Polyaphron Dispersion Technology, A Novel Topical Formulation and Delivery System Combining Drug Penetration, Local Tolerability and Convenience of Application

Abstract

Topical formulation and delivery technologies for pharmaceutical application should simultaneously address efficacy, safety and convenience of therapy. This has historically proven to be challenging, since formulation features that drive efficacy often have undesirable consequences for safety and convenience and vice versa. Polyaphron dispersion (PAD) technology is a novel topical formulation and drug delivery system developed with the purpose of preserving these key attributes. PAD formulations are typically oil-in-water dispersions consisting of oil droplets encapsulated in a multi-molecular shell structure. This shell structure protects potentially unstable active molecules solubilized in the oil from hydrolytic degradation. Example data are presented of enhanced drug penetration from PAD formulations, including dermal delivery of calcipotriene, betamethasone dipropionate and tacrolimus as well as ocular delivery of ciclosporin A. Local tolerability is an important safety parameter for topical formulations, where high levels of surfactants can cause skin irritation. In this regard, a key benefit of PAD formulations is the inherent reduced requirement for surfactants to generate stable formulations compared to conventional emulsion systems. Patients with chronic diseases with topical manifestations such as psoriasis or atopic dermatitis have been reported to miss up to 70% of planned topical applications, mainly due to a lack of satisfaction with their therapy. Patients generally prefer light, moisturizing, non-greasy and quickly absorbed vehicles that are simple to use on all body parts. PAD formulations can generally be designed to meet these criteria. In conclusion, PAD technology provides high flexibility in topical drug design and can be applied to several body locations without compromising efficacy, safety or convenience of therapy.Clinical Trial Register: Clinicaltrials.gov: NCT03802344.

Keywords: Adherence; Betamethasone dipropionate; Calcipotriene; Drug delivery; Polyaphron dispersion (PAD) technology; Topical formulation.

© 2022. The Author(s).

Figures

Fig. 1

a Schematic illustration of a PAD technology formulation of oil-in-water droplets. A multimolecular layer of organized surfactant, oil and water forms a robust three-dimensional bicontinuous structure around the oil droplet. PAD technology formulations are manufactured with a low level of surfactant in the water and oil phases, in contrast to conventional emulsions that require a large excess of surfactant in the water phase to maintain physical stability. b Scanning electron microscope image of a cleaved polyaphron oil droplet. The central, rough, region is oil (olive oil in this example) and the smoother outer shell structure is surfactant, water and oil. c Scanning electron microscope image of a cleaved polyaphron oil droplet. The central oil core (brominated vegetable oil in this case) sublimated off during sample preparation, leaving the outer shell structure of surfactant, water and oil

Fig. 2

PAD technology formulations are generally manufactured in a two-step process where the first step is the formation of an oil-in-water PAD with a high oil level. In the second step, one or more high-oil-content pre-stabilized PAD premix modules are dispersed in an aqueous phase environment typically containing a polymeric gellant to obtain a physically stable final formulation. The PAD premix modules can be designed to provide different functionalities to the final PAD technology formulation

Fig. 3

Comparisons of Franz cell human skin flux through epidermis: CAL/BDP PAD cream versus CAL/BDP topical suspension (TS)/gel (a, b) and variants of CAL PAD cream regarding the content and type of oils versus CAL ointment (c). Methodology: Human skin was kept frozen until preparation. Subcutaneous fat was removed mechanically, and epidermis was removed from dermis by heat separation and mounted on a Franz cell chamber filled with receptor phase (70% phosphate-buffered saline, pH 7.4, 50 mM; 30% isopropanol). Test products were applied to the skin at 0, 16, 40 and 64 h, similar to the methodology described in Simonsen et al. [62]. An isocratic HPLC method was used for the detection of CAL and BDP in the receptor fluid. Error bars are illustrated at the standard error of the mean. Results of a statistical assessment by Student’s t-test comparing CAL/BDP PAD cream and CAL/BDP TS/gel at 72 h are displayed as *** (for p < 0.001) and **** (for p < 0.0001) [29, 30]

Fig. 4

Prospective, vehicle and active-comparator controlled, randomized, phase 3 trial evaluating efficacy in patients with plaque psoriasis at multiple sites in Europe (MC2-01-C7; NCT03802344; N = 490). The design of the trial included a screening and 8-week treatment period. The trial population consisted of male and female patients above the age of 18 years with mild-to-moderate psoriasis according to PGA and with a treatment area of 2–30% of the body (trunk and/or limbs) (CAL/BDP PAD cream N = 213; PAD-cream vehicle N = 68). “Controlled disease” was defined as an improvement from baseline to clear or almost clear disease at the indicated time points. a Controlled disease assessed for the body. b Controlled disease assessed for patients with scalp psoriasis involving a minimum 10% of the scalp (CAL/BDP PAD cream N = 112; PAD-cream vehicle N = 38). Data are shown according to a treatment-policy strategy with multiple imputations, and p values represent a comparison of CAL/BDP PAD cream to vehicle calculated by a logistic regression model using randomized treatment, country and baseline PGA on the body as independent variables. The trial protocol was approved by institutional review boards for each site, and all patients provided written informed consent prior to any trial-related procedures. Detailed efficacy data from phase 3 trials are presented elsewhere [31, 63]

Fig. 5

Penetration of tacrolimus into minipig epidermis (a) and dermis (b). Test products [tacrolimus PAD cream 0.03%, tacrolimus PAD cream 0.1% and tacrolimus ointment 0.1% comparator (Protopic® 0.1%)] were applied twice daily to eight 2.5 × 2.5 cm application sites on the backs of four male Göttingen minipigs (25 mg product/cm2). Skin biopsies (n = 8 per treatment) for bioanalysis by LC–MS/MS were collected after 28 days of treatment, 4 h after the last dosing. Epidermis was separated from dermis and subcutaneous tissue was removed from the dermis using a scalpel. Stratum corneum and any residual formulation were removed by 40 tape strips before punching the biopsy. Error bars are shown as standard error of the mean. The study was conducted according to Good Laboratory Practice for Medicinal Products as required by the Danish Health and Medicines Authority and in accordance with the OECD Principles of Good Laboratory Practice [33]

Fig. 6

Pigmented rabbits received a single instillation of 30 µl PAD 0.06% CsA, PAD 0.1% CsA or a marketed 0.05% CsA emulsion (Restasis®) in both eyes. Rabbit corneas were sampled at 0.5, 1, 2, 5, 12 and 24 h after instillation. CsA was extracted and the content was determined by a RRLC-MS/MS method (n = 6 eyes per data point) [34]. All animals were treated according to the European Convention and the Association for Research in Vision and Ophthalmology (ARVO) Statement for the Use of Animals in Ophthalmic and Vision Research [64]

Fig. 7

Pictures of minipigs from a dermal toxicity study taken after 4 weeks of once-daily application of CAL/BDP PAD cream (left) and a marketed CAL/BDP ointment (Daivobet®, right). The dermal toxicity study was part of nonclinical requirements in support of regulatory submissions. The study was conducted according to Good Laboratory Practice for Medicinal Products as required by the Danish Health and Medicines Authority and in accordance with the OECD Principles of Good Laboratory Practice [65]