Date of Award


Degree Type


Degree Name

Master of Science (MS)


Pharmaceutical Sciences

First Advisor

Hossein Zia


Peptide and protein drugs are increasingly becoming popular with the advances in biotechnology. Although these compounds are highly potent and display superior pharmacological profiles, there are various barriers to their systemic delivery. Most of these barriers are related to the properties of the proteins and peptides which include high large molecular size, susceptibility to proteolytic breakdown, tendency to undergo aggregation, adsorption, and denaturation. Most of these molecules are delivered by parenteral administration due to the low bioavailability obtained by the oral route. Among the noninvasive routes of drug administration, the nasal route seems to be a potential alternative to parenteral administration of peptides and proteins. When compared to other noninvasive routes of administration, the nasal route offers some advantages; including avoidance of the first pass effect and enzymatic degradation in the gastrointestinal tract; and a relatively large surface area and adequate blood flow, resulting in rapid absorption of drugs through the nasal mucosa and providing high patient compliance. However, there are certain factors which could interfere with the nasal absorption of drugs such as the method and technique of administration , and pathological conditions of the nasal cavity. Surprisingly few animal models have been developed and characterized to study the basic physicochemical nature of the nasal mucosal absorption processes, in spite of the great potential offered by the intranasal route for systemic drug administration. Most of the mechanistic and absorption screening studies have been performed using the in situ rat nasal recirculation technique. The small nasal cavity and nostrils of the rat restrict the evaluation of nasal formulations such as metered sprays, powders and microspheres. The acute nature of the perfusion technique limits its application to small laboratory animals for economic reasons. Hence there is a need to develop chronic perfusion techniques in large laboratory animals which can give better representation of the nasal mucosal absorption processes in human beings. The objectives of this study were: (1) to develop and establish a non-surgical perfusion technique for use with large laboratory animals, (2) to compare the new technique with the existing techniques, (3) to identify the study conditions to establish and validate the animal model, ( 4) to evaluate various nasal formulations and/or modes of administration such as sprays, microparticles using the same animal model and compare with the results obtained from perfusion studies. Insulin was chosen as model polypeptide and the rabbit was selected as an animal model. A randomized crossover study design was used for evaluating the insulin effect in five rabbits. The absorption of insulin was measured by determining blood glucose levels using Accuchek II and ChemStrip bG strips. A new non-surgical perfusion technique was developed and established using the rabbit. The study conditions identified in establishing the animal model include: the angle at which the rabbit head is placed, the perfusion rate, the volume of the perfusate, the amount of the enhancer present in the perfusate and the pH of the solution. Spray formulations containing different levels of insulin (1.25, 2.5, 5 and IOU/kg) and sodium taurocholate (1 %) were evaluated in the same animal model. The nasal sprays resulted m an immediate reduction of glucose levels. A maximum hypoglycemic effect was observed approximately 60 minutes after administration. As the insulin dose was increased, there was an increase in glucose reduction. A polyacrylic acid gel formulation containing insulin loaded microparticles (lOU/kg) resulted in a hypoglycemic effect, but the overall effect was less when compared to the spray formulations and s.c injection. The apparent bioavailability was determined relative to subcutaneously injected insulin (0.25U/kg). This bioavailability increased for spray formulations as the dose of insulin was decreased. A maximum bioavailability of 18.8% was observed for the 1.250/kg spray and the minimum bioavailability (1.58%) was observed for the perfusion study carried out using the new technique.