TWI415631B - 室溫下安定之半合成的長春花生物鹼衍生物經冷凍乾燥之可注射的藥學組成物 - Google Patents
室溫下安定之半合成的長春花生物鹼衍生物經冷凍乾燥之可注射的藥學組成物 Download PDFInfo
- Publication number
- TWI415631B TWI415631B TW096149863A TW96149863A TWI415631B TW I415631 B TWI415631 B TW I415631B TW 096149863 A TW096149863 A TW 096149863A TW 96149863 A TW96149863 A TW 96149863A TW I415631 B TWI415631 B TW I415631B
- Authority
- TW
- Taiwan
- Prior art keywords
- vinorelbine
- composition
- carbohydrate
- room temperature
- stable
- Prior art date
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- 239000008194 pharmaceutical composition Substances 0.000 title claims description 8
- 229940122803 Vinca alkaloid Drugs 0.000 title abstract description 7
- 239000000203 mixture Substances 0.000 claims abstract description 33
- 150000001720 carbohydrates Chemical class 0.000 claims abstract description 12
- 229960002066 vinorelbine Drugs 0.000 claims description 31
- GBABOYUKABKIAF-IELIFDKJSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-IELIFDKJSA-N 0.000 claims description 23
- 150000003839 salts Chemical class 0.000 claims description 13
- 238000009472 formulation Methods 0.000 claims description 12
- 229960000922 vinflunine Drugs 0.000 claims description 8
- NMDYYWFGPIMTKO-HBVLKOHWSA-N vinflunine Chemical compound C([C@@](C1=C(C2=CC=CC=C2N1)C1)(C2=C(OC)C=C3N(C)[C@@H]4[C@@]5(C3=C2)CCN2CC=C[C@]([C@@H]52)([C@H]([C@]4(O)C(=O)OC)OC(C)=O)CC)C(=O)OC)[C@H]2C[C@@H](C(C)(F)F)CN1C2 NMDYYWFGPIMTKO-HBVLKOHWSA-N 0.000 claims description 8
- 229920001202 Inulin Polymers 0.000 claims description 5
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 5
- 229930006000 Sucrose Natural products 0.000 claims description 5
- 238000001990 intravenous administration Methods 0.000 claims description 5
- JYJIGFIDKWBXDU-MNNPPOADSA-N inulin Chemical group O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)OC[C@]1(OC[C@]2(OC[C@]3(OC[C@]4(OC[C@]5(OC[C@]6(OC[C@]7(OC[C@]8(OC[C@]9(OC[C@]%10(OC[C@]%11(OC[C@]%12(OC[C@]%13(OC[C@]%14(OC[C@]%15(OC[C@]%16(OC[C@]%17(OC[C@]%18(OC[C@]%19(OC[C@]%20(OC[C@]%21(OC[C@]%22(OC[C@]%23(OC[C@]%24(OC[C@]%25(OC[C@]%26(OC[C@]%27(OC[C@]%28(OC[C@]%29(OC[C@]%30(OC[C@]%31(OC[C@]%32(OC[C@]%33(OC[C@]%34(OC[C@]%35(OC[C@]%36(O[C@@H]%37[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O%37)O)[C@H]([C@H](O)[C@@H](CO)O%36)O)[C@H]([C@H](O)[C@@H](CO)O%35)O)[C@H]([C@H](O)[C@@H](CO)O%34)O)[C@H]([C@H](O)[C@@H](CO)O%33)O)[C@H]([C@H](O)[C@@H](CO)O%32)O)[C@H]([C@H](O)[C@@H](CO)O%31)O)[C@H]([C@H](O)[C@@H](CO)O%30)O)[C@H]([C@H](O)[C@@H](CO)O%29)O)[C@H]([C@H](O)[C@@H](CO)O%28)O)[C@H]([C@H](O)[C@@H](CO)O%27)O)[C@H]([C@H](O)[C@@H](CO)O%26)O)[C@H]([C@H](O)[C@@H](CO)O%25)O)[C@H]([C@H](O)[C@@H](CO)O%24)O)[C@H]([C@H](O)[C@@H](CO)O%23)O)[C@H]([C@H](O)[C@@H](CO)O%22)O)[C@H]([C@H](O)[C@@H](CO)O%21)O)[C@H]([C@H](O)[C@@H](CO)O%20)O)[C@H]([C@H](O)[C@@H](CO)O%19)O)[C@H]([C@H](O)[C@@H](CO)O%18)O)[C@H]([C@H](O)[C@@H](CO)O%17)O)[C@H]([C@H](O)[C@@H](CO)O%16)O)[C@H]([C@H](O)[C@@H](CO)O%15)O)[C@H]([C@H](O)[C@@H](CO)O%14)O)[C@H]([C@H](O)[C@@H](CO)O%13)O)[C@H]([C@H](O)[C@@H](CO)O%12)O)[C@H]([C@H](O)[C@@H](CO)O%11)O)[C@H]([C@H](O)[C@@H](CO)O%10)O)[C@H]([C@H](O)[C@@H](CO)O9)O)[C@H]([C@H](O)[C@@H](CO)O8)O)[C@H]([C@H](O)[C@@H](CO)O7)O)[C@H]([C@H](O)[C@@H](CO)O6)O)[C@H]([C@H](O)[C@@H](CO)O5)O)[C@H]([C@H](O)[C@@H](CO)O4)O)[C@H]([C@H](O)[C@@H](CO)O3)O)[C@H]([C@H](O)[C@@H](CO)O2)O)[C@@H](O)[C@H](O)[C@@H](CO)O1 JYJIGFIDKWBXDU-MNNPPOADSA-N 0.000 claims description 5
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- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims description 3
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- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims description 3
- 239000003963 antioxidant agent Substances 0.000 claims description 3
- 230000003078 antioxidant effect Effects 0.000 claims description 3
- 150000002016 disaccharides Chemical class 0.000 claims description 3
- 150000004676 glycans Chemical class 0.000 claims description 3
- 239000011261 inert gas Substances 0.000 claims description 3
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- 239000005017 polysaccharide Substances 0.000 claims description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- CILBMBUYJCWATM-HGBQGYOLSA-N vinorelbine D-tartrate Chemical group OC(=O)[C@@H](O)[C@H](O)C(O)=O.OC(=O)[C@@H](O)[C@H](O)C(O)=O.C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC CILBMBUYJCWATM-HGBQGYOLSA-N 0.000 claims 2
- 239000002552 dosage form Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 4
- 239000000824 cytostatic agent Substances 0.000 abstract 1
- 230000001085 cytostatic effect Effects 0.000 abstract 1
- 230000010534 mechanism of action Effects 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 238000003860 storage Methods 0.000 description 8
- 239000012535 impurity Substances 0.000 description 7
- JXLYSJRDGCGARV-CFWMRBGOSA-N vinblastine Chemical compound C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-CFWMRBGOSA-N 0.000 description 7
- CILBMBUYJCWATM-PYGJLNRPSA-N vinorelbine ditartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC CILBMBUYJCWATM-PYGJLNRPSA-N 0.000 description 7
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 5
- 235000014633 carbohydrates Nutrition 0.000 description 5
- 229960003048 vinblastine Drugs 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
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- 229960004528 vincristine Drugs 0.000 description 3
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- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 3
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- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 240000001829 Catharanthus roseus Species 0.000 description 2
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- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- 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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
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Description
本發明係有關室溫下安定之半合成的長春花生物鹼經冷凍乾燥之可注射的藥學組成物。
大致上，對長春花生物鹼的臨床興趣已經確立長達約略40年時間。從此此等化合物廣泛用作為抗癌劑。
長春鹼(vinblastine)及長春新鹼(vincristine)係首先分離自長春花(Catharanthus roseus G.Don)或長春花(Vinca rosea L.)之葉。此等生物鹼為兩個吲哚單位所組成之二元體：亦即長春花鹼(catharanthine)及文多林(vindoline)。長春鹼及長春新鹼分別於1963年及1964年以商品名微爾比(VELBE)及昂可文(ONCOVIN)於法國上市。對長春鹼進行合成研究，結果導致製造出長春地辛(vindesine)，長春地辛乃第一個非天然衍生物及藥學製劑艾迪新(ELDISINE)(1983年)的來源。
Poitier等人合成具有雙吲哚結構之第二種非天然藥物衍生物。此乃長春瑞濱(vinorelbine)，係經由基於使用長春花鹼及文多林，藉半合成途徑獲得的分子，具有全面性之抗腫瘤性質。長春瑞濱於1989年於法國由皮耶製藥公司(Pierre Fabre M e dicament)首次以商品名那微賓(NAVELBINE)註冊登記，用於非小細胞肺癌的治療，然後於1992年註冊登記用於轉移乳癌的治療。2001年於法國註冊口服劑型。
此等抗癌藥物可以即用溶液形式(昂可文、那微賓)或粉末形式(微爾比、艾迪新)購得。此等抗癌藥物於運送及儲存期間必須儲藏於冰箱之2℃至8℃溫度。
數年前利用化學反應手段於超酸介質中已經形成一個新家族。一種半合成二氟化衍生物、長春弗寧(vinflunine)目前正在臨床發展中。
與長春瑞濱之相同方式，長春弗寧係得自脫水長春鹼，脫水長春鹼的本身係由於長春花鹼與文多林間之生物模擬偶合反應獲得。
由於水中溶解度之相關理由，長春弗寧係呈水溶性鹽形式皂化。舉例言之，此鹽水溶液經凍乾後分離出二酒石酸鹽。
長春弗寧二酒石酸鹽為白色或近白色粉末，必須於惰性氣體氣氛諸如氮氣或氬氣下儲存於低於-15℃之負溫。此點對長春瑞濱二酒石酸鹽而言亦為如此。
申請人之法國專利申請案2 863 89 1(「腸道外投藥用之長春弗寧藥學組成物」、製備及使用程序)可注意焦點在於長春弗寧之水溶性鹽溶解於水性介質之安定化效果。其中一項申請專利範圍係有關組成物之良好安定性，於5℃±3℃可安定至少36個月。
出乎意外地，本發明可安定化長春弗寧及長春瑞濱之水溶性鹽同時該等鹽係處在粉化狀態。然後可儲存於室溫而非如前文說明之低於-15℃之溫度。
本發明係基於至少一種碳水化合物諸如單醣無論是否經還原、寡醣或多醣諸如菊糖存在下之長春花生物鹼經凍乾之半合成衍生物之安定配方，更特別係基於長春花生物鹼之半合成衍生物之水溶性鹽之安定配方，甚至更特別係基於於雙醣更特別為蔗糖、海藻糖或乳糖存在下長春弗寧及長春瑞濱之凍乾水溶性鹽之安定配方。
長春花生物鹼與碳水化合物之半合成衍生物之相對比例可於由1/1至1/20，更特別由1/1至1/10(w/w)之範圍。
第1圖顯示重新調製後溶液於25℃及60%相對濕度儲存6個月後之420奈米吸光比。
第2圖顯示於25℃及60%相對濕度經6個月後之總雜質，以百分比表示。
較佳於至少一種碳水化合物諸如單醣無論是否經還原、寡醣或多醣諸如菊糖存在下之長春花生物鹼經凍乾之半合成衍生物之安定配方，含有具有pH為3至4，更特別pH=3.5之緩衝劑系統，俾便於凍乾產物再度溶解於注射製劑用水後，所得溶液之pH值係可提升活性成分之良好安定性。
舉個非限制性實例，此等緩衝劑系統係由乙酸及乙酸鈉、檸檬酸及檸檬酸鈉、酒石酸及蘇打所組成。其莫耳濃度為0.005M至0.5M及更特別為0.05M至0.2M。
此等起始物料經腸道外途徑投藥無毒，因而可使用此等凍乾產物作為癌症治療之注射用藥物。
舉出下列配方作為非限制性實例，及配方比較起始物料之安定性結果用來舉例說明本發明。
其單元組成顯示於下表1之溶液係經製備然後經凍乾。
實例1：
應用下列製造程序：1).以攪拌連續將蔗糖及長春弗寧二酒石酸鹽溶解於製造所需之乙酸/乙酸鈉0.1M緩衝液pH=3.5之大部分，2).使用乙酸/乙酸鈉0.1M緩衝液pH=3.5調整至終體積且均化所得溶液，3).經由於親水性0.22微米聚偏氟乙烯膜過濾，滅菌溶液，且配送入第I型玻璃瓶內，4).於下列條件下進行凍乾操作：產物於-48℃冷凍，於0.100毫巴壓力下於0.03℃/分鐘速率初次乾燥37小時，於0.010毫巴壓力下於20℃/分鐘速率二次乾燥16小時，
5).停止加塞且旋上瓶蓋所得經凍乾產物連同一批起始物料長春弗寧二酒石酸鹽(批號503)，於25℃於60%相對濕度儲存6個月。
與產物分解相對應之雜質的出現係經由記錄下列變化來監視：
- 於25℃及60%相對濕度經6個月後，經重新調製溶液於420奈米之吸光比顯示於第1圖。
- 於25℃及60%相對濕度經6個月後之總雜質以百分比表示且顯示於第2圖。
蔗糖具有無庸置疑的安定效果。如由於420奈米之吸光比結果可知，隨著蔗糖含量的增高此種效果加大。
須注意此等全然出乎意外的絕佳效果更進一步改良。長春弗寧二酒石酸鹽為對氧化敏感之分子。熟諳技藝人士極為徹底瞭解將惰性氣體如氮氣或氬氣或親水性抗氧化劑諸如抗壞血酸及其衍生物、硫酸鹽諸如硫酸鈉及硫醇衍生物組合可提高此項安定性。
由碳水化合物諸如單醣無論是否還原、寡醣或多醣諸如菊糖更特別藉雙醣對凍乾的長春弗寧產生的保護並未出現於習用作為注射用凍乾產品之結構劑之其它賦形劑。
如下組成物經凍乾。
實例2：
凍乾產物於5℃、25℃-60%相對濕度及40℃-75%相對濕度儲存1個月。最末條件為高度所需俾便放大差異。
雜質總含量係以HPLC測定，且以相對於長春弗寧之百分比表示。下表所示結果為於25℃-60%相對濕度、40℃-75%相對濕度之測量值與於5℃之測量值間計算得的差異。
對配方MP1762(海藻糖)所得結果為良好，且於25℃60%相對濕度係與5℃相同。
對配方MP1766(普維隆)所得結果顯然不佳。
全部此等結果，特別為於25℃ 60%相對濕度儲存6個月所得結果，共同讓配方釋放可製作出於室溫具有超過18個月儲存壽命之抗癌組成物，而可免除於2℃至8℃溫度運送及儲存配方之限制。
較佳，本發明組成物含有超過50毫克長春弗寧之單位數量。
於較佳實施例中，本發明組成物可含有超過50毫克例如100毫克或250毫克長春弗寧之單位數量。由此觀點，於凍乾前之溶液配方含有相同配方，而只有配送溶液量之體積改變：對前述100毫克及250毫克長春弗寧劑量分別改變為4毫升及10毫升。
下表所列舉單元組成之溶液經製備然後經凍乾。
實例3：
所得凍乾產物於25℃ 60%相對濕度及30℃ 65%相對濕度儲存1個月，以及於5℃及25℃ 60%相對濕度儲存2個月。
雜質總含量係藉HPLC測定，且係相對於初值表示。
於相同儲存條件下，起始物料長春瑞濱二酒石酸鹽顯示分解雜質含量的改變，表示產物須儲存於T<-15℃(於5℃儲存3個月後平均改變等於+0.3%)。
就呈二鹽酸鹽形式存在且與碳水化合物共存之下凍乾之長春瑞濱於室溫之儲存而言，所得結果高度有利。
根據本發明組成物也含有單位數量小於或等於20毫克例如10毫克至50毫克之長春瑞濱。凍乾前之溶液配方恰維持相同而只有配送量改變：對市場上可購得之前述10毫克及50毫克劑量而言分別為1毫升及5毫升。
於本發明之特定實施例中，根據本發明之藥學組成物係於注射製劑用水重新調配，且於輸注溶液諸如0.9%氯化鈉溶液或5%葡萄糖溶液稀釋後，藉靜脈輸注途徑投藥。
本發明亦係關於根據本發明之藥學組成物用作為藥物，特別係用於癌症之治療，較佳係以優異方式藉靜脈輸注途徑經腸道外投予，又更佳係於化學治療期間作為抗贅生劑及抗腫瘤劑投予。
本發明亦係關於本發明組成物用於製造腸道外投藥用藥之用途，該藥物較佳係藉靜脈輸注途徑投予，可有利地用於癌症之治療。
腸道外投予，換言之經靜脈途徑投予根據本發明之長春
弗寧或長春瑞濱藥學組成物，可治療對長春弗寧或長春瑞濱之效果敏感之癌症。
第1圖顯示重新調製後溶液於25℃及60%相對濕度儲存6個月後之420奈米吸光比。
第2圖顯示於25℃及60%相對濕度經6個月後之總雜質，以百分比表示。
Claims (11)
- 一種藥學組成物，其係由長春弗寧(vinflunine)或長春瑞濱(vinorelbine)的水溶性鹽類所組成，其在室溫下安定，其中該長春弗寧或長春瑞濱之水溶性鹽類係於至少一種碳水化合物存在下所獲得之凍乾形式。
- 一種藥學組成物，其係由以下所組成：一長春弗寧或長春瑞濱水溶性鹽類，其在室溫下安定，其中該長春弗寧或長春瑞濱之水溶性鹽類係於至少一種碳水化合物存在下所獲得之凍乾形式；至少一緩衝劑系統；以及一親水性抗氧化劑。
- 如申請專利範圍第2項之組成物，其中該長春弗寧或長春瑞濱之水溶性鹽類係長春弗寧二酒石酸鹽或長春瑞濱二酒石酸鹽。
- 如申請專利範圍第2項之組成物，其中該(等)碳水化合物係選自於單醣類(無論其是否經還原)、寡醣或多醣。
- 如申請專利範圍第4項之組成物，其中該(等)碳水化合物係選自於蔗糖、海藻糖及乳糖。
- 如申請專利範圍第4項之組成物，其中該碳水化合物係雙醣。
- 如申請專利範圍第4項之組成物，其中該碳水化合物係菊糖。
- 如申請專利範圍第2項之組成物，其中該被選用來控制pH之緩衝劑系統具有一在3至4之間的pH值，以及具有一在0.005M及0.5M之間的莫耳濃度。
- 如申請專利範圍第8項之組成物，其中該被選用來控制pH之緩衝劑系統具有一在3.5區域中之pH值，以及具有一在0.05M及0.2M之間的莫耳濃度。
- 如申請專利範圍第2項之組成物，其中該組成物係於惰性氣體氛圍下及/或將一親水性抗氧化劑併入到一配方中來製造與包裝。
- 如申請專利範圍第2項之組成物，其中其係呈適合藉靜脈途徑輸注之劑型投予。
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| JO3112B1 (ar) * | 2010-03-29 | 2017-09-20 | Ferring Bv | تركيبة دوائية سريعة التحلل |
| CN102772373B (zh) * | 2011-05-11 | 2015-09-02 | 石药集团中奇制药技术（石家庄）有限公司 | 一种注射用酒石酸长春瑞滨粉针剂及其制备方法 |
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| CN1635871A (zh) * | 2002-02-22 | 2005-07-06 | 先灵公司 | 抗肿瘤剂,特别是替莫唑胺的药物制剂,其制备方法和用途 |
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| US4923876A (en) * | 1988-04-18 | 1990-05-08 | Cetus Corporation | Vinca alkaloid pharmaceutical compositions |
| CA2013600A1 (en) * | 1989-04-04 | 1990-10-04 | Michael J. Pikal | Pharmaceutical formulations |
| US6143276A (en) * | 1997-03-21 | 2000-11-07 | Imarx Pharmaceutical Corp. | Methods for delivering bioactive agents to regions of elevated temperatures |
| FR2761990B1 (fr) * | 1997-04-10 | 1999-06-25 | Pf Medicament | Derives halogenes antimitotiques d'alcaloides de vinca |
| FR2863891B1 (fr) * | 2003-12-23 | 2006-03-24 | Pf Medicament | Composition pharmaceutique de vinflunine destinee a une administration parentale, procede de preparation et utilisation |
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- 2007-12-28 AU AU2007341231A patent/AU2007341231B2/en not_active Ceased
- 2007-12-28 RU RU2009128327/15A patent/RU2449791C2/ru not_active IP Right Cessation
- 2007-12-28 CN CN2007800423856A patent/CN101534821B/zh not_active Expired - Fee Related
- 2007-12-28 MX MX2009006949A patent/MX2009006949A/es active IP Right Grant
- 2007-12-28 KR KR1020097012321A patent/KR20090097883A/ko not_active Ceased
- 2007-12-28 UA UAA200907929A patent/UA96977C2/ru unknown
- 2007-12-28 BR BRPI0722076-6A2A patent/BRPI0722076A2/pt not_active IP Right Cessation
- 2007-12-28 WO PCT/EP2007/064612 patent/WO2008080968A1/en not_active Ceased
- 2007-12-28 AR ARP070105992A patent/AR064715A1/es unknown
- 2007-12-28 CA CA002673232A patent/CA2673232A1/en not_active Abandoned
- 2007-12-28 JP JP2009543478A patent/JP2010514737A/ja active Pending
- 2007-12-28 NZ NZ576583A patent/NZ576583A/en not_active IP Right Cessation
- 2007-12-28 EP EP07866320.0A patent/EP2120934B1/en active Active
- 2007-12-29 SA SA7280720A patent/SA07280720B1/ar unknown
-
2009
- 2009-05-06 ZA ZA200903115A patent/ZA200903115B/xx unknown
- 2009-05-14 MA MA31876A patent/MA30892B1/fr unknown
- 2009-06-23 TN TNP2009000258A patent/TN2009000258A1/fr unknown
- 2009-06-25 IL IL199556A patent/IL199556A/en not_active IP Right Cessation
- 2009-07-20 NO NO20092726A patent/NO20092726L/no not_active Application Discontinuation
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1635871A (zh) * | 2002-02-22 | 2005-07-06 | 先灵公司 | 抗肿瘤剂,特别是替莫唑胺的药物制剂,其制备方法和用途 |
Also Published As
| Publication number | Publication date |
|---|---|
| US8304424B2 (en) | 2012-11-06 |
| BRPI0722076A2 (pt) | 2014-04-08 |
| US20100087473A1 (en) | 2010-04-08 |
| AU2007341231A1 (en) | 2008-07-10 |
| TN2009000258A1 (en) | 2010-10-18 |
| AU2007341231B2 (en) | 2013-03-21 |
| SA07280720B1 (ar) | 2012-02-07 |
| AR064715A1 (es) | 2009-04-22 |
| CL2007003838A1 (es) | 2008-07-04 |
| JP2010514737A (ja) | 2010-05-06 |
| EP2120934B1 (en) | 2014-05-07 |
| RU2009128327A (ru) | 2011-02-10 |
| UA96977C2 (ru) | 2011-12-26 |
| NZ576583A (en) | 2012-01-12 |
| HK1130439A1 (zh) | 2009-12-31 |
| KR20090097883A (ko) | 2009-09-16 |
| IL199556A (en) | 2014-09-30 |
| FR2910812B1 (fr) | 2009-03-20 |
| EP2120934A1 (en) | 2009-11-25 |
| CA2673232A1 (en) | 2008-07-10 |
| CN101534821B (zh) | 2012-01-25 |
| NO20092726L (no) | 2009-07-20 |
| MX2009006949A (es) | 2009-07-14 |
| RU2449791C2 (ru) | 2012-05-10 |
| FR2910812A1 (fr) | 2008-07-04 |
| WO2008080968A1 (en) | 2008-07-10 |
| TW200833369A (en) | 2008-08-16 |
| CN101534821A (zh) | 2009-09-16 |
| MA30892B1 (fr) | 2009-11-02 |
| ZA200903115B (en) | 2010-04-28 |
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