In vitro and in vivo preclinical evaluation of a minisphere emulsion-based formulation (SmPill®) of salmon calcitonin

Salmon calcitonin (sCT, MW3432 Da) is a benchmark molecule for an oral peptide delivery system because it is degraded and has low intestinal epithelial permeability. Four dry emulsion minisphere prototypes (SmPill (R)) containing sCT were co-formulated with permeation enhancers (PEs): sodium taurodeoxycholate (NaTDC), sodium caprate (C-10) or coco-glucoside (CG), or with a pH acidifier, citric acid (CA). Minispheres protected sCT from thermal degradation and the released sCT retained high bioactivity, as determined by cyclic AMP generation in T47D cells. Pre-minisphere emulsions of PEs combined with sCT increased absolute bioavailability (F) compared to native sCT following rat intra-jejunal (i.j.) and intra-colonic (i.c.) loop instillations, an effect that was more pronounced in colon. Minispheres corresponding to similar to 2000 I.U. (similar to 390 mu g) sCT/kg were instilled by i.j. or i.c. instillations and hypocalcaemia resulted from all prototypes. The absolute F (i.j.) of sCT was 11.0, 4.8, and 1.4% for minispheres containing NaTDC (10 mu mol/kg), CG (12 mu mol/kg) or CA (32 mu mol/kg) respectively. For i.c. instillations, the largest absolute F (22% in each case) was achieved for minispheres containing either C10 (284 mu mol/kg) or CG (12 mu mol/kg), whilst the absolute F was 8.2% for minispheres loaded with CA (32 mu mol/kg). In terms of relative F, the best data were obtained for minispheres containing NaTDC (i.j.), a 4-fold increase over sCT solution, and also for either C10 or CG (i.c.), where there was a 3-fold increase over sCT solution. Histology of instilled intestinal loops indicated that neither the minispheres nor components thereof caused major perturbation. In conclusion, selected SmPill (R) minisphere formulations may have the potential to be used as oral peptide delivery systems when delivered to jejunum or colon. (C) 2015 Elsevier B.V. All rights reserved.