| This subject is based on scientific principles of nonlinear complex systems and research ideas,in order to solve the key technical problem about "phase separation",which exsited in the design and preparation of composite particles for Chinese herbal compound dry powder inhalations,we combined the basic theory and method in pharmacy and materials science,and selected the composition of "Panax notoginseng saponins(PNS)-Tanshinone ? A" as model drugs,by using the composite particle technology,without accessories and carrier,we taked full advantage of the complementary physical and chemical properties of different effective components,in order to combine hydrophilic PNS and hydrophobic tanshinone ?A into one micron-sized particle,so as to overcome the phenomenon of "phase separation",realizing the synchronization inhalation of multi-component drugs.The first part of the study established in vitro evaluation methods of "PNS-Tanshinone ? A"composite particles,including the determination of the the main active components in the composite particles;micro characterization of the composite particles by using scanning electron microscopy(SEM),confocal laser scanning microscope(CLSM),dry laser particle size analyzer,X-ray diffraction(XRD),infrared analysis(IR),the diffuse reflection of the ultraviolet,atomic force microscopy(AFM),the surface energy analyzer(SEA);and macro characterization.by using dynamic water vapor adsorption analyzer(DVS),multifunction powder flow tester(FT-4),next generation pharmaceutical impactor(NGI).The second part of the study is to prepare composite particles via two different methods,including the spray drying of the suspension containing PNS?tanshinone ?A and the co-spray drying of the solution of them.A series of characterization results show that:by using the former method,we obtained hollow,smooth inner and rough outer porous composite particles,however the in vitro lung deposition results indicated that the amount of PNS and tanshinone ?A in each site of action was inconsistent,the amount of PNS was more than tanshinone ?A in stage 2 and stage 3 of NGI,whereas less than tanshinone ?A in stage 4?5?6?7?8.The composite particles prepared by co-spray drying also showed a hollow structure with much tanshinone IIA microcrystalline distributing in the outer layer,and the distribution ratio of the two types of components in all stages of NGI were very consistent,showed that they could be evenly distributed in micron particles.Therefore,we finally selected the co-spray drying method for further optimize research.In the third part,we conduct an optimal design of the composite particles,basing on the understanding of the particle formation mechanism in spray drying process.And according to the physical and chemical properties of the two types of effective components,three solvent systems were selected including ethanol,ethanol:acetone(9:1,v/v),ethanol:acetone(4:1,v/v),and three inlet temperature:110?.120?.130? to prepare seven different composite particle samples;each sample was characterized from both the micro and macro aspects,the results indicates that under the conditions of using the mixed solvent system of ethanol-acetone volume ratio of 9:1 and the inlet temperature of 110 ?,the resulting composite particles were surface roughness,with more tanshinone II A distributing in the outer layer,such composite particles have the best lung inhaled performance and the fine particle fraction(FPF)close to 60%.Finally,it is concluded that by adjusting the conditions in co-spray drying process,the distribution amount and existence form of tanshinone ?A in the outer layer of the particles can be changed so that to enhance lung inhaled performance of the drug composite particles.The fourth part of the study was to deliver the composite particles to the lung of the rats,and to evaluate the feasibility of using the pulmonary route for non-invasive systemic delivery of ginsenosides Rg1?Rb1,poorly orally absorbed saponins,to reache the systemic circulation,on the other hand,to evaluate the feasibility of lung targeting distribution of tanshinone ? A.The results showes that the bioavailability of ginsenoside Rgl and Rbl has been greatly improved,and ginsenoside Rbl,tanshinone ?A can stay in the lung for a long time by pulmonary administration. |
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