TW201605439A - 組合物 - Google Patents
組合物 Download PDFInfo
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- TW201605439A TW201605439A TW104123119A TW104123119A TW201605439A TW 201605439 A TW201605439 A TW 201605439A TW 104123119 A TW104123119 A TW 104123119A TW 104123119 A TW104123119 A TW 104123119A TW 201605439 A TW201605439 A TW 201605439A
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- TW
- Taiwan
- Prior art keywords
- pain
- compound
- pharmaceutically acceptable
- formula
- pregabalin
- Prior art date
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Abstract
本發明係關於一種治療疼痛之方法,包括分開、依序或同時投與給有此治療需要之個體治療上有效量之式(I)化合物
□或其醫藥上可接受之鹽,其中Y為-Cl或-CF3;及治療上有效量之加巴噴丁(gabapentin)或普瑞巴林(pregabalin),或其醫藥上可接受之鹽。
Description
本發明係關於使用醫藥活性劑組合物來治療疼痛。更特定言之,本發明係關於N-噻唑基-4-苯氧基苯磺醯胺衍生物與第二醫藥活性劑之組合物之用途、及含有其之醫藥組合物。
為本發明組合物第一組分之N-噻唑基-4-苯氧基苯磺醯胺衍生物係Nav1.7鈉通道之調節劑。該化合物揭示於國際專利申請案PCT/IB2010/050033(公開為WO2010/079443)中。
電壓閘控鈉通道發現於包括肌肉之肌母細胞及中樞與周邊神經系統之神經元的全部可興奮細胞中。在神經元細胞中,鈉通道主要負責產生作用電位之迅速上升衝程。以此方式鈉通道對神經系統中電訊號的起始及傳播係必不可少。由此正確及適當的鈉通道之功能對於神經元之正常功能係必不可少。因此,吾人認為異常鈉通道功能構成多種醫學疾病(關於遺傳離子通道疾病之綜述參見Hubner C.A.、Jentsch T.J.,Hum.Mol.Genet.,11(20):2435-45(2002)),該疾病包括癲癇症(Yogeeswari等人,Curr.Drug Targets,5(7):589-602(2004))、心律不齊(Noble D.,Proc.Natl.Acad.Sci.USA,99(9):5755-6(2002)、肌肉強直(Cannon,S.C.,Kidney Int. 57(3):772-9(2000))及疼痛(Wood,J.N.等人,J.Neurobiol.,61(1):55-71(2004))。
目前具有至少九種已知的電壓閘控鈉通道(VGSC)α亞單位家族成
員。用於此家族之名稱包括SCNx、SCNAx、及Navx.x。已將VGSC家族系統分為兩亞族Nav1.x(除SCN6A外全部)及Nav2.x(SCN6A)。可將Nav1.x亞族功能上再分為兩群組,彼等對由河豚毒素阻斷敏感者(TTX敏感性或TTX-S)及彼等抗由河豚毒素阻斷者(TTX-抗性或TTX-R)。
大量證據表明Nav1.7可在各種疼痛狀態(包括急性、炎症及/或神經病變性疼痛)中起重要作用。在小鼠之傷害感受性神經元中SCN9A基因之缺失導致降低機械及熱疼痛臨限值及降低或廢除炎症疼痛反應(Nassar等人,Proc Natl Acad Sci USA,101(34):12706-11(2004))。在人類中,Nav1.7蛋白質已經顯示在神經瘤(特定言之疼痛性神經瘤)中累積(Kretschmer等人,Acta.Neurochir.(Wien), 144(8):803-10(2002))。Nav1.7之功能獲得型突變(家族及偶發性兩者)與原發紅斑性肢痛(一種以肢體灼痛及炎症為特徵之疾病)(Yang等人,J.Med.Genet.,41(3):171-4(2004))及陣發極端疼痛疾病(Waxman,SG Neurology.7;69(6):505-7(2007))有關。與此觀察結果一致的係報導非選擇性鈉通道阻斷劑利卡多因(lidocaine)及美西律(mexiletine)可在家族紅斑性肢痛情況下提供症狀緩解(Legroux-Crepel等人,Ann.Dermatol Venereol.,130:429-433)及卡馬西平(carbamazepine)可有效降低在PEPD發作之數量及嚴重程度(Fertleman等人,Neuron;52(5):767-74(2006))。Nav1.7在疼痛中之作用之其他證據發現於SCN9A基因之功能喪失型突變之表現型。Cox及同仁(Nature,444(7121):894-8(2006))首先報導SNC9A之功能喪失型突變與先天性痛覺淡漠(CIP)(一種以對疼痛刺激完全無或不敏感為特徵之罕見嚴重隱性基因病症)間之關聯。隨後研究已揭示導致SCN9A基因功能喪失及CIP表現型之若干不同突變(Goldberg等人,Clin Genet.;71(4):311-9(2007),Ahmad等人,Hum Mol Genet.1;16(17):2114-21(2007))。
Nav1.7抑制劑由此潛在可用於治療廣泛疾病,特定言之疼痛。
本發明組合物之第二組分係選自加巴噴丁及普瑞巴林之醫藥活性劑。
加巴噴丁(2-[1-(胺基甲基)環己基]乙酸)及普瑞巴林((S)-3-(胺基甲基)-5-甲基己酸)係鈣通道之α2-δ亞單位之配位體。已經報導其有效用於治療神經病變性疼痛。加巴噴丁以商標名Neurontin售賣及普瑞巴林在商標名Lyrica售賣。
持續需要提供用於管理疼痛之改良方法。如本文揭示使用Nav1.7調節劑與在鈣通道α-2δ亞單位之活性之調節劑之組合物可提供治療方案,該方案提供:較高療效;及/或當與個別試劑相比時使用較低劑量組合物之能力;及/或對單獨使用任一試劑之改良耐受性。
在第一態樣A1中,本發明提供一種治療疼痛之方法。
在第一實施例A1E1中,本發明提供一種治療疼痛之方法,其包括投與給有此治療需要之個體治療上有效量之根據式(I)之化合物
或其醫藥上可接受之鹽,其中-Y為-Cl或-CF3;其中該方法進一步包括分開、依序或同時投與治療上有效量之選自加巴噴丁或普瑞巴林、或其醫藥可接受之鹽之第二醫藥活性化合物。
在又一實施例A1E2中,本發明提供如實施例A1E1之方法,其基本上由投與根據式(I)之化合物及選自加巴噴丁或普瑞巴林之第二醫藥
活性化合物、或一種或兩種該等化合物之醫藥上可接受之鹽組成。
在又一實施例A1E3中,本發明提供如實施例A1E1或A1E2之方法,其中該根據式(I)之化合物係4-[2-(5-胺基-1H-吡唑-4-基)-4-氯苯氧基]-5-氯-2-氟-N-(1,3-噻唑-4-基)苯磺醯胺(I A )或其醫藥上可接受之鹽。
在又一實施例A1E4中,本發明提供如實施例A1E1或A1E2之方法,其中該根據式(I)之化合物係4-[2-(5-胺基-1H-吡唑-4-基)-4-(三氟甲基)-苯氧基]-5-氯-2-氟-N-(1,3-噻唑-4-基)苯磺醯胺(I B )或其醫藥上可接受之鹽。
在又一實施例A1E5中,本發明提供如實施例A1E1、A1E2、A1E3及A1E4中任一項之方法,其中該第二醫藥活性化合物係加巴噴丁或其醫藥上可接受之鹽。
在又一實施例A1E6中,本發明提供如實施例A1E1、A1E2、A1E3及A1E4中任一項之方法,其中該第二醫藥活性化合物係普瑞巴林或其醫藥上可接受之鹽。
在又一實施例A1E7中,本發明提供如實施例A1E1、A1E2、
A1E3、A1E4、A1E5及A1E6中任一項之方法,其中該根據式(I)之化合物及該第二醫藥活性化合物係同時投與。
在又一實施例A1E8中,本發明提供如實施例A1E7之方法,其中該根據式(I)化合物及該第二醫藥活性化合物係一起作為單一醫藥劑型投與。
在又一態樣A2中,本發明提供一種醫藥活性劑之組合物。
在第一實施例A2E1中,本發明提供一種組合物,其包含如在實施例A1E1或A1E2中所定義之根據式(I)之化合物及第二醫藥活性化合物,或一種或兩種該等化合物之醫藥上可接受之鹽。
在又一實施例A2E2中,本發明提供根據實施例A2E1之組合物,其係選自:4-[2-(5-胺基-1H-吡唑-4-基)-4-氯苯氧基]-5-氯-2-氟-N-(1,3-噻唑-4-基)苯磺醯胺與加巴噴丁之組合物;4-[2-(5-胺基-1H-吡唑-4-基)-4-氯苯氧基]-5-氯-2-氟-N-(1,3-噻唑-4-基)苯磺醯胺與普瑞巴林之組合物;4-[2-(5-胺基-1H-吡唑-4-基)-4-(三氟甲基)-苯氧基]-5-氯-2-氟-N-(1,3-噻唑-4-基)苯磺醯胺與加巴噴丁之組合物;及4-[2-(5-胺基-1H-吡唑-4-基)-4-(三氟甲基)-苯氧基]-5-氯-2-氟-N-(1,3-噻唑-4-基)苯磺醯胺與普瑞巴林之組合物;或一種或兩種該等化合物之醫藥上可接受之鹽。
在又一態樣A3中,本發明提供一種醫藥劑型。
在第一實施例A3E1中,本發明提供一種醫藥劑型,其包含如在實施例A1E1、A1E2、A1E3、A1E4、A1E5及A1E6中任一項所定義之根據式(I)之化合物及第二醫藥活性化合物,或一種或兩種該等化合物之醫藥上可接受之鹽;及一或多種醫藥上可接受之賦形劑。
在又一實施例A3E2中,本發明提供根據實施例A3E1之醫藥劑
型,其用作藥劑。
在又一實施例A3E3中,本發明提供根據實施例A3E1或A3E2之醫藥劑型,其用於治療疼痛。
在又一態樣A4中,本發明提供一種用於治療疼痛之如在實施例A1E1中所定義之根據式(I)之化合物,或其醫藥上可接受之鹽,其中該治療進一步包括分開、依序或同時投與如在實施例A1E1中所定義之第二醫藥活性化合物,或其醫藥上可接受之鹽。
在又一實施例A4E1中,本發明提供用於治療疼痛之根據態樣A4之化合物,其中該治療進一步基本上由分開、依序或同時投與如在實施例A1E1中所定義之第二化合物、或其醫藥上可接受之鹽組成。
在又一態樣A5中,本發明提供一種如在實施例A2E1或A2E2中定義之組合物,或一種或兩種該等化合物之醫藥上可接受之鹽,其用於治療疼痛。
在又一態樣A6中,本發明提供如在實施例A1E1中所定義之根據式(I)之化合物、或其醫藥上可接受之鹽之用途,其用於製造用於治療疼痛之藥劑,其中該治療進一步包括分開、依序或同時投與如在實施例A1E1中所定義之第二醫藥活性化合物,或其醫藥上可接受之鹽。
在又一實施例A6E1中,本發明提供根據態樣A6之化合物之用途,其中該治療進一步基本上由分開、依序或同時投與如在技術方案1中所定義之第二化合物、或其醫藥上可接受之鹽組成。
在又一態樣A7中,本發明提供如在實施例A2E1或A2E2中所定義之組合物、或一種或兩種該等化合物之醫藥上可接受之鹽之用途,其用於製造用於治療疼痛之藥劑。
在又一態樣A8中,本發明提供一種套組,其包括:(i)包含如在實施例A1E1中所定義之根據式(I)之化合物、或其醫藥上可接受之鹽及醫藥上可接受之賦形劑的醫藥劑型;及
(ii)包含如在實施例A1E1中所定義之第二醫藥活性化合物、或其醫藥上可接受之鹽及醫藥上可接受之賦形劑的醫藥劑型;其用於治療疼痛。
在又一實施例A8E1中,本發明提供用於疼痛之態樣A8的套組,其基本上由醫藥劑型(i)及(ii)組成。
圖1係對於高劑量普瑞巴林(群組5)而言隨時間推移退縮程度之圖形表示。
圖2係對於高劑量式(I B )化合物(群組3)而言隨時間推移退縮程度之圖形表示。
圖3係對於式(I B )化合物與普瑞巴林之高劑量組合物(群組7)而言隨時間推移退縮程度之圖形表示。
圖4係對於低劑量普瑞巴林(群組4)而言隨時間推移退縮程度之圖形表示。
圖5係對於高劑量式(I B )化合物(群組2)而言隨時間推移退縮程度之圖形表示。
圖6係對於式(I B )化合物與普瑞巴林之低劑量組合物(群組6)而言隨時間推移退縮程度之圖形表示。
圖7.1係使用在2期期間高劑量組合物在對數尺度之後分佈曲線圖之可視化。
圖7.2係使用在2a期期間高劑量組合物在對數尺度之後分佈曲線圖之可視化。
如本文使用,術語「本發明組合物」指式(I)化合物與第二醫藥活性化合物之組合物,包括:4-[2-(5-胺基-1H-吡唑-4-基)-4-氯苯氧基]-5-氯-2-氟-N-(1,3-噻唑-
4-基)苯磺醯胺與加巴噴丁之組合物;4-[2-(5-胺基-1H-吡唑-4-基)-4-氯苯氧基]-5-氯-2-氟-N-(1,3-噻唑-4-基)苯磺醯胺與普瑞巴林之組合物;4-[2-(5-胺基-1H-吡唑-4-基)-4-(三氟甲基)-苯氧基]-5-氯-2-氟-N-(1,3-噻唑-4-基)苯磺醯胺與加巴噴丁之組合物;及4-[2-(5-胺基-1H-吡唑-4-基)-4-(三氟甲基)-苯氧基]-5-氯-2-氟-N-(1,3-噻唑-4-基)苯磺醯胺與普瑞巴林之組合物。
術語「治療」及類似術語係指減輕、治癒及預防性治療。在治療因損傷或病變條件所致之疼痛情況下,應瞭解係疼痛待治療而不是該疼痛之潛在病因。
「分開」投與係指其中根據獨立時間表投與兩種試劑之治療方案。其包括在投與各個試劑之多個劑量之情況下,則一些劑量可一起進行之可能性。
「依序」投與係指其中根據相同時間表投與兩種試劑之治療方案。
「同時」投與係指其中在單一行動中一起投與兩種試劑之治療方案。
「基本上由投與根據式(I)之化合物及選自加巴噴丁與普瑞巴林之第二醫藥活性化合物、或一種或兩種該等化合物之醫藥上可接受之鹽組成」的治療方法係指由投與兩種及僅兩種醫藥活性劑組成之方法。
術語「基本上由......組成」當與下列結合使用時:根據式(I)之化合物及第二醫藥活性化合物之組合物;用於治療疼痛之根據式(I)之化合物,其中該治療涉及第二醫藥活性化合物;根據式(I)之化合物於製造用於治療疼痛之藥劑之用途,其中該
治療涉及第二醫藥活性化合物;及根據式(I)之化合物及第二醫藥活性化合物之醫藥劑型之套組;具有如剛好在上文與治療方法結合描述之相同含義。
式(I)化合物可呈互變異構形式存在。明確言之,胺基吡唑部分可呈一或多種如下形式存在:
全部此等互變異構體及互變異構體之混合物係包含於本發明範圍內。應瞭解本文提及之特定化合物係指該化合物及/或其互變異構體。
式(I)化合物能用酸形成醫藥上可接受之加成鹽,及此等鹽可用於本發明。適宜酸加成鹽係由形成非毒性鹽之酸形成。實例包括乙酸鹽、己二酸鹽、天冬胺酸鹽、苯甲酸鹽、苯磺酸鹽、碳酸氫鹽/碳酸鹽、硫酸氫鹽/硫酸鹽、硼酸鹽、樟腦磺酸鹽、檸檬酸鹽、環己胺磺酸鹽、乙二磺酸鹽、乙磺酸鹽、甲酸鹽、富馬酸鹽、葡庚糖酸鹽、葡萄糖酸鹽、葡萄糖醛酸鹽、六氟磷酸鹽、海苯酸鹽、鹽酸鹽/氯化物、氫溴化物/溴化物、氫碘化物/碘化物、羥乙磺酸鹽、乳酸鹽、蘋果酸鹽、馬來酸鹽、丙二酸鹽、甲磺酸鹽、甲基硫酸鹽、萘酸鹽、2-萘磺酸鹽、煙鹼酸鹽、硝酸鹽、乳清酸鹽、草酸鹽、棕櫚酸鹽、雙羥萘酸鹽、磷酸鹽/磷酸氫鹽/磷酸二氫鹽、焦麩胺酸鹽、葡萄糖二酸鹽、硬脂酸鹽、琥珀酸鹽、丹寧酸鹽、酒石酸鹽、甲苯磺酸鹽、三氟乙酸鹽及羥萘甲酸鹽。
亦可形成酸及鹼之半鹽,例如,半硫酸鹽。
已報導加巴噴丁及普瑞巴林與酸及鹼兩者形成鹽。熟習此項技
術者應瞭解前述鹽包括其中抗衡離子係光學活性之鹽,例如d-乳酸鹽或l-離胺酸,或外消旋,例如dl-酒石酸鹽或dl-精胺酸。
關於適宜鹽之評論,參見由Stahl及Wermuth之「Handbook of Pharmaceutical Salts:Properties,Selection,and Use」(Wiley-VCH,Weinheim,Germany,2002)。
可藉由以下三種方法中之一或多者來製備式(I)化合物、加巴噴丁及普瑞巴林之醫藥上可接受之鹽:i)藉由使式(I)化合物、加巴噴丁或普瑞巴林與期望酸或鹼反應;ii)藉由使用期望酸或鹼從適宜式(I)化合物、加巴噴丁或普瑞巴林之前驅體中移除酸或鹼不穩定保護基;或iii)藉由與適當酸或鹼反應或藉由適宜離子交換管柱方式將式(I)化合物、加巴噴丁或普瑞巴林之一種鹽轉化為另一種。
全部三種反應通常在溶液中進行。所得鹽可沉澱出及藉由過濾收集或可藉由蒸發該溶劑回收。在所得鹽中離子化程度可從完全離子化至幾乎非離子化變化。
式(I)化合物、加巴噴丁及普瑞巴林,或其醫藥上可接受之鹽可呈非溶劑合物及溶劑合物形式存在。本文使用之術語「溶劑合物」用於描述包括式(I)化合物、加巴噴丁及普瑞巴林,或其醫藥上可接受之鹽,及一或多種醫藥上可接受之溶劑分子(例如乙醇)之分子錯合物。當該溶劑係水時,採用術語「水合物」。依照本發明之醫藥上可接受之溶劑合物包括彼等其中結晶溶劑可經同位素取代者,例如D2O、d6-丙酮及d6-DMSO。
用於有機水合物之目前接受的分類系統係一種定義孤立位點、通道或金屬離子配位水合物的系統,參見K.R.Morris之Polymorphism in Pharmaceutical Solids(編輯H.G.Brittain,Marcel Dekker,1995),其以引用的方式併入本文中。孤立位點水合物係其中水分子藉由介入
有機分子孤立免於彼此直接接觸之水合物。在通道水合物中,水分子位於晶格通道,在其中接近其他水分子。在金屬離子配位水合物中,水分子鍵結至金屬離子。
當牢固結合溶劑或水時,錯合物將可具有與濕度無關之良好限定之化學計量。然而,當溶劑或水係弱結合時,如在通道溶劑合物及吸濕性化合物中,該水/溶劑含量將取決於濕度及乾燥條件。在此等情況下,非化學計量可係常態。
式(I)化合物、加巴噴丁及普瑞巴林可呈從完全非晶態至完全晶態變化之固態連續體存在。術語「非晶態」指其中該材料在分子層級缺乏長程有序及取決於溫度可顯示固體或液體之物理性質之狀態。通常此等材料不給出獨特X射線繞射圖案及當顯示固體性質時係更正式被描述為液體。在加熱時,發生從固體至液體性質之改變,其以狀態改變為特徵,通常係二階(「玻璃化轉變」)。術語「晶態」指其中該材料在分子層級具有規則有序內部結構及提供具有限定峰之獨特X射線繞射圖案之固相。此等材料當充分加熱時將亦顯示液體性質,但是從固體至液體之改變係以相改變為特徵,通常係一階(「熔點」)。
可藉由在國際專利申請案PCT/IB2010/050033(公開為WO2010/079443,該揭示內容以引用的方式併入本文中)中所揭示之方法,或藉由用於製備類似結構化合物之相關技術中已知之任何其他方法來製備式(I)化合物。化合物(I A )係WO2010/079443之實例788及化合物(I B )係其實例1029。
加巴噴丁及普瑞巴林係為吾人所熟知之化合物及可藉由在參考文獻中所揭示之方法來製備。
可藉由諸如沉澱、結晶、冷凍乾燥、噴霧乾燥或蒸發乾燥的方法獲得式(I)化合物、加巴噴丁及普瑞巴林,例如,作為固體栓塞、粉末、或薄膜。微波或射頻乾燥可用於此目的。
式(I)化合物、加巴噴丁及普瑞巴林可分開或以組合投與。一般而言,其可作為與一或多種醫藥上可接受之賦形劑結合之調配物投與。術語「賦形劑」本文用來描述除式(I)化合物、加巴噴丁及普瑞巴林外之任何成分。賦形劑之選擇可較大程度上取決於諸如特定投與模式、賦形劑對溶解性及穩定性之效應、及劑型性質之因素。
適宜用於遞送本發明組合物的醫藥組合物及其製備方法對於熟習此項技術者輕易顯而易見。此等組合物及其製備方法可見於例如「Remington’s Pharmaceutical Sciences」,第19版(Mack Publishing Company,1995)。
適宜投與模式包括口服、非經腸、局部、吸入/鼻內、直腸/陰道內、及經眼/經耳投與。當分開投與式(I)化合物、加巴噴丁及普瑞巴林時,其可藉由不同途徑投與。
可將適宜用於先前提及投與模式之調配物調配為立即及/或改良釋放。改良釋放調配物包括延遲、維持、脈衝、控制、目標及程式化釋放。
可經口投與式(I)化合物、加巴噴丁及普瑞巴林,或其組合物。口服可涉及吞嚥,使得該化合物進入胃腸道,或可採用經頰或舌下投與,藉由其該化合物直接從口腔進入血流。適宜口服之調配物包括固體調配物,諸如錠劑、含顆粒、液體或粉末之膠囊、含片(包括液體填充)、咀嚼片、多及奈米顆粒、凝膠、固溶體、脂質體、膜、陰道栓劑、噴霧劑、液體調配物及經頰/黏膜貼片。
液體調配物包括懸浮液、溶液、糖漿及酏劑。此等調配物可用作在軟或硬膠囊中之填充物及通常包括載劑,例如,水、乙醇、聚乙二醇、丙二醇、甲基纖維素、或適宜油、及一或多種乳化劑及/或懸浮劑。亦可藉由例如從藥囊復水固體來製備液體調配物。
式(I)化合物、加巴噴丁及普瑞巴林,或其組合物,亦可用於快
速溶解、快速崩解劑型,諸如彼等在由Liang及Chen之Expert Opinion in Therapeutic Patents,11(6),981-986,(2001)中所述者。
對於錠劑劑型而言,取決於劑量,該藥物可構成該劑型的1重量%至80重量%,更通常該劑型的5重量%至60重量%。除藥物外,錠劑一般含有崩解劑。崩解劑之實例包括乙醇酸澱粉鈉、羧甲基纖維素鈉、羧甲基纖維素鈣、交聯羧甲基纖維素鈉、交聯聚維酮、聚乙烯吡咯啶酮、甲基纖維素、微晶纖維素、經低碳數烷基取代之羥丙基纖維素、澱粉、預膠化澱粉及海藻酸鈉。一般而言,該崩解劑將佔該劑型的1重量%至25重量%,較佳地5重量%至20重量%。
黏合劑一般用於賦予錠劑調配物內聚性。適宜黏合劑包括微晶纖維素、明膠、糖、聚乙二醇、天然及合成膠、聚乙烯吡咯啶酮、預膠化澱粉、羥丙基纖維素及羥丙基甲基纖維素。錠劑亦可含有稀釋劑,諸如乳糖(一水合物,噴霧乾燥的一水合物、無水等等)、甘露醇、木糖醇、葡萄糖、蔗糖、山梨糖醇、微晶纖維素、澱粉及二水合磷酸氫鈣。
錠劑亦可視情況包括表面活性劑,諸如月桂基硫酸鈉及聚山梨醇酯80,及助滑劑諸如二氧化矽及滑石。當存在時,表面活性劑可佔該錠劑的0.2重量%至5重量%,及潤滑劑可佔該錠劑的0.2重量%至1重量%。
錠劑一般亦含有潤滑劑諸如硬脂酸鎂、硬脂酸鈣、硬脂酸鋅、硬脂基富馬酸鈉、及硬脂酸鎂與月桂基硫酸鈉之混合物。潤滑劑一般佔該錠劑的0.25重量%至10重量%,較佳地0.5重量%至3重量%。其他可能成分包括抗氧化劑、著色劑、矯味劑、防腐劑及掩味劑。
例示性錠劑含有至多約80%藥物、約10重量%至約90重量%黏合劑、約0重量%至約85重量%稀釋劑、約2重量%至約10重量%崩解劑及約0.25重量%至約10重量%潤滑劑。錠劑摻合物可直接或藉由軋輥
壓縮以形成錠劑。在製錠之前,錠劑摻合物或部分摻合物可或者係濕潤、乾燥、或熔融造粒、熔融凝結、或擠出。最終調配物可包括一或多個層及可經塗覆或未經塗覆;其可甚至經囊封。錠劑調配物係論述於由H.Lieberman與L.Lachman之「Pharmaceutical Dosage Forms:Tablets」,卷1(Marcel Dekker,New York,1980)中。
用於本發明目的之適宜改良釋放調配物係描述於美國專利第6,106,864號中。其他適宜釋放技術諸如高能分散與滲透及塗覆粒子之詳情可見於由Verma等人之「Pharmaceutical Technology On-line」,25(2),1-14,(2001)。使用口香糖以達成控制釋放係描述於WO00/35298中。
式(I)化合物、加巴噴丁及普瑞巴林,或其組合物,亦可直接投與至血流、肌肉、或內臟中。用於非經腸投與之適宜方式包括靜脈內、腹膜內、腹膜腔內、鞘內、室內、尿道內、胸骨內、頭顱內、肌肉內及皮下。用於非經腸投與之適宜裝置包括針(包括微針)注射器、無針注射器及輸注技術。
非經腸調配物通常係可含有賦形劑諸如鹽、碳水化合物及緩衝劑(較佳地pH 3至9)之水溶液,但是對於一些應用而言,其可更適宜調配為無菌非水溶液或乾燥形式,其待與適宜媒劑諸如無菌、無熱原水結合使用。
在無菌條件下例如藉由凍乾製備非經腸調配物,可使用熟習此項技術者熟知之標準醫藥技術輕易達成。
可藉由使用適當調配技術,諸如併入溶解度增強劑來增加用於製備非經腸溶液之式(I)化合物、加巴噴丁及普瑞巴林之溶解度。可將用於非經腸投與之調配物調配為立即及/或改良釋放。改良釋放調配物包括延遲、維持、脈衝、控制、目標及程式化釋放。由此可將本發明化合物調配為用於作為植入式儲積物投與之固體、半固體、或觸變
型液體,其提供活性化合物之改良釋放。此等調配物之實例包括經藥物塗覆之血管內支架及聚(dl-乳酸-共乙醇)酸(PGLA)微球體。
式(I)化合物、加巴噴丁及普瑞巴林,或其組合物,亦可局部投與至皮膚或黏膜,即,經皮或透皮。用於此目的之典型調配物包括凝膠、水凝膠、乳液、溶液、膏、軟膏、敷粉、敷料、泡沫劑、薄膜、皮膚貼片、晶圓、植入物、海綿體、纖維、繃帶及微乳液。亦可使用脂質體。典型載劑包括醇、水、礦物油、液體石蠟、白凡士林、甘油、聚乙二醇及丙二醇。可併入滲透促進劑,參見,例如,由Finnin及Morgan之J Pharm Sci,88(10),955-958(1999年10月)。
其他局部投與方式包括藉藉由電穿孔法、離子導入法、超音藥物透入療法、超音波導入法及微針或無針(例如PowderjectTM、BiojectTM等)注射遞送。
式(I)化合物、加巴噴丁及普瑞巴林,或其組合物,亦可經鼻內或藉由吸入投與,通常呈從乾粉吸入器的乾粉之形式(或者單獨、作為混合物(例如,與乳糖之乾摻合物)或作為混合組分粒子(例如,與磷脂諸如卵磷脂混合))或作為從加壓容器、泵、噴射器、噴霧器(較佳地使用電流體動力學以產生精細霧之噴霧器)、或霧化器之噴霧劑,使用或不使用適宜推進劑,諸如1,1,1,2-四氟乙烷或1,1,1,2,3,3,3-七氟丙烷。對鼻內使用而言,該粉末可包括生物黏附劑,例如,殼聚糖或環糊精。
加壓容器、泵、噴射器、噴霧器或霧化器含有式(I)化合物、加巴噴丁或普瑞巴林,或其組合物之溶液或懸浮液,其包含,例如,乙醇、乙醇水溶液、或用於分散、溶解或延長活性物釋放之適宜替代劑;推進劑作為溶劑;及視情況可選之表面活性劑,諸如三油酸山梨糖醇酯、油酸或寡乳酸。
在用於乾粉末或懸浮液調配物之前,將該藥物微粉化至適宜藉
由吸入遞送之尺寸(通常小於5微米)。這可藉由任何適當粉碎方法,諸如螺旋噴射研磨、流體床噴射研磨、超臨界流體處理以形成奈米粒子、高壓均勻化或噴霧乾燥來達成。
可將用於吸入器或吹入器之膠囊(例如,由明膠或羥丙基甲基纖維素製成)、泡罩及濾筒調配為含有本發明化合物、適宜粉末基質諸如乳糖或澱粉及性能修飾劑諸如l-白胺酸、甘露醇、或硬脂酸鎂之粉末混合物。該乳糖可係無水或呈一水合物之形式,較佳係後者。其他適宜賦形劑包括葡聚糖、葡萄糖、麥芽糖、山梨糖醇、木糖醇、果糖、蔗糖及海藻糖。
用於使用電流體動力學以產生精細霧之噴霧器之適宜溶液調配物可含有每次致動1μg至20mg之式(I)化合物、加巴噴丁或普瑞巴林及致動體積可從1μl至100μl變化。典型調配物可包括式(I)化合物、丙二醇、無菌水、乙醇及氯化鈉。可用於替代丙二醇之替代溶劑包括甘油及聚乙二醇。
適宜調味劑,諸如薄荷腦及左旋薄荷腦,或甜味劑,諸如糖精或糖精鈉,可添加至預期用於吸入/鼻內投與之彼等本發明調配物。
就乾粉吸入器及氣霧劑而言,藉由遞送計量量之閥來測定該劑量單位。通常配置依照本發明之單位以投與含有1μg至100mg式(I)化合物、加巴噴丁及普瑞巴林之計量量或「吹量」。總日劑量通常在1μg至200mg範圍,其可以單一劑量投與或,更通常地,作為全天中之分劑量。
式(I)化合物、加巴噴丁及普瑞巴林,或其組合物,可經直腸或陰道投與,例如,以栓劑、子宮托、滅菌劑、陰道環或灌腸劑之形式。可可脂係傳統栓劑基質,但可按適當使用各種替代品。
式(I)化合物、加巴噴丁及普瑞巴林,或其組合物,亦可直接投與至眼睛或耳朵,通常以在等滲、經pH調節、無菌鹽水中之微粉化
懸浮液或溶液滴之形式。適合用於眼睛及耳朵投與之其他調配物包括軟膏、可生物降解(例如,可吸附凝膠海綿、膠原蛋白)及不可生物降解(例如聚矽氧)植入物、晶圓、透鏡及顆粒或囊狀系統,諸如類脂囊泡或脂質體。聚合物諸如交聯聚丙烯酸、聚乙烯醇、玻尿酸、纖維素聚合物(例如,羥丙基甲基纖維素、羥乙基纖維素、或甲基纖維素)或雜多元糖聚合物(例如,結冷膠)可與防腐劑諸如氯化苄二甲烴銨一起併入。亦可藉由離子導入法遞送此等調配物。
式(I)化合物、加巴噴丁及普瑞巴林可與可溶性大分子實體諸如環糊精及其適宜衍生物或含聚乙二醇聚合物組合以改良用於任何先前提及投與模式之其溶解度、溶解速率、遮味性、生物可利用率及/或穩定性。
例如,發現藥物-環糊精複合物一般用於多數劑型及投與途徑。可使用包合體及非包合體複合物。作為與藥物直接複合之替代,環糊精可用作輔助添加劑,即,載劑、稀釋劑或增溶劑。最普遍用於此等目的的係α-、β-及γ-環糊精,其實例見於國際專利申請案第WO91/11172號、第WO94/02518號及第WO98/55148號。
對於投與人類患者而言,式(I)化合物之總日劑量通常在10mg至5g,諸如100mg至3g,例如250mg至2g範圍,當然取決於投與模式及療效。加巴噴丁之總日劑量通常在200mg至3g,諸如500mg至2.5g,例如900mg至1.8g範圍。普瑞巴林之總日劑量通常在50mg至1g,諸如150mg至750mg,例如300mg至600mg範圍。例如,口服可需要300mg至2g之式(I)化合物及750mg至2g之加巴噴丁,或150mg至600mg之普瑞巴林的總日劑量。
總日劑量可以單一劑量或分次劑量投與及在醫生授權下可落於本文給定之典型範圍以外。此等劑量基於具有約60kg至70kg之體重之平均人類個體。醫生將能輕易確定體重不屬於此範圍之個體(諸如
嬰兒及老人)的劑量。
指示本發明組合物用於其之病症包括疼痛。疼痛可係急性或慢性及另外可係中樞及/或周邊起源。疼痛可係神經病變性及/或傷害感受性及/或炎症性質,諸如影響身體或內臟系統之疼痛,以及影響多個系統之功能異常疼痛。
生理疼痛係一種設計為警告來自外界環境之潛在傷害性刺激源之危險的重要保護性機制。該體系經由一特定組之原發性感覺神經元操作及由有害刺激經由周邊轉導機制活化(參見Meyer等人,2006,Wall and Melzack's Textbook of Pain(第五版),第1章)。此等感覺性纖維稱為傷害感受器,及係具有緩慢傳導速度之典型小直徑軸突,其中有兩種主要類型,A-δ纖維(有髓鞘)及C纖維(無髓鞘)。傷害感受器編碼有害刺激之強度、持續時間及品質及憑藉其表面形貌組織化凸起至脊髓,刺激之位置。由傷害感受器輸入產生之活動在背角中複雜處理後直接或經由腦幹中繼核,轉移至丘腦腹側基底核及隨後至其中產生疼痛感覺之皮層。
疼痛一般可分為急性或慢性。急性疼痛突然發生及係短暫(一般十二周或更短)。其係通常儘管非總是與特殊原因諸如限定損傷相關,係通常猛烈且嚴重及可源自數個起源,諸如手術、牙齒處理、拉傷或扭傷。急性疼痛一般不導致任何永久心裡響應。當實質損傷經由疾病或創傷發生於身體組織時,改變傷害感受器活化之特徵使得在周邊、損傷局部周圍及其中傷害感受器終止之中樞中具有敏感性。此等效應導致疼痛加劇感覺。在急性疼痛中,此等機制可用於促進保護行為,可更好地使修復過程發生。正常預期可係一旦損傷治癒,敏感性就恢復正常。然而,在眾多慢性疼痛狀態中,過敏性遠超癒合過程及通常歸因於與適應不良及異常活動相關聯之神經系統損傷或改變(Woolf及Salter,2000,Science,288,1765-1768)。因此,慢性疼痛
係長期疼痛,通常持續超過三個月及導致明顯心理及情感問題。慢性疼痛之常見實例係神經病變性疼痛(例如疼痛的糖尿病性神經病變或帶狀疱疹後遺神經痛)、腕隧道症候群、背痛、頭痛、癌症疼痛、關節炎疼痛及慢性術後疼痛,但可包括影響任何系統之任何慢性疼痛病狀,諸如彼等由國際疼痛研究協會(International Association for the Study of Pain)描述者(慢性疼痛分類(Classification of Chronic Pain),可於http://www.iasp-pain.org自由下載之出版物)。
當在患者症狀中有不舒適及異常敏感性特徵時,存在疼痛之臨床表現。患者趨於非常異質及可存在各種疼痛症狀。此等症狀包括:1)鈍痛、灼痛或刺痛之自發性疼痛;2)響應有害刺激之誇大的疼痛(痛覺過敏);及3)由普遍無害刺激產生之疼痛(異常性疼痛)(Meyer等人,2006,Wall and Melzack's Textbook of Pain(第五版),第1章)。儘管罹患各種急性及慢性疼痛形式之患者可具有相似症狀,但是潛在機制可係不同及可由此需要不同治療策略。除急性或慢性之外,疼痛亦可廣義上分為:可係性質上發炎之會影響身體或內臟系統之傷害感受性疼痛(與組織損傷及免疫細胞滲入相關聯);或神經病變性疼痛。
傷害感受性疼痛可定義為其中強熱、機械性、或化學刺激由周邊神經纖維亞群(稱為傷害感受器)檢測到之過程,及可由組織損傷或由潛在導致損傷之強烈刺激引發。疼痛傳入由在損傷部位之傷害感受器傳導刺激及於其終止水平活化脊髓中之神經元來活化。這隨後被轉出脊柱束至腦部,其中疼痛被感知(Meyer等人,2006,Wall and Melzack's Textbook of Pain(第五版),第1章)。有髓鞘的A-δ纖維迅速傳輸及負責尖銳及刺痛的感覺,而無髓鞘的C纖維以較慢速率傳輸及遞送鈍痛或酸痛。中度至重度急性傷害感受性疼痛係源自拉傷/扭傷、燒傷、心肌梗塞及急性胰腺炎、術後疼痛(在任何類手術過程後之疼痛)、創傷後疼痛、與痛風有關之疼痛、癌症疼痛及背痛之疼痛
的突出特徵。癌症疼痛可係慢性疼痛,諸如腫瘤有關之疼痛(例如骨痛、頭痛、面痛或內臟性疼痛)或癌症療法相關聯之疼痛(例如,響應於化學療法、免疫療法、激素療法或放射療法)。背痛可由於突出或破裂的椎間盤或腰椎小關節、骶髂關節、椎旁肌或後縱韌帶異常。背痛可自然解決,但在一些患者中,在持續超過12週之情況下,變得特別虛弱之慢性病狀。
傷害感受性疼痛亦可與炎症狀態有關。炎症過程係一系列複雜生物化學及細胞事件,響應於組織損傷或外來物質存在而活化,其導致腫脹及疼痛(McMahon等人,2006,Wall and Melzack's Textbook of Pain(第五版),第3章)。與疼痛相關聯之普遍炎症病狀係關節炎。據估計接近2700萬美國人具有症狀性骨關節炎(OA)或退化性關節疾病(Lawrence等人,2008,Arthritis Rheum,58,15-35);多數骨關節炎患者由於相關聯疼痛而尋求醫學關注。關節炎對心理及身體功能有重大影響及已知為後期生活失能之首要原因。類風濕性關節炎係主要影響周邊滑膜關節之免疫介導之慢性、炎症性多發性關節炎疾病。其係在已開發國家中最普遍慢性炎症之一及係疼痛之主要原因。
關於內臟起源之傷害感受性疼痛,內臟性疼痛因胸部、骨盆或腹部器官之傷害感受器活化導致(Bielefeldt及Gebhart,2006,Wall and Melzack's Textbook of Pain(第五版),第48章)。這包括生殖器官、脾臟、肝臟、胃腸道及尿路、氣道結構、心血管系統及含於腹腔中之其他器官。因此內臟性疼痛係指與此等器官病狀相關聯之疼痛,諸如疼痛性膀胱症候群、間質性膀胱炎、前列腺炎、潰瘍性結腸炎、克羅恩氏(Crohn’s)病、腎絞痛、刺激性腸症候群、子宮內膜異位及痛經(慢性疼痛之分類(Classification of Chronic Pain),於http://www.iasp-pain.org獲得)。目前關於內臟性疼痛狀態之潛在神經病變性原因(經由中樞改變或神經損傷/損害)知之甚少但在特定病症中
具有重要作用(Aziz等人,2009,Dig Dis 27,Suppl 1,31-41)。
神經病變性疼痛目前定義為作為影響體覺系統之病變或疾病之直接後果出現的疼痛。神經損害可由創傷與疾病導致及由此術語「神經病變性疼痛」包括具有不同病因之眾多疾病。此等包括但不限於周邊神經病變、糖尿病性神經病變、帶狀皰疹後神經痛、三叉神經痛、背痛、癌症神經病變、HIV神經病變、幻肢痛、腕隧道症候群、中樞中風後疼痛及與慢性酒精中毒、甲狀腺機能減退、尿毒症、多發性硬化症、脊髓損傷、帕金森氏病、癲癇症及維生素缺乏症相關聯之疼痛。神經病變性疼痛係病理性的,因為其不具有保護作用。其通常出現在初始病因消散後,普遍持續數年,大幅度降低患者生活品質(Dworkin,2009,Am J Med,122,S1-S2;Geber等人,2009,Am J Med,122,S3-S12;Haanpaa等人,2009,Am J Med,22,S13-S21)。神經病變性疼痛症狀難於治療,此係由於其通常甚至在具有相同疾病之患者間異質(Dworkin,2009,Am J Med,122,S1-S2;Geber等人,2009,Am J Med,122,S3-S12;Haanpaa等人,2009,Am J Med,122,S13-S21)。其包括連續、及陣發或異常誘發疼痛之自發性疼痛,諸如痛覺過敏(提升之對有害刺激之敏感性)及異常性疼痛(對普遍無害刺激之敏感性)。
應注意一些類型疼痛具有數個病因及由此可歸類為多個區域,例如背痛、癌症疼痛及甚至偏頭痛可包括傷害感受性及神經病變性組分。
類似地,也許尚未完全了解之其他類型慢性疼痛不容易由傷害感受性或神經病變性之簡單定義來定義。此等病症特定言之包括纖維肌痛症及慢性局部疼痛症候群,其通常描述為功能異常性疼痛狀態,例如纖維肌痛症或複雜局部性疼痛症候群(Woolf,2010,J Clin Invest,120,3742-3744),但是其包括於慢性疼痛狀態分類中(慢性疼
痛分類(Classification of Chronic Pain),於http://www.iasp-pain.org獲得)。
本發明組合物可視情況與一或多種其他醫藥活性化合物組合使用。此等組合物提供其他顯著優點之可能性,包括患者順服性,方便給藥及協同活性。
在以下組合物中,本發明組合物可與其他治療劑或試劑組合同時、依序或分開投與。
有用的其他醫藥活性劑包括一或多種選自下列之試劑:˙選擇性Nav1.3通道調節劑,諸如於WO2008/118758中揭示之化合物;˙選擇性Nav1.8通道調節劑,諸如於WO2013/114250中揭示之化合物;˙選擇性Nav1.9通道調節劑;˙調節超過一個Nav通道之活性之化合物,包括非選擇性調節劑諸如丁哌卡因(bupivacaine)、卡馬西平、樂命達(lamotrigine)、利卡多因、美西律或苯妥英(phenytoin)。
˙神經生長因子(NGF)信號傳導之任何抑制劑,諸如結合至NGF及抑制NGF生物活性及/或由NGF信號傳導介導之下游路徑之試劑(例如,她尼珠單抗(tanezumab))、TrkA拮抗劑或p75拮抗劑,或抑制關於NGF刺激之TrkA或P75信號傳導之下游信號傳導之試劑;˙神經營養路徑之抑制劑,其中此等抑制係藉由以下達成:(a)結合至神經生長因子(NGF)之試劑(例如,她尼珠單抗、法辛單抗(fasinumab)或芙蘭單抗(fulranumab))、腦源性神經營養因子(BDNF)、神經營養素-3(NT-3)或神經營養素-4(NT-4)、或數個先前提及之神經營養素(例如可溶P75);或(b)於正位位點、異位位點抑制TrKA、TrKB、TrKC或P75中一或多者之受體功能之試劑,或藉由抑制該(等)
受體的催化活性;˙增加內源性類大麻酚水平之化合物,諸如具有脂肪酸醯胺水解酶抑制(FAAH)或甘油單酯脂肪酶(MAGL)活性之化合物;˙止痛劑,特定言之撲熱息痛(paracetamol);˙類鴉片止痛劑,諸如:丁丙諾啡(buprenorphine)、布托啡諾(butorphanol)、古柯鹼(cocaine)、可待因(codeine)、雙氫可待因、芬太尼(fentanyl)、海洛因(heroin)、氫可待因酮(hydrocodone)、氫嗎啡酮(hydromorphone)、烯丙左嗎喃(levallorphan)、左啡烷(levorphanol)、哌替啶(meperidine)、持殺酮(methadone)、嗎啡(morphine)、納美芬(nalmefene)、納洛芬(nalorphine)、納洛酮(naloxone)、納曲酮(naltrexone)、納布啡(nalbuphine)、氧可酮(oxycodone)、羥嗎啡酮(oxymorphone)、丙氧芬(propoxyphene)或鎮痛新(pentazocine)。
˙優先刺激特定細胞內路徑之類鴉片止痛劑,例如相對於β抑制蛋白募集之G蛋白質,諸如TRV130;具有額外藥理之類鴉片止痛劑,諸如:去甲腎上腺素(正腎上腺素)再吸收抑制(NRI)活性,例如他喷他多(tapentadol);血清素及正腎上腺素再吸收抑制(SNRI)活性,例如曲馬多(tramadol);或傷害感受性受體(NOP)激動劑活性,諸如GRT6005;˙非類固醇消炎藥(NSAID),諸如非選擇性環氧合酶(COX)抑制劑,例如阿司匹林(aspirin)、雙氯芬酸(diclofenac)、二氟尼柳(diflusinal)、依托度酸(etodolac)、芬布芬(fenbufen)、非諾洛芬(fenoprofen)、氟苯沙酸(flufenisal)、氟比洛芬(flurbiprofen)、布洛芬(ibuprofen)、吲哚美辛(indomethacin)、酮基布洛芬(ketoprofen)、克多炎(ketorolac)、甲氯滅酸、甲滅酸、美儂西康(meloxicam)、萘布美酮(nabumetone)、奈普生(naproxen)、尼美舒利(nimesulide)、硝基氟吡洛芬(nitroflurbiprofen)、奥撒拉嗪(olsalazine)、丙嗪(oxaprozin)、丁
二苯吡唑二酮、吡羅昔康(piroxicam)、柳氮磺胺吡啶(sulfasalazine)、舒林酸(sulindac)、甲苯醯吡啶乙酸或氯苯醯二甲基吡咯乙酸;或COX-2選擇性抑制劑,例如塞利西蔔(celecoxib)、地拉西蔔(deracoxib)、依托西蔔(etoricoxib)、嗎伐西蔔(mavacoxib)或帕瑞西蔔(parecoxib);˙前列腺素E2亞型4(EP4)拮抗劑;˙微粒體前列腺素E合成酶1型(mPGES-1)抑制劑;˙鎮定劑,諸如導眠能(glutethimide)、眠爾通(meprobamate)、安眠酮(methaqualone)或二氯醛安替比林(dichloralphenazone);˙具有經由苯并二氮呯結合部位介導之廣泛亞型調節效應之GABAA調節劑,諸如利眠寧、阿普唑侖(alprazolam)、安定(diazepam)、勞拉西泮(lorazepam)、去甲羥基安定(oxazepam)、羥基安定(temazepam)、三唑侖、可那氮平(clonazepam)或氯巴佔(clobazam);˙具有經由苯并二氮呯結合部位介導之亞型選擇性調節效應的GABAA調節劑,其降低副作用(例如鎮靜作用),諸如TPA023、TPA023B、L-838,417、CTP354或NSD72。
˙經由在受體上之替代結合部位作用之GABAA調節劑,諸如巴比妥酸鹽(barbiturate),例如異戊巴比妥(amobarbital)、阿普比妥(aprobarbital)、他比妥(butabital)、甲基苯巴比妥(mephobarbital)、司可巴比妥(methohexital)、巴比特魯(pentobarbital)、巴比妥酸製劑(phenobartital)、戊巴比妥(secobarbital)、或戊硫代巴比妥(thiopental);神經類固醇諸如阿法沙龍(alphaxalone)、阿法多龍(alphadolone)或加奈索酮(ganaxolone);β-亞單位配位體,諸如艾替伏辛(etifoxine);或δ-優先配位體,諸如加波沙朵(gaboxadol);˙GlyR3激動劑或正向異位調節劑;
˙骨骼肌鬆弛劑,例如巴氯芬(baclofen)、肌安寧(carisoprodol)、氯唑沙宗(chlorzoxazone)、環苯扎林(cyclobenzaprine)、美他沙酮(metaxolone)、美索巴莫(methocarbamol)或鄰甲苯海拉明(orphrenadine);˙麩胺酸受體拮抗劑或負向異位調節劑,諸如NMDA受體拮抗劑,例如右美沙芬(dextromethorphan)、右啡烷(dextrorphan)、酮胺或、美金剛胺(memantine);或mGluR拮抗劑或調節劑;˙α-腎上腺素能藥,諸如可尼丁(clonidine)、胍法新(guanfacine)或地滅米丁(dexmetatomidine);˙β-腎上腺素能藥,諸如心得安(propranolol);˙三環抗抑鬱劑,例如脫甲丙咪嗪、丙咪唑、阿米曲替林(amitriptyline)或去甲替林(nortriptyline);˙速激肽(NK)拮抗劑,諸如阿瑞吡坦(aprepitant)或馬羅皮坦(maropitant);˙蕈毒鹼拮抗劑,例如奧斯必得寧(oxybutynin)、托特羅定(tolterodine)、丙哌維林(propiverine)、曲司氯銨(tropsium chloride)、達非那新(darifenacin)、素立芬辛(solifenacin)、替米維林(temiverine)及異丙托銨(ipratropium);˙膽鹼能(煙鹼)止痛劑,諸如異丙克蘭(ispronicline)(TC-1734)、伐尼克蘭(varenicline)或煙鹼;˙瞬時受體電位V1(TRPV1)受體激動劑(例如瑞新非辛(resinferatoxin)或辣椒素)或拮抗劑(例如辣椒平(capsazepine)或馬伐曲(mavatrap));˙瞬時受體電位A1(TRPA1)受體激動劑(例如肉桂醛或芥子油)或拮抗劑(例如GRC17536或CB-625);˙瞬時受體電位M8(TRPM8)受體激動劑(例如薄荷腦或碗豆球蛋白
(icilin))或拮抗劑;˙瞬時受體電位V3(TRPV3)受體激動劑或拮抗劑(例如GRC-15300);˙皮質類固醇諸如地塞米松(dexamethasone);˙5-HT受體激動劑或拮抗劑,特定言之5-HT1B/1D激動劑,諸如依來曲普坦(eletriptan)、舒馬替坦(sumatriptan)、諾拉替坦(naratriptan)、佐米曲替坦(zolmitriptan)或利扎曲坦(rizatriptan);˙5-HT2A受體拮抗劑;˙PDEV抑制劑,諸如威而剛(sildenafil)、他達拉非(tadalafil)或伐地那非(vardenafil);˙α-2-δ配位體,諸如加巴噴丁、加巴噴丁酯(gabapentin enacarbil)或普瑞巴林;˙血清素再吸收抑制劑(SRI),諸如樂復得(sertraline)、去甲基樂復得、氟西汀(fluoxetine)、諾氟西汀(norfluoxetine)、氟伏沙明(fluvoxamine)、克憂果(paroxetine)、西它普蘭(citalopram)、去甲基西它普蘭、草酸依西普蘭(escitalopram)、d,l-氟苯丙胺、非莫西汀(femoxetine)、伊福西汀(ifoxetine)、氰基度硫平(cyanodothiepin)、利托西汀(litoxetine)、達泊西汀(dapoxetine)、萘法唑酮(nefazodone)、西克拉明(cericlamine)及查諾頓(trazodone);˙NRI,諸如馬普替林(maprotiline)、洛非帕明(lofepramine)、米爾塔扎平(mirtazepine)、羥丙替林(oxaprotiline)、非唑拉明(fezolamine)、阿托西汀(tomoxetine)、米安色林(mianserin)、安非他酮(buproprion)、安非他酮代謝產物羥基安非他酮、諾米芬新(nomifensine)及維洛沙秦(viloxazine),特定言之選擇性去甲腎上腺素再吸收抑制劑諸如瑞波西汀(reboxetine);˙SNRI,諸如可洛米普明(venlafaxine)、O-去甲基可洛米普明、
氯米帕明(clomipramine)、去甲氯米帕明、度洛西汀(duloxetine)、米那普侖(milnacipran)及丙咪唑;˙誘導型一氧化氮合成酶(iNOS)抑制劑;˙白三烯B4拮抗劑;˙5-脂氧合酶抑制劑,諸如棄白通(zileuton);˙鉀通道打開劑或正向調節劑,諸如KCNQ/Kv7之打開劑或正向調節劑(例如瑞替加滨(retigabine)或氟吡丁(flupirtine))、G蛋白偶合內向性整流鉀通道(GIRK)、鈣活化鉀通道(Kca)或鉀電壓閘控通道諸如亞家族A成員(例如Kv1.1)、亞家族B成員(例如Kv2.2)或亞家族K成員(例如TASK、TREK或TRESK);˙P2X3受體拮抗劑(例如AF219)或含有P2X3亞單位作為其亞單位之一的受體之拮抗劑,諸如P2X2/3異質受體;˙Cav2.2鈣通道阻斷劑(N型),諸如齊考諾肽(ziconotide);及˙Cav3.2鈣通道阻斷劑(T型),諸如乙琥胺(ethosuximide)。
本發明組合物範圍內亦包括本發明組合物與一或多種降低本發明化合物代謝速度由此導致患者體內暴露增加之額外治療劑一起之組合。以此方式增加暴露稱為加強。這具有增加本發明化合物療效或降低為達成如未加強劑量相同療效所需劑量之優點。本發明化合物之代謝包括由P450(CYP450)酶(特定言之CYP 3A4)進行之氧化過程及由UDP葡萄糖醛酸基轉移酶及硫酸鹽化酶之共軛。因此,在可用於增加患者暴露於本發明化合物之試劑中係彼等可充當細胞色素P450(CYP450)酶之至少一同功異型物之抑制劑者。可被有利抑制之CYP450之同功異型物包括(但不限於)CYP1A2、CYP2D6、CYP2C9、CYP2C19及CYP3A4。可用於抑制CYP 3A4之適宜試劑包括利托那韋(ritonavir)、沙奎那韋(saquinavir)、酮康唑(ketoconazole)、N-(3,4-二氟苄基)-N-甲基-2-{[(4-甲氧基吡啶-3-基)胺基]磺醯基}苯甲醯胺及
N(1-(2-(5-(4-氟苄基)-3-(吡啶-4-基)-1H-吡唑-1-基)乙醯)哌啶-4-基)甲烷磺醯胺。
在本發明範圍中,至少其中一者含有式(I)化合物及其中一者含有加巴噴丁或普瑞巴林之兩種或更多種醫藥組合物可方便地組合為適宜用於共投與該等組合物之套組形式。由此本發明套組包括兩種或更多種分開的醫藥組合物,至少其中一者含有式(I)化合物及其中一者含有加巴噴丁或普瑞巴林,及用於分開保留該等組合物之構件,諸如容器、分瓶或分箔包裝。此套組實例係用於包裝錠劑、膠囊等等之熟悉泡罩包裝。本發明套組特定言之適宜用於投與不同劑型(例如口服或非經腸)、用於在不同劑量間隔投與分開組合物、或用於相對於另一組合物滴定分開組合物。為助於投藥順服性,該套組通常包括關於投與之指導及可提供有所謂之記憶輔助物。
實驗部分
小鼠體內評估
動物 :每日給藥之重27至36公克之雄性CD-1小鼠(Charles River,Raleigh,NC)以每籠子5隻圈養。動物可自由獲取食物與水及維持12:12小時光/暗時間表。
化合物及給藥溶液 :將式(I B )化合物及普瑞巴林在0.5%甲基纖維素中調配為溶液。在0.5%甲基纖維素中將高及低劑量組合物一起調配為用於口服給藥之單一懸浮液。化合物經由經口強飼以10mL/kg給藥。
實驗程序 :使用自動傷害感受分析儀(Yaksh等人,2001)測試動物對注射2.5%福馬林溶液(20μl,在鹽水中)之爪運動響應。此裝置使用磁檢測系統來測量定義為退縮之爪運動。將小金屬帶附著於在福馬林注射前60分鐘剛好放置於個別循環測試室(4隻小鼠/會期)之前小鼠後左爪。在福馬林注射前2小時,對小鼠經口投與測試化合物。為開始該實驗,在小鼠後左爪背面皮下注射20μl 2.5%福馬林及將小鼠放
置於測試室中。該儀器隨後記錄在一分鐘內計數之快速足運動,持續60分鐘。
將處理群組分配為跨實驗日及跨測試室平衡處理。
在60分鐘退縮觀察後,立即使小鼠安樂死及移除血液及腦組織以用於生物分析式(I B )化合物及普瑞巴林含量。
實驗群組: 表1概述在本研究中測試之群組。
群組6 低劑量組合物
群組7 高劑量組合物
排除之動物:由於不完全福馬林注射,一隻小鼠從媒劑群組及式(I B )化合物30mg/kg群組中排除。由於在退縮研究過程期間金屬足帶掉落,一隻小鼠從式(I B )化合物100mg/kg群組中排除。由於其僅接受部分劑量之測試化合物,一隻小鼠從普瑞巴林30mg/kg群組中排除。
資料分析 :在特定時間間隔或時期內計數總退縮數。在此研究中總結之時期係:
1期:0至9分鐘
2期:10至60分鐘
2a期:10至40分鐘
由自動傷害感受分析儀(Yaksh等人,2001)自動記錄退縮事件及自動計算各個時期退縮總數。各個實驗群組之結果在下文表2.1至2.7中示出。
高劑量及低劑量組合物兩者之退縮時間過程之圖形表示分別示於圖1至3及4至6中。
使用針對實驗日之線性模型,分別在對數尺度上分析各個時期內之退縮總數。使用平均值、差異、95%置信區間及p值進行及總結個別處理比較。其中觀察到統計上顯著相加效應之高劑量2期及2a期總退縮數之結果在圖7.1及7.2中可見,該等圖使用處理平均值在對數尺度上之後分佈曲線圖。
結果:
高劑量組合物產生在2期及2a期中之顯著相加效應(p<0.01)。在2
期中,藉由式(I B )化合物100mg/kg、普瑞巴林30mg/kg及組合物劑量,退縮分別減少30%、40%及69%。在2a期中,藉由式(I B )組合物100mg/kg,普瑞巴林30mg/kg及組合物劑量,退縮分別減少36%、38%及74%。
人體內評估
普瑞巴林與Nav1.7阻斷之組合效應亦可在臨床疼痛研究中檢測出。臨床研究可檢測單劑量或多劑量之任一或兩種試劑在健康志願者或患者之探索疼痛終點。臨床研究亦可在疼痛患者群體中進行,其採用例如平行群組、交叉或隨機退出型研究設計。
Claims (18)
- 一種式(I)化合物或其醫藥上可接受之鹽於製造用於治療疼痛之藥劑中之用途,
- 如請求項1之用途,其中該治療進一步基本上由投與根據式(I)之化合物及選自加巴噴丁及普瑞巴林、或一種或兩種該等化合物之醫藥上可接受之鹽之第二醫藥活性化合物組成。
- 如請求項1或2之用途,其中該根據式(I)之化合物係4-[2-(5-胺基-1H-吡唑-4-基)-4-氯苯氧基]-5-氯-2-氟-N-(1,3-噻唑-4-基)苯磺醯胺或其醫藥上可接受之鹽。
- 如請求項1或2之用途,其中該根據式(I)之化合物係4-[2-(5-胺基-1H-吡唑-4-基)-4-(三氟甲基)-苯氧基]-5-氯-2-氟-N-(1,3-噻唑-4-基)苯磺醯胺或其醫藥上可接受之鹽。
- 如請求項1或2之用途,其中該第二化合物係加巴噴丁或其醫藥上可接受之鹽。
- 如請求項1或2之用途,其中該第二化合物係普瑞巴林或其醫藥 上可接受之鹽。
- 如請求項1或2之用途,其中該根據式(I)之化合物及該第二化合物係同時投與。
- 如請求項7之用途,其中該根據式(I)之化合物及該第二化合物係作為單一醫藥劑型一起投與。
- 一種組合物,其包含如在請求項1或2中所定義之根據式(I)之化合物及第二醫藥活性化合物、或一種或兩種該等化合物之醫藥上可接受之鹽。
- 如請求項9之組合物,其係選自:4-[2-(5-胺基-1H-吡唑-4-基)-4-氯苯氧基]-5-氯-2-氟-N-(1,3-噻唑-4-基)苯磺醯胺與加巴噴丁之組合物;4-[2-(5-胺基-1H-吡唑-4-基)-4-氯苯氧基]-5-氯-2-氟-N-(1,3-噻唑-4-基)苯磺醯胺與普瑞巴林之組合物;4-[2-(5-胺基-1H-吡唑-4-基)-4-(三氟甲基)-苯氧基]-5-氯-2-氟-N-(1,3-噻唑-4-基)苯磺醯胺與加巴噴丁之組合物;及4-[2-(5-胺基-1H-吡唑-4-基)-4-(三氟甲基)-苯氧基]-5-氯-2-氟-N-(1,3-噻唑-4-基)苯磺醯胺與普瑞巴林之組合物;或一種或兩種該等化合物之醫藥上可接受之鹽。
- 一種組合物,其包含如在請求項3中所定義之根據(I)之化合物及普瑞巴林。
- 一種醫藥劑型,其包含如在請求項1至6中任一項所定義之根據式(I)之化合物及第二醫藥活性化合物、或一種或兩種該等化合物之醫藥上可接受之鹽,及一或多種醫藥上可接受之賦形劑。
- 如請求項12之醫藥劑型,其用作藥劑。
- 如請求項12或13之醫藥劑型,其用於治療疼痛。
- 一種如在請求項1中所定義之根據式(I)之化合物,或其醫藥上可 接受之鹽,其用於治療疼痛,其中該治療進一步包括分開、依序或同時投與如在請求項1中所定義之第二化合物,或其醫藥上可接受之鹽。
- 如請求項15之化合物,其用於治療疼痛,其中該治療進一步基本上由分開、依序或同時投與如在請求項1中所定義之第二化合物,或其醫藥上可接受之鹽組成。
- 一種套組,其包括:(i)包含如在請求項1中所定義之根據式(I)之化合物、或其醫藥上可接受之鹽,及醫藥上可接受之賦形劑之醫藥劑型;及(ii)包含如在請求項1中所定義之第二化合物、或其醫藥上可接受之鹽,及醫藥上可接受之賦形劑之醫藥劑型;其用於治療疼痛。
- 如請求項17之用於疼痛之套組,其基本上由醫藥劑型(i)及(ii)組成。
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