Polymeric Nanocapsules Containing Kojic Acid Dipalmitate and Rosehip Oil: Development and Evaluation of Preliminary Efficacy and Safety for Skin Whitening

Polymeric nanocapsules associated with kojic acid dipalmitate (KDP) and rosehip oil can be a strategy to obtain high-performance skin whitening/lightning formulations. Nanocapsules containing 0.1% of KDP and 5% of rosehip oil were developed with different polymers (Eudragit RS100, Eudragit S100, poly(ε-caprolactone) (PCL) and poly(d,l-lactide-co-glycolide) (PLGA)) to limit the contact of KDP with the external media and avoid its degradation. The nanocapsules had a diameter of less than 200 nm, with suitable size distribution, a pH range between 2.5 and 5.0, a KDP content of 0.9 mg/mL and an encapsulation efficiency above 99%. The zeta potential was positive for the Eudragit RS100 nanocapsules and negative for the other nanocapsules. The PLGA nanocapsules were selected due to better stability results, since there was no decay in KDP content after 180 days (refrigerated storage). The in vitro skin permeation assay showed that KDP reaches the epidermis. This formulation showed in vitro antioxidant activity through both the DPPH assay and the β-carotene/linoleic acid assay when used at 25 μg/mL of KDP, with higher activity than a kojic acid solution (KDP correspondent concentration) and, at 13.75 μg/mL, inhibited tyrosinase in vitro to 17%, significantly greater than the kojic acid solution. A 25% melanin reduction was obtained after normal human epidermal melanocytes (NHEM) were treated with 3.1 μg/mL of KDP. Cytocompatibility was observed after 24 h treatment with up to 6.25 μg/mL of the formulation in fibroblast-like cells (3T3-L1) and up to 3.1 μg/mL in NHEM. Therefore, PLGA nanocapsules containing KDP and rosehip oil have potential for use in skin whitening/lightning formulations.

Introduction

The interest in developing cosmetic formulations containing effective and safe bioactive compounds has increased, especially in regards to their stability, skin penetration and skin compatibility. (1) Kojic acid is an organic acid derived from fungi fermentation, such as Aspergillum and Penicillium, and it is widely studied for its skin whitening properties and its capacity to inhibit tyrosinase, the key enzyme in melanin synthesis. (2) However, its use is limited because of its low stability, sensitivity to light and heat, and oxidation. Additionally, adverse effects such as contact dermatitis and skin irritation have been reported. (3−5)

To overcome the limitations of kojic acid, kojic acid derivatives, such as kojic acid dipalmitate (KDP), appear to be promising alternatives. KDP is the esterified form of kojic acid, and it is stable to light and heat and in a wide pH range without suffering color alterations. (6,7) The KDP molecule is hydrolyzed by esterases located on the skin, releasing kojic acid in situ. (6) Due to KDP’s lipophilic characteristics, it may have increased affinity with the stratum corneum and thus greater cutaneous absorption. (3−5) KDP remains difficult to incorporate into aqueous formulations.

Rosehip oil is extracted from Rosa spp. seeds and is known for its skin regenerative properties, antioxidant, anti-inflammatory and skin whitening activities. (8,9) A serum containing rosehip oil was tested in a single-arm, open-label study and showed reduction in skin pigmentation in a time dependent manner, highlighting the potential of rosehip oil as a skin whitening agent. (10) This oil is rich in unsaturated fatty acids, phenolic compounds and transretinoic acid. (8,11,12) However, rosehip oil is easily oxidized. (12)

Nanotechnology has become an important technique in the development of high-performance and high-stability cosmetic formulations. Nanocarriers can be used to incorporate bioactive compounds, leading to a targeted delivery of active substances, improving skin penetration and protecting the active ingredients. (13) Polymeric nanocapsules are vesicular systems constituted by a polymeric wall that surrounds an aqueous or oily core. This type of nanocarrier can be used to incorporate lipophilic active substances, leading to protection of the active substances against chemical and physical degradation, to a controlled release of the substances, and to enhanced solubility, enabling their incorporation into aqueous vehicles. (14,15) Polymers such as Eudragit RS100, Eudragit S100, poly(ε-caprolactone) (PCL) and poly(d,l-lactide-co-glycolide) (PLGA) are frequently used in the synthesis of nanocapsules due to their barrier function and biocompatibility. (12,14,16−18)

The association of KDP and rosehip oil within a nanocarrier represents a promising strategy for the development of innovative cosmetic formulations with potential to overcome challenges related to stability and skin permeation. An oil-in-water nanoemulsion associating these two active ingredients has already been developed by our research group. (11) However, this system showed limited stability, as KDP underwent hydrolysis in the aqueous environment. (11) Other nanotechnological systems have already been proposed for the delivery of KDP, including nanoemulsions, (11,19,20) multiple emulsions, (6) liposomes, (21) ethosomes (7) and solid lipid nanoparticles. (22) To the best of our knowledge, polymeric nanocapsules containing KDP have not yet been described, and this nanocarrier may therefore represent a more stable and protective alternative for KDP delivery, limiting its contact with aqueous medium.

In view of the above, this investigation aimed at associating KDP and rosehip oil into polymeric nanocapsules, in order to obtain a high-performance and high-stability formulation. Different polymers were tested. The most promising formulation in terms of stability was also assayed regarding skin permeation, antioxidant and skin whitening performance, and cytocompatibility with skin cells.

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Materials

KDP was purchased from SM Empreendimentos Farmacêuticos Ltd.a. (São Paulo, Brazil), rosehip oil and caprylic/capric triglycerides were obtained from Delaware LTA (Porto Alegre, Brazil), and polysorbate 80 was obtained from Labsynth (Diadema, Brazil). Eudragit RS100 was kindly donated by Evonik (Essen, Germany), Eudragit S100 was obtained from Almapal S/A (São Paulo, Brazil), Poly(d,l-lactide-co-glycolide) 75/25 was obtained from Corbion (Amsterdam, Netherlands), and poly(ε-caprolactone) (number-average molecular mass, Mn 80,000) was obtained from Perstorp UK Limited (Warrington, England). Tetrahydrofuran (THF) was purchased from Química Moderna (Barueri, Brazil), and acetonitrile was purchased from J.T. Baker (Phillipsburg, NJ, USA). Methanol, 2,2-diphenyl-1-picrylhydrazyl (DPPH), betacarotene, linoleic acid and sorbitan monostearate were obtained from Sigma-Aldrich Brasil Ltd.a. (Cotia, Brazil). Tyrosinase (100 kU, 1560 U/mg, Worthington) was purchased from Sinapse biotecnologia (São Paulo, Brazil). The 3T3-L1 cell line was purchased from the Rio de Janeiro Cell Bank (BCRJ), Brazil. Fetal bovine serum (FBS) was purchased from Cripion (Andradina, SP, BR); phosphate-buffered saline (PBS) was purchased from Laborclin (São José do Rio Preto, SP, BR). Dulbecco’s Modified Eagle Medium (DMEM), 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), synthetic melanin, PBS, dimethyl sulfoxide (DMSO), penicillin/streptomycin, amphotericin, trypsin, and other reagents for cell culture were obtained from Sigma-Aldrich (St. Louis, MO, USA). All other chemicals or reagents were of analytical grade and used as received.

Polymeric Nanocapsules Containing Kojic Acid Dipalmitate and Rosehip Oil: Development and Evaluation of Preliminary Efficacy and Safety for Skin Whitening

Júlia Capp Zilles, Marya Alexandrina Vallenot Lemos, Larissa Pedron Duarte, Maria Paula Faccin Huth, Irene Clemes Kulkamp Guerreiro, Bonnie C. Carney, Aline Rigon Zimmer, and Renata Vidor Contri, ACS Omega Article ASAP, DOI: 10.1021/acsomega.5c08878