A preliminary investigation into the use of amino acids as potential ion pairs for diclofenac transdermal delivery

Ion pairing is a potential strategy used to increase the partition and permeation of ionisable drug molecules. This work outlines the process of identifying, selecting and testing potential counter ions for diclofenac (DF). Three screening criteria were considered in the initial selection process. The first, toxicity, was used to eliminate counter ion candidates that could not be used in topical formulations. The second related to the balancing of charges. As DF is a free acid in its unionised state, counter ions should be of a basic character. Finally, molecular size, as represented by molecular mass (Da), was used. Because of the impact on ion pair formation, the counter ion was required to have a lower molecular weight than diclofenac. Basic amino acids L-Arginine, L-Histidine, L-Lysine and their salts were chosen. The selection process concluded with Partition Coefficient (PC) studies. These were used to identify any counter ions able to interact electrostatically with the ionised DF, enabling the ‘neutral’ ion pair to partition from an aqueous into an organic layer. Permeation studies using porcine skin were performed to test the efficacy of any selected counter ion. These preliminary studies suggest that amino acids may be used as counter ions to increase the partition and permeation of ionisable drugs

Pig Ear Skin ex Vivo as a Model for in Vivo Dermatopharmacokinetic Studies in Man

Objective: The objective was to investigate pig ear skin as a surrogate for human skin in the assessment of topical drug bioavailability by sequential tape-stripping of the stratum corneum (SC). The potential benefits of ex vivo investigations are manifold: ethical approval is not required, multiple replicate experiments are more easily performed, and toxic compounds can be evaluated. Materials and Methods: Ex vivo experiments on isolated pig ears were compared with in vivo studies in human volunteers. Four formulations, comprising the model drug, ibuprofen, in different propylene glycol (PG)-water mixtures (25:75, 50:50, 75:25 and 100:0), were compared. Results: Derived dermatopharmacokinetic parameters characterizing the diffusion and partitioning of the drug in the SC ex vivo were consistent with those in vivo following a 30-minute application period. Further, the non-steady-state ex vivo results could be used to predict the in vivo concentration profile of the drug across the SC when a formulation was administered for 3h (i.e., close to steady-state). Conclusions: Taken together, the results obtained suggest that pig ear skin ex vivo has promise as a tool for topical formulation evaluation and optimizatio

Preparation, characterisation, and topical delivery of Terbinafine

Terbinafine (TBF) is commonly used in the management of fungal infections of the skin because of its broad spectrum of activity. Currently, formulations containing the free base and salt form are available. However, there is only limited information in the literature about the physicochemical properties of this drug and its uptake by the skin. In this work, we conducted a comprehensive characterisation of TBF, and we also examined its percutaneous absorption in vitro in porcine skin. TBF-free base was synthesised from the hydrochloride salt by a simple proton displacement reaction. Both the free base and salt form were further analysed using Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA). Delivery of TBF-free base in excised porcine skin was investigated from the following solvents: Isopropyl myristate (IPM), propylene glycol monolaurate (PGML), Transcutol® (TC), propylene glycol (PG), polyethylene glycol 200 (PEG 200), oleic acid (OL), ethanol (EtOH), and isopropyl alcohol (IPA). Permeation and mass balance studies confirmed that PG and TC were the most efficacious vehicles, delivering higher amounts of TBF-free base to the skin compared with a commercial gel (p < 0.05). These preliminary results are promising and will inform the development of more complex formulations in future work

A preliminary investigation of additive manufacture to fabricate human nail plate surrogates for pharmaceutical testing

In vitro permeation studies using nail clippings or nail plates are commonly used in the development of transungual formulations. However, there are ethical, safety and cost issues associated with sourcing such tissues. Herein, we describe a preliminary approach is described for the design and manufacture of a human nail model surrogate based on 3D printing. To evaluate these 3D printed constructs, nails were mounted in conventional glass Franz cells and a commercial antifungal lacquer formulation containing ciclopirox olamine was applied daily to the surrogate printed surfaces for a period of 14 days. On days 8 and 14, the surfaces of the 3D printed nails were washed with ethanol to remove excess formulation. Confocal Raman spectroscopy (CRS) was used to profile the drug in the 3D printed nail. At the end of the Franz cell studies, no drug was observed in the receptor phase. CRS studies confirmed penetration of the active into the model nails with reproducible depth profiles. Our ongoing work is focused on synthesising commercial and non-commercial printable resins that can replicate the physical and chemical characteristics of the human nail. This will allow further evaluation of actives for ungual therapy and advance the development of the surrogate nail tissue model

Topical delivery of Niacinamide: influence of binary and ternary solvent systems

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

Investigation of binary and ternary solvent systems for dermal delivery of methadone

Methadone appears to be a promising candidate for pain management. Previously, we conducted a comprehensive characterization study of methadone base and evaluated the dermal delivery of methadone from various neat solvents. Four solvents, namely d-limonene (LIM), ethyl oleate (EO), Transcutol® P (TC) and octyl salicylate (OSAL), were identified as the optimal neat solvents for skin delivery of the compound. To explore further approaches to improve methadone permeation, the present work investigated a range of binary and ternary vehicles. In vitro permeation studies in porcine skin confirmed that binary systems delivered significantly higher (p < 0.05) amounts of methadone through the skin compared with neat solvents. The highest skin permeation was observed for formulations composed of propylene glycol (PG) and TC. Nine formulations were subsequently examined in human skin. A good correlation (r2 = 0.80) for methadone permeation was obtained between porcine ear skin and human skin data. Solvent uptake studies indicated that the presence of PG not only increased methadone permeation but also TC permeation. The drug appears to “track” the permeation of TC. Future studies will expand further the range of potential vehicles for optimal delivery of the drug, that will ultimately to be investigated in clinical studies

Characterization and topical delivery of phenylethyl resorcinol

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: PR was characterised 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 logP (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 logP (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 – 106%. The limit of detection (LOD) and limit of quantification (LOQ) were 0.19 and 0.57 μg/mL, respectively. The solubility of PR in PG, DMI, glycerol was within the range of 367 to 877 mg/mL. The stability of PR in tested solvents were also confirmed by the 72 h stability studies. From the DVS studies, 70‐125% of applied formulations were recovered at 24h. The permeation through porcine skin at 24 h ranged from 4 to 13 μg/cm2, while the corresponding amounts of PR delivered through human skin were 2 to 10 μg/cm2. 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

A model binary system for the evaluation of novel ion pair formulations of diclofenac

Diclofenac (DF) is well established as a topical treatment option for conditions such as osteoarthritis. In investigating novel DF ion pairs for topical delivery, studies to determine the impact of various amino acids on the distribution of DF between octanol and aqueous environments were conducted. These studies identified the amino acid L-histidine hydrochloride monohydrate (LHSS) as an ion pair candidate for diclofenac sodium (DNa). Preliminary porcine skin permeation studies indicated that the addition of LHSS to DNa solutions increased the amount of DF that permeated through porcine skin. With increasing amounts of LHSS added, greater amounts of DF precipitated out of solution. In the present work, the solubility of DNa in various solvents was assessed, with the intention of identifying solvents in which DNa was most soluble. Binary systems comprising water and selected solvents were tested for both miscibility and the solubility of DNa and LHSS. The model system selected to evaluate novel ion pair formulations using porcine skin in vitro permeation studies under finite dose (10 µL) conditions comprised Transcutol® (TC) and water. The tested formulations contained DNa at concentrations of 5, 7.5 and 10 mg/ mL. Higher LHSS concentrations were possible when the DNa concentrations were lower, and ranged from 10 – 25 mg/mL. However, increasing the DNa concentration to 10 mg/mL, without adding LHSS, resulted in a significant reduction in the amount of DF that partitioned and permeated, relative to formulations that contained either 5 mg/mL DNa in combination with LHSS (at 12.5 or 25 mg/mL), or 7.5 mg/mL DNa together with 12.5 mg/mL LHSS. The current work confirms previous investigations, suggesting that the addition of LHSS to DNa in a formulation may increase the partition and permeation of DF

3D-printed Franz type diffusion cells

Franz cells are routinely used to measure in vitro skin permeation of actives and must be inert to the permeant under study. The aim of the present work was to develop and manufacture transparent Franz-type diffusion cells using 3D printing and test these using a range of model active compounds. The study also aims to identify the critical 3D printing parameters necessary for the process including object design, choice of printing resin, printout curing and post-curing settings and introduction of model coatings. Transparent Franz cells were constructed using an online computer aided design program and reproduced with different stereolithography 3D printers. The two acrylate-based resins used for the fabrication process were a commercially available product and a polymer synthesised in-house. Comparative studies between glass and 3D printed Franz cells were conducted with selected model actives: terbinafine hydrochloride (TBF), niacinamide (NIA), diclofenac free acid (DFA) and n-methyl paraben (MPB). In preliminary studies, MPB showed the lowest recovery when exposed to the receptor compartment of 3D printed cells. Consequently, in vitro permeation studies were carried out using only MPB with polydimethylsiloxane (PDMS) membrane. A decrease in the amounts of selected compounds was observed for transparent 3D printed Franz cells compared to glass cells. MPB showed the lowest recovery (53.8 ± 13.1%) when compared with NIA (74.9 ± 4.0%), TBF (81.5 ± 12.0%) and DFA (90.2 ± 12.9%) after 72 h. Permeation studies conducted using 3D printed transparent cells with PDMS membrane also showed a decrease in MPB recovery of 51.4 ± 3.7% for the commercial resin and 94.4 ± 3.5% for the polymer synthesised in-house, when compared to glass cells. Although hydrophobic coatings were subsequently applied to the 3D printed cells the same reduction in MPB concentration was observed in the receptor solution. Transparent Franz cells were successfully prepared using 3D printing and were observed to be robust and leak-proof. There are few resins currently available for preparation of transparent materials and incompatibilities between the actives investigated and the 3D printed cells were evident. Hydrophobic coatings applied as barriers to the printed materials did not prevent these interactions. This article is protected by copyright. All rights reserved. [Abstract copyright: This article is protected by copyright. All rights reserved.

Ion pairs for transdermal and dermal drug delivery: a review

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