Safety and Pharmacokinetics of Intranasally Administered Heparin Safety and Pharmacokinetics of Intranasally Administered Heparin

• Published in: Pharmaceutical research Vol. 39; no. 3; pp. 541 - 551
• Main Authors: Harris, Hannah M., Boyet, Katherine L., Liu, Hao, Dwivedi, Rohini, Ashpole, Nicole M., Tandon, Ritesh, Bidwell, Gene L., Cheng, Zhi, Fassero, Lauren A., Yu, Christian S., Pomin, Vitor H., Mitra, Dipanwita, Harrison, Kerri A., Dahl, Eric, Gurley, Bill J., Kotha, Arun Kumar, Chougule, Mahavir Bhupal, Sharp, Joshua S.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.03.2022; Springer; Springer Nature B.V
• Subjects: Adverse events; Animals; Anticoagulants; Anticoagulants - adverse effects; Background levels; Biochemistry; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Blood; Blood coagulation; COVID-19; Dosage; Heparin; Human subjects; Humans; Medical examination; Medical Law; Mice; Mice, Inbred C57BL; Nose; Partial Thromboplastin Time; Pharmacokinetics; Pharmacology/Toxicology; Pharmacy; Platelets; Polysaccharides; Research Paper; Safety; Safety and security measures; Sulfates; Thromboplastin; Toxicity; heparin; intranasal delivery; SARS-CoV-2; Covid-19
• ISSN: 0724-8741; 1573-904X; 1573-904X
• DOI: 10.1007/s11095-022-03191-4

Purpose Intranasally administered unfractionated heparin (UFH) and other sulfated polysaccharides are potential prophylactics for COVID-19. The purpose of this research was to measure the safety and pharmacokinetics of clearance of intranasally administered UFH solution from the nasal cavity. Methods Double-blinded daily intranasal dosing in C57Bl6 mice with four doses (60 ng to 60 μg) of UFH was carried out for fourteen consecutive days, with both blood coagulation measurements and subject adverse event monitoring. The pharmacokinetics of fluorescent-labeled UFH clearance from the nasal cavity were measured in mice by in vivo imaging. Intranasal UFH at 2000 U/day solution with nasal spray device was tested for safety in a small number of healthy human subjects. Results UFH showed no evidence of toxicity in mice at any dose measured. No significant changes were observed in activated partial thromboplastin time (aPTT), platelet count, or frequency of minor irritant events over vehicle-only control. Human subjects showed no significant changes in aPTT time, international normalized ratio (INR), or platelet count over baseline measurements. No serious adverse events were observed. In vivo imaging in a mouse model showed a single phase clearance of UFH from the nasal cavity. After 12 h, 3.2% of the administered UFH remained in the nasal cavity, decaying to background levels by 48 h. Conclusions UFH showed no toxic effects for extended daily intranasal dosing in mice as well as humans. The clearance kinetics of intranasal heparin solution from the nasal cavity indicates potentially protective levels for up to 12 h after dosing.