Development and evaluation of cannabidiol formulations for delivery to the central nervous system to treat neuropathic pain

Muresan, Paula Diana (2022) Development and evaluation of cannabidiol formulations for delivery to the central nervous system to treat neuropathic pain. PhD thesis, University of Nottingham.

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Abstract

Neuropathic pain is a great societal burden estimated to affect approx. 40% of the general population, being accompanied by a significant decline in normal functioning and quality of life. Moreover, it is a major economic burden, costing the NHS £5 billion annually. Pain has complex pathophysiology and is currently poorly managed due to the ineffectiveness of many therapies. The drawback associated with the development of novel analgesics is multifaceted. One of the limitations is linked to the lack of effective delivery of therapeutics to the site of action - the central nervous system (CNS). Effective drug delivery to the CNS is extremely challenging due to the presence of the blood-brain barrier (BBB) and the blood-cerebrospinal fluid-barrier (BCSFB), however a technique involving a direct intrathecal (IT) injection into the lumbar segment of the spinal cord by-passes these barriers. Additionally, numerous patients are also resistant to traditional opioids (i.e., morphine) used in the treatment of pain, leaving many with no alternative therapies. Nonetheless, cannabidiol (CBD) has been emerging as efficacious in treating pain, amongst other disease states such as depression, anxiety or inflammation. Therefore, in order to tackle neuropathic pain in patients resistant to traditional opioid therapies and by-pass the protective CNS barriers, the development of novel formulations coupled with effective interventional treatments is required.

CBD is non-psychoactive and has been shown to be efficacious in decreasing pain, however, it is limited in therapeutic action due to its poor pharmacokinetic profile observed in both humans and rodents after oral and intravenous administration. In order to overcome this drawback, I developed two different CBD formulations, a stable lipid based nanoemulsion (286 nm diameter and 0.135 PDI) and polymer-coated nanoparticles (PCNPs) (121 nm diameter and 0.079 PDI), with high CBD association and loading (1.28 mg/mL (65.1%) and 0.46 mg/mL (28.52%) respectively), for administration directly at the site of action via an IT injection. Furthermore, I also aimed to investigate how the biodistribution of CBD and its antinociceptive effects within the CNS were influenced by these two distinct formulations.

I found that both formulations exhibited anti-nociceptive effects within 10 mins of IT administration in rats, upon the stimulation with noxious von Frey hairs, in comparison to the blank vehicles. Both formulations were preferentially retained in the spinal cord with high concentrations reaching the brain immediately after injection. The CBD nanoemulsion reached Cmax in the brain at 210 ng/g within 120 mins (Tmax), whereas the CBD PCNPs had a Cmax of 94 ng/g at 30 mins (Tmax), indicating that rapid delivery can be achieved through the use of PCNPs. Moreover, the AUC 0-4 hrs of CBD in the brain was increased 3.7-fold through the delivery of the nanoemulsion as opposed to the PCNPs, indicating higher retention of CBD at this site. These data demonstrate that the concentration of therapeutics delivered to the brain can be increased through the use of a nanoemulsion formulation.

No CBD was detected in peripheral tissues or in circulating blood, suggesting that the drug was localised to the CNS throughout the time-points tested. These findings pose critical considerations for the development of nanotechnology for small lipophilic molecules for IT delivery. They allow the optimisation of colloidal formulation properties to attain rapid, sustained and widespread distribution within the spinal cord, with successful delivery to the brain, whilst being localised to the CNS.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Marlow, Maria
Gershkovich, Pavel
Rahman, Ruman
Keywords: Cannabidiol formulations, Central nervous system, Neuropathic pain
Subjects: R Medicine > RM Therapeutics. Pharmacology
Faculties/Schools: UK Campuses > Faculty of Science > School of Pharmacy
Item ID: 69309
Depositing User: Muresan, Paula
Date Deposited: 28 Jul 2022 04:40
Last Modified: 28 Jul 2022 04:40
URI: http://eprints.nottingham.ac.uk/id/eprint/69309

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