Browsing by Subject "Formulations"

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Formulation and processing technologies for enhanced oral bioavailability of poorly water soluble compounds
(2009-08) DiNunzio, James Carlo; McGinity, James W.; Williams, Robert O., 1956-
Developments in high throughput screening and combinatorial chemistry have contributed to the unprecedented success of the pharmaceutical industry over the last twenty years, leading to a multitude of blockbuster compounds that revolutionized treatment for a variety of clinical indications. This success, particularly in drug discovery, has been tempered by an increased number of moieties exhibiting delivery limitations due to molecular structure. One of the most pressing areas of pharmaceutical research today is addressing the reduced aqueous solubility of developmental chemical entities in pharmaceutical pipelines, which has been estimated to affect up to 90% of such compounds. Current technologies have focused on maximizing dissolution rates or equilibrium solubilities of such compounds using platforms such as microemulsions, polymorph engineering, particle size reduction, and complexation. While these technologies have been shown to improve oral bioavailability for a number of compositions, further improvement can be achieved by developing new production and formulation technologies for amorphous systems. Within the frame work of this dissertation, two unique technologies for bioavailability enhancement were investigated; formulation with concentration enhancing polymers to provide extended durations of supersaturation and the development of a novel fusion based solid dispersion production process based on thermo-kinetic mixing, termed KinetiSol® Dispersing, for the production of amorphous solid dispersions. Studies of solid dispersions containing concentration enhancing polymers prepared by ultra rapid freezing showed the ability of these formulations to provide improved oral bioavailability of itraconazole when compared to the currently marketed product, which is a conventional hydrophilic solid dispersion. KinetiSol® Dispersing was also extensively studied within this work and shown to be a viable platform for the production of hydrophilic solid dispersions, plasticizer free solid dispersions and solid dispersions containing heat sensitive active ingredients. In a culminating study, KinetiSol® Dispersing was utilized for the production of amorphous solid dispersions containing concentration enhancing polymers for improved oral bioavailability of itraconazole. Ultimately, this body of work demonstrated that concentration enhancing polymers could provide improved oral bioavailability for poorly water soluble compounds, while KinetiSol® Dispersing could be used for the production of such compositions, thereby presenting novel technologies for addressing future development of poorly water soluble active ingredients.
Importance of stability of pharmaceutical formulations
(2016-12) Hengsawas, Soraya; Williams, Robert O., 1956-; Cui, Zhengrong; Frei, Christopher R; Zhang, Feng; McGinity, James W
Stability is an essential quality attribute for pharmaceutical formulations. Evaluation of drug stability can prevent toxicity and increase safety, efficacy and quality of the final drug product. In this work, various factors affecting stability of both small molecule and biopharmaceutical compounds were investigated. In the first study, we initially hypothesized that albendazole, a poorly water soluble drug, could be prepared by melt extrusion to enhance its dissolution and bioavailability. However, it was found that albendazole was severely degraded by heat and shear during extrusion. When combined with methanesulfonic acid and Kollidon VA 64, amorphous albendazole solid dispersion was successfully prepared by an alternative process, spray drying, to enhance dissolution and shelf-stability. In the second study, the stability of a caveolin-1 scaffolding domain (CSP7), which is a newly developed peptide for the treatment of idiopathic pulmonary fibrosis, was investigated in order to achieve an optimal formulation for in vivo clinical studies. This study showed the physical instability of the peptide, which was aggregation induced by moisture, and the crystallization of bulking agent on its stabilizing effect. It was found that the moisture-induced aggregates were reversible and could be prevented by pH adjustment and incorporation of lactose in the composition. Lactose, a reducing sugar, stabilized the peptide possibly as a result of chemical interactions with CSP7 (e.g., formation of a Schiff base with the N-terminal amino group of CSP7). Based on these results, lactose stabilized CSP7 against moisture-induced aggregation in the solid state to a greater degree than mannitol. Additionally, stability of the CSP7-bulking agent formulations was not affected by nebulization using vibrating mesh nebulizers. Lastly, the effect of nebulization using vibrating mesh nebulizers on stability of tissue-type plasminogen activator (tPA) and single-chain urokinase plasminogen activator (scuPA), being studied for the treatment of inhalational smoke-induced acute lung injury (ISALI), was evaluated. For scuPA, the effect of lyophilization on its stability was also studied. The results showed that scuPA was stable after lyophilization (scuPA) and that both proteins were stable following reconstitution and nebulization. There were only slightly differences between the active and passive vibrating mesh nebulizers. In conclusion, from our work, the physical and chemical stability of small- and macromolecules was affected by formulation composition, processing and post-processing factors.