|dc.description.abstract||Transdermal drug delivery has the advantage over other routes of administration of avoiding the hepatic, first–pass metabolism that would result in better therapeutic efficacy, better patient medication compliance and reduced systemic side–effects (Kydoneieus & Berner, 1987:69). One disadvantage of this mode of drug delivery is the generally poor delivery of drugs through the skin. The intercellular lipid structure of the stratum corneum causes this membrane to be an excellent penetration barrier, which must be breached to enhance drug penetration through the skin.
Factors influencing the drug–skin distribution include the physicochemical properties of the drug, the choice of the delivery vehicle and the drug application mode (finite and infinite dose) being used (Chen et al., 2011:224). The permeability of the skin is thus influenced by the physicochemical properties of both the permeant and the penetration enhancer (Dias et al., 2007:65).
One way of overcoming this barrier function of the skin is to include penetration enhancer chemicals in the topical application. Such penetration enhancers partition into the stratum corneum and interact with the intercellular lipids, causing a temporary and reversible decrease in this barrier function. With the skin barrier function being reduced, drug transport through the skin increases (Magnusson et al., 2001:206). When a drug or the penetration enhancer vehicle does not have the ideal physicochemical properties, penetration through the skin is difficult and manipulation of the drug or the vehicle is necessary. By manipulating their physicochemical properties, or by making use of penetration enhancers, the transdermal absorption through the skin can be increased (Park et al., 2000:109).
Chemical penetration enhancers use different mechanisms of action to increase permeation across the skin (Moser et al., 2001:110). When chemical enhancers are used in combination, a synergistic action between these enhancers offers a method of overcoming limitations being experienced when single chemical enhancers are used in improving transdermal drug delivery (Williams & Barry, 2004:604). As mentioned, both the choice of vehicle and the physicochemical properties of the permeant and vehicle should be considered during drug skin distribution studies, as well as the mode of application (finite or infinite dose).
When consumers use commercial formulations to treat topical skin conditions, the vehicles applied are in varying doses lower than 30 mg/cm2, depending on the application. In clinical situations, the formulation being applied depends on the body surface area being treated, i.e. the larger the surface area, the lower the amount of vehicle applied.
When a cold sore is treated, for example, an average amount of 20 mg/cm2 of the vehicle is applied to the infected area, with the treated surface area generally being very small (Trottet et al., 2004:214). When sunscreens are applied to the skin, a very large surface area is treated and an average amount of only 0.5 mg/cm2 is applied (Azurdia et al., 1999:255; Bech & Wulf, 1992:242). It is thus clear that the transdermal absorption of an active compound depends on the concentration being applied and the surface area treated. Considering the above parameters is thus of high significance when in vitro transdermal diffusion tests are performed.
Risk assessment studies comprise another important area in which clinical relevant dose plays a significant role when data on transdermal absorption of a substance is produced.
During in vitro diffusion studies to determine the permeability profile of an active compound, an “infinite dose(s)” (> 150 ul) of the vehicle is applied to the membrane. One shortcoming of the infinite dose application is that in some instances it may fail to imitate the levels of active compound being applied to the skin when commercial formulations are applied. It may also fail to imitate exposure levels to toxic chemicals. Results from in vitro studies would differ from those obtained during in vivo studies, if the clinically applied concentrations are not taken into account.
The aims of this study were to determine the penetration enhancement effects of different penetration enhancer vehicles on the permeation of lipophilic ibuprofen through synthetic Carbosil® membrane, when used individually and in multi–component solvent mixtures, as well as to determine the effects of finite (< 150 ul) dose applications of these enhancers on the delivery of ibuprofen.
In order to achieve the aims of this study, the objectives were to determine the permeation of lipophilic ibuprofen through Carbosil® membrane by using:
u Water and propylene glycol as penetration enhancer vehicles in combinations of 0/100 (v/v), 20/80 (v/v), 50/50 (v/v), 80/20 (v/v) and 100/0 (v/v);
Mineral oil and Miglyol® as penetration enhancer vehicles in combinations of 0/100 (v/v), 20/80 (v/v), 50/50 (v/v), 80/20 (v/v) and 100/0 (v/v); and ;
These penetration enhancer vehicles individually and in multi–component mixtures at different finite and infinite volumes, i.e. 2 ul, 5 ul, 10 ul, 20 ul, 50 ul, 150 ul, 250 ul, 500 ul and 1,000 ul; and to determine
Which of the single or multi–component penetration enhancer vehicles would show the best transdermal delivery enhancement effect.
The solvents used all have different mechanisms of action by which they enhance penetration of drugs through skin. By using these solvents in combination, the expectation was that they would have a synergistic effect that would be higher than the penetration enhancement effect achieved with each individual solvent (Williams & Barry, 2004:604).
The outcomes of this study were as follows: The results for infinite dose applications of water and propylene glycol clearly showed that the best penetration enhancement of ibuprofen was achieved with 100% propylene glycol as the delivery vehicle. Contrary, water showed very little penetration enhancement properties for this drug. Results from this study also showed that the penetration enhancement effect of propylene glycol increased as the percentage of the propylene glycol in the solvent vehicle increase. This could have been as a result of the mechanism of action of propylene glycol to partition into the membrane and to increase the solubility of the permeant in and diffusion through the membrane (Squillante et al., 1998:266). Chen et al. (2011:224) suggest that the higher the applied volume, the larger the surface area being covered by the vehicle and the thicker the layer of the vehicle solvent on the surface of the membrane, which would result in an increase in the hydration of the membrane, which in turn would increase the permeability of the membrane for the drug.
Application of finite doses of the single penetration enhancer solvent, propylene glycol, achieved the highest penetration enhancement effect, with the ibuprofen concentration of diffused ibuprofen being the highest with this solvent. The concentration of diffused ibuprofen that had been delivered from application of a finite dose of the water delivery vehicle could not be measured, due to the lipophilic nature of ibuprofen (log Po/w of 3.6) (Beetge et al., 2000:164) and the low solubility of ibuprofen in water, resulting in permeation concentrations that were immeasurable.
Results for the infinite dose applications of the lipophilic, single phase solvents of 100% mineral oil and 100% Miglyol®, showed the lowest penetration enhancement effects, compared to all multi–component combinations of these two enhancer vehicles. Multi–component mixtures of these solvents also showed very similar permeation profiles for ibuprofen. This could have been as a result of synergistic action between the two penetration enhancer solvents if used in combination. According to Moser et al. (2001:106), Miglyol® is known to modify the intercellular lipids of the stratum corneum, causing disruption of the barrier properties thereof and hence an increase in diffusivity through the membrane. Since Carbosil® membrane and human epidermis share a common solubility–diffusion mechanism of drug transport, it can be hypothesised that the Miglyol® would change the polar structure of the membrane and as a result enhance the permeability of substances through the membrane. Mineral oil is a lipophilic solvent and while Miglyol® modifies the heteropolar structure of the membrane to make it more viable to
penetration, mineral oil would carry the active to the lipophilic section of the membrane and as a result enhance the permeation of the lipophilic drug, ibuprofen (Hori et al., 1991:33).
Results for finite dose applications of these solvents clearly showed that the 20/80 (v/v) mineral oil/Miglyol® combination achieved the best penetration enhancement effect for ibuprofen, compared to all other mineral oil and Miglyol® solvents, individually and in combination. Solvents and solvent mixtures containing 100% Miglyol®, 50/50 (v/v) and 80/20 (v/v) mineral oil/Miglyol® all showed similar penetration enhancement effects with finite dose applications. With solvent type permeant preparations applied to a membrane, three types of penetration influencing parameters should be taken into account, i.e. (a) thermodynamic effects resulting from different permeant solubilities in the different vehicles, (b) penetration enhancing effects between the vehicle and the membrane, (c) permeant depletion in the vehicle in the case of finite dose conditions. The extent of permeant depletion in the vehicle depends on the thickness of the applied solvent layer on the surface of the membrane (Leopold, 1998:167).
The results from this study confirmed the observations by Williams and Barry (2004:605) that:
1. Penetration enhancer properties appear to be drug specific (permeants with similar physico–chemical properties).
2. Penetration enhancers tend to work well with co–solvents, such as propylene glycol.
3. Most penetration enhancers have a complex concentration dependent effect.
4. Potential mechanisms of action of penetration enhancer solvents are different and can range from direct effects on the skin to modification of the formulation.
The outcomes of this study showed that increased levels of a penetration enhancer solvent, like propylene glycol in the delivery vehicle, not only increases the penetration of the active through the membrane, but it also improves penetration of the active through the membrane from finite dose applications.
The permeation profiles of the lipophilic, single phase mineral oil and Miglyol®, and combinations thereof, showed that permeation of the lipophilic ibuprofen was higher with small application volumes of these delivery vehicles. Chen et al. (2011:224) report that with an infinite dose application, the donor compartment is filled with a thick liquid layer covering the surface of the membrane, having a height of 1.6 mm, while the finite dose application forms only a thin layer of 0.1 mm. As a result, the hydration levels of the membrane are higher with infinite dose applications, which facilitate higher permeability of the membrane (Chen et al., 2011:224). Increased membrane hydration appears to increase the diffusion of both hydrophilic and low lipophilic compounds, due to the partitioning of the active into the membrane (Williams & Barry, 2004:605). This hydration effect on the membrane makes penetration of hydrophilic
mpounds through the membrane easier, whilst making it more difficult for strongly lipophilic compounds (log P >2) to partition into the hydrated membrane (Zhang et al., 2010:895). Ibuprofen is a strongly lipophilic drug (log P = 3.6) (Beetge et al., 2000:164), hence the lower permeation results for infinite dose applications. Except for mineral oil that showed higher permeation levels with larger volumes, as a result of the lipophilic nature of both mineral oil and ibuprofen, the permeability of the lipophilic active increased as the membrane became more hydrated with the lipophilic solvent when larger volumes were applied.
From the findings in this study it has become evident that:
* The lipophilic/hydrophilic nature of the solvent and the permeant play a significant role in the absorption of a permeant through the membrane. This is an important factor in risk assessment studies, especially;
* If the membrane is hydrated with a lipophilic delivery vehicle while carrying a lipophilic toxic permeant, the effect may be more harmful at lower levels of exposure; Lipophilic ibuprofen showed higher permeation levels with small application volumes of Miglyol® and of lipophilic mineral oil/Miglyol® combination delivery vehicles.
* When a lipophilic toxic permeant comes in contact with a hydrophilic delivery vehicle, like propylene glycol and water, the effect may not be as significant even with high levels of exposure; and
* The nature of the delivery vehicle and the permeant, as well as the level of exposure or application, play enormous roles in the prediction of permeant absorption through Carbosil® membrane or the skin.||en_US