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).
Subject(s)
Aerosols/chemistry , Oxytocin/chemistry , Powders/chemistry , Administration, Inhalation , Calorimetry, Differential Scanning/methods , Chemistry, Pharmaceutical/methods , Desiccation/methods , Drug Compounding/methods , Drug Stability , Dry Powder Inhalers/methods , Excipients/chemistry , Hot Temperature , Nanoparticles/chemistry , Particle Size , Trehalose/chemistry , X-Ray Diffraction/methodsABSTRACT
3-(Phenylacetamido)pyruvic acid and its methyl ester both exist in the enol form in the solid state and when dissolved in organic solvents. In aqueous solution, the pK(a)'s of the enol acid are 3.28 (CO(2)H) and 10.14 (enolic OH) and that of the ester is 8.14 (enolic OH). The thermodynamically stable form of both acid and ester in aqueous solution, however, is the keto species. Ketonization rates of 3-(phenylacetamido)pyruvic acid were determined spectrophotometrically in acid and in buffered solution at neutral pH. The dominant reaction at low pH is the pH-independent protonation of the enol carboxylate monoanion with a rate constant of 0.062 s(-)(1) M(-)(1). At neutral pH, the ketonization in water alone is very slow but is strongly catalyzed by buffer acids. Rapid, partial (ca. 30%) hydration of the keto form also occurs in aqueous solution. The pK(a) of the pyruvate as a carbon acid is around 12.5. These results are compared with literature data for pyruvic acid itself. Application of peptidyl pyruvates and their derivatives as protease inhibitors requires careful assessment of the complications illustrated by the behavior of 3-(phenylacetamido)pyruvic acid and its methyl ester in aqueous solution.
