Development of in vitro models to demonstrate the ability of PecSys®, an in situ nasal gelling technology, to reduce nasal run-off and drip.

UNLABELLED: Many of the increasing number of intranasal products available for either local or systemic action can be considered sub-optimal, most notably where nasal drip or run-off give rise to discomfort/tolerability issues or reduced/variable efficacy. PecSys, an in situ gelling technology, contains low methoxy (LM) pectin which gels due to interaction with calcium ions present in nasal fluid. PecSys is designed to spray readily, only forming a gel on contact with the mucosal surface. The present study employed two in vitro models to confirm that gelling translates into a reduced potential for drip/run-off: (i) Using an inclined TLC plate treated with a simulated nasal electrolyte solution (SNES), mean drip length [±SD, n = 10] was consistently much shorter for PecSys (1.5 ± 0.4 cm) than non-gelling control (5.8 ± 1.6 cm); (ii) When PecSys was sprayed into a human nasal cavity cast model coated with a substrate containing a physiologically relevant concentration of calcium, PecSys solution was retained at the site of initial deposition with minimal redistribution, and no evidence of run-off/drip anteriorly or down the throat. In contrast, non-gelling control was significantly more mobile and consistently redistributed with run-off towards the throat. CONCLUSION: In both models PecSys significantly reduced the potential for run-off/drip ensuring that more solution remained at the deposition site. In vivo, this enhancement of retention will provide optimum patient acceptability, modulate drug absorption and maximize the ability of drugs to be absorbed across the nasal mucosa and thus reduce variability in drug delivery.

Formulation development and manufacturing of a gastrin/CCK-2 receptor targeting peptide as an intermediate drug product for a clinical imaging study.

A DOTA-gastrin analogue (APH070) which, when labelled with (111)In, has high affinity for the gastrin/CCK-2 receptor (3nM) and low tumour to kidney ratio in animal models, has been formulated and manufactured for a clinical study. Oxidation of the peptide methionine residue greatly reduces receptor affinity, therefore development work focused on producing a stable intermediate drug product (iDP) whilst ensuring that the formulation, container, closure and manufacturing process did not inhibit the extremely sensitive radiolabelling reaction (itself a source of oxidation). Stress testing revealed that APH070 was stable at 2-8 degrees C at pH 6-9. Addition of an antioxidant (monothioglycerol) to the peptide formulation reduced stability when compared to buffer alone. Use of FluroTec (4023/50) stoppers (rather than FluroTec Plus (4110/40)) increased both the stability and radiolabelling efficiency of APH070. Long term stability (6 months) of the final formulation (1mg/ml APH070 in 0.01 M pH 7.2 phosphate buffer) stored at 5 degrees C in type I glass vials with FluroTec (4023/50) stoppers was 98.6+/-0.2% and 98.4+/-0.1% for upright and inverted samples, respectively. Clinical scale radiolabelling of the final formulation routinely achieves the specification of >85% (111)In-APH070 (unoxidised) stable for up to 2h after dilution with 0.9% w/v saline solution. Specific uptake of the radiopharmaceutical in CCK-2R-expressing AR42J tumours in nude mice has been demonstrated.