title: Novel polymeric bioerodable microparticles for prolonged-release intrathecal delivery of analgesic agents for relief of intractable cancer-related pain.
abstract: Intractable cancer-related pain complicated by a neuropathic component due to nerve impingement is poorly alleviated even by escalating doses of a strong opioid analgesic. To address this unmet medical need, we developed sustained-release, bioerodable, hydromorphone (potent strong opioid)- and ketamine (analgesic adjuvant)-loaded microparticles for intrathecal (i.t.) coadministration. Drug-loaded poly(lactic-co-glycolic acid) (PLGA) microparticles were prepared using a water-in-oil-in-water method with evaporation. Encapsulation efficiency of hydromorphone and ketamine in PLGA (50:50) microparticles was 26% and 56%, respectively. Microparticles had the desired size range (20-60 μm) and in vitro release was prolonged at ≥28 days. Microparticles were stable for ≥6 months when stored refrigerated protected from light in a desiccator. Desirably, i.t. injected fluorescent dye-labeled PLGA microparticles in rats remained in the lumbar region for ≥7 days. In a rat model of neuropathic pain, i.t. coinjection of hydromorphone- and ketamine-loaded microparticles (each 1 mg) produced analgesia for 8 h only. Possible explanations include inadequate release of ketamine and/or hydromorphone into the spinal fluid, and/or insufficient ketamine loading to prevent development of analgesic tolerance to the released hydromorphone. As sub-analgesic doses of i.t. ketamine at 24-48 h intervals restored analgesia on each occasion, insufficient ketamine loading appears problematic. We will investigate these issues in future work.
authors.affiliation: Centre for Integrated Preclinical Drug Development, The University of Queensland, Brisbane, QLD, Australia.|School of Pharmacy, The University of Queensland, Brisbane, QLD, Australia.|Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: Felicity Y
authors.initials: FY
authors.lastname: Han
authors.affiliation: Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, Australia.|Centre for Advanced Imaging, The University of Queensland, Brisbane, QLD, Australia.|ARC Centre of Excellence in Convergent BioNano Science and Technology, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: Kristofer J
authors.initials: KJ
authors.lastname: Thurecht
authors.affiliation: Centre for Integrated Preclinical Drug Development, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: Ai-Leen
authors.initials: AL
authors.lastname: Lam
authors.affiliation: Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, Australia.|Centre for Advanced Imaging, The University of Queensland, Brisbane, QLD, Australia.|ARC Centre of Excellence in Convergent BioNano Science and Technology, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Whittaker
authors.affiliation: Centre for Integrated Preclinical Drug Development, The University of Queensland, Brisbane, QLD, Australia.|School of Pharmacy, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: Maree T
authors.initials: MT
authors.lastname: Smith
mesh_terms: D000700:Analgesics / Q000737:chemistry* / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D003692:Delayed-Action Preparations / Q000737:chemistry* / Q000494:pharmacology*; D007649:Ketamine / Q000737:chemistry / Q000494:pharmacology; D019344:Lactic Acid / Q000737:chemistry; D008297:Male; D008863:Microspheres; D009369:Neoplasms / Q000150:complications; D010146:Pain / Q000188:drug therapy* / Q000209:etiology; D059408:Pain Management / Q000379:methods; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000700:Analgesics; D000701:Analgesics, Opioid; D003692:Delayed-Action Preparations; D011108:Polymers; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D007649:Ketamine
keywords: cancer chemotherapy; drug delivery; hydromorphone; intractable cancer-related pain; intrathecal; ketamine; microparticles; pharmacodynamics; poly(lactic-co-glycolic acid)(PLGA); rat model of chemotherapy-induced peripheral neuropathy (CIPN rats)