The pharmaceutical industry is at a critical juncture. With little remnants of the “Golden Age of the Pharmaceuticals” and applied pressure from large companies experiencing a dissipation of proprietary compounds, trends indicate a transition from a decade of stagnant productivity to one in which high throughput screening technologies and computational chemistry have diversified the discovery of new chemical entities (NCE). Despite these advances, drug discovery has been challenged by chemical entities that present delivery limitations due to the properties of their molecular structure. A recent evaluation of development pipelines indicated that approximately 70% of drug candidates exhibit poor aqueous solubility; thereby, resulting in erratic dissolution and insufficient bioavailability. Due to intrinsic physical properties, these compounds are known by the biopharmaceutics classification system (BCS) as class II compounds and are amendable to solubility and bioavailability enhancement platforms. Approaches such as pH adjustment, micronization, nanosuspensions, co-solvent solubilization, cyclodextrin inclusion complexation, salt formation, emulsified drug formulations and amorphous solid dispersions (ASD) are commonly utilized to maximize bioavailability and enrich in vivo absorption by prolonging exposure to high concentrations of dissolved drug in the gastrointestinal tract (GIT). Single-phase amorphous systems, such as solid dispersions, have been the focal point of the aforementioned practices as a result of their ability to promote a state of drug supersaturation over an extended duration of time. Within the structure of this dissertation, the application of concentration enhancing polymers for bioavailability enhancement of low solubility compounds was evaluated using solvent and fusion-based solid dispersion technologies. Exploiting a variety of analytical methodologies and tools, formulations produced by spray drying and hot melt extrusion (HME) techniques were investigated for sufficient dissolution enhancement. Studies revealed the selected formulation approaches provided a viable platform for manufacturing solid dispersions by illustrating systems that offered rapid and prolonged periods of supersaturation. While of the applications of single-phase amorphous solid dispersions are continuously expanding, their dissolution behavior is not as well understood. The overarching objective of dissolution testing during formulation development is to achieve biological relevance and predict in vivo performance. Proper in vitro dissolution testing can convey the influence of key in vivo performance parameters and be implemented for assessment and comparison of ASD formulations. Studies suggest that existing research fails to accurately address the intricacies associated with the supersaturated state. Upon solvation and during transit in the GIT, several high-energy drug-containing species are present in addition to free drug. Although these species are not absorbed in vivo, they play a pivotal role in generating and maintaining the supersaturation of a drug substance and function to replenish the supply of free drug as it permeates across the gastrointestinal membrane. Established dissolution apparatuses and methodologies in the United States Pharmacopeia (USP) focus on evaluation of total dissolved drug and may not be physiologically relevant for determining the amount of drug absorbed in vivo. Within the framework of this dissertation, a dissolution methodology was designed to reflect the physiochemical, physiological and hydrodynamic conditions that transpire throughout dissolution and absorption of an ASD during transit in the GIT. The apparatus and model present the ability to understand the kinetics and mechanisms of dissolution, supersaturation and nucleation. To support this hypothesis, analytical methods including high pressure liquid chromatography (HPLC) with ultraviolet (UV) detection were developed and fully validated. In parallel, a novel plasma membrane treatment was established to fabricate biomimetic membranes that possessed a hydrophilic and hydrophobic surface. The treated membranes are comprised of applied surface chemistries that emulate the unstirred aqueous layer created by microvilli protruding from the intestinal epithelial membrane as well as lipophilic constituents corresponding to the epithelial lipid membrane. Calculated in vitro similarity (f2) and difference (f1) factors support the hypotheses that plasma treated microporous polymer membranes exhibit biorelevant properties and demonstrate adequate biorelevance for in vitro dissolution studies. The described dissolution methodology has been applied as a tool for selection of candidates to move forward to pharmacokinetic studies. In a culminating study, in vitro – in vivo correlations (IVIVC) were performed employing the universal membrane-permeation non-sink dissolution method for formulations of Carbamazepine. To demonstrate the utility of the methodology, multiple level C correlations were established. The membrane-permeation model enables quantitative assessment of drug dissolution and absorption and offers a means to predict the relative in vivo performance of amorphous solid dispersions for BCS class II drug substances. / Chemistry
| Identifer | oai:union.ndltd.org:TEMPLE/oai:scholarshare.temple.edu:20.500.12613/2196 |
| Date | January 2017 |
| Creators | Puppolo, Michael McBride |
| Contributors | Jansen Varnum, Susan, Wunder, Stephanie L., Zdilla, Michael J., 1978-, Weber, Bruce A. |
| Publisher | Temple University. Libraries |
| Source Sets | Temple University |
| Language | English |
| Detected Language | English |
| Type | Thesis/Dissertation, Text |
| Format | 411 pages |
| Rights | IN COPYRIGHT- This Rights Statement can be used for an Item that is in copyright. Using this statement implies that the organization making this Item available has determined that the Item is in copyright and either is the rights-holder, has obtained permission from the rights-holder(s) to make their Work(s) available, or makes the Item available under an exception or limitation to copyright (including Fair Use) that entitles it to make the Item available., http://rightsstatements.org/vocab/InC/1.0/ |
| Relation | http://dx.doi.org/10.34944/dspace/2178, Theses and Dissertations |
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