The transdermal delivery of various anti–emetics / Kristin Holmes
Motion sickness, although viewed as a sickness, is in actuality a psychophysiological response to motion. The most common cause of motion sickness is the mismatch between the vestibular and visual systems. An increase in the activity of the sympatic nervous system and subsequently a decrease in the parasympatic nervous system are observed. Symptoms include stomach discomfort, nausea and actual vomiting. Numerous people would rate the severity of their motion sickness on the severity of their nausea. The severity of the symptoms will ultimately be determined by the stimulus and the individual's susceptibility (Muth, 2006:58). In general, the most frequent treatments include cyclizine, an antihistamine available over the counter, and scopolamine, a muscarinic antagonist, viewed as the only effective drug in combating motion sickness. New strategies to deliver these drugs are thus required to attain the maximum benefit of the drugs with the least possible side–effects. The skin offers an attractive route to deliver drugs, despite the numerous limitations (Naik et al., 2000:319). Being exposed to chemicals, physical torture and deliberately applied products like cosmetics; the barrier is constantly put to test (Zatz, 1993:11). Plentiful advantages exist when delivering cyclizine and scopolamine transdermally. The oral route might not always be available when treating nausea and vomiting and the first pass metabolism is ruled out (Ball & Smith, 2008:1337–1338). A new technology, the Pheroid technology was incorporated in this study in order to investigate whether it would enhance the permeation of anti–emetics through the skin. The Pheroid technology is a vesicular structure that contains neither phospholipids nor cholesterol. The structure is compiled of essential fatty acids and therefore natural to the body (Grobler et al., 2008:283). The aim of this study was to formulate cyclizine and scopolamine in solutions with and without Pheroid and subsequently formulated scopolamine in an emulgel with and without Pheroid. The octanol–buffer distribution coefficient (log D) and aqueous solubility were determined for both cyclizine and scopolamine at pH 7.4. The aqueous solubility and log D of cyclizine could not accurately be determined due to the insolubility of cyclizine in water and PBS. The literature values for cyclizine of 3.11 (Monene et al., 2005:243) for log D and 1 mg/ml (Drugbank, 2010a) for aqueous solubility was assumed to be correct. The aqueous solubility of scopolamine could not accurately be determined due to the immense amount of scopolamine dissolving in water, resulting in thick, syrup–like solution. The value of 1000 mg/ml was assumed to be correct (Drugbank, 2010b). A log D of 1.77 indicated that scopolamine would be a favourable drug to consider for transdermal delivery. A 0.5% cyclizine and a 1% scopolamine solution with and without Pheroid was formulated and a 12 h Franz cell diffusion study was conducted with full thickness skin, where after tape–stripping and analysis of the concentration in the dermis was done. The cyclizine solution did not penetrate the skin. This might be due to the low aqueous solubility of cyclizine. The scopolamine solution delivered a result of 14.012 ug.cm² and the scopolamine solution containing Pheroid a result of 6.486 ug/cm². The scopolamine solution delivered results of 0.0128 ug/cm² in the stratum corneum (SC)–epidermis and 0.2035 ug/cm² in the epidermis–dermis. For the scopolamine solution containing Pheroid, the concentrations in the SC–epidermis and epidermis–dermis were 0.0044 ug/cm² and 0.0525 ug/cm² respectively. A 12 h Franz cell diffusion study using only epidermis was performed with the scopolamine emulgel and scopolamine emulgel containing Pheroid. The emulgel delivered a concentration of 2.649 ug/cm² and the emulgel containing Pheroid delivered a concentration of 0.017 ug/cm². When the solutions were compared to the emulgel formulations, the scopolamine solution delivered the highest concentration scopolamine. The Pheroid formulations contain a higher oil content, thus decreasing diffusion through the skin (Barry, 2002:513). When previously formulated, scopolamine released only 30 % from its dosage form; the rest of the diffusion was ultimately determined by the patients' skin itself (Barry, 2007:591). Stability tests were conducted on the emulgel formulations for a period of 3 months. The emulgel formulations were stored at 25 C/60% relative humidity (RH), 30 °C/60% RH and 40 °C/70% RH. Concentration assays were done on the high performance liquid chromatography (HPLC) to determine the concentration of scopolamine, methyl paraben, propyl paraben, BHT (butylated hydroxytoluene) and tocopherol. Other stability tests included pH, viscosity, visual appearance, mass loss and confocal laser scanning microscopy. The emulgel formulations were not stable over the 3 months stability test period. A change in colour, viscosity and decreasing active ingredients were observed.
- ETD@PUK