Browsing by Subject "Formulation"
Now showing 1 - 5 of 5
Results Per Page
Sort Options
Item Advanced formulation and processing technologies in the oral delivery of poorly water-soluble drugs(2013-08) Lang, Bo, 1986-; Williams, Robert O., 1956-With the advance of combinational chemistry and high throughput screening, an increasing number of pharmacologically active compounds have been discovered and developed. A significant proportion of those drug candidates are poorly water-soluble, thereby exhibiting limited absorption profiles after oral administration. Therefore, advanced formulation and processing technologies are demanded in order to overcome the biopharmaceutical limits of poorly water-soluble drugs. A number of pharmaceutical technologies have been investigated to address the solubility issue, such as particle size reduction, salt formation, lipid-based formulation, and solubilization. Within the scope of this dissertation, two of the pharmaceutical technologies were investigated names thin film freezing and hot-melt extrusion. The overall goal of the research was to improve the oral bioavailability of poorly water-soluble drugs by producing amorphous solid dispersion systems with enhanced wetting, dissolution, and supersaturation properties. In Chapter 1, the pharmaceutical applications of hot-melt extrusion technology was reviewed. The formulation and process development of hot-melt extrusion was discussed. In Chapter 2, we investigated the use of thin film freezing technology combined with template emulsion system to improve the dissolution and wetting properties of itraconazole (ITZ). The effects of formulation variables (i.e., the selection of polymeric excipients and surfactants) and process variables (i.e., template emulsion system versus cosolvent system) were studied. The physic-chemical properties and dissolution properties of thin film freezing compositions were characterized extensively. In Chapter 3 and Chapter 4, we investigated hot-melt extrusion technology for producing amorphous solid dispersion systems and improving the dissolution and absorption of ITZ. Formulation variables (i.e., the selection of hydrophilic additives, the selection of polymeric carriers) and process variables (i.e., the screw configuration of hot-melt extrusion systems) were investigated in order to optimize the performance of ITZ amorphous solid dispersions. The effects of formulation and process variables on the properties of hot-melt extrusion compositions were investigated. In vivo studies revealed that the oral administration of advanced ITZ amorphous solid dispersion formulations rendered enhanced oral bioavailability of the drug in the rat model. Results indicated that novel formulation and processing technologies are viable approaches for enhancing the oral absorption of poorly water-soluble drugs.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 Inhaled voriconazole formulations for invasive fungal infections in the lungs(2011-12) Beinborn, Nicole Angela; Williams, Robert O., 1956-Attention has begun to focus on the pulmonary delivery of antifungal agents for invasive fungal infections as inhalation of the fungal spores is often the initial step in the pathogenesis of many of these infections. Invasive fungal infection in the lungs in immunocompromised patients has high mortality rates despite current systemic (oral or intravenous) therapies. However, drug delivery of antifungal agents directly to the lungs could potentially result in high concentrations of drug in the lungs, a quicker onset of action, and reduction of systemic side effects. Voriconazole (VRC) is a second, generation triazole antifungal agent with increased potency, a broad spectrum of antifungal activity, and a fairly poor aqueous solubility. It is the recommended therapeutic agent for the treatment of Invasive Pulmonary Aspergillosis (IPA), and its use has improved therapeutic outcomes in immunocompromised patients with IPA. Still, systemic administration by oral or intravenous delivery is limited by high inter- and intra-patient pharmacokinetic variability, many potential drug interactions, and a narrow therapeutic index with many adverse effects, leading to clinical failures. Therefore, development of novel particulate formulations containing VRC for targeted drug delivery to the lungs is critical to improving therapeutic outcomes in patients with invasive fungal infections in the lungs. Within the framework of this dissertation, two particle engineering processes, thin film freezing (TFF) and advanced evaporative precipitation into aqueous solution (AEPAS), were investigated. The goal was to investigate microcrystalline VRC, nanocrystalline VRC, and nanostructured amorphous VRC formulations suitable for pulmonary delivery and to determine the effect of morphology on the in vivo deposition and distribution of inhaled particulate VRC formulations. TFF process parameters significantly affected the solid state properties and aerodynamic performance of the dry powder formulations containing VRC. Following dry powder insufflation into the lungs of mice, microstructured crystalline TFF-VRC achieved higher and more prolonged concentrations of VRC in the lungs with slightly lower systemic bioavailability than nanostructured amorphous TFF-VRC-PVP K25. AEPAS and TFF of template nanoemulsions did not lead to production of crystalline nanoparticles, as predicted. In particular, VRC proved to be a difficult molecule to stabilize in the nanocrystalline and nanostructured amorphous states. Ultimately, this body of work demonstrated that the particle engineering process, TFF, could be used to develop voriconazole formulations suitable for dry powder inhalation with more favorable pharmacokinetic parameters compared to inhaled voriconazole solution.Item The manufacture and characterization of protein nanoclusters(2013-05) Dinin, Aileen Kathryn; Johnston, Keith P., 1955-; Maynard, Jennifer Anne, 1974-The ability to formulate monoclonal antibodies at high concentration in a low-viscosity form is of broad interest in drug delivery, as monoclonal antibody-based drugs are now prescribed for cancer, autoimmune disorders, and many other diseases. Herein, we create highly concentrated antibody dispersions (up to 260 mg/mL) via three different methods, utilizing proline as an interacting depletant or trehalose as a non-interacting depletant. These dispersions are able to achieve viscosities an order of magnitude lower than similarly concentrated antibody solutions over a range of formulation pHs. When diluted, these antibody dispersions return to monomer. The proline acts to minimize protein zeta potential, thus reducing the electrostatic repulsion on the protein, even when formulated 3 pH units away from the antibody pI. In addition, it acts as a depletant, forcing the monomers into cluster via osmotic effectsItem Modeling pre-existing immunity to adenovirus as a method to identify novel formulations for a protective Ebola vaccine(2012-12) Choi, Jin Huk; Croyle, Maria A.; Cui, Zhengrong; Fast, Walter L; Georgiou, George; Roy, KrishnenduMucosal delivery of recombinant adenovirus serotype 5 (rAd5)-based vaccine preparations are appealing for vaccine development in terms of lowering toxicity induced by high viral loads and substantial liver accumulation following systemic injection of the vaccine. However, this mode of delivery is currently under-developed due to the relatively low T-cell mediated immune responses generated against the encoded transgene. The first study described in this thesis demonstrated that sublingual immunization induces rapid migration of MHCII+, CD11C+ antigen presenting cells to the delivery site and elicit antigen-specific T and B cell-mediated immune responses in naïve mice and those with pre-existing immunity (PEI) to Ad5 at a level higher than that achieved after oral immunization. More importantly, this strategy improved protection of animals with PEI to Ad in contrast to poor protection after IM injection. The second study was designed to establish a method for inducing PEI that most accurately reflects natural infection in rodents and identifies the immunologic parameters elicited by rAd5-based Ebola vaccine necessary for protection against lethal infection. When immunization occurred by the same route in which PEI was induced, the antigen-specific multifunctional CD8+ T cell and antibody responses were significantly reduced. This correlated with poor survival after challenge with a lethal dose of Ebola Zaire in rodents. The data suggests that 1) establishment of PEI by the same route used for immunization is the most stringent test for a novel formulation designed to be effective in those with PEI to Ad5, and 2) for a formulation to be effective in those with PEI, it must be capable of restoring antigen-specific multifunctional CD8+ T cell and antibody responses, compromised by PEI. The third study screened novel formulations for their ability to improve in vitro transduction efficiency and immunogenicity and efficacy in vivo in the presence of anti-Ad5 neutralizing antibodies. Formulations consisting of pharmaceutically acceptable, non-immunogenic excipients that can prime the arms of immune response compromised by PEI improved survival after lethal challenge with Ebola Zaire challenge for rAd5-based Ebola vaccine in rodents with PEI. Taken together, these studies provide insight on how to reconstitute necessary immune responses in vaccine protocols by establishing a reliable PEI model in rodents, testing routes of administration, and formulations of the rAd5-based Ebola vaccine.