A CGRP receptor antagonist peptide formulated for nasal administration to treat migraine.

OBJECTIVES: To investigate the formulation of the peptide-based antagonist (34 Pro,35 Phe)CGRP27-37 , of the human calcitonin gene-related peptide (CGRP) receptor as a potential nasally delivered migraine treatment. METHODS: Peptide sequences were prepared using automated methods and purified by preparative HPLC. Their structure and stability were determined by LC-MS. Antagonist potency was assessed by measuring CGRP-stimulated cAMP accumulation in SK-N-MC, cells and in CHO cells overexpressing the human CGRP receptor. In vivo activity was tested in plasma protein extravasation (PPE) studies using Evans blue dye accumulation. Peptide-containing chitosan microparticles were prepared by spray drying. KEY FINDINGS: (34 Pro,35 Phe)CGRP27-37 exhibited a 10-fold increased affinity compared to αCGRP27-37 . Administration of (34 Pro,35 Phe)CGRP27-37 to mice led to a significant decrease in CGRP-induced PPE confirming antagonistic properties in vivo. There was no degradation of (34 Pro,35 Phe)CGRP27-37 and no loss of antagonist potency during formulation and release from chitosan microparticles. CONCLUSIONS: (34 Pro,35 Phe)CGRP27-37 is a potent CGRP receptor antagonist both in vitro and in vivo, and it can be formulated as a dry powder with no loss of activity indicating its potential as a nasally formulated anti-migraine medicine.

Development, characterisation and nasal deposition of melatonin-loaded pectin/hypromellose microspheres.

In this study, we present the development of spray-dried pectin/hypromellose microspheres as efficient melatonin carrier for targeted nasal delivery. Different pectin to hypromellose weight ratios in the spray-dried feed were employed (i.e. 1:0, 3:1, 1:1 and 1:3) in order to optimise microsphere physicochemical properties influencing overall powder behaviour prior, during and upon nasal delivery. All microspheres assured complete melatonin entrapment and increased dissolution rate in relation to pure melatonin powder. Among all combinations tested, combining pectin with hypromellose at 1:3 wt ratio resulted in the microspheres with the highest potential for melatonin nasal delivery as they assured highest swelling ability and most prominent mucoadhesive properties. Studies on deposition profile revealed adequate turbinate and olfactory deposition of microsphere/lactose monohydrate powder blend administered nasally using MIAT® device, complementing findings relevant for their therapeutic potential. In conclusion, developed microspheres bear the potential to ensure prolonged melatonin retention at the nasal mucosa, improved bioavailability and advanced therapeutic outcome.

Innovative sprayable in situ gelling fluticasone suspension: Development and optimization of nasal deposition.

The aim of this study was to develop an innovative in situ gelling suspension for effective nasal delivery of fluticasone. Pectin, gellan gum and sodium hyaluronate were used as gelling/thickening agents, and Tween 80 as a suspending agent. The influence of the formulation and/or administration parameters on formulation sprayability and nasal deposition was explored with an appropriate experimental design with the range for parameters in the design obtained from previous research and domain knowledge. All formulations exhibited appropriate sprayability and instant gelation upon mixing with simulated nasal fluid exhibiting weak gel properties convenient for nasal delivery. Targeted turbinate deposition depended on administration and formulation parameters, including their interactions. Decrease in the administration angle from horizontal plane, increase in inspiratory flow and presence of sodium hyaluronate significantly increased deposition in turbinate region. Parameters in interactions included concentration of polymers, surfactant and fluticasone, as well as administration angle. Selected formulations with high turbinate deposition exhibited significant increase in viscosity upon gelation, showing potential to prolong the drug retention at the nasal mucosa. The highest effect on the gel viscosity, strength and fluticasone release profile was observed for gellan gum, thus recognised as crucial parameter for the optimisation of overall therapeutic effect.