TY - JOUR
T1 - Using Salt Counterions to Modify β2‑Agonist Behavior in Vivo
AU - Patel, Aateka
AU - Rudman, Sandra Dhian
AU - Brown, Marc
AU - Hider, Robert Charles
AU - Jones, Stuart Allen
AU - Page, Clive Peter
PY - 2016/10/3
Y1 - 2016/10/3
N2 - There are a paucity of data describing the impact of salt counter-ions on the biological performance of inhaled medicines in vivo. The aim of this study was to determine if the co-administration of salt counter-ions influenced the tissue permeability and the 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) counter-ion, exhibited a superior bronchodilator effect (p< 0.05) compared to salbutamol base. The counter-ions 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 asigned 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 counter-ion in inhaled pharmaceutical salts should be considered carefully as it has the potential to alter drug action in vivo.
AB - There are a paucity of data describing the impact of salt counter-ions on the biological performance of inhaled medicines in vivo. The aim of this study was to determine if the co-administration of salt counter-ions influenced the tissue permeability and the 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) counter-ion, exhibited a superior bronchodilator effect (p< 0.05) compared to salbutamol base. The counter-ions 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 asigned 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 counter-ion in inhaled pharmaceutical salts should be considered carefully as it has the potential to alter drug action in vivo.
U2 - 10.1021/acs.molpharmaceut.6b00448
DO - 10.1021/acs.molpharmaceut.6b00448
M3 - Article
SN - 1543-8384
VL - 13
SP - 3439
EP - 3448
JO - Molecular Pharmaceutics
JF - Molecular Pharmaceutics
IS - 10
ER -