Topical delivery of anthramycin II. Influence of binary and ternary solvent systems

Abstract

Anthramycin (ANT) is a member of the pyrolobenzodiazepine family and is a potent cytotoxic agent. Previously, we reported the topical delivery of ANT from a range of solvents that may also act as skin penetration enhancers (SPEs). The skin penetration and uptake was monitored for simple solutions of ANT in propylene glycol (PG), dipropylene glycol (DiPG), Transcutol P (TC), isopropyl myristate (IPM), propylene glycol monocaprylate (PGMC) and propylene glycol monolaurate (PGML). The amounts of PG, DiPG and TC that were taken up by, and that penetrated the skin were also measured, with a clear dependence of ANT penetration on the rate and extent of PG and TC permeation. The present work investigates ANT skin delivery from a range of binary and ternary systems to determine any potential improvement in skin uptake compared with earlier results for the neat solvents. Following miscibility and stability studies a total of eight formulations were taken forward for evaluation in human skin in vitro. Binary systems of PG and water did not result in any skin permeation of ANT. Combining PG with either PGMC or PGML did promote skin penetration of ANT but no significant improvement was evident compared with PG alone. More complex ternary systems based on PG, DiPG, PGMC, PGML and water also did not show significant improvements on ANT permeation, compared with single solvents. Total skin penetration and retention of ANT ranged from 1 to 6% across all formulations studied. Where ANT was delivered to the receptor phase there were also high amounts of PG permeation with >50% and ~35% PG present for the binary systems and ternary vehicles, respectively. These findings along with our previous paper confirm PG as a suitable solvent / SPE for ANT either alone or in combination with PGML or PGMC. The results also underline the necessity for empirical testing to determine whether or not a vehicle is acting as a SPE for a specific active in a topical formulation.

Topical delivery of niacinamide: Influence of neat solvents

“…Even though the mechanism by which TC interacts with the skin is not known, its potential to act as a penetration enhancer has been reported for a number of compounds (Lane, 2013). Puglia and Bonina (2008) PG is a hydrophilic solvent that has been used in topical formulations as a solvent for many actives (Lane, 2013;Haque et al, 2017b;Haque et al, 2018;Paz-Alvarez et al, 2018;Hossain et al, 2019;Iliopoulos et al, 2019;Zhang et al, 2019b). In the present work, 5 μL doses of 3 % (w/w) NIA in PG were applied to porcine skin and the percentage permeation after 24 h was 19.2 %.…”

Topical Delivery of 3-O-ethyl l-ascorbic Acid from Complex Solvent Systems

“…Miscibility studies were conducted as described by Haque et al [12]. Briefly, for both binary and ternary miscibility determinations, the solvents were mixed at different percentages, varying by 10%.…”

“…The solubility parameters of the solvent mixtures were estimated by the Van-Krevelen and Hoftyzer approach using Molecular Modelling Pro ® software (Version 7.0.8, 2016, Norgwyn Montgomery Software, Inc., North Wales, PA, USA), as explained previously [12]. Solubility studies were conducted at 32 ± 1 • C and samples were analysed using the previously reported and validated HPLC method [5].…”

“…The binary solvent systems i.e., PG:PGML, HEX:PGML, and PG:IPA were miscible at all ratios. Ternary solvent vehicles consisting of PG:PGML:IPM, PG:PGML:ISIS, and PG:PGML:MCT were prepared based on their respective miscibility phase diagrams, as described previously [12]. The saturation solubility of EA in the mixtures as well as calculated solubility parameters of vehicles are shown in Figure 1.…”

Topical Delivery of Niacinamide: Influence of Binary and Ternary Solvent Systems

“…Miscibility studies of all vehicles were conducted to identify appropriate combinations of solvents for binary and ternary systems. The stability of NIA at a concentration of 5% (w/v) in PG:T-BA (90:10), PG:OA (10:90), PG:TC (50:50), PG:DMI (50:50), PG:LA (50:50), PG:TC:DMI (50:25:25), TC: T-BA (90:10) and TC:DMI (50:50), TC:CCT:DMI (50:25:25) and TC:PG:DMI (50:25:25) was examined at 32 ± 1 °C up to 72 h [14]. The concentration of NIA was determined at 0, 24, 48 and 72 h. Samples were analyzed using the HPLC method validated earlier with a Kinetix ® 5 mm Phenyl-Hexyl 250 × 4.6 mm reversed column (Phenomenex, Macclesfield, UK) with water:methanol (80:20) as the mobile The discovery and development of robust and accessible human skin surrogates continues to be an area of considerable interest to industry and regulatory authorities.…”