Study On The Principle Of Particle Design To Improve The Uniformity And Solubility Of Traditional Chinese Medicine Powder

Herbal powers are the main raw material of solid preparation of Traditional Chinese Medicine.Due to the complexity of the source,there are great difference in physical and chemical properties of different herbal powers.In the production process,herbal powers generally have common problems,such as great particle size differences,easy to be slaked,poor mixing uniformity and solubility,etc,which impose an impact not only on the preparation and properties of solid preparations in vitro,but also on absorption,clinical efficacy,safety of drug.Therefore,in order to realize the modernization of Chinese medicine formulations,the problem as how to effectively improve the adverse physicochemical properties of herbal power should be solved at first.In this paper,by taking two typical Chinese medicine,Xiaojin pills and andrographolide,as the research object,the composite particles with core-shell structure of drug-drug or drug-excipient were prepared by mechanical crushing methods based on particle design technology and were characterized by pharmaceutical and micromeritic properties using for materials science methods.which would illustrate on role and process principles of particle design technology in improveing uniformity and solubility of herbal powers.The dissertation was summarized as follows:1. Micromeritic properties of single herb in Xiaojin pillsTo determine classification in the mix smashing of herb in particle design,the grinding laws and micromeritic properties of Wulingzhi that was representative herbs in Xiaojin pills was studied.The results were as follows:with crushing time prolonged,powers particle size tends to be smaller,and there was a good correlation between the grinding time and the power particle size;the dispersion of particle size distribution of was 4.00,which pointed that the grindability of Wulingzhi was good;the test results of surface area,pore volume and bulk density showed an increasing trend,while the pore size firstly increased then decreased;the extraneous dissolution of Wulingzhi powers examined by dissolution tester,the results showed that the cumulative dissolution percentage of index components in herbs increased gradually with the particle size decreased and the dissolution time prolonged.Therefore,the micromeritic properties of Wulingzhi could meet requirements of shell particles in the core-shell composite particles.2. Preparation and characterization of Xiaojin pills composite particles powderTo verify the rationality of single type,multi-type core/shell composite particles coated process by the evaluation of powder and pharmacy science,the result showed that it is more feasible to make the friable materials included Wulingzhi,earthworm,prepared kusnezoff monkshood root,wine angelica,xiangmo, and accessories as shell particles,and to make the smash nuclear particles of materials hard to be crushed such as frankincense,myrrh,resina liquidamberis,semen momordicae,and artificial musk as single layer core/shell composite particles.The optimization tests for recombination technology demonstrated that the optium conditions were as follows:crushing at-15℃,grinding for 50 min,and composite for 3 min,respectively.The complex process validation test showed that the powder properties,particle surface functional groups,elemental compositon and crystalline structure of composite particles had good similarity with those of shell particles,and the thermal stability of volatile components in composite particles were superior to the control powder obviously.The test results of LR,solid surface energy,specific surface area,porosity,morphology and appearance demonstrated that the intermolecular forces,pore adsorption,and mechanical bite force maybe the important factor in the core/shell structure forming.3. Xiaojin pills quality uniformity evaluationTo evaluated the power characterization and content uniformity in Xiaojin composite particles powers and its pills,the control power,artificial mixing powers and their pills used as control group,The results showed that it had narrow size distribution,consistent power color which difference less than 1.and its quality uniformity were much better than that of control group by the characterization of mixing degree,mixing index,RGB color model and content uniformity of Ferulic acid,total single ester alkaloids and muscone.4. Preparation and characterize of andrographolide composite particles powerBased on cover model of core-shell structure of Xiaojinwan.the composite particles of lactose/andrographolide and PEG6000/andrographolide were successfully prepared and analysised by SEM,DSC,contact angle,internal friction angle and cohesion,XRD,surface elemental composition,dissolution.The results demonstrated that they could significantly improve the performance of dissolution in vitro.and of the two,the former was better than the latter.5. Bioavailability evaluation of andrographolide composite particlesTo study on the oral bioavailability of andrographolide composite particles,the drug concentration were measured by LC/MS/MS and the apparent permeability coefficients (.Papp) were investigated using MDCK-MDR1 cell monolayer transport model.The results suggested that the Papp of andrographolide composite particles compared with andrographolide significantly increased,which could effectively promote the transmembrane transport capacity and absorption of andrographolide.On this basis,andrographolide used as control,and the pharmacokinetic of andrographolide composite particles in rats was studied.The results were as follows:the two-peak concentrations of andrographolide were observed in rats plasma by non-compartmental model-statistical moment analysis;the half life(t1/2) of drugs in two kinds powers were almost the same;the AUC(0→180),peak time and concentration were significantly higher in lactose/andrographolide composite particles than that of in andrographolide;the Tmax and MRT(0→180) in composite particles was significantly less than that of in andrographolide.The correlation was evaluated among drug solubility,membrane permeability and absorption in vivo with Gray Relational Analysis method.The results demonstrated that there were a certain relevance on absorption and dissolution rate in vivo and apparent permeability of drug.Therefore,the mixing mode from chaotic to ordered could be achieved by particle design technology,which effectively improved the uniformity of herbal powers.And the composite particles that composed of hydrophilic excipients and drugs were prepared by particle design technology,which could not only improve the solubility of the drug in vitro,but also promote their transmembrane transport and improve effectively bioavailability.