Designing drugs for transmucosal delivery in the oral cavity. What are the optimum chemical properties?

A problem presented at the UK MMSG Keele 2012.

Presented by:
Dr Vanessa Hearnden (Clinical Dentistry, University of Sheffield)
N Begum , VL Hearnden, B Okrinya, DM Reddyhoff, GW Richardson, JP Ward, RJ Whittaker

Problem Description

Delivery of some drugs into the bloodstream can currently only be achieved via injection. This usually requires administration by a health worker, can be painful for the patient and can cause local tissue damage. While injections are practical for single doses an alternative delivery method is desirable where repeated treatment is required for chronic diseases.

The oral mucosa is the epithelial lining of the oral cavity, which includes the tongue, cheeks, palate and gums. The oral mucosa provides a unique opportunity to deliver drugs into the bloodstream thereby avoiding the harsh environment of the gastro-intestinal tract and first pass metabolism in the liver that prevent many drugs from being delivered orally. The oral mucosa has several features which make it an ideal site for drug delivery. The oral cavity is well hydrated aiding in the solubility of drugs and it is easily accessible for self administration. The oral mucosa repairs itself quickly and is well vascularised making entry into the bloodstream rapid and direct. Unfortunately, there are also limitations to this method of drug delivery, most importantly the permeability barrier.

The permeability barrier exists in the lipid-rich upper layers of the oral mucosa preventing the drugs to pass freely across the epithelium. Different areas of the mouth display different levels of permeability barrier. For example, the area below the tongue (floor of mouth) has a thin epithelium that is significantly more permeable than other areas of the oral mucosa making it an ideal site for drug delivery.

The Study Group participants are asked to help with answering the following questions:

  1. What drug properties are the best for diffusion across the oral mucosa?
  2. Which property contributes greatest to the permeability coefficient of a particular chemical (eg., size, lipophilicity, charge, etc.)?
  3. What data is needed to produce an accurately predictive model of drug delivery across the oral mucosa?
  4. What is the optimal concentration of drug that can be delivered per unit of time (drug stability may be a crucial factor) to reach the required therapeutic dose in the bloodstream?

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Study Group Report

We present a coupled non-linear PDE system which has been developed to predict the parameters which affect drug permeability as a function of lipophilicity. This model considers the different layers which the epithelium is comprised of and the relative importance of each layer. The model is able to predict qualitatively data profiles of drug delivery through lipophilic particles (spatial and temporal evolutions) reported by experimental data. The model has many limitations and future development of the model should consider drug internalisation by cells and long term experimental data that has the ability to validate the current model for varying lipophilicity within the epithelial tissue. The current assumptions surrounding the model may need some re-consideration to better understand the profiles seen experimentally.

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