Excipients: not so inert? When the excipient plays the role of an active substance, as exemplified by systemic lupus.
Fiche publication
Date publication
juin 2018
Journal
Swiss medical weekly
Lien Pubmed
Résumé
It is well recognised that the historical timeline required for developing a drug, beginning with target identification and validation, is long and often tedious. It requires a large set of competences in various areas of molecular and cellular biology, chemistry, pharmacology, imaging, and model animal experimentation. Once the active molecule appears to be ready for human testing in controlled clinical trials, then the question arises of how to formulate it to render it stable, adequately packaged, according to the chosen route of administration, and bioavailable to reach its target in the affected organs. Historically, excipients have been considered inert and devoid of medicinal effect or influence. In fact, excipients are seldom neutral and some of them have been found to play a significant role, for example by initiating or participating in chemical and physical interactions with the active substance, leading in certain cases to compromise its therapeutic activity. It is difficult today to appreciate the number of potential drugs that have been discarded as a result of limited efficacy due to inappropriate excipients. This matter is presented here, with the peptide P140 (Lupuzor™) as example. Two formulations of P140, differing in the excipients used (mannitol or trehalose), have been evaluated in patients affected by systemic lupus erythematosus in two successive phase IIb clinical trials. P140 was shown to reduce excessive autophagy activity discovered in some lupus immune cell subsets. One of the two excipients, namely trehalose, has been claimed to exert an intrinsic stimulating activity on autophagy process, which was found therefore to counteract the beneficial peptide effects.
Mots clés
Animals, Autophagy, physiology, Disease Models, Animal, Excipients, adverse effects, Humans, Lupus Erythematosus, Systemic, drug therapy, Mice, Peptide Fragments, adverse effects, Trehalose, adverse effects
Référence
Swiss Med Wkly. 2018 Jun 25;148:w14631