Preparation Of Dry Powder Inhaler Of Parathyroid Hormone By Supercritical Fluid Assisted Atomization With An Enhanced Mixer

Drug powders have extensive applications in the field of pharmacy and medicine.After being micronized,the dosage form of the drug is affected directly,which can enrich the routes of administration.It should be noted that different pharmaceutical formulations have special requirements on the properties of drug microparticles,such as particle size and size distribution,so the micronization technology is very important.Supercritical assisted atomization with an enhanced mixer(SAA-HCM)process is a green micronization technique that uses the high expansion power of supercritical CO2(SC-CO2)to obtain fine particles,in which a hydrodynamic cavitation mixer is introduced to intensify the mixng between SC-CO2 and liquid solution.SAA-HCM has strong controllability over the particle morphology and size under mild conditions.Since SAA-HCM is a newly developed technique,it is necessary to expand its application to the preparation of submicron-and nano-particles,as well as the composite microparticles loaded with pharmaceutical protein.In this work,the feasibility of SAA-HCM process in the preparation of submicron-and nano-particles was explored.At the same time,parathyroid hormone(PTH(1-34))-loaded microparticles as dry powder inhaler(DPI)suitable for pulmonary delivery were prepared and evaluated for its quality,which provided basic data for clinical practice.First,the relationship between nozzle diameter of the SAA-HCM device and particle size was established using chitosan oligosaccharide(CSO)as the hydrophilic polymeric material.Based upon that,azithromycin and 10-hydroxycamptothecin(HCPT)were selected as the model drugs to verify the feasibility of SAA-HCM to prepare particles with different scales.The results showed that the particle size decreased with the nozzle diameter decreasing in a certain range,and nozzles with diameters under 0.2 mm had little effect on the particle size.Using a nozzle of 0.2 mm diameter,the azithromycin submicronparticles and HCPT nanoparticles with an average particle size of 196 um were successfully obtained,demonstrating the feasibility of this technology for prqparing submicron-and nano-particles.Then,a nozzle of 1 mm diameter was selected to prepare PTH(1-34)/CSO composite microparticles by SAA-HCM,using PTH(1-34)as a pharmaceutical protein and CSO as the carrier.The effects of operating parameters on particle morphology and size were investigated,and the microparticles were detailedly characterized.Well-defined,separated and spherical PTH(1-34)/CSO composite microparticles were found.Precipitator temperature and feed ratio had a significant effect on particle morphology,and an increase in the proportion of PTH(1-34)would aggravate the wrinkles on the surface of composite microparticles.Mixer pressure,gas-liquid flow ratio,and solution concentration had a great influence on the particle size and distribution,which could be used to adjust the particle size distribution in the range of 1-5 ?m.After SAA-HCM process,the degradation of PTH(1-34)in the composite microparticles was not observed,and the helical content was partially converted into folded content in the solution.Composite microparticles showed amorphous state as the raw material,and its thermal stability was well preserved.The loading efficiency of PTH(1-34)/CSO composite microparticles was up to 92.8%.Finally,the physicochemical properties of PTH(1-34)/CSO powders as DPI formulation,such as hygroseopieity,density and angle of repose,were investigated.Also aerodynamic properties were analyzed using next generation impactor(NGI).The results revealed that PTH(1-34)/CSO powders were hygroscopic and easily aggregated in the air,resulting in ordinary flowability.Density measurement showed that the powders were lighter and solubility test showed that it had good aqueous dissolution.The aerodynamic diameters of three formulations of PTH(1-34)/CSO powder were 1.73 ?m,2.11 ?m,2.61 ?m respectively,and the maximum emitted dose and deposition fraction of these formulations could reach 90.86%and 63.51%,which meet the requirements of the Pharmacopoeia and laid the foundation for pulmonary delivery as DPI.In summary,compared with other supercritical fluid based technologies,SAA-HCM process could be applied to the preparation of microparticles with controllable particle morphology and size in aqueous systems,in the absence of organic solvents.The operating conditions were favorable for maintenance of the structure and activity of drugs,especially for protein drugs,so the SAA-HCH process would find good application prospects in the field of DPI formulations for pulmonary drug delivery system.