Page 184 - Biomedical Engineering and Design Handbook Volume 2, Applications

DESIGN OF CONTROLLED-RELEASE DRUG DELIVERY SYSTEMS 163

6.1 PHYSICOCHEMICAL PROPERTIES OF DRUG

Physicochemical properties such as solubility, stability, lipophilicity, and molecular interactions play
a major role in biological effectiveness of the drug. Solubility is a measure of the amount of solute
that can be dissolved in the solvent. For a drug to be absorbed, it must first dissolve in the physio-
logical fluids of the body at a reasonably fast dissolution rate. Drug molecules with very low aqueous
solubility often have lower bioavailability because of the limited amount of dissolved drug at the site
of absorption. In general, drugs with lower than 10 mg/mL in aqueous solutions are likely to exhibit
low and erratic oral bioavailability.
Once the drug is administered, biological fluids that are in direct contact with drug molecule may
influence the stability of the drug. Drugs may be susceptible to both chemical and enzymatic degra-
dation, which results in a loss of activity of the drug. Drugs with poor acidic stability, when coated
with enteric coating materials, will bypass the acidic stomach and release the drug at lower portion
of the gastrointestinal (GI) tract. Drugs can also be protected from enzymatic cleavage by modify-
ing the chemical structure to form prodrugs.
The ability of drug partitioning into lipid phase can be evaluated by the distribution of drug
between lipid and water phase at equilibrium. A distribution constant, the partition coefficient K, is
commonly used to describe the equilibrium of drug concentrations in two phases.
Drug
K = lipid (6.1)
Drug water
The partition coefficient of a drug reflects the permeability of a drug through the biological mem-
brane and/or the polymer membrane. Commonly, partition coefficient is determined by equilibrating
the drug in a saturated mixture of octanol (lipid phase) and water. Drugs with high partition coeffi-
cient can easily penetrate biological membranes as they are made of lipid bilayers, but are unable to
proceed further due to higher affinity to the membrane than the aqueous surroundings. Drugs with
low partition coefficient can easily move around the aqueous regions of the body, but will not cross
the biological membranes easily.
In addition to the inherent properties of drug molecules, molecular interactions such as
drug–drug, drug–protein, and drug–metal ion binding are important factors that can significantly
change the pharmacokinetic parameters of a drug. These factors should also be taken into consider-
ation when designing controlled drug delivery systems.

6.2 ROUTES OF DRUG ADMINISTRATION

Various routes of administration pose different challenges for product design. As a result of the dif-
ferent barriers and pathways involved, selection of an administration route is an important factor for
design of drug delivery system. For example, the oral route is the most widely utilized route because
of its ease of administration and large surface area of the GI tract (200 m ). The presence of microvilli
2
2 2
makes this the largest absorptive surface of the body (4500 m ). The challenges of oral administra-
tion are short GI transit time, extreme acidic pH, abundant presence of digestive enzymes, and first-
pass metabolism in the liver. Several products were designed to prolong the retention time of the drug
in the GI tract. A hydrodynamically balanced drug delivery system (HBS) is designed to achieve bulk
density of less than 1 when contacted with gastric fluids rendering the drug formulation to remain
buoyant. This dosage form is also called floating capsules or tablets because of this characteristic. 3
Another commonly used route for drug delivery is parenteral administration. The routes used for
parenteral therapy include intradermal, subcutaneous, intravenous, intracardiac, intramuscular, intra-
arterial, and intrasynovial. Parenteral administrations offer immediate response, in such situations as
cardiac arrest or shock, and good bioavailability for drugs that undergo degradation by digestive
enzymes in GI tract. The disadvantages of parenteral administrations are difficulty of administration,
requirement of sterile conditions, and cost of manufacturing.