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 pre...
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| Format: | Article |
| Language: | English |
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MDPI AG
2019-06-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/11/6/265 |
| _version_ | 1798003430361399296 |
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| author | Richard G. Pearson Tahir Masud Elaine Blackshaw Andrew Naylor Michael Hinchcliffe Kirk Jeffery Faron Jordan Anjumn Shabir-Ahmed Gareth King Andrew L. Lewis Lisbeth Illum Alan C. Perkins |
| author_facet | Richard G. Pearson Tahir Masud Elaine Blackshaw Andrew Naylor Michael Hinchcliffe Kirk Jeffery Faron Jordan Anjumn Shabir-Ahmed Gareth King Andrew L. Lewis Lisbeth Illum Alan C. Perkins |
| author_sort | Richard G. Pearson |
| collection | DOAJ |
| description | 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<sup>®</sup> HS15). We report here the plasma pharmacokinetics of PTH 1-34 in healthy human volunteers receiving the liquid nasal spray formulation containing Solutol<sup>®</sup> 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 C<sub>max</sub> 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<sup>®</sup> 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. |
| first_indexed | 2024-04-11T12:07:41Z |
| format | Article |
| id | doaj.art-835f2d5b3a3e42739c1270f537c2dac0 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-04-11T12:07:41Z |
| publishDate | 2019-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-835f2d5b3a3e42739c1270f537c2dac02022-12-22T04:24:41ZengMDPI AGPharmaceutics1999-49232019-06-0111626510.3390/pharmaceutics11060265pharmaceutics11060265Nasal Administration and Plasma Pharmacokinetics of Parathyroid Hormone Peptide PTH 1-34 for the Treatment of OsteoporosisRichard G. Pearson0Tahir Masud1Elaine Blackshaw2Andrew Naylor3Michael Hinchcliffe4Kirk Jeffery5Faron Jordan6Anjumn Shabir-Ahmed7Gareth King8Andrew L. Lewis9Lisbeth Illum10Alan C. Perkins11Division of Rheumatology, Orthopaedics and Dermatology, School of Medicine, Queen’s Medical Centre, University of Nottingham, Nottingham NG7 2UH, UKNottingham University Hospitals NHS Trust, Queen’s Med Centre, University of Nottingham, Nottingham NG7 2UH, UKRadiological Sciences, School of Medicine, Queen’s Medical Centre, University of Nottingham, Nottingham NG7 2UH, UKCritical Pharmaceuticals Ltd., Bio City, Pennyfoot Street, Nottingham NG1 1GF, UKParacelsis Ltd., BioCity Nottingham, Pennyfoot Street, Nottingham NG1 1GF, UKCritical Pharmaceuticals Ltd., Bio City, Pennyfoot Street, Nottingham NG1 1GF, UKCritical Pharmaceuticals Ltd., Bio City, Pennyfoot Street, Nottingham NG1 1GF, UKCritical Pharmaceuticals Ltd., Bio City, Pennyfoot Street, Nottingham NG1 1GF, UKCritical Pharmaceuticals Ltd., Bio City, Pennyfoot Street, Nottingham NG1 1GF, UKCritical Pharmaceuticals Ltd., Bio City, Pennyfoot Street, Nottingham NG1 1GF, UKIdentity, 19 Cavendish Crescent North, The Park, Nottingham NG71BA, UKRadiological Sciences, School of Medicine, Queen’s Medical Centre, University of Nottingham, Nottingham NG7 2UH, UKNasal 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<sup>®</sup> HS15). We report here the plasma pharmacokinetics of PTH 1-34 in healthy human volunteers receiving the liquid nasal spray formulation containing Solutol<sup>®</sup> 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 C<sub>max</sub> 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<sup>®</sup> 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.https://www.mdpi.com/1999-4923/11/6/265PTH 1-34teriparatidenasal deliverypharmacokineticsosteoporosismansheepclinical trialpreclinical |
| spellingShingle | Richard G. Pearson Tahir Masud Elaine Blackshaw Andrew Naylor Michael Hinchcliffe Kirk Jeffery Faron Jordan Anjumn Shabir-Ahmed Gareth King Andrew L. Lewis Lisbeth Illum Alan C. Perkins Nasal Administration and Plasma Pharmacokinetics of Parathyroid Hormone Peptide PTH 1-34 for the Treatment of Osteoporosis Pharmaceutics PTH 1-34 teriparatide nasal delivery pharmacokinetics osteoporosis man sheep clinical trial preclinical |
| title | Nasal Administration and Plasma Pharmacokinetics of Parathyroid Hormone Peptide PTH 1-34 for the Treatment of Osteoporosis |
| title_full | Nasal Administration and Plasma Pharmacokinetics of Parathyroid Hormone Peptide PTH 1-34 for the Treatment of Osteoporosis |
| title_fullStr | Nasal Administration and Plasma Pharmacokinetics of Parathyroid Hormone Peptide PTH 1-34 for the Treatment of Osteoporosis |
| title_full_unstemmed | Nasal Administration and Plasma Pharmacokinetics of Parathyroid Hormone Peptide PTH 1-34 for the Treatment of Osteoporosis |
| title_short | Nasal Administration and Plasma Pharmacokinetics of Parathyroid Hormone Peptide PTH 1-34 for the Treatment of Osteoporosis |
| title_sort | nasal administration and plasma pharmacokinetics of parathyroid hormone peptide pth 1 34 for the treatment of osteoporosis |
| topic | PTH 1-34 teriparatide nasal delivery pharmacokinetics osteoporosis man sheep clinical trial preclinical |
| url | https://www.mdpi.com/1999-4923/11/6/265 |
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