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In Vitro Testing Models for Nasal Drug Delivery

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Nasal drug delivery is a very promising alternative route for various drugs included hormones, vaccines, peptides, proteins or other large macromolecules.  Nasal drug delivery has also been generating widespread interest in the drug delivery field because it could not only be used in local treatment but in systematic administration.  Therefore, evaluation of these novel formulations requires reliable in vivo/in vitro testing models.  The nasal mucosa provides a moist and highly vascularized membrane, crucial to rapid absorption into the blood stream, thus facilitating faster transport to the site of action.

Compounds administrated via this route are absorbed directly into the circulation system, avoiding the first-pass hepatic metabolism.  This site of drug administration has been considered an ideal route for non-invasive delivery route.  However, there are a number of factors that limits the widespread utility of this route.  The two main disadvantages of nasal delivery are the limited maximum dose per spray and the rapidity of clearance from the nasal cavity, enzymatic degradation in the mucus layer and nasal epithelium.

Various factors that might affect the permeability of drugs through the nasal mucosa could be broadly classified into three categories:

1. Biological factors

2. Formulation aspects, and

3. Device-related factors

The physiology of the nasal cavity presents the most significant barrier to drug absorption.  However, the problem associated with low bioavailability has been solved recently by developing an inter-nasal micro-emulsion formulation delivery system.  Hence, a formulation that would increase residence time in the nasal cavity and at the same time increase absorption of a drug would be highly beneficial in all respects.  The use of bioadhesive polymers has been shown to lengthen the residence time and enhance the bioavailability of drugs delivered to the nasal cavity.

Excised animal tissue models are frequently used for nasal drug absorption studies due to methodological and ethical limitations associated with the use of human nasal specimens, although it is difficult enough to obtain human nasal tissue without these other issues.  The fresh nasal tissue removed from the nasal cavity of sheep is commonly used for this purpose.  The cumulative amounts of drug permeated within determination of the effective permeability coefficients across mucosal membrane are calculated.  The histology of treated nasal mucosa membranes also has to be investigated after the completion of the experiments.  The porcine nasal mucosa also seems to be feasible for in vitro studies that investigate the permeability of nasal tissue and predict the absorption of drugs after nasal administration in vivo.

Mainly there are three in vitro testing models:

1. Excised models: excised animal nasal mucosal tissue is obtained from various animals that are frequently used to study nasal transport and metabolism (rabbits, bovine, sheep tissue).  It is crucial to select the right part of the nasal mucosa tissue for in vitro investigation studies.  The different regions of ovine nasal mucosa cavity demonstrate quite different in vitro drug permeability properties.  It has been established that the middle turbinate mucosa is the suitable model for in vitro studies because of its many advantages such as large surface area, highest drug permeability coefficient and high reproducibility.

2. Cell line models: RPMI 2650 human nasal epithelial cell line derived from a spontaneously formed tumor.  These include primary and passaged cell culture, Liquid-Covered Culture method (LCC) and Air-Interfaced Culture method (AIC).  Cultures of human nasal epithelial cell layers on Transwell inserted under AIC or LCC conditions are useful for in vitro drug transport studies.  MatTek Corp. (200 Homer Avenue, Ashland, MA) offers EPI tissue models.  However it must be noted that efforts to develop and characterize various nasal cell culture systems are still in their infancy.

3. Several artificial membranes have also been proven to be a good model for nasal drug delivery studies.  For instance, the polydimethylsiloxan (PDMS) membranes have demonstrated good in vitro model properties during nasal mucosa drug permeation studies.