A Thermo-Responsive Buprenorphine-Naloxone Solid Lipid Nanoparticle Nasal Spray for the Treatment of Opioid Addiction

Abstract

In the treatment of chronic pain, the analgesic ladder protocol recommends an escalation to potent opioids, including morphine, fentanyl and related analogues, after reaching maximum dosing with NSAIDs and less potent opioids like codeine. When opioids are used on a regular basis, however, they lead to various side effects including dependence, addiction, tolerance, withdrawal, euphoria and severe respiratory depression, a condition known as opioid use disorder (OUD) or opioid addiction. OUD is a chronic and relapsing disorder of the brain caused by the repeated exposure to exogenous opioids. At present, opioid antagonists like naltrexone and naloxone (NLX) are used as a treatment option which acts immediately but being antagonistic in nature, they lead to sudden withdrawal symptoms. To overcome this, a partial opioid agonist-antagonist such as buprenorphine (BUP) if used in combination can provide a more preferred treatment. Currently, this combination is available in the market as a sublingual tablet, but due to the effects of the Blood-Brain Barrier (BBB), a low bioavailability and residence time is experienced resulting in frequent dosing to have the required therapeutic effect, which is less patient compliant. The application of nanotechnology in the therapeutic and diagnostic fields has proved to be effective in improving the physicochemical properties of the drugs and the delivery system including improve patient compliance. Solid lipid nanoparticles (SLNs) have emerged as a carrier system that can deliver APIs across the BBB with a novel controlled or sustained drug delivery approach, target specificity, higher bioavailability, enhanced efficacy and reduced toxicity. The presence of a biocompatible lipid or modified lipid core in the SLNs help in the encapsulation of both hydrophilic and lipophilic APIs and provides stability by prohibiting leakage and degradation of APIs. Additionally, the drug containing SLNs can easily enter the CNS through the olfactory region of the nasal cavity via trans and para cellular pathways and avoid undergoing first pass metabolism. Although the nasal route is advantageous, the mucociliary clearance mechanism plays a significant role as a barrier to the delivery mechanism and absorption of the therapeutic agents. However, with the addition of thermo- responsive and mucoadhesive polymers that increase the viscosity of the drug delivery system, the mucociliary clearance mechanism can be overcome. Therefore, a mucoadhesive in situ thermo-responsive BUP and NLX loaded SLN nasal spray was developed in this study as a potential treatment for OUD. The individual drug-loaded polymeric SLNs were formulated using the modified double emulsification technique, with each SLN optimized for particle size, entrapment efficiency and drug release using the Box-Behnken Design. The particle size, zeta potential and entrapment efficiency for NLX-loaded SLNs were found to be 142.2 nm, -18.2 mV and 78.7%, respectively, and for BUP-loaded SLNs were found to be 128.2 nm, -19.8 mV and 99.2%, respectively. The polymeric i.e. poly-caprolactone containing BUP- and NLX- loaded SLNs further allowed for the respective drugs to stay in the CNS and release over a period of week i.e. 7 days and as they were lipid i.e. glyceryl monostearate coated and in nano-size range, allowed an increased bioavailability of the drugs across the BBB. The quantification of NLX and BUP was done using a UV-Vis Spectrophotometer and HPLC, followed by the molecular structure viii assessment for both the NLX- and BUP- loaded SLNs using a FTIR and thermal behaviour characterization using a DCS and TGA. Thereafter, the optimized drug containing SLNs were loaded in an optimized mucoadhesive in situ thermo-responsive gel (ISTG) matrix formulated using the cold method composed of Pluronic F-127 and hydroxypropyl methylcellulose for nose-to-brain drug delivery. Through the characterization of the physicochemical properties, ISTG was found to be thermo- responsive at physiological nasal temperature i.e. 34 °C and mucoadhesive to overcome the mucociliary clearance rate of the nasal cavity. Additionally, ex vivo permeation studies were conducted where 72% of the drug containing SLNs were found to permeate across the porcine nasal membrane within 7 hours, indicating a good permeation rate. Lastly, the individual drug- loaded optimized SLNs i.e. NLX-loaded SLNs and BUP-loaded SLNs and the drug containing SLN-loaded ISTG were found to be biocompatible using HEK293 cells as 84.16%, 85.39% and 84.86% cell viability were observed after 72 hours, respectively. Therefore, from the results obtained it can be concluded that the drug containing SLN-loaded ISTG has the potential to become an effective and patient compliant treatment option for opioid use disorder.