pectins and saprisartan-potassium

There is an increasing need for nasal drug delivery systems that could improve the efficiency of the direct nose to brain pathway especially for drugs for treatment of central nervous system disorders. Novel approaches that are able to combine active targeting of a formulation to the olfactory region with controlled release bioadhesive characteristics, for maintaining the drug on the absorption site are suggested. If necessary an absorption enhancer could be incorporated. Low methylated pectins have been shown to gel and be retained in the nasal cavity after deposition. Chitosan is known to be bioadhesive and also to work as an absorption enhancer. Consequently, two types of pectins, LM-5 and LM-12, together with chitosan G210, were selected for characterisation in terms of molecular weight, gelling ability and viscosity. Furthermore, studies on the in vitro release of model drugs from candidate formulations and the transport of drugs across MDCK1 cell monolayers in the presence of pectin and chitosan were also performed. Bioadhesive formulations providing controlled release with increased or decreased epithelial transport were developed. Due to their promising characteristics 3% LM-5, 1% LM-12 pectin and 1% chitosan G210 formulations were selected for further biological evaluation in animal models.

Topics: Adhesiveness; Administration, Intranasal; Animals; Benzofurans; Brain; Cell Line; Cell Membrane Permeability; Central Nervous System Agents; Chemistry, Pharmaceutical; Chitosan; Delayed-Action Preparations; Diffusion; Dogs; Drug Carriers; Drug Compounding; Epithelial Cells; Gels; Kinetics; Mannitol; Methylation; Models, Chemical; Molecular Weight; Nasal Mucosa; Pectins; Polymers; Propranolol; Solubility; Tissue Adhesives; Viscosity

The effect of bioadhesive formulations on the direct transport of an angiotensin antagonist drug ((14)C-GR138950) from the nasal cavity to the central nervous system was evaluated in a rat model. Three different bioadhesive polymer formulations (3% pectin LM-5, 1.0% pectin LM-12 and 0.5% chitosan G210) containing the drug were administered nasally to rats by inserting a dosing cannula 7mm into the nasal cavity after which the plasma and brain tissue levels were measured. It was found that the polymer formulations provided significantly higher plasma levels and significantly lower brain tissue levels of drug than a control, in the form of a simple drug solution. Changing the depth of insertion of the cannula from 7 to 15mm, in order to reach the olfactory region in the nasal cavity significantly decreased plasma levels and significantly increased brain tissue levels of drug for the two formulations studied (1.0% pectin LM-12 and a simple drug solution). There was no significant difference between the drug availability for the bioadhesive formulation and the control in the brain when the longer cannula was used for administration. It is suggested that the conventional rat model is not suitable for evaluation of the effects of bioadhesive formulations in nose-to-brain delivery.

Topics: Absorption; Adhesiveness; Administration, Intranasal; Angiotensin II Type 1 Receptor Blockers; Animals; Benzofurans; Brain; Chemistry, Pharmaceutical; Chitosan; Male; Nasal Mucosa; Pectins; Rats; Rats, Wistar

It has been shown that vasoconstrictive drugs such as ephedrine derivatives are able to decrease systemic absorption of drugs administered by mucosal surfaces. The present paper set out to evaluate in the rat model the effect of co-administered nasal ephedrine on the absorption of GR138950 in a simple and in a pectin self-gelling formulation. It was hypothetised that a decrease in nasal systemic absorption would lead to an increase in direct nose-to-brain transport as demonstrated by the drug concentration in the olfactory lobes of the brain. It was found that ephedrine administered nasally with the drug in a simple aqueous solution resulted in a significant increase in nasal systemic absorption and also an increase in brain delivery; however, this trend was not observed with the pectin formulations. The pectin formulation with ephedrine resulted in lower systemic absorption of GR138950 and lower brain uptake compared to the simple solution formulation containing ephedrine.

Topics: Administration, Intranasal; Angiotensin II Type 1 Receptor Blockers; Animals; Area Under Curve; Benzofurans; Biological Availability; Biological Transport; Central Nervous System; Drug Evaluation, Preclinical; Ephedrine; Gels; Male; Molecular Structure; Nasal Cavity; Olfactory Bulb; Pectins; Rats; Rats, Wistar; Solutions; Time Factors; Tissue Distribution; Vasoconstrictor Agents; Water