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TW200803920A - Sustained release small molecule drug formulation - Google Patents

Sustained release small molecule drug formulation Download PDF

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Publication number
TW200803920A
TW200803920A TW095136121A TW95136121A TW200803920A TW 200803920 A TW200803920 A TW 200803920A TW 095136121 A TW095136121 A TW 095136121A TW 95136121 A TW95136121 A TW 95136121A TW 200803920 A TW200803920 A TW 200803920A
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formulation
small molecule
ratio
polymer
drug
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TW095136121A
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Andrew S Luk
Gunjan H Junnarkar
Guohua Chen
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Alza Corp
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    • A61K9/00—Medicinal preparations characterised by special physical form
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    • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Description

200803920 九、發明說明： 【發明所屬之技術領域】 遞 本發明-般係關於小分子藥物的傳 5 0 15 2〇 【先前技術】 此處’，小分子藥物，，係指且有八曰 劑通常係藉由有機化學合成丨。利益 物、真菌和微生物。.通常用於傳 =:源如植 服、注射、吸入和經皮。 刀子梁物的途徑為口 許多精神治療劑均為小分子藥物並且 或多次投藥的口服藥丸和點滴 J了母曰- 觀察到血浆濃度之牵和谷，口服=和於投藥後 ”於投與小分子精神治療劑的最佳途徑： = 和谷將分別伴隨著負作用及治療效果的喪失。辰度的峰 的小之二ΐίΞΓ!服藥丸和點滴注射形式投藥 為減其他？式的治療可受益於設計 拄絳 /、 水/辰度之變化至最小的持續釋出劑型。以 釋出配製物投與精神治療劑亦可提高病人的順從性。 【發明内容】 發明之摘要 物，並入亡向中，本發明係關於一種可注射儲存式配製 一生物可相容聚合物、與該生物可相容聚合物 、、。以形成黏性凝膠的一有機㈣，以及併入黏性凝膠內 5 200803920 製物在體内里現具有Cmax對Cmin比例小於200及延 、精間小物之釋出曲線的小分子藥物。 ，另面向中，本發明係關於一種以控釋方式投與小 为子樂物至個體的士 體的方法，包括植入個體一有效量之可注射 二Ί1，衣物，其含有一生物可相容聚合物、與該生物可 物組合以形成黏性凝膠的一有機溶劑，以及併入 i 内而使配製物在體内呈現具有Cmax對C—比例小 1及延滯時間小於Μ之釋出曲線的小分子藥物。 «下列的說明將更瞭解本發明的其他特性及優點。 本發明的詳細脫明 、#、將4考些較佳具體實施例以及配合附圖詳細描 15 20 睁解在下列的描述中，為了提供對本發明更充分地 瞭=兄明許多特定的細節。然而，熟習本技術之人士 ΠίΓ月可在無部分或全部這些特定細節之下進行操 ^在其他的實例中’為了避免模糊本發明的隹點，因此 的說明可對本” 驟。參考附圖及下列 1月的扣性和優點有更佳的瞭解。 膠載劑内二入少量難溶之小分子藥物於儲存凝 放的發現。其 藥=製物具有接近零級體内釋 則事實上無法達到低突釋、接近零級釋放的程i = 6 200803920 中已確為數種具有C酿X對C‘比例小於2〇〇及延滯時間小 於〇·2之體内釋出曲線的小分子配製物。 ，，雙數Cmin”為血漿或血清内的最低藥物濃度。變 數”Cmax”為血漿或血清内的最高藥物濃度。變數”Tlag，，為 Tvalley# Tt〇tal 的比值，其 Tvaiiey 係小於 τ_ι。變數，，丁ΜΙ: ^達，cvalley的時間。變數”Cvaiiey”係藥物釋出時血漿或血 /月内藥物濃度的第一個;皮谷。、變數，，τ_ ”為總釋藥時間。 10 20 根據本發明的小分子藥物配製物可被製備成儲存式注 射蜊/、使用部位為一液體環境並且可包括皮下、肌肉内、 肌内灰官外膜、腫瘤内、或大腦内、患部、密接合空 間或人類或動物的體腔。生物體可投與多次或重複的2 射例如备藥物的治療效果消退時或已超過該藥物有效治 ，的期間或當該生物體因任何理由需再一次投與該藥物 該配製物在注人生物體内之後作為-種植人式持續釋 樂物輸送系統。此類控釋可維持一週、超過一週、一個 f或超過一個月的時間。該控釋較佳為維持至少一週的 碥，更佳為至少一個月的時間。 、根據本發明具體實施例的小分子藥物配製物含有一 f式凝膠載劑。該儲存式凝膠載劑含有-生物可相容聚合 2即在使用ί辰境中不會造成刺激或壞死的聚合物。可 、:本發明的生物可相容聚合物為生物可崩解，即在原位置 被逐漸分解、溶解、水解和/或浸蝕。 二施=括’但不侷限於’聚丙交酷、聚乙 曰Λ齩酐、聚胺、聚胺基曱酸酯、聚酯醯胺、聚原酸酯 7 200803920 (polyorthoesters)、聚二σ惡酮（polydioxanones)、聚縮酸、聚 酮縮醇、聚碳酸酯、聚原碳酸酯（polyorthocarbonates)、聚 石粦腈（polyphospliazenes)、琥ίό酸、聚（韻果酸）、聚（胺基 酸）、聚乙烯吡咯啶酮、聚乙二醇、聚羥基纖維素、聚醣、 5 幾丁質、幾丁聚糖，以及共聚物、三共聚物和其混合物。 儲存式凝膠載劑内聚合物的含量一般為從約5至80%重量 比，較佳為從約20至70%，通常為從約40至60%重量比。 馨 在一具體實施例中，該聚合物為一聚丙交醋。聚丙交 酷聚合物為乳酸的聚合物或乳酸和乙醇酸的共聚物。該聚 10丙交酯聚合物可能含有少量實質上不影響本發明之有利效 盈的其他共聚單體（comonomers)。”乳酸，，一詞包括L-乳 酸、D-乳酸、DL-乳酸和丙交酯的異構物。，，乙醇酸，，一詞包 括乙交(glycohde)。該聚合物的乳酸對乙醇酸單體的比例 為從約100 : 0至15 : 85，較佳為從約60 : 40至75 : 25， 15通常為約50 : 50。該聚丙交酯聚合物的平均分子量以凝膠 滲透層析法测定時為從約1，〇〇〇至約12〇,〇⑽，較佳為從約 5,000至約30,0〇〇。可從市面上購得適合的聚丙交酯聚合 物0 該儲存式/旋膠载劑進一步含有可結合聚合物形成黏性 20凝膠的生物可相容溶_，其黏度一般為從約5〇〇泊（p〇ise) 至200,000泊’車父佳為從約^咖泊至刪泊。用於儲 存式凝膠載劑内的滋：添彳2 d —般為一有機溶劑，其可為單一溶 劑或溶劑混合物。A v % 了限制儲存式凝膠載劑吸收使用環境
中的水分，該溶劑壶炙山\ L ⑷4夕成分溶劑中的至少一種溶劑成分較 8 200803920 佳為限制其與水的混合度，例如小 於重量比，更佳為小於3%重4二!較佳為小 〜MM — A 1j 、以0重里比的與水混合度。適合 則,i的貫把例包括，但不偈限於，苯甲 醇（BA)、苯甲酸乙酯（EB)、 下曰1 ；本甲 XT m ^ 、’甘 /由二乙酸酯（triacetin)，及 =甲基·2·鱗烧_MP)。儲存式凝膠载劑内之溶劑的含 般為從約20至95%重量比，較佳為從約3〇至8〇%重 $比，通常為從約40至60%重量比。 10 根據本發明具體實施例的配製物含有分散或溶解於如 上述之儲存式凝膠載劑内的小分子藥物。，，分散或溶解，，一 詞包括使小分子藥物併入黏性凝膠内的全部方法，包括溶 予去等。用於本發明配製物内的小分子藥物 4 V里,谷於水。在一較佳具體實施例中，用於本發明配製 物内的小分子藥物在水中的溶解度小於1毫克/毫升。在一 15 具體實施例中，用於本發明配製物内的小分子藥物具有從 200至2,000jf耳頓（Dalt〇ns)的分子量。用於本發明配製物 内的小分子藥物可為狹效或廣效治療劑。然而，本發明之 具有狭效的小分子藥物京尤Cmax和毒性控制而言可獲^有兴 的，。配製物内的小分子藥物含量通常為從約「至5二 重量比’較佳為從約5至4〇%重量比，通常為從 〇 20 30%重量比。 王 ^ 一具體實施例中，本發明配製物内的小分子藥物包 括小分子精神治療劑如小分子抗精神病劑、多巴胺受體激 動剡、夕巴胺X體拮抗劑、血清素受體激動劑、血清素受 體拮抗劑，及血清素吸收抑制劑。下表1顯示一些小分子 9 200803920
10 精神治療劑的物理化學性質。R209130-鹼具有C19H2GFNO 之分子式。R209130-苯乙醇酸鹽（R209130)具有 C19H2〇FNO· C8H803 之分子式。R209130-酒石酸鹽（R167154) 具有C19H2〇FNO · C4H606之分子式。R209130和其類似物 具有公認典型的抗精神病性質以及在動物模式内已顯示具 有抗焦慮、抗憂鬱和社交化效應。這些性質歸因於中樞性 多巴胺D2受體、血清素5-HT2A* 5-HT2C受體的二元拮抗 作用，以及正腎上腺素攝取的抑制作用。利培酮 (risperidone)-鹼具有C23H27FN4〇2之分子式。利培酮-雙羥 萘酸鹽具有C23H27 FN402 · C23H1606之分子式。利培酮係 血清素（5-HT2)和多巴胺（D2)受體拮抗劑的結合物。 表1 性質 R209130 R167154 R209130 鹼 利培酮鹼 利培阕 雙羥萘酸鹽 pKa 9.2 9.2 9.2 8.2/3.1 8.2/3.1 水中溶解度 (毫克/亳升） 0.32(pH4.9) 41.84(pH3.4) 0·008(ρΗ9·5) 0·09(ρΗ8·8) 0·2(ρΗ7·2) 在pH7之溶解度 (毫克/亳升） 0.35 6.1(pH6.5) 2 1 0·2(ρΗ7-2) BB内溶解度 (微克/毫升) 58.6 於 40°C 10.3 於 40°C >200,000 32,000 50 BA内溶解度 (毫克/毫升） 7.3 於 40°C 41.3 於 40°C >200,000 407 2.97 本身溶解速率 (毫克/平方釐求分） 0.054 3.7 0.7 0.0025 無 LogP(C8OH/pH7 緩衝液） 3.9 4.0 無 3.04 無 分子量 449.5 447.5 297.4 410.5 798.5 15 進行測定從本發明儲存式凝膠載劑傳遞之小分子藥物 200803920 的pk曲線以及鹽類型式藥物、溶劑類型、聚合物類型、 聚合物分子量、聚合物/溶劑比例、藥物裝載和粒徑對ΡΚ 曲線的影響。 下列實施例僅供說明之用途而非限制本發明的專利申 5 請範圍。 【實施方式】
10 實施例1 依如下方法製備儲存式凝膠載劑：將HDPE容器置於 Mettler P J3 000頂裝天评上稱重。將聚DL -丙父醋-共聚-乙 交酯（？!^0人）（!^/0比例為‘50:50)之商品1^8〇]\4£1^110502 (PLGA-502)稱入容器内。稱取該含有PLGA-502之容器的 重量，並將對應之溶劑加入PLGA-502。各種PLGA-502 之组合以百分比表示其含量，以及其溶劑說明下表2。利 15 用一混成混合物混合PLGA-502和溶劑混合物，而產生溶 劑内之聚合物的透明凝膠狀溶液。 表2 配製物 PLGA-502 (wt%，g) 苯甲酸苄酯 (wt%，g) 苯甲醇 (wt%，g) A 50.067 50.044 B 50.023 24.988 24.988 C 50.365 45.093 5.1780 D 50.139 37.553 12.560 E 50350 45.193 20 以溶劑和聚合物製備其他的儲存式凝膠載劑，該溶劑 η 200803920 係選自苯甲酸苄酯（BB)、苯甲醇（BA)、苯甲酸乙酯（EB)、 無水乙醇（EtOH)、甘油三乙酸酯、N-甲基-2-吡咯烷酮（NMP) 和其混合物，以及該聚合物係選自聚DL-丙交酯的 RESOMER® L104、RESOMER⑧ R104、RESOMER® 202、 5 RESOMER® 203、RESOMER® 206、RESOMER® 207、 RESOMER® 208; L/G 比例為 50/50 之 PLGA 的 RESOMER® RG 502H ; L/G 比例為 50/50 之 PLGA 的 RESOMER® RG 0 503 ; L/G 比例為 50/50 之 PLGA 的 RESOMER® RG 755 ; 聚L-丙交酯分子量為2000的RESOMER® L 206、 10 RESOMER® L 207、RESOMER® L 209、RESOMER® L 214 ; L/G比例為90/10之聚1^丙交酯-共聚0山-丙交酯的 RESOMER® LR 209 ； L/G 比例為 75/25 之 PLGA 的 RESOMER® RG 752、RESOMER® RG 756; L/G 比例為 85/15 之 PLGA 的 RESOMER® RG 858 ; L/G 比例為 70/30 之聚 15 L-丙交酯·共聚-三亞曱基碳酸酯的RESOMER® LT 706，以
2 0 及聚二噁酮的RESOMER® X 210(百靈佳大藥廠，維吉尼亞 州匹茲堡市）；L/G比例為100/0之D，L-丙交酯/乙交酯（DL) 的MEDISORB®聚合物100DL高、MEDISORB®聚合物 100DL低；L/G比例為85/15之D，L-丙交酯/乙交酯（DL)的 MEDISORB® 聚合物 8515DL 高、MEDISORB® 聚合物 8515DL低；L/G比例為75/25之D，L-丙交酯/乙交酯（DL) 的 MEDISORB®聚合物 7525DL 高、MEDISORB®聚合物 7525DL低；L/G比例為65/35之D，L-丙交酯/乙交酯（DL) 的 MEDISORB®聚合物 6535DL 高、MEDISORB®聚合物 12 200803920 6535DL低；L/G比例為54/46之D，L-丙交酯/乙交酯（DL) 的 MEDISORB®聚合物 5050DL 高、MEDISORB®聚合物 5050DL 低；MEDISORB® 5050 聚合物 DL 2A(3)、 MEDISORB® 5050 聚合物 DL 3A(3)、MEDISORB® 5050 聚 5 合物DL 4A(3)(醫藥吸收技術公司，俄亥俄州辛辛那堤 市）；以及PLGA(L/G比例為50/50)、PLGA(L/G比例為 50/50)、PLGA(L/G 比例為 65/35)、PLGA(L/G 比例為
75/25)、PLGA(L/G 比例為 85/15)、聚 D，L-丙交酯、聚 L-丙交酯、聚乙交酯、聚ε -己内酯、聚D，L-丙交酯-共聚-己 ίο 内酯（L/C比例為25/75)和購自伯明罕聚合物公司，阿拉巴 馬州伯明罕市的聚D，L-丙交酯-共聚-己内酯（L/C比例為 75/25)。亦可單獨使用聚己内酯-乙醇酸-乳酸共聚物 (PCL-GA-LA)或混合聚乙烯吡咯啶酮（pVP)。這些聚合物的 分子量一般為在6,000至20,000的範圍内。 15 實施例2 依如下方法製備藥物顆粒：使R209130、R167154、利 培酮鹼或利培酮雙羥萘酸鹽藥物通過不同孔徑的篩網而獲 得具有特定粒徑分佈範圍内的藥物顆粒。所獲得的粒徑為 2〇 20至63微米、63至125微米、75至125微米，或小於38 微米。將該微粒化顆粒用作為藥物顆粒。 實施例3 依如下方法製備儲存式配製物：以〇至50%重量比的 13 200803920 自實施例2的篩濾、藥物顆粒加人製 式，刻内’然後手動混合直至藥物顆粒完! 器的習知混= 方頭金屬鏟之Caf_°機械攪拌 、、曰入物^ 刀此合该藥物顆粒和儲存式凝膠載劑的 =合物。最後將均質的凝膠配製物轉置於 ：:丨： 的可拋棄式針筒内以便儲藏或作為分散物。& 30先升 實施例4 0 大鼠述方法製備具代表性數目的可植人凝膠然後在 定。$仃血清或血漿内藥物濃度對時間的藥物釋放測 0 ^ 1 S試驗的進行係在經由本發明植入系統 後依π開放式之藥物（例如，R209130、
It Γ·利培崎、利培酮魅萘酸鹽）域濃度的測定。 〇 ^ 例所製備之含藥物的儲存式凝膠配製物置入 t二刹的田可^式針筒内。將可抛棄式針頭08號）套上針 ^ 彳循％水槽加熱至37C>c。將儲存式凝膠配製物注 、内。在特定的間隔時間點進行採血然後分析其藥物 含罝。全部血衆樣本在分析前儲藏於代下。 實施例5 十1舰此實^例Ϊ研究藥物鹽類型式對體内從儲存式凝膠載 別釋出小分子藥物的影響。 依知貝施例3的方法將適當大小的R209130和 0 200803920 R167154顆粒併入儲存式凝膠載劑内。獲得之配製物說明 於下列表2。將最後的均質儲存式配製物置入3、10或30 毫升的可拋棄式針筒内以供儲存或作為分散物。根據實施 例4的方法分析藥物於體内的釋出。配製物在體内的釋出 5 曲線示於第1圖。Cmax對Cmin的比例以及配製物的Tlag值 示於表2。R167154和R209130為相同藥物的不同鹽類。 配製物7(R209130)具有19·2的cmax對Cmin比例及0.61 鲁的Tlag值，同時配製物3(R167154)具有25.7的Cmax對Cmm 比例及0·33的Tlag值。此實施例顯示體内的釋放速率受配 1〇 製物之鹽類型式的影響。配製物7(11209130)之Tlag即使高 於配製物3(&167154)之Tlag，與配製物3相比較配製物7 仍具有較佳的釋放速率曲線及釋放時間。 表2 編號 PLGA (wt%) BA (wt%) BB (wt%) 甘油三乙酸酯 (wt%) 藥物 (wt%) C max/C mi η Tlag ^2,a,II,a,A 45 22.5 22.5 0 10 25.7 0.33 ηλ^ΙΙ,α,β 45 22.5 22.5 0 10 19.2 0.61 1=R209130 ； 2=R16715^ b=50/50 PLGA-502H(分 =^13,500) ；e=75/25PL( a=P/S 比例為 50/50 ; / 例為 55/45 ; A=63〜125 G=不適用；NV=無波谷 t ; 3=利培酮鹼；4=利培酮雙羥萘酸鹽；a=5〇/5〇p] 子量=11，000); c=50/50 PLGA(分子量=6400) ; d==4 认(分子量=14,300); f=80/20PCL-GA-LA/PVP ; g= 3=P/S 比例為 40/60 ; %=P/S 比例為 45出；5 =P/; 微米；B=20〜63微米；C=75〜125微米；D=<38微 LGA-502(分子量=16,000ΪΓ~ 0/55/5 PCL-GA-LA(分子量 =RG502 ： RG502H(1 ： 1)； s比例為60/40 ; e=P/S比 :米；E=微粒化；f=如同； 實施例6 此實施例係研究溶劑類型對體内從儲存式凝膠載劑釋 出小分子藥物的影響。 15 15 200803920 依照實施例1的方法以PLGA-502及選自BA、BB、 EB、EtOH、NMP以及和甘油三乙酸醋和其組合的溶劑製 備儲存凝膠載劑。依照實施例3的方法以適當含量將藥物 併入儲存式凝膠載劑内。獲得之配製物示於下列表3。將 5 最後的均質儲存式配製物置入3、10或30毫升的可拋棄式 針筒内以供儲存或作為分散物。表3内之配製物的體内釋 出曲線示於第2圖。Cmax對Cmin的比例以及配製物的Tlag I值示於表3。 表3 配製物内的目標含量(％重量/重量） 編號 PLGA BA BB EtOH NM 甘油三 乙酸酯 EB 藥物 C ni a χ/C min T|ag 22，a，II，a，A 45 0 45 0 0 0 0 10 59.86 N/V ^2,a,II, α,A 45 22.5 22.5 0 0 0 0 10 25.68 0.33 l〇l，a，III，a，C 40 40 0 0 0 0 0 20 4.35 0.61 40 20 20 0 0 0 0 20 3.15 0.50 63^,a,VII,a,c 43.3 0 0 0 0 433 0 13.4 1364.43 0.14 y ^3,a,VII, a,G 433 0 0 0 0 0 43.3 13.4 5.20 無 1=R209130 ; 2=R167154 ; 3=利培酮鹼；4=利培酮雙羥萘酸鹽；a=50/50PLGA-502(分子量=16,000); b=50/50PLGA-502H(分子量=11，000) ; c=50/50PLGA(分子量=6400) ; d=40/55/5PCL-GA-LA(分子量 〜13,500) ; e=75/25 PLGA(分子量=14,300) ; f=80/20 PCL-GA-LA/PVP ; g=RG502 : RG502H(1 : 1); a=P/S 比例為 50/50 ; y5=P/S 比例為 40/60 ; x=P/S 比例為 45/55 ; δ =P/S 比例為 60/40 ; ε =P/S 比 例為55/45 ; A=63〜125微米；B=20〜63微米；C=75〜125微米；D=<38微米；E=微粒化；F=如同； G=不適用；NV=無波谷 在上述表3中，配製物63(利培酮鹼/PLGA/甘油三乙 酸酯儲存凝膠）的Cmax對Cmin比例為1364.43。另一方面， 配製物73(利培酮鹼/PLGA/EB儲存凝膠）的Cmax對Cmin比 15 例為5·20，其明顯小於配製物的Cmax對Cmin比例。配製物 2(R167154/PLGA/BB儲存凝膠）的Cmax對Cmin比例為 59.86。另一方面，配製物 3(R167154/PLGA/BA/BB)的 Cmax 16 200803920 對Cmin比例為25·68，其小於配製物2之Cmax對Cmin比例 的1/2。此表示溶劑類型玎影響配製物體内的釋出曲線。 實施例7 5 此實施例係研究聚合物類型對體内從儲存式凝膠載劑 釋出小分子藥物的影響。 依照實施例3的方法製備不同聚合物及裝载適當粒徑 範圍之R209130的儲存式凝膠載劑。獲得之配製物示於下 _列表4。將最後的均質儲存式配製物置入3、10或30毫升 1 0的可拋棄式針筒内以供儲存或作為分散物。表4為配製物 體内釋出曲線的Cmax對cmin比例及Tlag值。 配製物内的目標含量(％重量 /重量） 編號 聚合物 BA BB 藥物 Cmax/Cmiu Tjag 35 ^ 35 0 30 9.86 0.17 35 0 35 30 6.83 0.17 2^1,a,IV,a,E 35 0 35 30 44.0 NV 2^1,c,IV,a,C 35 0 35 30 29.49 _ 0.45 22lAIV,a,C 35 0 35 30 10.65 0.12 %l，f；IV，cr，C 35 35 30 6.35 0.14 2^1,a,IV,a,C 35 35 0 30 8.75 _ 0.23 35 0 35 30 44.21 NV 4gl,c,IV,a,E 35 0 35 30 163.12 NV 53l，e，lV，a，E 35 0 35 30 31.16 0.25 59i，d，iv，《，。 35 0 35 30 6.26 0.07 b=50/50PLGA-502H(分子量=11，〇〇〇) ; c=5〇/50PLGA(分子量=6400) ; d=40/55/5 PCL-GA-LA(分子量 〜13,500) ; e=75/25 PLGA(分子量=14,300) ; f=80/20PCL-GA-LA/PVP ; g=RG502 : RG502H(1 : 1); a=P/S 比例為 50/50 ;冷=P/S 比例為 40/60 ; % =P/S 比例為 45/55 ; <5=P/S 比例為 60/40 ; ε=Ρ/8 比 例為55/45 ; Α=63〜125微米；Β=20〜63微米；C=75〜125微米；D=<38微米；微粒化；F=如同； G=不適用；NV=無波谷 17 200803920 實施例8 此實施例係研究聚合物分子量對體内從儲存式凝膠載 劑釋出小分子藥物的影響。 依照實施例3的方法製備不同分子量及裝載適當粒徑 5 範圍之藥物的儲存式凝膠載劑。獲得之配製物示於下列表 5。將最後的均質儲存式配製物置入3、10或30毫升的可 拋棄式針筒内以供儲存或作為分散物。表5為配製物體内 釋出曲線的Cmax對Cmin比例及Tlag值。 表5 編號 聚合物 BA BB 甘油三 乙酸酯 藥物 C max/Cm in Tiag l〇I，a，m，a，C 40 40 0 0 20 4.35 0.61 l〇l，a，III,a，C 40 40 0 0 20 12.06 0.61 J2I,a,IV>a>c 35 35 0 0 30 4.78 0.14 35 35 0 0 30 5.29 0.36 2il，c，ni，a，C 40 40 0 0 20 48.55 NV 251,c>lv,a,c 35 0 35 0 30 29.49 0.45 261>c，IV，a，〇 35 0 35 0 30 41.67 NV 4gl>c,IVia,E 35 0 35 0 30 163.12 NV 49!Αΐν,(5,Ε 42 0 28 0 30 66.31 0.39 43.3 0 0 433 13.4 1364.43 0.14 a，c 36.9 0 36.9 0 26.1 11.66 NV 694，a，VlII，a，E 36.9 0 36.9 0 26.1 14.12 0.90 7〇4，c，VIII，a，c 36.9 0 36.9 0 26.1 22.11 NV 723AVII，a，G 43.3 0 43.3 0 13.4 24.48 無 1=R209130 ； 2=R： b=50/50 PLGA-5C 量=-13,500); e=: 1) ; a=IVS 比例一 =P/S比例為55/4: F=如同；G=不摘 167154; 3=利培酮驗；4=利培酿 >2H(分子量=11,000) ; c=50/5(H 75/25 PLGA(分子量=14,300) ; f 备 50/50 ; /? =P/S 比例為 40/60 5 ; A=63〜125 微米；B=20〜63 > 用；NV=無波谷 雙羥萘酸鹽；a=50/50】 >LGA(分子量=6400) ; 1 =80/20 PCL-GA-LA^\ ;J=p/S 比例為 45/55 敵米；075〜125微米 3LGA-502(分子量= d=40/55/5 PCL-GA Φ ； g=RG502 ： RG :;5=P/S比例為（ ;D=<38 微米；E= 46,000)； -LAC分子 502H(1 ： Ϊ0/40 ； a 微粒化·， 甘油 18 200803920 實施例9 此實施例係研究聚合物/溶劑比例對體内從儲存式凝 膠載劑釋出小分子藥物的影響。 依照實施例3的方法製備不同聚合物/溶劑比例及裝 5 載適當粒徑範圍之藥物的儲存式凝膠載劑。獲得之配製物 示於下列表6。將最後的均質儲存式配製物置入3、10或 30毫升的可抛棄式針筒内以供儲存或作為分散物。表6為 配製物體内釋出曲線的Cmax對Cmin比例及Tlag值。 表6
配製物内的目標含量(°/〇重量/重量） 編號 PLGA BB EtOH 藥物 C max/C min Tlag 35 0 0 30 9.86 0.17 2^1,a,lV,a,C 35 35 0 30 6.83 0.17 241^° 3 35 35 0 30 44.00 NV 251,c>lv>a>c 35 35 0 30 29.49 0.45 261,c>IV,a,D 35 35 0 30 41.67 NV 2yi,c,iy^,c 28 42 0 30 54.16 NV 2g1>c>!V>/S,D 28 42 0 30 120.74 NV 291^1^山 c 31.5 34.65 3.85 30 1.93 NV SOWvj’d 31.5 34.65 3.85 30 7.07 0-29 4gl)c}iV,a,E 35 35 0 30 163.12 NV 491,0,1^53 42 28 0 30 66.31 0.39 52 28 42 0 30 47.86 NV 53!，e，IV，a，E 35 35 0 30 31.16 0.25 ~56^77~ 38.5 31,5 0 30 17.10 NV 654，c，v®，a，E 36.9 36.9 0 26.1 50.87 NV 664,c,vm：I^^ 40.6 33.2 0 26.1 38.39 NV 674，c，vijm，g 1 一Γ>ΟΛΛ1，λ . ^ 33.2 40.6 0 26.1 43.55 NV ----，么一八夏口, , 增網敵，鐸=不ί!增景吸货，这一fLvi八分子量=i6,000); b=5〇/5〇PLGA-5〇2H(分子量=ll，〇〇〇) ; c=5〇/5〇plga(分子量=6400) ; (!=40/55/5ΡαΧ5Α-ίΑ(^子詈 =-13,500) ; e=75/25 PLGA(分子量=14,300) ; f=80/20P(X.(3A_IA/PVP ; . α，比例為 50/50 ;卜P/s 比例為 4〇/6〇 ; χ=ρ 二RG502H(1 . 1)， 例為 55/45 ; A=63〜125 微米；B=20〜63 微米；C=75 為 45/55 ’ 5—P/S 比例為 60/40 ·，ε =P/S 比 G=不適用；NV=無波谷 〜125微米；D=<38微米；E=微粒化；F=如同； 19 200803920 實施例ίο 此實施例係研究截藥量對體内從儲存式凝膠載劑釋出 小分子藥物的影響。 依照實施例3的方法製備在適當粒徑範圍内之不同藥 5物百分比的儲存式凝膠載劑。獲得之配製物示於下列表 7。將最後的均質儲存式配製物置入3、1 〇或3〇毫升的可 拋棄式針筒内以供儲存或作為分散物。表7為配製物體内 釋出曲線的Cmax對Cmjn比例及Tiag值。 配製物内的目標含量(％重量/重量） 編號 PLGA BA BB 藥物 C max/C m| „ T|ag ct ,Β 45 45 0 10 4.37 0.50 40 20 20 20 10.66 0.61 〒l:a，II，a，B 45 22.5 22.5 10 19.17 0.61 101戊，C 40 40 0 20 435 0.61 40 40 0 20 12.06 0.61 |2l,a,lV,a,C 35 35 0 30 4.78 0.14 35 35 0 30 5.29 0.36 141，这，hi，a，c 40 20 20 20 3.15 0.50 40 20 20 20 9.60 0.61 2gl,a,IV,a,C 35 17.5 17.5 30 7.16 0.61 |yl,a,lV,a,D 35 17.5 17.5 30 1735 0.36 18l，a，V，a，C 30 30 0 40 3.54 0.39 I-R209130 ； 2=R167154 ； b=50/50 PLGA-502H(分子量= =M3,500) ; e=75/25 PLGA(分 a=P/S 比例為 50/50 ; /S=P/S 例為55/45 ; A=63〜125微米； G=不適用；nv=無波谷 Μ培酮鹼;4=利培酮雙羥萘酸鹽;a=50/50PLGA-502(分子 11，000) ; c=50/50PLGA(分子量=6400) ; d=40/55/5 PCL-G, 子量=14,300) ; f=80/20PCL-GA-LA/PVP ; g=RG502 : RG: 比例為40/60 ; %=P/S比例為45/55 ; δ =P/S比例為60/Φ ;B=2(K63微米；075〜125微米；D=<38微米；E=微粒4 量=16,000); \-LA(分子量 502H(1 : 1); 0 ; ε =P/S 比 b ; F=如同； 20 200803920 實施例11 此實施例係研究藥物粒徑對體内從儲存式凝膠載劑释 出小分子藥物的影響。 依照實施例3的方法製備及裝載適當粒徑之藥物的儲 5 存式凝膠載劑。獲得之配製物示於下列表8。將最後的均 質儲存式配製物置入3、10或30毫升的可拋棄式針筒内以 供儲存或作為分散物。表8為配製物體内釋出曲線的cmax 鲁對Cmin比例及Tlag值。 配製物内的目標含量(％重量/重量） 編號 PLGA BA BB 藥物 Cmax/Cmin Tlag γΙ,ΜΙ,α,β 45 22.5 22.5 10 19.17 0.61 JQl>a,IU,a,C 40 40 0 20 4.35 0.61 J 40 40 0 20 12.06 0.61 35 0 35 30 6.83 0.17 35 0 35 30 44.00 NV 35 0 35 30 29.49 0.45 D 35 0 35 30 41.67 NV 644,c,Vili,a,C 36.9 0 36.9 26.1 11.66 NV es^m^E 36.9 0 36.9 26.1 50.87 NV 40.6 0 33.2 26.1 38.39 NV 43.3 0 433 13.4 24.48 無 1=R209130 ; 2=R167154 ； 3=^ b=50/5〇 plga_502H(分子量= 〜^,500) ; e=75/25 PLGA(分 a=p/S 比例為 50/50; ^=P/S 例為55/45 ; A=63〜125微米； 無波谷 W培酮鹼；4=利培酮雙羥萘酸鹽；a=50/50PLGA-502(分子量=16,000); 11，000) ; c=50/50PLGA(分子量=6400) ; d=40/55/5 PCL-GA-LA(分子量 子量=14,300) ; f=80/20PCL-GA-LA/PVP ; g=RG502 : RG502H(1 : 1); 比例為 40/60 ; x=P/S 比例為 45/55 ; 5=P/S 比例為 60/40 ; e=P/S 比 ;B=20〜63微米·’ C=75〜125微米；d=<38微米；E=微粒化；F=如同； ------- ---- -----f 12 若cmax對cmin比例小於200,較佳為小於50,更佳為 21 200803920 小於30時則配製物被視為接近零級。配製物釋放之Tiag 值較佳為小於0.2。未出現Cvalley的配製物不呈現延滯現 象。表9顯示呈現零級釋放之特性的許多配製物。第4圖 顯示表9中選取之配製物的體内釋出曲線。
配製物内的目標含量(％重量/重量） 編號 聚合物 BA BB EtOH 藥物顆粒 C m a χ/C m i n Tjag |2Ua,IV,«,C 35 35 0 0 30 9.86 0.17 22^Μν,α,0 35 0 35 0 30 6.83 0.17 2^1,a,IV,A：,C 31.5 0 34.65 3.85 30 1.93 NV 22lAIV,a,C 35 35 0 0 30 10.65 0.12 2^1,f,IV,a,C 35 0 35 0 30 6.35 0.14 2^1,c,IV,a,C 35 0 35 0 30 44,21 . NV 35 0 35 0 30 6.33 0.11 56l，bJV，，F 38.5 0 31.5 0 30 17.10 NV 6〇l，cJV，a，C 25 0 25 0 50 12.90 0.07 gjl,c,IV,a,C 35 0 35 0 30 26.53 0.11 644,c,VIII,a,C 36.9 0 36.9 0 26.1 11.66 ~ —----- NV 7Q4,c,VIII,a,C 36.9 0 36.9 0 26.1 22.11 〜 NV 1=R209130 ; 2=R167154 ; 3=利培酮驗；4=利培酮雙經萘酸鹽；a=50/50 PLGA-502(^^^ =16,000) ; b=50/50 PLGA-502H(分子量=11，〇〇0); c=50/50 PLGA(分子量=6400) ; d=40/55/5 PCL-GA-LA(分子量〜13,5O0) ; e=75/25 PLGA(分子量=14,300) ; f=80/20PCL-GA-LA/PVP ; g=RG502:RG502H(l: 1); a=P/S 比例為 50/50; /8=P/S 比例為 40/60; x=P/S 比例為 45/55 ; 5=P/S 比例為 60/40 ; e=P/S 比例為 55/45 ; A=63〜125 微米；b=20〜63 微米；C=75〜125 微 米；D=<38微米；E=微粒化；F=如同；Γ户用；谷 _ 本發明雖然以有限數目的具体例進行說明，但是受益 於此揭示之熟習本技藝的人士將瞭解在不偏離本發明此處 10 所揭示之範圍下仍可設計出其他的具体例。 【圖式簡單說明】 22 200803920 第1圖顯示鹽類對根據本發明具體實施例之配製物在 體内釋出曲線的影響； 第2圖顯示〉谷劑類型對根據本發明具體實施例之配製 物在體内釋出曲線的影響； 、 5製物！物類型對根.據本發明具體實施例之配 μ擇出曲線的影響； 第4圖顯示根據本於明呈辦每 ❿出曲線的配製物。 監月之/、體貝苑例具有接近零級釋 號說明 主要元件符 無 23

Claims (1)

  1. 200803920 十、申請專利範圍： 1. 一種可注射儲存式配製物，其含有： 一生物可相容聚合物； 與該生物可相容聚合物組合以形成黏 r對性凝膠内而使配製物在體内以 其中該體内釋放 其中該小分子藥 其中該小分子於 其中該聚合物為 2·如申請專利範圍第1項之配製物 曲線的cmax對Cmin比例小於3〇。 3·如申請專利範圍第丨項之配製物 為僅少量溶於水。 4·如申睛專利範圍第1項之配製物 水的溶解度為小於1毫克/毫升。 15 20 5·如申睛專利範圍第1項之配製物 聚丙交醋。 二ΓΠ專利範圍第5項之配製物，請聚合物之 礼心對乙醉酸的單體比例為從100 : 〇至15 · 85。 選自7由二?Γ?圍第1項之配製物，其中該聚合物係 方 又日、聚乙交酯、聚己内酯、聚酸酐、聚胺、 ί二醇酸Γ:=酿胺、聚原酸酯、聚二噁_、聚縮駿、 ^ 來妷酸酯、聚原碳酸酯、聚磷腈、琥珀酸、聚（ 聚i胺基酸)、聚—聚乙二醇、聚= 'Π:!膽、幾丁質、幾丁聚糖’以及共聚物、三共ΐ 物和其混合物所構成之群組。 /、來 24 200803920 8·如申請專利範圍第1項之配製物，其中該溶劑係選 自由苯甲醇（ΒΑ)、苯甲酸苄酯（ΒΒ)、苯甲酸乙酯（ΕΒ)、無 水乙醇、甘油三乙酸酯、Ν-甲基-2-吡咯烷酮（ΝΜΡ)及其混 合物所構成之群組。 5 20 9·如申請專利範圍第1項之配製物，其中該小分子藥 物含有抗精神病劑。 ^ 1 〇.如申請專利範固第1項之配製物，其中該小分子 m自由多巴胺受體激動劑、多巴胺受體拮抗劑、血 月素又體&動劑、血清素受體拮抗劑、企清素吸收抑制劑 及其組合所構成之群組。 華物申請專利範目第1項之配製物，其巾該小分子 二=係、自由鹼和鹽類型式的R209130和利培酮所構成之 華物=八請專利範圍第1項之配製物，其中該小分子 梁物的刀子$為從2〇〇至2，_道耳頓。 13.如申請專利範圍第1項 g 甘士# 水的不可混合度為小於4量項比之配I物’其中該溶劑與 荜物Γ顆t申請專利範圍第1項之配製物，其中該小分子 桌物，顆粒型式並且其平均粒徑為從G1 i 125 )。刀子 藥物的釋mu範斤圍第1項之配製物，其中該小分子 :的釋出為在或接近目標速率下維持長達 25 200803920 17· —種以控釋方式投與小分子藥物至個體的方法， 其包括： 植入個體有效置之可注射儲存式配製物，其含有一 生物可相容聚合物、與該生物可相容聚合物組合以形 成黏性凝膠的-有機溶劑，以及併入黏性凝膠内而使 ^衣物在體内呈現具有Cmax對比例小於200及延 π日守間小於〇·2之釋出曲線的小分子藥物。 10 物择1L如申請專利範圍第17項之方法，其中該小分子藥 控釋方式全身性傳送一段釋放時間。 至少：—ζ申請專利範圍第17項之方法，其中該釋放時間 物含申請專利範圍第17項之方法，其中該小分子藥 穷3有抗精神病劑。
    26
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