Using Salt Counterions to Modify β2-Agonist Behavior in Vivo

Aateka Patel,Robert Hider,Clive P Page,Marc B Brown,Stuart A Jones,Sandra D Keir

doi:10.1021/acs.molpharmaceut.6b00448

Aateka Patel, Robert Hider + Show 4 more

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https://doi.org/10.1021/acs.molpharmaceut.6b00448

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Abstract

There is a paucity of data describing the impact of salt counterions on the biological performance of inhaled medicines in vivo. The aim of this study was to determine if the coadministration of salt counterions influenced the tissue permeability and airway smooth muscle relaxation potential of salbutamol, formoterol, and salmeterol. The results demonstrated that only salbutamol, when formulated with an excess of the 1-hydroxy-2-naphthoate (1H2NA) counterion, exhibited a superior bronchodilator effect (p < 0.05) compared to salbutamol base. The counterions aspartate, maleate, fumarate, and 1H2NA had no effect on the ability of formoterol or salmeterol to reduce airway resistance in vivo. Studies using guinea pig tracheal sections showed that the salbutamol:1H2NA combination resulted in a significantly faster (p < 0.05) rate of tissue transport compared to salbutamol base. Furthermore, when the relaxant activity of salbutamol was assessed in vitro using electrically stimulated, superfused preparations of guinea pig trachea, the inhibition of contraction by salbutamol in the presence of 1H2NA was greater than with salbutamol base (a total inhibition of 94.13%, p < 0.05). The reason for the modification of salbutamol's behavior upon administration with 1H2NA was assigned to ion-pair formation, which was identified using infrared spectroscopy. Ion-pair formation is known to modify a drug's physicochemical properties, and the data from this study suggested that the choice of counterion in inhaled pharmaceutical salts should be considered carefully as it has the potential to alter drug action in vivo.

Highlights

A pharmaceutical salt is susceptible to the composition of body fluids into which it dissolves because there is the potential that the drug can partake in a number of different noncovalent physical interactions
When a pharmaceutical salt is administered orally, the drug is exposed to a relatively large volume of liquid, and if a labile, noncovalent bond is formed between the drug and the counterion, it will most probably be broken when faced by rapid dilution and competition from charged species in the gut fluids, unless the ion-pair binding is very strong
Of the different drug−counterion combinations assessed only the salbutamol 1H2NA ion-pair had an effect on airway smooth muscle relaxation (ASM) when compared with salbutamol base

Summary

Introduction

A pharmaceutical salt is susceptible to the composition of body fluids into which it dissolves because there is the potential that the drug can partake in a number of different noncovalent physical interactions. Not every pharmaceutical salt will be susceptible to ion-pair formation upon dissolution in body fluids.[3] The formation of an ion-pair complex between the ionized drug and coadministered ionized counterion is dependent upon the physicochemical properties of the drug, the physicochemical properties of the ion-pair, the affinity of the two molecules, and the route of administration.[1] For example, when a pharmaceutical salt is administered orally, the drug is exposed to a relatively large volume of liquid, and if a labile, noncovalent bond is formed between the drug and the counterion, it will most probably be broken when faced by rapid dilution and competition from charged species in the gut fluids, unless the ion-pair binding is very strong. The biological consequences of delivering therapeutic agents as pharmaceutical salts via routes which do not expose the molecules to such a large volume of fluid, e.g., the skin and the airways, may be more significant compared to oral administration

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