Biomedical Engineering Reference
In-Depth Information
9.4.2 D
ESIGN
OF
P
RODRUGS
FOR
P
ROLONGED
D
RUG
A
CTION
The utility of prodrugs as a means to achieve prolonged pharmacological action of a drug has
been effective mainly in terms of intramuscular (IM) injection preparations and other local
administrations. For oral administration, the prodrug principle has not been investigated exten-
sively with the aim to prolong drug action and it is questionable if this approach will offer any
benei t to well-established formulation principles such as matrix systems, osmotic systems, and
pellet systems.
9.4.2.1 Intramuscular Depot Injections
Prodrugs have been used to prolong the pharmacological effect of drugs by providing a sustained
release of the prodrug form to the systemic circulation. The principle has provided long-term
(1-4 weeks) delivery of neuroleptic drugs such as haloperidole, l upentixole (Figure 9.16), and l u-
phenazine by IM preparations of highly lipophilic prodrug derivatives such as decanoate and other
long-chain fatty acid esters formulated in oily vehicles. This has offered a signii cant increase in
patient compliance and, thus, treatment of patients suffering from psychiatric disorders. The sus-
tained release over weeks of neuroleptic drugs from IM preparations was initially attributed to
the high afi nity of the lipophilic prodrugs to the vehicle leading to slow release from the vehicle.
Although this explains the prolonged drug presence in the bloodstream to a certain extent, parti-
tioning of the lipophilic prodrug derivatives into the lymphatic system is of equal importance. In
the lymph nodes, a slow biotransformation to the parent drug takes place, followed by the release
of parent drug to the systemic circulation that will all together play a signii cant role for the overall
release proi le.
OH
O
O
N
N
N
N
FF
FF
F
F
S
S
FIGURE 9.16
Flupentixole and its decanoate ester.
9.4.2.2 Macromolecular Prodrugs
Conjugation of small drug molecules to high molecular weight promoieties such as polyethylene gly-
cols (PEGs), polysaccharides such as dextrans or other polymers may be used to obtain prolonged
drug action. The high molecular weight conjugates may prevent rapid clearance of the active drug
and provide a long term circulating depot from which active drug is liberated at a rate dependent on
the nature of the drug-high molecular weight promoiety linkage. This principle has been primarily
investigated for anticancer drugs such as paclitaxel.
It should be noted that introducing a high molecular compound, for example, in the form of a
macromolecular prodrug to the body may give rise to an immunological response. This is of major
concern for drug development and should be investigated thoroughly.
9.4.3 D
ESIGN
OF
P
RODUGS
FOR
D
RUG
T
ARGETING
Drug targeting by site-specii c bioactivation was achieved using intelligent prodrug design of the
blockbuster drug omeprazole, which is widely used in the treatment of gastric ulcers. Omeprazole
