Abstract
Purpose: This Project was aiming into evaluating the effect of variable ultrasonic conditions on the permeation of drugs with range of physicochemical properties through different barrier models. This involved validating the applicability of utilizing artificial membranes and three dimension skin equivalent as human skin models for the sonophoresis studies.Method: Franz diffusion cell was used to study the effect of therapeutic ultrasound at 1 MHz and power ultrasound at 20 kHz on the permeation of diclofenac sodium, metronidazole and haematoporphyrin through cellulose, silicone polycarbonate and dimethyl silicone membranes and across the 3D skin equivalent EpiDermTM . HPLC methods were used for the determination of the concentration of diclofenac sodium and metronidazole in the receiving compartment and a spectrofluorometer was used for the measurements of haematoporphyrin permeation. Imaging experiments with optical microscopy was carried out to visualize the histological effect of ultrasound on the skin equivalent.
Results: The sonophoretic effect obtained utilizing therapeutic ultrasound at 1 MHz frequency was almost negligible through cellulose membrane for all investigated drugs. Better enhancement obtained through the EpiDermTM as about double the permeation of the investigated drugs was obtained with no apparent damage to skin culture.
The results indicate significant permeation enhancement with low frequency sonophoresis at 20 kHz frequency treatments through both silicone polycarbonate membrane and EpiDermTM skin equivalent. Three folds increase in the flux observed for metronidazole and diclofenac sodium flux across silicone polycarbonate and up to five folds enhancements experienced with the permeation of all investigated molecules
through EpiDermTM. The enhancement across cellulose membrane and dimethyl silicone membrane was moderate and less than two folds for all the molecules.
The microscopy study revealed creation of pores through the Epiderm and degradation of the stratum corneum layers following the power sonication. The severity of the observed structural alteration increased with the intensity of the irradiation performed on the tissue.
Thermal effect of ultrasound and the non thermal effects including solvent convections and microstreaming and stable and transient cavitations are responsible for the permeation of enhancements through all the barriers. The dominant factor is depending on the type of barrier and the conditions of ultrasonic utilized in the treatment.
The mechanism of action observed seemed highly dependent on the ultrasonic conditions and on the type of insonating barrier.
There was no energy density - permeation enhancement correlation for any of the artificial membranes. But across Epiderm 855 J/cm2 was required by haematoporphyrin and diclofenac sodium to achieve significant transport
improvement, double this energy was necessary for significant transport enhancement of metronidazole
Conclusion: The use of 3D skin equivalent EpiDermTM and silicone polycarbonate membrane as a model for the human skin to investigate the influence of the physical penetration enhancement of ultrasound was a success.
The most effective enhancing parameters were power sonication of 20 kHz frequency 10% amplitude at the continuous mode for 5 minutes for the lipophilic drugs penetration and 15% amplitude is required for the transport of hydrophilic drug.
The sonophoretic mechanism of the ultrasound is dependent on the ultrasonic conditions and on the type of the barrier.
| Date of Award | 2006 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Jacqueline Willis (Supervisor), Timothy Mason (Supervisor) & Raymond Carson (Supervisor) |