TWI826841B - 包含格米列汀與達格列淨的口服組合製劑及其製備方法 - Google Patents
包含格米列汀與達格列淨的口服組合製劑及其製備方法 Download PDFInfo
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- TWI826841B TWI826841B TW110138009A TW110138009A TWI826841B TW I826841 B TWI826841 B TW I826841B TW 110138009 A TW110138009 A TW 110138009A TW 110138009 A TW110138009 A TW 110138009A TW I826841 B TWI826841 B TW I826841B
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- diabetes
- combination preparation
- oral combination
- agent
- dapagliflozin
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Abstract
本發明涉及一種有效治療第2型糖尿病的口服組合製劑。更具體地,本發明涉及一種治療第2型糖尿病的口服組合製劑及其製備方法,該口服組合製劑包括作為活性成分之格米列汀或其藥學可接受的鹽與達格列淨或其藥學可接受的鹽;作為膨脹劑之乳糖及/或微晶纖維素;崩散劑;及助滑劑。
Description
本發明涉及一種有效治療第2型糖尿病的口服組合製劑。更具體地,本發明涉及一種治療第2型糖尿病的口服組合製劑及其製備方法,該口服組合製劑包括作為活性成分之格米列汀(Gemigliptin)或其藥學可接受的鹽與達格列淨(Dapagliflozin)或其藥學可接受的鹽;作為膨脹劑之乳糖及/或微晶纖維素;崩散劑;及助滑劑。
2011年,國際糖尿病聯盟(International Diabetes Federation,簡稱IDF)估計全球有3.66億糖尿病患者。據報導,其中80%集中於開發中國家,而其中約36%為包括韓國在內的西太平洋地區國家。惟,考慮到當前約有1.83億糖尿病患者尚未被診斷出糖尿病,預估全球糖尿病患者的實際人數將超過5.49億,且據報導,僅2011年就有460萬人死於糖尿病。
糖尿病為一種代謝性疾病,係由於胰島素分泌缺陷、胰島素作用缺陷或兩者兼有而導致血糖量級升高。第1型糖尿病為胰腺β細胞(β細胞)受到破壞的結果,為一種嚴重疾病,若不治療可能會導致酮症,且需要胰島素治療
以控制血糖量級。第1型糖尿病通常發展於兒童時期,但有時亦可能在不肥胖且於年紀較長時首次出現高血糖量級症狀的成年人中發展。第2型糖尿病則在當前呈現增加趨勢,佔所有糖尿病的90%到95%,為一種機制尚未明確闡明的複雜疾病,且通常發展於成年人,但亦可能於青春期期間發展。第2型糖尿病不具有嚴重症狀,發展形式多樣,複雜地涉及β細胞功能障礙、周邊胰島素阻抗、肝醣代謝異常等。在第2型糖尿病中,隨著時間推移,血糖量級越發難以控制,平均每3至4年需要使用新的降血糖藥,才能恰當控制血糖量級。此外,即便有組合用藥治療與胰島素治療,適當控制血糖量級仍屬困難。
傳統上用於治療糖尿病的口服藥物可分為四類:胰島素分泌劑,例如磺醯脲類(sulfonylureas)與美格替耐類(meglitinides);雙胍類(biguanides);噻唑烷二酮類(thiazolidinediones);以及α-葡萄糖酶抑制劑(α-glucosidase inhibitors)。磺醯脲類與雙胍類藥物長期以來一直被用作第2型糖尿病的藥物。磺醯脲類促進β細胞分泌胰島素,然而在β細胞的功能逐漸惡化下,最終需要其他藥物或胰島素治療。屬於雙胍類的代表性藥物為二甲雙胍(metformin),它是一種安全的藥物,且低血糖的副作用少,而被廣泛用作治療第2型糖尿病的首選藥物。由於第2型糖尿病為一種進展性疾病,於長期治療的情況下,無法充分控制血糖量級,因此於確診之後幾年內便需要使用組合用藥治療。
關於治療糖尿病的組合治療,韓國專利申請公開第10-2019-0130432號揭示了一種包括了包含達格列淨與利格列汀(linagliptin)作為活性成分的SGLT-2抑制劑與DPP-IV抑制劑的醫藥組成物。
[引文列表]
[專利文獻]
韓國專利申請公開第10-2019-0130432號
本發明的技術問題為提供一種組合製劑,其藉由不同機制藥物的協同組合,增加活性成分的生體可用率及安定性,並且減輕現有單一藥物的副作用,從而有效治療第2型糖尿病。
本發明的另一個技術問題為提供一種能以高生產力製備組合製劑,同時增加活性成分之安定性的方法。
為解決上述問題,本發明提供一種用於治療第2型糖尿病的口服組合製劑,包括作為活性成分之格米列汀或其藥學可接受的鹽與達格列淨或其藥學可接受的鹽;作為膨脹劑之乳糖及/或微晶纖維素;崩散劑;及助滑劑。
本發明復提供一種用於治療第2型糖尿病的口服組合製劑的製備方法,包括i)篩分作為活性成分之格米列汀或其藥學可接受的鹽與達格列淨或其藥學可接受的鹽,作為膨脹劑之乳糖及/或微晶纖維素,以及崩散劑,然後混合之;以及ii)將助滑劑加入步驟(i)中獲得的混合物中,混合之,再將該所得之混合物壓錠。
以下闡明本發明。
根據本發明的一個方面,提供一種治療第2型糖尿病的口服組合製劑,包括作為活性成分之格米列汀或其藥學可接受的鹽與達格列淨或其藥學可接受的鹽;作為膨脹劑之乳糖及/或微晶纖維素;崩散劑;助滑劑。
格米列汀為一種相對新近開發的有效且選擇性的二肽基肽酶IV(selective dipeptidyl peptidase IV,DPP-IV)抑制劑,及DPP-IV抑制劑是設計用於抑制DPP-IV降解類升糖素胜肽-1(glucagon-like peptide-1,GLP-1)的藥物。GLP-1為一種腸促胰素(incretin),可促進β細胞分泌胰島素、增加周邊組織的葡萄糖利用、抑制α細胞的升糖素分泌,並減少肝臟的葡萄糖產生。
格米列汀可以數種形式用作藥學可接受的鹽。在本發明中,格米列汀的藥學可接受的鹽包括例如鹽酸鹽、氫溴酸鹽、磷酸鹽、硫酸鹽、乙酸鹽、三氟乙酸鹽、檸檬酸鹽、甲酸鹽、順丁烯二酸鹽、草酸鹽、琥珀酸鹽、苯甲酸鹽、酒石酸鹽、延胡索酸鹽、苯乙醇酸鹽、抗壞血酸鹽、蘋果酸鹽及甲磺酸鹽,較佳可使用酒石酸鹽1.5水合物。
達格列淨為一種鈉葡萄糖協同轉運蛋白2(SGLT-2)抑制劑,且可藉由抑制腎小管中的SGLT-2抑制葡萄糖再吸收過程、從尿液中排出葡萄糖,從而壓制血糖量級的升高。在根據本發明的一個態樣中,達格列淨可為非晶與微粒型。
於根據本發明的一個態樣中,作為膨脹劑的乳糖可為無水乳糖或乳糖水合物。
於根據本發明的一個態樣中,崩散劑可為交聯羧甲基纖維素鈉或交聚維酮(交聯聚乙烯N-吡咯烷酮)。於根據本發明的一個態樣中,助滑劑可為延胡索硬脂酸鈉。
於根據本發明的一個態樣中,用於治療第2型糖尿病的口服組合製劑可包括:作為活性成分之20至60重量%的格米列汀或其藥學可接受的鹽與達格列淨或其藥學可接受的鹽,作為膨脹劑之20至70重量%的乳糖及/或微晶纖維素,0.5至15重量%的崩散劑,以及0.2至15重量%的助滑劑。於根據本發明的一個態樣中,用於治療第2型糖尿病的口服組合製劑可包括:作為活性成分之30至50重量%的格米列汀或其藥學可接受的鹽與達格列淨或其藥學可接受的鹽,作為膨脹劑之30至65重量%的乳糖及/或微晶纖維素,1至10重量%的崩散劑,以及0.5至10重量%的助滑劑。
於根據本發明的一個態樣中,用於治療第2型糖尿病的口服組合製劑可包含以游離型計重量比為2至10:1的格米列汀或其藥學可接受的鹽與達格列淨或其藥學可接受的鹽。於根據本發明的一個態樣中,用於治療第2型糖尿病的口服組合製劑可包含以游離型計重量比為3至7:1的格米列汀或其藥學可接受的鹽與達格列淨或其藥學可接受的鹽。於根據本發明的一個態樣中,用於治療第2型糖尿病的口服組合製劑可包含以游離型計重量比為5:1的格米列汀或其藥學可接受的鹽與達格列淨或其藥學可接受的鹽。舉例而言,根據本發明的用於治療第2型糖尿病的口服組合製劑可包含50mg格米列汀與10mg達格列淨。
於根據本發明的一個態樣中,用於治療第2型糖尿病的口服組合製劑復可包括包衣劑(coating agent)。於本發明的一個態樣中,可用的包衣劑可包括所屬領域常用的包衣劑,例如聚乙烯吡咯烷酮、共聚維酮、Opadry系列及Eudragit系列等,但不以此為限。於根據本發明的一個態樣中,包衣劑可為Opadry。
於根據本發明的一個態樣中,用於治療第2型糖尿病的口服組合製劑的形式可為顆粒劑、膠囊劑或錠劑。
根據本發明的另一方面,提供一種用於治療第2型糖尿病的口服組合製劑的製備方法,包括i)篩分作為活性成分之格米列汀或其藥學可接受的鹽與達格列淨或其藥學可接受的鹽,作為膨脹劑之乳糖及/或微晶纖維素,以及崩散劑,然後混合之;以及ii)將助滑劑加入步驟(i)中獲得的混合物中,予以混合,再將該所得之混合物壓錠。
於根據本發明的一個態樣中,該乳糖可為無水乳糖或乳糖水合物。於根據本發明的一個態樣中,該崩散劑可為交聯羧甲基纖維素鈉或交聚維酮。於根據本發明的一個態樣中,該助滑劑可為延胡索硬脂酸鈉。
一般情況下,對於含有少量活性成分如達格列淨的製劑,為保持較高的含量均一度,該製劑係採用濕法製粒或乾法製粒,但此製粒程序可能會因增加生產時間而使得生產成本提高,且可能降低其活性成分的安定性。在根據本發明的製備方法中,採直接壓錠,可實現高生產力(低生產成本與高產率),亦可提高活性成分的安定性。
根據本發明,藉由提供一種包含格米列汀或其藥學可接受的鹽與達格列淨或其藥學可接受的鹽的組合製劑,具有不同作用機制之藥物的協同組合能減輕單一藥物的副作用,並且藉由因活性成分之高溶離率導致的高生體利用率,以及活性成分的高安定性,能有效治療第2型糖尿病。
此外,根據本發明的製備方法,可藉由採直接壓錠,於高生產力下提供具有安定性提高之活性成分的組合製劑。
圖1為實施例16的藥錠(Zemiglo藥錠:格米列汀50mg藥錠)中格米列汀溶離率測定結果的圖式;以及
圖2為實施例16的藥錠(Forxiga藥錠:達格列淨10mg藥錠)中達格列淨溶離率測定結果的圖式。
下文中,將參酌實施例更詳細闡述本發明。惟,以下實施例僅用於闡明以幫助理解本發明內容,且本發明的範圍不以此為限。
實施例1至4及比較例1與2:錠劑的製備
根據下表1中的組成,篩分68.9mg酒石酸格米列汀(含50mg格米列汀)、10mg達格列淨、膨脹劑與崩散劑,隨後使用錐形磨混合,於其中加入助滑劑,再進行最終混合。將最終的混合物壓錠以製備單層錠劑。
[表1]
實驗例1:安定性實驗1
實施例1至4與對照例1、2的錠劑在加速條件(40℃、75%濕度)下進行6個月的安定性實驗,測定結果分別示於表2、表3。
[表2]
[表3]
DP-IMP-1:
2-[(2S)-6,6-二氟-2,3,5,6,7,8-六氫咪唑并[1,2-a]吡啶-2-基]-1-[2,4-二(三氟甲基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-7-基]-1-乙酮
DP-IMP-2:
2,4-二(三氟甲基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-8-酮
DP-IMP-3:
(3S)-3-胺基-4-(5,5-二氟-2-側氧基-N-哌啶基)-1-[8-羥基-2,4-二(三氟甲基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-7-基]丁烷-1-酮酒石酸鹽
由表2與表3的結果可見,實施例的錠劑相較於比較例的錠劑更為安定。
比較例3
根據下表4中的組成,以相同於比較例1與2的方式,製備含有68.9mg酒石酸格米列汀(含50mg格米列汀)與14.6mg達格列淨檸檬酸共晶(含10mg達格列淨)的錠劑。
實驗例2:安定性實驗2
以相同於實驗例1的方式,針對比較例3的錠劑進行兩次安定性實驗,結果如表5所示。
[表5]
由表5的結果可見,業已經證實達格列淨檸檬酸共晶的安定性顯著低於非晶達格列淨的安定性。
實施例5至15
根據下表6中的組成,以相同於實施例1至4的方式,製備含有不同含量的格米列汀酒石酸鹽、達格列淨、微晶纖維素、無水乳糖、交聯羧甲基纖維素鈉及延胡索硬脂酸鈉的錠劑。
實驗例3:溶離率的量測
於以下條件下量測實施例5至15中製備的錠劑之溶離率,結果示於表7。
- 溶離方法:pH 6.8的溶液
- 溶離介質容積:900mL
- 槳葉速度:50rpm
- 測試組數:4
- 樣品採集時間:15分鐘
實施例16
基於實施例5至15的實驗結果,根據下表8中的組成,以相同於實施例1至4的方式製備錠劑。
實驗例4:安定性與溶離率的量測
以相同於實驗例1的方式量測實施例16中製備的錠劑的安定性,結果分別示於表9與10中。以相同於實驗例3的方式於pH 1.2的溶液、pH 4.5的溶液、pH 6.8的溶液及水中量測溶離率,結果示於圖1與圖2中。
[表9]
[表10]
由以上結果,證實實施例16的組合製劑賦予格米列汀與達格列淨安定性,並且組合製劑中格米列汀與達格列淨各自的溶離率與其個別製劑中的溶離率相當。
Claims (14)
- 一種用於治療第2型糖尿病的口服組合製劑,包括:作為活性成分之格米列汀或其藥學可接受的鹽與達格列淨或其藥學可接受的鹽;作為膨脹劑之乳糖及/或微晶纖維素;崩散劑;及助滑劑,其中,該口服組合製劑包含50mg之格米列汀與10mg之達格列淨;以及該助滑劑為延胡索硬脂酸鈉。
- 如請求項1所述之用於治療第2型糖尿病的口服組合製劑,其中,該格米列汀之藥學可接受的鹽係選自由下列組成之群組:鹽酸鹽、氫溴酸鹽、磷酸鹽、硫酸鹽、乙酸鹽、三氟乙酸鹽、檸檬酸鹽、甲酸鹽、順丁烯二酸鹽、草酸鹽、琥珀酸鹽、苯甲酸鹽、酒石酸鹽、延胡索酸鹽、苯乙醇酸鹽、抗壞血酸鹽、蘋果酸鹽及甲磺酸鹽。
- 如請求項2所述之用於治療第2型糖尿病的口服組合製劑,其中,該格米列汀之藥學可接受的鹽為酒石酸鹽。
- 如請求項1所述之用於治療第2型糖尿病的口服組合製劑,其中,該達格列淨為非晶達格列淨。
- 如請求項1所述之用於治療第2型糖尿病的口服組合製劑,其中,該乳糖為無水乳糖或乳糖水合物。
- 如請求項1所述之用於治療第2型糖尿病的口服組合製劑,其中,該崩散劑為交聯羧甲基纖維素鈉或交聚維酮。
- 如請求項1所述之用於治療第2型糖尿病的口服組合製劑,其包括20至60重量%的該活性成分,20至70重量%的該膨脹劑,0.5至15重量%的該崩散劑,以及0.2至15重量%的該助滑劑。
- 如請求項7所述之用於治療第2型糖尿病的口服組合製劑,其包括30至50重量%的該活性成分,30至65重量%的該膨脹劑,1至10重量%的該崩散劑,以及0.5至10重量%的該助滑劑。
- 如請求項1所述之用於治療第2型糖尿病的口服組合製劑,其復包括包衣劑。
- 如請求項9所述之用於治療第2型糖尿病的口服組合製劑,其中,該包衣劑為Opadry。
- 如請求項1所述之用於治療第2型糖尿病的口服組合製劑,其為顆粒劑、膠囊劑或錠劑形式。
- 一種如請求項1所述之用於治療第2型糖尿病的口服組合製劑的製備方法,其包括:i)篩分作為活性成分之格米列汀或其藥學可接受的鹽與達格列淨或其藥學可接受的鹽,作為膨脹劑之乳糖及/或微晶纖維素,以及崩散劑,然後予以混合;以及ii)將助滑劑加入步驟(i)中獲得的混合物中,予以混合,再將該所得之混合物壓錠,其中,該口服組合製劑包含50mg之格米列汀與10mg之達格列淨;以及該助滑劑為延胡索硬脂酸鈉。
- 如請求項12所述之用於治療第2型糖尿病的口服組合製劑的製備方法,其中,該乳糖為無水乳糖或乳糖水合物。
- 如請求項12所述之用於治療第2型糖尿病的口服組合製劑的製備方法,其中,該崩散劑為交聯羧甲基纖維素鈉或交聚維酮。
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