(636c) Advanced Modeling of Oral Drug Delivery -- Innovation in Tablet Design

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. 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 following a time schedule. Good
computational models are needed to predict the drug release and transport into
the blood plasma. This would help in reducing the expense, time and effort
involved in drug design. Several models are available in literature describing
either the release of drug from the tablet into the gastrointestinal (GI) tract
or the transport of drug through GI tract into the blood plasma. Our first
objective was to develop a composite computational model for an oral drug
delivery system (involving a drug active within a solid polymer matrix), which describes
the release as well as the transport of drug from the tablet through GI tract
into the blood plasma.

We employ a modified form of the drug release model
proposed by Balaji and Peppas [1] 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. Therefore we couple the drug release model
with a compartmental absorption and transit model (CAT), see for example Yu and
Amidon [2]. The drug release model (Stage 1)
is a moving boundary problem consisting of partial differential equations (PDEs)
and ordinary differential equations (ODEs) which describe the diffusion of (i)
bodily fluid into the drug tablet; (ii) drug out of the tablet; and (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 GI tract is divided
into a number of compartments representing the stomach, small intestine, colon
and the enterocyte membrane. These are represented as 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 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 Stage 1 and Stage 2 would be useful for
predicting the release, distribution, absorption and elimination of an oral drug
through the GI tract to obtain plasma concentration profile and pharmacokinetic
characteristics. The developed model can also be used to inform drug tablet design
for target pharmacokinetic characteristics.

The geometric characteristics and the make-up of the
drug tablet have a large impact on the drug release profile in the GI tract. Our
second objective was to develop a strategy for tablet customization, namely
designing the dosage form of the tablet based on a desired release profile inspired
by a desired plasma concentration profile (therapeutic effect). Our efforts
include the systematic identification of tablet geometry and designs that could
give specific desired drug release profiles such as a constant release profile
or a pulsatile release profile. We expect the proposed approach to aid in the drug
development process and contribute to the development of personalized medicine.

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

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