Formulation and dermal delivery of a new active pharmaceutical ingredient in an in vitro wound model for the treatment of chronic ulcers

The aim of this study was to investigate dermal delivery of the new active pharmaceutical ingredient (API) TOP-N53 into diabetic foot ulcer using an in vitro wound model consisting of pig ear dermis and elucidate the impact of drug formulation and wound dressing taking into consideration clinical relevance and possible bacterial infection. Different formulation approaches for the poorly water-soluble API including colloidal solubilization, drug micro-suspension and cosolvent addition were investigated; moreover, the effect of (micro-)viscosity of hydrogels on delivery was assessed.

Addition of Transcutol® P as cosolvent to water improved solubility and was significantly superior to all other approaches providing a sustained three-day delivery that reached therapeutic drug levels in the tissue. Solubilization in micelles or liposomes, on the contrary, did not boost delivery while micro-suspensions exhibited sedimentation on the tissue surface. Microbial contamination was responsible for considerable metabolism of the drug leading to tissue penetration of metabolites which may be relevant for therapeutic effect. Use of hydrogels as primary wound dressing under semi-occlusive conditions significantly reduced drug delivery in a viscosity-dependent fashion. Micro-rheologic analysis of the gels using diffusive wave spectroscopy confirmed the restricted diffusion of drug particles in the gel lattice which correlated with the obtained tissue delivery results.

Hence, the advantages of hydrogel dressings from the applicatory characteristic point of view must be weighed against their adverse effect on drug delivery. The employed in vitro wound model was useful for the assessment of drug delivery and the development of a drug therapy concept for chronic diabetic foot ulcer in the home care setting. Mechanistic insights about formulation and dressing performance may be applied to drug delivery in other skin conditions such as digital ulcer.

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Materials

The compounds TOP-N53 and TOP-52 were kindly provided by Topadur Pharma AG (Schlieren, Switzerland). The phosphate buffered saline (PBS) contained sodium chloride EMPROVE® ESSENTIAL (NaCl, 137 mM), potassium dihydrogen phosphate EMPROVE® bio (KH2PO4, 3.5 mM) and di-sodium hydrogen phosphate dehydrate EMPROVE® bio (Na2HPO4 x 2 H2O, 14 mM) purchased from Merck KGaA (Darmstadt, Germany) and dissolved in purified water. For the preserved PBS, PBS was supplemented with 1 % parabens concentrate 10 % w/w, made by dissolving methyl parahydroxybenzoate (7 % w/w) and propyl parahydroxybenzoate (3 % w/w) in propylene glycol at 70 °C, both purchased from Hänseler AG (Herisau, Switzerland).

Kolliphor® ELP (polyoxyl 35 castor oil) was a gift from BASF (Ludwigshafen am Rhein, Germany), Tween 80 from CRODA (Snaith, UK), Lipoid S 100 from Lipoid GmbH (Ludwigshafen, Germany), Blanose™ 7MF and Blanose™ 7H4XF (sodium carboxymethylcellulose) from Ashland (Wilmington, DE, USA), Vivastar® P (sodium starch glycolate) from JRS (Rosenberg, Germany), Transcutol® P (diethylene glycol monoethyl ether) from Gattefossé (Saint-Priest, France) and benzyl alcohol special grade (benzaldehyde ≤ 0.05 %) EMPROVE® EXPERT from Merck KGaA (Darmstadt, Germany). Transcutol® P is referred to in the rest of this paper simply as Transcutol.

Super refined® PEG 400-LQ-(MH) (polyethylene gylcol 400) was purchased from CRODA (Snaith, UK), glycerol and potassium carbonate from Hänseler AG (Herisau, Switzerland), and the antibiotic antimycotic solution (100 x) with penicillin (10 000 units/mL), streptomycin (10 mg/mL) and amphotericin B (25 µg/mL) as well as the gentamicin sulfate were obtained from Merck KGaA (Darmstadt, Germany). Acetonitrile and formic acid were bought from Merck KGaA (Darmstadt, Germany) and were of HPLC grade. Water purified by reversed osmosis or ion exchange resin with the water purification system arium® 61,215 or arium® pro, respectively, from Sartorius (Goettingen, Germany) was used throughout.

Ursula Thormann, Selina Marti, Elizabeth Lensmith, Michael Lanz, Susanne Herzig, Reto Naef, Georgios Imanidis,
Formulation and dermal delivery of a new active pharmaceutical ingredient in an in vitro wound model for the treatment of chronic ulcers, European Journal of Pharmaceutics and Biopharmaceutics, 2024, 114373, ISSN 0939-6411, https://doi.org/10.1016/j.ejpb.2024.114373.