(一)技术领域(1) Technical field
本发明涉及一种含埃坡霉素的抗癌缓释剂，属于药物技术领域。具体而言，本发明提供一种含埃坡霉素及其增效剂的缓释注射剂和缓释植入剂。The invention relates to an anticancer sustained-release agent containing epothilone, which belongs to the technical field of medicines. Specifically, the invention provides a sustained-release injection and a sustained-release implant containing epothilone and its synergist.
(二)背景技术(2) Background technology
癌症的治疗主要包括手术、放疗及化疗等方法。其中手术治疗不能清除散在的瘤细胞，因此常复发或导致肿瘤细胞因手术刺激而扩散转移；放疗和传统的化疗不具选择性，难于肿瘤局部形成有效药物浓度或治疗剂量，效果差，毒性大，单纯提高药物或放射剂量又受到全身毒性反应的限制。参见孔等“瘤内放置顺铂加系统卡莫司汀治疗大鼠脑肿瘤”《外科肿瘤杂志》69期76-82页，1998年(Kong Q et al.，J Surg Oncol.1998 Oct；69(2)：76-82)。Cancer treatment mainly includes surgery, radiotherapy and chemotherapy. Among them, surgical treatment cannot remove scattered tumor cells, so it often recurs or causes tumor cells to spread and metastasize due to surgical stimulation; radiotherapy and traditional chemotherapy are not selective, and it is difficult to form an effective drug concentration or therapeutic dose in the local tumor, resulting in poor efficacy and high toxicity. Simply increasing the dose of drugs or radiation is limited by systemic toxicity. See Kong et al. "Intratumoral placement of cisplatin plus systemic carmustine in the treatment of rat brain tumors" "Journal of Surgical Oncology" 69 pages 76-82, 1998 (Kong Q et al., J Surg Oncol.1998 Oct; 69 (2): 76-82).
低剂量的抗癌药物治疗不仅能够增加癌细胞的药物耐受性，而且还可促进其浸润性生长”，参见梁等“抗癌药物脉冲筛选后增加了人肺癌细胞的药物耐受性及体外浸润能力并伴有基因表达的改变”《国际癌症杂志》111期484-93页，2004年(Liang Y，et al.，Int JCancer.2004；111(4)：484-93)。Low-dose anticancer drug treatment can not only increase the drug resistance of cancer cells, but also promote their invasive growth", see Liang et al. "Anticancer drug pulse screening increases the drug resistance of human lung cancer cells and Invasive ability accompanied by changes in gene expression" International Journal of Cancer 111, pp. 484-93, 2004 (Liang Y, et al., Int J Cancer. 2004; 111(4): 484-93).
实体肿瘤由肿瘤细胞和肿瘤间质组成，其中肿瘤间质中的血管不仅为肿瘤细胞的生长提供了支架及必不可少的营养物质，还影响了化疗药物在肿瘤周围及肿瘤组织内的渗透和扩散，参见尼提等“细胞外间质的状况对实体肿瘤内药物运转的影响”《癌症研究》60期2497-503页，2000年(Netti PA，Cancer Res.2000，60(9)：2497-503)。Solid tumors are composed of tumor cells and tumor stroma. The blood vessels in the tumor stroma not only provide scaffolds and essential nutrients for the growth of tumor cells, but also affect the penetration of chemotherapy drugs around the tumor and in the tumor tissue. Diffusion, see Netti et al. "The influence of the condition of the extracellular matrix on the movement of drugs in solid tumors", "Cancer Research" 60, pp. 2497-503, 2000 (Netti PA, Cancer Res.2000, 60(9): 2497 -503).
肿瘤间质中的血管及结缔组织中的纤维蛋白及胶原蛋白等成分与过度增生的肿瘤细胞导致实体肿瘤的间质压力(interstitial pressure)高、间质粘性(interstitialviscosity)大、组织张力系数(tissue tensile modulus)大、间质液导率(hydraulicconductance)低。以上诸因素大大限制了药物进入实体肿瘤以及在肿瘤内的有效扩散，因此构成肿瘤化疗的主要障碍。The blood vessels in the tumor stroma, the fibrin and collagen in the connective tissue and the excessively proliferating tumor cells lead to high interstitial pressure, high interstitial viscosity, and tissue tension coefficient in solid tumors. Tensile modulus) large, interstitial fluid conductivity (hydraulic conductance) low. The above factors greatly limit the effective diffusion of drugs into solid tumors and tumors, thus constituting the main obstacle of tumor chemotherapy.
抗肿瘤药物局部注射或放置能够较好地克服以上缺陷，不仅能够明显提高肿瘤局部的药物浓度，而且可以显著降低全身毒性反应。大量体内外试验已显示出对实体肿瘤的治疗效果，参见孔庆忠等“瘤内放置顺铂加系统卡莫司汀治疗大鼠脑肿瘤”《外科肿瘤杂志》69期76-82页，1998年(Kong Q et al.，J Surg Oncol.1998 Oct；69(2)：76-82)和孔庆忠等“瘤内放置顺铂治愈大鼠原发脑肿瘤”《外科肿瘤杂志》64期268-273页(1997年)(Kong Q etal.，J Surg Oncol.1997 Oct；64：268-273)。还可参见中国专利ZL00111093.4；ZL96115937.5；申请号001111264，001111272及美国发明专利专利号6,376,525B1；5,651,986；5,626,862。Local injection or placement of antitumor drugs can better overcome the above defects, not only can significantly increase the local drug concentration in the tumor, but also can significantly reduce systemic toxicity. A large number of in vivo and in vitro tests have shown therapeutic effects on solid tumors, see Kong Qingzhong et al. "Intratumoral placement of cisplatin plus systemic carmustine in the treatment of rat brain tumors" "Journal of Surgical Oncology" 69 pages 76-82, 1998 ( Kong Q et al., J Surg Oncol.1998 Oct; 69(2):76-82) and Kong Qingzhong et al. "Intratumoral placement of cisplatin cured primary brain tumors in rats" "Journal of Surgical Oncology" 64, pp. 268-273 (1997) (Kong Q et al., J Surg Oncol. 1997 Oct;64:268-273). Also refer to Chinese patents ZL00111093.4; ZL96115937.5; application numbers 001111264, 001111272 and US invention patent numbers 6,376,525B1; 5,651,986; 5,626,862.
然而，单药化疗常导致肿瘤细胞对抗癌药物的耐受性增加，其结果是治疗失败。However, single-agent chemotherapy often leads to increased resistance of tumor cells to anticancer drugs, resulting in treatment failure.
(三)发明内容(3) Contents of the invention
本发明针对现有技术的不足，提供一种新的药物组合物，含埃坡霉素衍生物，与抗癌药物合用可使其增效。更具体而言，该药物组合物是抗实体肿瘤的缓释剂，主要为缓释植入剂和缓释注射剂。除能抑制肿瘤生长外，还能增加肿瘤细胞对抗癌药物的敏感性。The invention aims at the deficiencies of the prior art, and provides a new pharmaceutical composition, which contains epothilone derivatives, and can be used in combination with anticancer drugs to enhance their efficacy. More specifically, the pharmaceutical composition is a sustained-release agent against solid tumors, mainly sustained-release implants and sustained-release injections. In addition to inhibiting tumor growth, it can also increase the sensitivity of tumor cells to anticancer drugs.
除此之外，将埃坡霉素和或抗癌药物制成缓释剂(主要为缓释注射剂和缓释植入剂)不仅能够极大地提高肿瘤局部的药物浓度、降低药物在循环系统中的药物浓度、降低药物对正常组织的毒性，还能够极大方便药物注射、减少手术操作的并发症、降低病人的费用。抗癌药物除能抑制肿瘤生长外，还能增加肿瘤细胞对埃坡霉素及其衍生物的敏感性。In addition, making epothilone and or anticancer drugs into slow-release preparations (mainly slow-release injections and slow-release implants) can not only greatly increase the local drug concentration in the tumor, but also reduce the drug concentration in the circulatory system. The concentration of drugs can be reduced, the toxicity of drugs to normal tissues can be reduced, the injection of drugs can be greatly facilitated, the complications of surgical operations can be reduced, and the cost of patients can be reduced. In addition to inhibiting tumor growth, anticancer drugs can also increase the sensitivity of tumor cells to epothilone and its derivatives.
本发明抗实体肿瘤缓释剂包括抗癌有效成分和药用辅料，抗癌有效成分为埃坡霉素与磷酸肌醇3-激酶(P13K)抑制剂、嘧啶类似物和/或DNA修复酶抑制剂的组合。The anti-solid tumor sustained-release agent of the present invention includes anticancer active ingredients and pharmaceutical excipients, and the anticancer active ingredients are epothilone and phosphoinositide 3-kinase (P13K) inhibitors, pyrimidine analogs and/or DNA repair enzyme inhibitors combination of agents.
埃坡霉素衍生物选自下列之一或组合：埃坡霉素(Epothilone)或埃坡霉素衍生物，埃坡霉素衍生物选自埃坡霉素A、埃坡霉素B(Patupilone，EPO-906)、埃坡霉素C(去氧埃坡霉素，desoxyepothilone)、埃坡霉素D(epothilone D(EpoD)，12，13-desoxyepothilone B，去氧埃坡霉素B，dEpoB，KOS-862或NSC-703147)、埃坡霉素E、埃坡霉素F等以及它们的衍生物。Epothilone derivatives are selected from one or a combination of the following: Epothilone (Epothilone) or Epothilone derivatives, Epothilone derivatives are selected from Epothilone A, Epothilone B (Patupilone , EPO-906), Epothilone C (deoxyepothilone, desoxyepothilone), Epothilone D (epothilone D (EpoD), 12,13-desoxyepothilone B, deoxyepothilone B, dEpoB , KOS-862 or NSC-703147), epothilone E, epothilone F, etc. and their derivatives.
其中，埃坡霉素C的衍生物如，但不限于，4-去甲基-9-酮-埃坡霉素C、12，13-二氢-13-氧埃坡霉素C(12，13-dihydro-13-oxoepothilone C)；Among them, derivatives of epothilone C such as, but not limited to, 4-desmethyl-9-keto-epothilone C, 12,13-dihydro-13-oxoepothilone C (12, 13-dihydro-13-oxoepothilone C);
埃坡霉素B的衍生物如，但不限于，21和26位分别或同时被氨基取代的埃坡霉素B、9，10位去氢埃坡霉素B、10，11位去氢埃坡霉素B、26，27位被卤素取代的埃坡霉素B、9位，10位，11位，14位，21位，26位分别被羟基取代的埃坡霉素B、21，26-二羟基埃坡霉素B、21-羟基-10，11去氢埃坡霉素B、4-去甲基-9-酮-埃坡霉素B、4-去甲基-9，10-二去氢埃坡霉素B、4-去甲基-10，11-二去氢埃坡霉素B、6-去甲基-10，11-二去氢埃坡霉素B、21-氨基埃坡霉素B、21-羟基埃坡霉素B、26-羟基埃坡霉素B、26-氟埃坡霉素B、26-氨基埃坡霉素B、12，13位环丙基埃坡霉素B、12，13位环丁基埃坡霉素B、ixabepilone(BMS-247550)、氮杂埃坡霉素B(Azaepothilone B，内脂环中的氧被氮取代)、26-三氟-(E)-9，10-去氢-12，13-去氧埃坡霉素B(26-Trifluoro-(E)-9，10-dehydro-12，13-desoxyepothilone B[Fludelone(Flu)])；埃坡霉素D的衍生物如，但不限于，21和26位分别或同时被氨基取代的埃坡霉素D、9和10位去氢埃坡霉素D、10，11位去氢埃坡霉素D、26，27位被卤素取代的埃坡霉素D、9位，10位，11位，14位，21位，26位分别被羟基取代的埃坡霉素D、21，26-二羟基埃坡霉素D、21-羟基-10，11去氢埃坡霉素D、4-去甲基-9-酮-埃坡霉素D、4-去甲基-9，10-二去氢埃坡霉素D、4-去甲基-10，11-二去氢埃坡霉素D、6-去甲基-10，11-二去氢埃坡霉素D、21-羟基埃坡霉素D、21-氨基埃坡霉素D、26-羟基埃坡霉素D、26-氨基埃坡霉素D、26-氟埃坡霉素D、6-乙基，16-氟，17-吡啶埃坡霉素(或异埃坡霉素)、异埃坡霉素D、9，10去氢埃坡霉素D、10，11去氢埃坡霉素D、呋喃埃坡霉素D(furano-epothilone D)，(E)-9，10-去氢-12，13-去氧埃坡霉素D(E)-9，10-dehydro-12，13-desoxyepothiloneD)，BMS-310705，6-乙基，16-氟，17-吡啶埃坡霉素(ZK-EPO)，11，12-去氢-12，13-去氢-13-去氧埃坡霉素D 11，12-dehydro-12，13-dihydro13-oxoepothilone D、12，13-去氢-13-去氧埃坡霉素D(12，13-dihydro13-oxoepothilone D)、9-氧基埃坡霉素D(9-oxoepothilone D)、8-表-9-氧基埃坡霉素D(8-epi-9-oxoepothilone D)。Derivatives of epothilone B such as, but not limited to, epothilone B substituted by amino groups at positions 21 and 26 respectively or simultaneously, dehydroepothilone B at positions 9 and 10, dehydroepothilone B at positions 10 and 11 Pothilone B, epothilone B, 26, 27 substituted by halogen, 9, 10, 11, 14, 21, 26 epothilone B, 21, 26 respectively substituted by hydroxyl -Dihydroxyepothilone B, 21-hydroxy-10,11 dehydroepothilone B, 4-desmethyl-9-keto-epothilone B, 4-desmethyl-9,10- Didepothilone B, 4-demethyl-10,11-didehydroepothilone B, 6-demethyl-10,11-didehydroepothilone B, 21-amino Epothilone B, 21-hydroxyepothilone B, 26-hydroxyepothilone B, 26-fluoroepothilone B, 26-aminoepothilone B, 12, 13 cyclopropyl Pothilone B, 12,13 cyclobutyl epothilone B, ixabepilone (BMS-247550), azaepothilone B (Azaepothilone B, the oxygen in the inner aliphatic ring is replaced by nitrogen), 26-three Fluoro-(E)-9,10-dehydro-12,13-deoxyepothilone B (26-Trifluoro-(E)-9,10-dehydro-12,13-desoxyepothilone B[Fludelone(Flu) ]); derivatives of epothilone D such as, but not limited to, epothilone D, 9 and 10 dehydroepothilone D, 10, 11 Dehydroepothilone D, epothilone D substituted by halogen at positions 26 and 27, epothilone D substituted by hydroxyl at positions 9, 10, 11, 14, 21 and 26, respectively 21,26-dihydroxyepothilone D, 21-hydroxy-10,11 dehydroepothilone D, 4-desmethyl-9-keto-epothilone D, 4-desmethyl-9 , 10-Didehydroepothilone D, 4-Demethyl-10, 11-Didehydroepothilone D, 6-Demethyl-10, 11-Didehydroepothilone D, 21-Hydroxyepothilone D, 21-aminoepothilone D, 26-hydroxyepothilone D, 26-aminoepothilone D, 26-fluoroepothilone D, 6-ethyl, 16-fluoro, 17-pyridine epothilone (or isopothilone), isopothilone D, 9,10 dehydroepothilone D, 10,11 dehydroepothilone D, furan Epothilone D (furano-epothilone D), (E)-9, 10-dehydro-12, 13-deoxyepothilone D (E)-9, 10-dehydro-12, 13-desoxyepothilone D) , BMS-310705, 6-ethyl, 16-fluoro, 17-pyridine epothilone (ZK-EPO), 11, 12-dehydro-12, 13-dehydro-13-deoxyepothilone D 11,12-dehydro-12,13-dihydro13-oxoepothilone D, 12,13-dehydro-13-deoxyepothilone D (12,13-dihydro13-oxoepothilone D), 9-oxoepothilone D (9-oxoepothilone D), 8-epi-9-oxoepothilone D (8-epi-9-oxoepothilone D).
上述埃坡霉素及埃坡霉素衍生物优选埃坡霉素、埃坡霉素A、埃坡霉素B、埃坡霉素C、埃坡霉素D、异埃坡霉素D、埃坡霉素E、埃坡霉素F、ixabepilone(BMS-247550)、氮杂埃坡霉素B、呋喃埃坡霉素D、BMS-310705中的一种或其组合。The above-mentioned epothilone and epothilone derivatives are preferably epothilone, epothilone A, epothilone B, epothilone C, epothilone D, isopothilone D, epothilone One of pothilone E, epothilone F, ixabepilone (BMS-247550), azaepothilone B, furan epothilone D, BMS-310705, or a combination thereof.
埃坡霉素及埃坡霉素衍生物在组合物中所占的比例因具体情况而定，可为0.1％-50％，以1％-30％为佳，5％-20％为最佳。The proportion of epothilone and epothilone derivatives in the composition depends on the specific circumstances, it can be 0.1%-50%, preferably 1%-30%, and 5%-20% is the best .
磷酸肌醇3-激酶(phosphoinositide 3-kinase，简称P13K)抑制剂选自下列之一或组合：7-氢氧基-星状孢子素、7-O-烷基星状孢子素、β-甲氧星状孢子素、烷基磷酸胆碱、六癸基磷酸胆碱、十八基-(1，1-二甲基-4-哌啶)磷酸盐、1-O-六癸基-2-O-甲基-rac-丙三基-3-磷酸胆碱、1-O-十八基-2-O-甲基-rac-丙三基-3-磷酸胆碱、1-O-十八基-2-O-甲基-sn-丙三基-3-磷酸胆碱、肌醇聚磷酸盐、十四(烷)基磷酸胆碱、六葵基磷酸(N-N-N-三甲基)己醇胺、十八基磷酸胆碱或十八基-[2-(N-甲基哌啶)乙基]-磷酸盐。其中以7-氢氧基-星状孢子素、7-O-烷基-星状孢子素、β-甲氧星状孢子素、烷基磷酸胆碱、六癸基磷酸胆碱为优选。Phosphoinositide 3-kinase (phosphoinositide 3-kinase, P13K) inhibitors are selected from one or a combination of the following: 7-hydroxyl-staurosporine, 7-O-alkyl staurosporine, β-formazine Oxystaurosporine, alkylphosphocholine, hexadecylphosphorylcholine, octadecyl-(1,1-dimethyl-4-piperidine) phosphate, 1-O-hexadecyl-2- O-methyl-rac-glyceryl-3-phosphocholine, 1-O-octadecyl-2-O-methyl-rac-glyceryl-3-phosphocholine, 1-O-octadecyl 2-O-Methyl-sn-Glyceryl-3-Phosphocholine, Inositol Polyphosphate, Tetradecyl Phosphocholine, Hexacyl Phosphate (N-N-N-Trimethyl)hexanol amine, octadecylphosphorylcholine or octadecyl-[2-(N-methylpiperidinium)ethyl]-phosphate. Among them, 7-hydroxyl-staurosporine, 7-O-alkyl-staurosporine, β-methoxystaurosporine, alkylphosphocholine, and hexadecylphosphorylcholine are preferred.
嘧啶类似物主要选自O4-苄基叶酸、2，4，5-三氨基-6-苄氧基嘧啶、2，4-二氨基-6-苄氧基-5-亚硝基嘧啶、2，4-二氨基-6-苄氧基-5-溴基嘧啶、2-氨基-4-苄氧基-5-硝基嘧啶、2-氨基-4-苄氧基-6-甲基-5-硝基嘧啶、2，4-二氨基-6-苄氧基-s-三嗪、2氨基-O4-苄基喋啶的一种或多种。The pyrimidine analogs are mainly selected from O4-benzyl folic acid, 2,4,5-triamino-6-benzyloxypyrimidine, 2,4-diamino-6-benzyloxy-5-nitrosopyrimidine, 2, 4-Diamino-6-benzyloxy-5-bromopyrimidine, 2-amino-4-benzyloxy-5-nitropyrimidine, 2-amino-4-benzyloxy-6-methyl-5- One or more of nitropyrimidine, 2,4-diamino-6-benzyloxy-s-triazine, and 2-amino-O4-benzylpteridine.
DNA修复酶抑制剂可为任何一种DNA依赖的蛋白激酶抑制剂和/或聚(ADP-核糖)聚合酶抑制剂，但以咪唑并哌嗪、咪唑并吡啶、渥曼青霉素、苯并吡喃、6-芳香基-2-吗啡酚-4-基-吡喃-4-基、2-(4-吗琳基)-8-苯基色酮、7-乙基-10-羟基喜树碱、3-氰基-6-亚肼基甲基-5-(4-吡啶基)吡啶-[1H]-2-1、苯基丁酸、甲氧胺、羟基胺、肌醇聚磷酸盐、十四(烷)基磷酸胆碱、六葵基磷酸(N-N-N-三甲基)己醇胺、十八基磷酸胆碱、十八基-[2-(N-甲基哌啶)乙基]-磷酸盐、氨基三唑(AT)和丁基硫堇硫肟为优选。DNA repair enzyme inhibitors can be any DNA-dependent protein kinase inhibitors and/or poly(ADP-ribose) polymerase inhibitors, but in the form of imidazopiperazine, imidazopyridine, wortmannin, benzopyran , 6-aryl-2-morpholin-4-yl-pyran-4-yl, 2-(4-morpholinyl)-8-phenylchromone, 7-ethyl-10-hydroxycamptothecin, 3-cyano-6-hydrazinomethyl-5-(4-pyridyl)pyridine-[1H]-2-1, phenylbutyric acid, methoxyamine, hydroxylamine, inositol polyphosphate, deca Tetra(alkyl)phosphorylcholine, hexacylphosphoric acid (N-N-N-trimethyl)hexanolamine, octadecylphosphorylcholine, octadecyl-[2-(N-methylpiperidinyl)ethyl]- Phosphate, aminotriazole (AT) and butylthionine are preferred.
缓释辅料粘度范围IV(dl/g)为0.1～0.8，选自外消旋聚乳酸(D，L-PLA)、外消旋聚乳酸/乙醇酸共聚物(D，L-PLGA)、单甲基聚乙二醇/聚乳酸(MPEG-PLA)、单甲基聚乙二醇/聚乳酸共聚物(MPEG-PLGA)、聚乙二醇/聚乳酸(PLA-PEG-PLA)、聚乙二醇/聚乳酸共聚物(PLGA-PEG-PLGA)、端羧基聚乳酸(PLA-COOH)、端羧基聚乳酸/乙醇酸共聚物(PLGA-COOH)、聚苯丙生、双脂肪酸与癸二酸共聚物(PFAD-SA)、聚(芥酸二聚体-癸二酸)[P(EAD-SA)]、聚(富马酸癸二酸)[P(FA-SA)]、乙烯乙酸乙烯酯共聚物(EVAc)、聚乳酸(PLA)、聚乙醇酸和羟基乙酸的共聚物(PLGA)、聚对二氧环己酮(PDO)、聚三亚甲基碳酸酯(PTMC)、木糖醇、低聚糖、软骨素、甲壳素、壳聚糖、透明质酸、胶原蛋白、明胶、泊洛沙姆、蛋白胶之一或其组合；助悬剂选自羧甲基纤维素钠、(碘)甘油、二甲硅油、丙二醇、卡波姆、甘露醇、山梨醇、表面活性物质、土温20、土温40和土温80之一或其组合。Sustained-release excipients with a viscosity range of IV (dl/g) of 0.1 to 0.8, selected from racemic polylactic acid (D, L-PLA), racemic polylactic acid/glycolic acid copolymer (D, L-PLGA), single Methyl polyethylene glycol/polylactic acid (MPEG-PLA), monomethyl polyethylene glycol/polylactic acid copolymer (MPEG-PLGA), polyethylene glycol/polylactic acid (PLA-PEG-PLA), polyethylene glycol Glycol/polylactic acid copolymer (PLGA-PEG-PLGA), carboxyl-terminated polylactic acid (PLA-COOH), carboxyl-terminated polylactic acid/glycolic acid copolymer (PLGA-COOH), polyphenylene propane, difatty acid and decane Acid copolymer (PFAD-SA), poly(erucic acid dimer-sebacic acid) [P(EAD-SA)], poly(fumaric acid sebacic acid) [P(FA-SA)], ethylene acetic acid Vinyl ester copolymer (EVAc), polylactic acid (PLA), polyglycolic acid and glycolic acid copolymer (PLGA), polydioxanone (PDO), polytrimethylene carbonate (PTMC), xylose Alcohol, oligosaccharide, chondroitin, chitin, chitosan, hyaluronic acid, collagen, gelatin, poloxamer, protein glue one or its combination; suspending agent is selected from sodium carboxymethylcellulose, (iodo)glycerin, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surface active substances, one of TWen 20, TWen 40 and TWen 80 or a combination thereof.
药用辅料有数百种以上，具有缓释作用的药用辅料，特别是能将本发明中所选的有效成份在人体或动物体内于一定的时间内缓慢释放并非显而易见，特定的缓释辅料与可缓释药物组合的选择需要经过大量的创造性劳动才能确定。相关数据，特别是动物体内释放特性的数据需要经过体内外大量创造性的实验才能获得，并非经过有限的实验就能确定，具有非显而易见性。There are more than hundreds of pharmaceutical excipients, and it is not obvious that the pharmaceutical excipients with slow-release effect, especially those that can slowly release the active ingredients selected in the present invention within a certain period of time in the human or animal body, the specific sustained-release excipients The choice to combine with an extended-release drug requires a lot of creative work to determine. Relevant data, especially data on the release characteristics in animals, can only be obtained through a large number of creative experiments in vivo and in vitro, and cannot be determined through limited experiments, which is non-obvious.
本发明的组合物可按已知的方法制备药物，例如，通过常规的混合、溶解、制拉、制糖衣丸、磨细、乳化、制胶囊、包埋、或冷冻干燥的方法。其中的载体包括各种赋形剂和辅助剂。可根据所选择的给药途径制成合适的制剂。如制备注射、口服、吸入、栓、贴、植入等剂型。对于经粘膜的和经皮的给药，在制剂中使用适合于渗透屏障的渗透剂是本领域通常已知的。The composition of the present invention can be prepared into medicaments according to known methods, for example, by conventional methods of mixing, dissolving, drawing, dragee-making, levigating, emulsifying, encapsulating, entrapping, or freeze-drying. The carrier therein includes various excipients and auxiliary agents. Suitable formulations can be prepared according to the chosen route of administration. Such as preparation of dosage forms such as injection, oral administration, inhalation, suppository, paste, and implantation. For transmucosal and transdermal administration, the use of penetrants in formulations appropriate to the permeation barrier is generally known in the art.
用于口服制剂可成片剂、丸剂、崩解剂、糖锭剂、胶囊、推合胶囊、封闭软胶囊、液体、凝胶、糖浆剂、泥浆剂、悬浮液等。For oral preparations, it can be made into tablets, pills, disintegrating agents, dragees, capsules, push-fit capsules, sealed soft capsules, liquids, gels, syrups, slurries, suspensions, etc.
在各种制剂中，以长效性制剂为优选，以局部应用长效制剂为最优选。后者可通过植入法(直肠的、经粘膜的、经皮的、肠内的、肌内的、皮下的、髓内的注射，以及鞘内的、直接心室内的、静脉内的、腹膜内的、鼻内的、或眼内的注射)应用于肿瘤局部，在有效获得并维持局部药物浓度的同时明显降的其全身毒性。Among various preparations, long-acting preparations are preferred, and local application of long-acting preparations is the most preferred. The latter can be achieved by implantation (rectal, transmucosal, percutaneous, enteral, intramuscular, subcutaneous, intramedullary injection, as well as intrathecal, direct intraventricular, intravenous, peritoneal Intranasal, intraocular, or intraocular injection) is applied locally to the tumor, and its systemic toxicity is significantly reduced while effectively obtaining and maintaining the local drug concentration.
局部方式给药，例如，通过直接注射至特定组织，通常以储存或持续释放制剂的形式。Administration is localized, for example, by direct injection into a particular tissue, usually in a depot or sustained release formulation.
本发明的主要形式为缓释剂，包括缓释植入剂和缓释注射剂。The main forms of the present invention are sustained-release preparations, including sustained-release implants and sustained-release injections.
本发明的一种主要形式为缓释注射剂，由缓释微球和溶媒组成。具体而言，该抗癌缓释注射剂由以下成分组成：A main form of the present invention is a sustained-release injection, which consists of sustained-release microspheres and a vehicle. Specifically, the anticancer sustained-release injection consists of the following components:
(A)缓释微球，包括：(A) slow-release microspheres, including:
抗癌有效成分 0.5-60％Anti-cancer active ingredients 0.5-60%
缓释辅料 40-99％Sustained release excipients 40-99%
助悬剂 0.0-30％Suspending agent 0.0-30%
以上为重量百分比The above is weight percentage
和and
(B)溶媒，为普通溶媒或含助悬剂的特殊溶媒。(B) The solvent is a common solvent or a special solvent containing a suspending agent.
其中，in,
抗癌有效成分为P13K抑制剂、嘧啶类似物和/或DNA修复酶抑制剂与埃坡霉素衍生物的组合；The anticancer active ingredient is a combination of P13K inhibitors, pyrimidine analogs and/or DNA repair enzyme inhibitors and epothilone derivatives;
缓释辅料选自下列之一或其组合：Sustained-release excipients are selected from one or a combination of the following:
a)聚乳酸(PLA)；a) polylactic acid (PLA);
b)聚乙醇酸和羟基乙酸的共聚物(PLGA)；b) Copolymers of polyglycolic acid and glycolic acid (PLGA);
c)聚苯丙生；c) Polyphenylene;
d)聚苯丙生与PLA或PLGA的组合；d) combinations of polyphenylene and PLA or PLGA;
e)双脂肪酸与癸二酸共聚物；e) difatty acid and sebacic acid copolymer;
f)聚(芥酸二聚体癸二酸)共聚物；f) poly(erucic acid dimer sebacic acid) copolymer;
g)聚(富马酸癸二酸)共聚物。g) Poly(sebacic acid fumarate) copolymers.
助悬剂选自羧甲基纤维素钠、碘甘油、二甲硅油、丙二醇、卡波姆、甘露醇、山梨醇、表面活性物质、土温20、土温40和土温80之一或其组合，The suspending agent is selected from sodium carboxymethylcellulose, iodoglycerin, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surface active substances, one of soil temperature 20, soil temperature 40 and soil temperature 80 or its combination,
助悬剂的黏度为100cp-3000cp(20℃-30℃时)。The viscosity of the suspending agent is 100cp-3000cp (at 20°C-30°C).
缓释注射剂微球中的抗癌有效成分优选如下，均为重量百分比：The anti-cancer active ingredients in the sustained-release injection microspheres are preferably as follows, all in percent by weight:
本发明抗癌缓释注射剂微球中的抗癌有效成分优选为：The anti-cancer active ingredients in the anti-cancer sustained-release injection microspheres of the present invention are preferably:
(1)1-40％的埃坡霉素、埃坡霉素A、埃坡霉素B、埃坡霉素C、埃坡霉素D、异埃坡霉素D、埃坡霉素E、埃坡霉素F、ixabepilone(BMS-247550)、氮杂埃坡霉素B、呋喃埃坡霉素D、BMS-310705与1-40％的7-氢氧基-星状孢子素、7-O-烷基-星状孢子素、β-甲氧星状孢子素、烷基磷酸胆碱或六癸基磷酸胆碱的组合；(1) 1-40% epothilone, epothilone A, epothilone B, epothilone C, epothilone D, isopothilone D, epothilone E, Epothilone F, ixabepilone (BMS-247550), azaepothilone B, furan epothilone D, BMS-310705 with 1-40% of 7-hydroxyl-staurosporine, 7- Combinations of O-alkyl-staurosporine, beta-methoxystaurosporine, alkylphosphocholine or hexadecylphosphorylcholine;
(2)1-40％的埃坡霉素、埃坡霉素A、埃坡霉素B、埃坡霉素C、埃坡霉素D、异埃坡霉素D、埃坡霉素E、埃坡霉素F、ixabepilone(BMS-247550)、氮杂埃坡霉素B、呋喃埃坡霉素D、BMS-310705与1-40％的O4-苄基叶酸、2，4，5-三氨基-6-苄氧基嘧啶、2，4-二氨基-6-苄氧基-5-亚硝基嘧啶、2，4-二氨基-6-苄氧基-5-溴基嘧啶、2-氨基-4-苄氧基-5-硝基嘧啶、2-氨基-4-苄氧基-6-甲基-5-硝基嘧啶、2，4-二氨基-6-苄氧基-s-三嗪或2-氨基-O4-苄基喋啶的组合；或(2) 1-40% epothilone, epothilone A, epothilone B, epothilone C, epothilone D, isopothilone D, epothilone E, Epothilone F, ixabepilone (BMS-247550), azaepothilone B, furan epothilone D, BMS-310705 with 1-40% O4-benzyl folic acid, 2,4,5-tris Amino-6-benzyloxypyrimidine, 2,4-diamino-6-benzyloxy-5-nitrosopyrimidine, 2,4-diamino-6-benzyloxy-5-bromopyrimidine, 2- Amino-4-benzyloxy-5-nitropyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitropyrimidine, 2,4-diamino-6-benzyloxy-s- A combination of triazine or 2-amino-O4-benzylpteridine; or
(3)1-40％的1-40％的埃坡霉素、埃坡霉素A、埃坡霉素B、埃坡霉素C、埃坡霉素D、异埃坡霉素D、埃坡霉素E、埃坡霉素F、ixabepilone(BMS-247550)、氮杂埃坡霉素B、呋喃埃坡霉素D、BMS-310705与1-40％的咪唑并哌嗪、咪唑并吡啶、渥曼青霉素、苯并吡喃、6-芳香基-2-吗啡酚-4-基吡喃-4-基、2-(4-吗琳基)-8-苯基色酮、7-乙基-10-羟基喜树碱、3-氰基-6-亚肼基甲基-5-(4-吡啶基)吡啶-[1H]-2-1、苯基丁酸、甲氧胺、羟基胺、肌醇聚磷酸盐、十四(烷)基磷酸胆碱、六葵基磷酸(N-N-N-三甲基)己醇胺、十八基磷酸胆碱、十八基-[2-(N-甲基哌啶)乙基]-磷酸盐、氨基三唑或丁基硫堇硫肟的组合；或(3) 1-40% of 1-40% epothilone, epothilone A, epothilone B, epothilone C, epothilone D, isopothilone D, epothilone Pothilone E, Epothilone F, ixabepilone (BMS-247550), Azaepothilone B, Furanepothilone D, BMS-310705 and 1-40% imidazopiperazine, imidazopyridine , wortmannin, benzopyran, 6-aryl-2-morpholin-4-ylpyran-4-yl, 2-(4-morpholinyl)-8-phenylchromone, 7-ethyl -10-Hydroxycamptothecin, 3-cyano-6-hydrazonomethyl-5-(4-pyridyl)pyridine-[1H]-2-1, phenylbutyric acid, methoxyamine, hydroxylamine , inositol polyphosphate, tetradecyl (decyl) phosphorylcholine, hexacyl phosphoric acid (N-N-N-trimethyl) hexanolamine, octadecyl phosphorylcholine, octadecyl-[2-(N-methyl) a combination of (piperidinyl)ethyl]-phosphate, aminotriazole or butylthionine; or
(4)1-40％的埃坡霉素、埃坡霉素A、埃坡霉素B、埃坡霉素C、埃坡霉素D、异埃坡霉素D、埃坡霉素E、埃坡霉素F、BMS-247550、氮杂埃坡霉素B、呋喃埃坡霉素D或BMS-310705。(4) 1-40% epothilone, epothilone A, epothilone B, epothilone C, epothilone D, isopothilone D, epothilone E, Epothilone F, BMS-247550, Azaepothilone B, Furanepothilone D, or BMS-310705.
本发明缓释微球中缓释辅料及其重量百分比最优选如下：In the slow-release microspheres of the present invention, the slow-release auxiliary materials and their weight percentages are most preferably as follows:
(1)55-90％的PLA；(1) 55-90% PLA;
(2)50-90％的PLGA；(2) 50-90% PLGA;
(3)50-85％的聚苯丙生；(3) 50-85% polyphenylene;
(4)55-90％的双脂肪酸与癸二酸共聚物；(4) 55-90% difatty acid and sebacic acid copolymer;
(5)25-60％的聚苯丙生与25-60％的PLA或25-60％的PLGA的组合；(5) Combination of 25-60% polyphenylene and 25-60% PLA or 25-60% PLGA;
(6)40-95％的木糖醇、低聚糖、软骨素、甲壳素、壳聚糖、透明质酸、胶原蛋白、明胶、泊洛沙姆或白蛋胶；或(6) 40-95% xylitol, oligosaccharides, chondroitin, chitin, chitosan, hyaluronic acid, collagen, gelatin, poloxamer, or albumin glue; or
(7)40-95％的外消旋聚乳酸、外消旋聚乳酸/乙醇酸共聚物、单甲基聚乙二醇/聚乳酸、单甲基聚乙二醇/聚乳酸共聚物、聚乙二醇/聚乳酸、聚乙二醇/聚乳酸共聚物、端羧基聚乳酸或端羧基聚乳酸/乙醇酸共聚物。(7) 40-95% racemic polylactic acid, racemic polylactic acid/glycolic acid copolymer, monomethyl polyethylene glycol/polylactic acid, monomethyl polyethylene glycol/polylactic acid copolymer, poly Ethylene glycol/polylactic acid, polyethylene glycol/polylactic acid copolymer, carboxy-terminated polylactic acid, or carboxy-terminated polylactic acid/glycolic acid copolymer.
以上组合中，各种辅料的总量不超过制剂重的98％。In the above combinations, the total amount of various auxiliary materials does not exceed 98% of the weight of the preparation.
除上述辅料外，还可选用其他物质见美国专利(专利号4757128；4857311；4888176；4789724)及《药用辅料大全》(第123页，四川科学技术出版社1993年出版，罗明生和高天惠主编)中已有详细描述。另外，中国专利(申请号96115937.5；91109723.6；9710703.3；01803562.0)及美国发明专利(专利号5,651,986)也列举了某些药用辅料，包括充填剂、增溶剂、吸收促进剂、成膜剂、胶凝剂、制(或致)孔剂、赋型剂或阻滞剂等。In addition to the above-mentioned excipients, other substances can also be used, see US Patent (Patent No. 4757128; 4857311; 4888176; 4789724) and "Compendium of Pharmaceutical Excipients" (page 123, published by Sichuan Science and Technology Press in 1993, edited by Luo Mingsheng and Gao Tianhui ) has been described in detail. In addition, Chinese patents (application Nos. 96115937.5; 91109723.6; 9710703.3; 01803562.0) and U.S. invention patents (patent No. 5,651,986) also list certain pharmaceutical excipients, including fillers, solubilizers, absorption accelerators, film-forming agents, gelling agents, etc. agent, preparation (or) porogen, excipient or blocker, etc.
为调节药物释放速度或改变本发明的其它特性，可以改变聚合物的单体成分或分子量、添加或调节药用辅料的组成及配比，添加水溶性低分子化合物，如，但不限于，各种糖或盐等。其中糖可为，但不限于，木糖醇、低聚糖、(硫酸)软骨素及甲壳素等，其中盐可为，但不限于，钾盐和钠盐等。In order to adjust the drug release rate or change other characteristics of the present invention, the monomer composition or molecular weight of the polymer can be changed, the composition and proportion of pharmaceutical excipients can be added or adjusted, and water-soluble low-molecular compounds can be added, such as, but not limited to, each sugar or salt etc. Wherein the sugar can be, but not limited to, xylitol, oligosaccharide, (sulfate) chondroitin and chitin, etc., wherein the salt can be, but not limited to, potassium salt and sodium salt, etc.
缓释注射剂中，药物缓释系统可制成微球、亚微球、微乳、纳米球、颗粒或球形小丸，然后与注射溶媒混合后制成注射剂使用。在各种缓释注射剂中以混悬型缓释注射剂为优选，混悬型缓释注射剂是将含抗癌成分的药物缓释系统悬浮于注射液中所得的制剂，所用的辅料为上述缓释辅料中的一种或其组合，所用溶媒为普通溶媒或含助悬剂的特殊溶媒。普通溶媒为，但不限于，蒸馏水、注射用水、生理冲液、无水乙醇或各种盐配制的缓冲液。助悬剂的目的在于有效悬浮含药微球，从而利于注射之用。In sustained-release injections, the drug sustained-release system can be made into microspheres, submicrospheres, microemulsions, nanospheres, granules or spherical pellets, and then mixed with injection vehicles to make injections for use. Suspension-type sustained-release injections are preferred among various sustained-release injections. Suspension-type sustained-release injections are preparations obtained by suspending drug sustained-release systems containing anticancer ingredients in injections. The auxiliary materials used are the above-mentioned sustained-release injections. One or a combination of excipients, the solvent used is a common solvent or a special solvent containing a suspending agent. Common solvents are, but not limited to, distilled water, water for injection, physiological flushing solution, absolute ethanol or buffers prepared with various salts. The purpose of the suspending agent is to effectively suspend the drug-containing microspheres, thereby facilitating injection.
助悬剂选自羧甲基纤维素钠、(碘)甘油、二甲硅油、丙二醇、卡波姆、甘露醇、山梨醇、表面活性物质、土温20、土温40和土温80之一或其组合。The suspending agent is selected from one of sodium carboxymethylcellulose, (iodo)glycerin, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surface active substances, earth temperature 20, earth temperature 40 and earth temperature 80 or a combination thereof.
助悬剂在普通溶媒中的含量因其的特性而定，可为0.1-30％因具体情况而定。优选助悬剂的组成为：The content of the suspending agent in the common solvent depends on its characteristics, and can be 0.1-30% depending on the specific situation. The composition of preferred suspending agent is:
A)0.5-5％羧甲基纤维素钠+0.1-0.5％土温80；或A) 0.5-5% sodium carboxymethylcellulose + 0.1-0.5% Tween 80; or
B)5-20％甘露醇+0.1-0.5％土温80；或。B) 5-20% mannitol + 0.1-0.5% Tween 80; or.
C)0.5-5％羧甲基纤维素钠+5-20％山梨醇+0.1-0.5％土温80。C) 0.5-5% sodium carboxymethylcellulose + 5-20% sorbitol + 0.1-0.5% Tween 80.
溶媒的制备则取决于溶媒的种类，普通溶媒有市售，也可以自制，如蒸馏水、注射用水、生理冲液、无水乙醇或各种盐配制的缓冲液，但必需严格按照有关标准。特殊溶媒需考虑到助悬剂的种类及其组成、溶媒所悬浮的药物、缓释微球(或微囊)的组成、性质及其需要量及注射剂的制备方法，如将羧甲基纤维素钠(1.5％)+甘露醇和/或山梨醇(15％)和/或土温80(0.1％)溶于生理盐水中得相应的溶媒，黏度在10ep-650cp(20℃-30℃时)。The preparation of the solvent depends on the type of the solvent. Common solvents are commercially available or self-made, such as distilled water, water for injection, physiological flushing solution, absolute ethanol or buffer solutions prepared with various salts, but must strictly follow the relevant standards. Special solvents need to take into account the type and composition of the suspending agent, the drug suspended in the solvent, the composition, properties and required amount of the sustained-release microspheres (or microcapsules), and the preparation method of the injection, such as carboxymethylcellulose Sodium (1.5%) + mannitol and/or sorbitol (15%) and/or Tween 80 (0.1%) is dissolved in physiological saline to obtain the corresponding solvent, the viscosity is 10ep-650cp (at 20°C-30°C).
本发明发现影响药物和/或缓释微球悬浮和/或注射的关键因素是溶媒的黏度，黏度越大，悬浮效果越好，可注射性越强。这种意外发现构成了本发明的主要指数特征之一。溶媒的黏度取决于助悬剂的黏度，助悬剂的黏度为100cp-3000cp(20℃-30℃时)，优选1000cp-3000cp(20℃-30℃时)，最优选1500cp-3000cp(20℃-30℃时)。按照此条件所制得的溶媒的黏度为10cp-650cp(20℃-30℃时)，优选20cp-650cp(20℃-30℃时)，最优选60cp-650cp(20℃-30℃时)。The present invention finds that the key factor affecting the suspension and/or injection of the drug and/or sustained-release microspheres is the viscosity of the solvent. The greater the viscosity, the better the suspension effect and the stronger the injectability. This unexpected discovery constitutes one of the main index features of the present invention. The viscosity of the vehicle depends on the viscosity of the suspending agent. The viscosity of the suspending agent is 100cp-3000cp (at 20°C-30°C), preferably 1000cp-3000cp (at 20°C-30°C), most preferably 1500cp-3000cp (at 20°C -30°C). The viscosity of the solvent prepared according to this condition is 10cp-650cp (at 20°C-30°C), preferably 20cp-650cp (at 20°C-30°C), most preferably 60cp-650cp (at 20°C-30°C).
注射剂的制备有多种方法，一种是将助悬剂为“0”的缓释微粒(A)直接混于特殊溶媒中，得到相应的缓释微粒注射剂；另一种是将助悬剂不为“0”的缓释微粒(A)混于特殊溶媒或普通溶媒中，得到相应的缓释微粒注射剂；再一种是将缓释微粒(A)混于普通溶媒中，然后加入助悬剂混匀，得到相应的缓释微粒注射剂。除外，还可先将缓释微粒(A)混于特殊溶媒中制得相应的混悬液，然后用真空干燥等办法去除混悬液中的水分，之后再用特殊溶媒或普通溶媒混悬，得到相应的缓释微粒注射剂。以上方法只是用于说明而非限制本发明。值得注意的是，悬浮药物或缓释微球(或微囊)在注射剂中的浓度因具体需要而定，可为，但不限于，10-400mg/ml，但以30-300mg/ml为优选，以50-200mg/ml最优选。注射剂的黏度为50cp-1000cp(20℃-30℃时)，优选100cp-1000cp(20℃-30℃时)，最优选200cp-650cp(20℃-30℃时)。如此黏度适用于18-22号注射针头和特制的内径更大的(至3毫米)注射针头。There are many methods for the preparation of injections. One is to directly mix the sustained-release microparticles (A) with a suspending agent of "0" in a special solvent to obtain the corresponding sustained-release microparticle injections; the other is to mix the suspending agent without The slow-release microparticles (A) with "0" are mixed in special solvents or ordinary solvents to obtain the corresponding sustained-release microparticle injections; the other is to mix the slow-release microparticles (A) in ordinary solvents, and then add suspending agent Mix evenly to obtain the corresponding sustained-release microparticle injection. In addition, the slow-release microparticles (A) can also be mixed with a special solvent to prepare a corresponding suspension, and then vacuum drying is used to remove the water in the suspension, and then the special solvent or common solvent is used to suspend. The corresponding sustained-release microparticle injection was obtained. The above methods are only for illustration but not limitation of the present invention. It is worth noting that the concentration of suspended drug or sustained-release microspheres (or microcapsules) in the injection depends on specific needs, and can be, but not limited to, 10-400 mg/ml, but preferably 30-300 mg/ml , most preferably at 50-200mg/ml. The viscosity of the injection is 50cp-1000cp (at 20°C-30°C), preferably 100cp-1000cp (at 20°C-30°C), most preferably 200cp-650cp (at 20°C-30°C). This viscosity is suitable for 18-22 gauge needles and special needles with larger inner diameter (up to 3mm).
缓释注射剂的制备方法是任意的，可用若干种方法制备：如，但不限于，混合法、熔融法、溶解法、喷雾干燥法制备微球、溶解法结合冷冻(干燥)粉碎法制成微粉、脂质体包药法及乳化法等。其中以溶解法(即溶剂挥发法)、干燥法、喷雾干燥法和乳化法为优选。微球则可用于制备上述各种缓释注射剂，其方法是任意的。所用微球的粒径范围可在5-400um之间，以10-300um之间为优选，以20-200um之间为最优选。The preparation method of sustained-release injection is arbitrary, and several methods can be used for preparation: as, but not limited to, mixing method, melting method, dissolution method, spray drying method to prepare microspheres, dissolution method combined with freeze (dry) pulverization method to make micropowder, Liposome encapsulation method and emulsification method, etc. Among them, the dissolution method (that is, the solvent evaporation method), the drying method, the spray drying method and the emulsification method are preferred. Microspheres can be used to prepare the above-mentioned various sustained-release injections, and the method is arbitrary. The particle size range of the microspheres used may be between 5-400um, preferably between 10-300um, most preferably between 20-200um.
微球还可用于制备其他缓释注射剂，如凝胶注射剂、嵌段共聚物胶束注射剂。其中，嵌段共聚物胶束由疏水-亲水嵌段共聚物在水溶液中形成，具有球形内核-外壳结构，疏水嵌段形成内核，亲水嵌段形成外壳。载药胶束注射进入体内达到控制药物释放或靶向治疗的目的。所用药物载体为上述任意一种或其组合。其中优选分子量为1000-15000的聚乙二醇(PEG)作为胶束共聚物的亲水嵌段，优选生物降解聚合物(如PLA、聚丙交酯、聚己内酯及其共聚物(分子量1500-25000))作为胶束共聚物的疏水嵌段。嵌段共聚物胶束的粒径范围可在10-300um之间，以20-200um之间的为优选。凝胶注射剂系将生物降解聚合物(如PLA、PLGA或DL-LA和ε-己内酯共聚物)溶于某些两亲性溶媒，再加入药物与之混溶(或混悬)后形成流动性较好的凝胶，可经瘤周或瘤内注射。一旦注入，两亲性溶媒很快扩散至体液，而体液中的水分则渗入凝胶，使聚合物固化，缓慢释放药物。Microspheres can also be used to prepare other sustained-release injections, such as gel injections and block copolymer micelles injections. Among them, the block copolymer micelle is formed by hydrophobic-hydrophilic block copolymer in aqueous solution, has a spherical core-shell structure, the hydrophobic block forms the core, and the hydrophilic block forms the shell. The drug-loaded micelles are injected into the body to achieve the purpose of controlled drug release or targeted therapy. The drug carrier used is any one or combination of the above. Wherein preferred molecular weight is polyethylene glycol (PEG) of 1000-15000 as the hydrophilic block of micelle copolymer, preferred biodegradable polymer (such as PLA, polylactide, polycaprolactone and copolymer thereof (molecular weight 1500 -25000)) as the hydrophobic block of the micellar copolymer. The particle size range of the block copolymer micelles can be between 10-300um, preferably between 20-200um. Gel injection is formed by dissolving biodegradable polymers (such as PLA, PLGA or DL-LA and ε-caprolactone copolymer) in certain amphiphilic solvents, and then adding drugs to mix (or suspend) them The gel with good fluidity can be injected through the peritumoral or intratumoral. Once injected, the amphiphilic vehicle quickly diffuses into body fluids, and moisture from the body fluids penetrates the gel, solidifying the polymer and slowly releasing the drug.
缓释微球还可用于制备缓释植入剂，所用的药用辅料可为上述药用辅料中的任何一种或多种物质，但以水溶性高分子聚合物为主选，在各种高分子聚合物中，以聚乳酸、葵二酸、含聚乳酸或葵二酸的高分子多聚物的混合物或共聚物为首选，混合物和共聚物可选自，但不限于，PLA、PLGA、PLA与PLGA的混合物、葵二酸与芳香聚酐或脂肪族聚酐的混合物或共聚物。聚乳酸(PLA)与聚乙醇酸的共混比例是10/90-90/10(重量)，最好是25/75-75/25(重量)。共混的方法是任意的。乙醇酸和乳酸共聚时的含量分别为重量百分比10-90％和90-10％。芳香聚酐的代表物是对羧苯基丙烷(p-CPP)，对羧苯基丙烷(p-CPP)与葵二酸共聚时的含量分别为重量百分比10-60％和20-90％，共混重量比是10-40∶50-90，最好是重量比15-30∶65-85。Sustained-release microspheres can also be used to prepare sustained-release implants, and the pharmaceutical excipients used can be any one or more of the above-mentioned pharmaceutical excipients, but water-soluble polymers are the main choice. Among high molecular polymers, polylactic acid, sebacic acid, mixtures or copolymers of high molecular weight polymers containing polylactic acid or sebacic acid are preferred, and mixtures and copolymers can be selected from, but not limited to, PLA, PLGA , the mixture of PLA and PLGA, the mixture or copolymer of sebacic acid and aromatic polyanhydride or aliphatic polyanhydride. The blending ratio of polylactic acid (PLA) and polyglycolic acid is 10/90-90/10 (weight), preferably 25/75-75/25 (weight). The method of blending is arbitrary. The contents of glycolic acid and lactic acid in copolymerization are respectively 10-90% and 90-10% by weight. The representative of aromatic polyanhydride is p-carboxyphenylpropane (p-CPP), and the content of p-carboxyphenylpropane (p-CPP) and sebacic acid copolymerization is respectively 10-60% and 20-90% by weight, The blending weight ratio is 10-40:50-90, preferably 15-30:65-85.
本发明抗癌药物缓释剂的又一种形式是抗癌药物缓释剂为缓释植入剂。抗癌植入剂的有效成分可均匀地包装于整个药用辅料中，也可包装于载体支持物中心或其表面；可通过直接扩散和/或经多聚物降解的方式将有效成分释放。Another form of the sustained-release anticancer drug of the present invention is that the sustained-release anticancer drug is a sustained-release implant. The active ingredient of the anticancer implant can be uniformly packaged in the whole pharmaceutical excipient, or can be packaged in the center or the surface of the carrier support; the active ingredient can be released through direct diffusion and/or polymer degradation.
缓释植入剂的特点在于所用的缓释辅料除高分子聚合物外，还含有上述任意一种或多种其它辅料。添加的药用辅料统称为添加剂。添加剂可根据其功能分为充填剂、致孔剂、赋型剂、分散剂、等渗剂、保存剂、阻滞剂、增溶剂、吸收促进剂、成膜剂、胶凝剂等。The feature of the slow-release implant is that the slow-release auxiliary materials used include any one or more of the above-mentioned other auxiliary materials in addition to high molecular polymers. Added pharmaceutical excipients are collectively referred to as additives. Additives can be divided into fillers, porogens, excipients, dispersants, isotonic agents, preservatives, retarders, solubilizers, absorption accelerators, film-forming agents, gelling agents, etc. according to their functions.
缓释植入剂的主要成份可制成多种剂型。如，但不限于，胶囊、缓释剂、植入剂、缓释剂植入剂等；呈多种形状，如，但不限于，颗粒剂、丸剂、片剂、散剂、球形、块状、针状、棒状、柱状及膜状。在各种剂型中，以体内缓慢释放植入剂为优选。体积大小取决于病灶的部位、大小等因素。可为0.1-5mm(粗)×1-10mm(长)的棒状，也可为片状等其它形状。The main components of sustained-release implants can be made into various dosage forms. Such as, but not limited to, capsules, sustained-release agents, implants, sustained-release agent implants, etc.; in various shapes, such as, but not limited to, granules, pills, tablets, powders, spherical, block, Needle, rod, column and film. Among various dosage forms, slow-release implants in vivo are preferred. The volume depends on factors such as the location and size of the lesion. It can be in the form of a rod of 0.1-5 mm (thickness) x 1-10 mm (length), or other shapes such as sheet.
缓释植入剂的最佳剂型为生物相容性、可降解吸收的缓释剂植入，可因不同临床需要而制成各种形状及各种剂型。其主要成份的包装方法和步骤在美国专利中(US5651986)已有详细描述，包括若干种制备缓释制剂的方法：如，但不限于，(i)把载体支持物粉末与药物混合然后压制成植入剂，即所谓的混合法；(ii)把载体支持物熔化，与待包装的药物相混合，然后固体冷却，即所谓的熔融法；(iii)把载体支持物溶解于溶剂中，把待包装的药物溶解或分散于聚合物溶液中，然后蒸发溶剂，干燥，即所谓的溶解法；(iv)喷雾干燥法；及(v)冷冻干燥法等。The best dosage form of sustained-release implants is biocompatible, degradable and absorbable sustained-release implants, which can be made into various shapes and dosage forms according to different clinical needs. The packaging method and steps of its main components have been described in detail in U.S. Patent (US5651986), including several methods for preparing sustained-release preparations: such as, but not limited to, (i) mixing the carrier support powder with the drug and then compressing it into Implants, the so-called mixing method; (ii) melting the carrier support, mixing with the drug to be packaged, and then cooling the solid, the so-called melting method; (iii) dissolving the carrier support in a solvent, putting The drug to be packaged is dissolved or dispersed in the polymer solution, and then the solvent is evaporated and dried, which is the so-called dissolution method; (iv) spray drying method; and (v) freeze drying method, etc.
缓释植入剂中的抗癌有效成分及重量百分比可参照其缓释注射剂，但优选如下：The anti-cancer active ingredient and weight percentage in the slow-release implant can refer to its slow-release injection, but it is preferably as follows:
(1)1-40％的埃坡霉素、埃坡霉素A、埃坡霉素B、埃坡霉素C、埃坡霉素D、异埃坡霉素D、埃坡霉素E、埃坡霉素F、ixabepilone(BMS-247550)、氮杂埃坡霉素B、呋喃埃坡霉素D、BMS-310705与1-40％的7-氢氧基-星状孢子素、7-O-烷基-星状孢子素、β-甲氧星状孢子素、烷基磷酸胆碱或六癸基磷酸胆碱的组合；(1) 1-40% epothilone, epothilone A, epothilone B, epothilone C, epothilone D, isopothilone D, epothilone E, Epothilone F, ixabepilone (BMS-247550), azaepothilone B, furan epothilone D, BMS-310705 with 1-40% of 7-hydroxyl-staurosporine, 7- Combinations of O-alkyl-staurosporine, beta-methoxystaurosporine, alkylphosphocholine or hexadecylphosphorylcholine;
(2)1-40％的埃坡霉素、埃坡霉素A、埃坡霉素B、埃坡霉素C、埃坡霉素D、异埃坡霉素D、埃坡霉素E、埃坡霉素F、ixabepilone(BMS-247550)、氮杂埃坡霉素B、呋喃埃坡霉素D、BMS-310705与1-40％的O4-苄基叶酸、2，4，5-三氨基-6-苄氧基嘧啶、2，4-二氨基-6-苄氧基-5-亚硝基嘧啶、2，4-二氨基-6-苄氧基-5-溴基嘧啶、2-氨基-4-苄氧基-5-硝基嘧啶、2-氨基-4-苄氧基-6-甲基-5-硝基嘧啶、2，4-二氨基-6-苄氧基-s-三嗪或2-氨基-O4-苄基喋啶的组合；或(2) 1-40% epothilone, epothilone A, epothilone B, epothilone C, epothilone D, isopothilone D, epothilone E, Epothilone F, ixabepilone (BMS-247550), azaepothilone B, furan epothilone D, BMS-310705 with 1-40% O4-benzyl folic acid, 2,4,5-tris Amino-6-benzyloxypyrimidine, 2,4-diamino-6-benzyloxy-5-nitrosopyrimidine, 2,4-diamino-6-benzyloxy-5-bromopyrimidine, 2- Amino-4-benzyloxy-5-nitropyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitropyrimidine, 2,4-diamino-6-benzyloxy-s- A combination of triazine or 2-amino-O4-benzylpteridine; or
(3)1-40％的1-40％的埃坡霉素、埃坡霉素A、埃坡霉素B、埃坡霉素C、埃坡霉素D、异埃坡霉素D、埃坡霉素E、埃坡霉素F、ixabepilone(BMS-247550)、氮杂埃坡霉素B、呋喃埃坡霉素D、BMS-310705与1-40％的咪唑并哌嗪、咪唑并吡啶、渥曼青霉素、苯并吡喃、6-芳香基-2-吗啡酚-4-基-吡喃-4-基、2-(4-吗琳基)-8-苯基色酮、7-乙基-10-羟基喜树碱、3-氰基-6-亚肼基甲基-5-(4-吡啶基)吡啶-[1H]-2-1、苯基丁酸、甲氧胺、羟基胺、肌醇聚磷酸盐、十四(烷)基磷酸胆碱、六葵基磷酸(N-N-N-三甲基)己醇胺、十八基磷酸胆碱、十八基[2-(N-甲基哌啶)乙基]-磷酸盐、氨基三唑或丁基硫堇硫肟的组合；或(3) 1-40% of 1-40% epothilone, epothilone A, epothilone B, epothilone C, epothilone D, isopothilone D, epothilone Pothilone E, Epothilone F, ixabepilone (BMS-247550), Azaepothilone B, Furanepothilone D, BMS-310705 and 1-40% imidazopiperazine, imidazopyridine , wortmannin, benzopyran, 6-aryl-2-morpholin-4-yl-pyran-4-yl, 2-(4-morpholinyl)-8-phenylchromone, 7-ethyl Base-10-hydroxycamptothecin, 3-cyano-6-hydrazonomethyl-5-(4-pyridyl)pyridine-[1H]-2-1, phenylbutyric acid, methoxyamine, hydroxyl Amine, Inositol Polyphosphate, Tetradecyl Phosphocholine, Hexacyl Phosphate (N-N-N-Trimethyl) Hexanolamine, Octadecyl Phosphocholine, Octadecyl[2-(N-Methyl) a combination of (piperidinyl)ethyl]-phosphate, aminotriazole or butylthionine; or
(4)1-40％的埃坡霉素、埃坡霉素A、埃坡霉素B、埃坡霉素C、埃坡霉素D、异埃坡霉素D、埃坡霉素E、埃坡霉素F、BMS-247550、氮杂埃坡霉素B、呋喃埃坡霉素D或BMS-310705。(4) 1-40% epothilone, epothilone A, epothilone B, epothilone C, epothilone D, isopothilone D, epothilone E, Epothilone F, BMS-247550, Azaepothilone B, Furanepothilone D, or BMS-310705.
本发明缓释植入剂中缓释辅料及其重量百分比最优选如下：In the sustained-release implant of the present invention, the most preferred slow-release auxiliary materials and their weight percentages are as follows:
(1)55-90％的PLA；(1) 55-90% PLA;
(2)50-90％的PLGA；(2) 50-90% PLGA;
(3)50-85％的聚苯丙生；(3) 50-85% polyphenylene;
(4)55-90％的双脂肪酸与癸二酸共聚物；(4) 55-90% difatty acid and sebacic acid copolymer;
(5)25-60％的聚苯丙生与25-60％的PLA或25-60％的PLGA的组合；(5) Combination of 25-60% polyphenylene and 25-60% PLA or 25-60% PLGA;
(6)40-95％的木糖醇、低聚糖、软骨素、甲壳素、壳聚糖、透明质酸、胶原蛋白、明胶、泊洛沙姆或白蛋白胶；或(6) 40-95% xylitol, oligosaccharides, chondroitin, chitin, chitosan, hyaluronic acid, collagen, gelatin, poloxamer, or albumin glue; or
(7)40-95％的外消旋聚乳酸、外消旋聚乳酸/乙醇酸共聚物、单甲基聚乙二醇/聚乳酸、单甲基聚乙二醇/聚乳酸共聚物、聚乙二醇/聚乳酸、聚乙二醇/聚乳酸共聚物、端羧基聚乳酸或端羧基聚乳酸/乙醇酸共聚物。(7) 40-95% racemic polylactic acid, racemic polylactic acid/glycolic acid copolymer, monomethyl polyethylene glycol/polylactic acid, monomethyl polyethylene glycol/polylactic acid copolymer, poly Ethylene glycol/polylactic acid, polyethylene glycol/polylactic acid copolymer, carboxy-terminated polylactic acid, or carboxy-terminated polylactic acid/glycolic acid copolymer.
以上组合中，各种辅料的总量不超过制剂重的98％。In the above combinations, the total amount of various auxiliary materials does not exceed 98% of the weight of the preparation.
给药途径取决于多种因素，为于原发或转移肿瘤所在部位获得有效浓度，药物可经多种途径给予，如皮下、腔内(如腹腔、胸腔及椎管内)、瘤内、瘤周注射或放置、选择性动脉注射、淋巴结内及骨髓内注射。以选择性动脉注射、腔内、瘤内、瘤周注射或放置为优选。The route of administration depends on many factors. In order to obtain an effective concentration at the site of the primary or metastatic tumor, the drug can be administered through various routes, such as subcutaneous, intracavitary (such as abdominal cavity, thoracic cavity and spinal canal), intratumoral, tumor Weekly injection or placement, selective arterial injection, intralymph node and intramedullary injection. Selective arterial injection, intracavitary, intratumoral, peritumoral injection or placement is preferred.
本发明可以用于制备治疗人及动物的各种肿瘤的药物制剂，主要为缓释注射剂或缓释植入剂，所指肿瘤包括起源于大脑、中枢神经系统、肾脏、肝、胆囊、头颈部、口腔、甲状腺、皮肤、黏膜、腺体、血管、骨组织、淋巴结、肺脏、食管、胃、乳腺、胰腺、眼睛、鼻咽部、子宫、卵巢、子宫内膜、子宫颈、前列腺、膀胱、结肠、直肠的原发或转移的癌或肉瘤或癌肉瘤。The present invention can be used to prepare pharmaceutical preparations for treating various tumors in humans and animals, mainly slow-release injections or slow-release implants. Mouth, mouth, thyroid, skin, mucous membrane, gland, blood vessel, bone tissue, lymph node, lung, esophagus, stomach, breast, pancreas, eye, nasopharynx, uterus, ovary, endometrium, cervix, prostate, bladder , primary or metastatic carcinoma or sarcoma or carcinosarcoma of the colon or rectum.
临床应用的抗癌剂量取决于病人的具体情况，可从0.1到3000mg/kg体重，0.5到2000mg/kg为优选，0.8到1000mg/kg为最有选。The anticancer dosage for clinical application depends on the specific conditions of the patient, and can range from 0.1 to 3000 mg/kg body weight, preferably 0.5 to 2000 mg/kg, and most preferably 0.8 to 1000 mg/kg.
本发明所制的缓释注射剂或缓释植入剂中还可加入其它药用成分，如，但不限于，抗菌素、止疼药、抗凝药、止血药等。The sustained-release injection or sustained-release implant prepared by the present invention can also add other medicinal ingredients, such as, but not limited to, antibiotics, painkillers, anticoagulants, hemostatic drugs and the like.
通过如下试验和实施例对本发明的技术方法作进一步的描述：Technical method of the present invention is described further by following test and embodiment:
试验1、不同方式应用埃坡霉素后的局部药物浓度比较Experiment 1. Comparison of local drug concentration after different methods of application of epothilone
以大白鼠为试验对象，将2×105个前列腺肿瘤细胞皮下注射于其季肋部，待肿瘤生长至1厘米直径后将其分组。每组均为2.5mg/kg埃坡霉素B。测定不同时间肿瘤内药物含量(％)，结果表明，埃坡霉素B经不同方式应用后的局部药物浓度差异显著，局部给药能够明显提高并有效维持肿瘤所在部位的有效药物浓度，其中以瘤内放置缓释植入剂和瘤内注射缓释注射剂的效果最好。然而，瘤内注射缓释注射剂操作最方便、容易。这一发现构成本发明的重要特征。以下的相关抑瘤试验进一步证实了这一点。Rats were used as test subjects, and 2×105 prostate tumor cells were subcutaneously injected into their ribs, and the tumors were divided into groups after the tumors grew to 1 cm in diameter. Each group was 2.5mg/kg epothilone B. The drug content (%) in the tumor was measured at different times, and the results showed that the local drug concentration of epothilone B was significantly different after being applied in different ways, and local administration could obviously improve and effectively maintain the effective drug concentration at the tumor site. Intratumoral placement of slow-release implants and intratumoral injection of slow-release injections have the best results. However, intratumoral injection of sustained-release injections is the most convenient and easy to operate. This finding constitutes an important feature of the present invention. The following related tumor suppression experiments further confirmed this point.
试验2、不同方式应用埃坡霉素D后的体内抑瘤作用比较Experiment 2. Comparison of anti-tumor effects in vivo after application of epothilone D in different ways
以大白鼠为试验对象，将2×105个乳腺肿瘤细胞皮下注射于其季肋部，待肿瘤生长至0.5厘米直径后将其分组。每组剂量均为5mg/kg埃坡霉素D。治疗后第20天测量肿瘤体积大小，比较治疗效果。结果表明，埃坡霉素D经不同方式应用后的抑瘤作用差异显著，局部给药能够明显提高并有效维持肿瘤所在部位的有效药物浓度，其中以瘤内放置缓释植入剂和瘤内注射缓释注射剂的效果最好。然而，瘤内注射缓释注射剂操作最方便、容易。不仅疗效好，毒副作用也小。Rats were used as test subjects, and 2×105 mammary tumor cells were subcutaneously injected into their flanks, and they were divided into groups after the tumors grew to a diameter of 0.5 cm. The dose of each group was 5mg/kg epothilone D. On the 20th day after treatment, the tumor volume was measured, and the treatment effect was compared. The results showed that the tumor-inhibiting effect of epothilone D was significantly different after being applied in different ways, and local administration could significantly increase and effectively maintain the effective drug concentration at the tumor site. It works best when given as an extended-release injection. However, intratumoral injection of sustained-release injections is the most convenient and easy to operate. Not only the curative effect is good, but also the side effects are small.
试验3、含埃坡霉素和抗癌药物(缓释注射剂)的体内抑瘤作用Test 3, In vivo antitumor effect containing epothilone and anticancer drug (sustained release injection)
以大白鼠为试验对象，将2×105个胰腺肿瘤细胞皮下注射于其季肋部，待肿瘤生长14天后将其分为以下10组(见表1)。第一组为对照，第2到10组为治疗组，药物均经瘤内注射。埃坡霉素B为2.5mg/kg，抗癌药物为10mg/kg。治疗后第21天测量肿瘤体积大小，比较治疗效果(见表1)。Rats were used as test subjects, and 2×105 pancreatic tumor cells were subcutaneously injected into their flanks. After 14 days of tumor growth, they were divided into the following 10 groups (see Table 1). The first group was the control group, and the second to tenth groups were the treatment groups, and the drugs were all injected into the tumor. Epothilone B is 2.5mg/kg, and anticancer drugs are 10mg/kg. On the 21st day after treatment, the tumor volume was measured, and the treatment effects were compared (see Table 1).
表1Table 1
以上结果表明，埃坡霉素B及所用抗癌药物-磷酸肌醇3-激酶(PI3K)抑制剂(其中UCN-01：7-氢氧基-星状孢子素；UCN-02：7-O-烷基星状孢子素；MIL：Miltefosine；D-21266：十八基-(1，1-二甲基-4-哌啶)磷酸盐或perifosine)在该浓度单独应用时对多种肿瘤细胞生长均有明显的抑制作用，当联合应用时可表现出显著的增效作用。The above results show that epothilone B and the used anticancer drug-phosphoinositide 3-kinase (PI3K) inhibitor (wherein UCN-01: 7-hydroxyl-staurosporine; UCN-02: 7-O - Alkyl staurosporine; MIL: Miltefosine; D-21266: octadecyl-(1,1-dimethyl-4-piperidine) phosphate or perifosine) at this concentration alone on a variety of tumor cells Both have obvious inhibitory effect on growth, and can show significant synergistic effect when combined application.
试验4、埃坡霉素B和抗癌药物(缓释注射剂)的抑瘤作用Test 4, the antitumor effect of epothilone B and anticancer drug (sustained release injection)
所用的肿瘤细胞包括CNS-1、C6、胃腺上皮癌(SA)、骨肿瘤(BC)、乳腺癌(BA)、肺癌(LH)、甲状腺乳头状腺癌(PAT)等。药物经瘤内注射。治疗效果(见表2)。埃坡霉素B为7.5mg/kg，抗癌药物均为2.5mg/kg。治疗后第20天测量肿瘤体积大小，用肿瘤生长抑制率(％)作指标比较治疗效果(见表2)。The tumor cells used include CNS-1, C6, gastric glandular carcinoma (SA), bone tumor (BC), breast cancer (BA), lung cancer (LH), papillary thyroid carcinoma (PAT), etc. Drugs are injected into the tumor. Treatment effect (see Table 2). Epothilone B is 7.5mg/kg, anticancer drugs are 2.5mg/kg. On the 20th day after treatment, the tumor volume was measured, and the tumor growth inhibition rate (%) was used as an index to compare the therapeutic effect (see Table 2).
表2Table 2
以上结果表明，所用埃坡霉素D及抗癌药物(O4-BA：O4-苄基尿酸；UCN-01：7-氢氧基星状孢子素；UCN-02：7-O-烷基-星状孢子素)在该浓度单独应用时对多种肿瘤细胞生长均有明显的抑制作用，当联合应用时可表现出显著的增效作用。The above results show that the epothilone D and anticancer drugs used (O4-BA: O4-benzyluric acid; UCN-01: 7-hydroxystaurosporine; UCN-02: 7-O-alkyl- Staurosporine) has obvious inhibitory effect on the growth of various tumor cells when applied alone at this concentration, and can show a significant synergistic effect when applied in combination.
试验5、异埃坡霉素D及抗癌药物(缓释注射剂)的抑瘤作用Test 5, the antitumor effect of isopothilone D and anticancer drugs (sustained release injection)
以大白鼠为试验对象，将2×105个肝肿瘤细胞皮下注射于其季肋部，待肿瘤生长14天后将其分为以下10组(见表3)。第一组为对照，第2到10组为治疗组，缓释植入剂经瘤内放置。异埃坡霉素D为2.5mg/kg，抗癌药物为15mg/kg。治疗后第20天测量肿瘤体积大小，用肿瘤生长抑制率(％)作指标比较治疗效果治疗(见表3)。Rats were used as test subjects, and 2×105 hepatic tumor cells were subcutaneously injected into their flanks. After 14 days of tumor growth, they were divided into the following 10 groups (see Table 3). The first group is the control group, and the 2nd to 10th groups are the treatment groups, and the slow-release implants are placed in the tumor. Isopothilone D is 2.5mg/kg, and anticancer drugs are 15mg/kg. On the 20th day after the treatment, the tumor volume was measured, and the tumor growth inhibition rate (%) was used as an index to compare the therapeutic effects of the treatments (see Table 3).
表3table 3
以上结果表明，所用埃坡霉素(透明质酸酶)及抗癌药物-PI3K抑制剂(其中，AMG-PC：1-O-六癸基-2-O-甲基-rac-丙三基-3-磷酸胆碱；edelfosine：1-O-十八基-2-O-甲基-rac-丙三基-3-磷酸胆碱；ilmofosine：1-O-十八基-2-O-甲基-sn-丙三基-3-磷酸胆碱；IDOU：5-碘-2’-脱氧鸟苷)在该浓度单独应用时对多种肿瘤细胞生长均有明显的抑制作用，当联合应用时可表现出显著的增效作用。The above results show that the epothilone (hyaluronidase) used and the anticancer drug-PI3K inhibitor (among them, AMG-PC: 1-O-hexadecyl-2-O-methyl-rac-glyceryl -3-phosphocholine; edelfosine: 1-O-octadecyl-2-O-methyl-rac-glyceryl-3-phosphocholine; ilmofosine: 1-O-octadecyl-2-O- Methyl-sn-glyceryl-3-phosphocholine; IDOU: 5-iodo-2'-deoxyguanosine) has obvious inhibitory effect on the growth of various tumor cells when applied alone at this concentration. showed significant synergistic effect.
试验6、埃坡霉素D和抗癌药物(缓释注射剂)的抑瘤作用Test 6, the antitumor effect of epothilone D and anticancer drug (sustained release injection)
以大白鼠为试验对象，将2×105个前列腺肿瘤细胞皮下注射于其季肋部，待肿瘤生长14天后将其分为阴性对照(空白)、单药治疗组(埃坡霉素D或抗癌药物)和联合治疗组(埃坡霉素D和抗癌药物)。埃坡霉素D(2mg/kg)经瘤内注射，抗癌药物(18mg/kg)经腹腔注射。治疗后第20天测量肿瘤体积大小，用肿瘤生长抑制率作指标比较治疗效果(见表4)Rats were used as test subjects, and 2×105 prostate tumor cells were subcutaneously injected into their quarter ribs. After 14 days of tumor growth, they were divided into negative control (blank) group and monotherapy group (epothilone D or anticancer drugs) and combination therapy groups (epothilone D and anticancer drugs). Epothilone D (2mg/kg) was injected intratumorally, and anticancer drugs (18mg/kg) were injected intraperitoneally. On the 20th day after treatment, the tumor volume was measured, and the tumor growth inhibition rate was used as an index to compare the therapeutic effects (see Table 4)
表4Table 4
以上结果表明，所用埃坡霉素D及抗癌药物-DNA-依赖的蛋白激酶抑制剂(其中，咪唑并哌嗪、咪唑并吡啶、渥曼青霉素、苯并吡喃)在该浓度单独应用时对多种肿瘤细胞生长均有明显的抑制作用，当联合应用时可表现出显著的增效作用。The above results show that the epothilone D used and the anticancer drug-DNA-dependent protein kinase inhibitors (among them, imidazopiperazine, imidazopyridine, wortmannin, benzopyran) when used alone at this concentration It has obvious inhibitory effect on the growth of various tumor cells, and can show a significant synergistic effect when used in combination.
试验7、埃坡霉素B及抗癌药物(缓释注射剂)的抑瘤作用Experiment 7. Antitumor effect of epothilone B and anticancer drugs (sustained release injection)
以大白鼠为试验对象，将2×105个乳腺肿瘤细胞皮下注射于其季肋部，待肿瘤生长14天后将其分为阴性对照(空白)、单药治疗组、联合治疗组。埃坡霉素B(18mg/kg)经腹腔注射，抗癌药物(2mg/kg)经瘤周注射。治疗后第21天测量肿瘤体积大小，用肿瘤生长抑制率作指标比较治疗效果(见表5)。Rats were used as test subjects, and 2×105 mammary gland tumor cells were subcutaneously injected into their flanks. After 14 days of tumor growth, they were divided into negative control (blank), monotherapy group, and combination therapy group. Epothilone B (18mg/kg) was injected intraperitoneally, and anticancer drugs (2mg/kg) were injected around the tumor. On the 21st day after treatment, the tumor volume was measured, and the tumor growth inhibition rate was used as an index to compare the therapeutic effects (see Table 5).
表5table 5
以上结果表明，所用埃坡霉素B及抗癌药物-DNA-依赖的蛋白激酶抑制剂(其中，LY294002：2-(4-吗琳基)-8-苯基色酮；SU11752：激酶抑制剂；SN-38：7-乙基-10-羟基喜树碱；OK-1035：3-氰基-6-亚肼基甲基-5-(4-吡啶基)吡啶-[1H]-2-1)在该浓度单独应用时对多种肿瘤细胞生长均有明显的抑制作用，当联合应用时可表现出显著的增效作用。The above results show that the epothilone B used and the anticancer drug-DNA-dependent protein kinase inhibitor (among them, LY294002: 2-(4-morpholinyl)-8-phenylchromone; SU11752: kinase inhibitor; SN-38: 7-ethyl-10-hydroxycamptothecin; OK-1035: 3-cyano-6-hydrazonomethyl-5-(4-pyridyl)pyridine-[1H]-2-1 ) has obvious inhibitory effect on the growth of various tumor cells when applied alone at this concentration, and can show a significant synergistic effect when applied in combination.
试验8、埃坡霉素C和抗癌药物(缓释植入剂)的抑瘤作用Experiment 8, the tumor inhibitory effect of epothilone C and anticancer drugs (sustained-release implants)
以大白鼠为试验对象，将2×105个乳腺肿瘤细胞皮下注射于其季肋部，待肿瘤生长14天后将其分为阴性对照(空白)、单药治疗组、联合治疗组。缓释植入剂均经瘤内放置。埃坡霉素C(5mg/kg)经腹腔注射，抗癌药物(10mg/kg)经瘤周注射。治疗后第21天测量肿瘤体积大小，用肿瘤生长抑制率作指标比较治疗效果(见表6)。Rats were used as test subjects, and 2×105 mammary gland tumor cells were subcutaneously injected into their flanks. After 14 days of tumor growth, they were divided into negative control (blank), monotherapy group, and combination therapy group. Sustained-release implants were placed intratumorally. Epothilone C (5 mg/kg) was injected intraperitoneally, and anticancer drugs (10 mg/kg) were injected around the tumor. On the 21st day after treatment, the tumor volume was measured, and the tumor growth inhibition rate was used as an index to compare the therapeutic effects (see Table 6).
表6Table 6
以上结果表明，所用埃坡霉素C及抗癌药物-DNA-依赖的蛋白激酶抑制剂在该浓度单独应用时对多种肿瘤细胞生长均有明显的抑制作用，当联合应用时可表现出显著的增效作用。The above results show that the epothilone C and the anticancer drug-DNA-dependent protein kinase inhibitor used alone at this concentration have obvious inhibitory effects on the growth of various tumor cells, and can show significant inhibitory effects when used in combination. synergistic effect.
试验9、埃坡霉素和抗癌药物(缓释植入剂)的抑瘤作用Experiment 9. Tumor inhibitory effect of epothilones and anticancer drugs (sustained-release implants)
按试验8所述方法测定埃坡霉素及抗癌药物(缓释植入剂)的抑瘤作用，其肿瘤生长抑制率见表7。The tumor inhibitory effects of epothilone and anticancer drugs (sustained-release implants) were determined according to the method described in Test 8, and the tumor growth inhibition rates are shown in Table 7.
表7Table 7
以上结果表明，所用埃坡霉素及抗癌药物-聚(ADP-核糖)聚合酶抑制剂(其中，3-AB：3-氨基苯甲酰胺；苯甲酰胺；PD 128763：3，4-二氢甲氧异喹啉-1(2H)-苯甲酰胺；AG14361：聚合酶抑制剂)在该浓度单独应用时对多种肿瘤细胞生长均有明显的抑制作用，当联合应用时可表现出显著的增效作用。The above results show that the epothilone used and the anticancer drug-poly(ADP-ribose) polymerase inhibitor (wherein, 3-AB: 3-aminobenzamide; benzamide; PD 128763: 3,4-di Hydromethoxyisoquinoline-1(2H)-benzamide; AG14361: polymerase inhibitor) has obvious inhibitory effect on the growth of various tumor cells when applied alone at this concentration, and can show significant inhibitory effect when used in combination synergistic effect.
试验10、埃坡霉素E及抗癌药物(缓释注射剂)的抑瘤作用Experiment 10. Antitumor effect of epothilone E and anticancer drug (sustained release injection)
按试验8所述方法测定埃坡霉素及抗癌药物(缓释植入剂)的抑瘤作用，其肿瘤生长抑制率见表8。The tumor inhibitory effect of epothilones and anticancer drugs (sustained release implants) was measured according to the method described in Test 8, and the tumor growth inhibition rates are shown in Table 8.
表8Table 8
以上结果表明，所用埃坡霉素E及抗癌药物-聚(ADP-核糖)聚合酶抑制剂(其中，BZ1-6：苯并咪唑-4-羧酰胺；TI1-5：三环内酰胺硫化氢；TBC：三环苯并咪唑羧酰胺、苯并咪唑)在该浓度单独应用时对多种肿瘤细胞生长均有明显的抑制作用，当联合应用时可表现出显著的增效作用。The above results show that the epothilone E used and the anticancer drug-poly(ADP-ribose) polymerase inhibitor (wherein, BZ1-6: benzimidazole-4-carboxamide; TI1-5: tricyclic lactam vulcanization Hydrogen; TBC: tricyclic benzimidazole carboxamide, benzimidazole) has obvious inhibitory effect on the growth of various tumor cells when applied alone at this concentration, and can show a significant synergistic effect when used in combination.
试验11、氮杂埃坡霉素B和/或抗癌药物(缓释植入剂)的抑瘤作用Test 11. Antitumor effect of azaepothilone B and/or anticancer drugs (sustained release implants)
按试验8所述方法测定埃坡霉素和/或抗癌药物(缓释植入剂)的抑瘤作用，其肿瘤生长抑制率见表9。The tumor inhibitory effect of epothilones and/or anticancer drugs (sustained-release implants) was determined according to the method described in Test 8, and the tumor growth inhibition rates are shown in Table 9.
表9Table 9
以上结果表明，所用氮杂埃坡霉素B及抗癌药物-聚(ADP-核糖)聚合酶抑制剂(其中，PBC：2-苯基-1H-苯并咪唑-4-羧酰胺；MPBC：2-(3-甲氧苯基)-1H-苯并咪唑-4-羧酰胺(2-(3-methoxyphenyl)-1H-benzimidazole -4-carboxamide)；NU1025：8-羟基-2-甲基喹唑啉酮；NU1085：2-(4-羟苯基)苯并咪唑-4-羧酰胺)在该浓度单独应用时对多种肿瘤细胞生长均有明显的抑制作用，当联合应用时可表现出显著的增效作用。The above results show that the used azaepothilone B and anticancer drug-poly(ADP-ribose) polymerase inhibitor (wherein, PBC: 2-phenyl-1H-benzimidazole-4-carboxamide; MPBC: 2-(3-methoxyphenyl)-1H-benzimidazole-4-carboxamide (2-(3-methoxyphenyl)-1H-benzimidazole-4-carboxamide); NU1025: 8-hydroxy-2-methylquin Azolinone; NU1085: 2-(4-hydroxyphenyl)benzimidazole-4-carboxamide) has obvious inhibitory effect on the growth of various tumor cells when applied alone at this concentration, and can show Significant synergy.
试验12、Ixabepilone和/或抗癌药物(缓释植入剂)的抑瘤作用Test 12. Inhibitory effect of Ixabepilone and/or anticancer drug (sustained release implant)
按试验6所述方法测定Ixabepi lone和/或抗癌药物(缓释植入剂)的抑瘤作用，其肿瘤生长抑制率见表10。Measure the tumor inhibitory effect of Ixabepilone and/or anticancer drug (sustained-release implant) by the method described in test 6, and its tumor growth inhibition rate is shown in Table 10.
表10Table 10
以上结果表明，所用Ixabepilone及抗癌药物聚(ADP-核糖)聚合酶抑制剂(其中，BSO为丁基硫堇硫肟)在该浓度单独应用时对多种肿瘤细胞生长均有明显的抑制作用，当联合应用时可表现出显著的增效作用。The above results show that the used Ixabepilone and the anticancer drug poly(ADP-ribose) polymerase inhibitor (wherein, BSO is butylthionine thioxime) have obvious inhibitory effects on the growth of various tumor cells when this concentration is used alone , can show significant synergistic effect when combined application.
试验13、不同分子量聚乳酸制成的呋喃埃坡霉素D缓释植入剂的体内释放比较Test 13. In vivo release comparison of Epothilone D sustained-release implants made of polylactic acid with different molecular weights
以大白鼠为试验对象，分组(3只/组)并于皮下给予含不同分子量(MW)的聚乳酸(PLA)承载的等量呋喃埃坡霉素D缓释植入剂。然后分别于1、3、7、14、21、28和35天测药物于植入剂内的剩余量，进而得出其体内释放速度(％)。结果表明，分子量为20000的释放为：1天(12％)、3(26％)、7(56％)、14(80％)、21(86％)、28(92％)和35(94％)。比较不同分子量聚乳酸制成的缓释植入剂的体内释放发现，随分子量增加而变慢，以第7天为例，与全身给药组相比，肿瘤抑制率随聚乳酸分子量增加而提高，依次为68％(MW：5000)、62％(MW：15000)、54％(MW：25000)、52％(MW：40000)和46(MW：60000)。Rats were taken as test subjects, divided into groups (3 rats/group) and subcutaneously administered with equal amounts of epothilone furan D sustained-release implants loaded with polylactic acid (PLA) of different molecular weight (MW). Then the remaining amount of the drug in the implant was measured at 1, 3, 7, 14, 21, 28 and 35 days respectively, and then its in vivo release rate (%) was obtained. The results showed that the release with a molecular weight of 20000 was: 1 day (12%), 3 (26%), 7 (56%), 14 (80%), 21 (86%), 28 (92%) and 35 (94%) %). Comparing the in vivo release of sustained-release implants made of polylactic acid with different molecular weights, it was found that the release slowed down as the molecular weight increased. Taking the 7th day as an example, compared with the systemic administration group, the tumor inhibition rate increased with the increase of the molecular weight of polylactic acid , followed by 68% (MW: 5000), 62% (MW: 15000), 54% (MW: 25000), 52% (MW: 40000) and 46 (MW: 60000).
同样的结果还见于用聚乳酸为辅料制成的含BMS-310705和抗癌药的缓释剂。The same result was also seen in the sustained-release preparation containing BMS-310705 and anticancer drugs made of polylactic acid as an auxiliary material.
特别注意的是，本发明的缓释剂，特别是缓释注射剂操作简单方便、重复性好。不仅疗效好，毒副作用小。It is particularly noted that the sustained-release preparation of the present invention, especially the sustained-release injection, is simple and convenient to operate and has good repeatability. It not only has good curative effect, but also has little toxic and side effects.
不同的药物包装与不同的生物降解高分子的释药特性不同。进一步的研究发现，最适宜于本发明药物缓释的缓释辅料为外消旋聚乳酸、外消旋聚乳酸/乙醇酸共聚物、单甲基聚乙二醇/聚乳酸、单甲基聚乙二醇/聚乳酸共聚物、聚乙二醇/聚乳酸、聚乙二醇/聚乳酸共聚物、端羧基聚乳酸、端羧基聚乳酸/乙醇酸共聚物、聚苯丙生、双脂肪酸与癸二酸共聚物、聚(芥酸二聚体-癸二酸)、聚(富马酸-癸二酸)、乙烯乙酸乙烯酯共聚物、聚乳酸、聚乙醇酸和羟基乙酸的共聚物、木糖醇、低聚糖、软骨素、甲壳素、壳聚糖、透明质酸、胶原蛋白、明胶、泊洛沙姆、白蛋白胶之一或其组合；最适宜的助悬剂为甲基纤维素、羟甲基纤维素、羧甲基纤维素钠、(碘)甘油、二甲硅油、丙二醇、卡波姆、甘露醇、山梨醇、表面活性物质、土温20、土温40、土温80之一或其组合。Different drug packages and different biodegradable polymers have different drug release characteristics. Further studies have found that the sustained-release excipients most suitable for the sustained release of the drug of the present invention are racemic polylactic acid, racemic polylactic acid/glycolic acid copolymer, monomethyl polyethylene glycol/polylactic acid, monomethyl polylactic acid Ethylene glycol/polylactic acid copolymer, polyethylene glycol/polylactic acid, polyethylene glycol/polylactic acid copolymer, carboxyl-terminated polylactic acid, carboxyl-terminated polylactic acid/glycolic acid copolymer, polyphenylene, difatty acid and Sebacic acid copolymer, poly(erucic acid dimer-sebacic acid), poly(fumaric acid-sebacic acid), ethylene vinyl acetate copolymer, polylactic acid, polyglycolic acid and glycolic acid copolymer, One or a combination of xylitol, oligosaccharides, chondroitin, chitin, chitosan, hyaluronic acid, collagen, gelatin, poloxamer, albumin glue; the most suitable suspending agent is methyl Cellulose, hydroxymethyl cellulose, sodium carboxymethyl cellulose, (iodo)glycerin, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, TW 20, TW 40, TW One or a combination of temperature 80.
总之，所用埃坡霉素衍生物及各种抗癌药物单独应用时对多种肿瘤细胞生长均有明显的抑制作用，当联合应用时可表现出显著的增效作用。因此，本发明所述的有效成分为埃坡霉素衍生物与任意一种(或一种以上)抗癌药物的组合。含有以上有效成分的药物可制成缓释微球，进而制成缓释注射剂和植入剂，其中以与含助悬剂的特殊溶媒组合形成的混悬注射剂为优选。In a word, the epothilone derivatives and various anticancer drugs used alone have obvious inhibitory effects on the growth of various tumor cells, and can show significant synergistic effects when used in combination. Therefore, the active ingredient of the present invention is a combination of epothilone derivatives and any (or more than one) anticancer drugs. Drugs containing the above active ingredients can be made into sustained-release microspheres, and then made into sustained-release injections and implants, among which suspension injections formed by combining with a special vehicle containing a suspending agent are preferred.
缓释注射剂或缓释植入剂还可通过以下实施方式得以进一步说明。上述实施例及以下实施例只是对本发明作进一步说明，并非对其内容和使用作任何限制。The sustained-release injection or sustained-release implant can also be further illustrated by the following embodiments. The above-mentioned embodiment and the following embodiment are only to further illustrate the present invention, but not to limit its content and use in any way.
(四)具体实施方式(4) Specific implementation methods
实施例1.Example 1.
将80mg聚苯丙生(对羧苯基丙烷(p-CPP)∶葵二酸(SA)为20∶80)共聚物放入容器中，加100毫升二氯甲烷，溶解混匀后，加入10mg埃坡霉素B和10mg7-氢氧基-星状孢子素，重新摇匀后用喷雾干燥法制备含10％埃坡霉素B和10％7-氢氧基-星状孢子素的注射用微球。然后将微球悬浮于含15％甘露醇的生理盐水中，制得相应的混悬型缓释注射剂。注射剂的黏度为200cp-400cp(20℃-30℃时)，该缓释注射剂在体外生理盐水中的释药时间为18-25天，在小鼠皮下的释药时间为20-30天左右。Put 80mg of polyphenylpropane (p-CPP: 20:80 of sebacic acid (SA)) copolymer into a container, add 100ml of dichloromethane, dissolve and mix well, then add 10mg Epothilone B and 10mg 7-hydroxyl-staurosporine, re-shake and spray-dry to prepare injection containing 10% epothilone B and 10% 7-hydroxyl-staurosporine Microspheres. Then suspend the microspheres in physiological saline containing 15% mannitol to prepare the corresponding suspension-type sustained-release injection. The viscosity of the injection is 200cp-400cp (at 20°C-30°C), the release time of the slow-release injection in physiological saline in vitro is 18-25 days, and the release time of the subcutaneous mouse is about 20-30 days.
实施例2.Example 2.
加工成缓释注射剂的方法步骤与实施例1相同，但所不同的是聚苯丙生为50∶50，所含抗癌有效成分及其重量百分比为：5％的埃坡霉素、埃坡霉素A、埃坡霉素B、埃坡霉素C、埃坡霉素D、异埃坡霉素D、埃坡霉素E、埃坡霉素F、ixabepilone(BMS-247550)、氮杂埃坡霉素B、呋喃埃坡霉素D或BMS-310705与15％的7-氢氧基-星状孢子素、7-O-烷基-星状孢子素、β-甲氧星状孢子素、烷基磷酸胆碱或六癸基磷酸胆碱的组合，The method step of being processed into sustained-release injection is the same as that of Example 1, but the difference is that polyphenylene is 50:50, and the contained anticancer active ingredient and weight percentage thereof are: 5% epothilone, epothilone Epothilone A, Epothilone B, Epothilone C, Epothilone D, Isopothilone D, Epothilone E, Epothilone F, ixabepilone (BMS-247550), aza Epothilone B, furan epothilone D or BMS-310705 with 15% of 7-hydroxy-staurosporine, 7-O-alkyl-staurosporine, β-methoxystaurosporine Combinations of ketones, alkylphosphocholines, or hexadecylphosphorylcholines,
注射剂的黏度为200cp-400cp(20℃-30℃时)。The viscosity of the injection is 200cp-400cp (at 20°C-30°C).
实施例3.Example 3.
将70mg分子量峰值为10000-20000的聚乳酸(PLA)放入容器中，加100毫升二氯甲烷，溶解混匀后，加入20mg埃坡霉素D和10mg7-乙基-10-羟基喜树碱，重新摇匀后真空干燥去除有机溶剂。将干燥后的含药固体组合物冷冻粉碎制成含20％埃坡霉素D和10％7-乙基-10-羟基喜树碱的微粉，然后悬浮于含1.5％羧甲基纤维素钠的生理盐水中，制得相应的混悬型缓释注射剂。注射剂的黏度为240cp-420ep(20℃-30℃时)，该缓释注射剂在体外生理盐水中的释药时间为20-35天，在小鼠皮下的释药时间为35-50天左右。Put 70 mg of polylactic acid (PLA) with a peak molecular weight of 10,000-20,000 into a container, add 100 ml of dichloromethane, dissolve and mix well, then add 20 mg of epothilone D and 10 mg of 7-ethyl-10-hydroxycamptothecin , shake again and dry in vacuo to remove the organic solvent. Freezing and pulverizing the dried drug-containing solid composition to make micropowder containing 20% epothilone D and 10% 7-ethyl-10-hydroxycamptothecin, and then suspending in 1.5% sodium carboxymethylcellulose The corresponding suspension-type sustained-release injection was prepared in normal saline. The viscosity of the injection is 240cp-420ep (at 20°C-30°C), and the release time of the slow-release injection in physiological saline in vitro is 20-35 days, and the release time of the subcutaneous mouse is about 35-50 days.
实施例4Example 4
加工成缓释注射剂的方法步骤与实施例3相同，但所不同的是分子量峰值为40000-60000的聚乳酸(PLA)，所含抗癌有效成分及其重量百分比为：The method steps of being processed into sustained-release injections are the same as in Example 3, but the difference is that the peak molecular weight is polylactic acid (PLA) of 40000-60000, and the contained anticancer active ingredients and their weight percentages are:
15％的埃坡霉素、埃坡霉素A、埃坡霉素B、埃坡霉素C、埃坡霉素D、异埃坡霉素D、埃坡霉素E、埃坡霉素F、ixabepilone(BMS-247550)、氮杂埃坡霉素B、呋喃埃坡霉素D或BMS-310705与20％的咪唑并哌嗪、咪唑并吡啶、渥曼青霉素、苯并吡喃、6-芳香基-2-吗啡酚-4-基-吡喃-4-基、2-(4-吗琳基)-8-苯基色酮、7-乙基-10-羟基喜树碱、3-氰基-6-亚肼基甲基-5-(4-吡啶基)吡啶-[1H]-2-1、苯基丁酸、甲氧胺、羟基胺、肌醇聚磷酸盐、十四(烷)基磷酸胆碱、六葵基磷酸(N-N-N-三甲基)己醇胺、十八基磷酸胆碱、十八基-[2-(N-甲基哌啶)乙基]-磷酸盐、氨基三唑或丁基硫堇硫肟的组合。15% epothilone, epothilone A, epothilone B, epothilone C, epothilone D, isopothilone D, epothilone E, epothilone F , ixabepilone (BMS-247550), azaepothilone B, furan epothilone D or BMS-310705 with 20% imidazopiperazine, imidazopyridine, wortmannin, benzopyran, 6- Aryl-2-morpholin-4-yl-pyran-4-yl, 2-(4-morpholinyl)-8-phenylchromone, 7-ethyl-10-hydroxycamptothecin, 3-cyano Base-6-hydrazonomethyl-5-(4-pyridyl)pyridine-[1H]-2-1, phenylbutyric acid, methoxyamine, hydroxylamine, inositol polyphosphate, tetradecane ) base phosphorylcholine, hexacyl phosphoric acid (N-N-N-trimethyl) ethanolamine, octadecyl phosphorylcholine, octadecyl-[2-(N-methylpiperidine) ethyl]-phosphate, Combinations of aminotriazoles or butylthionine.
实施例5.Example 5.
将70mg分子量峰值为10000-20000的聚乳酸(PLGA，50∶50)放入容器中，加入100毫升二氯甲烷溶解混匀后，加入20毫克异埃坡霉素D和10毫克苯并咪唑，重新摇匀后用喷雾干燥法制备含20％异埃坡霉素D和10％苯并咪唑的注射用微球。然后将微球悬浮于含5-15％山梨醇的注射液中，制得相应的混悬型缓释注射剂。注射剂的黏度为260cp-480cp(20℃-30℃时)，该缓释注射剂在体外生理盐水中的释药时间为10-15天，在小鼠皮下的释药时间为20-30天左右。Put 70 mg of polylactic acid (PLGA, 50:50) with a peak molecular weight of 10,000-20,000 into a container, add 100 ml of dichloromethane to dissolve and mix well, then add 20 mg of isopothilone D and 10 mg of benzimidazole, Microspheres for injection containing 20% iso-epothilone D and 10% benzimidazole were prepared by spray-drying method after re-shaking. Then suspend the microspheres in the injection solution containing 5-15% sorbitol to prepare the corresponding suspension sustained-release injection. The viscosity of the injection is 260cp-480cp (at 20°C-30°C), and the release time of the slow-release injection in physiological saline in vitro is 10-15 days, and the release time in mice subcutaneously is about 20-30 days.
实施例6.Example 6.
加工成缓释注射剂的方法步骤与实施例5相同，但所不同的是所含抗癌有效成分为：10％的埃坡霉素、埃坡霉素A、埃坡霉素B、埃坡霉素C、埃坡霉素D、异埃坡霉素D、埃坡霉素E、埃坡霉素F、ixabepilone、氮杂埃坡霉素B、呋喃埃坡霉素D或BMS-310705与10％的O4-苄基叶酸、2，4，5-三氨基-6-苄氧基嘧啶、2，4-二氨基-6-苄氧基-5-亚硝基嘧啶、2，4-二氨基-6-苄氧基-5-溴基嘧啶、2-氨基-4-苄氧基-5-硝基嘧啶、2-氨基-4-苄氧基-6-甲基-5-硝基嘧啶、2，4-二氨基-6-苄氧基-s-三嗪或2-氨基-O4-苄基喋啶的组合。The method steps of being processed into sustained-release injections are the same as in Example 5, but the difference is that the contained anticancer active ingredients are: 10% epothilone, epothilone A, epothilone B, epothilone Epothilone C, epothilone D, isopothilone D, epothilone E, epothilone F, ixabepilone, azaepothilone B, furan epothilone D or BMS-310705 with 10 %O4-Benzylfolate, 2,4,5-triamino-6-benzyloxypyrimidine, 2,4-diamino-6-benzyloxy-5-nitrosopyrimidine, 2,4-diamino -6-benzyloxy-5-bromopyrimidine, 2-amino-4-benzyloxy-5-nitropyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitropyrimidine, Combinations of 2,4-diamino-6-benzyloxy-s-triazine or 2-amino-O4-benzylpteridine.
实施例7.Example 7.
将70mg分子量峰值为20000-40000的聚乳酸(PLGA，50∶50)放入容器中，加100毫升二氯甲烷，溶解混匀后，加入20mg BMS-247550和10mg丁基硫堇硫肟，重新摇匀后用喷雾干燥法制备含20％BMS-247550与10％丁基硫堇硫肟的注射用微球。然后将微球悬浮于含1.5％羧甲基纤维素钠和0.5％吐温80的生理盐水中，制得相应的混悬型缓释注射剂。注射剂的黏度为300cp-480cp(20℃-30℃时)，该缓释注射剂在体外生理盐水中的释药时间为18-25天，在小鼠皮下的释药时间为25-35天左右。Put 70 mg of polylactic acid (PLGA, 50:50) with a peak molecular weight of 20,000-40,000 into a container, add 100 ml of dichloromethane, dissolve and mix well, add 20 mg of BMS-247550 and 10 mg of butylthionine thioxime, and re- After shaking well, microspheres for injection containing 20% BMS-247550 and 10% butylthionine thioxime were prepared by spray-drying method. Then suspend the microspheres in physiological saline containing 1.5% sodium carboxymethylcellulose and 0.5% Tween 80 to prepare the corresponding suspension-type sustained-release injection. The viscosity of the injection is 300cp-480cp (at 20°C-30°C), and the release time of the slow-release injection in physiological saline in vitro is 18-25 days, and the release time in mice subcutaneously is about 25-35 days.
实施例8.Example 8.
加工成缓释注射剂的方法步骤与实施例7相同，但所不同的是分子量峰值为40000-60000的聚乳酸(PLGA，75∶25)所不同的是所含抗癌有效成分为：10％的埃坡霉素、埃坡霉素A、埃坡霉素B、埃坡霉素C、埃坡霉素D、异埃坡霉素D、埃坡霉素E、埃坡霉素F、ixabepilone、氮杂埃坡霉素B、呋喃埃坡霉素D或BMS-310705与15％的O4-苄基叶酸的组合。The method steps of being processed into sustained-release injections are the same as in Example 7, but the difference is that the polylactic acid (PLGA, 75:25) with a peak molecular weight of 40,000-60,000 is different in that the anticancer active ingredient contained is: 10% Epothilone, Epothilone A, Epothilone B, Epothilone C, Epothilone D, Isopothilone D, Epothilone E, Epothilone F, ixapothilone, Azaepothilone B, Furanepothilone D or BMS-310705 in combination with 15% O4-benzylfolate.
实施例9Example 9
将40mg聚苯丙生(对羧苯基丙烷(p-CPP)∶葵二酸(SA)为50∶50)共聚物和30mg分子量峰值为10000-20000的聚乳酸(PLA)放入容器中，加100毫升二氯甲烷，溶解混匀后，加入20mg氮杂埃坡霉素B和10mgO4-苄基叶酸，重新摇匀后用喷雾干燥法制备含20％氮杂埃坡霉素B和10％O4-苄基叶酸的注射用微球。然后将微球悬浮于含1.5％羧甲基纤维素钠和15％山梨醇和0.2％吐温80的生理盐水中，制得相应的混悬型缓释注射剂。该缓释注射剂在体外生理盐水中的释药时间为24-35天，在小鼠皮下的释药时间为28-40天左右。Put 40mg of polyphenylpropane (p-carboxyphenylpropane (p-CPP): 50:50 of sebacic acid (SA)) copolymer and 30mg of polylactic acid (PLA) with a peak molecular weight of 10000-20000 into the container, Add 100 ml of dichloromethane, dissolve and mix well, add 20 mg of azaepothilone B and 10 mg of O4-benzyl folic acid, re-shake and use the spray drying method to prepare 20% azaepothilone B and 10% Injectable microspheres of O4-benzylfolate. Then the microspheres were suspended in physiological saline containing 1.5% sodium carboxymethylcellulose, 15% sorbitol and 0.2% Tween 80 to prepare the corresponding suspension-type sustained-release injection. The drug release time of the slow-release injection in physiological saline in vitro is 24-35 days, and the drug release time in mice subcutaneous is about 28-40 days.
实施例10Example 10
加工成缓释注射剂的方法步骤与实施例9相同，但所不同的是所用缓释辅料为40mg聚苯丙生(50∶50)共聚物和30mg分子量峰值为20000-40000的PLGA(50∶50)，所含抗癌有效成分为：10-30％的埃坡霉素B、埃坡霉素C、埃坡霉素D、异埃坡霉素D、埃坡霉素E、埃坡霉素F、ixabepilone、氮杂埃坡霉素B、呋喃埃坡霉素D或BMS-310705与10-40％的O4-苄基叶酸、2，4，5三氨基-6-苄氧基嘧啶、2，4-二氨基-6-苄氧基-5-亚硝基嘧啶、2，4-二氨基-6-苄氧基-5-溴基嘧啶、2-氨基-4-苄氧基-5-硝基嘧啶、2-氨基-4-苄氧基-6-甲基-5-硝基嘧啶、2，4-二氨基-6-苄氧基-s-三嗪或2-氨基-O4-苄基喋啶的组合。The method step that is processed into sustained-release injection is identical with embodiment 9, but difference is that used sustained-release adjuvant is 40mg polyphenylene propane (50: 50) copolymer and 30mg molecular weight peak value is 20000-40000 PLGA (50: 50 ), the anti-cancer active ingredients contained are: 10-30% epothilone B, epothilone C, epothilone D, isopothilone D, epothilone E, epothilone F, ixabepilone, azaepothilone B, furan epothilone D or BMS-310705 with 10-40% O4-benzyl folic acid, 2,4,5 triamino-6-benzyloxypyrimidine, 2 , 4-diamino-6-benzyloxy-5-nitrosopyrimidine, 2,4-diamino-6-benzyloxy-5-bromopyrimidine, 2-amino-4-benzyloxy-5- Nitropyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitropyrimidine, 2,4-diamino-6-benzyloxy-s-triazine or 2-amino-O4-benzyl Combinations of pteridines.
实施例11Example 11
将70mg聚苯丙生(对羧苯基丙烷(p-CPP)∶葵二酸(SA)为30∶70)共聚物放入容器中，加100毫升二氯甲烷，溶解混匀后，加入10mg7-氢氧基-星状孢子素和20mg呋喃埃坡霉素D，重新摇匀后用喷雾干燥法制备含10％7-氢氧基-星状孢子素和20％呋喃埃坡霉素D的注射用微球。然后将微球经压片法制得相应的缓释植入剂。该缓释植入剂在体外生理盐水中的释药时间为21-25天，在小鼠皮下的释药时间为30-40天左右。Put 70mg of polyphenylpropane (p-CPP: 30:70 of sebacic acid (SA)) copolymer into a container, add 100ml of dichloromethane, dissolve and mix well, then add 10mg7 -Hydroxy-staurosporine and 20mg epothilone furan D, re-shake and prepare 10% 7-hydroxyl-staurosporine and 20% epothilone furan D by spray drying Microspheres for injection. Then the microspheres are pressed into tablets to prepare the corresponding slow-release implants. The release time of the sustained-release implant in physiological saline in vitro is 21-25 days, and the drug release time in mice subcutaneous is about 30-40 days.
实施例12Example 12
加工成缓释植入剂的方法步骤与实施例11相同，但所不同的是所含抗癌有效成分为：20％的BMS-310705与10％的7-氢氧基-星状孢子素、7-O-烷基-星状孢子素、β-甲氧星状孢子素、烷基磷酸胆碱或六癸基磷酸胆碱的组合。The method steps of processing into sustained-release implants are the same as in Example 11, but the difference is that the anticancer active ingredients contained are: 20% of BMS-310705 and 10% of 7-hydroxyl-staurosporine, Combinations of 7-O-alkyl-staurosporine, beta-methoxystaurosporine, alkylphosphocholine or hexadecylphosphorylcholine.
实施例13Example 13
将70mg分子量峰值为60000-80000的PLGA(50∶50)放入容器中，加100毫升二氯甲烷，溶解混匀后，加入10mg BMS-310705和20mg新鬼臼霉素，重新摇匀后用喷雾干燥法制备含10％BMS-310705和20％新鬼臼霉素的注射用微球。然后将微球经压片法制得相应的缓释植入剂。该缓释植入剂在体外生理盐水中的释药时间为25-30天，在小鼠皮下的释药时间为35-50天左右。Put 70 mg of PLGA (50:50) with a peak molecular weight of 60,000-80,000 into a container, add 100 ml of dichloromethane, dissolve and mix well, add 10 mg of BMS-310705 and 20 mg of neopodophyllotoxin, re-shake and use Microspheres for injection containing 10% BMS-310705 and 20% neopodophyllotoxin were prepared by spray-drying method. Then the microspheres are pressed into tablets to prepare the corresponding slow-release implants. The drug release time of the sustained release implant in physiological saline in vitro is 25-30 days, and the drug release time in mice subcutaneous is about 35-50 days.
实施例14Example 14
加工成缓释植入剂的方法步骤与实施例11、13相同，但所不同的是分子量峰值为40000的PLGA(70∶25)，所含抗癌有效成分为：The method steps of being processed into slow-release implants are the same as in Examples 11 and 13, but the difference is that the peak molecular weight is PLGA (70:25) of 40,000, and the contained anticancer active ingredients are:
10％的BMS-310705与20％的氨基三唑、丁基硫堇硫肟、马勃菌酸、S-己基谷胱甘肽、新鬼臼霉素、六环核喜树碱或四并苯羧酰胺的组合。10% of BMS-310705 with 20% of aminotriazole, butylthionine, puffulanic acid, S-hexylglutathione, neopodophyllotoxin, hexacyclic nucleocamptothecin or tetracene combination of carboxamides.
实施例15Example 15
加工成缓释剂的方法步骤与实施例1-14相同，但所不同的是所用的缓释辅料为下列之一或其组合：The method step of being processed into slow-release preparation is identical with embodiment 1-14, but difference is that the slow-release auxiliary material used is one of following or its combination:
a)分子量峰值为5000-10000、10000-30000、30000-60000、60000-100000或100000-150000的聚乳酸(PLA)；a) Polylactic acid (PLA) with a peak molecular weight of 5,000-10,000, 10,000-30,000, 30,000-60,000, 60,000-100,000 or 100,000-150,000;
b)分子量峰值为5000-10000、10000-30000、30000-60000、60000-100000或100000-150000的聚乙醇酸和羟基乙酸的共聚物(PLGA)，其中，聚乙醇酸和羟基乙酸的比例为50-95∶50-50；b) A copolymer of polyglycolic acid and glycolic acid (PLGA) with a peak molecular weight of 5,000-10,000, 10,000-30,000, 30,000-60,000, 60,000-100,000 or 100,000-150,000, wherein the ratio of polyglycolic acid to glycolic acid is 50 -95: 50-50;
c)乙烯乙酸乙烯酯共聚物(EVAc)；c) ethylene vinyl acetate copolymer (EVAc);
d)10∶90、20∶80、30∶70、40∶60、50∶50或60∶40的对羧苯基丙烷(p-CPP)∶葵二酸(SA)共聚物(聚苯丙生)；d) 10:90, 20:80, 30:70, 40:60, 50:50, or 60:40 p-carboxyphenylpropane (p-CPP):sebacic acid (SA) copolymer (polyphenylpropane );
e)双脂肪酸与癸二酸共聚物；e) difatty acid and sebacic acid copolymer;
f)聚(芥酸二聚体癸二酸)共聚物；f) poly(erucic acid dimer sebacic acid) copolymer;
g)聚(富马酸癸二酸)共聚物；g) poly(fumarate sebacic acid) copolymer;
h)木糖醇、低聚糖、软骨素、甲壳素、壳聚糖、钾盐、钠盐、透明质酸、胶原蛋白、明胶、泊洛沙姆或白蛋白胶；h) xylitol, oligosaccharides, chondroitin, chitin, chitosan, potassium salt, sodium salt, hyaluronic acid, collagen, gelatin, poloxamer or albumin glue;
i)外消旋聚乳酸、外消旋聚乳酸/乙醇酸共聚物、单甲基聚乙二醇/聚乳酸、单甲基聚乙二醇/聚乳酸共聚物、聚乙二醇/聚乳酸、聚乙二醇/聚乳酸共聚物、端羧基聚乳酸或端羧基聚乳酸/乙醇酸共聚物。i) Racemic polylactic acid, racemic polylactic acid/glycolic acid copolymer, monomethylpolyethylene glycol/polylactic acid, monomethylpolyethylene glycol/polylactic acid copolymer, polyethylene glycol/polylactic acid , polyethylene glycol/polylactic acid copolymer, carboxyl-terminated polylactic acid or carboxyl-terminated polylactic acid/glycolic acid copolymer.
实施例16Example 16
加工成缓释注射剂的方法步骤与实施例1-15相同，但所不同的是所用的助悬剂分别为下列之一或其组合：The method step of being processed into sustained-release injection is identical with embodiment 1-15, but difference is that used suspending agent is respectively following one or its combination:
a)0.5-3.0％羧甲基纤维素(钠)；a) 0.5-3.0% carboxymethylcellulose (sodium);
b)5-15％甘露醇；b) 5-15% mannitol;
c)5-15％山梨醇；c) 5-15% sorbitol;
d)0.1-1.5％表面活性物质；d) 0.1-1.5% surface active substances;
e)0.1-0.5％吐温20。e) 0.1-0.5% Tween 20.
实施例17Example 17
加工成缓释注射剂的方法步骤与实施例11-15相同，但所不同的是所含抗癌有效成分为：The method steps of processing into sustained-release injections are the same as those in Examples 11-15, but the difference is that the contained anticancer active ingredients are:
(1)5-30％的埃坡霉素B、埃坡霉素C、埃坡霉素D、异埃坡霉素D、埃坡霉素E、埃坡霉素F、ixabepilone、氮杂埃坡霉素B、呋喃埃坡霉素D或BMS-310705与5-30％的7-氢氧基-星状孢子素、7-O-烷基-星状孢子素、β-甲氧星状孢子素、烷基磷酸胆碱或六癸基磷酸胆碱的组合；(1) 5-30% of epothilone B, epothilone C, epothilone D, isopothilone D, epothilone E, epothilone F, ixabepilone, aza Pothyromycin B, Furanepothilone D or BMS-310705 with 5-30% of 7-hydroxyl-staurosporine, 7-O-alkyl-staurosporine, β-methoxystar Combinations of sporins, alkylphosphocholines, or hexadecylphosphocholines;
(2)5-30％的埃坡霉素B、埃坡霉素C、埃坡霉素D、异埃坡霉素D、埃坡霉素E、埃坡霉素F、ixabepilone、氮杂埃坡霉素B、呋喃埃坡霉素D或BMS-310705与5-30％的O4-苄基叶酸、2，4，5-三氨基-6-苄氧基嘧啶、2，4-二氨基-6-苄氧基-5-亚硝基嘧啶、2，4-二氨基-6-苄氧基-5-溴基嘧啶、2-氨基-4-苄氧基-5-硝基嘧啶、2-氨基-4-苄氧基-6-甲基-5-硝基嘧啶、2，4-二氨基-6-苄氧基-s-三嗪或2-氨基-O4-苄基喋啶的组合；或(2) 5-30% of epothilone B, epothilone C, epothilone D, isopothilone D, epothilone E, epothilone F, ixabepilone, aza Pothyromycin B, Epothilone D or BMS-310705 with 5-30% O4-benzyl folic acid, 2,4,5-triamino-6-benzyloxypyrimidine, 2,4-diamino- 6-benzyloxy-5-nitrosopyrimidine, 2,4-diamino-6-benzyloxy-5-bromopyrimidine, 2-amino-4-benzyloxy-5-nitropyrimidine, 2- Combinations of amino-4-benzyloxy-6-methyl-5-nitropyrimidine, 2,4-diamino-6-benzyloxy-s-triazine or 2-amino-O4-benzylpteridine; or
(3)5-30％的埃坡霉素B、埃坡霉素C、埃坡霉素D、异埃坡霉素D、埃坡霉素E、埃坡霉素F、ixabepilone、氮杂埃坡霉素B、呋喃埃坡霉素D或BMS-310705与5-30％的咪唑并哌嗪、咪唑并吡啶、渥曼青霉素、苯并吡喃、6-芳香基-2-吗啡酚-4-基-吡喃-4-基、2-(4-吗琳基)-8-苯基色酮、7-乙基-10-羟基喜树碱、3-氰基-6-亚肼基甲基-5-(4-吡啶基)吡啶-[1H]-2-1、苯基丁酸、甲氧胺、羟基胺、肌醇聚磷酸盐、十四(烷)基磷酸胆碱、六葵基磷酸(N-N-N-三甲基)己醇胺、十八基磷酸胆碱、十八基-[2-(N-甲基哌啶)乙基]-磷酸盐、氨基三唑或丁基硫堇硫肟的组合。(3) 5-30% of epothilone B, epothilone C, epothilone D, isopothilone D, epothilone E, epothilone F, ixabepilone, aza Pothyromycin B, furan epothilone D or BMS-310705 with 5-30% imidazopiperazine, imidazopyridine, wortmannin, benzopyran, 6-aryl-2-morphol-4 -yl-pyran-4-yl, 2-(4-morpholinyl)-8-phenylchromone, 7-ethyl-10-hydroxycamptothecin, 3-cyano-6-hydrazonomethyl -5-(4-pyridyl)pyridine-[1H]-2-1, phenylbutyric acid, methoxyamine, hydroxylamine, inositol polyphosphate, tetradecylphosphorylcholine, hexacyl (N-N-N-trimethyl)hexanolamine phosphate, octadecylphosphorylcholine, octadecyl-[2-(N-methylpiperidinyl)ethyl]-phosphate, aminotriazole or butylthionine combination of oximes.
本发明并不限定于所举例的实施方式范围内，该实施方式旨在作为本发明个别的举例说明。实际上，除本文所示和所述之外的本发明的各种改变，对于本领域熟练技术人员来说都可从说明书和图表中显而易见。当然这些改变应在所附的权利要求的范围内。因此，应该认识到前面的说明书着重公开了本发明的某些特定实施方式及对其所做的等同改变或替换都是在所附权利要求书所述的构思和范围内。The present invention is not to be limited in scope by the illustrated embodiments, which are intended as individual illustrations of the invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the specification and diagrams. Such changes are of course intended to be within the scope of the appended claims. Therefore, it should be recognized that the foregoing specification focuses on disclosing certain specific embodiments of the present invention and equivalent changes or replacements thereto are all within the concept and scope of the appended claims.
以上实施例仅用于说明，而并非局限本发明的应用。本发明所公开和保护的内容见权利要求。The above embodiments are for illustration only, and do not limit the application of the present invention. See the claims for the disclosed and protected contents of the present invention.
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2006102012704ACN1969816A (en) | 2006-12-12 | 2006-12-12 | A kind of anticancer sustained-release agent containing epothilone |
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2006102012704ACN1969816A (en) | 2006-12-12 | 2006-12-12 | A kind of anticancer sustained-release agent containing epothilone |
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2008103050030ADivisionCN101433520A (en) | 2006-12-12 | 2006-12-12 | Anticancer sustained-release agent containing epothilone |
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| CN1969816Atrue CN1969816A (en) | 2007-05-30 |
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006102012704APendingCN1969816A (en) | 2006-12-12 | 2006-12-12 | A kind of anticancer sustained-release agent containing epothilone |
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| CN (1) | CN1969816A (en) |
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