ECTS Abstracts (2015) 1 P341

Intranasal administration of PTH(1-34) for the treatment of osteoporosis - equivalence to subcutaneous injection at the neck of femur in the Food and Drug Administration (FDA) mandated preclinical model

Allan Williams1, Faron Jordan2, Gareth King2, Tahir Masud3, Alan Perkins1 & Richard Pearson1

1University of Nottingham, Nottingham, UK; 2Critical Pharmaceuticals Limited, Nottingham, UK; 3Nottingham University Hospitals NHS Trust, Nottingham, UK.

Background: Osteoporosis affects 200 million people worldwide, it is characterised by low bone mass and micro-architectural deterioration, increasing risk of fracture. PTH(1-34) is a proven anti-osteoporotic drug, self-administered by subcutaneous (SC) daily injection. Patient compliance to PTH(1-34) therapy can be sub-optimal for some patients. There is therefore an urgent unmet clinical need to offer alternative administration regimens. Intranasal (IN) delivery of PTH(1-34) offers an attractive non-invasive approach to improve compliance. We show, for the first time, using a proven intranasal nano-enabled delivery system, an equivalent anabolic effect on bone with the same dose of PTH(1-34) administered either SC or IN. The aim was to determine the anabolic effect of PTH(1-34) delivered intranasally in the US FDA pre-clinical model for research into osteoporosis.

Methods: PTH(1-34) liquid formulations for IN delivery were analysed for stability. Following ethical approval, ovariectomised (OVX) rats were randomly divided into groups receiving an equal dose of SC or IN PTH(1-34). Bone tissue was assessed using micro computed tomography following ovariectomy or SHAM and treatment with PTH(1-34) IN or SC, or no PTH(1-34) IN and SC controls. Data were subject to Kolomogorov-Smirnov tests for normality followed by ANOVA.

Results: Stability of formulations was confirmed using HPLC analysis >12 months. Ovariectomy induced bone loss was confirmed in neck of femur (NOF) trabeculae: 50% reduction in bone volume, 51% reduction in trabecular number and 37% increase in trabecular porosity (p<0.05). Post treatment NOF trabecular bone volume significantly increased 58% (OVX 21.22±1.6% vs IN 33.5±2.5%) trabecular number significantly increased 50% (OVX 3.27±0.2mm-1 vs IN 4.91±0.29mm-1) and trabecular porosity significantly decreased 16% (OVX 78.78±1.6% vs IN 66.50±2.5%) (p<0.05). There was no significant difference in bone microarchitecture between SC and IN administration of PTH(1-34) at equivalent doses (p>0.05).

Conclusion: Intranasal delivery of PTH(1-34) is a viable alternative to subcutaneous injection to improve patient compliance.

Disclosure: The authors declared no competing interests. This work was supported by EPSRC grant no EP/K502364/1.

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