Original Article
‬‬‬‬‬‬‬‬Development and characterization of polymeric nanoparticle-based formulation of adapalene for topical acne therapy‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬

https://doi.org/10.1016/j.nano.2016.08.008Get rights and content

Abstract

The purpose of this study is to develop a new formulation of adapalene for the topical treatment of acne. We investigated applicability of polymeric nanocarriers based on tyrosine-derived nanospheres (TyroSpheres) for adapalene delivery. TyroSpheres effectively encapsulated adapalene and substantially enhanced its aqueous solubility, while decreasing the crystallinity of the drug in the formulation. Skin distribution of adapalene via TyroSphere formulation was evaluated ex vivo using human cadaver and porcine ear skin, and this was compared with the commercial adapalene formulation, Differin®. Sustained drug release across stratum corneum in 51 h was observed from TyroSpheres. Additionally, in vitro skin irritation studies demonstrated that encapsulation of adapalene in TyroSpheres significantly reduced the irritancy of the drug to monolayer HaCaTs and reconstituted human epidermis (EpiDerm™, MatTek Corp.). The results suggest that TyroSpheres provide a promising carrier system to deliver hydrophobic drugs to hair follicles and upper epidermis while minimizing skin irritation of the encapsulated drug.

Graphical Abstract

An aqueous formulation based on tyrosine-derived nanospheres (TyroSpheres) was developed for topical delivery of adapalene, a comedolytic agent used in treatment of early stages of acne. Ex vivo skin distribution studies confirmed that TyroSpheres can enhance delivery of adapalene to upper skin layers and pilosebaceous unit, where acne originates. In vitro skin irritation studies showed that this new formulation of adapalene is less irritant compared to the commercial adapalene formulation.

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Section snippets

Preparation and characterizations of adapalene-TyroSphere formulations

ABA triblock copolymer PEG5K-b-oligo(desaminotyrosyl-tyrosine octyl ester suberate)-b-PEG5K was used for the preparation of TyroSpheres. Adapalene-TyroSpheres and empty TyroSpheres (without drug) were prepared and purified by methods described previously.20, 21 The Nile Red-TyroSphere formulation was prepared as described previously,19, 20, 21, 22 using Nile Red TyroSphere ratio of 1:300 (w/w).

For characterization (see supplementary materials), the size and size distribution of

Adapalene-TyroSpheres: characterization of the liquid formulation

Due to its amphiphilic nature, PEG5K-b-oligo(DTO-SA)-b-PEG5K can self-assemble to form micellar-like spherical-shaped nanocarriers (TyroSpheres) in aqueous media and encapsulate hydrophobic drugs. Table 1 provides the solubility of adapalene in PBS either as loaded in the TyroSpheres or supplemented with various concentrations of Tween 80. Adapalene aqueous solubility in plain PBS pH 7.4 was below HPLC detection limit (10 ng/ml). The maximum solubility in 3% TyroSphere dispersion was

Discussion

Adapalene is a topical synthetic retinoid analog with anti-inflammatory properties that normalize differentiation of follicular epithelial cells.29 Adapalene is practically insoluble in aqueous media and possesses low solubility in many vehicles that make it very challenging to formulate. Topical application of retinoids can generate an adverse effect known as retinoid reaction, which is also reported at lower extend with adapalene commercial gel, Differin®.13 In Differin®, the drug exists in

References (44)

  • DJ Davies et al.

    Multi-species assessment of electrical resistance as a skin integrity marker for in vitro percutaneous absorption studies

    Toxicol In Vitro

    (2004)
  • A Teichmann et al.

    Differential stripping: determination of the amount of topically applied substances penetrated into the hair follicles

    J Invest Dermatol

    (2005)
  • A Lauterbach et al.

    Development, formulation, and characterization of an adapalene-loaded solid lipid microparticle dispersion for follicular penetration

    Int J Pharm

    (2014)
  • J Shaikh et al.

    Nanoparticle encapsulation improves oral bioavailability of curcumin by at least 9-fold when compared to curcumin administered with piperine as absorption enhancer

    Eur J Pharm Sci

    (2009)
  • AS Raber et al.

    Quantification of nanoparticle uptake into hair follicles in pig ear and human forearm

    J Control Release

    (2014)
  • J Lademann et al.

    Nanoparticles – an efficient carrier for drug delivery into the hair follicles

    Eur J Pharm Biopharm

    (2007)
  • GA Castro et al.

    Formation of ion pairing as an alternative to improve encapsulation and stability and to reduce skin irritation of retinoic acid loaded in solid lipid nanoparticles

    Int J Pharm

    (2009)
  • H Schaefer et al.

    Skin permeability

    (1982)
  • R Agarwal et al.

    The pilosebaceous unit: a pivotal route for topical drug delivery

    Methods Find Exp Clin Pharmacol

    (2000)
  • P Desai et al.

    Interaction of nanoparticles and cell-penetrating peptides with skin for transdermal drug delivery

    Mol Membr Biol

    (2010)
  • D Papakostas et al.

    Nanoparticles in dermatology

    Arch Dermatol Res

    (2011)
  • JP Ryman-Rasmussen et al.

    Penetration of intact skin by quantum dots with diverse physicochemical properties

    Toxicol Sci

    (2006)
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