Browsing by Subject "Pulmonary drug delivery"
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Item Dry powder antibiotics for inhaled anti-tuberculosis therapy(2010-12) Son, Yoen Ju; McConville, Jason Thomas; McGinity, James W.; Williams, Robert O.; Wiederhold, Nathan; Roy, KrishnenduThe aim of this research was to develop and fully investigate a novel method of antibiotic drug delivery to the lung that will address problems with current therapeutic regimens for treatment of airway infections. To demonstrate the performance of prepared formulations, the design of suitable characterization methods were also aimed. A novel dissolution method for evaluating the in vitro dissolution behavior of inhalation formulations was developed. The membrane holder was designed to enclose previously air-classified formulations so that they could be uniformly tested in the dissolution apparatus. Dissolution procedures, the apparatus, the dose collection, the medium, and test conditions were developed and the dissolution behaviors of test compounds were evaluated by experimental and mathematical analysis. It was proved that the aerodynamic separation of formulation prior to dissolution assessment have a significant influence on the dissolution profiles. The optimized test method using the membrane holder was applied to evaluate in vitro dissolution profiles of the manufactured formulations of rifampicin (RF). The carrier/excipient-free RF dry powder formulation was investigated. The rifampicin dihydrate (RFDH) powders having MMAD of 2.2 um were prepared using a simple recrystallization process. The RFDH powders have a thin flaky structure, and this unique morphology provides improved aerosolization properties at maximal API loading. The manufactured RFDH formulation showed 80% drug release within 2 hours. To retard the release rate of RF, the prepared RFDH crystals were coated with hydrophobic polymer, PLA or PLGA, using spray-dryer equipped with multi-channel spray nozzles. The multi-channel spray nozzle used in this study has two separate nozzles for aqueous solution and one for gas fluid. The RFDH crystals and the coating solutions were sprayed through the two separate liquid nozzles at the same time. The coated RFDH formulations were prepared using multi-channel spray nozzles. The coated formulations contained at least 50% w/w of RF with no change of their flaky morphology. The initial RF release was lowered by coating; the lowest initial RF release was observed from the coated powders with PLA polymer as 32% among the coated formulations. Overall, the 80% of RF was released within 8 hours. The RFDH and coated RFDH formulations delivered via the pulmonary route would be anticipated to provide higher local (lung) drug concentrations than that of orally delivered powders. Particularly, the coated RFDH powders deposited in the alveolar region may prolong the drug residence time in the site of infections. Additionally, it was proved that the RFDH and coated RFDH formulations provided much better stability than the amorphous RF.Item Influence of carrier particle size and surface roughness on the aerosol performance of DPI formulations(2011-08) Donovan, Martin Joseph; Smyth, Hugh D. C.The influence of the size and morphology of carrier particles on drug dispersion performance from passive dry powder inhalers has been extensively studied topic, and a consensus has been reached regarding the adverse effect that larger carrier particle diameters impart to aerosol performance. However, previous studies have generally employed only a few carrier particle size fractions, generally possessing similar surface characteristics. Accordingly, theories developed to explain the influence of the physical characteristics of carrier particles on performance relied heavily on both extrapolation and interpolation. To fill in the gaps from the literature and simultaneously evaluate the influence of carrier particle size and morphology, a comprehensive study was undertaken using 4 lactose grades, each sieved into 13 contiguous sizes, to prepare 52 formulations incorporating a unique lactose grade-size population. The aerosol performance results indicated that large carrier particles possessing extensive surface roughness can improve drug dispersion, in contrast to what has been previously reported. It is proposed that this may be attributed to mechanical detachment forces arising from collisions between the carrier particle and inhaler during actuation. Based on these observations, a novel dry powder inhaler platform was developed, employing carrier particles much larger (> 1 mm) than previously explored in both the scientific and patent literature. Optimization of this technology required the judicious selection of a carrier material, and following an extensive screening process, low-density polystyrene was selected as a model candidate. Given its low mass, diameters in excess of 5-mm could be employed as carriers while still generating high detachment forces. To minimize drug particle aggregation, a novel drug-coating method employing piezo-assisted particle dispersion was developed to compensate for the reduced surface area of the novel carrier particles. In addition, the selection of a suitable inhalation device prototype was instrumental to the overall performance of the technology. In vitro testing of the novel large carrier particles yielded emitted fractions in excess of 85%, and overall drug delivery of up to 69% of the nominal dose.Item Inhalable dosage forms containing difficult-to-formulate drugs : compositions and processing design space(2020-06-22) Sahakijpijarn, Sawittree; Williams, Robert O., III, 1956-; Cui , Zhengrong; Smyth, Hugh D.C.; Koleng, John J.; Watts , Alan B.Pulmonary drug delivery has recently gained much importance in the health care research area as it enables to target the drug delivery directly to lung both for local and systemic treatment. Despite extensive studies in the last decade, the development of inhaled formulations is still challenging, especially for difficult-to-formulate drugs such as macromolecule drugs and amorphous small molecule drugs. Due to the fragile nature of macromolecules, they are prone to degrade when exposed to physicochemical stress such as temperatures, pH, storage humidity, formulation component, atomization. The first two studies demonstrate the strategies to overcome the stability challenge of proteins and peptide in order to deliver a drug to the lung by nebulization. By the right selection of nebulizer and formulation optimization, the stability of fibrinolysins can be preserved after lyophilization, reconstitution, and nebulization using vibrating mesh nebulizers. Furthermore, the effect of counterion on the stability of peptide was studied in the second study. The formulation and processing were optimized to preserve volatile counterions, thus minimizing the pH change of reconstituted solutions and maintaining the stability of peptide. In addition to macromolecules, amorphous small molecules drug is another type of difficult-to-formulate drugs since they are thermodynamically unstable and thus tend to undergo crystallization during storage, which can affect the drug aerosolization and drug release upon deposition in the airway. The third study aimed to investigate the feasibility of thin film freezing to prepare dry powder for inhalation containing a high potency of amorphous tacrolimus. We found that using ultra-rapid freezing can increase drug loading up to 95% while maintaining good aerosol performance and stability. Finally, a new strategy to overcome the challenge in developing ordered mixture dry powder for inhalation was developed in the last study. We found that powders made by TFF ordered mixing process exhibited superior aerosol performance and less variation in content uniformity, compared to powders made by conventional powder blending. Throughout these studies, we can conclude that the right design of formulation and process can help to overcome the challenges in developing inhaled formulations of difficult-to-formulate drugsItem Optimization of next generation inhalable powders for the treatment of pulmonary infections(2020-12-09) Brunaugh, Ashlee Dawn; Smyth, Hugh D. C.; Williams, Robert; Zhang, Feng; Koleng, JohnRespiratory infections are a major cause of morbidity and mortality worldwide, particularly in low- or middle-income countries. Direct drug delivery to the lungs is a promising approach for the treatment of respiratory infections, as it enables rapid achievement of high drug payloads at the site of the infection while minimizing systemic drug exposure and side effects. However, traditional, low-potency DPIs are not optimized to meet the challenges of infectious disease therapy (high doses, narrow therapeutic indices, and delivery of labile molecules). Next generation DPIs must exhibit efficient powder aerosolization, promote drug stability, and ensure reproducible lung deposition independent of lung function. To achieve wide-spread global utilization, particularly in developing economies, cost-constraints and scalability of manufacturing techniques must be considered. These barriers necessitate a systematic and streamlined development approach. Multiple aspects of next generation inhaled powder delivery were examined. First, the feasibility of high-dose dry powder delivery was investigated through the development of a macrophage-targeted, excipient-free clofazimine powder for treatment of pulmonary mycobacteria infections. By working with rather than against the innate physicochemical properties of clofazimine, efficient, flow-rate independent aerosol performance was achieved, and systemic drug exposure was reduced. Next, the design space for pulmonary delivery of therapeutic proteins was optimized through two separate studies, which balanced the requirements for protein stability and efficient aerosolization. Physicochemical properties of respirable protein powders were related to aerosol performance metrics through multilinear regression modeling, and the effect of particle engineering techniques on the stability of a monoclonal antibody was investigated. The result was the generation of a template formulation and particle engineering approach which can generate stable and respirable therapeutic biologic powders. Lastly, small molecule and macromolecule delivery approaches were combined through the development of a fixed-dose combination powder of niclosamide and human lysozyme for the treatment of COVID-19. The formulation was optimized to be suitable for three forms of respiratory drug delivery (DPI, nasal spray, and nebulizer) in order to reach a broad patient population with varying disease severity. These studies demonstrate the feasibility of treatment of pulmonary infections using inhaled drug powders and provide the basis for future development and commercialization efforts.