Phenomenological Analysis of Drug Transport through Stratum Corneum
Wang Hong
Purpose
To illustrates the phenomenological relationship of drug permeable process through SC and provides theory and method for research of transdermal drug delivery (TDD).
Results
(1) Not only drug transdermal permeation, but also volume loss of solution occurs in the system (2) According to experimental data, phenomenological coefficient is time variable, the action of surface force on mass flow and physical force on physical flow decreases as time expands (3) Volume flow may be generated by velocity gradient arising from solution convection on the surface of stratum corneum (SC)
Conclusion
The permeation chamber is a non-linear and time-variable system.
INTRODUCTION
advances in biotechnology A lot of therapeutic macromolecules are reaching the clinical application bioactive macromolecules limited A novel delivery system needed Transdermal drug delivery (TDD)
TDD (Transdermal drug delivery)
TDD is that patching the drug on the skin, the drug molecules permeate through the skin into the subcutaneous capillary vessels TDD is an alternative method of drug delivery that draws people’s attention as a potential administration of biological pharmacy.
Exist diffculty
very few drugs can be administered transdermally at therapeutic levels to the barrier of stratum corneum (SC), the skin’s outer layer.
Method to enhance
iontophoresis electroporation photomechanical wave sonophoresis magnetophoresis chemical enhancers
Non-equilibrium theory of permeation cell
System of permeation cell and its hypothesis Permeation cell Phenomenological equation of permeation cell
System of permeation cell
Permeation cell, the basic equipment of TDD experiment in vitro is composed of a donor compartment and a receptor compartment, among which SC sample is loaded and a couple of electrodes were put at their sides The solution in donor is saturated liquid containing solute, while the solution in receptor is physiological saline
System hypothesis
The system is constant temperature; there is no heat flow between donor compartment and receptor compartment. There is no chemical reaction in the system. The physiological saline or buffer solution is not viscous fluid. The species in the system are no more than pattern drug and physiological saline or buffer solution. The subsystems of donor and receptor are local equilibrium, i.e. it is equilibrium in the volume element, but non-equilibrium between one volume element and other.
Phenomenological equation of permeation cell
dcs zs Fcs d du J s L11 ( ) L12 ( ) dx kT dx dx
dcs zs Fcs d du J v L21 ( ) L22 ( ) dx kT dx dx
here L11 、L12 、L21 、L22 are phenomenological coefficient, zs electrovalence of molecule or ion, cs concentration of molecule or ion, F = 96500 Faraday constant, k gaseity constant, T absolute temperature. On the basis of Onsager reciprocity relations, L12 = L21 .
Materials
Chemicals : Tinidazole Skin preparation: heat separately in 60oC
and gently removing the SC.
water for 2 min
Equipments: side-by-side permeation chambers,
Multi-Pulse Generator for Electroporation, oscilloscope
Pulse protocols : table 1
Fig 1: experiment system
Table 1:Pulse protocols
R (ppm) energy(J) 4 0.02 0.10 0.30 2 1.00 1.64 1 3.50 8.00
4.7mF (SL) 92 V (SL1) 206V (SL2) 357V (SL3)
22mF (L)
47mF (M)
100mF (H)
95 V (L1) 165 V (L2) 302 V (L3) 393 V (L4) 113 V (M1) 206 V (M2) 269 V (M3) 386 V (M4) 141 V (H1) 184 V (H2) 265 V (H3) 400 V (H4)
Methods
Prepared SC sample was loaded into the permeation orifice between donor and receptor, outer surface of SC face to donor and inner surface face to receptor. Adding Tinidazole saturated solution into donor and physiological saline (0.9% NaCl) into receptor. Electrical pulses were applied to side-byside permeation chambers by Multi-Pulse Generator for Electroporation of TDD according to determined pulse protocols. Each group consisted of one control test (passive permeation) and three pulse tests (electrical pulse permeation) with different pulse protocols. The receptor was sampled periodically i.e. 0, 0.33, 0.67, 1.0, 1.5, 2hr after pulse by emptying its contents and replacing it with fresh physiological saline (0.9% NaCl). The concentration of samples was measured after filtration by HPLC with measure limit of 0.01 μg/ml and sampling injection of 20μl. The retention time of Tinidazole was 10.42 min. Tinidazole permeation flux across SC at every sampling time was calculated.
Results and discussion
Determination of Thermodynamic Force and Flow
Tinidazole mass flow Js came into being from donor to receptor in the permeation cell no matter in passive or electric pulse permeation. Volume loss of donor in both groups was observed simultaneously, it occurred in control and pulse group for 7/17 = 41.1% and 11/33 = 33.3% , respectively, the control was greater than the pulse. High level of Tinidazole permeation through SC went with great volume loss, but great volume loss not always meant high level of permeation through SC. In fact, volume loss in donor was observed at each sampling time .
table 2:receptor tinidazole concentration ci(μg/ml) and donor volume loss V(μl) at sampling times (control test and protocol M1, L2, SL3)
Fig 2: tinidazole cumulative(mg/cm3) and volume loss V(ml) after 2 hours.
Experiential Formula of Phenomenological Coefficient
phenomenological coefficient is time dependent. Supposing phenomenological coefficient L11, L12, L21and L22 are exponential function:
L11 a0 a1 exp(k1t )
L12 L21 b0 b1 exp(k2t )
L22 c0 c1 exp(k3t )
where a0,a1,k1,b0,b1,k2,c0,c1,k 3 are experimentally fitted coefficient, fitted function is supposed as:
y(t ) L11L22 L12 L21 [a0 a1 exp(k1t )][c0 c1 exp(k1t )] [b0 b1 exp(k2t )]2
Data function is
yi L22ci L12Vi [c0 c1 exp(k3t )]ci [b0 b1 exp(k2t )]Vi
Criterion function that evaluates fitting degree is
Table 3: Phenomenological Coefficients