(717a) On the Modeling of Oral Drug Delivery

On the
Modeling of Oral Drug Delivery

Naresh Pavurala, Luke E.K Achenie

Department of Chemical Engineering,
Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24060

The oral administration route is by far the most
common way of administering pharmacological substances. It is estimated that
90% of all medicines are oral formulations and oral drug delivery systems
comprise more than half the drug delivery market. The core business of the
pharmaceutical industry is to discover, synthesize and bring to market new
drugs for health interventions. The acceptance of the drug depends on several
factors including the efficacy/selectivity of the drug and the drug delivery
vehicle. By following good manufacturing practices (GMP regulations), high
quality oral delivery products are prepared in a reliable and reproducible
manner. In oral drug delivery the challenge is for the drug active to be
released in a controlled way from the solid tablet into the blood circulatory
system in order to maintain the therapeutic blood plasma concentration levels
for a desired amount of time. In the current literature, there is consensus
that a good computational model is needed to predict the drug release into the
blood plasma. This would help in reducing the expense, time and effort involved
in drug design. In this paper we present a composite computational model for an
oral drug delivery system involving a drug active within a solid polymer
matrix.

We employ a modified form of the drug release model proposed by Balaji and
Peppas (Narasimhan and Peppas 1997) based on the
following assumptions. As the polymer matrix comes into contact with bodily
fluid (modeled as water) inside the digestive system, it penetrates the polymer
matrix; the latter then swells forming a gel layer. Drug molecules are released
through the gel layer into the digestive system, crossing the enterocyte
membrane into the blood stream. In our strategy, we envision two stages in the
transport of drug into the blood. This involves coupling the drug release model
with a compartmental absorption and transit model (CAT, see for example (Yu and Amidon 1999). The drug release model (Stage 1) is a
moving boundary problem consisting of PDEs (partial differential equations) and
ODEs (ordinary differential equations) which describe the diffusion of (i)
bodily fluid into the drug tablet; (ii) drug out of the tablet; (iii) polymer
chains through a boundary layer. The model accounts for two moving interfaces
(namely, tablet/gel interface and gel/bodily fluids interface in the digestive
system).

In the CAT
model (Stage 2), the gastrointestinal tract is divided into a number of
compartments representing the stomach, small intestine, colon and the
enterocyte membrane. Specifically it is a system of ODE's with linear transfer
kinetics and nonlinear metabolism/transport kinetics, which describe absorption
and transit of drug through three kinds of compartments, namely unreleased,
released and dissolved. The model takes into account physicochemical properties
such as pKa, solubility, particle-size, particle density, and permeability. It
also accounts for physiological factors such as gastric emptying, intestinal
transit rate, first pass metabolism, and luminal transport. Finally the model
accounts for factors such as the shape and size of the tablet and the dosage.
The coupling of the two stages leads to a complete pharmaco-kinetic model for
predicting the drug release profile. We have successfully developed a
pharmaco-kinetic model by coupling the working models for Stage 1 and Stage 2
and combined it with an optimization model to predict system variables (e.g.
tablet geometry, size and dosage). This would yield plasma concentration
profiles within the therapeutically acceptable range.

We are
currently working on a triphasic release profile (Rothstein and Little 2011), comprising of an
initial burst, lag phase and final release of the drug. This study aids in controlling
the different phases of drug release through optimization. The advantage of the
suggested framework is that it can be used to test hypothesis about the
mechanism involved in drug delivery into the blood circulatory system. We
expect to employ the composite model to hypothesize the optimal diffusion
coefficient (and other physico-chemical properties) that a new drug needs in
order to obtain a desired drug release profile. This is expected to be useful
for drug design.

Narasimhan, B. and N. A. Peppas (1997).
"Molecular analysis of drug delivery systems controlled by dissolution of
the polymer carrier." Journal of Pharmaceutical Sciences 86(3):
297-304.

Rothstein, S. N. and S. R. Little
(2011). "A "tool box" for rational design of degradable
controlled release formulations." Journal of Materials Chemistry 21(1):
29-39.

Yu, L. X. and G. L. Amidon
(1999). "A compartmental absorption and transit model for estimating oral
drug absorption." International Journal of Pharmaceutics 186(2):
119-125.