Pharmacokinetic properties of TNX-102 SL, a sublingual formulation of cyclobenzaprine hydrochloride

Title : Pharmacokinetic properties of TNX-102 SL, a sublingual formulation of cyclobenzaprine hydrochloride

Abstract:

TNX-102 SL is a sublingual formulation for cyclobenzaprine (CBP) hydrochloride (HCl) designed for bedtime dosing that is being developed for fibromyalgia (FM) via improvement in sleep quality. TNX-102 SL is a eutectic formulation of CBP and D-mannitol (see companion abstracts, Fogarty et al., and Nebuloni et al.,), which contains potassium phosphate dibasic as a basifying agent, which formulation disintegrates in saliva and rapidly dissolves. The addition of the basifying agent results in a higher local pH, thereby rendering CBP in an un-ionized state at the mucosal membrane, thus rapidly driving CBP across the mucosa into the systemic circulation. TNX-102 SL tablets were produced and used in a pharmacokinetic (PK) study in healthy human volunteers. TNX-102 SL was well tolerated, and side effects were similar to those of oral CBP although some subjects experienced local numbness in the mouth that was transient and self-limited. Our data show that TNX-102 SL 2.8 mg tablets deliver CBP rapidly across the sublingual mucosal membrane into plasma resulting in 12 times faster absorption relative to oral CBP immediate release (IR) 5 mg tablets and provides significantly increased plasma CBP levels during the first 2 hours post-dose (mean exposure was 338% higher at 1 hour and 83% at 2 hours post-dose). The relative bioavailability was 154% higher when compared to the oral CBP IR. Sublingual administration of CBP via TNX-102 SL bypasses hepatic “first-pass” metabolism resulting in substantially lower levels (via reduction of C_max and AUC) of the long-lived undesired active metabolite, norcyclobenzaprine (nCBP). Our data show during typical sleep hours (0-8 hours post-dose), CBP steady state and AUC are higher than nCBP post TNX-102 SL administration, which optimizes the effects of CBP on the sleeping brain. Cyclobenzaprine has a unique receptor binding profile with high potency binding and antagonist activity at serotonin 5-HT_2A, a₁-adrenergic, H₁-histaminergic and M₁-muscarinic acetylcholine receptors. Antagonism at these receptors has been suggested to have roles in enhancing different aspects of sleep quality. The pharmacokinetic properties of TNX-102 SL in humans appear to be well-suited for its development as a potential chronic bedtime treatment for fibromyalgia.

Audience Take Away Notes:

• Addition of a basifying agent promotes rapid transmucosal absorption, Sublingual administration by-passes first pass metabolism
• Expand their knowledge in the field of drug delivery
• This research helps other faculty to expand their research or teaching by  providing alternative approaches for the delivery of pharmaceuticals

Biography:

Dr. Daugherty received his AB degree in Biology at Washington University in St. Louis and went on to receive his MS and PhD in Molecular Genetics, both from Rutgers University. Dr. Daugherty has held multiple positions at Hoffman La-Roche, Merck, and Tonix Pharmaceuticals, and has worked as a consultant for academia and industry. Dr. Daugherty also holds an MBA from Emory University. He has published more than 50 original research articles, has been an invited speaker at multiple international conferences, and is an inventor on several issued patents and patent applications.