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Spray freezing into liquid to produce protein microparticlesYu, Zhongshui 14 May 2015 (has links)
Recent advances in molecular biology have led to an explosive growth in the number of peptide and protein drugs derived from both recombinant technology and conventional peptide drug design. However, development of peptide and protein therapeutics has proven to be very challenging because of inadequate physical and chemical stability. In recent years, particle engineering processes have become promising approaches for enhancement of protein stability as well as provide options for more delivery routes. In this research program, spray freezing into liquid (SFL) process was developed and optimized in order to achieve broad platform and application in protein and peptide drug delivery systems. The overall goal of this research was to produce stabilized protein and peptide microparticles for various drug delivery systems by using SFL particle engineering technology. Firstly, the use of the SFL process to produce peptide microparticles was investigated. Insulin microparticles produced by the SFL process were highly porous, low tap density and narrow particle size distribution. The influence of the SFL process parameters and excipients on the physicochemical properties of peptide microparticles was determined and compared to the widely used particle formation technique--freeze-drying. The SFL process was further used to produce protein microparticles. In the study, bovine serum albumin (BSA), a medium sized protein, was used as a model drug. The influence of SFL process parameters and excipients on the stability of BSA was studied. Very low monomer loss of BSA was found in this study even though the specific surface area of the powder was very high. Results also demonstrated that the SFL process had minimal influence on protein structure. The SFL process was further investigated by comparing the SFL process to spray freeze drying process (SFD), which is a relatively new process to produce protein and peptide microparticles. The influence of atomization, freezing and drying on the stability of lysozyme was investigated for both the SFL and SFD process. This study tested the hypothesis that the SFL process is a better process than SFD process because of avoiding air-liquid interface and minimum interfacial surface absorption of protein in SFL process. The particle size of protein and peptide microparticles produced by SFL process was further reduced to nanoparticles by sonication or homogenization processes in organic solvent. In this study, the influence of process parameters on the particle size and enzyme activity of lysozyme was investigated. The results showed that sonication or homogenization did not influence the enzyme activity of lysozyme. Lastly, insulin and insulin/dextran microparticles produced by SFL the process was encapsulated into polymer microspheres for oral delivery. Complexation and polymer composition was studied in order to optimize release and stability of insulin. Insulin nanoparticles in microspheres minimized the release of insulin in acid with high drug loading compared to other studies. The stability of insulin was decreased by complexation to dextran sulfate. The results of this research demonstrated that the SFL process offers a highly effective approach to produce protein and peptide powders suitable for different drug delivery systems. The microparticles produced by the SFL process had desirable characteristics such as narrow particle size distribution and high porosity. The stability of protein and peptide was well maintained through the SFL process. Therefore, SFL process is an effective particle engineering process for protein and peptide pharmaceuticals. / text
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A novel cryogenic particle engineering technology to micronize water-insoluble drugs and enhance their dissolution properties : spray-freezing into liquidRogers, True Lawson 14 May 2015 (has links)
Poorly water-soluble and insoluble chemical agents are routinely investigated in the pharmaceutical industry for pharmacological activity, but many of these are never commercialized due to inadequate dissolution and subsequent low oral bioavailability following oral administration. The bioavailability of many hydrophobic active pharmaceutical ingredients (APIs) can be increased by enhancing their aqueous dissolution. Spray-Freezing into Liquid (SFL) is a novel particle engineering technology that has been demonstrated in the following studies to significantly enhance the dissolution of insoluble APIs. The ultimate goal throughout the studies was to produce micronized SFL powders where the inherently insoluble API would be completely dissolved in aqueous dissolution media within a minimal amount of time (less than ca. 10 minutes). The SFL particle engineering technology is a novel process that was developed, investigated and optimized in order to broaden its applications in pharmaceutical drug delivery systems. Micronized SFL powders were compared head-to-head with powders produced from milling, co-grinding with excipients and slow freezing of liquids containing dissolved API and excipients followed by lyophilization. To strengthen the applicability of the SFL particle engineering technology, studies were conducted where micronized SFL powders were exposed to various stability storage conditions, and characterized to determine the influences of the exposure conditions and time on the physicochemical properties of the powder containing the API. The utility of the SFL process was further enhanced by developing an atmospheric freeze-drying (ATMFD) technique to obtain dry micronized SFL powders. Micronized SFL powders dried by ATMFD were compared to micronized SFL powders dried by vacuum-freeze drying to determine any changes in physicochemical properties or dissolution profiles as a function of the drying technique utilized. The usefulness of the SFL particle engineering technology was broadened when it was found that highly concentrated emulsions could be processed by SFL to produce micronized powders that rapidly wetted and dissolved in dissolution media. Micronized SFL powders produced from emulsion were investigated and compared to slowly frozen agglomerates from emulsion and a micronized SFL powder from solution. As a result of the following studies, the enabling examples using the SFL platform were designed to illustrate applications of the SFL technology as a tool to enhance the aqueous dissolution of poorly water-soluble and insoluble APIs. Therefore, it was demonstrated that this novel particle engineering technology is a feasible method that may be used in the pharmaceutical industry to solve the ever-present solubility and dissolution problems associated with poorly water-soluble or insoluble APIs, or chemical agents being investigated for pharmacological activity as future APIs / text
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