Using Biorelevant Testing to Characterize Release of Non Oral Dosage Forms as another Tool for Safety

Abstract

Non-oral dosage forms often comprise of complex dosage forms such as parenterals, implants, drug eluting stents, transdermal patches, liposomes, microspheres and nano-particles as injectable. With the rapid advances in genetic engineering and recombinant DNA technology, the active drug moiety can also be a bio therapeutic (i.e. peptide or protein), which adds an additional layer of complexity to the drug product. In vitro dissolution tests/models for oral dosage forms such as tablets and suspensions have long been an indicator of in vivo performance of the drug. In commercial manufacturing processes, they act as an evaluative quality control tool. A dissolution test in oral dosage forms ensures minimal inter-batch variability and hence works as a check that the dosage form meets the requisite regulatory and quality standards. These in vitro models may also work as a tool for safety (i.e., predict in vivo performance and streamline clinical studies). The predictive in vitro data from these tests could often help in minimizing steps of clinical trials. In the case of non-oral dosage forms, similar tests that ensure performance verification of the drug are often called “in vitro release tests” rather than dissolution tests [1-3]. The rationale being non-oral dosage forms are frequently placed at diverse locations in the body e.g. transdermal patches on skin, drugeluting stents in coronary arteries [4], suppositories in rectum or urethra, subcutaneous or intramuscular implants (all of which have a different physiological environment). As a result, the action of the drug largely depends on its release from the dosage form. The drug moiety may be carried in complex delivery systems e.g. in a lipid based system such as liposomes, absorbable carrier scaffolds e.g. collagen matrix, injectable biodegradable polymer based matrix which solidifies at the site of action (e.g. ATRIGEL°). In cases like transdermal patches, the release needs to occur through multiple membranes and needs to penetrate through the skin and layers of external barriers before reaching the site of action. In subcutaneous and intramuscular implants the blood flow conditions might affect the time taken by the drug to reach the targeted site. Furthermore, the release mechanism, rate of release, and the time required by the drug to reach the site of action thus varies notably in each unique case. Hence the in vivo performance of these complex (non-oral) dosage forms can be characterized more precisely by carefully designed in vitro release tests, with design space criteria that are ‘biorelevant’. Unlike oral dosage forms where a single standardized USP method or apparatus can be used for dissolution testing of a class of compounds to determine in vivo performance (i.e., systemic release). Non-oral dosage forms can release locally with minimal systemic exposure. In such cases the standardized tests may not predict local release. The testing apparatus and method parameters have to be selected or modified accordingly to design a biorelevant reproducible and predictable in vitro release test. Biorelevance in Non-Oral Dosage Forms