Alternatives to Conventional Topical Dosage Forms for Targeted Skin Penetration of Diclofenac Sodium

Skin penetration of an active pharmaceutical ingredient is key to developing topical drugs. This penetration can be adjusted for greater efficacy and/or safety through the selection of dosage form. Two emerging dosage forms, cream–gel and gel-in-oil emulsion, were tested for their ability to deliver diclofenac into the skin, with the target of maximising skin retention while limiting systemic exposure. Prototypes with varying amounts of solvents and emollients were formulated and evaluated by in vitro penetration testing on human skin. Cream–gel formulas showed better skin penetration than the emulgel benchmark drug even without added solvent, while gel-in-oil emulsions resulted in reduced diffusion of the active into the receptor fluid. Adding propylene glycol and diethylene glycol monoethyl ether as penetration enhancers resulted in different diclofenac penetration profiles depending on the dosage form and whether they were added to the disperse or continuous phase. Rheological characterisation of the prototypes revealed similar profiles of cream–gel and emulgel benchmark, whereas gel-in-oil emulsion demonstrated flow characteristics suitable for massaging product into the skin. This study underlined the potential of cream–gel and gel-in-oil emulsions for adjusting active penetration into the skin, broadening the range of choices available to topical formulation scientists.

1. Introduction

Targeted skin delivery of the active pharmaceutical ingredient (API) contained in a drug product is key to maximising its efficacy, while also reducing side-effects arising from unnecessary exposure. Skin diffusion is intrinsically linked to the physicochemical properties of the active, but also to the excipients used and the overall dosage form [1].

Recent studies have highlighted interest in new dosage forms for their impact on skin penetration of active pharmaceutical ingredients as compared to conventional semi-solid dosage forms like gels, emulgels, creams, or ointments. Microneedles can be one example, with their potential to by-pass the stratum corneum, the main skin barrier, and deliver therapeutic compounds directly into the epidermis or dermis [2]. Nanoemulsions and nanocarriers (nanosize vesicles, nanocrystals, or nanolipids often introduced in a gel) have also shown promising results for encapsulation and enhanced skin delivery of actives [1,3,4,5,6]. However, these emerging technologies are inherently complex to develop and can have drug loading limitations that might restrict their adoption. Multiple water-in-oil-in-water emulsion was also reported as enhancing skin permeability but required a two-step emulsification procedure [7], increasing complexity and lengthening industrial production time.

There exist alternatives to conventional topical dosage forms that do not require complex manufacturing equipment or formulation processes. Cream–gel (CG) [8] is an oil-in-water system where the lipophilic phase is stabilised by a gel polymer network, not requiring the addition of surfactant, unlike emulgels. This kind of dosage form has recently gained exposure with the launch of a new retinoid for acne [9]. On the other hand, gel-in-oil (GIO) emulsions comprise a large volume of internal aqueous gel phase within a continuous lipophilic phase [10]. Both dosage forms have a relatively straightforward formulation process, with emulsification being possible even with low to medium shear agitation at room temperature [8,11,12]. There appear to be limited data available for the impact of these dosage forms on skin penetration of actives. Previous human skin experiments with cream–gel only have demonstrated superior API penetration, although the results are limited to one formulation with high variability and no characterisation of active content in skin compartments [13]. Our study is an attempt to bridge this gap, evaluating API penetration into and across human skin samples from both dosage forms with various excipient compositions.

Topical administration of diclofenac, a non-steroidal anti-inflammatory drug, enables localised treatment while limiting systemic exposure linked to gastrointestinal side-effects when compared to oral treatment. While the exact mechanism of diffusion through skin layers to the underlying layers has not yet been elucidated, it has been shown that muscular tissue concentration of diclofenac after topical applications in rats is not directly correlated to systemic concentration but mostly originates from direct skin diffusion [14]. Further microdialysis studies in human volunteers have shown that increased systemic concentration of diclofenac after cutaneous application was not linked to higher active content in subcutaneous adipose tissues or skeletal muscles, with lower concentration being observed for several treatments evaluated [15]. Based on these results, our target for a suitable diclofenac penetration profile for in vitro penetration testing (IVPT) was to maximise the API content in the skin sublayers (stratum corneum, epidermis, and dermis) while having similar or less diffusion in the fluid receptor, modelling systemic exposure, when compared to a market benchmark.

To achieve this goal, the study was conducted step by step. Starting from cream–gel and gel-in-oil emulsion formulations with well-known penetration enhancers, compositions were then adjusted based on the first IVPT results to further investigate the impact of removing the penetration enhancers and adjusting the oily phase. The testing plan is described in Figure 1.

4.1. Chemicals

The benchmark product (Voltarenactigo 1%) was purchased from a local pharmacy. Diclofenac sodium was purchased from “Axo Industry International SA, Wavre, Belgium”. Propylene glycol (penetration enhancer) was purchased from “Brenntag S.A., Chassieu, France”. Diethylene glycol monoethyl ether (Transcutol^® P; penetration enhancer) was a kind gift from “Gattefossé, Saint-Priest, France”. Isopropyl myristate (DUB IPM; emollient) and medium-chain triglycerides (caprylic/capric triglyceride: DUB MCT 5545; emollient) were purchased from “Stéarinerie Dubois, Boulogne-Billancourt, France”. Liquid paraffin (Primol^® 352; emollient) was purchased from “Esso, Courbevoie, France”. AMPS-based polymer (Sepineo™ P 600: acrylamide/sodium acryloyldimetyltaurate copolymer and isohexadecane and polysorbate 80), cetearyl alcohol/cetearyl glucoside (Sepineo™ SE 68; surfactant), PEG-30 dipolyhydroxystearate (surfactant), coco-caprylate/caprate (emollient), and preservatives (Sepicide™ HB: phenoxyethanol and methylparaben and ethylparaben and propylparaben and butylparaben) were directly sourced from “Seppic SA, La Garenne Colombes, France”. Purified water was obtained through filtration by Elix^® Advantage 3 from “Merck KGaA, Darmstadt, Germany”.

Download the full study as PDF here: Alternatives to Conventional Topical Dosage Forms for Targeted Skin Penetration of Diclofenac Sodium

or read it here

Gavinet, B.; Sigurani, S.; Garcia, C.; Roso, A. Alternatives to Conventional Topical Dosage Forms for Targeted Skin Penetration of Diclofenac Sodium. Int. J. Mol. Sci. 2024, 25, 7432.
https://doi.org/10.3390/ijms25137432

excipients formulation