Browsing by Subject "Dry powder inhaler"
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Item Carrier-free high-dose dry-powder inhaler formulation of non-steroidal anti-inflammatory drugs(2016-08) Yazdi, Ashkan Khakparvar; Smyth, Hugh D. C.; Williams III, Robert O; Frei, Christopher R; Watts, Alan B; McWilliams, Bennie CIbuprofen (IBU) is a non-steroidal anti-inflammatory agent (NSAID) is administered orally as tablets and suspensions. It is indicated for pain, fever, and other inflammatory conditions. More recently, a slower rate of respiratory decline is shown in cystic fibrosis (CF) patients on high, oral doses of IBU in comparison to placebo. The use of this treatment modality has not been well adopted or widespread due to high doses, side effects, contraindications, and black box warnings regarding the use of IBU. Pulmonary delivery may be an attractive alternative to high-dose oral administration in CF since lungs are the desired targets for the anti-inflammatory and antibiotic activities of IBU. Typically with inhaled powders, a binary formulation of a drug with a carrier, such as lactose, significantly improves their performance; however, this strategy is not practical for the delivery of a large drug dose via a dry powder inhaler (DPI). Other inhalation devices such as nebulizers require significantly more time for drug delivery and metered dose inhalers may be incapable of metering sufficiently large drug doses. Therefore, carrier-free DPIs have been explored for large drug dose delivery. IBU exists as the stable polymorph I (in its acicular crystal habit), or as the less stable polymorph II. Low melting point (75.85°C), water solubility, and crystal habit of ibuprofen make its processing challenging. A novel air-jet milled carrier-free formulation of IBU was developed using the design of experiment approach, which possessed superior flowability, in-vitro aerodynamic performance determined by Next Generation Impactor. Furthermore, the developed formulation possessed at least one-year stability at room temperature in the desiccator under vacuum.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 Improved inhalation therapies of brittle powders(2013-12) Carvalho, Simone Raffa; Williams, Robert O., 1956-Advancements in pulmonary drug delivery technologies have improved the use of dry powder inhalation therapy to treat respiratory and systemic diseases. Despite remarkable improvements in the development of dry powder inhaler devices (DPIs) and formulations in the last few years, an optimized DPI system has yet to be developed. In this work, we hypothesize that Thin Film Freezing (TFF) is a suitable technology to improve inhalation therapies to treat lung and systemic malignancies due to its ability to produce brittle powder with optimal aerodynamic properties. Also, we developed a performance verification test (PVT) for the Next Generation Cascade Impactor (NGI), which is one of the most important in vitro characterization methods to test inhalation. In the first study, we used TFF technology to produce amorphous and brittle particles of rapamycin, and compared the in vivo behavior by the pharmacokinetic profiles, to its crystalline counterpart when delivered to the lungs of rats via inhalation. It was found that TFF rapamycin presented higher in vivo systemic bioavailability than the crystalline formulation. Subsequently, we investigated the use of TFF technology to produce triple fixed dose therapy using formoterol fumarate, tiotropium bromide and budesonide as therapeutic drugs. We investigated applications of this technology to powder properties and in vitro aerosol performance with respect to single and combination therapy. As a result, the brittle TFF powders presented superior properties than the physical mixture of micronized crystalline powders, such as excellent particle distribution homogeneity after in vitro aerosolization. Lastly, we developed a PVT for the NGI that may be applicable to other cascade impactors, by investigating the use of a standardized pressurized metered dose inhaler (pMDI) with the NGI. Two standardized formulations were developed. Formulations were analyzed for repeatability and robustness, and found not to demonstrate significant differences in plate deposition using a single NGI apparatus. Variable conditions were introduced to the NGI to mimic operator and equipment failure. Introduction of the variable conditions to the NGI was found to significantly adjust the deposition patterns of the standardized formulations, suggesting that their use as a PVT could be useful and that further investigation is warranted.