Abstract
Objective: The present research work aims to develop a microemulsion loaded sublingual film for rapid absorption of fentanyl citrate in transient breakthrough pain.
 Methods: The Fentanyl citrate microemulsion loaded sublingual film was prepared using Capmul MCM C8 (oil), tween 20 (surfactant) and propylene glycol (co-surfactant) with different grades of film-forming polymer (HPMC) using a film casting machine. The films were evaluated for in vitro disintegration study, tensile strength, folding endurance, content uniformity, drug content, in vitro dissolution, pH, thickness and weight variation, scanning electron microscopy, ex vivo permeation study, droplet size, polydispersity index, zeta potential, % moisture content and stability study were evaluated.
 Results: The optimized film formulation showed desired mechanical properties (tensile strength of 0.291 kg/cm2) and a minimum disintegration time of 20 s. The optimized sublingual film formulation exhibited 43.16 % of FC microemulsion loading. Morphological study showed the absence of drug crystals on the polymeric surface. Permeation studies through goat sublingual mucosa indicated 89% fentanyl citrate release through fentanyl citrate microemulsion loaded sublingual film, whereas only 40% fentanyl citrate release was obtained when it was directly added to film without microemulsion strategy.
 Conclusion: The present study indicated that extend of permeation of fentanyl citrate when added to the sublingual film in microemulsion form was around 2.225 folds higher than when added directly to film without microemulsion. The present microemulsion embedded film technology could be a promising alternative to conventional drug delivery systems and traditional routes of administration for breakthrough pain management.
Highlights
Fentanyl citrate (FC) is a small and potent μ-receptor agonist that is given in low doses (100-1000 μg), and lacks the bitter taste associated with some other opioids [1, 2]
In the present study FC microemulsion was incorporated into the sublingual film and for that ME with Smix ratio of 2:1 was selected and quantities of each ME was fixed as per solubility, to incorporate 1.26 mg dose of FC
In F1 trial batch the amount of HPMC E15 was added to obtain the complete incorporation of microemulsion into the sublingual film
Summary
Fentanyl citrate (FC) is a small and potent μ-receptor agonist that is given in low doses (100-1000 μg), and lacks the bitter taste associated with some other opioids [1, 2]. FC is known to be effective in the treatment of breakthrough pain which is estimated in more than half of cancer patients [3]. For the successful treatment of transient breakthrough pain, the analgesic used must be fast-acting and provide immediate pain relief. Fentanyl is a highly lipophilic compound (octanol-water partition coefficient at pH 7.4 is 816:1) having peak analgesic effects within a few minutes of IV administration and a duration of action, after small to moderate doses, of 30 to 60 min [9]. Parenteral administration of fentanyl is usually unsuitable or inconvenient for the patient for the self-management of breakthrough pain, especially in the home environment. Sublingual administration is noninvasive, and the transmucosal absorption of lipophilic drugs is rapid [23,24,25]. Whereas the sublingual route offers good bioavailability (57%) and which further can be increased by proposed strategy
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