TWI429437B - 經加衣之藥球及彼於除去或減輕徵狀(諸如嘔吐和腹瀉)之用途 - Google Patents
經加衣之藥球及彼於除去或減輕徵狀(諸如嘔吐和腹瀉)之用途 Download PDFInfo
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- TWI429437B TWI429437B TW99138517A TW99138517A TWI429437B TW I429437 B TWI429437 B TW I429437B TW 99138517 A TW99138517 A TW 99138517A TW 99138517 A TW99138517 A TW 99138517A TW I429437 B TWI429437 B TW I429437B
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
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Description
本發明關於口服藥學調製劑,其係設計用以減輕或除去藥物的不良作用,該等藥物通常伴隨著諸如嘔吐與腹瀉之副作用。具體而言,本發明關於口服藥學調製劑,該調製劑包含一藥物或其藥學上可接受之鹽,且所含藥物係例如(E
)-N-(4-(3-氯-4-(吡啶-2-基甲氧基)苯胺基)-3-氰基-7-乙氧喹啉-6-基)-4-(二甲胺基)丁-2-烯醯胺,亦稱諾拉替尼(neratinib)。此類調製劑通常以膠囊或其他劑型的形式提供,且該膠囊與其他劑型包含具有腸衣的球形顆粒。
蛋白質激酶在引起細胞複製的生化訊息傳遞作用中肩負重責。蛋白質激酶是一種酶,其催化ATP的磷酸根轉移作用,使磷酸根從ATP轉移至胺基酸殘基上,例如轉移至蛋白質上的酪胺酸(tyrosine)、絲胺酸(serine)、羥丁胺酸(threonine,或稱蘇胺酸或息寧胺酸)或組胺酸。為控制包括增生與遷移在內的各種細胞事件,必需調控這些蛋白質激酶。已知有多種不良症狀牽涉數種特定蛋白質激酶,包括癌症〔Traxler,P.M.,Exp.Opin.Ther.Patents
,8,1599(1998);Bridges,A.J.,Emerging Drugs
,3,279(1998)〕、再狹窄〔Mattsson,E.,Trends Cardiovas.Med.
5,200(1995);Shaw,Trends Pharmacol.Sci.
16,
401(1995)〕、動脈粥狀硬化〔Raines,E.W.,Bioessays,
18,271(1996)〕、血管新生〔Shawver,L.K.,Drug Discovery Today,
2,50(1997);Folkman,J.,Nature Medicine,
1,27(1995)〕及骨質疏鬆症〔Boyce,J.,Clin.Invest.,
90,1622(1992)〕。已知能抑制受體型酪胺酸激酶活性的化合物可用於治療哺乳動物的中風與癌症,該等癌症係包括,例如但不限於,非小細胞肺癌(NSCLC)、乳癌、多囊性腎臟病、大腸息肉。
具體的激酶抑制劑包括多種化合物,例如(E
)-N-(4-(3-氯-4-(吡啶-2-基甲氧基)苯胺基)-3-氰基-7-乙氧喹啉-6-基)-4-(二甲胺基)丁-2-烯醯胺(neratinib,音譯:諾拉替尼);4-〔(2,4-二氯-5-甲氧基苯基)胺基〕-6-甲氧基-7-〔3-(4-甲基哌-1-基)丙氧基〕喹啉-3-羧腈(bosuitinib,音譯:伯舒替尼);N-〔2-(二乙胺基)乙基〕-5-〔(Z)-(5-氟-1,2-二氫-2-氧代-3H-吲哚-3-亞基)甲基〕-2,4-二甲基-1H-吡咯-3-甲醯胺(sunitinib,音譯:蘇尼替尼);4-〔(4-甲基哌-1-基)甲基〕-N-〔4-甲基-3-〔(4-吡啶-3-基嘧啶-2-基〕胺基〕苯基〕苯甲醯胺(imatinib,音譯:伊馬替尼);4-〔4-〔〔4-氯-3-(三氟甲基)苯基)胺甲醯基胺基〕苯氧基〕-N-甲基-吡啶-2-甲醯胺(sorafinib,音譯:索拉非尼);N-(3-乙炔苯基)-6,7-雙(2-甲氧基乙氧基)喹唑啉-4-胺(erlotinib,音譯:埃羅替尼);4-甲基-N-〔3-(4-甲基-1H-咪唑-1-基)-5-(三氟甲基)苯基〕-3-〔(4-吡啶-3-基嘧啶-2-基
)胺基〕苯甲醯胺(nilotinib,音譯:尼羅替尼);N-〔3-氯-4-〔(3-氟苯基)甲氧基〕苯基〕-6-〔5-〔(2-甲磺醯乙胺基)甲基〕-2-呋喃基〕喹唑啉-4-胺(laratinib,音譯:拉帕替尼)及其他化合物。已知多種激酶抑制劑擁有抗腫瘤活性,因此可用於治療某些疾病狀態,例如癌症,這些疾病至少部分是因受體失去調控所造成。
「諾拉替尼」激酶抑制劑是一種弱鹼,其生物利用性低,並且在水和乙醇中都具有低溶解度。某些含順丁烯二酸鹽形式之諾拉替尼的錠劑調製劑,能以口服劑型裝載,但提供有限的活性藥量(小於40重量%)。故期望能提供一種可供口服的諾拉替尼順丁烯二酸鹽調製劑,允許以口服劑型提供更大的活性藥量(大於40重量%)。
特別是,目前的激酶抑制劑口服調製劑,例如諾拉替尼錠劑或膠囊調製劑,經常帶來嚴重的腹瀉與噁心感。這類利用習知方法製備的口服調製劑已用於或正用於諾拉替尼的臨床研究,並且在這些臨床研究中經常伴隨發生嚴重的嘔吐與腹瀉。例如可參閱Wong等人所發表標題為「諾拉替尼(HKI-272),一種不可逆之Pan ErbB受體型酪胺酸激酶抑制劑,用於實性瘤患者之第一階段臨床研究
」的論文(見Clinical Cancer Research
April 1,2009,15
,2552)。注意到其它激酶抑制劑的口服調製劑有類似的副作用。因此,非常希望能提供諾拉替尼或其他激酶抑制劑的調製劑,其可供口服用藥並能減輕或除去嘔吐與腹瀉之副作用。
本發明有關於一種增進的含藥口服腸衣球形顆粒,其典型採膠囊劑型,且通常包含諾拉替尼或其他激酶抑制劑,設計用以避免使用目前用於臨床研究中之現行諾拉替尼速釋錠調製劑所帶來的不良事件,如嘔吐、腹瀉、噁心感。一般認為使用口服速釋錠帶來的不良事件是局部發生於胃腸系統(GI system)中。使用口服速釋錠調製劑進行漸增型單藥劑量濃度測試(SAD)及漸增型多藥劑量濃度測試(MAD),亦顯示可能是因局部作用而導致發生該等不良事件。藉著使用腸衣包覆調製劑以避免藥物暴露於胃中,相信能防止發生這些不良事件。
本發明提供適合口服用藥的藥學上可接受之固體組成物,該等組成物包含經加衣之球粒,該等球粒含活性激酶抑制劑,例如諾拉替尼,包括順丁烯二酸鹽形式之諾拉替尼。在某些實施例中提供一種膠囊,該等膠囊包含具有腸衣的諾拉替尼球粒。在一些實施例中,本發明提供一種如膠囊、錠劑或其他藥劑形式的單位劑型,該單位劑型包含活性激酶抑制劑(例如諾拉替尼)的經加衣球。
本發明提供一種藥學上可接受之組成物,其包含:(i)複數個球形顆粒,該等球形顆粒包含(a)30~70重量%的選自諾拉替尼、伯舒替尼、蘇尼替尼、伊馬替尼、索拉非尼、埃羅替尼、尼羅替尼、拉帕替尼或彼等之藥學上可接受之鹽的活性成分;(b)20~30重量%的一或多種填充
劑;(c)5~15重量%的一或多種潤濕劑,該等球形顆粒占該總組成物的70~83重量%;(ii)塗覆於該等球形顆粒上之底衣,該底衣進一步包含1~4重量%的一或多種藥學上可接受之纖維素系聚合物;及(iii)16~30重量%的一或多種藥學上可接受之聚合物,其作為塗覆於該底衣上之腸衣,該底衣成分(ii)及腸衣成分(iii)共同占該總組成物的17~30重量%。
本發明提供一種藥學上可接受之組成物,其包含:(i)複數個球形顆粒,該等球形顆粒包含(a)30~70重量%的諾拉替尼或其藥學上可接受之鹽類;(b)20~30重量%的一或多種填充劑;(c)5~15重量%的一或多種潤濕劑,該等球形顆粒占該總組成物的70~83重量%;(ii)塗覆於該等球形顆粒上之底衣,該底衣進一步包含1~4重量%的一或多種藥學上可接受之纖維素系聚合物;及(iii)16~30重量%的一或多種藥學上可接受之聚合物,其作為塗覆於該底衣上之腸衣,該底衣成分(ii)及腸衣成分(iii)共同占該總組成物的17~30重量%。
本發明提供一種藥學上可接受之組成物,其包含:(i)複數個球形顆粒,該等球形顆粒包含(a)30~70重量%的順丁烯二酸鹽形式之諾拉替尼;(b)20~30重量%的微晶纖維素;(c)5~15重量%的聚山梨醇酯,該等球形顆粒占該總組成物的70~83重量%;(ii)塗覆於該等球形顆粒上之底衣,該底衣進一步包含1~4重量%的羥丙基纖維素;及(iii)16~30重量%的一種甲基丙烯酸聚合物,其作為
塗覆於該底衣上之腸衣,該底衣成分(ii)及腸衣成分(iii)共同占該總組成物的17~30重量%。
本發明亦提供用以治療癌症且同時減輕或除去諸如嘔吐與腹瀉之副作用的方法,該方法包括對一個體施用一有效量的上述含諾拉替尼之球形藥學可接受調製劑。
用於本文中時,「有效量」的化合物或藥學上可接受之組成物能達到期望的治療及/或預防疾病之功效。在一些實施例中,「有效量」是指一化合物或含化合物之組成物的最小用量,該最小用量至少足以治療與蛋白質酪胺酸激酶調節作用相關之失調與疾病的一或多種症狀。在某些實施例中,一「有效量」的化合物或含化合物之組成物足以治療與異常酪胺酸激酶受體有關的症狀或疾病,例如癌症,包含惡性或良性的腫瘤生長。
文中使用之「個體」一詞係指哺乳動物,且包含人類及動物個體,例如馴養動物,如馬、狗、貓,等等。
文中使用之「罹患」或「患有」之術語,係指患者經診斷具有或懷疑具有一或多種症狀。
文中使用之「治療」或「醫療」之用語,係指部份或完全地減輕、抑制、延後發作、預防、改善及/或舒緩一種失調、疾病或一或多種失調或疾病的症狀。
「治療性活性藥劑(therapeutically active agent)」
或「活性藥劑」係指用於治療(例如人類治療或動物治療)的物質,該物質包括生物活性物質,且該治療包括預防與治療處理。治療性活性藥劑包含有機分子,其可為藥物化合物、胜肽、蛋白質、碳水化合物、單糖類、寡糖類、多糖類、核蛋白(nucleoprotein)、黏蛋白、脂蛋白、合成聚胜肽或蛋白質、連接於蛋白質上的小分子、醣蛋白、類固醇、核酸、DNA、RNA、核苷酸(nucleotide)、核苷(nucleoside)、寡聚核苷酸、反義寡聚核苷酸、脂肪、激素及維生素。治療性活性藥劑包含可做為治療、預防、延遲、減輕或舒緩疾病、症狀、失調徵狀之藥物的任何物質。適用於本發明調製劑中的治療性活性藥物為鴉片受體拮抗化合物、鴉片類止痛劑及諸如此類者。
以下提供可做為治療性活性藥劑之化合物的進一步詳細說明。一治療性活性藥物包含一種化合物,該化合物可例如藉著增進一第二化合物的效力,或減輕第二化合物的不良作用,而提高該第二化合物的作用或效果。
文中使用之「單位劑型」一詞係指適用於待治療個體之本發明調製劑的物理分裝單位。然而,將可理解到,將由主治醫師在審慎醫療判斷範圍內決定本發明組合物的每日總使用量。且根據不同因素來決定針對特定個體或器官的明確有效劑量,該等因素包括欲治療的疾病及其嚴重程度、所採用之特定活性藥劑的活性、所採用之特定組成物、個體的年齡、體重、整體健康狀態、性別與飲食、用藥時間、所採用之特定活性藥劑的排放率、療程時間、與所
使用之特定化合物結合使用或恰巧同時間使用的藥物及/或額外治療法,以及醫學上習知的此類因素。
在某些實施例中,本發明提供一種用於口服的藥學上可接受之組成物,其含有諾拉替尼或其藥學上可接受之鹽類。尤其在美國專利案6,002,008、6,288,082、6,297,258、6,384,051及7,399,865號中揭示已知諾拉替尼及其它化合物可做為激酶抑制劑。諾拉替尼具有下列化學結構:
諾拉替尼可以自由鹼的形式分離出,或以藥學上可接受之鹽類形式製備而得,例如順丁烯二酸鹽之形式。諾拉替尼是一種弱鹼,其本身在水中具有低溶解度。
在某些實施例中,本案之發明調製劑包含具腸衣的諾拉替尼順丁烯二酸鹽之球形顆粒。藉著擠出由諾拉替尼順丁烯二酸鹽添加一或多種填充劑及一或多種潤濕劑所形成的混合物,以製備出諾拉替尼順丁烯二酸鹽的球形顆粒。此技術的一項優點在於,相較於以習知濕式造粒法所製備的諾拉替尼順丁烯二酸鹽調製劑而言,製造本發明之球形顆粒需要相對少量的輔劑。包含一或多種纖維素系聚合物(cellulose based polymers)的一底衣塗覆於擠出的諾拉
替尼順丁烯二酸鹽球形顆粒上,且隨後包含一或多種藥學上可接受之丙烯酸聚合物的腸衣進一步塗覆於該已具底衣的諾拉替尼順丁烯二酸鹽球形顆粒上。本發明之另一優點是,相較於目前的調製劑與調製技術而言,該等經加衣的諾拉替尼順丁烯二酸鹽顆粒具有高的諾拉替尼順丁烯二酸鹽活性成分承載量,占調製劑重量的40~70重量%。
在某些實施例中,本發明之調製劑包含至少一腸衣。任何腸衣均能用於本發明中,其包括但不限於,甲基丙烯酸及甲基丙烯酸酯共聚物、乙酸鄰苯二甲酸纖維素(cellulose acetate phthalate)、鄰苯二甲酸羥丙基甲基纖維素(hydroxypropyl methylcellulose phthalate)、醋酸丁二酸羥丙基甲基纖維素(hydroxypropyl methylcellulose acetate succinate)、聚醋酸乙烯鄰苯二甲酸酯(polyvinyl acetate phthalate)、丙烯酸乙酯/甲基丙烯酸共聚物(ethyl acrylate/methacrylic acid copolymer)、USNF甲基丙烯酸共聚物A型(Eudragit LTM
)、B型(Eudragit STM
)、C型(Eudragit L 100-55TM
)、Eudragit NE 30D、Eudragit E、Eudragit RL、Eudragit RS、乙酸偏苯三甲酸纖維素(cellulose acetate trimellitate)、蟲膠及上述材料之組合物的溶液或分散液。此外,用於本發明調製劑中的腸衣可製備成單層或多層。熟悉該項技術者能輕易決定該腸衣之厚度,但其厚度需足以在胃內的酸性環性中保護該調製劑。依據該調製劑之總重量計,該腸衣占16~30重量%,包括占16~20重量%,及佔約17重量%。在一
實施例中,該腸衣包含Acryl-Eze MPTM
,其為添加有其它成分的甲基丙烯酸。
在某些實施例中,本發明之調製劑包含至少一底衣,該底衣包含一或多種纖維素系聚合物。適合的纖維素系聚合物包括例如羥丙基甲基纖維素及羥丙基纖維素。依據該調製劑之總重量計,該底衣占1~4重量%,包括占1~2重量%,及佔約1重量%。在一實施例中,該底衣包含羥丙基甲基纖維素酸。
黏合劑亦稱為「稀釋劑」及/或「填充劑」,適合的黏合劑為該領域中之習知者。例如,適合的黏合劑與填充劑包括,但不限於,澱粉、糊精、蔗糖、山梨醇、糖精鈉、乙醯磺胺酸鉀(acesulfame potassium)、木糖醇、阿斯巴甜(aspartame)、甘露糖醇、澱粉、聚乙烯吡咯烷酮(polyvinyl pyrrolidone,PVP)、低分子量之羥丙基纖維素(低分子量HPC)、微晶纖維素(MCC)、低分子量之羥丙基甲基纖維素(低分子量HPMC)、低分子量之羧甲基纖維素、乙基纖維素、褐藻酸鹽/酯(alginate)、明膠、聚環氧乙烷(polyethylene oxide)、阿拉伯膠、糊精、蔗糖、矽酸鋁鎂及聚甲基丙烯酸酯。填充劑包含選自於下列群組中之藥劑:微晶纖維素(MCC)、澱粉、乳糖醇、乳糖、適合的無機鈣鹽、蔗糖、果糖、甘露糖醇、矽酸或彼等之組合物。在一些實施例中,依據該調製劑之總重量計,黏合劑與填充劑占約20重量%至約30重量%,占25~30重量%,包括佔約27.3重量%。在一些實施例中,黏合劑為
一或多種等級的微晶纖維素,包括,但不限於,Avicel PH 101TM
及Avicel PH 102TM
。
潤濕劑亦為該領域中之習知者,且通常係用以幫助藥物釋放與吸收。示範的潤濕劑包含泊洛沙姆(poloxamer之音譯名)、聚氧乙烯醚(polyoxyethylene ether)、聚伸乙氧基去水山梨醇脂肪酸酯(polyoxyethylene sorbitan fatty acid ester)、聚伸乙氧基脂肪酸酯(polyoxyethylene fatty acid ester)、聚乙二醇脂肪酸酯(Polyethylene glycol fatty acid ester)、聚伸乙氧基氫化蓖麻油(polyoxyethylene hydrogenated castor oil)、聚伸乙氧基烷基醚(polyoxyethylene alkyl ether)、聚山梨醇酯、十六烷醇、脂肪酸甘油酯(例如,三乙酸甘油酯(triacetin)、單硬酯酸甘油酯(glycerol monostearate)及諸如此類者)、聚伸甲氧基硬脂酸酯(polyoxymethylene stearate)、十二烷基硫酸鈉、去水山梨醇脂肪酸酯、蔗糖脂肪酸酯、氯化苯甲烷銨(benzalkonium chloride)、聚乙氧化蓖麻油、丁二酸二辛酯磺酸鈉(docusate sodium)其類似物及其組合物。在一些實施例中,潤濕劑包含,但不限於,例如聚山梨醇酯80TM
、甘油、聚山梨醇酯65TM
、聚山梨醇酯60TM
USP、聚山梨醇酯40TM
USP、聚山梨醇酯20TM
USP、生物木聚糖(octoxynol-9)、壬基酚聚醚-10TM
USP(nonoxynol-10TM
USP)、泊洛沙姆235TM
、泊洛沙姆188TM
USP。在一些實施例中,以該調製劑之總重量計,提供的潤濕劑占約5至約15重量%,占約7至約10重
量%,或佔約9重量%。
在包含諾拉替尼順丁烯二酸鹽之組成物中添加一或多種保存劑可能特別有用,且保存劑可提供保護以避免組成物降解及/或沈澱。適合的保存劑為該領域中熟悉該項技術者所熟知,並可包含任何藥學上可接受之保存劑。習知的保存劑包含,但不限於,苯甲酸鈉、對羥基苯甲酸丙酯(propyl parahydroxybenzoate)、山梨酸、對羥基苯甲酸丙酯(propylparaben)、對羥基苯甲酸甲酯、丁基化羥基甲苯、丙酯類、山梨酸鉀、Indinavir及其組合物。在某些實施例中,以該調製劑之總重量計,提供的保存劑占約0.05重量%至約0.25重量%,或約0.1重量%。
根據一實施例,該活性成分係配製成該領域中具有通常知識者所熟知的單位劑型。在某些實施例中,本發明提供一種調製劑,其包含固體劑型,例如膠囊。在一些實施例中,一單位劑型包含50毫克(mg)、75毫克、100毫克、125毫克、150毫克、175毫克、200毫克、225毫克、250毫克、275毫克、300毫克、325毫克、350毫克、375毫克、400毫克、425毫克、450毫克、475毫克、500毫克、525毫克、550毫克、575毫克、600毫克、625毫克、650毫克、675毫克、700毫克、725毫克、750毫克、775毫克、800毫克、825毫克、850毫克、875毫克、900毫克、925毫克、950毫克、975毫克、1000毫克、1025毫克、1050毫克、1075毫克、1100毫克、1125毫克、1150毫克、1175毫克、1200毫克、1225毫克、1250毫克、1275毫克、1300毫克、
1325毫克、1350毫克、1375毫克、1400毫克、1425毫克、1450毫克、1475毫克、1500毫克的諾拉替尼順丁烯二酸鹽。在一些實施例中,一單位劑型包含介於5毫克至500毫克整個範圍內,或包含介於10毫克至450毫克整個範圍內的諾拉替尼順丁烯二酸鹽。在一些實施例中,一單位劑型包含40毫克、80毫克、100毫克、120毫克、240毫克、360毫克或480毫克。在一些實施例中,一單位劑型含有超過500毫克的諾拉替尼順丁烯二酸鹽。
在一些實施例中,採用的諾拉替尼順丁烯二酸鹽之有效量可能依據所採用的特定化合物、給藥模式及待治療之症狀的嚴重程度而改變。然而,當本發明之化合物的每日給藥劑量以每公斤體重而言介於約0.5毫克/kg至約1000毫克/公斤時,通常可獲得滿意的結果,且選擇性地,可於一天內將該劑量分成兩次至四次給藥,或以持續釋放劑型給藥。每日總劑量預計可介於約1至1000毫克,較佳介於約2至500毫克。適用於內服的劑型包含介於約0.5至1000毫克的活性化合物,且該等化合物為經加衣之球形顆粒。此種劑型給藥方式可經調整,以提供最適的治療反應。例如,每日可給予數個分裝劑量(divided doses),或依據治療情況的迫切性按比例降低該劑量。
用於癌症治療時,本發明之諾拉替尼順丁烯二酸鹽調製劑能與其它抗腫瘤物質或放射治療結合使用。這些他種物質或放射治療可與本發明之化合物同時施用,或於不同時間施用。這些結合使用的治療可能提供協同作用,並產
生增進的效果。例如,本發明之化合物可與下列藥劑結合使用,例如有絲分裂抑制劑,如紫杉醇或長春鹼;烷化劑,例如順鉑或環磷醯胺;抗代謝劑,例如5-氟尿嘧啶或羥基脲;DNA嵌入劑,如阿黴素(adriamycin)或博萊黴素(bleomycin);定位異構轉化酶抑制劑,例如表鬼臼毒吡喃葡萄糖苷(etoposide)或喜樹鹼(camptothecin);抗血管新生劑,例如血管靜止蛋白(angiostatin);及,抗動情激素,例如它莫西芬(tamoxifen之音譯名)。
在某些實施例中,該新穎組成物及其調製劑可單獨給藥,以治療如文中所述之一或多種失調症狀,或者與可用以治療文中所述之一或多種失調症狀的一或多種其它活性藥劑結合給藥(同時給藥或先後給藥)。因此,該新穎組成物及其調製劑能與一或多種活性藥劑同時給藥、在該一或多種活性藥劑之前給藥,或在該一或多種活性藥劑之後給藥。
在某些實施例中,除了含諾拉替尼順丁烯二酸鹽之外,該等新穎組成物包含一或多種其它活性藥劑。在一些實施例中,該等新穎調製劑包含另一抗癌化合物及諾拉替尼順丁烯二酸鹽兩者。
在本發明之結合組成物中之額外活性藥劑的藥量,通常不超過該活性藥劑在一組成物中做為唯一治療劑時所正常給予的藥量。在本發明之某些實施例中,額外活性藥劑
的藥量範圍係介於該活性藥劑在一組成物中做為唯一治療劑時正常給予之藥量的50%至100%。
所提供的組成物及其調製劑亦可用於治療包含癌症在內之疾病。
在又一些實施例中,提供該等新穎組成物及其調製劑於獸醫學應用上的用途,例如治療馴養動物,如馬、狗、貓等等。因此,預期所提供之調製劑在獸醫應用中的用途係類似於上述討論用於人類個體的該等用途。
亦將明白,新穎組成物及其調製劑能用於結合治療中,即是,新穎組合物或其調製劑能與一或多種其它期望治療或醫學程序同時施用,或在該一或多種其它期望治療或醫學程序之前或之後施用。在結合給藥方式中欲採用的特定結合治療(療法或程序)將考慮該等期望療法及/或程序的相容性及所欲達到的期望療效。亦將明白,所採用的多種治療可對相同疾病達到期望效果,例如,一調製劑可與用來治療相同疾病的另一化合物同時用藥,或者該等治療可能達到不同作用,例如控制任何不良作用。如本文中所使用者,該等正常給藥以治療或預防一特定疾病的額外治療性化合物係「適用於欲治療之疾病或症狀者」。
在其他實施例中,新穎的組成物、其調製劑及其單位劑型可用於製備藥品,包括,但不限於,用於癌症治療的藥品。
本發明又進一步涵蓋一種藥學包裝及/或藥劑組,其包含本發明之新穎組成物及其調製劑,及一容器(例如,鋁箔包或塑膠包裝,或其他適合容器)。隨意願地,此類藥劑組中可額外提供使用說明書。
為求更加完全瞭解文中所述之發明,提供下列多個實施例。應瞭解,這些實施例僅作為示範之用,而非用以於各方面上限制本發明。
本發明各種形態的所有特徵可經過適當修正後,應用於所有其它形態。
以袋式混練法於一塑膠容器中混合諾拉替尼順丁烯二酸鹽(140克)及Avicel PH 101(60克)三分鐘後,再轉移至一Hobart混合器內。乾燥混合該等成分持續30秒。製備0.25% w/w的聚山梨醇-80TM
溶液。隨後,將100克的此溶液以分次小量加入的方式添加至該Hobart混合器中,同時持續攪拌該等成分,可獲得一濕團塊。將Nica擠出器之餽入器速度設定為40rpm且攪拌器速度設為80rpm,而透過該Nica擠出器擠出該濕團塊,獲得許多小擠出塊。隨後,在Nica搓圓器中以900rpm的速度搓圓該等擠出塊持續三分鐘。該等球粒置於托盤上乾燥,至其最終含水率為
2.5%(範圍介於2~3%之間)。該等球粒經過18-網目(1000微米)及35-網目(500微米)之篩網篩選。該等留在35-網目篩網上的經篩選之球形材料係用於底衣塗覆步驟。
該等球粒裝載至一流體化床處理器(fluid bed processor)中,該流體化床處理器具有一底部Wuster噴霧器。製備15% w/w的羥丙基甲基纖維素溶液,其黏度為3cps。使用50°±5℃的入料溫度來施加該羥丙基甲基纖維素(HMPC)溶液。執行該製程直至獲得1.2%(範圍介於1~4%)的重量增加量。該等球粒隨後在該流體化床中乾燥15分鐘。
該等已塗覆HMPC的球粒裝載至一流體化床處理器中,該處理器具有一底部Wuster噴霧器。隨後製備含有20%固體成分的Acryl-Eze MPTM
溶液,並且使用32°±3℃的入料溫度來施加該腸衣溶液。執行該製程直至獲得16.9%(範圍介於16~30%)的重量增加量。該等已塗覆腸衣的球粒隨後在該流體化床中乾燥15分鐘。之後,該等球粒儲存於一塑膠容器內。
根據所需要的強度,將該等已塗覆腸衣的球粒填充至HPMC膠囊內。該等已塗覆腸衣之球粒的功效決定每個膠囊中的填充量。
以六隻禁食的雄性小獵犬(10.2~15.7公斤)評估本發明及其他兩種用於口服之諾拉替尼順丁烯二酸鹽調製劑,其結果整理於表1及第1圖中。
給藥之後,於0(給藥前)、0.5、1、2、4、6、8、12、24及48小時抽取血液樣本,分離出血漿,且分析該血漿之諾拉替尼順丁烯二酸鹽含量。對給予口服錠劑後之各別小獵犬的血中諾拉替尼順丁烯二酸鹽濃度-時間分佈模式進行無室式(non-compartmental)藥物動力分析(WinNonlin,Model 200)。針對每隻小獵犬測量下列藥物動力參數,並計算其敘述性統計,該等參數為:AUC、Cmax
、tmax
及t1/2
。以各別動物體重對劑量進行標準化(normalizing),以計算出經劑量標準化的AUC值。口服給藥後,從諾拉替尼順丁烯二酸鹽之Cmax
與AUC值中觀察到高變化性。自腸衣球粒取得的諾拉替尼順丁烯二酸鹽之Cmax
與AUC值其性質類似於臨床研究中所使用之其它諾拉替尼順丁烯二酸鹽錠劑調製劑的Cmax
與AUC值。
膠囊調製劑中之諾拉替尼順丁烯二酸鹽腸衣球粒的口服生物利用性(21%)則稍高於目前臨床使用的他種HKI順丁烯二酸鹽錠劑調製劑(17%)。相較於這類的諾拉替尼順丁烯二酸鹽錠劑調製劑,該腸衣球粒調製劑除了延遲時間增加以外,其Cmax
與Tmax
亦明顯較高。
臨床使用之諾拉替尼順丁烯二酸鹽錠劑調製劑的濕式造粒錠而言,該腸衣球粒膠囊形式的新穎諾拉替尼順丁烯二酸鹽調製劑可防止發生不良事件(嘔吐、腹瀉、噁心)。實施例3之研究中所出現的不良事件係整理並顯示於表2
。
使用該濕式造粒的諾拉替尼順丁烯二酸鹽錠劑調製劑時,觀察到嘔吐/稀便現象;然而,使用本發明之諾拉替尼順丁烯二酸鹽調製劑卻未發生嘔吐/稀便現象。
在一臨床研究中,給予192名健康個體五種單劑量(single dose)的諾拉替尼順丁烯二酸鹽。觀察其不良事件,並將之分類如下:
- 一級胃腸不良事件(GI AEs)~25至40%
- 二級胃腸不良事件(GI AEs)~15%
在健康個體之臨床研究中所觀察到的不良事件主要為一級與二級腸胃不良事件。在進一步研究中,使用兩種不同單一劑量(400毫克與800毫克)的健康個體數據顯示,諾拉替尼因局部作用而引起胃腸不良事件,其結果整理於第2圖中。事實上,以所觀察到之不良事件的程度而言,
介於400毫克至800毫克之間帶來的胃腸不良事件之頻率與嚴重度受劑量影響最為顯著,但不受Cmax
與AUC影響。結果顯示不良事件局部產生於胃腸系統。
使用諾拉替尼順丁烯二酸鹽(單一藥劑及組合藥)針對超過400名癌症患者進行六項不同的多劑量(multiple dose)臨床研究,該等研究亦顯示在癌症患者之臨床研究中所觀察到的不良事件主要為腸胃不良事件。觀察癌症患者之臨床研究中的不良事件,並將之分類如下:
- 噁心、嘔吐、腹瀉、脫水、厭食(~95%)
- 無力、疲勞(~30至60%)
- 發疹(~20至25%)
- ALT、AST升高情形(<10%)
進行暴露性研究,以判斷胃腸耐受性與全身暴露於諾拉替尼順丁烯二酸鹽下是否相關。其結果顯示胃腸耐受性(腹瀉)與全身性暴露並無關連。
患者回報之胃腸不良事件
第1圖整理經禁食之雄性小獵犬口服各種諾拉替尼順丁烯二酸鹽調製劑後其體內的藥物動力情況。
第2圖係整理於健康個體中進行諾拉替尼順丁烯二酸鹽調製劑之漸增型單藥劑量濃度試驗的過程中,發生胃腸不良事件的頻率與嚴重度之比較結果。
Claims (12)
- 一種藥學上可接受之組成物,其包含:(i)複數個球形顆粒,其包含(a)30~70重量%的(E )-N-(4-(3-氯-4-(吡啶-2-基甲氧基)苯胺基)-3-氰基-7-乙氧喹啉-6-基)-4-(二甲胺基)丁-2-烯醯胺或其藥學上可接受之鹽;(b)20~30重量%的一或多種填充劑;及(c)5~15重量%的一或多種潤濕劑,該等球形顆粒占該總組成物之70~83重量%;(ii)塗覆於該等球形顆粒上之底衣,該底衣進一步包含1~4重量%的一或多種藥學上可接受之纖維素系聚合物;及(iii)16~30重量%的一或多種藥學上可接受之聚合物,其作為塗覆於該底衣上之腸衣,該底衣成分(ii)及腸衣成分(iii)占該總組成物之17~30重量%。
- 一種藥學上可接受之組成物,其包含:(i)複數個球形顆粒,其包含(a)30~70重量%的(E )-N-(4-(3-氯-4-(吡啶-2-基甲氧基)苯胺基)-3-氰基-7-乙氧喹啉-6-基)-4-(二甲胺基)丁-2-烯醯胺順丁烯二酸鹽;(b)20~30重量%的微晶纖維素;及(c)5~15重量%的聚山梨醇酯,該等球形顆粒占該總組成物之70~83重量%;(ii)塗覆於該等球形顆粒上之底衣,該底衣進一步 包含1~4重量%的羥丙基纖維素;及(iii)17~30重量%的甲基丙烯酸聚合物,其作為塗覆於該底衣上之腸衣,該底衣成分(ii)及腸衣成分(iii)占該總組成物之16~30重量%。
- 如申請專利範圍第2項之組成物,其中該(E )-N-(4-(3-氯-4-(吡啶-2-基甲氧基)苯胺基)-3-氰基-7-乙氧喹啉-6-基)-4-(二甲胺基)丁-2-烯醯胺順丁烯二酸鹽占55~65重量%。
- 如申請專利範圍第2項之組成物,其中該(E )-N-(4-(3-氯-4-(吡啶-2-基甲氧基)苯胺基)-3-氰基-7-乙氧喹啉-6-基)-4-(二甲胺基)丁-2-烯醯胺順丁烯二酸鹽占63.6重量%。
- 如申請專利範圍第2項之組成物,其中該聚山梨醇酯占7~10重量%。
- 如申請專利範圍第2項之組成物,其中該聚山梨醇酯占約9重量%。
- 如申請專利範圍第2項之組成物,其中該微晶纖維素占約27重量%。
- 如申請專利範圍第2項之組成物,其係呈40毫克之口服劑型。
- 如申請專利範圍第2項之組成物,其係呈80毫克之口服劑型。
- 如申請專利範圍第2項之組成物,其係呈240毫克之口服劑型。
- 一種如申請專利範圍第2項之組成物於製備用以治療癌症之藥物的用途。
- 一種藥學上可接受之組成物,其包含:(i)複數個球形顆粒,其包含(a)30~70重量%的選自諾拉替尼、伯舒替尼、埃羅替尼或彼等之藥學上可接受之鹽的活性成分;(b)20~30重量%的一或多種填充劑;及(c)5~15重量%的一或多種潤濕劑,該等球形顆粒占該總組成物之70~83重量%;(ii)塗覆於該等球形顆粒上之底衣,該底衣進一步包含1~4重量%的一或多種藥學上可接受之纖維素系聚合物;及(iii)16~30重量%的一或多種藥學上可接受之聚合物,其作為塗覆於該底衣上之腸衣,該底衣成分(ii)及腸衣成分(iii)占該總組成物的17~30重量%。
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TW201138775A (en) | 2011-11-16 |
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JP5982020B2 (ja) | 2016-08-31 |
WO2011056741A3 (en) | 2011-06-30 |
JP5866116B2 (ja) | 2016-02-17 |
AU2010315362B2 (en) | 2015-01-22 |
CA2780332A1 (en) | 2011-05-12 |
US9211264B2 (en) | 2015-12-15 |
CN107308130A (zh) | 2017-11-03 |
US8524281B2 (en) | 2013-09-03 |
JP2011098965A (ja) | 2011-05-19 |
AR078951A1 (es) | 2011-12-14 |
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