Coated minispheres of salmon calcitonin target rat intestinal regions to achieve systemic bioavailability: Comparison between intestinal instillation and oral gavage

Abstract

Achieving oral peptide delivery is an elusive challenge. Emulsion-based minispheres of salmon calcitonin (sCT) were synthesized using single multiple pill (SmPill ® ) technology incorporating the permeation enhancers (PEs): sodium taurodeoxycholate (NaTDC), sodium caprate (C 10 ), or coco-glucoside (CG), or the pH acidifier, citric acid (CA). Minispheres were coated with an outer layer of Eudragit ® L30 D-55 (designed for jejunal release) or Surelease ® /Pectin (designed for colonic release). The process was mild and in vitro biological activity of sCT was retained upon release from minispheres stored up to 4 months. In vitro release profiles suggested that sCT was released from minispheres by diffusion through coatings due to swelling of gelatin and the polymeric matrix upon contact with PBS at pH 6.8.X-ray analysis confirmed that coated minispheres dissolved at the intended intestinal region of rats following oral gavage. Uncoated minispheres at a dose of ~2000 I.U. sCT/kg were administered to rats by intra-jejunal (i.j.) or intra-colonic (i.c.) instillation and caused hypocalcaemia. Notable sCT absolute bioavailability (F) values were: 5.5% from minispheres containing NaTDC (i.j), 17.3% with CG (i.c.) and 18.2 % with C 10 (i.c.). Coated minispheres administered by oral gavage at threefold higher doses also induced hypocalcaemia. A highly competitive F value of 2.7% was obtained for orally-administered sCT-minispheres containing CG (45 μmol/kg) and coated with Eudragit ® . In conclusion, the SmPill ® technology is a potential dosage form for several peptides when formulated with PEs and coated for regional delivery. PK data from instillations over-estimates oral bioavailability and poorly predicts rank ordering of formulations .

Synthesis and In Vivo Evaluation of Insulin-Loaded Whey Beads as an Oral Peptide Delivery System

“…In situ rat jejunal instillations were carried out to assess the lyophilised encapsulator-synthesised insulin-dWPI beads. The method was according to previous descriptions [ 33 , 34 ], but with modifications to accommodate the beads. A midline laparotomy was performed under anaesthesia and the jejunum was identified.…”

Oral Delivery of Biologics for Precision Medicine

“…Its mechanism of action was envisaged as a combination of i) maintenance of insulin in its monomeric active form; ii) paracellular permeation enhancement, demonstrated in Caco‐2 cells; iii) inhibition of proteolytic enzymes; and iv) mucus layer thinning. Also worth mentioning is the strategy presented as single multiple pill (SmPill),43 consisting of enteric‐coated emulsion‐based minispheres incorporating several permeation enhancers.…”

Untitled

“…The images were recorded at the tie intervals of 4, 8, 16, and 28 h using an online computer system, stored on magnetic disk, and analyzed to determine the distribution of activity in the stomach and intestine and colonic region. [12] Pharmacokinetic studies…”

“…Reduction in size of capsule indicated that the capsules were broken down and released the drug in colon at 28 th h. The results are in accordance with the fact that the optimized formulation could be targeted specifically to the colon, without any premature drug release in the stomach and small intestine. [12]…”