A prodrug is a pharmacologically inactive derivative of an active parent drug, and it that is bioconverted to the active drug in vivo. Through the chemical modification of a drug to a prodrug, we are able to deliver drugs into to the target site, to optimize therapy and minimize toxicity. A major pathway for the bioconversion of prodrugs to the active parent drugs is via carboxylesterase (CES) activity. Among human CES isozymes, hCES1 and hCE2 predominantly participate in the hydrolysis of prodrugs in the liver and small intestine, respectively, although the substrate specificity is quite different between two isozymes. Since the expression levels of CES vary among individuals, there is a range of pharmacological responses following prodrug administration. Species differences are caused by the tissue-dependent hydrolase activity mediated by CES, which makes it difficult to predict effectiveness in humans from a preclinical study using animals. The hydrolysis parameter of several ester prodrugs in the in situ rat jejunal single pass perfusion has been related to the in vitro hydrolysis parameter in the intestinal S9, in order to propose the noble quantitative prediction of intestinal first pass metabolism by in vitro-in situ correlation. We have developed a novel experimental method for predicting the human intestinal absorption of prodrugs using Caco-2 cells in which CES-mediated hydrolysis has been inhibited. The expression of hCE1 and hCE2 shows inter-individual variation and is regulated by several mechanisms, such as gene polymorphism and epigenetic processes. Understanding of the regulation of CES expression and species difference of CES catalytic properties will be helpful in the design of prodrugs with increased specificity and enhanced physicochemical and biological properties.
This report aimed to predict the tableting problems such as sticking and capping in the production scale of manufacturing tablets with only a small quantity of drug substances in an early stage of drug development. First, the tableting properties of drug substances which included formability and adhesive property were evaluated by using a Micro Powder Characterizer (MPC) and tableting problems were predicted. Next, continuous tableting was performed using a rotary tableting machine used in production, and the relation between the properties of obtained tablets and the predicted tableting problems was studied. Aspirin and ascorbic acid were used as the drug substances. Testing of compression and ejection was conducted using MPC with a sample of about 10 mg which consisted of the drug substance and excipients. The formability was evaluated from the total energy and the tensile strength of tablets, and the adhesive property was evaluated from the ejection energy and the tensile strength of tablets. The prediction of incidence of tableting problems based on the evaluation of formability and adhesive property corresponded well with the actual incidence of tableting problems at continuous tableting by a rotary tableting machine.
From these results, it was inferred that the tablet formulation without tableting problems at continuous tableting was enabled in an early stage of drug development, in the so-called pre-formulation by the evaluation of formability and adhesive property with an infinitesimal quantity of samples by using MPC.