Date of Award

Fall 2006

Document Type


Degree Name

Doctor of Philosophy (PhD)


Biomedical Engineering

First Advisor

Yuri Lvov


Non-invasive drug delivery systems for therapeutic drugs are gaining prominence. One such system, the nasal delivery system, shows good prospect for effective delivery of some drugs, however, it is yet to be well established for others. The preparation of a reformulated drug and studying its in vitro characteristics is a crucial step in the process of adapting the new drug for nasal delivery systems. The purpose of this research is to study the effect of electrostatic layer by layer assembly of polyelectrolytes on PROMAXX®insulin microparticles and to study the chemical, physical and corresponding release properties of the resulting formulations. PROMAXX® insulin microparticles of recombinant human insulin prepared and provided by Epic Therapeutics Inc®. During reformulation the temperature, pH, salt concentration and excepient concentrations were controlled to achieve maximum yield of final product and minimize raw material consumption. In vitro release studies were performed to study the release properties of various formulations prepared by electrostatic layer-by-layer assembly and compared with a standard insulin formulation. A key finding involved that the control release of insulin can be achieved by suitable selection of first polycation layer, and the consequent polyelectrolyte layers can be used to fine-tune the release. In addition, polyelectrolyte requirements were established for production of grams of final product.

To retard the permeability of thin films prepared with electrostatic layer-by-layer assembly, lipid bilayers were incorporated in layer by layer assembly. Study of diffusion properties of the composite multilayer films demonstrated that outermost lipid layer on hollow polyelectrolyte microcapsules acts as an effective diffusion barrier for FITC-dextran (MW 4300), which is comparable to insulin (MW 5800), and hence an important development towards imparting stealth and sustained release properties to low molecular weight drugs.

Hydrophobic drugs pose a problem for entrapment in polymeric matrices due to their poor solubility in aqueous media. In an effort to the study cores other than protein and drug microcrystals for nasal drug delivery, calcium carbonate microparticles incorporating phospholipids and hydrophobic molecules were prepared and characterized. The hydrophobic molecules were co-entrapped with anionic phospholipids in the calcium carbonate matrix with a near homogenous distribution of the molecules in the matrix, with loading up to 4% (w/w) of calcium carbonate. Further, the anionic phospholipids influence the crystal morphology of calcium carbonate resulting in a decrease in release of hydrophobic molecules due to decreased rate of re-crystallization.

Included in

Pharmacology Commons