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Pharmaceutics. 2019 Jun 7;11(6). pii: E265. doi: 10.3390/pharmaceutics11060265.

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

Author information

1
Division of Rheumatology, Orthopaedics and Dermatology, School of Medicine, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK. richard.pearson@nottingham.ac.uk.
2
Nottingham University Hospitals NHS Trust, Queen's Med Centre, University of Nottingham, Nottingham NG7 2UH, UK. tahir.masud@nuh.nhs.uk.
3
Radiological Sciences, School of Medicine, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK. elaine.blackshaw@nottingham.ac.uk.
4
Critical Pharmaceuticals Ltd., Bio City, Pennyfoot Street, Nottingham NG1 1GF, UK. anaylor@upperton.com.
5
Paracelsis Ltd., BioCity Nottingham, Pennyfoot Street, Nottingham NG1 1GF, UK. mh@paracelsis.com.
6
Critical Pharmaceuticals Ltd., Bio City, Pennyfoot Street, Nottingham NG1 1GF, UK. kjeffery@upperton.com.
7
Critical Pharmaceuticals Ltd., Bio City, Pennyfoot Street, Nottingham NG1 1GF, UK. faron.jordan@hotmail.co.uk.
8
Critical Pharmaceuticals Ltd., Bio City, Pennyfoot Street, Nottingham NG1 1GF, UK. anjumnshabir@yahoo.com.
9
Critical Pharmaceuticals Ltd., Bio City, Pennyfoot Street, Nottingham NG1 1GF, UK. gareth.king@catapult-ventures.com.
10
Critical Pharmaceuticals Ltd., Bio City, Pennyfoot Street, Nottingham NG1 1GF, UK. andrew.lewis@quotientsciences.com.
11
Identity, 19 Cavendish Crescent North, The Park, Nottingham NG71BA, UK. lisbeth.illum@illumdavis.com.
12
Radiological Sciences, School of Medicine, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK. alan.perkins@nottingham.ac.uk.

Abstract

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.

KEYWORDS:

PTH 1-34; clinical trial; man; nasal delivery; osteoporosis; pharmacokinetics; preclinical; sheep; teriparatide

PMID:
31181662
DOI:
10.3390/pharmaceutics11060265
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