Formulation, in vitro release and transdermal diffusion of atropine by implementation of the delivery gap principle
Van der Westhuizen, Jani
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The transdermal delivery route has become a popular alternative to more conventional routes, such as oral administration, but has not yet reached its full potential (Prausnitz & Langer, 2008:1261). Although the transdermal route proves to have several advantages over the conventional route, the greatest challenge is to overcome the effective barrier of the skin (Jepps et al., 2012:153). The permeation of the active pharmaceutical ingredient (API) through the skin is a complex, multi-step process and therefore predicting the permeability of the API is difficult (Jepps et al., 2012:153; Williams, 2003:30). Various approaches have been developed to overcome the skin barrier and it is recognised that the nature of the vehicle in which the API is applied plays a significant role in promoting transdermal delivery (Foldvari, 2000:417). It is important to consider the fate of the formulation ingredients and the API after application and how this changes the composition of the formulation on the skin when developing a vehicle for transdermal delivery (Lane et al., 2012:496; Otto et al., 2009:2). Wiechers (2012) proposed the Skin Delivery Gap (SDG) as an indicator for the permeability of an API. An API with a SDG < 1 will readily permeate the skin, whilst an SDG > 1 indicates a more complex delivery system is required. The partitioning of the API between the skin and the formulation is influenced by the formulation and by altering the formulation properties it is possible to manipulate the transdermal delivery of the API. The relative polarity index (RPI), based on the octanol-water partition coefficient (log P) of the stratum corneum, formulation and the API, was initially developed by Wiechers as a tool for developing formulations with an optimal polarity, to ensure the transdermal delivery of at least 50% of the API (Lane et al., 2012:498; Wiechers, 2008:94; Wiechers et al., 2004:174). The use of log P as an indicator of polarity was considered impractical by Hansen (2013) and acknowledged by both Wiechers and Abbott, who consequently developed the Formulating for Efficacy™ (FFE™) software which uses Hansen solubility parameters (HSP) instead of log P to indicate polarity (Hansen, 2013). The FFE™ calculates HSP distances, known as gaps, between the skin, API and the formulation to indicate the solubility of the different components in each other. A smaller HSP gap indicates a high solubility. The FFE™ enables the formulator to develop a formulation with a good balance between the active-formulation gap (AFG) and the skin-formulation gap (SFG) to ensure sufficient diffusion of the API into the skin. The FFE™ software was used to develop formulations containing 1.5% atropine as a model drug. Formulations of different polarity (optimised towards the stratum corneum, more hydrophilic and more lipophilic) were developed to determine the effect of the polarity of the formulation and the relevant HSP gaps on the transdermal delivery of the API. The same formulations were utilised for atropine sulphate to determine the effect the salt form has on the transdermal delivery of the API compared to the base compound. The log P and octanol-buffer partition coefficient (log D) of both atropine and atropine sulphate were determined. Log D is a more reliable indicator of distribution compared to log P, since, it considers the degree of ionisation of the API (Ashford, 2007:294). The log P and log D of atropine (0.22 and -1.26) and atropine sulphate (-1.32 and -1.23) both predicted poor skin penetration (Brown et al., 2005:177). The aqueous solubility of atropine (0.9 mg/ml) also predicted limited transdermal delivery, while the solubility of atropine in phosphate buffer solution (PBS pH 7.4) (5.8 mg/ml) indicated favourable permeation (Naik et al., 2000:321). The high degree of ionisation of the API (99.68 %), at pH 7.4, predicts only a small amount will penetrate the skin (Barry, 2007:576). The membrane release study confirmed the API was released from the different formulations and subsequently skin diffusion studies were conducted, followed by tape stripping after 12 h, to determine which formulation resulted in the highest transdermal delivery of the API. The atropine hydrophilic formulation released the highest percentage of API after 6 h (13.930%). This was explained by the low affinity the lipophilic atropine has towards the hydrophilic formulation (Otto et al., 2009:9). The highest percentage transdermal delivery (0.065%) was observed with the lipophilic formulation containing atropine. The higher SFG compared to the AFG of the lipophilic formulation initially predicted poor transdermal delivery, but when considering the HSP profile and molar volume of the different ingredients, it was observed the dimethyl isosorbide (DMI) penetrated and provided a desirable environment for the API in the skin. The residual formulation (containing less DMI and more polyethylene glycol 400 (PEG 8) and liquid paraffin) was less desirable for the API and was therefore forced out of the formulation (Abbott, 2012:219). Both these factors contributed to the high transdermal delivery of atropine from the lipophilic formulation. The atropine sulphate hydrophilic formulation had the highest percentage in the stratum corneum-epidermis (0.29 μg/ml) and the hydrophilic formulation of both atropine and atropine sulphate had the highest concentration in the epidermis-dermis (both 0.55 μg/ml). The hydrophilic formulations had the lowest driving force provided by the AFG and the only driving force for the API to leave the formulation was the concentration gradient. These formulations had the lowest transdermal delivery which indicates the API had not fully traversed through the skin after 12 h. According to Wiechers, a minimised SFG would indicate the formulation is optimised towards the stratum corneum and should essentially deliver the highest percentage of API through the skin. The results obtained are contrary to this belief and it is concluded that the total HSP profile and the molar volume of the formulation and the API should be considered when developing a formulation with optimal transdermal delivery rather than just the SFG.
- Health Sciences