Pharmaceutical and pharmacokinetic characterization of a novel sublingual buprenorphine/naloxone tablet formulation in healthy volunteers

Abstract

ContextBitter taste, as well as dissolve time, presents a significant challenge for the acceptability of formulations for oral transmucosal drug delivery.ObjectiveTo characterize a novel sublingual tablet formulation of buprenorphine/naloxone with regards to pharmacokinetics, dissolve time and formulation acceptability.MethodsDry mixing techniques were employed to produce a small and fast dissolving buprenorphine/naloxone sublingual tablet formulation, OX219 (Zubsolv®), using sucralose and menthol as sweetener and flavor to mask the bitter taste of the active ingredients. Two cross-over studies were performed in healthy volunteers to evaluate pharmacokinetics, dissolve time and acceptability of OX219 5.7/1.4 mg tablets compared to the commercially available buprenorphine/naloxone formulations Suboxone® tablets and films (8/2 mg).ResultsBuprenorphine exposure was equivalent in OX219 and Suboxone tablets. Sublingual dissolve times were significantly shorter for OX219 than for Suboxone tablets and were similar to Suboxone films. The OX219 formulation received significantly higher subjective ratings for taste and overall acceptability than both Suboxone formulations. OX219 was preferred over Suboxone tablet and film formulations by 77.4% and 88.9% of subjects, respectively.ConclusionsA sublingual tablet formulation with an improved acceptability has been successfully developed.

Randomised Comparison of a Novel Buprenorphine Oral Lyophilisate versus Existing Buprenorphine Sublingual Tablets in Opioid-Dependent Patients: A First-in-Patient Phase II Randomised Open Label Safety Study

“…The low bio-availability of buprenorphine in “bup-SL” has been reported previously, with approximately half the bioavailability when compared with the original buprenorphine liquid [22,23]. The combination buprenorphine/naloxone tablets (“Suboxone”) was found to have 20% increased bioavailability versus “bup-SL” [24], and a new generic buprenorphine/naloxone had approximately 40% increased bioavailability to Suboxone [25] (hence presumably even more bioavailable versus “bup-SL”). Furthermore, some countries have a large proportion of patients receiving buprenorphine doses below recommended maintenance doses [26]: will the introduction of a formulation with better bio-availability result in either lower dose or alternatively higher effective dosing?…”

Effects of a Higher-bioavailability Buprenorphine/Naloxone Sublingual Tablet Versus Buprenorphine/Naloxone Film for the Treatment of Opioid Dependence During Induction and Stabilization: A Multicenter, Randomized Trial

“…Subsequently, a sublingual BNX film formulation † was approved in 2010 for use as maintenance treatment of opioid dependence in adults and in 2014 for the induction of treatment in those transitioning from short-acting opioids. 9,10 No BNX formulation is licensed for induction therapy in both patients dependent on long-acting opioids and patients dependent on short-acting opioids. The induction of therapy in patients dependent on long-acting opioids (eg, methadone) might be complicated by an increased risk for precipitated or prolonged withdrawal.…”

“…This higher-bioavailability BNX sublingual product allows for the administration of a 30% lesser dose of buprenorphine with systemic exposure (ie, bioavailability) equivalent to that of a previously available BNX sublingual tablet formulation; the development of this tablet formulation also incorporated specific characteristics to address patients' preferences. 9 The technology used in the formulation, comprising micronized buprenorphine in an associative admixture with a citric acid buffer system, demonstrates rapid disintegration, an immediate but temporary reduction in pH, and synchronized buprenorphine release in vitro. These properties contribute to its increased dissolution rate and improved bioavailability.…”

“…16 In addition, successful maintenance therapy might integrate psychosocial treatment to promote behavioral and/or lifestyle changes, as well as to address psychosocial challenges that might contribute to a patient's addiction. 9,11 A higher-bioavailability BNX sublingual tablet formulation ‡ was approved by the FDA in July 2013 for use as maintenance treatment in adult patients with opioid dependence and was made available for clinical use in September 2013. An indication for induction treatment in adult patients with opioid dependence followed in August 2015.…”

Anti-addiction Agents

“…A different formulation used a dry mixing manufacturing method producing a small and fast-dissolving tablet (OX219) that used menthol and sucralose as a sweetener to mask the bitter taste [ 66 ]. This formulation was reported to be bioavailable as the Suboxone ® oral tablet and SL products.…”