Browsing by Subject "Nebulization"
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Item Development of an inhalational formulation of Coenzyme Q₁₀ to treat lung malignancies(2011-12) Carvalho, Thiago Cardoso; McConville, Jason ThomasCancer is the second leading cause of death in the United States and its onset is highly incident in the lungs, with very low long-term survival rates. Chemotherapy plays a significant role for lung cancer treatment, and pulmonary delivery may be a potential route for anticancer drug delivery to treat lung tumors. Coenzyme Q₁₀ (CoQ₁₀) is a poorly-water soluble compound that is being investigated for the treatment of carcinomas. In this work, we hypothesize that formulations of CoQ10 may be developed for pulmonary delivery with a satisfactory pharmacokinetic profile that will have the potential to improve a pharmacodynamic response when treating lung malignancies. The formulation design was to use a vibrating-mesh nebulizer to aerosolize aqueous dispersions of CoQ₁₀ stabilized by phospholipids physiologically found in the lungs. In the first study, a method was developed to measure the surface tension of liquids, a physicochemical property that has been shown to influence the aerosol output characteristics from vibrating-mesh nebulizers. Subsequently, this method was used, together with analysis of particle size distribution, zeta potential, and rheology, to further evaluate the factors influencing the capability of this nebulizer system to continuously and steadily aerosolize formulations of CoQ₁₀ prepared with high pressure homogenization. The aerosolization profile (nebulization performance and in vitro drug deposition of nebulized droplets) of formulations prepared with soybean lecithin, dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC) and distearoylphosphatidylcholine (DSPC) were evaluated. The rheological behavior of these dispersions was found to be the factor that may be indicative of the aerosolization output profile. Finally, the pulmonary deposition and systemic distribution of CoQ₁₀ prepared as DMPC, DPPC, and DSPC dispersions were investigated in vivo in mice. It was found that high drug amounts were deposited and retained in the mouse lungs for at least 48 hours post nebulization. Systemic distribution was not observed and deposition in the nasal cavity occurred at a lower scale than in the lungs. This body of work provides evidence that CoQ₁₀ may be successfully formulated as dispersions to be aerosolized using vibrating-mesh nebulizers and achieve high drug deposition in the lungs during inhalation.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 drugs