D. Mix

Stabilization and intestinal absorption of human calcitonin

The effect of different excipients and/or surface active compounds on the stability of human calcitonin in aqueous solution was studied. Calcitonin solution was partially stabilized with dilute acetic acid (0.01% (w/v) or higher), and among many tested surfactants, only lauryl sulfate proved to be a very efficient long-term stabilizer (1 year or more). Concentration dependency studies indicated that lauryl sulfate micelles were necessary to achieve long-term stabilization of human calcitonin in solution. Another liquid formulation was developed that also stabilized human calcitonin over a long period of time (3 months or more). Calcitonin was dissolved in polar, nontoxic, nonaqueous solvents, such as propylene glycol or polyethylene glycol 200 and this solution was emulsified in an oil phase composed of medium-chain glycerides. Medium and long-term stabilized formulations of human calcitonin were then studied for intestinal absorption via the duodenum and colon in rats. Using aqueous formulations containing 1% sodium dodecyl sulfate or 6.6% dodecyl maltoside as the enhancer, bioavailability values greater than 10% were achieved by intracolonic route of administration, demonstrating that the colon is better suited for calcitonin delivery and absorption. Pharmacodynamic responses and time profiles obtained were significant and comparable to those observed for intramuscular injection of human calcitonin.

Mucosal delivery of macromolecules

Low molecular weight heparin (LMWH), a glycosaminoglycan of approximately 6000 molecular weight, is currently used in the prevention of postsurgical thrombosis and in the treatment of deep vein thrombosis. Current dosing regimens entail subcutaneous injections of 2500–5000 anti-factor Xa units per day. Transbuccal delivery of LMWH may provide significant advantages over the current injectable dosage forms. The kinetics and extent of LMWH absorption from prototype buccal dosage forms were evaluated. Based on pharmacokinetic analysis, over 3000 anti-factor Xa units (i.e., 20 mg) could be delivered from a single application. These results demonstrate the feasibility of administering macromolecular drugs, such as LMWH, via the buccal route.

Physical Stabilization of Insulin through Chemical Modification: Site-Specific Glycosylation or Pegylation

The modification of human insulin by the covalent attachment of p-succinamidophenyl glucoside or monomethoxy monosuccinyl polyethylene glycol 600 and 2000 moieties to the protein remarkably alters the physical stability of insulin in solution. The synthesized derivatives were purified to homogeneity using ion exchange chromatography and then attachment site(s) were determined. The biological activity of the modified insulins was well preserved and covalent attachment of any hydrophilic group to any insulin amino group(s) improved insulin solution stability. However, the most significant impact on increased stability was the site-specific modification at PheB 1 site. Moreover, as the number of groups attached to insulin increased, the solution stability of insulin derivatives also improved.