Nasal drug absorption enhancement by chemical promoter incorporation and ester prodrug design

Zezhi Shao, Purdue University

Abstract

Nasal drug administration has been regarded as one of the most potential routes for nonparenteral delivery of peptides, proteins, and conventional organic compounds. However, the nasal systemic bioavailability of large proteins and hydrophilic penetrants is usually low and variable. Studies were initiated to explore feasible means to enhance the nasal absorption of such drug candidates using insulin, a 5.7 KD protein, and acyclovir, an antiviral acycloguanosine analogue as model compounds using an in situ perfusion method. Groups of chemical promoters were evaluated with regard to their enhancing effects and mucotoxic irritation potential. Cyclodextrins and their derivatives were found to markedly promote nasal insulin uptake owing to their ability to partially dissociate insulin oligomers to smaller diffusing units. The membrane and cytosolic damaging effects associated with these agents were found to depend on the torus size and nature of chemical modification, with dimethyl-$\beta$-cyclodextrin being the strongest. The overall information generated from the nasal release of total protein, phospholipid, 5$\sp\prime$-nucleotidase, and lactate dehydrogenase provided ample biochemical information on the nasal mucotoxicity of cyclodextrins. Using the same in situ perfusion technique, the effectiveness of a variety of bile salts in enhancing acyclovir nasal absorption was found to depend on the hydrophobicity of the bile salt steroidal nucleus. Hydrophobic bile salts and bile salt/fatty acid mixed micelles penetrate the nasal lipid bilayers much more efficiently than their hydrophilic counterparts resulting in much greater mucosal irritation. Another approach involving chemical modification of acyclovir structure to generate bioreversible ester prodrugs was also examined. Derivatization of acyclovir by conjugation with lipophilic promoieties resulted in significant improvement in lipid/water partition coefficient, which in turn moderately increased nasal acyclovir uptake. Simultaneous bioconversion of acyclovir ester prodrugs contributed negatively to this effort, resulting in presystemic prodrug cleavage. In vitro nasal homogenate studies further confirmed that nasal carboxylesterase possesses a much stronger activity, on a unit protein basis, compared to plasma ester hydrolases and carboxylesterases in the pulmonary and tracheobronchial regions.

Degree

Ph.D.

Advisors

Mitra, Purdue University.

Subject Area

Pharmaceuticals

COinS