A Computational Model of Oral Transmucosal Carvedilol Delivery

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Abstract
In the past few decades, there has been a rapid growth in alternative drug delivery routes. The oral cavity has gained attention as an attractive drug delivery site because it enhances drug bioavailability, allows for rapid transport to the systemic circulation, and provides a convenient delivery route. The buccal mucosa is one of the most common routes for oral drug delivery because it is relatively permeable and robust in comparison to other mucosal tissues. The buccal mucosa offers a large surface for absorption, allows for prolonged localized therapy, and avoids first-pass metabolism effects and degradation in the gastrointestinal environment. One potential form of buccal drug therapy currently being investigated is the application of bioadhesive polymer patches to the buccal region of the mouth. Direct contact between a patch and the buccal mucosa allows a drug concentration gradient to favor diffusion into the tissue. Researchers have recently begun to use this innovative method of drug delivery with carvedilol, a non-selective β-adrenergic antagonist used to treat heart failure and high blood pressure. Recent studies have investigated the formulation of bioadhesive patches of carvedilol. The goals of the project are to model drug delivery from a biodegradable carvedilol patch prepared with the PLGA polymer and optimize carvedilol concentration in the blood. The COMSOL Multiphysics 4.3 simulation software was used to model drug diffusion through the buccal mucosa and solve the governing equations used in our simulation. Drug diffusion was modeled using the species mass transport equation through a two-dimensional cross section including the carvedilol patch and surrounding tissue. Saliva flow over the patch and in the mucus region was modeled with one-dimensional Navier-Stokes fluid flow equations. Concentration and flux profiles over the course of the three hour treatment confirm that carvedilol is able to diffuse from the patch and be delivered to the tissue and bloodstream. Approximately 100% of the patch is delivered within three hours. We evaluated patch efficiency using the concentration in the blood as a fraction of the initial patch concentration. The peak carvedilol concentration is reached at 1.8 hours. Drug degradation in the submucosa results in an observable reduction in carvedilol concentration in the bloodstream. Our results were validated based on cumulative drug release and peak concentration data from in vitro and in vivo studies. Since the availability of property data is limited, we performed sensitivity analysis over a range of diffusivity values and saliva flow velocities. Multiple drugs are currently being evaluated for oral mucosal therapy, but the high costs associated with developing these drug delivery systems have limited commercial availability. Computational fluid dynamics (CFD) modeling is necessary to determine the ideal parameters and properties to maximize drug efficacy and the percentage of drug that leaves the patch in an economical and safe method. Our observations will allow carvedilol treatment to be optimized by investigating initial drug concentration in the patch and treatment time. This computer model could potentially aid the design of clinical trials testing different patch configurations and treatment times.
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2014-05-26
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Computational Modeling; Oral Transmucosal Carvedilol Delivery
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