| Sartan drugs have been used in treatment of hypertension disease,as a kind of highly selective antagonist of angiotensin II.By comparison with angiotensin-converting enzyme inhibitors,sartan drugs have the great advantages such as a stable blood pressure reduction,an absence of dry cough and a well-tolerated side-effect profile.However,almost all of them are suffering a low oral bioavailability,which has limited their clinical application.Mechanochemistry is an environment-friendly technique with simple operations,which leads starting materials to taking some variations such as propagation of dislocations,phase transformation and molecular interactions,by transferring mechanical energy into the surfaces of materials.In this study,the modern strategies of mechanochemistry were applied to prepare sartan drugs systems with enhanced solubility,in order to improve their dissolution rate and oral bioavailability.The main contents of this thesis include the following six aspects:?1?A description of the strategies to increase the solubility of poor-soluble drugs,the development and principles of mechanochemistry,and its pharmaceutical application.?2?The micronized systems of valsartan and olmesartan medoxomil?OM?were separately prepared using a planetary mill.In valsartan micronized system,the particle size was decreased from 1.30?m to 0.32?m.However,the solubility of valsartan was decreased from 0.243 g·L-1to 0.194 g·L-1,and the total drug release of 60 minutes was also decreased from 38%to 36%.In OM micronized system,the particle size was decreased from 1.66?m to 0.70?m.At the same time,the solubility of OM was found to be increased from 0.013 g·L-1 to 0.032 g·L-1,and the total drug release of 60 minutes was also increased from 31%to 55%.Based on this,it is concluded that valsartan micronized system limited the dissolution of valsartan,and OM micronized system promoted the dissolution of OM in water solution.?3?The inclusion complexes of valsartan and OM were separately synthesized with polysaccharide arabinogalactan?AG?and hydroxypropyl-?-cyclodextrin?HP-?-CD?using a rolling mill.From the investigations of the inclusion systems on preliminary pharmaceutical properties,it is found the solubility of valsartan in its complexes with AG and HP-?-CD was separately increased to 0.308 g·L-1 and 0.819 g·L-1,and the total drug release of 60 minutes was increased to 45%and 70%,respectively.Similarily,the solubility of OM in its complexes with AG and HP-?-CD was separately increased to 0.069 g·L-1 and 0.085 g·L-1,and the total drug release of 60 minutes was increased to 61%and 81%,respectively.Based on this,it is concluded that these inclusion complexes promoted the dissolution of valsartan and OM in water solution,and the inclusion complexes with HP-?-CD behaved better than complexes with AG.?4?The co-crystal of telmisartan was synthesized with citric acid using a vibrating mill.Based on the investigations of this co-crystal on preliminary pharmaceutical properties,it is found the the solubility of telmisartan was increased from 0.14 mg·L-1 to 6.97 mg·L-1 and the total drug release of 60 minutes was also increased from 7.7%to 46%.Based on this,it is concluded that the co-crystal of telmisartan with citric acid promoted the dissolution of telmisartan in water solution.?5?The normal solid dispersions of valsartan and OM were separately synthesized with disodium glycyrrhizinate?Na2GA?and pectin using a rolling mill.From the investigations of the solid dispersions on preliminary pharmaceutical properties,it is found the solubility of valsartan was increased to 2.838 g·L-1 in valsartan-Na2GA complex,and its total drug release was also increased to 95%in 60 minutes.Additionally,the anti-hypertensive activity of valsartan-Na2GA complex in ISIAH rats was investigated and found to be increased at least 5 times by comparison with pure valsartan.Similarly,the solubility of OM in its complexes with Na2GA and pectin was separately increased to 0.155g·L-1 and 0.378 g·L-1,and the total drug release of 60 minutes was increased to 52%and 88%,respectively.Based on this,it is concluded that these solid dispersion complexes promoted the dissolution of valsartan and OM in water solution,and OM-pectin complexes behaved better than OM complex with Na2GA.On the other hand,valsartan complex with Na2GA improved its anti-hypertensive activity in vivo.?6?The novel pH modified solid dispersions of valsartan and OM were separately synthesized with CaCO3 and N-methyl-D-glucamine?MG?using a rolling mill.From the investigations of the solid dispersions on preliminary pharmaceutical properties,it is found the solubility of valsartan in its complexes with CaCO3 and MG was separately increased to 2.861 g·L-1 and 2.092 g·L-1,and the total drug release of 60 minutes was increased to 98%and 95%,respectively.Similarily,the solubility of OM in its ternary complex with MG and HP-?-CD was increased to 1.598g·L-1,and the total drug release was also increased to 94%in 60 minutes.In the further study,the oral bioavailability of OM ternary complex in SD rats was found to be 333.3%by compared with pure OM.Based on this,it is concluded that these pH modified solid dispersions promoted the dissolution of valsartan and OM in water solution,and valsartan-CaCO3complex behaved better than valsartan complex with MG.On the other hand,OM ternary complex with MG and HP-?-CD showed an enhanced oral bioavailability. |
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