Iontophoresis on Porcine and Human Gingiva

Abstract

Purpose

Iontophoresis is a noninvasive method that enhances drug delivery using an electric field. This method can improve drug delivery to the tissues in the oral cavity. The effects of iontophoresis on gingival drug delivery have not been investigated. The objectives of this study were to (a) determine the flux enhancement of model permeants across porcine and human gingiva during iontophoresis, (b) examine the transport mechanisms of gingival iontophoresis, and (c) evaluate the potential of iontophoretically enhanced delivery for three model drugs lidocaine, ketorolac, and chlorhexidine.

Methods

Passive and iontophoretic fluxes were determined with porcine and human gingiva using a modified Franz diffusion cell and model drugs and permeants. To investigate the transport mechanisms of iontophoresis, the enhancement from the direct-field effect was determined by positively and negatively charged model permeants. The electroosmosis enhancement effect was determined with neutral permeants of different molecular weight. The alteration of the gingival barrier due to electropermeabilization was evaluated using electrical resistance measurements.

Results

Significant flux enhancement was observed during gingival iontophoresis. The direct-field effect was the major mechanism governing the iontophoretic transport of the charged permeants. Electroosmosis was from anode to cathode. The effective pore radius of the iontophoretic transport pathways in the porcine gingiva was ~0.68 nm. Irreversible electropermeabilization was observed after 2 and 4 h of iontophoresis under the conditions studied.

Conclusion

Iontophoresis could enhance drug delivery and reduce transport lag time, showing promise for gingival drug delivery.

Appendix

For hindered transport across a porous membrane assuming cylindrical pores, the H factor describes transport hindrance for diffusion and the W factor describes transport hindrance for convection of parabolic flow [19].

$$H\left(\lambda \right)=\frac{6\pi {\left(1-\lambda \right)}^2}{K_t}$$

(10)

where $\lambda =\frac{r_s}{R_p}$, ${K}_t=\frac{9}{4}{\pi}^2\sqrt{2}{\left(1-\lambda \right)}^{-\frac{5}{2}}\left[1+{\sum}_{n=1}^2{a}_n{\left(1-\lambda \right)}^n\right]+{\sum}_{n=0}^4{a}_{n+3}{\lambda}^{\eta }$, and a₁ = -1.217, a₂ = 1.534, a₃ = -22.51, a₄ = -5.612, a₅ = -0.3363, a₆ = -1.216, and a₇ = 1.647. r_s is the solute hydrodynamic radius and R_p is the effective pore radius of the membrane.

$$W\left(\lambda \right)=\frac{{\left(1-\lambda \right)}^2\left(2-{\left(1-\lambda \right)}^2\right){K}_s}{2{K}_t}$$

(11)

where${K}_s=\frac{9}{4}{\pi}^2\sqrt{2}{\left(1-\lambda \right)}^{-\frac{5}{2}}\left[1+{\sum}_{n=1}^2{b}_n{\left(1-\lambda \right)}^n\right]+{\sum}_{n=0}^4{b}_{n+3}{\lambda}^{\eta }$ and b₁ = 0.11667, b₂ = -0.04489, b₃ = 4.018, b₄ = -3.979, b₅ = -1.9215, b₆ = 4.392, and b₇ = 5.006. Eqs. 10 and 11 are the hindered transport equations used in Eqs. 4, 7, and 15.

To model the changes in porosity due to electropermeabilization, membrane porosity ratio (ε_ratio) is related to the membrane porosity for permeant i during iontophoresis (ε_total,i) which is the total porosity from the newly created pores (ε_iont,i) and the existing pores before iontophoresis (ε_passive,i).

$${\varepsilon}_{total,i}={\varepsilon}_{iont,i}+{\varepsilon}_{passive,i}$$

(12)

Membrane electrical resistance can be used to evaluate membrane porosity. The ratio of the membrane electrical resistance during iontophoresis to passive transport is related to the ratio of the fluxes of the ions in the background electrolyte (i.e., fluxes of NaCl) during iontophoresis to passive transport.

$$\textrm{Therefore},\frac{R_{passive}}{R_{iont}}=\frac{J_{iont, NaCl}}{J_{passive, NaCl}}=\frac{\varepsilon_{total, NaCl}}{\varepsilon_{passive, NaCl}}=\frac{\varepsilon_{iont, NaCl}+{\varepsilon}_{passive, NaCl}}{\varepsilon_{passive, NaCl}}=\frac{\varepsilon_{iont, NaCl}}{\varepsilon_{passive, NaCl}}+1\ \textrm{and}\ \frac{R_{passive}}{R_{iont}}-1=\frac{\varepsilon_{iont, NaCl}}{\varepsilon_{passive, NaCl}}$$

(13)

The membrane porosity ratio (ε_ratio) can be expressed as:

$${\varepsilon}_{ratio}=\frac{\varepsilon_{total,i}}{\varepsilon_{passive,i}}=\frac{\varepsilon_{iont,i}+{\varepsilon}_{passive,i}}{\varepsilon_{passive,i}}=\left(\frac{\varepsilon_{iont,i}}{\varepsilon_{passive,i}}+1\right)$$

(14)

To correct for the difference in transport hindrance on permeant i and NaCl,

$${\varepsilon}_{ratio}=\left(\frac{\varepsilon_{iont,NaCl}}{\varepsilon_{passive, NaCl}\ }\right)\frac{H_{iont,i}/{H}_{iont,NaCl}}{H_{passive,i}/{H}_{passive,NaCl}}+1$$

(15)

Combining Eqs. 13 and 15,

$${\varepsilon}_{ratio}=\left(\frac{R_{passive}}{R_{iont}}-1\right)\frac{H_{iont,i}/{H}_{iont,NaCl}}{H_{passive,i}/{H}_{passive,NaCl}}+1$$

(16)

Eq. 16 describes the effect of electropermeabilization on iontophoretic delivery using the electrical resistance data (Eq. 4).