Niacinamide (NIA) is the amide form of vitamin B3 and has been widely used in pharmaceutical and personal care formulations. Previously, we reported a comparative study of NIA permeation from neat solvents using the Skin Parallel Artificial Membrane Permeability Assay (PAMPA) and mammalian skin. A good correlation between NIA permeation in the different models was found. In the present work, ten binary and ternary systems were evaluated for their ability to promote NIA delivery in the Skin PAMPA model, porcine skin and human epidermis. Penetration enhancement was evident for binary systems composed of propylene glycol and fatty acids in human skin studies. However, propylene glycol and oleic acid did not promote enhancement of NIA compared with other systems in the Skin PAMPA model. A good correlation was obtained for permeation data from Skin PAMPA and porcine skin. However, data from the Skin PAMPA model and from human skin could only be correlated when the PG-fatty acid systems were excluded. These findings add to our knowledge of the potential applications of Skin PAMPA for screening dermal/transdermal preparations.
Ion pairing is a strategy used to increase the permeation of topically applied ionised drugs. Formation occurs when the electrostatic energy of attraction between oppositely charged ions exceeds their mean thermal energy, making it possible for them to draw together and attain a critical distance. These ions then behave as a neutral species, allowing them to partition more readily into a lipid environment. Partition coefficient studies may be used to determine the potential of ions to pair and partition into an organic phase but cannot be relied upon to predict flux. Early researchers indicated that temperature, size of ions and dielectric constant of the solvent system all contributed to the formation of ion pairs. While size is important, this may be outweighed by improved lipophilicity of the counter ion due to increased length of the carbon chain. Organic counter ions are more effective than inorganic moieties in forming ion pairs. In addition to being used to increase permeation, ion pairs have been used to control and even prevent permeation of the active ingredient. They have also been used to stabilise solid lipid nanoparticle formulations. Ion pairs have been used in conjunction with permeation enhancers, and permeation enhancers have been used as counter ions in ion pairing. This review attempts to show the various ways in which ion pairs have been used in drug delivery via the skin. It also endeavours to extract and consolidate common approaches in order to inform future formulations for topical and transdermal delivery.
In vivo human studies are considered to be the “gold standard” when investigating (trans)dermal delivery of actives. Previously, we reported the effects of a range of vehicles on the delivery of niacinamide (NIA) using conventional Franz cell studies. In the present work, dermal delivery of NIA was investigated in vivo in human subjects using confocal Raman spectroscopy (CRS) and tape stripping (TS). The vehicles investigated included propylene glycol (PG), Transcutol® P (TC), binary combinations of PG with oleic acid (OA) or linolenic acid (LA) and a ternary system comprising of TC, caprylic/capric triglyceride (CCT) and dimethyl isosorbide (DMI). For the CRS studies, higher area under curve (AUC) values for NIA were observed for the PG:LA binary system compared with PG, TC and TC:CCT:DMI (p < 0.05). A very good correlation was found between the in vitro cumulative permeation of NIA and the AUC values from Raman intensity depth profiles, with a Pearson correlation coefficient (R2) of 0.84. In addition, an excellent correlation (R2 = 0.97) was evident for the signal of the solvent PG and the active. CRS was also shown to discriminate between NIA in solution versus crystalline NIA. The findings confirm that CRS is emerging as a powerful approach for dermatopharmacokinetic studies of both actives and excipients in human.
Objective Phenylethyl resorcinol (PR) has been used widely in the personal care industry as a novel skin lightening ingredient. Surprisingly, there is only limited information describing the physicochemical properties of this active. Therefore, the primary objective of this study was to perform a comprehensive characterization of PR. A secondary objective was to investigate the delivery of this molecule to mammalian skin. Methods Phenylethyl resorcinol was characterized using differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and nuclear magnetic resonance (NMR). A new high‐performance liquid chromatographic (HPLC) method for analysis of PR was developed and validated. The log P (octanol water partition coefficient), value, solubility and short‐term stability of PR in a series of vehicles were also determined using HPLC. The evaporation of the selected vehicles was examined using dynamic vapour sorption (DVS). The permeation profiles of PR were investigated under finite dose conditions in porcine and human skin. Results The melting point of PR was determined to be 79.13 °C and the measured log P (octanol water partition coefficient) at 21 °C was 3.35 ± 0.03. The linearity of the HPLC analytical method was confirmed with an r2 value of 0.99. Accuracy of the method was evaluated by average recovery rates at three tested concentrations, and the values ranged from 99 to 106%. The limit of detection (LOD) and limit of quantification (LOQ) were 0.19 and 0.57 μg mL−1, respectively. The solubility of PR in PG, DMI, glycerol was within the range of 367 to 877 mg mL−1. The stability of PR in tested solvents was also confirmed by the 72 h stability studies. From the DVS studies, 70–125% of applied formulations were recovered at 24 h. The permeation through porcine skin at 24 h ranged from 4 to 13 μg cm−2, while the corresponding amounts of PR delivered through human skin were 2 to 10 μg cm−2. Conclusion The physicochemical properties of PR confirm it is suitable for dermal delivery. In this study, propylene glycol was the most promising vehicle for PR delivery to human skin. Future work will expand the range of vehicles studied and explore the percutaneous absorption from more complex formulations.
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