Page 186 - Biomedical Engineering and Design Handbook Volume 2, Applications

DESIGN OF CONTROLLED-RELEASE DRUG DELIVERY SYSTEMS 165

TABLE 6.1 Examples of Marketed Prodrugs
Product Name Prodrug Active Drug Principle for Prodrug Approach
®
Vasotec (Merck) Enalapril Enalaprilat
®
Valtrex (GSK) Valaciclovir Aciclovir
®
Sinemet (BMS) Levedopa Dopamine
®
Tamiflu (Roche) Oseltamivir Oseltamivir
phosphate carboxylate
®
Benicar (Daichi) Olmesartan Olmesartan To cross a biological barrier
Sankyo (Forest) medoxomil at the site of absorption
®
Famvir (Novartis) Famciclovir Penciclovir
®
Vantin (Pfizer) Cefpodoxime Cefpodoxime
proxetil
®
Valcyte (Roche) Valganciclovir Ganciclovir
®
Monopril (BMS) Fosinopril Fosinoprilat
®
Cerebyx (Pfizer) Fosphenytoin Phenytoin For ease of intravenous
administration
unless this characteristic is improved. Attaching the drug to a polymer as part of a pendent will
enhance its half-life. Modification of the drug to protect the site of degradation or metabolism is
another method to achieve longer half-life.
To Cross a Biological Barrier. Drugs with unbalanced hydrophilic or hydrophobic properties will
not effectively cross the biological barriers. Attachment of labile functional groups can change the
properties of the parent drug and allow the prodrug to cross the barrier.
To Increase Retention Time. When intended for a part of the body with high tissue turnover rate,
such as intestinal mucosa, a drug linked to a mucoadhesive polymer can increase adhesion to the site
and have better bioavailability.
To Target a Specific Site. Connecting specialized functional groups that have site-specific affinity
(peptide, antibody, etc.) can allow the parent drug to be delivered to targeted area of the body to produce
site-specific therapeutic action. Some of the prodrugs available in the market are listed in Table 6.1.

6.5 DIFFUSION-CONTROLLED DELIVERY SYSTEMS

Diffusion process has been utilized in design of controlled-release drug delivery systems for several
decades. This process is a consequence of constant thermal motion of molecules, which results in net
movement of molecules from a high-concentration to a low-concentration region. The rate of diffu-
sion is dependent on temperature, size, mass, and viscosity of the environment.
Molecular motion increases as temperature is raised due to a higher average kinetic energy in the
system:
kT mv 2
E = = (6.2)
2 2
where E = kinetic energy
k = Boltzmann’s constant
T = temperature
m = mass
v = velocity
2
This equation shows that an increase in temperature is exponentially correlated to velocity (v ). Size
and mass are also significant factors in the diffusion process. At a given temperature, the mass of molecule
is inversely proportional to velocity [Eq. (6.2)]. Larger molecules interact more with the surrounding
environment, causing them to have slower velocity. Accordingly, large molecules diffuse much slower