TWI827000B - 直接壓錠之包含鞘胺醇-1-磷酸酯受體促效劑的醫藥組成物 - Google Patents
直接壓錠之包含鞘胺醇-1-磷酸酯受體促效劑的醫藥組成物 Download PDFInfo
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- TWI827000B TWI827000B TW111114269A TW111114269A TWI827000B TW I827000 B TWI827000 B TW I827000B TW 111114269 A TW111114269 A TW 111114269A TW 111114269 A TW111114269 A TW 111114269A TW I827000 B TWI827000 B TW I827000B
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Classifications
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- A—HUMAN NECESSITIES
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- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
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- A—HUMAN NECESSITIES
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- A61K9/00—Medicinal preparations characterised by special physical form
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- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
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- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Landscapes
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- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
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- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
本發明涉及直接壓錠之包含鞘胺醇-1-磷酸酯受體促效劑的醫藥組成物。更具體地,本發明涉及一種直接壓錠的醫藥組成物,其包含作為活性成分的下式1的1-[1-氯-6-(3-氯-1-異丙基-1H-吲唑-5-基甲氧基)-3,4-二氫-萘-2-基甲基]-哌啶-4-羧酸或其藥學上可接受的鹽、作為稀釋劑的乳糖或其水合物、作為黏合劑的羥丙基纖維素、作為潤滑劑的硬脂富馬酸鈉,以及作為崩解劑的交聯羧甲基纖維素鈉:
Description
本發明涉及直接壓錠之包含鞘胺醇-1-磷酸酯受體促效劑的醫藥組成物。更具體地,本發明涉及一種直接壓錠的醫藥組成物,其包含作為活性成分的下式1的1-[1-氯-6-(3-氯-1-異丙基-1H-吲唑-5-基甲氧基)-3,4-二氫-萘-2-基甲基]-哌啶-4-羧酸或其藥學上可接受的鹽、作為稀釋劑的乳糖或其水合物、作為黏合劑的羥丙基纖維素、作為潤滑劑的硬脂富馬酸鈉,以及作為崩解劑的交聯羧甲基纖維素鈉:
鞘胺醇-1-磷酸酯(S1P)係藉由細胞內神經醯胺路徑產生,其中神經醯胺係起始原料。神經醯胺藉由兩種路徑產生,其中第一種係從頭(de novo)生物合成路徑。神經醯胺亦藉由細胞中的細胞膜成分的神經鞘磷脂的降解產生。各組織中的S1P水平係由兩種生物合成鞘胺醇激酶(SphK)及兩種生物降解的S1P磷酸酶(S1P裂解酶及水解磷酯磷酸酶)調控。已知藉由鞘胺醇激酶對鞘胺醇的磷酸化而產生的S1P可調節各種細胞反應,例如細胞增生、細胞骨架的組織及遷移、黏附及緊密連接(tight junction)部件以及形態發生。S1P於血漿中與包括白蛋白的血漿蛋白呈結合形式並以高含量(100-1,000nM)存在,而於組織中則處於低含量。
S1P與S1P受體(一種G-蛋白偶聯受體)結合,以顯示出各種生物功能。作為S1P受體亞型,S1P1至S1P5是迄今為止已知的,分別被命名為內皮分化基因(EDG)受體1、5、3、6及8。已知S1P受體參與各種生物功能,例如白血球再循環、神經細胞增生、形態變化、遷移、內皮功能、血管調節及心血管發育。
與此同時,常規的口服固體製劑可採用直接壓錠法製備,其將所有成分混合後直接壓錠;乾式製粒(granulation)法,其將混合物揉合(knead)、製粒及篩分(sieve)以製成乾顆粒,然後壓製成錠劑;而濕式製粒法係將以水或有機溶劑製備成的黏合劑溶液加入混合物中,經揉合、製粒、乾燥、整粒(sizing)等工序製成濕顆粒,然後壓製成錠劑。
於直接壓片法的情況下,由於加工步驟少,製造成本降低且活性成分損失小,且由於不需要溶劑,因此可預期將改善對熱或濕度不穩定的活性成分的穩定性。然而,為了賦予直接壓錠所需的特性,需選擇特
定的賦形劑,具體而言,於含有相對少量活性成分的錠劑中,可能難以製備具有均勻含量(uniform content)的錠劑。
本發明旨在提供一種可製備錠劑的組成物,其中下式1的1-[1-氯-6-(3-氯-1-異丙基-1H-吲唑-5-基甲氧基)-3,4-二氫-萘-2-基甲基]-哌啶-4-羧酸或其藥學上可接受的鹽係於確保穩定性的同時藉由直接壓錠法以均勻含量被包含:
為了解決上述技術問題,本發明提供一種組成物,其可藉由直接壓錠法製備其中包含均勻含量的活性成分的錠劑,同時藉由結合作為活性成分的1-[1-氯-6-(3-氯-1-異丙基-1H-吲唑-5-基甲氧基)-3,4-二氫-萘-2-基甲基]-哌啶-4-羧酸或其藥學上可接受的鹽與特定的賦形劑以確保穩定性。
以下詳細描述本發明。
根據本發明的一個方面,係提供一種用於直接壓錠的醫藥組成物,其包含作為活性成分的1-[1-氯-6-(3-氯-1-異丙基-1H-吲唑-5-基甲氧基)-3,4-二氫-萘-2-基甲基]-哌啶-4-羧酸或其藥學上可接受的鹽、作為稀釋
劑的乳糖或其水合物、作為黏合劑的羥丙基纖維素、作為潤滑劑的硬脂富馬酸鈉,以及作為崩解劑的交聯羧甲基纖維素鈉。
於根據本發明的一實施態樣中,該用於直接壓錠的醫藥組成物可包含0.2至2重量%的作為活性成分的1-[1-氯-6-(3-氯-1-異丙基-1H-吲唑-5-基甲氧基)-3,4-二氫-萘-2-基甲基]-哌啶-4-羧酸或其藥學上可接受的鹽、85.25至90.55重量%的作為稀釋劑的乳糖或其水合物、4.5至5.5重量%的作為黏合劑的羥丙基纖維素、0.75至1.25重量%的作為潤滑劑的硬脂富馬酸鈉,以及4至6重量%的作為崩解劑的交聯羧甲基纖維素鈉(croscarmellose sodium)。
於根據本發明的一個實施態樣中,該藥學上可接受的鹽可選自由氫氯酸、硫酸、硝酸、磷酸、氫溴酸、氫碘酸、酒石酸、甲酸、檸檬酸、乙酸、三氯乙酸、三氟乙酸、葡萄糖酸、苯甲酸、乳酸、富馬酸、馬來酸、甲磺酸、苯磺酸、對甲苯磺酸及萘磺酸所組成的群組。根據本發明的一個實施態樣中,該藥學上可接受的鹽可為氫氯酸。
於根據本發明的一個實施態樣中,該乳糖水合物可為乳糖一水合物(monohydrate)。
於根據本發明的一個實施態樣中,可於5至11kN的壓力進行壓錠。於根據本發明的一個實施態樣中,如果成型壓力小於5kN,則可能無法確保適當的易碎性(friability),而如果成型壓力超過11kN,則硬度降低及易碎性增加可能是由成分之間增加的斥力所引起的。
於根據本發明的一個實施態樣中,該醫藥組成物可更包含被覆劑。
於根據本發明的一實施態樣中,該被覆劑可為基於聚乙烯醇(PVA)的被覆劑或基於羥丙基甲基纖維素(HPMC)的被覆劑,但不限於此。
於根據本發明的一實施態樣中,作為基於羥丙基甲基纖維素被覆劑的實例,可使用OpadryTM,但不限於此。
根據本發明的另一個方面,係提供一種製備包含鞘胺醇-1-磷酸酯受體促效劑的口服固體製劑的方法,其包含混合作為活性成分的1-[1-氯-6-(3-氯-1-異丙基-1H-吲唑-5-基甲氧基)-3,4-二氫-萘-2-基甲基]-哌啶-4-羧酸或其藥學上可接受的鹽、作為稀釋劑的乳糖或其水合物、作為黏合劑的羥丙基纖維素、作為潤滑劑的硬脂富馬酸鈉及作為崩解劑的交聯羧甲基纖維素鈉;以及直接壓錠。
根據本發明的一實施態樣,於該製備方法中,可混合0.2至2重量%的作為活性成分的1-[1-氯-6-(3-氯-1-異丙基-1H-吲唑-5-基甲氧基)-3,4-二氫-萘-2-基甲基]-哌啶-4-羧酸或其藥學上可接受的鹽、85.25至90.55重量%的作為稀釋劑的乳糖或其水合物、4.5至5.5重量%的作為黏合劑的羥丙基纖維素、0.75至1.25重量%的作為潤滑劑的硬脂富馬酸鈉以及4至6重量%的作為崩解劑的交聯羧甲基纖維素鈉。
於根據本發明的一個實施態樣中,可於5至11kN的壓力進行壓錠。於根據本發明的一個實施態樣中,如果成型壓力小於5kN,則可能無法確保適當的易碎性,而如果成型壓力超過11kN,則硬度降低及易碎性增加可能是由成分之間增加的斥力所引起的。
根據本發明的醫藥組成物能夠經由直接壓錠法製備含有鞘胺醇-1-磷酸酯受體促效劑的口服固體製劑,從而以更少的加工步驟以降低製造成本及活性成分的損失,並於確保穩定性的同時提供具均勻含量的活性成分。
圖1係RRT 0.62雜質於高溫高濕條件(80℃/75%RH)的主效應圖及交互作用圖的比較。
圖2係RRT 0.72雜質於高溫高濕條件(80℃/75%RH)的主效應圖及交互作用圖的比較。
圖3係測量於壓錠過程中的硬度隨壓錠力度變化的曲線圖。
圖4係測量於壓錠過程中的易碎性隨壓錠力度變化的曲線圖。
在下文中,藉由以下實施例更詳細地解釋本發明。然而,必須理解,本發明的保護範圍並不限於這些實施例。
製備實施例:1-[1-氯-6-(3-氯-1-異丙基-1H-吲唑-5-基甲氧基)-3,4-二氫-萘-2-基甲基]-哌啶-4-羧酸鹽酸鹽的合成
1-[1-氯-6-(3-氯-1-異丙基-1H-吲唑-5-基甲氧基)-3,4-二氫-萘-2-基甲基]-哌啶-4-羧酸乙酯之合成係參照國際公開號WO2014/129796 A1的製備例153-1中所述方法,將酯以NaOH水解,以HCl酸化,然後結晶以獲得氫氯酸鹽形式(以下簡稱「API」)。
實施例1:錠劑的製備
根據下表1所示的組成混合成分後,藉由直接壓錠以製備錠劑。
實施例2:含量均勻度
根據下表2的組成,使用3D混合器混合API及賦形劑
從上述得到的混合物的10處取樣並測量活性成分之含量後,將理論值與實際值之間的百分比差異總結並呈現於在表3中。結果,經證實上述製劑構成均勻混合物。
實施例3:穩定性研究
以表2之組成所製備的錠劑在嚴苛條件下於HDPE瓶中儲存50錠,然後測量成分變化之穩定性,其結果如表4所示。
經以上結果確認,本發明之錠劑即使於嚴苛條件下亦具有適當的穩定性。
比較例
使用下表5的組成,以與實施例2相同的方式製備含有作為稀釋劑的微晶纖維素(替代乳糖一水合物)及作為潤滑劑的硬脂酸鎂(替代Pruv)的混合物。
並且,以與實施例2同樣的方法,從上述得到的混合物的10處取樣並測量活性成分之含量,其理論值與實際值之間的百分比差異總結並呈現於表6中。結果,經證實上述製劑構成均勻混合物。
另外,以與實施例3同樣方法進行穩定性測定後,其結果如表7所示。
經上述結果證實,基於微晶纖維素的配方可獲得與基於乳糖的配方相似的均勻混合物,但其對濕度(70℃/75% RH)及熱(80℃/50% RH)的含量變化非常敏感。
實施例4:根據成分含量的穩定性確認
執行本實驗以檢測CQA(含量、含量均勻度、溶解及雜質)如何受賦形劑比例變化的影響。本實驗設計為部分因子設計(fractional factorial design),200g/批次,而賦形劑範圍設定標準係依據SUPAC-IR指南(1級變化,劑型總重量標準)如下。
- API:0.2至1.5mg/錠
- HPC-L(黏合劑)±0.5%
- 交聯羧甲基纖維素鈉(CCS)(崩解劑)±1%
- Pruv(潤滑劑)±0.25%
就Pruv而言,SUPAC指引之1級變化標準為±1%,但由於沒有Pruv無法壓錠,故將其任意設定為±0.25%。
RRT 0.62雜質於高溫高濕條件(80℃/75% RH)的主效應圖及交互作用圖之比較如圖1所示。RRT 0.72雜質於高溫高濕條件(80℃/75% RH)的主效應圖及交互作用圖之比較如圖2所示。
從圖1之主效應圖中可看出,HPC-L及Pruv於80℃/75% RH降低了RRT 0.62的雜質,交聯羧甲基纖維素鈉(CCS)於80℃/75% RH增加了RRT 0.62的雜質,而API含量越低,於80℃/75% RH時RRT 0.62
的雜質越高。經圖1之交互作用圖確認,當Pruv含量低時,HPC-L不影響雜質含量,但當Pruv含量高時,HPC-L於80℃/75% RH時降低RRT 0.62的雜質;而當API含量高時,HPC-L對雜質含量沒有影響,但當API含量低時,HPC-L降低了RRT 0.62的雜質。
此外,從圖2之主效應圖中可看出,CCS-L於80℃/75% RH降低了RRT 0.72的雜質,HPC-L及Pruv於80℃/75% RH增加了RRT 0.72的雜質,而API含量越低,於80℃/75% RH時RRT 0.72的雜質越高。經圖2之交互作用圖確認,當Pruv含量低時,HPC-L沒有增加雜質,但當Pruv含量高時,HPC-L於80℃/75% RH時增加了RRT 0.72的雜質。
實施例5:壓錠加工條件的設定
對於錠劑成型,需藉由確保一定程度的易碎性以防止製劑於流動過程中變形(損壞)。因此,測量了於直接壓錠過程中該錠劑的硬度及易碎性隨壓錠力度的變化,其結果分別如圖3及圖4所示。從圖3可以看出,在超過約11kN的壓力,由於模製過程中成分之間的斥力增加,故硬度降低,而易碎性增加。此外,從圖4中可以看出,在低於約5kN的壓力,於模製過程中無法確保適當程度的易碎性。由以上結果確認,適當的模製範圍應為5至11kN。
實施例6:被覆錠穩定性之確認
於製備具下表9所示組成的未被覆錠劑後,進行三種不同類型的被覆。
獲取之被覆錠於嚴苛條件下儲存以檢測其穩定性。於以下分析條件下,藉由改變RRT 0.80的有機雜質以估計穩定性。結果如表10所示。
分析條件:
經以上結果確認,使用本發明之組成的被覆錠即使於嚴苛條件下亦具有適當的穩定性。
實施例8:組成物長期穩定性之確認
為確認根據本發明的組成物的長期儲存穩定性,以表11的組成製備被覆錠。包含從API至Pruv的錠劑採用直接壓錠法製備,然後採用水性被覆法完成被覆。
於室溫及加速儲存條件下證實了製備的錠劑的儲存穩定性。儲存穩定性試驗中的含量變化及有機雜質的分析結果如表12所示。
經以上結果確認,本發明之組成物即使於長期保存條件下亦具有適當的穩定性。
Claims (8)
- 一種直接壓錠的醫藥組成物,其包含作為活性成分的1-[1-氯-6-(3-氯-1-異丙基-1H-吲唑-5-基甲氧基)-3,4-二氫-萘-2-基甲基]-哌啶-4-羧酸或其藥學上可接受的鹽、作為稀釋劑的乳糖或其水合物、作為黏合劑的羥丙基纖維素、作為潤滑劑的硬脂富馬酸鈉,以及作為崩解劑的交聯羧甲基纖維素鈉。
- 如請求項1所述之醫藥組成物,其包含0.2至2重量%的活性成分、85.25至90.55重量%的稀釋劑、4.5至5.5重量%的黏合劑、0.75至1.25重量%的潤滑劑,以及4至6重量%的崩解劑。
- 如請求項1所述之醫藥組成物,其中該藥學上可接受的鹽係選自由氫氯酸、硫酸、硝酸、磷酸、氫溴酸、氫碘酸、酒石酸、甲酸、檸檬酸、乙酸、三氯乙酸、三氟乙酸、葡萄糖酸、苯甲酸、乳酸、富馬酸、馬來酸、甲磺酸、苯磺酸、對甲苯磺酸及萘磺酸所組成的群組。
- 如請求項3所述之醫藥組成物,其中該藥學上可接受的鹽係氫氯酸。
- 如請求項1所述之醫藥組成物,其中該乳糖水合物係乳糖一水合物。
- 如請求項1所述之醫藥組成物,其中該壓錠係於5至11kN之壓力進行。
- 如請求項1所述之醫藥組成物,其更包含被覆劑。
- 如請求項7所述之醫藥組成物,其中該被覆劑係基於聚乙烯醇(PVA)的被覆劑或基於羥丙基甲基纖維素(HPMC)的被覆劑。
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CN101820916A (zh) * | 2007-10-12 | 2010-09-01 | 诺瓦提斯公司 | 包含鞘氨醇1磷酸(s1p)受体调节剂的组合物 |
TW201444794A (zh) * | 2013-02-20 | 2014-12-01 | Lg Life Sciences Ltd | 鞘胺醇-1-磷酸酯受體促效劑、其製造方法及包含該促效劑作爲活性劑之醫藥組成物 |
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US11180489B2 (en) * | 2016-03-30 | 2021-11-23 | U niversity of Virginia Patent Foundation | Sphingosine kinase inhibitor amidoxime prodrugs |
EP3949967A4 (en) * | 2019-04-23 | 2023-01-18 | Chia Tai Tianqing Pharmaceutical Group Co., Ltd. | SOLID PHARMACEUTICAL COMPOSITION WITH TLR7 AGONISTS |
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CN101820916A (zh) * | 2007-10-12 | 2010-09-01 | 诺瓦提斯公司 | 包含鞘氨醇1磷酸(s1p)受体调节剂的组合物 |
TW201444794A (zh) * | 2013-02-20 | 2014-12-01 | Lg Life Sciences Ltd | 鞘胺醇-1-磷酸酯受體促效劑、其製造方法及包含該促效劑作爲活性劑之醫藥組成物 |
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KR20220142376A (ko) | 2022-10-21 |
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