Nasal Administration and Plasma Pharmacokinetics of Parathyroid Hormone Peptide PTH 1-34 for the Treatment of Osteoporosis.

Nasal delivery of large peptides such as parathyroid 1-34 (PTH 1-34) can benefit from a permeation enhancer to promote absorption across the nasal mucosa into the bloodstream. Previously, we have published an encouraging bioavailability (78%), relative to subcutaneous injection in a small animal preclinical model, for a liquid nasal spray formulation containing the permeation enhancer polyethylene glycol (15)-hydroxystearate (Solutol® HS15). We report here the plasma pharmacokinetics of PTH 1-34 in healthy human volunteers receiving the liquid nasal spray formulation containing Solutol® HS15. For comparison, data for a commercially manufactured teriparatide formulation delivered via subcutaneous injection pen are also presented. Tc-99m-DTPA gamma scintigraphy monitored the deposition of the nasal spray in the nasal cavity and clearance via the inferior meatus and nasopharynx. The 50% clearance time was 17.8 min (minimum 10.9, maximum 74.3 min). For PTH 1-34, mean plasma Cmax of 5 pg/mL and 253 pg/mL were obtained for the nasal spray and subcutaneous injection respectively; relative bioavailability of the nasal spray was ≤1%. Subsequently, we investigated the pharmacokinetics of the liquid nasal spray formulation as well as a dry powder nasal formulation also containing Solutol® HS15 in a crossover study in an established ovine model. In this preclinical model, the relative bioavailability of liquid and powder nasal formulations was 1.4% and 1.0% respectively. The absolute bioavailability of subcutaneously administered PTH 1-34 (mean 77%, range 55-108%) in sheep was in agreement with published human data for teriparatide (up to 95%). These findings have important implications in the search for alternative routes of administration of peptides for the treatment of osteoporosis, and in terms of improving translation from animal models to humans.

Sustained-Release Hydromorphone Microparticles Produced by Supercritical Fluid Polymer Encapsulation.

Chronic cancer pain remains prevalent and severe for many patients, particularly in those with advanced disease. The effectiveness of analgesic/adjuvant drug treatments in routine practice has changed little in the last 30 years. To address these issues herein, we have developed sustained-release poly(lactic-co-glycolic acid) microparticles of hydromorphone for intrathecal injection aimed at producing prolonged periods of satisfactory analgesia in patients, as a novel strategy for alleviation of intractable cancer-related pain. These hydromorphone-loaded microparticles were produced successfully using organic solvent-free supercritical fluid polymer encapsulation. Drug loading at 9.2% and encapsulation efficacy at 92% were achieved for particles in the desired size range (20-45 µm) with sustained release over a 5-week period in vitro.

Formulation of Bioerodible Ketamine Microparticles as an Analgesic Adjuvant Treatment Produced by Supercritical Fluid Polymer Encapsulation.

Pain is inadequately relieved by escalating doses of a strong opioid analgesic such as morphine in up to 25% of patients with cancer-related severe pain complicated by a neuropathic (nerve damage) component. Hence, there is an unmet medical need for research on novel painkiller strategies. In the present work, we used supercritical fluid polymer encapsulation to develop sustained-release poly(lactic-co-glycolic acid) (PLGA) biodegradable microparticles containing the analgesic adjuvant drug ketamine, for injection by the intrathecal route. Using this approach with a range of PLGA co-polymers, drug loading was in the range 10⁻60%, with encapsulation efficiency (EE) of 60⁻100%. Particles were mainly in the size range 20⁻45 µm and were produced in the absence of organic solvents and surfactants/emulsifiers. Investigation of the ketamine release profiles from these PLGA-based microparticles in vitro showed that release took place over varying periods in the range 0.5⁻4.0 weeks. Of the polymers assessed, the ester end-capped PLGA5050DLG-1.5E gave the best-controlled release profile with drug loading at 10%.