Prodrug Technology for Improving Drug Properties

Precursor drug can make certain drugs with poor chemical stability, poor solubility and poor oil-water partition coefficient into esters into precursor drugs, which can significantly improve the stability of the parent drug, improve solubility and optimize the oil-water partition coefficient. CD Formulation can provide precursor drug design for esters, carbamates, sugar derivatives, etc.

What is Precursor Drug Technology

Precursor drug technology is an effective technical tool to enable injectable agents to achieve long-lasting effects. Many steroids often use this technology for non-gastrointestinal drug delivery. Ester precursors are particularly suitable for derivatization of central nervous system drugs. The hydrolysis of ester precursors out of the prodrug after entering the body is catalyzed by esterases. As long as the hydrolysis rate of the precursor drug is slow enough, the release of the active parent compound can be effectively controlled, thus achieving the effect of prolonging the duration of action of the active drug. In addition, long-chain aliphatic ester derivatization can make the compound more lipophilic, which can improve the solubility of the drug in the injectable oil and is more conducive to making long-acting injectables, while the slow release of the low-solubility precursor drug at the site of administration also achieves the effect of prolonging the active drug action time.

Features of Precursor Drug Technology

(1) The precursor drug should be inactive or less active than the original drug;

(2) The prodrug and the carrier are generally linked by covalent bonds and converted into the prodrug in vivo, and this process can be an acid or base hydrolysis process or an enzymatic conversion process;

(3) The rate of conversion of the prodrug into the prodrug in vivo should be fast to ensure that the prodrug has sufficient drug concentration at the target site; however, when the purpose of modifying the prodrug is to prolong the duration of action, a slow metabolizing prodrug can be designed;

(4) The precursor drug and the carrier molecule should be non-toxic, and the carrier molecule should be rapidly cleared from the body.

How to Perform Bioassay of Precursor Drugs

Bioanalysis of precursor drugs is the key to bioequivalence and clinical trial evaluation of new drugs. The main challenges for bioanalysis of precursor drugs are firstly, how to ensure the stability of precursor drugs in the intended biological matrix during the collection, processing, storage and sample preparation of biological samples before quantification; and secondly, how to simultaneously detect precursor drugs and prodrugs with large differences in compound polarity.

Specific Services for Precursor Drug Design

• Phospholipid moieties

Phospholipids improve the aqueous solubility of orally and non-intestinally administered drugs. Phospholipid moieties allow for rapid release of parent drugs through the action of endogenous phosphatases, which are particularly abundant in enterocytes and plasma.

• Amino acid ester groups

After being attached to the parent drug molecule, amino acid groups can improve the water solubility of the drug. Amino acid esters, amides or aminoalkyl esters can be rapidly biotransformed into the parent drug molecule by various esterases in plasma or other tissues for oral and non-intestinal administration. These ionizable anions or cations can be attached to the hydroxyl, amine or carboxylic acid groups of the parent drug molecule.

• Sugar derivatives

Glucose, galactose or glucuronide can be used to improve the water solubility of a drug. The sugar group can be attached to the hydroxyl or amine group of the parent and the precursor drug can be converted to the parent drug by β-glucosidase, β-galactosidase or β-glucuronidase.