A 3rd generation 'perisone' and an appropriate formulation for improved treatment of acute back pain and spasticity
Description: Lower back pain is a disabling condition that is difficult to treat effectively. The standard therapy for lower back pain involves the use of NSAIDs together with muscle relaxants, with specific analgesics being added in the case of severe pain. Tolperisone-HCl, the prototype of the 'perisones' was introduced into Hungary by Gedeon Richter, is marketed successfully in Japan by a couple of companies, and is market leader for treatment of back pain in Germany. Advantageous features of Tolperisone include a low adverse event profile, a lack of sedation and no interaction with alcohol as well as no potential for tolerance and addiction. However, Tolperisone, which nowadays is generic compound, still has several pharmacological limitations, mainly a high first pass effect in various species which requires high daily doses for compensation and a metabolism which is dependent on the genetic background of the patients and thus open for a considerable interindividual pharmacokinetic variation. BDD-10103 is a Tolperisone-like compound that emerged from the BDD/CDRD Groupīs Atomic Substitution Technology platform and addresses current drawbacks of Tolperisone by simultaneously keeping all its advantageous features. Various animal models confirmed that oral doses of BDD-10103 are more potent than the corresponding doses of Tolperisone both in selected preclinical rodent and non-rodent animal models: BDD-10103 and Tolperisone inhibited the monosynaptic ventral root reflex roughly to the same extent. However, BDD-10103 showed superiority in the tremorine test in mice after oral administration. Metabolic degradation of BDD-10103 and Tolperisone was assessed in hepatic liver microsomes. The results indicated that longer elimination half life can be expected for BDD-10103 in man than that published for Tolperisone. BDD-10103 follows a typical CYP 2D6, CYP 2C19 metabolism as does Tolperisone. The compound is however more stable against biodegradation by liver enzymes of the CYP family. Interestingly, formation of certain metabolites that occurred in the course of plain tolperisone biodegradation is suppressed within the BDD-10103 metabolism. Interestingly, a first pharmacokinetic study in man revealed an enhanced overall bioavailability of BDD-10103 compared to tolperisone. Pharmaceutical development includes the evaluation of an improved oral formulation to enhance the bioavailability of BDD-10103 in the human body. |
