TWI468171B - 含glp-1激動劑及甲硫胺酸之醫藥組成物 - Google Patents
含glp-1激動劑及甲硫胺酸之醫藥組成物 Download PDFInfo
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- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/2278—Vasoactive intestinal peptide [VIP]; Related peptides (e.g. Exendin)
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- A61K38/26—Glucagons
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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Description
本申請案係關於一種液態組成物,其包含一種GLP-1激動劑或/及其藥理上可耐受鹽及任選至少一種醫藥上可接受賦形劑,其中該組成物包含甲硫胺酸。
本申請案進一步關於本發明用於治療糖尿病的組成物。本申請案進一步關於本發明組成物於製造用於治療糖尿病之藥劑的用途。本申請案進一步關於製造本發明組成物的方法,包含配製GLP-1激動劑或/及其藥理上可耐受鹽與甲硫胺酸,以及任選至少一種醫藥上可接受賦形劑。本申請案進一步關於一種以本發明組成物於治療病患的方法,包含將該組成物投與至病患。
胰島素和GLP-1化合物的習知組成物包含滲透改質劑、用於調節pH的緩衝劑及防腐劑。
WO 01/04156(Zealand Pharmaceutical)中揭示一種Ser39
-艾塞那肽(exendin)-4(1~39)NH2
、磷酸二氫鈉和防腐劑的液態組成物。
WO 2004/035623(Zealand Pharmaceutical)揭示一種包含穩定化艾塞那肽;50 mM組胺酸;100至200 mM蔗糖、甘露糖醇或其他可接受糖、20 mM甲硫胺酸、20mM天冬醯胺酸-麩醯胺酸或天冬胺酸(Asp)於pH 5.3的液態組成物。藉由艾塞那肽-4(1~39)胺基酸建構單元的某些修飾可強化安定性,例如於位置Gln13、Met14、Trp25,或Asn28。
WO 2005/021022(Novo Nordisk)中揭示一種包含乙醯化GLP-1、苯酚作為防腐劑、甘露糖醇和甘油作為滲透改質劑及任選一緩衝劑的液態組成物。
WO 2006/051110(Novo Nordisk)揭示包含利拉魯肽(liraglutide)(GLP-1化合物)、作為表面活性物質之泊洛沙姆-188(poloxamer-188)或泊洛沙姆-407(pluronic F-127)、苯酚、丙二醇和磷酸鈉(pH 7.7)的液態組成物。加入泊洛沙姆-188或泊洛沙姆-407可增加穩定性。
艾塞那肽係能降低血糖濃度的一群胜肽。艾塞那肽具有某些類似GLP-1(7~36)的序列(53%;Goke等人,J. Biol. Chem.
268:19650~55)。艾塞那肽-3和艾塞那肽-4藉由與艾塞那肽受體的相互作用,刺激天竺鼠胰臟之腺泡細胞增加細胞cAMP的產生(Raufman;1996,Reg. Peptides
;61:1~18)。艾塞那肽-3與艾塞那肽-4對照,則增加胰臟的腺細胞釋出澱粉酶。艾塞那肽係作為GLP-1激動劑。
類升糖激素肽1(GLP-1)係於攝取葡萄糖或脂肪之後增強胰島素反應的一種內分泌激素。通常,GLP-1可降低升糖激素濃度、減慢胃排空、刺激(前)胰島素合成、增強對胰島素敏感度,及刺激胰島素-依賴性肝糖的合成(Holst(1999)Curr. Med. Chem.
6:1005;Nauck等人(1997)Exp Clin Endocrinol Diabetes
105:187;Lopez-Delgado等人(1998)Endocrinology
139:2811)。人類GLP-1具有37個胺基酸殘基(Heinrich等人,Endocrinol
. 115:2176(1984);Uttenthal等人,J. Clin. Endocrinol Metabol.
(1985)61:472)。GLP-1的活性片段包括GLP-1(7~36)和GLP-1(7~37)。
艾塞那肽-3、艾塞那肽-4和艾塞那肽激動劑藉由減少胃運動和胃排空,已建議被用於治療糖尿病及預防高血糖症(US 5,424,286和WO 98/05351)。
艾塞那肽類似物的特徵可為胺基酸取代及/或C端截斷的天然艾塞那肽-4序列。此類艾塞那肽類似物已描述於WO 99/07404、WO 99/25727和WO 99/25728。
WO 01/04156A1描述AVE0010的固相合成。AVE0010具有下述序列:desPro36
艾塞那肽-4(1~39)-Lys6
-NH2
。此物質於WO 01/04156中被標示為序列辨識編號:93:H-G-E-G-T-F-T-S-D-L-S-K-Q-M-E-E-E-A-V-R-L-F-I-E-W-L-K-N-G-G-P-S-S-G-A-P-P-S-K-K-K-K-K-K-NH2
(序列辨識編號:1)艾塞那肽-4(39 AS)的序列:H-G-E-G-T-F-T-S-D-L-S-K-Q-M-E-E-E-A-V-R-L-F-I-E-W-L-K-N-G-G-P-S-S-G-A-P-P-P-S-NH2
(序列辨識編號:2)艾塞那肽-3的序列(J. Bio. Chem
.,267,1992:7402~7405):H-His-Ser-Asp-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
(序列辨識編號:3)GLP-1的序列:H-A-E-G-T-F-T-S-D-V-S-S-Y-L-E-G-Q-A-A-K-E-F-I-A-W-L-V-K-G-R-NH2
(序列辨識編號:4)
本發明的一目的係增加包含GLP-1激動劑之液態配製物的穩定性。更明確而言,本發明的一目的係改善物理和化學完整性。我們已發現藉由GLP-1激動劑與甲硫胺酸的配製可達到此目的。
已發現甲硫胺酸能增加含GLP-1激動劑(如AVE0010)之組成物的儲存安定性。甲硫胺酸不影響這些組成物的物理完整性。
已驚奇地發現,加入甲硫胺酸能藉由降低甲硫胺酸、高分子蛋白質和總雜質之氧化產物比例而改善本發明組成物的儲存穩定性。這些參數分別或共同作為測定組成物化學完整性的指標。
又進一步驚奇地發現加入甲硫胺酸可增加本發明組成物的生物活性。
許多機制會損害醫藥活性多肽的安定性,這些包括pH、溫度、光線以及某些成分的效應。
GLP-1激動劑配製物的許多習知組成分不利於含GLP-1激動劑之配製物的化學或/及物理完整性和儲存安定性。此例如聚山梨糖醇酯-20、聚山梨糖醇酯-80、泊洛沙姆-188、氯化芐烷銨(benzalkonium chloride),及離胺酸。因此,本發明組成物較佳為不含有這些組成分。
因此,本發明的液態組成物包含GLP-1激動劑或/及其藥理上可耐受鹽,以及視需要至少一種醫藥上可接受賦形劑,其中該組成物包含甲硫胺酸。
本發明的組成物較佳為包含從0.5至20 mg/mL,更佳為從1至5 mg/mL的甲硫胺酸。可使用D型的甲硫胺酸。同樣,亦可使用L型的甲硫胺酸。同樣,亦可使用任何所欲比例之D型和L型的混合物。
更明確而言,本發明的組成物不含有表面活性劑,例如多元醇以及多元醇的部分和脂肪酸酯及多元醇之醚類,如甘油和山梨糖醇。本發明組成物特別不含選自由 所構成群組之脂肪酸酯及甘油醚和山梨糖醇的部分。此外,本發明組成物特別不含選自由聚丙二醇、聚乙二醇、泊洛沙姆、普朗尼克(Pluronics)、特蔥(Tetronics)所構成群組的多元醇。更明確而言,本發明的組成物不含至少一種選自由聚山梨糖醇、聚山梨糖醇和泊洛沙姆所構成群組的物質。
更明確而言,本發明組成物實質上或較佳為不含聚山梨糖醇,舉例如polysorbate 20。
更明確而言,本發明組成物實質上或較佳為不含polysorbate 80。
更明確而言,本發明組成物實質上或較佳為不含泊洛沙姆,舉例如poloxamer 188。
更明確而言,本發明組成物實質上或較佳為不含有氯化芐烷銨。
更明確而言,本發明組成物實質上或較佳為不含有組胺酸。
更明確而言,本發明組成物實質上或較佳為不含有EDTA,特別指EDTA鈉。
本發明組成物包含一或多種常用於緩衝pH的物質(緩衝劑)。此類緩衝劑物質為醋酸鹽、檸檬酸鹽和磷酸鹽,例如高至5 mg/ml、高至4 mg/ml、高至3 mg/ml,或高至2 mg/ml的含量。
本發明組成物可同樣實質上不含緩衝物質。本發明的組成物較佳為不含緩衝物質。
本發明組成物可實質上不含有檸檬酸鹽、醋酸鹽及/或磷酸鹽,或者無檸檬酸鹽、醋酸鹽及/或磷酸鹽。
更明確而言,本發明組成物實質上無或較佳為不含組胺酸和EDTA鈉。
更明確而言,胰島素不存在於本發明的組成物內。
本發明醫藥組成物具有酸性或生理pH。酸性pH的範圍較佳為pH 1~6.8、pH 3.5~6.8,或pH 3.5~5。生理pH的範圍較佳為pH 2.5~8.5,更佳為pH 4.0~8.5,又更佳為pH 4.0~6.0。最佳的pH為約4.5。就pH調節而言,可使用生理上安全的稀釋酸(通常為HCl)和稀釋鹼(通常為NaOH)。
本發明組成物包含適當的防腐劑。適當防腐劑為例如苯酚、間甲苯酚、芐醇,及/或對羥基苯甲酸酯。較佳為間甲苯酚。
此外,本發明的組成物包含適當的滲透改質劑。適當滲透改質劑為例如甘油、右旋糖、乳糖、山梨糖醇、甘露糖醇、葡萄糖、NaCl、鈣或鎂化合物如CaCl2
等。甘油、右旋糖、乳糖、山梨糖醇、甘露糖醇和葡萄糖習慣上的濃度範圍為100~250 mM,NaCl的濃度為高至150 mM。較佳為使用甘油。
更明確而言,該組成物係被用於腸道外投藥。本發明組成物較佳為可注射組成物,更佳為被用於皮下注射。更明確而言,本發明組成物適合每天注射一次。
更明確而言,本發明的配製物於+5℃或25℃儲存1、2、4或6個月之後可保留至少80%、至少90%、至少95%,或至少98%的初始儲存活性。
本申請案中,「活性」意指用於本發明配製物內之GLP-1激動劑的活性。熟習本領域之技術者已習知測定GLP-1激動劑活性的方法。
本發明組成物較佳為在25℃儲存6個月之後具有至少89%或至少90%的GLP-1激動劑生物活性。本發明的組成物較佳為在40℃儲存6個月之後具有至少45%或至少50%的GLP-1激動劑生物活性。
更明確而言,本發明配製物於儲存1、2、3、4或6個月之後仍具有化學完整性。更明確而言,化學完整性意指該配製物於+5℃、25℃或40℃的溫度下儲存之後與儲存初期比較可包含至少80%、至少90%、至少95%,或至少98%實質上化學未變化型式的活性成分。
化學完整性意指GLP-1激動劑的化學完整性。GLP-1激動劑可包含甲硫胺酸殘基(如AVE0010內的位置14)。更明確而言,GLP-1激動劑的化學完整性意指可防止甲硫胺酸殘基的氧化作用。更明確而言,此處化學完整性意指相對GLP-1激動劑全部甲硫胺酸含量,儲存1、2、3、4或6個月後的氧化甲硫胺酸比例低於0.7%、低於0.6%、低於0.5%、低於0.4%,或低於0.3%。其可被有效地儲存於5℃、25℃,或40℃。較佳為於5℃儲存6個月,此時該氧化甲硫胺酸的比例為低於0.3%。同樣,較佳為於25℃儲存6個月,此時該氧化甲硫胺酸的比例為低於0.7%、低於0.6%、低於0.5%、低於0.4%,或低於0.3%。同樣,較佳為於40℃儲存6個月,此時該氧化甲硫胺酸的比例為低於1%、低於0.7%、低於0.6%、低於0.5%、低於0.4%,或低於0.3%。
化學完整性意指本發明配製物內含有極低比例的總雜質含量。更明確而言,相對於配製物內存在GLP-1激動劑的全部質量,於40℃儲存6個月後的總雜質比例為低於50%,儲存於25℃之後為低於10%,或/及儲存於5℃之後為低於1.8%。
化學完整性意指本發明配製物內含有極低比例的高分子量蛋白質。更明確而言,相對配製物內存在GLP-1激動劑總質量,於40℃儲存6個月之後,該高分子量蛋白質的比例低於5%、低於4%、低於3%,或低於2%。更明確而言,相對配製物內存在GLP-1激動劑總質量,於25℃儲存6個月之後,該高分子量蛋白質的比例低於0.8%、低於0.7%,或低於0.6%。
更明確而言,本發明的配製物於儲存1、2、4或6個月之後仍具有物理完整性。更明確而言,物理完整性意指該配製物於+5℃、25℃或40℃的溫度下儲存之後,與儲存初期比較該配製物可保留至少80%、至少90%、至少95%,或至少98%實質上物理未變化型式的活性成分。
物理完整性意指GLP-1激動劑的物理完整性。更明確而言,物理完整性意指該GLP-1激動劑不形成凝集體,舉例如纖絲(fibrils)。
該GLP-1激動劑較佳為選自由艾塞那肽-3及其類似物和衍生物、艾塞那肽-4及其類似物和衍生物所構成的群組,此時GLP-1激動劑更佳為選自由AVE0010和艾塞那肽-4所構成的群組。
艾塞那肽-3、艾塞那肽-3的類似物和衍生物、艾塞那肽-4,及艾塞那肽-4的類似物和衍生物可參考WO 01/04156、WO 98/30231、US 5,424,286、EP申請案99610043.4和WO 2004/005342。這些文件併入本文作為參考資料。可在經過選擇性地修飾之後藉由此處所述的方法合成述於這些文件中的艾塞那肽-3、艾塞那肽-4,及其類似物和衍生物。
AVE0010(序列辨識編號:1)、艾塞那肽-4(序列辨識編號:2)和艾塞那肽-3(序列辨識編號:3)的序列具有高度相似性。AVE0010和艾塞那肽-4的序列在位置1~37為相同。來自艾塞那肽-4的序列1~39其於39個位置的37個與艾塞那肽-3序列的位置48~86相同(94%)。根據該序列,本領域技術者可輕易地轉換此處所述與特定序列(例如AVE0010或艾塞那肽-4序列)有關的位置至其他序列。
艾塞那肽-3或/及艾塞那肽-4的類似物和衍生物更特別含有一經修飾的胺基酸序列。例如,可刪除單一胺基酸(例如於艾塞那肽-4內的desPro36、desPro37、desAsp28、desMet(O)14和艾塞那肽-3內的對應位置)。同樣,單一位置可被取代(例如於艾塞那肽-4內的Met(O)14
、Trp(O2
)25
、IsoAsp28
、Asp28
Pro38
和艾塞那肽-3內的對應位置),此時亦可使用非天然胺基酸,例如Met(O)(甲硫胺酸亞碸或甲硫胺酸碸)、Trp(O2
)(N-甲醯犬尿胺酸(formylkynurenine)),或/及IsoAsp(β-天冬酸鹽或異天冬酸鹽)。非天然胺基酸序列可輕易地被插入建構單元型的對應胺基酸。
此外,可修飾其C-端或/及N-端,例如藉由一附加序列如-(Lys)-、-(Lys)2
-、-(Lys)3
-、-(Lys)4
-、-(Lys)5
-、-(Lys)6
-、-Asn-(Glu)5
-,其中以-(Lys)4
-、-(Lys)5
-、-(Lys)6
-、-Asn-(Glu)5
-較佳。C-端的羧基較佳為被修飾成醯胺基(-NH2
)。可於合成完成之後任意地進一步修飾C-端或/及N-端。
於完成本發明方法的合成循環之後,可進一步製造醫藥上可耐受鹽。製造胜肽的醫藥上可耐受鹽已為本領域技術者所習知,一種較佳的醫藥上可耐受鹽為醋酸鹽。
GLP-1激動劑較佳為選自由艾塞那肽-4、艾塞那肽-4的類似物和衍生物及其醫藥上可耐受鹽所構成的群組。
進一步較佳GLP-1激動劑為選自由下列構成之群組的艾塞那肽-4類似物:H-desPro36
-艾塞那肽-4-Lys6
-NH2
;H-des(Pro36,37
)-艾塞那肽-4-Lys4
-NH2
;H-des(Pro36,37
)-艾塞那肽-4-Lys5
-NH2
及其醫藥上可耐受鹽。
進一步較佳GLP-1激動劑為選自由下列構成之群組的艾塞那肽-4類似物:desPro36
[Asp28
]-艾塞那肽-4(1~39);desPro36
[IsoAsp28
]-艾塞那肽-4(1~39);desPro36
[Met(O)14
,Asp28
]-艾塞那肽-4(1~39);desPro36
[Met(O)14
,IsoAsp28
]-艾塞那肽-4(1~39);desPro36
[Trp(O2
)25
,Asp28
]-艾塞那肽-2(1~39);desPro36
[Trp(O2
)25
,IsoAsp28
]-艾塞那肽-2(1~39);desPro36
[Met(O)14
Trp(O2
)25
,Asp28
]-艾塞那肽-4(1~39);desPro36
[Met(O)14
Trp(O2
)25
,IsoAsp28
]-艾塞那肽-4(1~39)及其醫藥上可耐受鹽。
進一步較佳GLP-1激動劑為選自述於前段所構成之群組的艾塞那肽-4類似物,其中該胜肽-Lys6
-NH2
係被連接至艾塞那肽-4類似物的C-端。
進一步較佳GLP-1激動劑為選自由下列構成之群組的艾塞那肽-4類似物:H-(Lys)6
-desPro36
[Asp28
]-艾塞那肽-4(1~39)-Lys6
-NH2
;desAsp28
Pro36
,Pro37
,Pro38
艾塞那肽-4(1~39)-NH2
;H-(Lys)6
-desPro36
,Pro37
,Pro38
[Asp28
]-艾塞那肽-4(1~39)-NH2
;H-Asn-(Glu)5
desPro36
,Pro37
,Pro38
[Asp28
]-艾塞那肽-4(1~39)-NH2
;desPro36
,Pro37
,Pro38
[Asp28
]艾塞那肽-4(1~39)-(Lys)6
-NH2
;H-(Lys)6
-desPro36
,Pro37
,Pro38
[Asp28
]-艾塞那肽-4(1~39)-(Lys)6
-NH2
;H-Asn-(Glu)5
-desPro36
,Pro37
,Pro38
[Asp28
]-艾塞那肽-4(1~39)-(Lys)6
-NH2
;H-(Lys)6
-desPro36
[Trp(O2
)25
,Asp28
]-艾塞那肽-4(1~39)-Lys6
-NH2
;H-desAsp28
Pro36
,Pro37
,Pro38
[Trp(O2
)25
]-艾塞那肽-4(1~39)-NH2
;H-(Lys)6
-desPro36
,Pro37
,Pro38
[Trp(O2
)25
,Asp28
]-艾塞那肽-4(1~39)-NH2
;H-Asn-(Glu)5
-desPro36
,Pro37
,Pro38
[Trp(O2
)25
,Asp28
]-艾塞那肽-4(1~39)-NH2
;desPro36
,Pro37
,Pro38
[Trp(O2
)25
,Asp28
]-艾塞那肽-4(1~39)-(Lys)6
-NH2
;H-(Lys)6
-desPro36
,Pro37
,Pro38
[Trp(O2
)25
,Asp28
]-艾塞那肽-4(1~39)-(Lys)6
-NH2
;H-Asn-(Glu)5
-desPro36
,Pro37
,Pro38
[Trp(O2
)25
,Asp28
]-艾塞那肽-4(1~39)-(Lys)6
-NH2
;H-(Lys)6
-desPro36
[Met(O)14
,Asp28
]-艾塞那肽-4(1~39)-Lys6
-NH2
;desMet(O)14
Asp28
Pro36
,Pro37
,Pro38
-艾塞那肽-4(1~39)-NH2
;H-(Lys)6
-desPro36
,Pro37
,Pro38
[Met(O)14
,Asp28
]-艾塞那肽-4(1~39)-NH2
;H-Asn-(Glu)5
-desPro36
,Pro37
,Pro38
[Met(O)14
,Asp28
]-艾塞那肽-4(1~39)-NH2
;desPro36
,Pro37
,Pro38
[Met(O)14
,Asp28
]-艾塞那肽-4(1~39)-(Lys)6
-NH2
;H-(Lys)6
-desPro36
,Pro37
,Pro38
[Met(O)14
,Asp28
]-艾塞那肽-4(1~39)-Lys6
-NH2
;H-Asn-(Glu)5
-desPro36
,Pro37
,Pro38
[Met(O)14
,Asp28
]-艾塞那肽-4(1~39)-(Lys)6
-NH2
;H-(Lys)6
-desPro36
[Met(O)14
,Trp(O2
)25
,Asp28
]-艾塞那肽-4(1~39)-Lys6
-NH2
;desAsp28
Pro36
,Pro37
,Pro38
[Met(O)14
,Trp(O2
)25
]-艾塞那肽-4(1~39)-NH2
;H-(Lys)6
-desPro36
,Pro37
,Pro38
[Met(O)14
,Trp(O2
)25
,Asp28
]-艾塞那肽-4(1~39)-NH2
;H-Asn-(Glu)5
-desPro36
,Pro37
,Pro38
[Met(O)14
,Asp28
]-艾塞那肽-4(1~39)-NH2
;desPro36
,Pro37
,Pro38
[Met(O)14
,Trp(O2
)25
,Asp28
]-艾塞那肽-4(1~39)-(Lys)6
-NH2
;H-(Lys)6
-desPro36
,Pro37
,Pro38
[Met(O)14
,Trp(O2
)25
,Asp28
]-艾塞那肽-4(1~39)-(Lys)6
-NH2
;H-Asn-(Glu)5
-desPro36
,Pro37
,Pro38
[Met(O)14
,Trp(O2
)25
,Asp28
]-艾塞那肽-4(1~39)-(Lys)6
-NH2
及其醫藥上可耐受鹽。
同樣,該GLP-1激動劑可選自由GLP-1及GLP-1類似物和衍生物所構成的群組。更佳的GLP-1激動劑為選自由Arg34
,Lys26
(Nε
(γ-麩胺醯基(Nα
-十六醯基)))GLP-1(7~37)[長效(liraglutide)]及其醫藥上可耐受鹽所構成的群組。
更佳的GLP-1激動劑為AVE0010。AVE0010具有desPro36
-艾塞那肽-4(1~39)-Lys6
-NH2
(序列辨識編號:1)的序列。同樣,較佳為使用AVE0010的醫藥上可耐受鹽。
如AVE0010之GLP-1激動劑特別指從0.01至0.5 mg/ml或0.05至1.5 mg/ml範圍的用量。
在一特定具體實施例中,本發明配製物包含下列的成分:
(a) desPro36
-艾塞那肽-4(1~39)-Lys6
-NH2
(如約0.1 mg/mL);
(b) 三水醋酸鈉(約3.5 mg/mL);
(c) 間甲苯酚(約2.7 mg/mL);
(d) L-甲硫胺酸(約3 mg/mL);
(e) 85%甘油(約18 mg/mL);
(f) 約0.1N鹽酸,若需將pH調節至約4.5時;
(g) 約0.1N NaOH溶液,若需將pH調節至約4.5時;以及
(h) 水。
更明確而言,本發明配製物係由(a)至(h)所述的成分所構成。
本申請案中,「約」意指本發明組成物中該成分可在特定值的約例如±10、±20或±30範圍內。
當本發明組成物包含多於一種GLP-1激動劑時,則這些可為彼此獨立被選擇的GLP-1激動劑。
用於本發明組成物的適合包裝為視需要可抽取個別治療有效劑量之經適當密封的針筒或玻璃瓶。亦可使用適合用於投與藥劑的注射筆;此類筆包含容納本發明醫藥組成物的容器(如液體匣)。
本發明進一步提供一種以本發明組成物治療病患的方法,其包括將該組成物投與至病患。
本發明組成物係特別指用於治療糖尿病,更特別指用於治療第I型或第II型糖尿病。其他適應症為伴隨糖尿病的症狀。本發明的組成物較佳為被用於控制空腹、餐後或/及吸收後血糖濃度以改善葡萄糖耐性、預防低血糖症、預防胰臟β細胞的功能喪失、有效減重,或/及預防體重增加。
本發明進一步提供本發明組成物於製造用以治療特別是第I型或第II型之糖尿病,或/及伴隨其之症狀的用途。
本申請案進一步提供製造本發明組成物的方法,其包含配製GLP-1激動劑或/及其藥理上可耐受鹽與甲硫胺酸,以及任選至少一種醫藥上可接受賦形劑。
本發明進一步提供本發明組成物以及投與甲弗明、磺醯尿素、格列酮(glitazones)、長效胰島素/胰島素衍生物及/或其組合,特別指投與甲弗明作為輔助療法的用途。
本發明進一步提供本發明組成物於無法藉由投與甲弗明、磺醯尿素、格列酮、長效胰島素/胰島素衍生物及/或其組合控制血糖濃度之病人的用途。
本發明進一步提供本發明組成物作為第II型糖尿病患者之輔助食品以改善血糖控制的用途。
更明確而言,該組成物包含desPro36
-艾塞那肽-4(1~39)-Lys6
-NH2
(AVE0010)、格列酮及/或藥理上可耐受鹽以及甲硫胺酸及/或藥理上可耐受鹽。
更明確而言,使用、NεB29
-十四醯基des(B30)人類胰島素或作為長效胰島素衍生物。
利用甲弗明及/或長效胰島素/胰島素衍生物及/或其藥理上可耐受鹽的輔助療法最佳為用於治療第II型糖尿病及/或肥胖,更特別指50歲以下及/或體質指數至少30以上的病人。
在本發明中,該輔助療法更特別指藉由甲弗明和AVE0010治療第II型糖尿病。甲弗明和AVE0010的投藥間隔時間為24小時。甲弗明和AVE0010可分別以每日一次的劑量被投藥。可藉由不同的途徑投與甲弗明和AVE0010,可經由口服投與甲弗明,以及經由皮下投與AVE0010。
本發明以輔助療法治療的病人具有在7至10%範圍內的HbAlc值。其較佳年齡為在18至50歲。
本發明的輔助療法更明確而言被應用於無法單獨以甲弗明控制第II型糖尿病的患者。
更明確而言,依如下方法投與甲弗明:至少1.0 g/天,較佳為至少1.5 g/天投與3個月。
進一步藉由下列實例和圖示說明本發明。
本試驗之目的為評估含和不含甲硫胺酸之AVE0010配製物(0.1 mg/ml注射液)產品在長期和加速老化條件下儲存6個月的化學或/及物理穩定性。
下列為受測組成物:
該配製物以欲用於臨床試驗及銷售和配送的單位儲存。
儲存時間、儲存條件、時間點被摘錄於下表。
以水平放置儲存配製物。RH指相對濕度。時間點0為儲存初期。以時間點0的測定值作為全部測試條件的參考值。測定期間該樣本被儲存於+5±3℃。
藉由下列試驗之助,判定經儲存配製物的物理和化學穩定性:
● 描述
● 溶液透明度及其顏色
● pH
● 化學穩定性(藉由HPLC測定純度和雜質,特別指氧化產物和總雜質的比例)
● 高分子亮蛋白質,由HPSEC測定
● 可視雜質
● 配製物的生物學活性
下列參數分開測定該平行批次(894和897)的配製物:
● AVE0010的生物學活性。
於5℃和25℃儲存6個月之後可保留至少96%的最初活性。本發明組成物的活性大於比較組成物的活性。無甲硫胺酸之下於40℃儲存6個月之後保留約43%。含有甲硫胺酸時則保留約51%的活性,此明顯高於無甲硫胺酸者。
● 氧化產物。
利用100%峰面積法於Water Systems的HPLC儀(型號:alliance)上進行測定。就分離而言,使用以0.1% TFA和乙腈的梯度作為流動相,以及C18反相柱(Jupiter)作為固定相。於5℃時,無甲硫胺酸之AVE0010內氧化甲硫胺酸Met(ox)的比例為0.3%。於25℃時,該比例在0.6~0.8%的範圍內,於40℃時為1.3%。當配製物含有甲硫胺酸時,該氧化甲硫胺酸的比例明顯較低。在全部測試條件之下,其從未超過0.2%。於25℃時,該比例僅約不含甲硫胺酸者之含量的1/4至1/3,即使於40℃亦僅約1/6(詳見第1和2圖)。
● 高分子量蛋白質。
於5℃時,該比例介於0.1和0.3%之間並且在全部儲存期間維持實質上不變。於25℃時,無甲硫胺酸者的比例分別上升至0.9和1.3%。存在甲硫胺酸者,該比例約減半為0.4至0.5%。於40℃時,無甲硫胺酸者的比例分別為5.4%和6.2%,而存在甲硫胺酸者分別明顯降低至1.6和1.7%(詳見第3和4圖)。
● 總雜質。
於5℃時,其總雜質在6個月全程儲存期間緩慢從1.2增加至1.8或1.9%(無甲硫胺酸)。當存在甲硫胺酸時,可減緩其上升速度。於25℃時,觀察到分別上升至10.6%和11.8%。存在甲硫胺酸時,該值低於10%。於40℃時,其上升比例高至54%(無甲硫胺酸)。當存在甲硫胺酸時,該比例僅約47%(詳見第5和6圖)。
該百分比值為氧化產物、總雜質和高分子量蛋白質(HMWP)的含量值(雜質百分比值)。
全部數值以所謂的100%測量法藉由HPLC測定。此處,特別指涉及反相HPLC(C18管柱),其中梯度法用於流動相:
(a) 0.1% TFA,15% ACN;以及
(b) 0.1% TFA,75% ACN。
於215 nm(UV)進行偵測
藉由用於胰島素注射液製劑之歐洲藥典6.0中所述的HPSEC偵測高分子量蛋白(HMWP)。
其資料摘錄於下表:
氧化產物、高分子量蛋白質和總雜質的比例可用於測定配製物的化學完整性。從上述實例組成物的結果,包含
● GLP-1激動劑或/及其藥理上可耐受鹽(特別指AVE0010或/及其藥理上可耐受鹽);
● 任選至少一種醫藥上可接受賦形劑;以及
● 甲硫胺酸
之本發明液態組成物可改善穩定性或/及化學完整性。與比較組成物相比,本發明組成物具有較低的氧化甲硫胺酸、總雜質量和高分子量蛋白質比例。本發明組成物(批次894_B和897_B)和比較組成物(批次894_A和897_A)之間的差異在於有或無甲硫胺酸。因此,本發明組成物內的甲硫胺酸成分有助於改善穩定性或/及化學完整性。
在進一步試驗中,研究EDTA鈉和組胺酸對本發明組成物的影響。
在一標準實驗設計中,以組成物B或C或生理鹽水經由皮下(sc)或肌肉內(im)投與兔子。為判定急性或亞急性之藥物組織學變化的效應,於24或120小時之後分別犧牲一半的兔子。同時,觀察是否發生修補/再生的任何變化。
與生理鹽水組比較,皮下注射組成物C的動物在24小時之後於皮下結締組織發生輕微至中度的炎症反應。在皮下注射120小時之後,可明顯發現纖維母細胞反應的修補作用。因此,其仍具有中度的相容性(並非不相容)。
與生理鹽水的對照比較,皮下注射組成物B的動物並無或有輕微的差異(相容性佳)。
肌肉內注射組成物C之後,該動物明顯出現與生理鹽水對照不同的肌肉壞死(多灶性或散播性),其僅在注射的周圍部位清礎看到壞死區。在120小時之後,組成物C組別在壞死肌肉組織產生礦化作用,其甚至出現於屍檢的動物。兔子體內的許多部位可發現小或局部性的礦化作用,該注射組成物C之後的礦化明顯與壞死區有關。因此,因注射所導致之病灶毫無疑問具有可逆性。這些發現,經兔子肌肉注射之後,組成物C被視為具有不相容性。
組成物B經肌肉內注射之後具有良好相容性(與生理鹽水對照比較無或微小差異)。
從上述資料可看出組成物B與組成物C比較可改善對肌肉內或皮下投藥的相容性。包含此申請案中所述特別指AVE0010之GLP-1激動劑的組成物皮下注射為較佳的投藥途徑。
因此,包含特別指AVE0010之GLP-1激動劑的本發明組成物可不含有EDTA或/及組胺酸。同樣,本發明組成物可實質上無EDTA和組胺酸。
第1和2圖顯示,相對於AVE0010之全部甲硫胺酸含量,儲存於不同溫度之後氧化甲硫胺酸Met(ox)的含量百分比。1:儲存初期t0;2:儲存1個月;3:儲存3個月;4:儲存6個月。第1圖:批號894。第2圖:批號897。
第3和4圖顯示儲存於不同溫度之後高分子量之蛋白雜質(相對AVE0010)的含量百分比。1:儲存初期t0;2:儲存1個月;3:儲存3個月;4:儲存6個月。第3圖:批號894。第4圖:批號897。
第5和6圖顯示儲存於不同溫度之後全部雜質(相對AVE0010)的含量百分比。1:儲存初期t0;2:儲存1個月;3:儲存3個月;4:儲存6個月。第5圖:批號894。第6圖:批號897。
Claims (20)
- 一種液態組成物,其包含選自desPro36-艾塞那肽-4(1~39)-Lys6 -NH2 和艾塞那肽-4所構成群組之GLP-1激動劑或/及其藥理上可耐受鹽,以及視需要至少一種醫藥上可接受賦形劑,其中該組成物包含甲硫胺酸且不含組胺酸。
- 如申請專利範圍第1項之液態組成物,其中該組成物包含醫藥上可接受防腐劑。
- 如申請專利範圍第2項之液態組成物,其中該防腐劑為甲苯酚。
- 如申請專利範圍第1項之液態組成物,其中該組成物包含甘油。
- 如申請專利範圍第1項之液態組成物,其中該組成物具有從3.5至5範圍內的pH。
- 如申請專利範圍第1項之液態組成物,其中該組成物包含從0.5至20mg/mL。
- 如申請專利範圍第1項之液態組成物,其中該組成物包含從1至5mg/mL的甲硫胺酸。
- 如申請專利範圍第1項之液態組成物,其中該組成物於+25℃儲存6個月之後仍呈現化學完整性。
- 如申請專利範圍第1項之液態組成物,其中該組成物於+25℃儲存6個月之後仍呈現物理完整性。
- 如申請專利範圍第1項之液態組成物,其中該組成物包含下列的成分: (a)desPro36 -艾塞那肽-4(1~39)-Lys6 -NH2 ;(b)醋酸鈉;(c)間甲苯酚;(d)L-甲硫胺酸;(e)85%甘油;(f)約0.1N鹽酸,若需將pH調節至約4.5時;(g)約0.1N NaOH溶液,若需將pH調節至約4.5時;以及(h)水。
- 如申請專利範圍第1項之液態組成物,其中該組成物係一種可注射組成物。
- 如申請專利範圍第1至11項中任一項之液態組成物,其被用於治療糖尿病。
- 一種如申請專利範圍第1至11項中任一項之液態組成物於製造藥劑的用途,該藥劑用於治療糖尿病。
- 如申請專利範圍第13項之用途,其中該糖尿病為第II型糖尿病。
- 一種製造如申請專利範圍第1至11項中任一項之液態組成物的方法,其包含配製GLP-1激動劑或/及其藥理上可耐受鹽與甲硫胺酸,以及視需要至少一種醫藥上可接受賦形劑。
- 一種如申請專利範圍第1至11項中任一項之液態組成物於製造治療第II型糖尿病及/或肥胖之藥劑之用途,其中該藥劑用於與甲弗明(metformin)、磺醯尿素、格 列酮(glitazone)及/或長效胰島素/胰島素衍生物及/或其組合、及/或藥理上可耐受鹽合併投與。
- 如申請專利範圍第16項之用途,其包含無法以甲弗明、磺醯尿素、格列酮及/或長效胰島素/胰島素衍生物控制病患血糖的輔助療法。
- 如申請專利範圍第16或17項之用途,其中該被治療病患具有從7%至10%範圍的HbA1c值。
- 如申請專利範圍第16項之用途,其中該藥劑用以投與第II型糖尿病患者作為改善血糖控制之輔助食品。
- 如申請專利範圍第16項之用途,其中該藥劑每天投與病患一次。
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