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, flupentixole (Figure 9.16), and flu-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 significant increase in patient compliance and, thus, treatment of patients suffering from psychiatric disorders. The sustained release over weeks of neuroleptic drugs from IM preparations was initially attributed to the high affinity 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, partitioning 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 significant role for the overall release profile.

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 glycols (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 Design of Produgs for Drug Targeting

Drug targeting by site-specific bioactivation was achieved using intelligent prodrug design of the blockbuster drug omeprazole, which is widely used in the treatment of gastric ulcers. Omeprazole

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 glycols (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.

specifically inhibits the enzyme gastric H+-K+-ATPase that is responsible for the gastric acid production and is located in the secretory membranes of parietal cells. Omeprazole itself does not inhibit this enzyme but is biotransformed within the acid compartments of the parietal cells into the active inhibitor cyclic sulfonamide, which reacts with cysteine thiol groups of the enzyme thereby inactivating it (Figure 9.17).

Since omeprazole is only converted to the active molecule at acidic conditions, bioactivation almost exclusively takes place at the low pH at the parietal cells where high concentrations of the active species are generated.

Another example of site-specific delivery using the prodrug approach is olsalazine, which is being used in the treatment of ulcerative colitis. The active drug 5-aminosalicylic acid (mesalazine) is delivered from olsalazine to the colon due to specific bioactivation mediated by azo-reductases produced by anaerobic colonic bacteria. Olsalazine acts as a so-called twin prodrug in that it is cleaved to yield two molecules of the parent drug (Figure 9.18).

Drug targeting to the brain has been investigated using uptake transporters in the blood-brain barrier as targets for prodrugs. For example, glucose and mannose derivatives of levodopa and dopamine have shown increased in vivo activity in animal models compared to parent compounds. This has been attributed to enhanced drug transport into the brain by prodrugs utilizing the glucose transporter in the blood-brain barrier. Other brain uptake systems such as the large amino acid transporter have been the target for prodrugs.

Finally, it should be mentioned that the use of monoclonal antibodies as potential promoieties for anticancer agents may be of interest since such antibodies offer high specificity toward its target. The principle of using antibodies as promoieties will theoretically offer selective drug attachment to cancer cell antigens followed by release of the active drug leading to a higher drug accumulation at the site of action and thereby increased therapeutic effectiveness.

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OCH,

OCH, ch3

OCH,

OCH, ch3

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FIGURE 9.17 Omeprazole—bioconversion and mechanism of action.

FIGURE 9.18 Bioactivation olsalazine—a twin prodrug.

FIGURE 9.18 Bioactivation olsalazine—a twin prodrug.

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