The stability of lidocaine and epinephrine solutions exposed to electric current and comparative administration rates of the two drugs into pig bladder wall

Abstract

Intravesical electromotive administration of local anesthetics is clinically successful but electrochemistry, cost and effectiveness limit the choice of drugs to diluted lidocaine HCl 4% mixed with epinephrine. These studies address the stability of lidocaine and epinephrine both over time and when exposed to electric current, i.e. transport rates with passive diffusion and electromotive administration. The drug mixture used was 50 ml lidocaine 4%, 50 ml H₂O and 1 ml epinephrine 1/1000. For stability, the solution was placed either in bowls for 7 days or in a two chamber cell with the donor compartment (drugs) separated from the receptor compartment (NaCl solution) by a viable pig bladder wall. This was subjected to 30 mA for 45 min. Stability was measured with mass spectrometry. The cell was also used to determine transport rates with passive diffusion and currents of 20 mA and 30 mA, over 20, 30 and 45 min. Drug measurements in both compartments and bladder were made with HPLC. Lidocaine remained stable throughout the 7 days, epinephrine on day 1 only and both drugs were stable with 30 mA for 45 min. Comparing 20 mA and 30 mA with passive diffusion, there were significant differences in 6/6 donor compartment lidocaine levels, 4/6 receptor compartment levels and 6/6 bladder tissue levels and also in 6/6 epinephrine donor levels and 6/6 tissue levels. The combination lidocaine and epinephrine remains stable for 1 day and when exposed to 30 mA for 45 min. Electric current accelerates the transport of lidocaine and epinephrine.

Appendix

The following table describes the iontophoresis of lidocaine hydrochloride.

$Ji(mol/\sec ) = {I \over {\left| z \right| \cdot F}}$	(1) Ji is the flux of all ions; I is current in amperes; |z| is absolute valency; F=96,486 C/mol (Faraday's Constant)
$Ji({\rm{mmol/min}}) = I(6.2)x10^{ - 4} /z$	(2) I is current in mA
$Ji({\rm{mg/mA}} \cdot \min ) = M \cdot 6.2x10^{ - 1} /z$	(3) M is molecular weight (Da)
For any solution of lidocaine hydrochloride (L+, Cl-):
$dL/dt({\rm{mg/mA}} \cdot \min ) = 235\left( {6.2x10^{ - 1} } \right) \cdot tr_L$	(4) trL is the transference # lidocaine. (z=unity)
$tr_L = {{C_L \cdot \mu _L \cdot z_L } \over {\mathop \Sigma \limits_{i = 0}^n \left( {C_i \cdot \mu _i \cdot z_i } \right)}}$	(5) C is concentration; µ is mobility; i is the summation index of all ions in solution
For a pure solution of lidocaine hydrochloride:
$tr_L = {{C_L \cdot \mu _L \cdot z_L } \over {\left( {C_{Cl} \cdot \mu _{Cl} \cdot z_{Cl} } \right) + \left( {C_L \cdot \mu _L \cdot z_L } \right)}}$	(6)
And as CCl·zCl=CL·zL (charge neutrality):
$tr_L = {1 \over {{{\mu _{Cl} } \over {\mu _L }} + 1}}$	7)
$dL/dt = 235\left( {6.2x10^{ - 1} } \right)\left( {{1 \over {{{\mu _{Cl} } \over {\mu _L }} + 1}}} \right)\mu g/mA \cdot \min$	(8)
$\mu _{Cl} /\mu _L = 2/1$	(9) Estimated
$dL/dt = 48.7\;{\rm{\mu g/mA}} \cdot \min$	(10)

Note: Eq. 5 in the table above states that significant quantities of small, highly mobile ions (H⁺, Na⁺, Cl^-) in the drug solution will cause a precipitous decline in dL/dt.