| Drug microparticles have extensive applications in the field of both traditional and novel drug delivery systems. The composition of drug and medical polymer can protect the drug molecule, and achieve targeting drug delivery, sustained/controlled drug release as well as enhanced drug absorption. It should be noted that a certain drug delivery system, for example, pulmonary drug delivery (inhalation) has restrict requirements on the properties of drug microparticles, such as particle size and size distribution. Therefore, the micronization techniques for fabrication of microparticulate drug formulations, which could determine the quality and effectiveness of drug, are of crucial importance. Supercritical assisted atomization with an enhanced mixer (SAA-HCM) process is a green micronization technique using the supercritical fluid as co-solute and atomization medium. SAA-HCM is a continuous and efficient process which introduces a hydrodynamic cavitation mixer to intensify the mixing between SC-CO2 and liquid solution, and has strong controllability over the particle morphology and size under mild conditions. Besides, this process can be operated not only on organic solvents, but also aqueous solutions which make up the inefficiency of other supercritical micronization methods. Since SAA-HCM is a newly developed technique, most of the existing work focused on preparation of single-component microparticles. However, there are still few studies on Ihe microparticle preparation from aqueous solutions, especially lack of preparation of drug-loaded polymer microparticles from aqueous solution. In this work, in order to explore the advantage of processing aqueous solution, the applications of SAA-HCM process were expanded to the preparation of hydrophilic medical polymer microparticles, small molecule drug/macromolecular drug microparticles, and drug-loaded polymer microparticles from aqueous solutions by one step. The fundamental process of micronizing hydrophilic polymers, small molecule and macromolecular drugs, as well as formation of drug-loaded polymer particles was comprehensively investigated The SAA-HCM prepared drug-loaded polymer microparticles could be used as effective dry powder inhaler (DPI) for pulmonary delivery, which provided technical reference for novel practical application-oriented particulate drug delivery systems.Firstly, chitosan, hydroxypropyl methyl cellulose (HPMC) and copovidone were chosed as typical hydrophilic medical polymers, SAA-HCM process was adopted to verify its processability of these polymers from aqueous solutions. The influences of process parameters including precipitator t mixer temperature and pressure, mass flow ratio of CO2/solution, solution concentration and solution type on the polymer particle morphology and particle size were investigated in detail. Well-defined spherical chitosan microparticles (three different molecular weights, i.e.3 kDa,50 kDa and 300 kDa) with controlled particle size distribution could be prepared at proper process conditions, while HPMC (K4 M and Kl 5 M) microparticles prepared were with partially spherical shape and copovidone spherical microparticles were with smooth surface. Whatever, the particle size of these polymers could be tailored to mainly range in 1-5 μm, which would be potential drug carriers for preparation of DPI in pulmonary delivery. Meanwhile, the main structures of polymers were maintained after SAA-HCM processing, while a decrease in crystallinity (usually amorphous state) and slight or no change in thermal stability were observed.Amoxicillin and theophylline were chosen as model drugs with small molecules, which could be used for anti-infection and anti-asthma, respectively. SAA-HCM process was used to micronize these two drug molecules from aqueous solutions, and the effects of various process parameters on particle properties were also studied thoroughly. Well-defined spherical amoxicillin microparticles in amorphous state with controlled particle size distribution (<3μm) could be prepared, while maintaining its molecule structure and thermal stability. In contrast, theophylline microparticles could not present perfect spherical particle and still had decreased crystallinity. The structure of micronized theophylline was well retained, while the melting point decreased slightly. Then, using chitosan and HPMC as carriers, amoxicillin-loaded polymer microparticles with amorphous state and high loading efficiency were successfully produced by SAA-HCM from aqueous solutions by one step. The polymer/amoxicillin feed ratio could influence the morphology, while the solution concentration significantly affected the particle size of composite microparticles. The particle size could be controlled in 0.2-5μm through adjusting process parameters. Amoxicillin molecules were uniformly dispersed in the chitosan matrix and could obtain a sustained release. This kind of formulation with good aerodynamic performance would find potential application in pulmonary delivery. On the other hand, the SAA-HCM produced theophylline-loaded polymer (chitosan, HPMC and copovidone) microparticles from aqueous solutions had different morphology and crystallinity degree with the change of polymer/theophylline feed ratio. The increase of polymer proportion could favor the composite particles present the morphology and size of the corresponding polymer particles with decreased crystallinity. After all, the composition of theophylline and polymer could modify the particle properties, and these results would help the design and development of theophylline formulations.Trypsin was adopted as a labile protein (macromolecule model drug), and was successfully micronized using SAA-HCM from aqueous solutions. The trypsin microparticles produced had various morphologies but hardly spherical particles with smooth surface under different process conditions, with particle diameters ranging from 0.2 to 4μm. The shell formation mechanism of protein could be used for the explanation. Then, chitosan with different molecular weights (3 kDa,50 kDa and 300 kDa) were selected as carriers in an effort to prepare trypsin-loaded composite microparticles by SAA-HCM process from aqueous solutions by one step. The chitosan/trypsin composite microparticles presented wrinkled surface, and grew with the increase of protein content The particle morphology and size could be suitably tailored by tuning chitosan molecule weight and process parameters. Composite microparticles were in amorphous state and had high loading efficiency above 90%. Although the molecule integrity was confirmed, trypsin could retained >70% of the enzymatic activity, which might be related to the perturbation of secondary and tertiary structure. Besides, the spatial distribution of the protein within the composite particles was characterized and evidences showed the protein was entrapped with surface accumulation trend, which could be related to the protein release profiles. The above results would promote the preparation of protein-loaded polymer mircoparticles.Then, the N-trimethyl chitosan (TMC) with excellent water solubility and mucoadhesive absorption, enhancement was derived from chitosan, and was then successfully micronized from aqueous solution using SAA-HCM process. Subsequently, well-defined spherical inuslin-loaded TMC microparticles with good insulin stability and loading efficiency above 90% were prepared by SAA-HCM process from aqueous solutions by one step. TMC/insulin feed ratio and solution concentration could influence the morphology and particle size distribution. Next generation impactor (NGI) experiment demonstrated that the TMC/insulin particulate formulations had good aerodynamic properties with the mass median aerodynamic diameter (MMAD) inside the inhalable range of 1-3μm and fine particle fraction (FPF<5μm) above 60%. In vivo study through intratracheal administration of the composite microparticles as DPI into SD rat lungs demonstrated that TMC could enhance the absorption of insulin with a pharmacological bioavailability of 57.2%. These results suggested that TMC microparticles were promising vehicle for DPI.Finally, SAA-HCM process was explored to the production of coprecipitates formed by hydroxyapatite (HA) nanometric particles and chitosan from the nanoparticles-suspended chitosan solutions. Well-defined spherical composite microparticles could be obtained. The application of SAA-HCM process was expanded, allowing the combination of functional nanoparticles and polymers.In summary, SAA-HCM technique could be extensively applied to the preparation of hydrophilic polymer, small molecule and macromolecular drug microparticles, as well as drug-loaded polymer microparticles from aqueous solutions without use of organic solvents. The SAA-HCH produced microparticulate formulations would find great potential especially in the pulmonary drug delivery system as DPI preparation. |
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