Hinchcliffe, Michael
(1996)
The novel application of chitosan for the intranasal delivery of insulin.
PhD thesis, University of Nottingham.
Abstract
The findings of this project have added to the pool of information reported in the literature regarding the application of the nasal route for the delivery of insulin and other peptide drugs. The preliminary studies reported in this project were apparently the first studies performed to investigate the potential use of chitosan in nasal delivery systems. Nasal delivery systems were investigated in rat and sheep models. The efficacy of chitosan as a nasal absorption enhancer for insulin was compared to that of several other compounds which had been reported in the literature to enhance nasasl [i.e. nasal] drug absorption. Erythrocyte haemolysis studies were also performed to evaluate the membrane damaging effects of the various compounds tested.
The grade of chitosan predominantly used was a medium viscosity glutamate salt (MVCSN) which was 82% deacetylated and had a molecular weight of about 162,000. Other grades of chitosan of similar degree of deacetylation were also investigated for comparison with MVCSN (low viscosity grades of chitosan glutamate (LVCSN) and lactate (CSN lactate), medium viscosity chitosan hydrochloride (CSN HC1) and high viscosity chitosan base (HVCSN)).
The efficacy of chitosan in enhancing the nasal absorption of both insulin and salmon calcitonin, used as an alternative peptide, was demonstrated in rat and sheep models. Nasal insulin delivery systems were extensively investigated in rat and sheep models. In the rat model, insulin / LVCSN formulations at pH -4 were more effective than formulations at pH -7 in enhancing intranasal insulin absorption which was assessed indirectly from the degree of hypoglycaemia following dose administration. The reduced absorption in the latter formulation which was in the form of a suspension was attributed to complex formation between insulin and LVCSN. In the rat model, the absorption enhancing efficacy of MVCSN was second only to that of LPC. This was encouraging in view of the severe membrane damaging effects that LPC solutions have been shown to cause. In contrast, chitosan solutions have been shown to be relatively non-toxic to biomembranes. In the sheep model, a formulation incorporating MVCSN was much more effective than a formulation containing LPC in promoting nasal insulin absorption. These differences were attributed to the animal models used to investigate nasal absorption.
The degree of nasal absorption enhancement was improved by increasing the solution concentration of MVCSN until an optimal concentration was attained (approximately 0.5% and 0.35% in rat and sheep models, respectively). Further evaluation of nasal insulin / chitosan formulations in sheep, suggested that the formulation concentration of
chitosan was important for its absorption enhancing efficacy and at optimal chitosan concentration nasal insulin absorption was limited by the dose concentration of insulin. In both rat and sheep models, the nasal administration of hypotonic or isotonic formulations of insulin with chitosan did not influence the degree of nasal absorption enhancement attained. However, in rats, a hypertonic formulation was shown to further improve nasal insulin absorption which was attributed to the combined effects of the chitosan and the increased tonicity of the formulation on the nasal membrane.
The grade of chitosan used in the nasal absorption studies appeared to influence the degree of absorption enhancement obtained. In the rat model there was no difference in the absorption enhancing efficacy of CSN lactate and MVCSN although the performance of HVCSN was marginally reduced. In contrast, in the sheep model, MVCSN was more effective than LVCSN and CSN lacate in enhancing nasal insulin absorption although there was no difference in the performance of MVCSN and CSN HCL.
In studies in the rat, MVCSN was shown to have a transient effect on the permeability of the nasal mucosa to insulin which lasted about 30 minutes. This supports the claims that chitosan is non-damaging to the nasal mucosa. Erythrocyte haemolysis studies showed that MVCSN was non-damaging to rat erythrocyte membranes at concentrations which were higher than the concentrations used in nasal absorption studies. This was encouraging since the other compounds investigated for comparison with chitosan in this project were shown to be potent haemolytic agents at concentrations which were much lower than the concentrations which were effective for nasal absorption enhancement. MVCSN was less damaging to erythrocyte membranes than the other grades of chitosan tested.
This project demonstrated that chitosan enhanced the nasal absorption of insulin in rat and sheep models. In the sheep model the bioavailability of nasal insulin, relative to the subcutaneous route, was generally less than 5%. However, the hypoglycaemia which followed nasal insulin / chitosan dose administration was encouraging and a similar degree of efficacy in humans could be feasible for the therapeutic application of nasal insulin.
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