Application of Hansen Solubility Parameters and FFE Software in Predicting Drug Permeation and for the Selection of Best Pharmaceutical Excipients for Delivery of Specific Active Molecules Through the Skin
Purpose: To provide data on applicability of Hansen Solubility Parameters used by the FFE (Formulating for EfficacyTM - ACT Solutions Corp) Software for in-vitro diffusion studies in transdermal arena in place of human or animal skin and/or synthetic membranes as a model. Applicability of Hansen Solubility Parameters and FFE Software in permeability studies is discussed. Results: It was demonstrated that the permeation of drug can be predicted by analyzing different physico-chemical and solubility parameters of drug and ingredients that were assessed using FFE Software. There is a linear correlation between measured and calculated flux of nicotine from various formulation using different ingredients. The amount of nicotine permeated per square cm from formulation 3 (Nicotine 1% in Propylene Glycol + 5% Azone) and from formulation 5 (Nicotine 1% in Propylene Glycol + 5% Oleic Acid) after 8 hours (Q8) were significantly greater when compared to control and all other formulations (p<0.05). The formulation with 5% N-Methyl Pyrrolidone did not show any enhancement effect on nicotine permeation through human cadaver skin. Eucalyptol and Tween 80 shared similar trends by providing lower nicotine flux in comparison to the formulation containing 5% Oleic Acid, 5% Azone, and higher flux of nicotine when compared to N-Methyl Pyrrolidone (5%). The rank order of each enhancer/ingredient for the enhancement of Nicotine skin permeation was as follows: Oleic Acid>Azone>Eucalyptol + Tween 80>N-Methyl Pyrrolidone. This permeation ranking can be further understood by analyzing the ratio of SolV and SolS, IAG and ISG values. By using FFE Software it was found that the SolV and SolS ratio of NMP is 100:100, which is the same as Nicotine. For this reason, in spite of having lowest ISG (3.41) value among all other ingredients, most likely N-Methyl Pyrrolidone could not provide enough thermodynamic to drive the active from the formulation efficiently and to enter and pass through the skin. On the other hand, Oleic Acid, with SolV and SolS ratio (100:0.2) and low IAG (4.66) value compared to all other ingredients used in this experiment, was found to be best in providing maximum Nicotine flux. Additionally, Azone shares the same SolV and SolS values with Oleic acid, but showed lower Nicotine flux than Oleic Acid due likely to higher IAG and ISG values. There appears to be an inverse relationship between measured flux and IAG values given that there is an optimum ingredient skin gap, SolV and SolS ratio. Conclusions: Permeability of actives can be modelled and optimized by using Hansen Solubility Parameters as employed by the FFE Software. This study suggests that IAG, ISG, SolV and SolS values are equally important and should be considered while characterizing the permeability of active compounds with various excipients. The FFE software can be successfully used as a screening tool in order to choose the best performing chemical enhancers or ingredients.
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Methods: Hansen Solubility Parameters of actives, excipients, and the skin are used by the FFE Software to derive various physico-chemical properties including ingredient active gap (IAG), ingredient skin gap (ISG), solubility of active in the formulation (SolV) and the formulation solubility in the skin (SolS). These are vital factors in the determination of the most effective formulation for delivery of a particular active into the skin. The FFE Software can derive the Hansen Solubility Parameters of actives and excipients with the input of a linear chemical structure input called SMILES; from there, solubility profiles, permeation and different physico-chemical properties of drug actives and excipient ingredients are calculated automatically. Measured drug permeation data were compared with the calculated permeation data and solubility parameters of the drugs. Eight hours diffusion studies were modeled for each formulation were run using the software. Permeation of nicotine through human cadaver skin using various chemical penetration enhancers were measured. Formulations were prepared adding 5% of one chemical penetration enhancer to separate formulas. Vertical Franz cells were used with phosphate buffered saline (pH 7.4) receptor media and were maintained 37°C at 600 rpm continuous stirring. Permeation studies were carried out over 8 hours, with 300 µL samples were collected at regular time intervals. The cumulative amounts of nicotine permeated per unit area were plotted against time. The flux was calculated by determination of the slope of the linear portion of the permeation profile.