Formulation prodrug approach

To improve the oral properties of enalaprilat, Patchett and colleagues turned to a prodrug approach. Esters were made of only one and of both carboxyls, and fortunately only esters of the N-carboxyalkyl group were needed for good oral absorption. When the proline carboxyl is esterified, the resultant inhibitor would have been difficult to formulate, since closure to a diketopiperazine easily takes place. Although various esters were tried, none were clearly superior to the ethyl ester 20 (Table IV). 

Once the physicochemical and biopharmaceutical properties of the drug are determined and the desired plasma concentration profile is defined, the pharmaceutical scientist can select and develop an efficacious dosage form by utilizing a formulation approach, a prodrug approach, a device approach, or an alternative administration route approach. 

An alternative to the formulation approach is the prodrug approach. A prodrug is defined as a drug that is prepared by chemically modifying a pharmacologically... 

The prodrug approach described above also can be used to alter the solubility characteristics, which, in turn, can increase the flexibility in formulating dosage forms. The solubility of methylprcdnisolonc can be altered from essentially water-insoluble methylpredni.solone acetate to slightly water-insoluble methylprednisolone to water-soluble meth-ylprednisolone. sodium succinate. The water-soluble sodium hemisuccinate salt is used in oral, intravenous, and intramuscular dosage forms. Methylprednisolone itself is normally found in tablels. The acetate ester is found in topical ointments and sterile aqueous suspensions for intramuscular injection. Both the succinate and acetate esters are hydrolyzed to the active methylprednisolone by the patient s own systemic hydrolytic enzymes (esterases). 

As reviewed in this chapter, certain means can be utilized to improve the bioavailability of lipophilic drugs, whether by formulative approach or molecular changes strategies. These means present a number of attractive propositions to the scientist, ranging from an enhancement of drug dissolution and solubilization by lipid-based formulation, increased solubility via the synthesis of a prodrug, specific delivery to the intestinal lymphatics, and reduction in enterocyte-hepatic presystemic metabolism and efflux systems. 

Various formulation concepts have been introduced as potential ways to protect peptide and protein drugs from the hostile GI environment to increase their oral absorption such as use particulate drug carriers (microspheres, lipo-somes, and lectins), coadministration of enzyme inhibitors and absorption enhancers, use of chemical modification (prodrug), and site-specific delivery to the colon or rectum. Some of these approaches are discussed later. 

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