(M1230-03-16) Enhanced Skin and Follicular Delivery of Tazarotene from PLGA Nanoparticles for the Treatment of Acne and Psoriasis

Purpose: Acne vulgaris and plaque psoriasis are the most common inflammatory skin conditions, with an estimated 117.4 million cases of acne vulgaris and 64.6 million cases of psoriasis worldwide (1,2). Acne vulgaris is characterized by inflamed nodules, pustules, and papules localized at hair follicles, whereas plaque psoriasis is a chronic immune-mediated disease caused by the hyperproliferation of keratinocytes. Tazarotene is a retinoid prodrug that converts to tazarotenic acid in the skin and is commonly prescribed for acne and psoriasis. Tazarotene is available commercially as Tazorac® gel and cream with strengths of 0.05% to 1% of tazarotene. However, tazarotene causes skin irritation, dryness, flaking, and photosensitivity upon topical application. Hence, it is important to target follicular delivery of tazarotene for longer contact and bioavailability at the site of action. Polymeric nanoparticles can enhance targeted delivery in hair follicles and improve their residence time on the skin, potentially reducing skin irritation due to the drugs' limited contact with the skin. The objective of the present study was to develop tazarotene-loaded PLGA nanoparticles, optimize various formulation and process parameters, and evaluate the in vitro release and permeation (IVPT) across the full-thickness porcine skin model.

Methods: A summary of study design is mentioned in Fig.1. Tazarotene was encapsulated in various PLGA grades (EXPANSORB® DLG 50-5A and 50-2A) using nanoprecipitation technique. Tazarotene and PLGA were dissolved in acetone and injected into the aqueous phase (1% w/w polyvinyl alcohol EMPROVE®18-88) at 1 mL/min rate and 800 RPM, followed by solvent evaporation. The nanoparticles were collected by centrifugation, washed, and lyophilized. Seven batches of nanoparticles with varying polymer types and drug-polymer ratios were developed and characterized for critical parameters (Figure 2a). Based on particle size, formulations F3 to F7 were further evaluated for Scanning Electron Microscopy (SEM), Fourier Transform Infrared Spectroscopy (FTIR), in vitro drug release study using a dialysis membrane (MWCO: 14,000kDa) on vertical Franz diffusion cells. The data from the release study was fitted into various models to understand the release mechanism of tazarotene from the nanoparticles. IVPT was performed on full-thickness porcine skin on Franz cells, where nanoparticles were suspended in a propylene glycol vehicle (1.2 mg/mL) and applied as a finite dose on the skin using an inverted UPLC sample vial and rubbed in a circular motion for 30 seconds. Receptor samples were taken at predetermined time points. The amounts in the hair follicles and the skin were determined using a differential tape-stripping technique. Tazarotene was extracted from the skin, cyanoacrylate glue, and the tape strips and analyzed using a validated Ultra Performance Liquid Chromatography (UPLC) method. The bioconversion ability of tazarotene to tazarotenic acid from nanoparticles was assessed by quantifying the amount of tazarotenic acid in the skin after IVPT studies.

Results: Tazarotene showed no potential interactions with PLGA, as all the characteristic FTIR peaks were present in the nanoparticles. Batches F1-F7 with different types of PLGA and drug-polymer ratio were formulated, out of which F3 to F7 showed optimal particle size and distribution and, hence, were chosen for further analysis (Fig.2a). SEM studies showed the successful formation of nanoparticles along with relatively uniform particle size and FTIR showed no potential interaction. As the drug concentration was increased, a decrease in the particle size and a decrease in the polydispersity index, up to a ratio of 1:2. The in vitro release study results (Fig.2b and 2c) indicated that a sustained release of tazarotene was observed from all the nanoparticle groups. At the end of 36 h, the highest release was observed for batch F6 (69.38 ± 2.26%), followed by F5 (58.39 ± 3.23%), F4 (48.28 ± 6.15%), followed closely by F7 (46.31 ± 1.35%) and lastly F3 (44.84 ± 3.71%). A significant difference was observed between the total release from F3 and F6 (p=0.0035), F4 and F6 (p=0.0115), and F6 and F7 (p=0.0105). Formulations F3, F4, F6, and F7 best fit into the Higuchi model, while F5 followed the Korsmeyer-Peppas model, indicating diffusion-based drug release. IVPT study results (Fig.3 a-d) indicated tazarotene delivery to the hair follicles significantly increased from F3 (p=0.0123) and F7 (p=0.0294), along with a significant increase in the total skin delivery of tazarotene from F3 (p=0.0207), compared to the control. Additionally, 1% of the applied dose of tazarotene was converted to tazarotenic acid, indicating the retained bioconversion ability of tazarotene encapsulated in nanoparticles.

Conclusion: Tazarotene-loaded PLGA nanoparticles were formulated, and the effect of formulation and processing variables on drug loading, encapsulation, particle size, and zeta potential of the nanoparticles was compared. Nanoparticles with particle size < 500 nm and narrow distribution showed the highest follicular and skin delivery of tazarotene and conversion to tazarotenic acid compared to passive control. The in vitro release study followed a non-Fickian diffusion pattern. Thus, the feasibility of developing a topical nanoparticle-based formulation of tazarotene to achieve higher follicular and skin delivery was demonstrated in this study.

References: 1. H. Chen, T.C. Zhang, X.L. Yin, J.Y. Man, X.R. Yang, M. Lu, Magnitude and temporal trend of acne vulgaris burden in 204 countries and territories from 1990 to 2019: an analysis from the Global Burden of Disease Study 2019, British Journal of Dermatology, Volume 186, Issue 4, 1 April 2022, Pages 673–683
2. AlQassimi S, AlBrashdi S, Galadari H, Hashim MJ. Global burden of psoriasis - comparison of regional and global epidemiology, 1990 to 2017. Int J Dermatol. 2020 May;59(5):566-571. doi: 10.1111/ijd.14864. Epub 2020 Apr 6. PMID: 32250451.

Acknowledgements: This project was funded by Merck KGaA, Frankfurter Str. 250, 64293 Darmstadt, Germany.


Figure 1: Schematic representing the overall objective, methodology of nanoparticle formation, characterization, in vitro release, and permeation testing


Figure 2: a) Table displaying a summary of formulation batches F1 to F7 of tazarotene-loaded PLGA nanoparticles along with the critical characterizations; b) In vitro release testing profile of F3 to F7 up to 36 h and c) total drug release observed from F3 to F7 batches. Statistical analysis was conducted using ordinary one-way ANOVA with Tukey’s multiple comparisons test. * Indicates p<0.05, ** indicates p<0.01.


Figure 3: a) Table denoting the values for receptor delivery, skin delivery, and the overall total delivery of tazarotene from F3 to F7 nanoparticle batches; b) graphical representation of follicular delivery c) delivery to stratum corneum and d) total skin delivery. Statistical analysis was conducted using ordinary one-way ANOVA with Dunnett’s multiple comparisons test. * Indicates p<0.05.