CN103550138B - 一种索拉非尼有机凝胶及其制备方法 - Google Patents
一种索拉非尼有机凝胶及其制备方法 Download PDFInfo
- Publication number
- CN103550138B CN103550138B CN201310517525.8A CN201310517525A CN103550138B CN 103550138 B CN103550138 B CN 103550138B CN 201310517525 A CN201310517525 A CN 201310517525A CN 103550138 B CN103550138 B CN 103550138B
- Authority
- CN
- China
- Prior art keywords
- sorafenib
- organogel
- preparation
- gel
- requires
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 239000005511 L01XE05 - Sorafenib Substances 0.000 title claims abstract description 51
- 229960003787 sorafenib Drugs 0.000 title claims abstract description 51
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 title claims abstract description 49
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 239000003814 drug Substances 0.000 claims abstract description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000003960 organic solvent Substances 0.000 claims abstract description 12
- 239000003381 stabilizer Substances 0.000 claims abstract description 4
- 239000003349 gelling agent Substances 0.000 claims abstract description 3
- 239000000243 solution Substances 0.000 claims description 21
- 239000000203 mixture Substances 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- 238000009472 formulation Methods 0.000 claims description 10
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 10
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 8
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 claims description 6
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 6
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 claims description 6
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 4
- -1 F127 Polymers 0.000 claims description 3
- 229960004756 ethanol Drugs 0.000 claims description 3
- 239000002245 particle Substances 0.000 claims description 3
- 229940077388 benzenesulfonate Drugs 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 claims description 2
- 238000001647 drug administration Methods 0.000 claims description 2
- 229950007655 esilate Drugs 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 229920006316 polyvinylpyrrolidine Polymers 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 241000700159 Rattus Species 0.000 abstract description 6
- 238000004090 dissolution Methods 0.000 abstract description 5
- 238000001879 gelation Methods 0.000 abstract description 5
- 238000000338 in vitro Methods 0.000 abstract description 5
- 238000001816 cooling Methods 0.000 abstract description 4
- 239000006185 dispersion Substances 0.000 abstract description 3
- 150000004936 Sorafenib derivatives Chemical class 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 description 24
- 239000000499 gel Substances 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000000034 method Methods 0.000 description 8
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 229920001983 poloxamer Polymers 0.000 description 5
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 4
- 229960001680 ibuprofen Drugs 0.000 description 4
- 229960000502 poloxamer Drugs 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 230000008595 infiltration Effects 0.000 description 3
- 238000001764 infiltration Methods 0.000 description 3
- 238000011068 loading method Methods 0.000 description 3
- 230000036470 plasma concentration Effects 0.000 description 3
- 229920001993 poloxamer 188 Polymers 0.000 description 3
- 229940044519 poloxamer 188 Drugs 0.000 description 3
- 230000002441 reversible effect Effects 0.000 description 3
- IVDHYUQIDRJSTI-UHFFFAOYSA-N sorafenib tosylate Chemical compound [H+].CC1=CC=C(S([O-])(=O)=O)C=C1.C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 IVDHYUQIDRJSTI-UHFFFAOYSA-N 0.000 description 3
- 229960000487 sorafenib tosylate Drugs 0.000 description 3
- 235000012424 soybean oil Nutrition 0.000 description 3
- 239000003549 soybean oil Substances 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- ULQISTXYYBZJSJ-UHFFFAOYSA-N 12-hydroxyoctadecanoic acid Chemical compound CCCCCCC(O)CCCCCCCCCCC(O)=O ULQISTXYYBZJSJ-UHFFFAOYSA-N 0.000 description 2
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 2
- 108010036949 Cyclosporine Proteins 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 102100033479 RAF proto-oncogene serine/threonine-protein kinase Human genes 0.000 description 2
- 208000006265 Renal cell carcinoma Diseases 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229960001265 ciclosporin Drugs 0.000 description 2
- 238000005352 clarification Methods 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 210000002381 plasma Anatomy 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000001338 self-assembly Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 238000011105 stabilization Methods 0.000 description 2
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- KKVYYGGCHJGEFJ-UHFFFAOYSA-N 1-n-(4-chlorophenyl)-6-methyl-5-n-[3-(7h-purin-6-yl)pyridin-2-yl]isoquinoline-1,5-diamine Chemical compound N=1C=CC2=C(NC=3C(=CC=CN=3)C=3C=4N=CNC=4N=CN=3)C(C)=CC=C2C=1NC1=CC=C(Cl)C=C1 KKVYYGGCHJGEFJ-UHFFFAOYSA-N 0.000 description 1
- 229940114072 12-hydroxystearic acid Drugs 0.000 description 1
- HVUMOYIDDBPOLL-UHFFFAOYSA-N 2-(3,4-Dihydroxyoxolan-2-yl)-2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)C1OCC(O)C1O HVUMOYIDDBPOLL-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical group CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 1
- ZBNZXTGUTAYRHI-UHFFFAOYSA-N Dasatinib Chemical compound C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1Cl ZBNZXTGUTAYRHI-UHFFFAOYSA-N 0.000 description 1
- 229920003139 Eudragit® L 100 Polymers 0.000 description 1
- 101000692455 Homo sapiens Platelet-derived growth factor receptor beta Proteins 0.000 description 1
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 1
- 239000002067 L01XE06 - Dasatinib Substances 0.000 description 1
- 239000002136 L01XE07 - Lapatinib Substances 0.000 description 1
- 239000005536 L01XE08 - Nilotinib Substances 0.000 description 1
- 101100381978 Mus musculus Braf gene Proteins 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 102100026547 Platelet-derived growth factor receptor beta Human genes 0.000 description 1
- 229920002556 Polyethylene Glycol 300 Polymers 0.000 description 1
- 229920002582 Polyethylene Glycol 600 Polymers 0.000 description 1
- 102000009516 Protein Serine-Threonine Kinases Human genes 0.000 description 1
- 108010009341 Protein Serine-Threonine Kinases Proteins 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 101710141955 RAF proto-oncogene serine/threonine-protein kinase Proteins 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- NWGKJDSIEKMTRX-MDZDMXLPSA-N Sorbitan oleate Chemical compound CCCCCCCC\C=C\CCCCCCCC(=O)OCC(O)C1OCC(O)C1O NWGKJDSIEKMTRX-MDZDMXLPSA-N 0.000 description 1
- 108091008605 VEGF receptors Proteins 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 229930182912 cyclosporin Natural products 0.000 description 1
- 229960002448 dasatinib Drugs 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 229960004891 lapatinib Drugs 0.000 description 1
- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229960004296 megestrol acetate Drugs 0.000 description 1
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N megestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- LBWFXVZLPYTWQI-IPOVEDGCSA-N n-[2-(diethylamino)ethyl]-5-[(z)-(5-fluoro-2-oxo-1h-indol-3-ylidene)methyl]-2,4-dimethyl-1h-pyrrole-3-carboxamide;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C LBWFXVZLPYTWQI-IPOVEDGCSA-N 0.000 description 1
- 229960001346 nilotinib Drugs 0.000 description 1
- HHZIURLSWUIHRB-UHFFFAOYSA-N nilotinib Chemical compound C1=NC(C)=CN1C1=CC(NC(=O)C=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)=CC(C(F)(F)F)=C1 HHZIURLSWUIHRB-UHFFFAOYSA-N 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 210000004279 orbit Anatomy 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 231100000683 possible toxicity Toxicity 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 201000001514 prostate carcinoma Diseases 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000003578 releasing effect Effects 0.000 description 1
- 201000010174 renal carcinoma Diseases 0.000 description 1
- 208000015347 renal cell adenocarcinoma Diseases 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000008279 sol Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 229940051454 sorafenib 200 mg Drugs 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229940034785 sutent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000008542 thermal sensitivity Effects 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 230000005760 tumorsuppression Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
Abstract
本发明提供一种新型索拉非尼有机凝胶及其制备方法。该索拉非尼有机凝胶由有机胶凝剂、有机溶剂、分散稳定剂、活性药物组成，该有机凝胶是热敏型有机凝胶，胶凝温度为40-50℃，高温呈溶液，冷却后呈凝胶，并且遇水能迅速分散成纳米溶液。本发明的有机凝胶具有显著提高索拉非尼体外溶出速率和大鼠口服生物利用度；凝胶中凝胶剂用量较少，安全性好；制备方法简单；用途广，能加工成多种给药途径的制剂等特点，具有良好的应用前景。
Description
技术领域
本发明涉及索拉非尼的一种药物新剂型和新技术，特别是涉及一种有机凝胶及其制备方法。
背景技术
索拉非尼(sorafenib)化学名4-{4-[3-(4-氯-3-三氟甲基-苯基-酰脲]-苯氧基}-吡啶-2-羧酸甲胺，分子式：C21H16ClF3N4O3，分子量464.8g／mol。临床使用的是索拉非尼的甲苯磺酸盐形式，分子结构式如下：
索拉非尼是一种新型多靶点药物，主要通过两种途径发挥抗癌活性。①抑制Raf-1和B-Raf丝氨酸和苏氨酸激酶的活性，从而抑制RAS／RAF／MEK／ERK信号传导通路，抑制肿瘤细胞的增殖。②抑制肿瘤新生血管生成。肿瘤的生长依赖新生血管的形成，索拉非尼通过抑制血管内皮生长因子受体VEGFR和PDGFR的酪氨酸激酶活性阻断肿瘤新生血管的形成和切断肿瘤细胞的营养供应，间接抑制肿瘤细胞的生长。
索拉非尼可显著延长晚期肾癌、原发性肝癌患者的生存期，成为治疗肝癌和肾癌首选化疗药物，同时也可用于非小细胞肺癌、前列腺癌、卵巢癌等治疗。
甲苯磺酸索拉非尼片剂含甲苯磺酸索拉非尼274mg／片，相当于索拉非尼200mg，每日服用2次，总剂量为548mg。一期临床研究表明，单剂400mg给药后的平均最大浓度为1.67-2.13mg／l，，达峰时间为4-8小时，半衰期24-48小时，与口服溶液比较相对生物利用度38-49％，与高脂性食物同食时生物利用度降低至29％。
由此可知该药物片剂吸收慢(达峰时间长)，生物利用度低，这可能是由于索拉非尼溶解性能差(它水中不溶，油中溶解度也较差)的缘故。因此急需研究索拉非尼研究新剂型或新制剂，提高生物利用度(包括增加吸收速度和程度)，减少给药剂量，降低成本。本专利中发明正是通过有机凝胶这一新型制剂技术来达到此目的。
有机凝胶系由低浓度的凝胶剂在有机溶剂中通过物理或化学键相互作用自组装、相互缠绕形成的三维网状结构固定有机溶剂而形成的半固体系统。简言之，有机凝胶系主要由具有自组装有机凝胶剂的三维网络固定有机溶剂组成的半固体体系。其中有机凝胶剂(organogelator)大都是通过低能键物理作用(如氢键和范德华键等)而形成凝胶的，这种物理凝胶一般是可逆凝胶，而少数是通过化学共价键连接获得凝胶的，化学凝胶一般是不可逆的。目前文献报道应用于药剂学领域的有机凝胶用的凝胶剂有卵磷脂、卵磷脂-泊洛沙姆、山梨醇脂肪酸衍生物、脂肪酸衍生物、氨基酸衍生物及聚丙烯酸、甲基丙烯酸-甲基丙烯酸甲酯共聚物等。与使用水作为溶剂的水凝胶不同，有机凝胶不使用水，大多数采用植物油，酯类液体化合物(如十四烷酸异丙酯、司盘)为有机溶剂。令人遗憾的是，仅有为数不多研究描述有机凝胶在给药中的应用，这可能是研究中多数有机凝胶剂可能有潜在的毒性或缺乏毒理学研究。
目前研究最多的是卵磷脂泊洛沙姆有机凝胶，用于提高难溶性药物生物利用度，但仅用做外用制剂。最近有一些口服有机凝胶的报道，例如布洛芬有机凝胶(IwanagaK.etal.，IntJPharm，388：123-128，2010)是用12-羟基硬脂酸为有机凝胶剂，大豆油为有机溶剂而制成的，该有机凝胶制剂布洛芬口服绝对生物利用度达98％，血药浓度曲线下面积(AUC)是布洛芬大豆油溶液的1.3倍，布洛芬水性混悬剂的1.5倍，但是吸收速度慢，有机凝胶峰浓度(Cmax)<大豆油溶液<水性混悬剂，显示缓释效应。环孢素有机凝胶(MurdanS.etal.，IntJPharm，300：113-124，2005)是以司盘60为凝胶剂，吐温或与司盘80的混合物为有机溶剂而制备的，最佳有机凝胶处方口服生物利用度的参数(如AUC和Cmax)与上市环孢素制剂均相近。
有机凝胶的制备方法通常采用加热熔融-冷却法，该方法用于载药量较大的制剂时药物存在沉淀致含药量不均的问题，这也是水凝胶制剂在载入水难溶性药物时普遍存在的问题。
至今亲水性和亲脂性都差的索拉非尼的有机凝胶仍处于空白。
发明内容
本发明提供一种索拉非尼有机凝胶及其制备方法。
本发明有机凝胶由活性药物、有机胶凝剂、有机溶剂、稳定剂组成。
本发明有机凝胶中各组分质量百分含量为：
本发明有机凝胶中的活性药物包括索拉非尼及其类似物(如尼罗替尼，舒尼替尼，达沙替尼、拉帕替尼)，或其药学上可接受的盐(如甲苯磺酸盐，苯磺酸盐，乙磺酸盐)，优选索拉非尼或索拉非尼甲苯磺酸盐，其中载药量为10％-35％。
本发明有机胶凝中有机凝胶剂包括泊洛沙姆407，或泊洛沙姆407与同系物(如泊洛沙姆188)组成的混合物，用量小于16％，优选10-15％。
本发明有机胶凝中有机溶剂包括PEG400及其同系物(如PEG300，PEG400，PEG600)，或者PEG400与其他药学上可接受的有机溶剂(如无水乙醇、丙二醇、甘油)的混合物，优选PEG400。
本发明有机胶凝中稳定剂为聚乙烯吡咯烷酮类，如聚乙烯吡咯烷酮K-12、聚乙烯吡咯烷酮K-15、聚乙烯吡咯烷酮K-30和聚乙烯吡咯烷酮K-90中的一种或两种以上混合物，优选聚乙烯吡咯烷酮K-15，用量为3％-10％。
本发明中有机凝胶采用溶剂挥发-冷却法制备，其制备方法是：取处方量聚乙二醇400、泊洛沙姆407、聚乙烯吡咯烷酮、索拉非尼于烧杯中，加入无水乙醇适量，50-70℃加热搅拌溶解，在挥尽乙醇后，4℃冰浴搅拌下得索拉非尼有机凝胶。
本发明特征在于：有机凝胶为热敏性凝胶，胶凝温度为40-50℃，在胶凝温度下为凝胶，温度上升至胶凝温度以上可以缓慢融化成溶胶，且该过程是可逆的(见图1)，该索拉非尼有机凝胶适用于制成口服制剂(如胶囊剂)和外用制剂。
本发明特征在于：索拉非尼有机凝胶在适量的pH4.0-7.0水中经搅拌或振摇，能迅速分散，形成具蓝色乳光的纳米溶液，粒径小于300nm。这种特性使得该有机凝胶适用于加工成注射制剂、外用制剂(如眼用)和口服制剂，在临用前加水给药。
本发明中提供一种新型索拉非尼有机凝胶，大大提高了难溶性药物在制剂中的分散度，加快药物体外溶出的速度，增加药物的生物利用度，索拉非尼有机凝胶大鼠口服给药，与原料药混悬液比较，能使索拉非尼体内血药峰浓度增加6.7倍，体内生物利用度增加9.8倍；该有机凝胶处方中凝胶剂等表面活性剂用量较低(<16％)，大大提高用药安全性；该凝胶制剂载药量高和均匀度好，且稳定性好，与脂质体，微乳，胶束等常见增溶技术比较，无需经过冷冻干燥工艺使制剂稳定；在制备过程中加入低沸点亲水性有机溶剂(如无水乙醇、甲醇、异丙醇等)，采用溶解-挥发-冷却工艺制备有机凝胶，使水溶性差和亲脂性也较差的索拉非尼药物在凝胶中均匀分散，较好地解决了大剂量药物有机凝胶含量不均的问题。
该有机凝胶特点1)处方工艺简单，便于大生产，成本大大降低，2)药物处于凝胶状态，不仅增加药物载药量和分散均匀性，而且体外稳定，3)能增加药物在体内吸收速率和体内生物利用度4)适用于多种给药途径的制剂，如口服制剂和外用制剂，5)遇水能形成纳米溶液，便于注射给药。
附图说明
图1泊洛沙姆有机凝胶在胶凝温度上下的可逆转变图。
图2泊洛沙姆有机凝胶与原料药的体外溶出曲线图。
图3大鼠口服索拉非尼原料药、有机凝胶、有机凝胶纳米溶液后体内血药浓度曲线图。
具体实施方式
实施例1索拉非尼有机凝胶制备
处方：
制备方法：称取处方量中各物质和适量无水乙醇于三颈烧瓶中，60℃加热搅拌至溶液澄清后，缓慢挥尽甲醇，4℃冰浴搅拌下成凝胶。
实施例2索拉非尼有机凝胶制备
处方：
制备方法：称取处方中各物质于烧杯和适量无水乙醇于三颈烧瓶中，60℃加热搅拌至溶液澄清后，缓慢挥尽乙醇，4℃冰浴搅拌下成凝胶。
实施例3索拉非尼有机凝胶纳米溶液制备
分别取实施例1和实施例2中凝胶0.07g，加入纯化水1ml，迅速搅拌，均得凝胶完全分散的纳米溶液，粒径小于300nm。
实施例4索拉非尼有机凝胶体外溶出度考察
样品：实施例1索拉非尼有机凝胶和索拉非尼原料药
溶出方法：转蓝法测定，溶出介质为0.1MHCL1％SDS溶液，体积为900ml，转速75r／min，取样时间点设为5，10，15，20，30，45，60，90，120min，原料药与有机凝胶的体外溶出曲线如图2。结果表明索拉非尼有机凝胶体外溶出速率大大提高。
实施例5索拉非尼有机凝胶大鼠体内相对生物利用度研究
1.样品：
原料组：适量索拉非尼用0.5％CMC-Na溶液2ml混悬，即得；有机凝胶组：实施例1有机凝胶；纳米溶液组：适量有机凝胶，加2ml纯净水，搅拌成纳米溶液。
2.实验方法：SD雌性大鼠(186g-200g)，随机分为三组，每组6只，按200mg／kg剂量(指相当于原料药甲苯磺酸索拉非尼的质量)，分别灌胃原料药、有机凝胶和纳米溶液，给药后0.5，1，2，3，4，6，8，12，24，36，48，60，72h眼眶取血，每次0.25ml，离心分离出血浆，测定血药浓度。
3.血药浓度测定：取大鼠血浆100μL，加入10ul醋酸甲地孕酮溶液(40ug／ml)，混匀，加入乙腈300μL，涡旋20s，10000rpm离心6min，取上清液置离心管中，25℃N2吹干，适量甲醇溶解，20ul进样HPLC分析，计算血药浓度。图3是血药浓度经时曲线。统计矩法计算的药动学参数见表1，其中相对生物利用度Fr计算方程是：
Fr％=AUC0-72，有机凝胶或纳米溶液／AUC0-72，原料药
表1索拉非尼原料药、有机凝胶组、有机凝胶纳米溶液的药动学参数
*P<0.05，**P<0.01，***P<0.001vs原料药组
结果表明有机凝胶组和纳米溶液组大大提高索拉非尼口服生物利用度，分别是原料药的9.81倍和6.93倍，且吸收速度也大幅度提高，有机凝胶组和纳米溶液组的Cmax分别是原料药组的6.39倍和9.67倍。
Claims (5)
1.一种索拉非尼有机凝胶，由活性药物、有机胶凝剂、有机溶剂、稳定剂组成，其具体组成和用量为：
其制备方法是：取处方量聚乙二醇400、泊洛沙姆P407、聚乙烯吡咯烷酮、索拉非尼于烧杯中，加入无水乙醇适量，搅拌加热溶解，挥尽乙醇后，4℃冰浴搅拌下得索拉非尼有机凝胶。
2.如权利要求1要求的索拉非尼有机凝胶，其特征在于：活性药物索拉非尼为索拉非尼，或其药学上可接受的盐索拉非尼甲苯磺酸盐、索拉非尼苯磺酸盐或者索拉非尼乙磺酸盐。
3.如权利要求1要求的索拉非尼有机凝胶，其特征在于：聚乙烯吡咯烷酮为聚乙烯吡咯烷酮K-12、聚乙烯吡咯烷酮K-15、聚乙烯吡咯烷酮K-30或者聚乙烯吡咯烷酮K-90。
4.如权利要求1要求的索拉非尼有机凝胶，其特征在于：所述的有机凝胶适用于口服制剂和外用制剂。
5.如权利要求1要求的索拉非尼有机凝胶，其特征在于：该有机凝胶在pH4.0-7.0水中可搅拌或振摇迅速分散，得粒径小于300nm的纳米溶液，便于注射给药。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310517525.8A CN103550138B (zh) | 2013-10-29 | 2013-10-29 | 一种索拉非尼有机凝胶及其制备方法 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310517525.8A CN103550138B (zh) | 2013-10-29 | 2013-10-29 | 一种索拉非尼有机凝胶及其制备方法 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103550138A CN103550138A (zh) | 2014-02-05 |
| CN103550138B true CN103550138B (zh) | 2015-11-25 |
Family
ID=50004623
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310517525.8A Active CN103550138B (zh) | 2013-10-29 | 2013-10-29 | 一种索拉非尼有机凝胶及其制备方法 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103550138B (zh) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105801584B (zh) * | 2016-03-16 | 2019-03-05 | 中国药科大学 | 新型芳酰胺类Raf激酶抑制剂及其制备方法和用途 |
| CN116159018A (zh) * | 2023-03-01 | 2023-05-26 | 中国药科大学 | 一种新型外用溴莫尼定凝胶剂 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7641900B2 (en) * | 2005-03-30 | 2010-01-05 | Research Foundation Of State University Of New York | Wound treatment utilizing collagenase and a phosphotidylcholine organogel |
| CN102264352A (zh) * | 2008-11-14 | 2011-11-30 | 阿彻丹尼尔斯米德兰德公司 | 有机凝胶组合物及其生产方法 |
| CN102711835A (zh) * | 2009-11-27 | 2012-10-03 | 努沃研究股份有限公司 | 局部布洛芬制剂 |
-
2013
- 2013-10-29 CN CN201310517525.8A patent/CN103550138B/zh active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7641900B2 (en) * | 2005-03-30 | 2010-01-05 | Research Foundation Of State University Of New York | Wound treatment utilizing collagenase and a phosphotidylcholine organogel |
| CN102264352A (zh) * | 2008-11-14 | 2011-11-30 | 阿彻丹尼尔斯米德兰德公司 | 有机凝胶组合物及其生产方法 |
| CN102711835A (zh) * | 2009-11-27 | 2012-10-03 | 努沃研究股份有限公司 | 局部布洛芬制剂 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103550138A (zh) | 2014-02-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Dollo et al. | Spray-dried redispersible oil-in-water emulsion to improve oral bioavailability of poorly soluble drugs | |
| Majeed et al. | Preparation, characterization and applications of nanoemulsions: An insight | |
| WO2020253689A1 (zh) | 一种绿原酸自乳化组合物及其用途 | |
| TWI425914B (zh) | 含高濃度奈米／次微米疏水性機能化合物之水相分散液之製備方法 | |
| JP2002531492A (ja) | ナノ粒子状コア／シェル系、ならびに医薬品および化粧品におけるその使用 | |
| CN102824356A (zh) | 一种黄芩苷纳晶混悬剂、纳晶干粉及其制备方法 | |
| CN101627969B (zh) | 一种姜黄素自乳化给药系统及其制备 | |
| CN105147607A (zh) | 一种塞来昔布纳米混悬剂及其制备方法 | |
| US20040180961A1 (en) | Compositions and preparation methods for bioavailable oral aceclofenac dosage forms | |
| KR20030018083A (ko) | 이트라코나졸을 함유하는 조성물 및 그 제조방법 | |
| CA3116298A1 (en) | Pharmaceutical formulation | |
| CN108289832A (zh) | 用于以输注或注射形式进行静脉给药的左西孟旦以及输注浓缩液的改善配方 | |
| Hansen et al. | In vivo evaluation of tablets and capsules containing spray-dried o/w-emulsions for oral delivery of poorly soluble drugs | |
| Li et al. | Development and evaluation of optimized sucrose ester stabilized oleanolic acid nanosuspensions prepared by wet ball milling with design of experiments | |
| CN103550138B (zh) | 一种索拉非尼有机凝胶及其制备方法 | |
| CN101103962A (zh) | 长春西汀口服自微乳化释药系统及其制备方法 | |
| CN104434797B (zh) | 一种氟苯尼考固体自乳化制剂 | |
| CN110251487B (zh) | 一种提高多西他赛载药量和口服生物利用度的醇溶蛋白纳米粒的制备方法及其应用 | |
| CN109692155B (zh) | 一种聚醚类抗生素不饱和脂肪酸复合物油溶液剂的制备方法和应用 | |
| CN104415340A (zh) | 一种固体药物制剂及其制备方法 | |
| CN103735513A (zh) | 一种20(s)-原人参二醇纳米粒及其制备方法 | |
| CN102872002B (zh) | 羟基红花黄色素a油溶液及其制备方法和应用 | |
| CN104095816B (zh) | 叶黄素酯纳米颗粒及其制备方法 | |
| CN101401788B (zh) | 联苯双酯自乳化制剂及其制备方法 | |
| Chengaiah et al. | Self emulsifying drug delivery system: a novel approach for drug delivery |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20190719 Address after: Room 609-1, Building A, Phase I, Zhongdan Eco-life Science Industrial Park, 3-1 Xinjinhu Road, Nanjing High-tech Development Zone, Jiangsu Province Patentee after: Nanjing Puhui Pharmaceutical Technology Co.,Ltd. Address before: 211198 No. 639 Longmian Avenue, Jiangning University Town, Jiangning District, Nanjing City, Jiangsu Province Patentee before: China Pharmaceutical University |
|
| CP02 | Change in the address of a patent holder |
Address after: Room 12011211-1212, block B, phase I, Zhongdan Ecological Life Science Industrial Park, No. 3-1, xinjinhu Road, Jiangbei new district, Nanjing, Jiangsu Province Patentee after: Nanjing Puhui Pharmaceutical Technology Co.,Ltd. Address before: Room 609-1, Building A, Phase I, Zhongdan Eco-life Science Industrial Park, 3-1 Xinjinhu Road, Nanjing High-tech Development Zone, Jiangsu Province Patentee before: Nanjing Puhui Pharmaceutical Technology Co.,Ltd. |
|
| CP02 | Change in the address of a patent holder | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20230413 Address after: Room 201-0806, Building 2, Jinghu Dianjin Business Plaza, No. 101 Nanjiao Shuyuan Road, Chengxiang Town, Taicang City, Suzhou City, Jiangsu Province, 215413 Patentee after: Suzhou New Aidi Pharmaceutical Technology Co.,Ltd. Address before: Room 12011211-1212, block B, phase I, Zhongdan Ecological Life Science Industrial Park, no.3-1, xinjinhu Road, Jiangbei new district, Nanjing, Jiangsu, 211161 Patentee before: Nanjing Puhui Pharmaceutical Technology Co.,Ltd. |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20231107 Address after: Room 12011211-1212, block B, phase I, Zhongdan Ecological Life Science Industrial Park, no.3-1, xinjinhu Road, Jiangbei new district, Nanjing, Jiangsu, 211161 Patentee after: Nanjing Puhui Pharmaceutical Technology Co.,Ltd. Address before: Room 201-0806, Building 2, Jinghu Dianjin Business Plaza, No. 101 Nanjiao Shuyuan Road, Chengxiang Town, Taicang City, Suzhou City, Jiangsu Province, 215413 Patentee before: Suzhou New Aidi Pharmaceutical Technology Co.,Ltd. |
|
| TR01 | Transfer of patent right |