TW201540322A - 依那西普之安定的液體調配劑 - Google Patents
依那西普之安定的液體調配劑 Download PDFInfo
- Publication number
- TW201540322A TW201540322A TW104108045A TW104108045A TW201540322A TW 201540322 A TW201540322 A TW 201540322A TW 104108045 A TW104108045 A TW 104108045A TW 104108045 A TW104108045 A TW 104108045A TW 201540322 A TW201540322 A TW 201540322A
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- Prior art keywords
- etanercept
- formulation
- pharmaceutically acceptable
- methionine
- acceptable salt
- Prior art date
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Abstract
本發明係關於依那西普(Etanercep)之安定的液體調配劑(重組體p75 sTNFR:Fc融合蛋白質),且更具體係關於液體調配劑,其包含減少儲存期間依那西普副產物形成之足量的一種或多種選自下列所組成群組之安定劑:甲硫胺酸、離胺酸、組氨酸、和其藥學上可接受的鹽。根據本發明之液體調配劑,有效地減少依那西普之副產物之生成,且在長時間儲存下,安定地維持其藥學療效。因此在投藥前不需重建程序,且可將無菌的調配劑投藥病人以確保病人安全。於是,它能被應用於需要依那西普治療之領域。
Description
本發明關於依那西普之安定的液體調配劑(重組體p75 sTNFR:Fc融合蛋白),且更具體係關於液體調配劑,其包含減少儲存期間依那西普副產物形成之足量的一種或多種選自下列所組成群組之安定劑:甲硫胺酸、離胺酸、組氨酸、和其藥學上可接受的鹽所組成之安定劑。
依那西普係生物發炎調節因子(作為結合至細胞表面腫瘤壞死因子(TNF-α)受體之TNF-α的競爭性抑制劑),以抑制TNF-α媒介的免疫反應。依那西普係分子量接近150千道爾頓(kDa)之大分子,且為兩個Fc融合蛋白藉由二硫鍵連結之同質二聚體,各Fc融合蛋白係由耦合至人類免疫球蛋白G亞型1之Fc部分的人類可溶的p75 TNF受體所組成(Goldenberg,Clinical Therapeutics,21(1):75-87,1999;Moreland et al.,Ann.Intern.Med.,130(6):478-486,1999)。
此原型融合蛋白質在1990年初,首先由Bruce A.Beutler在德州大學西南醫學中心(University of Texas Southwestern Medical Center)合成,並在2002年以恩博
(Enbrel)之商標名由安進(Amgen)上市銷售。依那西普係為用於治療類風溼性關節炎、牛皮癬和關節黏連性脊椎炎之TNF-α抑制劑,且業進行血管炎、阿茲海默症和克隆氏症(Crohn’s disease)治療之臨床試驗。
如同蛋白質藥物,抗體藥物具有非常短的半衰期,且不適宜的溫度、剪應力(shear stress)、振動、凍融(freeze-thawing)、紫外線曝光、過度的pH變化、有機溶劑和微生物污染容易造成化學和物理變性。化學變性包括二聚物解離、氧化、脫醯胺作用、異構化和聚合,其係受構成抗體之胺基酸和包含該抗體之溶劑狀態(鹽、pH和溫度)所影響。物理變性包括喪失三級結構、共價/非共價聚集(aggregation)和單體之黏附,其係受蛋白質表面上的疏水性區域所影響,該疏水性區域受包含抗體的外圍環境如溶劑、複合蛋白質結構(如電荷分布、和熱安定性)所改變。該抗體之物理或化學變性造成其生理活性喪失。由於變性係不可逆程序,抗體一旦變性,可能無法恢復其原有特性至初始狀態,導致降低其治療效果。已有建議單體之聚集造成免疫反應。因此,許多研究已於無聚集之包含生理有效量之抗體調配劑進行(Ishikawa et al.,Biol.Pharm.Bull.,33(8):1413-1417,2010;Levin et al.,The Development of Therapeutic Monoclonal Antibody Products,editors.Boston(MA):BioProcess Technology Consultants,Inc,Chapter 9)。
有許多方法可用於防止液體調配劑中蛋白質的變性。於一些蛋白質藥物中,安定性問題經由冷凍乾燥獲得解
決。例如,美國專利第7,592,004號揭露賽尼哌(daclizumab)之冷凍乾燥調配劑,其係使用5至25mM組氨酸緩衝劑溶液(pH 5.5至6.5)、0.005至0.03%非離子性介面活性劑(聚山梨醇酯),和100至300mM非還原性糖(蔗糖)加以安定。美國專利公開第2010-0158925號揭露爾必得舒(cetuximab)之冷凍乾燥調配劑,其係使用組氨酸緩衝劑溶液和乳糖酸加以安定。然而,冷凍乾燥過程產生冷凍和乾燥應力,例如冰晶之生成、pH改變、和高濃度之溶質,且該些應力可能造成抗體變性。此外,由於在生產期間冷凍乾燥過程需要大容量的冷凍乾燥器,而在大規模生產期間提高生產成本。為了在使用前重建,將冷凍乾燥的產物溶解在無菌的水性介質中亦造成不便。
作為一種解決這些限制之替代方法,於水性調配劑中添加安定劑,以增進抗體安定性。介面活性劑、血清白蛋白、多醣、胺基酸、聚合物、鹽或其類似者係已知為蛋白質(包含抗體)的安定劑(Wang,Int.J.Pharm.,185:129-188,1999;Wang et al.,J.Pharm.Sci.,96(1):1-26,2007)。
美國專利公開第2011-0070231號揭露IgG抗體之安定液體組成物,其中該安定的藥學液體調配劑包括,溶於20至60mM的琥珀酸緩衝劑溶液(pH 5.5至6.5)中之50mg/mL或更多之賽尼哌,0.02至0.04%的聚山梨醇酯和75至150mM的氯化鈉。
美國專利公開第2011-0020328號揭露治療有效量之抗-CD20抗體調配劑,其中該藥學上安定的組成物包括10至
100mM的乙酸鈉,25至100mM的氯化鈉,0.5至5%的精胺酸游離鹼,0.02至0.2mM的EDTA和0.01至0.2%的聚山梨醇酯80,且其pH係5.0至7.0。
美國專利第7,785,592號揭露安定的調配劑,其中75mg/mL或更多的西那吉斯(palivizumab)係藉由使用組氨酸緩衝劑溶液和無離子鹽之甘胺酸和介面活性劑而安定之,且其安定性在2℃至8℃至少維持15個月。
美國專利第6,991,790號揭露安定的水性藥學調配劑,包括治療有效量之抗體、接近pH 4.8至5.5之乙酸鹽緩衝劑溶液,介面活性劑及多元醇,無等滲透壓劑(如氯化鈉)。
美國專利第7,648,702號揭露液體調配劑,其中將人類免疫球蛋白G1(IgG1)之Fc部分連結至人類p75腫瘤壞死因子受體之融合蛋白質,係藉由使用接近10至200mM的L-精胺酸作為聚集防止劑而安定。此專利係唯一使用依那西普作為有效成分之技術。
然而,為了製備安定的調配劑,適當的安定劑的使用應考慮各有效組成分之物理化學特性。當安定劑組合使用,安定劑之間的競爭和負面影響可能導致不良效果。此外,抗體濃度應在適合安定的範圍內,且該濃度係相對高於蛋白質藥的濃度。於是,安定溶液中抗體需要許多精力與注意(Shire et al.,J.Pharm.Sci.,93(6):1390-1402,2004)。
很少研究針對依那西普之安定的液體調配劑,且發明者所知安定依那西普之唯一方法係於液體調配劑中使用
L-精胺酸。因此,迫切需要發展新液體調配劑,其可長時間安定地維持依那西普活性,且其相較於已知包含L-精胺酸之調配劑對於依那西普之安定更有效。
本案之發明者已致力於發展製備可安定地維持依那西普活性之液體調配劑之方法。結果,他們發現一種或多種選自甲硫胺酸、離胺酸和組氨酸所組成群組之安定劑係顯示對溶液中依那西普之安定有顯著效果,從而完成本發明。
本發明之目的係提供水性調配劑,其包含用以在溶液儲存期間減少依那西普副產物生成且長時間維持依那西普活性之安定劑。
根據本發明之液體調配劑,在長時間儲存下,有效地避免依那西普之副產物之生成,且安定地維持其藥物功效。因此在投藥前不需重建程序,且無菌的調配劑可被投藥於病人以確保病人安全。於是,其可預期應用於需要依那西普治療之領域。
於一方面,為了達成上述目的,本發明提供液體調配劑,其包含一種或多種選自甲硫胺酸、離胺酸、組氨酸、
和其藥學上可接受的鹽所組成群組之安定劑。
本發明之調配劑可為依那西普之液體調配劑,包含依那西普;和一種或多種選自甲硫胺酸、離胺酸、組氨酸、和其藥學上可接受的鹽所組成群組之安定劑。
該調配劑藉由減少由於儲存期間變性所產生之依那西普副產物,而顯示增加儲存安定性。
作為安定劑,甲硫胺酸、離胺酸、組氨酸或其藥學上可接受的鹽,可以0.1至250mM含量存在於調配劑。
於調配劑中之依那西普可以1至100mg/mL含量存在。
調配劑可進一步包括一種或多種選自緩衝劑、等滲透壓劑、賦形劑和防腐劑所組成群組之材料。
緩衝劑可選自檸檬酸鹽、磷酸鹽、琥珀酸鹽、酒石酸鹽、富馬酸鹽、葡萄糖酸鹽、草酸鹽、乳酸鹽、乙酸鹽、組氨酸和三羥甲基氨基甲烷(Tris)所組成群組,且可以0.1至100mM含量存在。
等滲透壓劑可選自氯化鈉、氯化鉀、硼酸、硼酸鈉、甘露糖醇、甘油、丙二醇、聚乙二醇、麥牙糖、蔗糖、赤藻糖醇、***糖醇、木糖醇、山梨醇和葡萄糖所組成群組、且可以1至1000mM含量存在。
根據本發明之依那西普之調配劑可為液體調配劑,其包含1至100mg/mL的依那西普,0.1至250mM的甲硫胺酸或其藥學上可接受的鹽,0.1至100mM的磷酸緩衝劑和1至1000mM的氯化鈉。
根據本發明之依那西普之調配劑可為液體調配劑,其
包含1至100mg/mL的依那西普,0.1至250mM的離胺酸或其藥學上可接受的鹽,0.1至100mM的磷酸鹽緩衝劑和1至1000mM的氯化鈉。
根據本發明之依那西普之調配劑可為液體調配劑,包含1至100mg/mL的依那西普,0.1至250mM的組氨酸或其藥學上可接受的鹽,0.1至100mM的磷酸鹽緩衝劑和1至1000mM的氯化鈉。
根據本發明之依那西普之調配劑可為液體調配劑,其包含1至100mg/mL的依那西普,0.1至250mM的組氨酸或其藥學上可接受的鹽,0.1至250mM的離胺酸或其藥學上可接受的鹽,0.1至100mM的磷酸鹽緩衝劑和1至1000mM的氯化鈉。
根據本發明之依那西普之調配劑可為液體調配劑,其包含1至100mg/mL的依那西普,0.1至250mM的組氨酸或其藥學上可接受的鹽,0.1至250mM的甲硫胺酸或其藥學上可接受的鹽,0.1至100mM的磷酸鹽緩衝劑和1至1000mM的氯化鈉。
根據本發明之依那西普之調配劑可為液體調配劑,其包含1至100mg/mL的依那西普,0.1至250mM的甲硫胺酸或其藥學上可接受的鹽,0.1至250mM的離胺酸或其藥學上可接受的鹽,0.1至100mM的磷酸鹽緩衝劑和1至1000mM的氯化鈉。
以下將詳細描述本發明。
本發明首次證明,甲硫胺酸、離胺酸、組氨酸和其藥
學上可接受的鹽,具有減少在長期儲存時溶液中依那西普副產物生成並安定地維持其活性的效果,於是建議了其作為藥學上有效量之依那西普的安定劑之新穎用途。
為了製備安定的調配劑,適當的安定劑的使用應考慮各有效組成分之物理化學特性。根據包含在調配劑中材料之不同型態、濃度和組合,調配劑中材料間的競爭可能導致不良效果。於是,製備安定的藥物具體調配劑係困難的。
鑑於上述脊景,本發明者已發現該包含一種或多種選自甲硫胺酸、離胺酸、組氨酸和其藥學上可接受的鹽所組成群組之安定劑之液體調配劑,相較於無安定劑之調配劑,係藉由減少儲存期間溶液中依那西普副產物而增加依那西普之儲存安定性。
具體地,在本發明之具體實施例中,為了調查作為最佳製備依那西普之安定液體調配劑之安定劑,加入各種胺基酸、介面活性劑和聚合物以測試其安定效果。結果發現離胺酸、組氨酸、甲硫胺酸或其組合顯示,藉由防止依那西普在儲存期間於高溫的溶液變性,具有顯著安定依那西普的效果。
進一步地發現,根據本發明之調配劑顯示安定依那西普之效果,其效果相當於或高於已知之包含L-精胺酸的依那西普安定調配劑。(美國專利第7,648,702號)。尤其是發現甲硫胺酸顯示優於L-精胺酸之非常好的安定依那西普之效果。
具體地,儲存期間所形成的依那西普副產物,藉由粒
徑排阻高效液相層析(SE-HPLC)檢驗。結果,與美國專利第7,648,702使用L-精胺酸作為安定劑而製備之依那西普調配劑所具不純物的總量相比,使用離胺酸作為安定劑製備之調配劑顯示具有相似量的不純物,而使用組氨酸或甲硫胺酸作為安定劑製備之調配劑顯示具有較低量之不純物(見表2)。疏水交互作用分析(HI-HPLC)亦顯示相似結果。這些結果指出組氨酸、離胺酸和甲硫胺酸防止依那西普變性以抑制其副產物之生成(見表3)。
因此,根據本發明之液體調配劑,能藉由有效地減少依那西普副產物之生成,而長時間安定地維持依那西普之藥物療效。
於此所用術語「依那西普(重組體p75 sTNFR:Fc融合蛋白)」意指一種蛋白質,其係兩個Fc融合蛋白藉由雙硫鍵連結之同質二聚體,各Fc融合蛋白質由人類可溶75千道耳頓(p75)TNF(腫瘤壞死因子)受體耦合至人類IgG1之Fc部分所組成。
具體地,依那西普係為藉由三個雙硫鍵所連結之兩個Fc融合蛋白之同質二聚體結構,各Fc融合蛋白由人類可溶p75 TNF受體之細胞外配體結合部份連結至人類IgG1之Fc部分所組成。依那西普之Fc成分包含IgG1之CH2區域(domain)、CH3區域和鉸鍊區,但不包含CH1區域。依那西普可具有接近150千道耳頓(kDa)之分子量。此依那西普可為目前以商標名恩博®(ENBREL®)販售(安進公司(Amgen Inc.),Thousand Oaks,CA.),且具有CAS號碼
185243-69-0。
依那西普可藉由重組體DNA技術製備,但不侷限於此。
本發明之依那西普係生物發炎調節因子(其作為結合至細胞表面腫瘤壞死因子(TNF-α)受體之TNF-α的競爭性抑制劑),以抑制TNF-α媒介的免疫反應,並用來治療風溼性關節炎、牛皮癬和關節黏連性脊椎炎,且業進行血管炎、阿茲海默症和克隆氏症治療之臨床試驗。
根據本發明之液體調配劑中,依那西普係以治療有效量被包含。較佳地,依那西普係以1至100mg/mL含量存在。
於此所用術語「經安定的液體調配劑」或「安定的液體調配劑」意指於儲存期間,保留溶液中治療有效成分(依那西普)之物理和化學身分和整體性之調配劑。依那西普之安定性之分析測量可藉由該技藝廣泛習知之蛋白質安定性試驗施行。可在預定時間、預定溫度測量安定性。為了快速檢測,調配劑可被儲存在較高或「升高的」溫度,例如於40℃儲存2周至1個月或更久,此時測量其隨時間變化的安定性。
於此所用術語「安定劑」意指具體的化學品,其與調配劑中的生物分子及/或一般藥學賦形劑相互作用以增進安定性。安定劑一般保護蛋白質免受空氣/溶液界面引起的應力和溶液/表面引起的應力(其造成蛋白質聚集)傷害。在本發明中,安定劑係一種在儲存期間減少溶液中依那西普
副產物之生成以長時間維持其活性的成分,且較佳係一種或多種選自甲硫胺酸、離胺酸、組氨酸和其藥學上可接受的鹽所組成群組。
至於胺基酸,L式和D式都包含在本發明之範圍中。不僅胺基酸本身,例如甲硫胺酸、離胺酸和組氨酸,也包括其之類似物、溶劑合物、水合物、立體異構物和藥學上可接受的鹽,皆在本發明之範圍中,只要彼等具體地顯示實質上相同的效果。
於此所用術語「藥學上可接受的鹽」意指以該胺基酸(例如甲硫胺酸、離胺酸和組氨酸)之鹽的形式所製備的化合物,其落在保持彼等之功能為作為本發明之安定劑的範圍內。具體地,可藉由酸加成而形成鹽,例如其可與無機酸(如氫氯酸、氫溴酸、磷酸、硝酸、硫酸等)、有機羧酸(如乙酸、鹵乙酸例如三氟乙酸、丙酸、順丁烯二酸、琥珀酸、羥丁二酸、檸檬酸、酒石酸、水楊酸)、糖酸(葡萄糖醛酸、半乳糖醛酸、葡萄糖酸、抗壞血酸)、酸性多醣(如玻尿酸、硫酸軟骨膠、精胺酸)、有機磺酸包括磺酸糖酯例如硫酸軟骨膠(如甲烷磺酸、ρ-甲苯磺酸)形成鹽。
於此所用術語「類似物」意指顯示如用作本發明之安定劑的胺基酸(例如甲硫胺酸、離胺酸和組氨酸)相同功能的化合物。本發明中,胺基酸(例如甲硫胺酸、離胺酸和組氨酸)包括其類似物。本發明中,類似物之實例可包括甲硫胺酸類似物,亦即硒代甲硫胺酸、羥基甲基丁酸、乙硫胺酸和三氟甲硫胺酸,但不侷限於此。
於此所用術語「副產物」意指非所欲之產物,其減少在調配劑中依那西普之治療有效成分之比值。典型的副產物包括「低分子量產物」(其係藉由脫胺或水解而從依那西普變性而來)、「高分子量產物」(例如低聚物和聚集體),或其混合物。
於此所用術語「高分子量產物」,包括變性(如由於脫胺或水解產生的多肽降解)後聚集的依那西普片段或其混合物。典型地,高分子量產物係具有比治療性單體依那西普更高分子量的複合物,且可具有超過大約150kDa的分子量。
於此所用術語「低分子量產物」,包括藉由脫胺或水解產生的治療性多肽,亦即依那西普片段。典型地,低分子量產物係具有比治療性單體依那西普更低分子量的複合物,且可具有低於大約150kDa的分子量。
本發明之液體調配劑,包括一種或多種選自甲硫胺酸、離胺酸、組氨酸和其藥學上可接受的鹽所組成群組之安定劑。具體地,液體調配劑包括甲硫胺酸、離胺酸或組氨酸作為安定劑,或兩種安定劑例如甲硫胺酸和離胺酸、甲硫胺酸和組氨酸、或離胺酸和組氨酸,或三種安定劑例如甲硫胺酸、離胺酸和組氨酸。於上述包含胺基酸之組合的調配劑中,可以進一步添加甲硫胺酸、離胺酸、組氨酸之分別的藥學上可接受的鹽,或甲硫胺酸、離胺酸和組氨酸可能為該藥學上可接受的鹽分別之修飾形式。液體調配劑較佳係包括甲硫胺酸、離胺酸、組氨酸、甲硫胺酸和離
胺酸、甲硫胺酸和組氨酸、或離胺酸和組氨酸,且更佳係甲硫胺酸作為安定劑。
甲硫胺酸係必需胺基酸,並具有C5H11NO2S之化學式和149.21之分子量。甲硫胺酸係非極性胺基酸,且其支鏈包含硫醚基(-S-CH3)。其具有2.28之pK1值,9.21之pK2值,和5.74之等電點(PI)值。甲硫胺酸藉由與抗體中甲硫胺酸殘基競爭與羥基自由基間之反應而防止液體調配劑中抗體之氧化,並安定抗體(Lam et al.,J.Pharm.Sci.,86(11):1250--1255,1997;Wang,Int.J.Pharm.,185:129-188,1999)。
離胺酸係必需胺基酸,並具有C6H14N2O2之化學式和146.19之分子量。離胺酸係鹼性胺基酸,並具有2.18之pK1值,8.95之pK2值,10.53之pK3值和9.74之PI值。
組氨酸係有咪唑官能基之必需胺基酸,其支鏈具有正電荷並具有C6H9N3O2之化學式和155.15之分子量。組胺酸係鹼性胺基酸,並具有1.82之pK1值,9.17之pK2值,6.0之pK3值和7.59之PI值。
相反地,包含於已知可商購的依那西普之調配劑中之L-精胺酸係必要的胺基酸,並具有C6H14N4O2之化學式和174.2之分子量。精胺酸係鹼性胺基酸,並具有2.17之pK1值,9.04之pK2值、12.48之pK3值和10.76之PI值。也就是說,本發明中使用作為安定劑之甲硫胺酸、離胺酸和組氨酸,與作為依那西普之已知安定劑之精胺酸,在構造、化學式、物理化學特性和離子化傾向係完全不同的。本發明首次證明,例如甲硫胺酸、離胺酸和組氨酸的胺基酸是
依那西普之適當的安定劑。
於本發明之液體調配劑中的安定劑含量係0.1至250mM,較佳係1至100mM,且更佳係5至50mM。
除了會惡化本發明之功能者外,本發明之根據一種或多種選自甲硫胺酸、離胺酸、組氨酸和其藥學上可接受的鹽所組成群組之安定劑的液體調配劑,可進一步包括一般包含於蛋白質藥或抗體藥之調配劑的任何材料,以增加依那西普安定性。例如已知作為依那西普安定劑之L-精胺酸可添加至本發明之液體調配劑。
除了安定劑外,根據本發明之液體調配劑可進一步包括緩衝劑。於此所用術語「緩衝劑」意指增進調配劑的等滲透壓性和化學安定性之成分,且其作用為維持生理合適的pH。為了依那西普之安定,緩衝劑防止液體調配劑之快速pH改變以維持溶液之pH。較佳緩衝劑之實例包括檸檬酸鹽、磷酸鹽、琥珀酸鹽、酒石酸鹽、反丁烯二酸鹽、葡萄糖酸鹽、草酸鹽、乳酸鹽、乙酸鹽、組氨酸和三羥甲基氨基甲烷,但不侷限於此。在該具體實施例中,緩衝劑係磷酸鹽緩衝劑。緩衝劑可單獨或以兩種或更多種之組合使用。
在本發明之各種實施例中,調配劑應具有接近5至7.5之pH或接近5.8至6.8之pH。在具體實施例中,調配劑具有接近6.0至6.6之pH。自中間值至上述pH水平的範圍,例如接近pH 5.2至接近pH 6.4(如pH 6.2)也為此發明之一部分。例如,意欲涵蓋包括使用任何上述數值作為上限和/
或下限之組合的範圍。若需要,pH可藉由技藝中已知相關技術調整。若需要,例如pH可藉由HCl之添加或組氨酸之添加調整至任何所欲之範圍。
在另一個實施例中,緩衝劑係以0.1至100mM,較佳係以1至50mM,且更佳係以5至25mM之濃度存在。自中間值至上述濃度的範圍也為此發明之一部分。例如,意欲涵蓋包括使用任何上述濃度作為上限和/或下限之組合濃度的範圍。在具體實施例中,緩衝劑應以足夠維持生理足夠pH含量存在。
除了安定劑外,根據本發明之液體調配劑可進一步包括等滲透壓劑。於此所用術語「等滲透壓劑」意指其功能為部分維持調配劑之等滲透壓性和蛋白質水平,並部分維持存在於調配劑中之治療性活性多肽之水平、比值或比例之成分。等滲透壓劑擁有如血漿之相同滲透壓,因此可以靜脈輸送到個體內,而不改變個體血漿的滲透壓。在一根據本發明之實施例中,等滲透壓劑確實係以足以使調配劑適合用於靜脈輸液含量存在。等滲透壓劑通常也作為一種增容填充劑。因此,等滲透壓劑可允許蛋白質克服各種如冷凍和剪切之應力。
當溶液中的依那西普投藥至身體,等滲透壓劑作為維持身體之適當滲透壓。等滲透壓劑之實例可包括常用的氯化鈉、氯化鉀、硼酸、硼酸鈉、甘露醣醇、甘油、丙二醇、聚乙二醇、麥牙糖、蔗糖、赤藻醣醇、***糖醇、木糖醇、山梨醇和葡萄糖,但不侷限於此。在具體實施例中,
等滲透壓劑係NaCl。彼等滲透壓劑可單獨或以兩種或更多種之組合使用。
在又一個實施例中,等滲透壓劑(如NaCl)係以1至1000mM,較佳係以10至500mM,更佳係以50至250mM之濃度存在。自中間值至上述濃度的範圍也為此發明之一部分。例如,意欲涵蓋包括使用上述任何濃度作為上限和/或下限之組合濃度的範圍。等滲透壓劑應以足以維持調配劑滲透之含量存在。
根據本發明之液體調配劑可進一步包括藥學上可接受的賦形劑,且賦形劑之實例可包括糖和多元醇、介面活性劑、或聚合物等。糖和多元醇之實例可包括蔗糖、海藻糖、乳糖、麥牙糖、半乳糖、甘露醣醇、山梨醇、甘油,介面活性劑之實例可包括非離子介面活性劑例如聚山梨醇酯20、聚山梨醇酯80和泊洛沙姆(poloxamer),以及聚合物之實例可包括聚葡萄糖、聚乙二醇、羧甲基織維素、玻尿酸和環糊精。
根據本發明之液體調配劑可進一步包括防腐劑。防腐劑意即添加至藥學的調配劑作為抗菌劑之化學品。防腐劑之實例可包括羥基氯苯胺、芐索銨(benzethonium)、氯己定(chlorhexidine)、酚、間甲酚、芐醇、對羥苯甲酸甲酯、對羥苯甲酸丙酯、氯丁醇、鄰甲酚、對甲酚、氯甲酚、硝酸苯汞、和安息香酸,但不侷限於此。彼等防腐劑可單獨或以兩種或更多種之組合使用。
在具體的實施例中,本發明之調配劑係pH 6.0至6.6
之包含1至100mg/mL的依那西普,0.1至250mM的甲硫胺酸或其藥學上可接受的鹽、0.1至100mM的磷酸鹽緩衝劑,和1至1000mM的氯化鈉之安定的液體調配劑。更具體而言,本發明之調配劑係包含1至100mg/mL的依那西普,0.1至100mM的甲硫胺酸或其藥學上可接受的鹽,0.1至50mM的磷酸鹽緩衝劑、和1至500mM的氯化鈉之安定的液體調配劑。
在具體的實施例中,本發明之調配劑係pH 6.0至6.6之包含1至100mg/mL的依那西普,0.1至250mM的組氨酸或其藥學上可接受的鹽,0.1至100mM的磷酸鹽緩衝劑,和1至1000mM的氯化鈉之安定的液體調配劑。更具體而言,本發明之調配劑係包含1至100mg/mL的依那西普,0.1至100mM的組氨酸或其藥學上可接受的鹽,0.1至50mM的磷酸鹽緩衝劑,和1至500mM的氯化鈉之安定的液體調配劑。
在具體的實施例中,本發明之調配劑係包含1至100mg/mL的依那西普,0.1至250mM的離胺酸或其藥學上可接受的鹽,0.1至100mM的磷酸鹽緩衝劑,和1至1000mM的氯化鈉之安定的液體調配劑。更具體而言,本發明之調配劑係pH 6.0至6.6之包含1至100mg/mL的依那西普,0.1至100mM的離胺酸或其藥學上可接受的鹽,0.1至50mM的磷酸鹽緩衝劑,和1至500mM的氯化鈉之安定的液體調配劑。
在具體的實施例中,本發明之調配劑係包含1至100
mg/mL的依那西普,0.1至250mM的組胺酸或其藥學上可接受的鹽,0.1至250mM的離胺酸或其藥學上可接受的鹽、0.1至100mM的磷酸鹽緩衝劑,和1至1000mM的氯化鈉之安定的液體調配劑。更具體而言,本發明之調配劑係pH 6.0至6.6之包含1至100mg/mL的依那西普,1至50mM的組胺酸或其藥學上可接受的鹽,1至100mM的離胺酸或其藥學上可接受的鹽,0.1至50mM的磷酸鹽緩衝劑,和1至500mM的氯化鈉之安定的液體調配劑。
在具體的實施例中,本發明之調配劑係包含1至100mg/mL的依那西普,0.1至250mM的組胺酸或其藥學上可接受的鹽,0.1至250mM的甲硫胺酸或其藥學上可接受的鹽,0.1至100mM的磷酸鹽緩衝劑,和1至1000mM的氯化鈉之安定的液體調配劑。更具體而言,本發明之調配劑係pH 6.0至6.6之包含1至100mg/mL的依那西普,1至50mM的組胺酸或其藥學上可接受的鹽、1至100mM的甲硫胺酸或其藥學上可接受的鹽,0.1至50mM的磷酸鹽緩衝劑,和1至500mM的氯化鈉之安定的液體調配劑。
在具體的實施例中,本發明之調配劑係包含1至100mg/mL的依那西普,0.1至250mM的甲硫胺酸或其藥學上可接受的鹽,0.1至250mM的離胺酸或其藥學上可接受的鹽,0.1至100mM的磷酸鹽緩衝劑,和1至1000mM的氯化鈉之安定的液體調配劑。更具體而言,本發明之調配劑係pH 6.0至6.6之包含1至100mg/mL的依那西普,1至50mM的甲硫胺酸或其藥學上可接受的鹽,1至50mM的
離胺酸或其藥學上可接受的鹽,0.1至50mM的磷酸鹽緩衝劑,和1至500mM的氯化鈉之安定的液體調配劑。
本發明之調配劑可被用於治療其中依那西普係治療有效的疾病上。依那西普係生物發炎調節因子以抑制TNF-α媒介的免疫反應,且本發明之調配劑可被用在治療風溼性關節炎、牛皮癬、關節黏連性脊椎炎、血管炎、阿茲海默症或克隆氏症,但不侷限於此。本發明之調配劑可藉由口服或非經腸(如皮下、肌肉、腹膜、腹腔、經皮路徑和/或靜脈)投藥,但不侷限於此。
在另一方面中,本發明提供使用包含一種或多種選自甲硫胺酸、離胺酸、組氨酸、和其藥學上可接受的鹽所組成群組之安定劑之液體調配劑而增加依那西普之安定性之方法。液體調配劑藉由減少在儲存期間因變性而產生之依那西普副產物,可增加依那西普之儲存安定性。
下文中,將參照實施例詳述本發明。然而,這些實施例僅用於說明的目的,本發明並限於這些實施例。
為了調查用於製備安定的依那西普水性調配劑之最佳的安定劑,添加作為安定劑之組氨酸至5mM的磷酸鹽溶液(於磷酸鹽溶液中已添加濃度50mg/mL的依那西普),並添加氯化鈉於其中作為等滲透壓劑以製備調配劑1。
此外,添加依那西普至10mM的磷酸鹽溶液,使濃度
為50mg/mL,並添加氯化鈉於其中作為等滲透壓劑。然後添加各離胺酸、精胺酸、甲硫胺酸、甘胺酸、聚山梨醇酯20、聚山梨醇酯80、泊洛沙姆188、丙二醇、硫酸魚精蛋白、蔗糖和胍鹽酸鹽以製備調配劑2至12。
最後,添加作為等滲透壓劑之氯化鈉至10mM磷酸鹽溶液(於磷酸鹽溶液中已添加濃度50mg/mL的依那西普)以製備無安定劑之調配劑。調配劑之安定劑組成係顯示如下表1。所製備的調配劑之各0.5mL被置於1.0mL的玻璃注射器,密封,並儲存於50℃。
於50℃儲存7天後,表1之調配劑1至12和無安定劑之調配劑係以SE-HPLC分析,檢驗低分子量產物和高分子量產物(例如依那西普變性所產生的低聚物和聚集體)的類型,且這些產物的總量以總不純物表示。此外,依那西普之結構改變係以HI-HPLC檢驗。在HI-HPLC中,依那西普相關物質被分離成4個峰,包括前峰、峰1、峰2和峰3。前峰和峰1表示低分子量產物,峰2表示依那西普,峰3表示低聚集或低活性之二聚物。於是,前峰、峰1和峰3之總量表示總不純物(Total Impurity)。結果分別顯示於表2和表3。
如表2之SE-HPLC結果顯示,當於50℃儲存7天,包含組氨酸作為安定劑之調配劑1顯示22.2%之總不純物,包含離胺酸作為安定劑之調配劑2顯示24.8%之總不純物,包含精胺酸作為安定劑之調配劑3顯示24.2%之總不純物,包含甲硫胺酸作為安定劑之調配劑4顯示20.8%之總不純物。相較於無安定劑之調配劑顯示30.2%之總不純物,它們都顯示非常低的總不純物。當這些調配劑相較於
使用L-精胺酸作為安定劑之調配劑3(美國專利第7,628,702號),包含離胺酸之調配劑2顯示相似的24.8%之總不純物,而包含組氨酸之調配劑1和包含甲硫胺酸之調配劑4分別顯示減少的22.2%和20.8%之總不純物。
表3之HI-HPLC結果與SE-HPLC結果相似。無安定劑之調配劑顯示41.9%之總不純物。反之,各調配劑1、2、3和4分別顯示33.7%、34.9%、34.3%和30.3%之總不純物,這表示添加於各調配劑中之組氨酸、離胺酸、L-精胺酸和甲硫胺酸具有防止依那西普變性之效果。尤其是包含甲硫胺酸之調配劑4顯示最少的總不純物,這表示甲硫胺酸在安定依那西普上效果最好。
於是,本發明證明離胺酸、組氨酸和甲硫胺酸具有藉由防止依那西普變性而安定依那西普之效果,該效果相當於或高於L-精胺酸所具者,尤其是甲硫胺酸相較於L-精胺酸在安定依那西普上效果更好。實施例2根據甲硫胺酸濃度之依那西普水性調配劑的安定性測試
為了調查用於依那西普之安定的甲硫胺酸最佳的濃度,將120mM的氯化鈉加至10mM的磷酸鹽溶液,且將各25mM和12.5mM的甲硫胺酸加至其中,之後添加依那西普使其濃度為50mg/mL,而分別製備調配劑13和14。根據可商購的依那西普水性調配劑之製備,將25mM的L-精胺酸添加至含100mM氯化鈉和1%蔗糖的10mM的磷酸鹽溶液中,且加入依那西普至50mg/mL之濃度以製備對
照組。各0.5mL之調配劑被置放在1.0mL的玻璃注射器,密封,並儲存於40℃、25℃和4℃。所製備的水性調配劑之組成顯示於下表4。
調配劑13、調配劑14和對照組各於40℃儲存1週和3週和於25℃及4℃儲存4週和8週後,其總不純物以如實施例1之SE-HPLC和HI-HPLC測量。結果分別顯示於表5和表6。
如表5和表6之結果顯示,相較於根據可商購的依那西普水性調配劑之製備方法製備的對照組,在所有40℃、25℃和4℃之儲存狀態下,包含甲硫胺酸作為安定劑之調配劑13和調配劑14顯示低不純物產生。特別是相較於對照組,SE-HPLC和HI-HPLC結果顯示,在40℃和3週以及在25℃和8週,包含25mM甲硫胺酸之調配劑13和包含12.5mM甲硫胺酸之調配劑14顯示較低的不純物產生,而在4℃和8週,包含25mM甲硫胺酸之調配劑13和包含12.5mM甲硫胺酸之調配劑14顯示相似的不純物產生。這些結果表示相較於可商購的調配劑,本發明之含甲硫胺酸之調配劑係在長時間下維持依那西普活性之更安定的調配劑。
總而言之,本發明證明包含甲硫胺酸之依那西普水性調配劑防止依那西普之變性以長時間維持其活性,且在依那西普水性調配劑中,甲硫胺酸係非常有效的安定劑。
作為安定劑之5mM組氨酸和25mM離胺酸加至10mM的磷酸鹽溶液(其中該磷酸鹽溶液中已加入依那西普至50mg/mL之濃度),並加入作為等滲透壓劑之氯化鈉至其中以製備調配劑15。
此外,作為安定劑之5mM組氨酸和25mM甲硫胺酸加至10mM的磷酸鹽溶液(其中該磷酸鹽溶液中已加入依那西普至50mg/mL之濃度),並加入作為等滲透壓劑之氯化鈉至其中以製備調配劑16。
最後,作為等滲透壓劑之氯化鈉加至10mM的磷酸鹽溶液(其中該磷酸鹽溶液中已加入依那西普至50mg/mL之濃度),而製備無安定劑之調配劑。
各製備的0.5mL調配劑之被置放在1.0mL的玻璃注射器,密封,並儲存於50℃。
調配劑之安定劑組成顯示於下表7。
於50℃儲存7天後,表7之調配劑15、16和無安定劑之調配劑,以如實施例1之SE-HPLC分析以測量其總不純物,結果顯示於表8。
如表8之SE-HPLC結果顯示,當於50℃儲存7天,相較於無安定劑之調配劑顯示30.2%之總不純物,包含組氨酸作為安定劑之調配劑16顯示21.5%之總不純物,其顯示顯著低的總不純物。且相較於包含10mM組氨酸之調配劑1顯示22.2%之總不純物,和包含賴胺酸25mM之調配劑2顯示24.8%之總不純物,調配劑16顯示顯著低的總不純物。
亦即,本發明證明相較於無安定劑之調配劑和分別包含組氨酸、離胺酸和甲硫胺酸之各調配劑,包含組氨酸和離胺酸之調配劑,具有藉由減少儲存時總不純物含量而防止依那西普變性之顯著優異的效果。
此外,如表8之SE-HPLC結果顯示,當於50℃儲存7天,相較於無安定劑之調配劑顯示30.2%之總不純物,包含組氨酸作為安定劑之調配劑16顯示20.9%之總不純物,其係顯著低。尤其是相較於包含組氨酸和離胺酸作為安定劑之調配劑15,調配劑16顯示低總不純物。
亦即,本發明證明包含組氨酸和甲硫胺酸之調配劑,相較於無安定劑之調配劑,具有藉由減少儲存時總不純物
含量而防止依那西普變性之顯著優異效果。
作為安定劑之12.5mM甲硫胺酸和12.5mM離胺酸加至10mM的磷酸鹽溶液(其中該磷酸鹽溶液中已加入依那西普至50mg/mL之濃度),並加入作為等滲透壓劑之氯化鈉至其中以製備調配劑17。
此外,作為等滲透壓劑之氯化鈉加至10mM磷酸鹽溶液(其中該磷酸鹽溶液中已加入依那西普至50mg/mL之濃度),製備無安定劑之調配劑。
各製備的0.5mL調配劑被放置在1.0mL的玻璃注射器,密封,並儲存於50℃。調配劑之安定劑組成係顯示於下表9。
在50℃儲存7天後,表9之調配劑17和無安定劑之調配劑,以如實施例1之SE-HPLC分析以測量總不純物。結果顯示於表10。
如表10之SE-HPLC結果顯示,當於50℃儲存7天,相較於無安定劑之調配劑顯示32.8%之總不純物,包含甲硫胺酸和離胺酸作為安定劑之調配劑17顯示27%之總不純物,其係顯著低。
亦即,本發明證明相較於無安定劑之調配劑,包含甲硫胺酸和離胺酸之調配劑,藉由減少總不純物含量對安定依那西普具有顯著的效果。
Claims (16)
- 一種依那西普之液體調配劑,包含依那西普;和一種或多種選自甲硫胺酸、離胺酸、組氨酸和其藥學上可接受的鹽所組成群組之安定劑。
- 根據申請專利範圍第1項所述之液體調配劑,其中該安定劑係甲硫胺酸及/或其藥學上可接受的鹽。
- 根據申請專利範圍第1項所述之液體調配劑,其中該安定劑係以0.1至250mM含量存在。
- 根據申請專利範圍第1項所述之液體調配劑,其中該依那西普係以1至100mg/mL含量存在。
- 根據申請專利範圍第1項所述之液體調配劑,相較於無安定劑之該調配劑,其藉由減少因儲存期間之變性所產生之依那西普副產物而具有增加之依那西普儲存安定性。
- 根據申請專利範圍第1項所述之液體調配劑,進一步包括一種或多種選自緩衝劑、等滲透壓劑、賦形劑及防腐劑所組成群組之材料。
- 根據申請專利範圍第6項所述之液體調配劑,其中該緩衝劑係選自檸檬酸鹽、磷酸鹽、琥珀酸鹽、酒石酸鹽、反丁烯二酸鹽、葡萄糖酸鹽、草酸鹽、乳酸鹽、乙酸鹽、組氨酸和三羥甲基氨基甲烷所組成群組。
- 根據申請專利範圍第6項所述之液體調配劑,其中該緩衝劑係以0.1至100mM含量存在。
- 根據申請專利範圍第6項所述之液體調配劑,其中該 等滲透壓劑係選自氯化鈉、氯化鉀、硼酸、硼酸鈉、甘露糖醇、甘油、丙二醇、聚乙二醇、麥牙糖、蔗糖、赤藻糖醇、***糖醇、木糖醇、山梨醇和葡萄糖所組成群組。
- 根據申請專利範圍第6項所述之液體調配劑,其中該等滲透壓劑係以1至1000mM含量存在。
- 根據申請專利範圍第1項所述之液體調配劑,包含1至100mg/mL的依那西普;0.1至250mM的甲硫胺酸或其藥學上可接受的鹽;0.1至100mM的磷酸鹽緩衝劑和1至1000mM的氯化鈉。
- 根據申請專利範圍第1項所述之液體調配劑,包含1至100mg/mL的依那西普;0.1至250mM的離胺酸或其藥學上可接受的鹽;0.1至100mM的磷酸鹽緩衝劑和1至1000mM的氯化鈉。
- 根據申請專利範圍第1項所述之液體調配劑,包含1至100mg/mL的依那西普;0.1至250mM的組氨酸或其藥學上可接受的鹽;0.1至100mM的磷酸鹽緩衝劑和1至1000mM的氯化鈉。
- 根據申請專利範圍第1項所述之液體調配劑,包含1至100mg/mL的依那西普;0.1至250mM的組氨酸或其藥學上可接受的鹽;0.1至250mM的離胺酸或其藥學上可接受的鹽;0.1至100mM的磷酸鹽緩衝劑和1至1000mM的氯化鈉。
- 根據申請專利範圍第1項所述之液體調配劑,包含1至 100mg/mL的依那西普;0.1至250mM的組氨酸或其藥學上可接受的鹽;0.1至250mM的甲硫胺酸或其藥學上可接受的鹽;0.1至100mM的磷酸鹽緩衝劑和1至1000mM的氯化鈉。
- 根據申請專利範圍第1項所述之液體調配劑,包含1至100mg/mL的依那西普;0.1至250mM的甲硫胺酸或其藥學上可接受的鹽;0.1至250mM的離胺酸或其藥學上可接受的鹽;0.1至100mM的磷酸鹽緩衝劑和1至1000mM的氯化鈉。
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