SG144140A1/en unknown
- 2004-07-13 US US10/889,729 patent/US20050037062A1/en not_active Abandoned
- 2004-07-14 PA PA20048606601A patent/PA8606601A1/es unknown
- 2004-07-15 AR ARP040102494A patent/AR045912A1/es not_active Application Discontinuation
- 2004-07-16 MY MYPI20042870A patent/MY142076A/en unknown
- 2004-07-16 UY UY28422A patent/UY28422A1/es unknown
- 2004-07-16 TW TW093121230A patent/TW200522946A/zh unknown
- 2004-07-16 GT GT200400134A patent/GT200400134A/es unknown
- 2004-08-07 UA UAA200601706A patent/UA82539C2/uk unknown
-
2006
- 2006-01-06 CR CR8178A patent/CR8178A/es not_active Application Discontinuation
- 2006-01-12 IL IL173113A patent/IL173113A0/en unknown
- 2006-01-16 MA MA28725A patent/MA27921A1/fr unknown
- 2006-01-17 ZA ZA200600489A patent/ZA200600489B/xx unknown
- 2006-01-17 HR HR20060021A patent/HRP20060021A2/hr not_active Application Discontinuation
- 2006-01-17 TN TNP2006000012A patent/TNSN06012A1/en unknown
- 2006-01-17 EC EC2006006291A patent/ECSP066291A/es unknown
- 2006-01-31 NO NO20060510A patent/NO20060510L/no not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
SG144140A1 (en) | 2008-07-29 |
WO2005013972A1 (en) | 2005-02-17 |
MY142076A (en) | 2010-08-30 |
AU2004262497A2 (en) | 2005-02-17 |
US20050037062A1 (en) | 2005-02-17 |
CN1822830A (zh) | 2006-08-23 |
AU2004262497A1 (en) | 2005-02-17 |
EP1498123A1 (en) | 2005-01-19 |
KR20060040690A (ko) | 2006-05-10 |
HRP20060021A2 (en) | 2006-02-28 |
MXPA06000478A (es) | 2006-04-05 |
RU2006105000A (ru) | 2006-07-10 |
TNSN06012A1 (en) | 2007-10-03 |
IL173113A0 (en) | 2006-06-11 |
EP1648441A1 (en) | 2006-04-26 |
PE20050699A1 (es) | 2005-09-15 |
ZA200600489B (en) | 2007-04-25 |
ECSP066291A (es) | 2006-07-28 |
UY28422A1 (es) | 2005-02-28 |
CR8178A (es) | 2007-12-04 |
MA27921A1 (fr) | 2006-06-01 |
OA13190A (en) | 2006-12-13 |
GT200400134A (es) | 2005-02-22 |
UA82539C2 (en) | 2008-04-25 |
BRPI0412239A (pt) | 2006-09-12 |
NZ544707A (en) | 2009-01-31 |
JP2009513559A (ja) | 2009-04-02 |
RS20050971A (en) | 2008-06-05 |
CA2532668A1 (en) | 2005-02-17 |
AR045912A1 (es) | 2005-11-16 |
RU2348615C2 (ru) | 2009-03-10 |
NO20060510L (no) | 2006-01-31 |
PA8606601A1 (es) | 2005-03-03 |
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