title: Heat-Stable Dry Powder Oxytocin Formulations for Delivery by Oral Inhalation.
abstract: In this work, heat stable dry powders of oxytocin (OT) suitable for delivery by oral inhalation were prepared. The OT dry powders were prepared by spray drying using excipients chosen to promote OT stability including trehalose, isoleucine, polyvinylpyrrolidone, citrate (sodium citrate and citric acid), and zinc salts (zinc chloride and zinc citrate). Characterization by laser diffraction indicated that the OT dry powders had a median particle size of 2 μm, making them suitable for delivery by inhalation. Aerodynamic performance upon discharge from proprietary dry powder inhalers was evaluated by Andersen cascade impaction (ACI) and in an anatomically correct airway (ACA) model, and confirmed that the powders had excellent aerodynamic performance, with respirable fractions up to 77% (ACI, 30 L/min). Physicochemical characterization demonstrated that the powders were amorphous (X-ray diffraction) with high glass transition temperature (modulated differential scanning calorimetry, MDSC), suggesting the potential for stabilization of the OT in a glassy amorphous matrix. OT assay and impurity profile were conducted by reverse phase HPLC and liquid chromatography-mass spectrometry (LC-MS) after storage up to 32 weeks at 40°C/75%RH. Analysis demonstrated that OT dry powders containing a mixture of citrate and zinc salts retained more than 90% of initial assay after 32 weeks storage and showed significant reduction in dimers and trisulfide formation (up to threefold reduction compared to control).
authors.affiliation: Mannkind Corporation, One Casper Street, Danbury, Connecticut, 06810, USA. kfabio@mannkindcorp.com.
authors.forename: Karine
authors.initials: K
authors.lastname: Fabio
authors.affiliation: Mannkind Corporation, One Casper Street, Danbury, Connecticut, 06810, USA.
authors.forename: Kieran
authors.initials: K
authors.lastname: Curley
authors.affiliation: Mannkind Corporation, One Casper Street, Danbury, Connecticut, 06810, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Guarneri
authors.affiliation: Mannkind Corporation, One Casper Street, Danbury, Connecticut, 06810, USA.
authors.forename: Benoit
authors.initials: B
authors.lastname: Adamo
authors.affiliation: Mannkind Corporation, One Casper Street, Danbury, Connecticut, 06810, USA.
authors.forename: Brendan
authors.initials: B
authors.lastname: Laurenzi
authors.affiliation: Mannkind Corporation, One Casper Street, Danbury, Connecticut, 06810, USA.
authors.forename: Marshall
authors.initials: M
authors.lastname: Grant
authors.affiliation: Mintaka Foundation, Geneva, Switzerland.
authors.forename: Robin
authors.initials: R
authors.lastname: Offord
authors.affiliation: Mannkind Corporation, One Casper Street, Danbury, Connecticut, 06810, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Kraft
authors.affiliation: Mannkind Corporation, One Casper Street, Danbury, Connecticut, 06810, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Leone-Bay
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols / Q000737:chemistry*; D002152:Calorimetry, Differential Scanning / Q000379:methods; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003890:Desiccation / Q000379:methods; D004339:Drug Compounding / Q000379:methods; D004355:Drug Stability; D058995:Dry Powder Inhalers / Q000379:methods; D005079:Excipients / Q000737:chemistry; D006358:Hot Temperature; D053758:Nanoparticles / Q000737:chemistry; D010121:Oxytocin / Q000737:chemistry*; D010316:Particle Size; D011208:Powders / Q000737:chemistry*; D014199:Trehalose / Q000737:chemistry; D014961:X-Ray Diffraction / Q000379:methods
chemical_list: D000336:Aerosols; D005079:Excipients; D011208:Powders; D010121:Oxytocin; D014199:Trehalose
keywords: dry powder; oral inhalation; oxytocin; peptide delivery; postpartum hemorrhage