Use of polymeric gelling system to improve intranasal residence time effect of viscoelasticity on mucociliary transport.
Yu, Danny Man-sum
1993
Abstract
The objective of this research was to investigate the use of polymeric materials in the formulation of nasal delivery systems to increase the intranasal residence time in order to improve the rate and extent of absorption of drugs administered intranasally. The polymeric systems evaluated were neutralized polyacrylic acid (Carbopol$\sp{\circler}$ 934P), poly(ethylene oxide) (Polyox$\sp{\circler}$) and hydroxypropyl methyl-cellulose (HPMC). The storage modulus ($G\sb1$), loss modulus ($G\sb2$) and loss tangent (tan $\delta$) of the polymers were examined over a frequency range of 10$\sp{-3}$ to 10 Hz using an oscillatory viscoelastic rheometer at 30$\sp\circ$C. The results indicated that neutralized Carbopol is at the plateau region of viscoelasticity and exhibited solid-like behavior, while Polyox and HPMC are at the terminal region of viscoelasticity and showed liquid-like behavior. As the molecular weight of Polyox or HPMC is increased, the elastic or storage component becomes more dominant due to entanglement formation. In addition, the relationship between steady shear and complex viscosities for Polyox follows the Cox-Merz rule over the shear rate and frequency region examined. Unlike neutralized Carbopol, the viscoelastic parameters of aqueous Polyox gels were relatively unaffected by salt addition of up to 2% sodium chloride. The polymers can be dispersed in non-aqueous solvent mixtures consisting of propylene glycol and glycerol formal without appreciable viscosity build up or gelling. However, upon increasing the proportion of water in the solvent mixture, both $G\sb1$ and $G\sb2$ increased greatly and a gel with significant elastic behavior was formed. Mucociliary transportability was tested on the frog palate mucociliary model. An apparent negative relationship is observed between the transport rate and the storage ($G\sb1$) or loss ($G\sb2$) modulus of the polymer. The propagation of wave through a linear viscoelastic media was used to gain some insight into the effect of viscoelastic characteristics on mucociliary transport. The analysis isolated the loss tangent (tan $\delta$) and the magnitude of the complex modulus ($\vert G\sp\*\vert$) as the important viscoelastic parameters for mucociliary transport. Optimum rheological characteristics with respect to slow transport rate can be achieved by using hydrophilic polymer gels with a large complex modulus and a loss tangent equal to 1.74. In vivo studies in dogs showed a significant increase in bioavailability of propranolol is obtained by nasal administration as compared to administration by the oral route. A physiological multi-compartment model is applied to the nasal, gastrointestinal, liver and systemic compartments to describe the kinetics of propranolol in dogs. An additional enhancement of bioavailability over that of the intranasal saline formulation were achieved by means of polymeric gelling formulations. The increase in bioavailability has been attributed to an increase in the intranasal residence time resulting in the avoidance of first-pass metabolism by the liver.Other Identifiers
(UMI)AAI9319668
Subjects
Health Sciences, Pharmacology Biology, Animal Physiology Health Sciences, Pharmacy
Types
Thesis
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