Karen Polowy

Oral Human Brain Natriuretic Peptide Activates Cyclic Guanosine 3′,5′-Monophosphate and Decreases Mean Arterial Pressure

Background—The objective of this study was to address the feasibility and the biological activity of orally administered human brain natriuretic peptide (hBNP). Proprietary technology has been developed in which short, amphiphilic oligomers are covalently attached to peptides. The conjugated peptides are intended to have an improved pharmacokinetic profile and to enable oral administration. We hypothesized that novel oral conjugated hBNP (CONJ-hBNP) increases plasma hBNP, activates cGMP, and reduces mean arterial pressure (MAP). Methods and Results—This randomized crossover-designed study tested the biological activity of oral CONJ-hBNP compared with oral native hBNP in normal conscious dogs. Measurements of MAP, plasma hBNP, and cGMP were made at baseline (BL) and repeated at 10, 30, 60, 120, 180, and 240 minutes after oral administration. Plasma hBNP was not detectable in dogs at BL. Plasma hBNP was detected after native hBNP and CONJ-HBNP administration. However, plasma hBNP concentration was significantly higher after CONJ-hBNP than after native hBNP administration (P=0.0374 between groups). Plasma cGMP increased after CONJ-hBNP for 60 minutes (from 10.8±3 to 36.8±26 pmol/mL; P<0.05), whereas it did not change after native hBNP (P=0.001 between groups). MAP decreased at 10 minutes and remained decreased for 60 minutes after CONJ-hBNP (from 113±8 to 101±12 mm Hg after 10 minutes to 97.5±10 mm Hg after 30 minutes to 99±13 mm Hg after 60 minutes) while remaining unchanged after native hBNP (P=0.0387 between groups). Conclusions—This study reports for the first time that novel conjugated oral BNP activates cGMP and significantly reduces MAP, thus implying an efficacious coupling of CONJ-hBNP to the natriuretic receptor-A. These data advance a new concept of orally administered chronic BNP therapy for cardiovascular diseases.

Identification of a pharmaceutical packaging off-odor using solid phase microextraction gas chromatography/mass spectrometry

The use of a solid phase microextraction (SPME) sampling technique, in conjunction with gas chromatography/mass spectrometry (GC/MS) analysis, to identify an off-odor in a heat-stressed pharmaceutical packaging material is described. The ability of the commercially available polydimethylsiloxane (PDMS) coated microfiber to concentrate a trace volatile compound of interest enabled identification of the odor compound of interest. Despite being present at levels that defied detection using conventional headspace sampling techniques, ethyl-2-mercaptoacetate was determined to be the compound responsible for the offending odor. Formation of the thioester resulted from an unanticipated reaction (either esterification or transesterification) between a common residual solvent (ethanol), present in a commonly used pharmaceutical tablet dispersant, and low-level amounts of reactants or synthetic intermediates of an FDA-approved polyvinyl chloride (PVC)-resin thermal stabilizing agent.

CD101, a novel echinocandin with exceptional stability properties and enhanced aqueous solubility.

The echinocandins are an important class of antifungal agents. However, instability and, in some cases, lack of solubility have restricted their use to situations in which daily infusions are acceptable. CD101 is a novel echinocandin in development for topical and weekly i.v. administration that exhibits prolonged stability in plasma and aqueous solutions up to 40 °C. After incubation for 44 h in rat, dog, monkey and human plasma at 37 °C, the percent of CD101 remaining (91%, 79%, 94% and 93%, respectively) was consistently greater than that of anidulafungin (7%, 15%, 14% and 7%, respectively). Similarly, after incubation in phosphate-buffered saline at 37 °C, the CD101 remaining (96%) was greater than that of anidulafungin (42%). CD101 exhibited <2% degradation after long-term storage at 40 °C as a lyophilized powder (9 months) and at room temperature in 5% dextrose (15 months), 0.9% saline (12 months) and sterile water (18 months). Degradation was <7% at 40 °C in acetate and lactate buffers (6 to 9 months at pH 4.5–5.5). The chemical stability and solubility of CD101 contribute to dosing, pharmacokinetic, formulation and safety advantages over other echinocandins and should expand utility beyond daily i.v. therapy.