TWI729562B - 包含用於治療因骨密度降低或軟骨損失導致之疾病的治療劑的緩釋藥物組合物及其用途 - Google Patents
包含用於治療因骨密度降低或軟骨損失導致之疾病的治療劑的緩釋藥物組合物及其用途 Download PDFInfo
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Abstract
本發明關於一種具有高藥物脂質比及高包埋效率的藥物組合物,所述藥物組合物包含至少一微脂體及一用於治療因骨密度降低或軟骨損失導致之疾病的治療劑。所述藥物組合物改善藥物動力學圖譜及維持治療劑的釋放。本發明亦提供使用本文所揭露的藥物組合物用於治療因骨密度降低或軟骨損失導致之疾病的方法。
Description
本發明是針對一種用於治療因骨密度降低或軟骨損失導致之疾病的緩釋藥物組合物,其使用至少一捕獲劑並具有高藥物脂質比(drug to lipid ratio)及高包埋效率(encapsulation efficiency)。此藥物組合物之高藥物脂質比、高包埋效率及藥物組合物持續的釋放圖譜(release profile)減少施予之頻率、增加患者順從性(patient compliance)並改善治療效果(therapeutic outcome)。
骨重塑是一個生理程序,由涉及蝕骨細胞和成骨細胞,以及骨細胞、炎性細胞以及介質之依序和協調交互作用所決定。成骨細胞與蝕骨細胞活性之間的平衡維持了骨恆定。蝕骨細胞的功能缺損增加骨再吸收,並造成各種骨頭與關節疾病,舉例來說,骨質疏鬆症(osteoporosis)、骨石化症(osteopetrosis)、類風溼性關節炎(rheumatoid arthritis)、骨關節炎(osteoarthritis)、骨癌及Paget氏病(Paget’s bone disease)。
組織蛋白酶(Cathepsin) K是一種在蝕骨細胞中高度表現的半胱胺酸蛋白酶,並且在羥磷灰石及蛋白質(特別是第I型膠原蛋白)構成的骨基質衰退作用中扮演關鍵角色。組織蛋白酶K也涉及人類關節軟骨中第II型膠原蛋白裂解。最近的研究顯示,每日口服一次或兩次組織蛋白酶K抑制劑,可以預防骨質流失及軟骨退化。因此維持組織蛋白酶K抑制劑的治療濃度,並將治療因骨密度降低及軟骨損失導致的疾病之給藥頻率最小化是非常值得嚮往的。
微脂體已被廣泛地用於各種藥物之緩釋配方的開發。藥物裝載至微脂體中可經被動地(passively) (在微脂體形成的期間包埋藥物)或遠端地(remotely)/主動地(actively) (在微脂體形成的期間製造跨膜(transmembrane) pH-或離子梯度,而後藥物在微脂體形成後藉由因梯度產生的驅動力裝載)達成(美國專利號5,192,549及5,939,096)。儘管文獻中詳細記載藥物裝載至微脂體的一般方法,僅有極少數的治療劑得以高包埋效率的裝載至微脂體中。各種因子能夠影響微脂體藥物的藥物脂質比及包埋效率,其包含但不限於治療劑的物理及化學特性,例如親水性/疏水性特徵、解離常數、溶解度及分配係數,脂質組成、捕獲劑、反應溶劑及粒徑(Proc Natl Acad Sci U S A. 2014; 111(6): 2283-2288以及Drug Metab Dispos. 2015; 43 (8):1236-45)。
對於具有高藥物脂質比及高藥物包埋效率以降低組織蛋白酶K抑制劑的給藥頻率並改善治療效果的緩釋配方仍存在未被滿足的需求。本發明解決此需求以及其他需求。
在一實施例中,提供的是一種緩釋藥物組合物包含(a)至少一微脂體,其包含一雙層膜,所述雙層膜包含至少一脂質;(b)一捕獲劑;以及(c)一治療劑,用以治療因骨密度降低或軟骨損失引起的疾病,其中治療劑對脂質的莫耳比值等於或大於大約0.1。
根據本發明的另一實施例,提供用以治療因骨密度降低或軟骨損失導致之疾病的方法,所述方法包含對所需的個體施予本文所描述的藥物組合物的步驟。
亦提供本文所描述的藥物組合物在製造用於治療和/或預防性治療因骨密度降低導致疾病之藥物的用途。
進一步提供包含治療有效劑量之本文所描述的藥物組合物用於治療因骨密度降低或軟骨損失導致之疾病的藥物。
在本專利中所使用的用語「發明(invention)」、「該發明(the invention)」、「此發明(this invention)」以及「本發明(the present invention)」意於廣泛指的是本專利及下列的申請專利範圍的所有申請標的。包含這些用語的敘述應理解為不限制本文所描述的申請標的、或不限制下列申請專利範圍的含義或範疇。藉由本專利涵蓋的本發明之實施例係藉由下列申請專利範圍定義,而非此發明內容。此發明內容為本發明各種態樣的高層次概述(high-level overview),並引導進一步描述於下列實施方式的段落中的部分概念。此發明內容不意於定義所請申請標的的關鍵或必要特徵,亦非意於用在單獨使用而定義所請申請標的的範疇。申請標的應藉由參考說明書全文、任何或所有圖式及各申請專利範圍合適的部分而理解。
可藉由參照說明書的其餘部分及圖式進一步理解本發明的本質及優點。
除非本文中另行明確地表示,否則如上及本揭露全文所採用的下列用語,「一(a)」、「一(an)」以及「該(the)」等單數型式包含複數型式。
本文的所有數字可被理解成藉由「大約(about)」修飾。如本文所用,用語「大約(about)」指的是特定值±10%的範圍。
如本文所用,用語「有效劑量(effective amount)」指的是降低因骨再吸收和骨密度降低而引起的疾病之症狀或病徵,例如骨質量減少/增加、軟骨下硬骨或軟骨損失、關節炎的關節疼痛或關節腫脹。用語「有效劑量(effective amount)」及「治療有效劑量(therapeutically effective amount)」可互換使用。
如本文所用,用語「治療(treating)」、「治療(treated)」或「治療(treatment)」包含預防(preventative) (例如,預防(prophylactic))、舒緩(palliative)及治療方法(curative methods)、用途或結果。用語「治療(treatment)」或「治療(treatments)」亦可指的是組合物或藥物。本發明中,治療是指增加骨密度或減少軟骨損失的方法,因而減少或延緩因骨密度降低或軟骨損失引起的一或多個疾病之症狀或病徵、或是完全緩解因骨密度降低或軟骨損失引起的疾病。前述骨密度降低或軟骨損失均可以透過本領域已知的技術來測得。現有先前技術公認的方法可用於檢測因骨密度降低或軟骨損失導致之疾病及其症狀。這包含,但不限於,臨床檢查、造影檢查(例如:骨礦物質密度計、X射線造影、雙能X射線吸光測定法、磁振成像、電腦斷層掃描、超音波及核子造影)、測量體液(例如:血清、尿液或滑液)中的生物標記(例如:檢測C反應蛋白、抗環瓜胺胜肽(anti-cyclic citrullinated peptide)、血清鹼性磷酸酶、肌酸激酶BB同功酶、耐酒石酸磷酸酶、基質金屬蛋白酶-3、第I型膠原蛋白的C-端肽鏈(telopeptide)、第II型膠原蛋白的C-端肽鏈、第I型膠原蛋白的N-端肽鏈、第IIA型膠原蛋白的N端前肽以及血清玻尿酸)、或是生物檢體/組織病理學評估(舉例來說,軟骨及軟骨下硬骨染色),等等。舉例來說,與治療之前或是與控制組個體相比,如果一個體藉由骨礦物質密度計測得的骨密度至少增加1%,或該個體由骨密度降低或軟骨缺少導致疾病的一或多種症狀減少大約1%,則本揭示方法被認為是一種治療方法。因此,此減少可為大約1、5、10、20、30、40、50、60、70、80、90、100%,或是任何在其之間減少的數值。
如本文所用,用語「因骨密度降低或軟骨損失引起之疾病(disease due to reduced bone density or cartilage loss)」,其包含各種類型與子類型的骨疾病與關節疾病,由骨再吸收或軟骨退化導致的各種已知或未知的病因學及成因,包含但不限於:骨質疏鬆症、骨石化症、類風溼性關節炎、骨關節炎、骨癌、骨折及Paget氏病。
如本文所用,用語「個體(subject)」可指患有或有發展因骨密度降低或軟骨損失引起的疾病風險之脊椎動物,或視為需要治療以增加骨密度和/或修復軟骨之脊椎動物。個體包含所有恆溫動物,如哺乳動物、如靈長類動物且更佳為人類。非人類靈長類動物亦為個體。用語個體包含如貓、狗等的馴養動物、家畜(例如,牛、馬、豬、羊、山羊等)及實驗動物(例如,小鼠、兔、大鼠、沙鼠(gerbil)、豚鼠(guinea pig)等)。因此,本文涵蓋獸醫用途及醫藥劑型。
微脂體
如本文所用,用語「微脂體(liposome)」、「微脂體(liposomal)」及相關用語的特徵為藉由一或多層雙層膜形成的囊泡,將內部水性空間(interior aqueous space)與外部介質(outer medium)隔離。在某些實施例中,微脂體的內部水性空間實質上不含中性脂質,如三磷酸脂(triglyceride)、非水(non-aqueous)相(油相)、水-油乳液或其它含有非水相的混合物。微脂體的非限制性實例包含小單層囊泡(small unilamellar vesicles,SUV)、大單層囊泡(large unilamellar vesicles,LUV)及多層囊泡(multilamellar vesicle,MLV),其具有平均直徑範圍從50-500 nm、50-450 nm、50-400 nm、50-350 nm、50-300 nm、50-250 nm、50-200 nm、100-500 nm、100-450 nm、100-400 nm、100-350 nm、100-300 nm、100-250 nm或100-200 nm。
微脂體的雙層膜通常藉由至少一脂質形成,即,包含空間上分離之疏水域及親水域的合成或天然的兩性分子(amphiphilic molecules)。脂質的實例包含但不限於,如磷脂(phospholipids)、雙甘油酯(diglycerides)、二脂肪基醣脂(dialiphatic glycolipids)的雙脂鏈脂質(dialiphatic chain lipids),如鞘磷脂(sphingomyelin)及鞘醣脂(glycosphingolipid)的單脂質及其組合物。根據本發明之磷脂的實例包含但不限於1,2-二月桂醯基-sn
-甘油-3-磷酸膽鹼(1,2-dilauroyl-sn
-glycero-3-phosphocholine,DLPC)、1,2-二肉荳蔻醯基-sn
-甘油-3-磷酸膽鹼(1,2-dimyristoyl-sn
-glycero-3-phosphocholine,DMPC)、1,2-二棕櫚醯基-sn
-甘油-3-磷酸膽鹼(1,2-dipalmitoyl-sn
-glycero-3-phosphocholine,DPPC)、1-棕櫚醯基-2-硬脂醯基-sn
-甘油-3-磷酸膽鹼(1-palmitoyl-2-stearoyl-sn
-glycero-3-phosphocholine,PSPC)、1-棕櫚醯基-2-油醯基-sn
-甘油-3-磷脂醯膽鹼(1-palmitoyl-2-oleoyl-sn
-glycero-3-phosphatidylcholine,POPC)、1,2-二硬脂醯基-sn
-甘油-3-磷酸膽鹼(1,2-distearoyl-sn
-glycero-3-phosphocholine,DSPC)、1,2-二油醯基-sn
-甘油-3-磷脂醯膽鹼(1,2-dioleoy1-sn
-glycero-3-phosphocholine,DOPC)、氫化大豆磷脂醯膽鹼(hydrogenated soy phosphatidylcholine,HSPC)、1,2-二肉荳蔻醯-sn
-甘油-3-磷酸-(1’-rac-甘油) (鈉鹽) (1,2-dimyristoyl-sn
-glycero-3-phospho-(1’-rac-glycerol) (sodium salt),DMPG)、1,2-二棕櫚醯-sn
-甘油-3-磷酸-(1’-rac-甘油) (鈉鹽) (1,2-dipalmitoyl-sn
-glycero-3-phospho-(1’-rac-glycerol) (sodium salt),DPPG)、1-棕櫚醯基-2-硬脂醯基-sn
-甘油-3-磷酸-(1’-rac-甘油) (鈉鹽) (1-palmitoyl-2-stearoyl-sn
-glycero-3-phospho-(1’-rac-glycerol) (sodium salt),PSPG)、1,2-二硬脂醯-sn
-甘油-3-磷酸-(1’-rac-甘油) (鈉鹽) (1,2-distearoyl-sn
-glycero-3-phospho-(1’-rac-glycerol) (sodium salt),DSPG)、1,2-二油醯-sn
-甘油-3-磷酸-(1’-rac-甘油) (1,2-dioleoyl-sn
-glycero-3-phospho-(1’-rac-glycerol) ,DOPG)、1,2-二肉荳蔻醯-sn
-甘油-3-磷酸-L-絲胺酸(鈉鹽) (1,2-dimyristoyl-sn
-glycero-3-phospho-L-serine (sodium salt),DMPS)、1,2-二棕櫚醯-sn
-甘油-3-磷酸-L-絲胺酸(鈉鹽) (1,2-dipalmitoyl-sn
-glycero-3-phospho-L-serine (sodium salt),DPPS)、1,2-二硬脂醯-sn
-甘油-3-磷酸-L-絲胺酸(鈉鹽) (1,2-distearoyl-sn
-glycero-3-phospho-L-serine (sodium salt),DSPS)、1,2-二油醯-sn
-甘油-3-磷酸-L-絲胺酸(1,2-dioleoyl-sn
-glycero-3-phospho-L-serine,DOPS)、1,2-二肉荳蔻醯-sn
-甘油-3-磷酸(鈉鹽) (1,2-dimyristoyl-sn
-glycero-3-phosphate (sodium salt),DMPA)、1,2-二棕櫚醯-sn
-甘油-3-磷酸(鈉鹽) (1,2-dipalmitoyl-sn
-glycero-3-phosphate (sodium salt),DPPA)、1,2-二硬脂醯-sn
-甘油-3-磷酸(鈉鹽) (1,2-distearoyl-sn
-glycero-3-phosphate (sodium salt),DSPA)、1,2-二油醯-sn
-甘油-3-磷酸(鈉鹽) (1,2-dioleoyl-sn
-glycero-3-phosphate (sodium salt),DOPA)、1,2-二棕櫚醯-sn
-甘油-3-磷酸乙醇胺(1,2-dipalmitoyl-sn
-glycero-3-phosphoethanolamine,DPPE)、N
-(羰基-甲氧基聚乙二醇)-1,2-二棕櫚醯-sn
-甘油-3-磷酸乙醇胺(N
-(carbonyl-methoxypolyethyleneglycol)-1,2-dipalmitoyl-sn
-glycero-3-phosphoethanolamine,PEG-DPPE)、1-棕櫚醯基-2-油醯基-sn
-甘油-3-磷酸乙醇胺(1-palmitoyl-2-oleoyl-sn
-glycero-3-phosphoethanolamine,POPE)、1,2-二硬脂醯-sn
-甘油-3-磷酸乙醇胺(1,2-distearoyl-sn
-glycero-3-phosphoethanolamine,DSPE)、N
-(羰基-甲氧基聚乙二醇)-1,2-二硬脂醯-sn
-甘油-3-磷酸乙醇胺(N
-(carbonyl-methoxypolyethyleneglycol)-1,2-distearoyl-sn
-glycero-3-phosphoethanolamine,PEG-DSPE)、1,2-二油醯-sn
-甘油-3-磷酸乙醇胺(1,2-dioleoyl-sn
-glycero-3-phosphoethanolamine,DOPE)、1,2-二棕櫚醯-sn
-甘油-3-磷酸-(1’-肌醇) (銨鹽) (1,2-dipalmitoyl-sn
-glycero-3-phospho-(1’-myo-inositol) (ammonium salt),DPPI)、1,2-二硬脂醯基-sn
-甘油-3-磷酸肌醇(銨鹽) (1,2-distearoyl-sn
-glycero-3-phosphoinositol) (ammonium salt),DSPI)、1,2-二硬脂醯基-sn
-甘油-3-磷酸-(1’-肌醇) (銨鹽) (1,2-dioleoyl-sn
-glycero-3-phospho-(1’-myo-inositol) (ammonium salt),DOPI)、心磷脂(cardiolipin)、L-α-磷脂醯膽鹼(L-α-phosphatidylcholine,EPC)及L-α-磷脂醯乙醇胺(L-α-phosphatidylethanolamine,EPE)。在一些實施例中,脂質為一種或多種前述脂質的脂質混合物,或一種或多種前述脂質與一種或多種未列出的脂質、薄膜穩定劑(membrane stabilizer)或抗氧化劑的混合物。
在一些實施例中,在微脂體雙層膜中的脂質之莫耳百分比係等於或少於大約80、79、78、77、76、75、74、73、72、71、70、69、68、67、66、65、64、63、62、61、60、59、58、57、56、55、54、53、52、51、50、49、48、47、46、45或在其之間的任何值或範圍(例如,大約45-80%、大約45-75%、大約45-70%、大約45-65%、大約50-80%、大約50-75%、大約50-70%或大約50-65%)。
在一些實施例中,雙層膜中的脂質是第一脂質及第二脂質的混合物。在一些實施例中,第一脂質選自基本上由磷脂醯膽鹼(phosphatidylcholine,PC)、HSPC、DOPC、POPC、DSPC、DPPC、DMPC、PSPC及其組合所組成之群組,而第二脂質選自基本上由磷脂醯乙醇胺(phosphatidylethanolamine)、磷脂醯甘油(phosphatidylglycerol)、PEG-DSPE、DPPG、DOPG及其組合所組成之群組。在另一實施例中,在雙層膜中第一脂質的莫耳百分比為等於或少於大約79.9、79.5、79.1、78、77、76、75、74、73、72、71、70、69、68、67、66、65、64、63、62、61、60、59、58、57、56、55、54、53、52、51、50、49、48、47、46、45、44、43、42、41、41、40、39、38、37、36、35、34、33、32、31、30或在其之間的任何值或範圍(例如,大約30-79.9%、大30-79.5%、大約30-79.1%、大約30-70%、大約35-65%或大約40-60%),而雙層膜中第二脂質的莫耳百分比為等於或高於0.1或0.5至少於大約25、24、23或在其之間的任何值或範圍(例如,大約0.1-25%、大約0.1-24%、大約0.1-23%、大約0.5-25%、大約0.5-24%、大約0.5-23%、大約0.7-25%、大約0.7-24%或大約0.7-23%)。
微脂體的雙層膜進一步包含小於大約55莫耳百分比的類固醇,較佳為膽固醇。在某些實施例中,雙層膜中膽固醇之莫耳%為大約20-55%、大約20-50%、大約20-45%、大約25-55%、大約25-50%、大約25-45%、大約30-55%、大約30-50%或大約30-45%。
在一例示性實施例中,雙層膜中脂質及膽固醇的莫耳百分比為大約45-80%:20-55%或是50-75%:25-50%。在另一例示性實施例中,雙層膜中第一脂質、第二脂質與膽固醇的莫耳百分比是大約30-79.9%:0.1%-25%:20-55%、30-75%:0.1-25%:20-50% 或是35-70%:0.5-25%: 20-45%,且第一脂質是HSPC,而第二脂質是DSPE-PEG2000。
遠端裝載
如本文所用,用語「遠端裝載(remote loading)」為涉及藉由多原子離子梯度(polyatomic ion-gradient)將治療劑從外部介質跨越微脂體的雙層膜傳輸至內部水性空間之程序的藥物裝載法。這些梯度藉由在微脂體的內部水性空間中包埋至少一多原子離子作為捕獲劑,並以例如,純水、蔗糖溶液(sucrose solution)或生理食鹽水等具有較低多原子離子濃度的額外介質藉由如管柱分離(column separation)、透析(dialysis)或離心(centrifugation)等已知技術置換微脂體的外部介質而產生。在微脂體的內部水性空間及外部介質之間製造多原子離子梯度以將治療劑捕獲於微脂體的內部水性空間。作為捕獲劑之例示性多原子離子包含但不限於硫酸鹽(sulfate)、亞硫酸鹽(sulfite)、磷酸鹽(phosphate)、磷酸(hydrogen phosphate)、鉬酸鹽(molybdate)、碳酸鹽(carbonate)及硝酸鹽(nitrate)。例示性的捕獲劑包含但不限於硫酸銨(ammonium sulfate)、磷酸銨(ammonium phosphate)、鉬酸銨(ammonium molybdate)、蔗糖八硫酸酯銨(ammonium sucrose octasulfate)、蔗糖八硫酸酯三乙銨(triethylammonium sucrose octasulfate)及硫酸葡聚醣(dextran sulfate) 其組合。
在一實施例中,蔗糖八硫酸酯三乙銨的濃度為大約10至大約200 mM、大約50至大約150 mM或大約60至大約100 mM。在另一實施例中,硫酸銨的濃度為大約100至大約600 mM、大約150至大約500 mM或大約200至大約400 mM。
根據本發明,包埋捕獲劑的微脂體可藉由任何已知或後來開發的技術製備。例如,可藉由將經選擇的脂質組成物與捕獲劑藉由水合脂膜(hydrated lipid film)、噴霧乾燥粉末或凍乾餅(lyophilized cake)直接形成MLV微脂體;藉由音振處理(sonication)、均質化(homogenization)、微射流作用(microfluidization)或擠壓(extrusion)將MLV微脂體依尺寸製作為SUV微脂體及LUV微脂體。
藥物組合物
本發明針對緩釋藥物組合物,其包含:(a)至少一包含雙層膜的微脂體;(b) 一捕獲劑;及(c) 一治療劑,用以治療因骨密度降低或軟骨損失引起的疾病,其中雙層膜由至少一脂質組成且治療劑對該脂質的莫耳比值係大於或等於大約0.1。
在一個實施例中,緩釋藥物組合物進一步包含至少一藥學上可接受的賦形劑、稀釋劑、用於活性成分的介質、防腐劑、冷凍保護劑或其組合。在一個例示性實施例中,雙層膜的重量百分比為大約0.1-15%;捕獲劑的重量百分比為大約0.1-12%;及藥學上可接受的賦形劑(如蔗糖、組胺酸(histidine)、氯化鈉及超純水)、稀釋劑、用於活性成分的介質、防腐劑、冷凍保護劑或其組合的重量百分比為大約75.0-99.9%。
在特定實施例中,用於治療因骨密度降低軟骨缺損引起之疾病的治療劑是組織蛋白酶K抑制劑。組織蛋白酶K抑制劑的非限制性示例包含巴利卡替(balicatib,C23
H33
N5
O2
)、奧當卡替(odanacatib,C25
H27
F4
N3
O3
S)、L-006235 (C24
H30
N6
O2
S)、ONO-5334 (C21
H34
N4
O4
S)、MIV-711以及瑞拉卡替(relacatib,C27
H32
N4
O6
S)。在其他實施例中,用於治療因骨密度降低或軟骨缺損引起之疾病的治療劑是非水溶性或疏水性的。此藥物組合物的緩釋曲線延長了用於治療因骨密度降低或軟骨缺損引起之疾病的治療劑之半衰期、治療濃度以及作用期間,因而,維持該治療劑的治療效果並減少給藥頻率。
在一方面,藥物組合物的緩釋曲線是由於高的藥物包埋效率。這些藥物組合物的包埋效率為至少50%、55%、60%、65%、70%、75%、80%、85%或90%。
在另一方面,藥物組合物的緩釋曲線是由於較高的治療劑對脂質莫耳比值。在一例示性實施例中,用於治療因骨密度降低或軟骨損失引起的疾病之治療劑對一種或多種脂質的莫耳比值為大於或等於大約0.1,選擇性地從大於或等於0.1至小於大約20、小於大約15、小於大約10、小於大約5、小於大約4、小於大約3、小於大約2或小於大約1.5。
在又一方面,相較於用於治療因骨密度降低或軟骨缺損引起之疾病的游離治療劑,在本文用於治療因骨密度降低或軟骨缺損引起之疾病的治療劑之半衰期延長至少2倍、至少5倍、至少7.5倍、至少10倍或至少20倍。
本發明亦提供治療因骨密度降低或軟骨缺損引起之疾病的方法,所述方法包含對所需的個體施予本文所描述的藥物組合物之有效劑量,因而減輕在所需個體中因骨密度降低或軟骨缺損引起之疾病的症狀及/或病徵。
藥物組合物配製成適於注射,例如關節內(intraarticular)、皮下(subcutaneous)、表皮下(subdermal)、皮內(intradermal)、經皮(transdermal)或肌內(intramuscular)途徑。藥物組合物亦配製成以經皮貼片施予。
本發明之藥物組合物劑量可由所屬技術領域具有專業知識者根據實施例決定。涵蓋各在某些臨床環境中提供優勢的單劑量或多劑量形式。根據本發明,被施予之藥物組合物的實際量可根據被治療的個體之年齡、體重、條件、任何存在的醫療條件,並取決於醫學專家之判斷。
在一實施例中,本揭示內容的藥物組合物展現出用於治療因骨密度降低或軟骨缺損引起之疾病的治療劑具有顯著的延長釋放曲線。舉例來說,本發明的藥物組合物將L-006235在大鼠的半衰期延長至56.6小時,這是L-006235於大鼠中經由口服給藥半衰期(3.4小時)的16.6倍(J Med Chem 2005 1:48(24):7520-34)。這些藥物組合物是被開發用以降低給藥頻率,從每日一至兩次降至每兩日一次、每三日一次、每四日一次、每五日一次、每六日一次、每周一次、每兩周一次、每一個月一次、每兩個月一次、每三個月一次、每四個月一次、每五個月一次或每六個月一次。
實例
本發明之實施例藉由下列實例說明,其不應以任何方式解釋為對其範圍強加限制。相反地,應被清楚理解的是在不脫離本發明的精神下,所屬技術領域具有專業知識者在閱讀本文說明書之後,可採取各種其它實施例、修改及其等效物。除非另有指出,在下列實例中描述的研究中,將遵循習知程序。
實例1:製備L-006235微脂體配方
空的微脂體藉由脂質膜水合擠壓法(lipid film hydration-extrusion method)製備。將雙層膜成分,HSPC、膽固醇及DSPE-PEG2000 (莫耳百分比為59.5/39.6/0.9),溶解於有機溶劑中,舉例來說:氯仿及二氯甲烷。藉由旋轉蒸發器於真空下去除有機溶劑以形成一薄脂質膜。此乾燥脂質膜以含有300 mM硫酸銨水溶液於60℃水合30分鐘,而形成水性中心(aqueous core)包埋硫酸銨之空的微脂體。也可以使用其他捕獲劑,像是蔗糖八硫酸酯三乙銨。在液態氮與60℃水之間進行五次冷凍-解凍循環之後,隨後將空的微脂體穿過孔徑為0.2 µm的聚碳酸酯過濾器擠壓10次。未包埋的捕獲劑則藉由透析方法(dialysis method)或滲濾方法(diafiltration method)以9.4%蔗糖溶液或0.9%氯化鈉(NaCl)溶液置換移除,以在空的微脂體內部水相及外部水相之間製造一個多原子離子梯度。
將含有3.0 mg/mL的L-006235 (由DC Chemicals購得,中國)、空的微脂體(含有6.0 mM的脂質)以及50 mM的組胺酸緩衝液(pH 6.5)之混合物於60°C下反應15分鐘。反應混合物中未包埋的L-006235藉由SephadexTM
G-50細膠粒(fine gel) (GE Healthcare)或透析袋(Spectrum Labs)以9.4%蔗糖溶液分離,以獲得L-006235微脂體配方。為了計算L-006235微脂體配方中藥物對脂質的莫耳比值(D/L),L-006235微脂體配方中包埋的L-006235濃度經由高效液相層析儀(HPLC)測量而該L-006235微脂體配方中脂質濃度則使用紫外線/可見光(UV/Vis)分光光譜儀測量。
包埋效率由L-006235微脂體配方之藥物對脂質莫耳比值(D/L)與反應混合物之標稱(nominal) D/L比較計算而得,標稱D/L係將L-006235的濃度除以空微脂體的脂質濃度而得。粒徑分布藉由動態光散射儀(Zetasizer Nano-ZS90, Malvern,美國)測量。
使用300 mM硫酸銨作為捕獲劑,L-006235微脂體配方的最終 D/L為1.00,包埋效率為93.4%,且微脂體的平均粒徑為193.7 nm。
實例2:各種組織蛋白酶K抑制劑微脂體配方的製備
本文使用的組織蛋白酶K抑制劑包含L-006235及巴利卡替 (MedChem Express,美國)。空的微脂體根據實例1並包含以下捕獲劑製備:(1) 300 mM的硫酸銨以及(2) 75 mM的蔗糖八硫酸酯三乙銨。L-006235微脂體配方的裝載步驟是基於實例1。巴利卡替微脂體配方製備如下:將含有2 mg/mL的巴利卡替、空的微脂體以及50 mM的組胺酸緩衝液(pH 6.5)的反應混合物在60°C下反應15分鐘。經由SephadexTM
G-50細膠粒(GE Healthcare)移除未包埋的藥物,以獲得巴利卡替微脂體配方。根據實例1的步驟計算此實例中微脂體配方的D/L。表1呈現L-006235及巴利卡替的裝載曲線。
表1、不同組織蛋白酶K抑制劑的裝載曲線
實例3: L-006235微脂體配方的藥物動力學(PK)研究
雙層膜(莫耳百分比) | 化合物 | 捕獲劑 | 經純化的D/L (莫耳/莫耳) | EE (%) | 平均粒徑 (nm) | |
HSPC/膽固醇/DSPE-PEG2000 (59.5/39.6/0.9) | L-006235 | 1 | 1.00 | 93.4 | n.d. | |
HSPC/膽固醇/DPPG (59.5/39.6/0.9) | L-006235 | 1 | 1.13 | 87.7 | 193.7 | |
HSPC/膽固醇(60/40) | L-006235 | 2 | 0.92 | 86.3 | 185.5 | |
HSPC/膽固醇/DSPE-PEG2000 (59.5/39.6/0.9) | 巴利卡替 | 1 | 0.28 | 59.4 | n.d. | |
HSPC/膽固醇/DSPE-PEG2000 (40.3/37.2/22.5) | 巴利卡替 | 2 | 0.40 | 82.2 | 218.4 | |
EE,包埋效率;n.d.,未測得。 |
使用七至八周雌性SD (Sprague-Dawley)大鼠執行L-006235微脂體配方的體內PK評估。大鼠眷養於12小時光照/12小時黑暗之晝夜循環操作且不限制飲水及攝食的繫留室(holding room)中。
將大鼠分成兩組(每組n = 4)。第一組的大鼠接受2.5 mg/kg游離L-006235的關節內注射,該游離L-006235以L-00623溶於含有0.06 N鹽酸(HCl)的9.4%蔗糖溶液製備而得,最終濃度為10.0 mg/mL,而第二組的每隻大鼠則接受5.0 mg/kg L-006235微脂體配方關節內注射,所述L-006235微脂體配方根據實例1製備,其最終濃度為18.1 mg/mL。於注射後5分鐘、15分鐘、30分鐘、1小時、2小時、4小時、8小時、24小時、48小時、72小時、96小時以及168小時收集血液樣品。藉由離心取得血漿樣品,並使用液相色層-串聯質譜儀分析。血漿濃度對應時間曲線使用在PKSolver (Comput Methods Programs Biomed. 2010;99(3):306-314)中的非區室模型分析模組分析。兩種L-006235配方的PK參數則總結於表2。
表2顯示L-006235微脂體配方的劑量標準化Cmax
(Cmax
/D)是游離L-006235配方的40.5%,且L-006235微脂體配方的半衰期(t1/2
) (56.6小時)明顯地長於游離L-006235配方(4.5小時)。相較於游離L-006235配方的AUC0-t
/D (其象徵100%的L-006235於注射後24小時釋放), L-006235微脂體配方的劑量標準化曲線下面積(AUC0-t
/D)指出注射168小時後,89.7%的L-006235從L-006235微脂體配方釋放。
表2、於大鼠單次關節內注射游離L-006235配方或L-006235微脂體配方後衍生的PK參數
參數 | 單位 | 游離L-006235配方 | L-006235 微脂體配方 |
劑量 | mg ∙ kg-1 | 2.5 | 5.0 |
t1/2 | h | 4.5 | 56.6 |
Cmax | ng ∙ mL-1 | 424.3 | 343.7 |
Cmax /D | 10-6 ∙ kg ∙ mL-1 | 169.7 | 68.7 |
AUC0-t | h ∙ ng ∙ mL-1 | 801.5 | 1437.9 |
AUC0-t /D | 10-6 ∙ h ∙ kg ∙ mL-1 | 320.6 | 287.6 |
AUC0-inf | h ∙ ng ∙ mL-1 | 811.4 | 1703.0 |
AUC0-inf /D | 10-6 ∙ h ∙ kg ∙ mL-1 | 324.6 | 340.6 |
Cmax /D,劑量標準化的Cmax ;AUC0-t /D,劑量標準化的AUC0-t ;AUC0-inf /D,劑量標準化的AUC0-inf 。 |
此外,第1圖顯示注射游離L-006235後24小時,已無法於血漿中偵測到L-006235,然而施予本發明的L-006235微脂體配方後168小時,仍可於血漿中測得L-006235。所述結果顯示本發明藥物組合物可緩慢釋放組織蛋白酶K抑制劑。
無
第1圖顯示大鼠經關節內注射游離L-006235及L-006235微脂體後血漿L-006235濃度的折線圖。
Claims (13)
- 一種藥物組合物,其包含:(a)至少一微脂體,其包含一雙層膜,其中該雙層膜包含至少一脂質及膽固醇;(b)一捕獲劑,該捕獲劑係選自由蔗糖八硫酸酯三乙銨(triethylammonium sucrose octasulfate)、硫酸銨(ammonium sulfate)及其組合物所組成之群組;以及(c)一治療劑,該治療劑係為組織蛋白酶K抑制劑,其中該治療劑對該脂質的莫耳比係等於或大於大約0.2。
- 如申請專利範圍第1項所述之藥物組合物,其中該微脂體的平均粒徑係從大約50nm至500nm。
- 如申請專利範圍第1項所述之藥物組合物,其中該雙層膜進一步包含膽固醇。
- 如申請專利範圍第3項所述之藥物組合物,其中在該雙層膜中,該膽固醇的莫耳百分比係大約20至約55%。
- 如申請專利範圍第1項所述之藥物組合物,其中蔗糖八硫酸酯三乙銨濃度係大約10至200mM。
- 如申請專利範圍第1項所述之藥物組合物,其中硫酸銨的濃度係大約100至600mM。
- 如申請專利範圍第1項所述之藥物組合物,其中該治療劑係選自基本上由巴利卡替(balicatib)、奧當卡替(odanacatib)、L-006235、ONO-5334、MIV-711、瑞拉卡替(relacatib)及其組合所組成之群組。
- 如申請專利範圍第1項所述之藥物組合物,其中該治療劑是包埋於微脂體中,其包埋效率大於大約50%。
- 一種如申請專利範圍第1項至第8項任一項所述之藥物組合物用於製備用於治療因骨密度降低或軟骨損失引起之疾病藥物之用途,其中該藥物組合物包含:(a)至少一微脂體,其包含一雙層膜,其中該雙層膜包含至少一脂質及膽固醇;(b)一捕獲劑,該捕獲劑係選自由蔗糖八硫酸酯三乙銨(triethylammonium sucrose octasulfate)、硫酸銨(ammonium sulfate)及其組合物所組成之群組;以及(c)一治療劑,該治療劑係為組織蛋白酶K抑制劑,其中該治療劑對該脂質的莫耳比係等於或大於大約0.2。
- 如申請專利範圍第9項所述之用途,其中該治療劑的半衰期相較於游離的該治療劑的半衰期延長至少2倍、至少5倍、至少7.5倍、至少10倍或至少20倍。
- 如申請專利範圍第9項所述之用途,其中該藥物組合物是係至少每三天一次、至少每週一次、至少每兩週一次或至少每月一次給予。
- 如申請專利範圍第9項所述之用途,其中該藥物組合物是透過注射給予。
- 如申請專利範圍第12項所述之用途,其中該注射包含關節內(intraarticular)、皮下的(subcutaneously)、表皮下(subdermal)、皮內(intradermal)或肌內(intramuscular)途徑。
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