Nanotechnology-Enabled Strategies to Enhance Topical Bioavailability, 2nd Edition

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Nanomedicine and Nanotechnology".

Deadline for manuscript submissions: closed (20 October 2023) | Viewed by 20458

Special Issue Editors

Department of Pharmaceutical Technology, Faculty of Pharmacy, “Victor Babes” University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania
Interests: topical bioavailability; solid-state preformulation; nanoparticles
Special Issues, Collections and Topics in MDPI journals
Department of Pharmaceutical Physics, Faculty of Pharmacy, “Victor Babes” University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania
Interests: topical delivery; solid polymeric nanoparticles; nanomedicine
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The design and development of new topical formulations are trending topics, especially in the biomedical field, as they can be conceived to not only address protective and cosmetic needs, but also target therapeutic outcomes.

Because one of the main functions of human skin is protection—the skin acts as a barrier to the penetration of various external factors—the penetration of active substances through the skin is impaired, thus limiting their therapeutic potential. To overcome this, innovative strategies are required to increase skin permeability by means of penetration promoters.

In this regard, modern nanotechnology-based formulations are under development, such as derived liposomal formulations (transferosomes, ethosomes, cubosomes, nanostructured lipid carriers or other lipid-based nanocarriers), nanogels, nanoemulsions, cyclodextrin-based formulations and other modern approaches.

For the current Special Issue, original research and review articles addressing recent advances in nanopharmaceutical formulations with enhanced topical bioavailability and complex biological in vitro and/or in vivo profiles are welcomed.

Dr. Lenuţa Şuta
Dr. Claudia Geanina Watz
Guest Editors

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Keywords

  • nanotechnology-based formulations
  • drug-in nanocarriers
  • cyclodextrin-in nanocarriers
  • polymer-based nanocarriers
  • topical drug-delivery systems
  • bioavailability enhancement
  • drug release in vitro and in vivo
  • skin models
  • biological assessments

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Published Papers (10 papers)

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Research

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15 pages, 3933 KiB  
Article
Lipid-Based Nanosystems for the Topical Application of Ferulic Acid: A Comparative Study
by Maddalena Sguizzato, Francesca Ferrara, Markus Drechsler, Anna Baldisserotto, Leda Montesi, Stefano Manfredini, Giuseppe Valacchi and Rita Cortesi
Pharmaceutics 2023, 15(7), 1940; https://doi.org/10.3390/pharmaceutics15071940 - 12 Jul 2023
Cited by 2 | Viewed by 937
Abstract
In this study, we examined and compared two different lipid-based nanosystems (LBNs), namely Transferosomes (TFs) and Monoolein Aqueous Dispersions (MADs), as delivery systems for the topical application of Ferulic Acid (FA), an antioxidant molecule derived from natural sources. Our results, as demonstrated through [...] Read more.
In this study, we examined and compared two different lipid-based nanosystems (LBNs), namely Transferosomes (TFs) and Monoolein Aqueous Dispersions (MADs), as delivery systems for the topical application of Ferulic Acid (FA), an antioxidant molecule derived from natural sources. Our results, as demonstrated through Franz-cell experiments, indicate that the LBNs produced with poloxamer 188 in their composition create a multilamellar system. This system effectively controls the release of the drug. Nonetheless, we found that the type of non-ionic surfactant can impact the drug release rate. Regarding FA diffusion from the MAD, this showed a lower diffusion rate compared with the TF. In terms of an in vivo application, patch tests revealed that all LBN formulations tested were safe when applied under occlusive conditions for 48 h. Additionally, human skin biopsies were used to determine whether FA-containing formulations could influence skin tissue morphology or provide protection against O3 exposure. Analyses suggest that treatment with TFs composed of poloxamer 188 and MAD formulations might protect against structural skin damage (as observed in hematoxylin/eosin staining) and the development of an oxidative environment (as indicated by 4-hyroxinonenal (4HNE) expression levels) induced by O3 exposure. In contrast, formulations without the active ingredient did not offer protection against the detrimental effects of O3 exposure.Inizio modulo. Full article
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11 pages, 2104 KiB  
Article
Polymeric Nanoparticles’ Accumulation in Atopic Dermatitis: Clinical Comparison between Healthy, Non-Lesional, and Lesional Skin
by Céline Try, Mona M. A. Abdel-Mottaleb, Arnaud Béduneau, Brice Moulari, Lionel Pazart, Chrystelle Vidal, Gaëlle Brunotte, Florence Castelain, Alf Lamprecht, Philippe Humbert and Yann Pellequer
Pharmaceutics 2023, 15(7), 1927; https://doi.org/10.3390/pharmaceutics15071927 - 11 Jul 2023
Cited by 1 | Viewed by 1236
Abstract
A major limitation in the current topical treatment strategies for inflammatory skin disorders is the inability to selectively target the inflamed site with minimal exposure of healthy skin. Atopic dermatitis is one of the most prevalent types of dermatitis. The use of polymeric [...] Read more.
A major limitation in the current topical treatment strategies for inflammatory skin disorders is the inability to selectively target the inflamed site with minimal exposure of healthy skin. Atopic dermatitis is one of the most prevalent types of dermatitis. The use of polymeric nanoparticles for targeting inflamed skin has been recently proposed, and therefore the aim of this proof-of-concept clinical study was to investigate the skin penetration and deposition of polymeric biodegradable nanoparticles in the atopic dermatitis lesions and compare the data obtained to the deposition of the particles into the healthy skin or lesion-free skin of the atopic dermatitis patients. For that, fluorescent PLGA nanoparticles in sizes of approximately 100 nm were prepared and applied to the skin of healthy volunteers and the lesional and non-lesional skin of atopic dermatitis patients. Skin biopsies were examined using confocal laser scanning microscopy to track the skin deposition and depth of penetration of the particles. Immunohistochemistry was performed to investigate the alteration in tight-junction protein distribution in the different types of skin. Results have shown that nanoparticles were found to have higher deposition into the atopic dermatitis lesions with minimal accumulation in healthy or non-lesional skin. This has been primarily correlated with the impaired barrier properties of atopic dermatitis lesions with the reduced production of Claudin-1. It was concluded that polymeric nanoparticles offer a potential tool for selective drug delivery to inflamed skin with minimal exposure risk to healthy skin. Full article
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21 pages, 5666 KiB  
Article
Synthesis, Characterization, and In Vitro Cytotoxicity Evaluation of Doxorubicin-Loaded Magnetite Nanoparticles on Triple-Negative Breast Cancer Cell Lines
by Jano Markhulia, Shalva Kekutia, Vladimer Mikelashvili, Liana Saneblidze, Tamar Tsertsvadze, Nino Maisuradze, Nino Leladze, Zsolt Czigány and László Almásy
Pharmaceutics 2023, 15(6), 1758; https://doi.org/10.3390/pharmaceutics15061758 - 17 Jun 2023
Cited by 5 | Viewed by 1773
Abstract
In this study, we investigated the cytotoxicity of doxorubicin (DOX)-loaded magnetic nanofluids on 4T1 mouse tumor epithelial cells and MDA-MB-468 human triple-negative breast cancer (TNBC) cells. Superparamagnetic iron oxide nanoparticles were synthesized using sonochemical coprecipitation by applying electrohydraulic discharge treatment (EHD) in an [...] Read more.
In this study, we investigated the cytotoxicity of doxorubicin (DOX)-loaded magnetic nanofluids on 4T1 mouse tumor epithelial cells and MDA-MB-468 human triple-negative breast cancer (TNBC) cells. Superparamagnetic iron oxide nanoparticles were synthesized using sonochemical coprecipitation by applying electrohydraulic discharge treatment (EHD) in an automated chemical reactor, modified with citric acid and loaded with DOX. The resulting magnetic nanofluids exhibited strong magnetic properties and maintained sedimentation stability in physiological pH conditions. The obtained samples were characterized using X-ray diffraction (XRD), transmission electron microscopy (TEM), Fourier-transform infrared spectroscopy, UV-spectrophotometry, dynamic light scattering (DLS), electrophoretic light scattering (ELS), vibrating sample magnetometry (VSM), and transmission electron microscopy (TEM). In vitro studies using the MTT method revealed a synergistic effect of the DOX-loaded citric-acid-modified magnetic nanoparticles on the inhibition of cancer cell growth and proliferation compared to treatment with pure DOX. The combination of the drug and magnetic nanosystem showed promising potential for targeted drug delivery, with the possibility of optimizing the dosage to reduce side-effects and enhance the cytotoxic effect on cancer cells. The nanoparticles’ cytotoxic effects were attributed to the generation of reactive oxygen species and the enhancement of DOX-induced apoptosis. The findings suggest a novel approach for enhancing the therapeutic efficacy of anticancer drugs and reducing their associated side-effects. Overall, the results demonstrate the potential of DOX-loaded citric-acid-modified magnetic nanoparticles as a promising strategy in tumor therapy, and provide insights into their synergistic effects. Full article
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39 pages, 13735 KiB  
Article
10-Hydroxy Decanoic Acid-Based Vesicles as a Novel Topical Delivery System: Would It Be a Better Platform Than Conventional Oleic Acid Ufasomes for Skin Cancer Treatment?
by Bassant Atef, Rania A. H. Ishak, Sabry S. Badawy and Rihab Osman
Pharmaceutics 2023, 15(5), 1461; https://doi.org/10.3390/pharmaceutics15051461 - 11 May 2023
Cited by 1 | Viewed by 1882
Abstract
10-hydroxy decanoic acid (HDA), a naturally derived fatty acid, was used for the preparation of novel fatty acid vesicles for comparison with oleic acid (OA) ufasomes. The vesicles were loaded with magnolol (Mag), a potential natural drug for skin cancer. Different formulations were [...] Read more.
10-hydroxy decanoic acid (HDA), a naturally derived fatty acid, was used for the preparation of novel fatty acid vesicles for comparison with oleic acid (OA) ufasomes. The vesicles were loaded with magnolol (Mag), a potential natural drug for skin cancer. Different formulations were prepared using the thin film hydration method and were statistically evaluated according to a Box–Behnken design in terms of particle size (PS), polydispersity index (PDI), zeta potential (ZP), and entrapment efficiency (EE). The ex vivo skin permeation and deposition were assessed for Mag skin delivery. In vivo, an assessment of the optimized formulae using 7,12-dimethylbenz[a]anthracene (DMBA)-induced skin cancer in mice was also conducted. The PS and ZP of the optimized OA vesicles were 358.9 ± 3.2 nm and −82.50 ± 7.13 mV compared to 191.9 ± 6.28 nm and −59.60 ± 3.07 mV for HDA vesicles, respectively. The EE was high (>78%) for both types of vesicles. Ex vivo permeation studies revealed enhanced Mag permeation from all optimized formulations compared to a drug suspension. Skin deposition demonstrated that HDA-based vesicles provided the highest drug retention. In vivo, studies confirmed the superiority of HDA-based formulations in attenuating DMBA-induced skin cancer during treatment and prophylactic studies. Full article
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21 pages, 3045 KiB  
Article
Nanoencapsulation of Methylene-Blue for Enhanced Skin Cancer Cell Phototoxicity and Cutaneous Penetration in Association with Sonophoresis
by Thayane Soares Lima, Monalisa Sthefani Silva de Oliveira, Alice Vitoria Frota Reis, Raquel Petrilli and Josimar O. Eloy
Pharmaceutics 2023, 15(5), 1371; https://doi.org/10.3390/pharmaceutics15051371 - 29 Apr 2023
Cited by 1 | Viewed by 2138
Abstract
Photodynamic therapy (PDT) using methylene blue (MB) as a photosensitizer has emerged as an alternative treatment for skin cancers, such as squamous cell carcinoma (SCC). To increase the cutaneous penetration of the drug, some strategies are used, such as the association of nanocarriers [...] Read more.
Photodynamic therapy (PDT) using methylene blue (MB) as a photosensitizer has emerged as an alternative treatment for skin cancers, such as squamous cell carcinoma (SCC). To increase the cutaneous penetration of the drug, some strategies are used, such as the association of nanocarriers and physical methods. Thus, herein we address the development of nanoparticles based on poly-Ɛ-caprolactone (PCL), optimized with the Box–Behnken factorial design, for topical application of MB associated with sonophoresis. The MB-nanoparticles were developed using the double emulsification-solvent evaporation technique and the optimized formulation resulted in an average size of 156.93 ± 8.27 nm, a polydispersion index of 0.11 ± 0.05, encapsulation efficiency of 94.22 ± 2.19% and zeta potential of −10.08 ± 1.12 mV. Morphological evaluation by scanning electron microscopy showed spherical nanoparticles. In vitro release studies show an initial burst compatible with the first-order mathematical model. The nanoparticle showed satisfactory generation of reactive oxygen species. The MTT assay was used to assess cytotoxicity and IC50; values of 79.84; 40.46; 22.37; 9.90 µM were obtained, respectively, for the MB-solution and the MB-nanoparticle without and with light irradiation after 2 h of incubation. Analysis using confocal microscopy showed high cellular uptake for the MB-nanoparticle. With regard to skin penetration, a higher concentration of MB was observed in the epidermis + dermis, corresponding to 9.81, 5.27 μg/cm2 in passive penetration and 24.31 and 23.81 μg/cm2 after sonophoresis, for solution-MB and nanoparticle-MB, respectively. To the best of our knowledge, this is the first report of MB encapsulation in PCL nanoparticles for application in skin cancer using PDT. Full article
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19 pages, 7259 KiB  
Article
Combined Nanofibrous Face Mask: Co-Formulation of Lipases and Antibiotic Agent by Electrospinning Technique
by Diána Balogh-Weiser, Alexandra Molnár, Gergő D. Tóth, Gábor Koplányi, József Szemes, Balázs Decsi, Gábor Katona, Maryana Salamah, Ferenc Ender, Anita Kovács, Szilvia Berkó, Mária Budai-Szűcs and György T. Balogh
Pharmaceutics 2023, 15(4), 1174; https://doi.org/10.3390/pharmaceutics15041174 - 07 Apr 2023
Cited by 2 | Viewed by 1781
Abstract
The application of enzyme-based therapies has received significant attention in modern drug development. Lipases are one of the most versatile enzymes that can be used as therapeutic agents in basic skin care and medical treatment related to excessive sebum production, acne, and inflammation. [...] Read more.
The application of enzyme-based therapies has received significant attention in modern drug development. Lipases are one of the most versatile enzymes that can be used as therapeutic agents in basic skin care and medical treatment related to excessive sebum production, acne, and inflammation. The traditional formulations available for skin treatment, such as creams, ointments or gels, are widely applied; however, their use is not always accompanied by good drug penetration properties, stability, or patient adherence. Nanoformulated drugs offer the possibility of combining enzymatic and small molecule formulations, making them a new and exciting alternative in this field. In this study polymeric nanofibrous matrices made of polyvinylpyrrolidone and polylactic acid were developed, entrapping lipases from Candida rugosa and Rizomucor miehei and antibiotic compound nadifloxacin. The effect of the type of polymers and lipases were investigated, and the nanofiber formation process was optimized to provide a promising alternative in topical treatment. Our experiments have shown that entrapment by electrospinning induced two orders of magnitude increase in the specific enzyme activity of lipases. Permeability investigations indicated that all lipase-loaded nanofibrous masks were capable of delivering nadifloxacin to the human epidermis, confirming the viability of electrospinning as a formulation method for topical skin medications. Full article
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18 pages, 4392 KiB  
Article
Myricetin Nanofibers Enhanced Water Solubility and Skin Penetration for Increasing Antioxidant and Photoprotective Activities
by Tzu-Ching Lin, Chun-Yin Yang, Tzu-Hui Wu, Chih-Hua Tseng and Feng-Lin Yen
Pharmaceutics 2023, 15(3), 906; https://doi.org/10.3390/pharmaceutics15030906 - 10 Mar 2023
Cited by 3 | Viewed by 1833
Abstract
Excessive exposure to ultraviolet radiation (UV) can induce oxidative stress through the over-production of reactive oxygen species (ROS) on the skin. Myricetin (MYR), a natural flavonoid compound, significantly inhibited UV-induced keratinocyte damage; however, its bioavailability is limited by its poor water solubility and [...] Read more.
Excessive exposure to ultraviolet radiation (UV) can induce oxidative stress through the over-production of reactive oxygen species (ROS) on the skin. Myricetin (MYR), a natural flavonoid compound, significantly inhibited UV-induced keratinocyte damage; however, its bioavailability is limited by its poor water solubility and inefficient skin penetration ability, which subsequently influences its biological activity. The purpose of the study was to develop a myricetin nanofibers (MyNF) system of hydroxypropyl-β-cyclodextrin (HPBCD)/polyvinylpyrrolidone K120 (PVP)-loaded with MYR that would enhance the water solubility and skin penetration by changing the physicochemical characteristics of MYR, including reducing the particle size, increasing the specific surface area, and amorphous transformation. The results also revealed that the MyNF can reduce cytotoxicity in HaCaT keratinocytes when compared with MYR; additionally, MyNF had better antioxidant and photoprotective activity than raw MYR for the UVB-induced HaCaT keratinocytes damage model due to the MyNF increased water solubility and permeability. In conclusion, our results demonstrate that MyNF is a safe, photostable, and thermostable topical ingredient of antioxidant nanofibers to enhance the skin penetration of MYR and prevent UVB-induced skin damage. Full article
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19 pages, 6559 KiB  
Article
Boosting the In Vivo Transdermal Bioavailability of Asenapine Maleate Using Novel Lavender Oil-Based Lipid Nanocapsules for Management of Schizophrenia
by Fatma Sa’eed El-Tokhy, Mona M. A. Abdel-Mottaleb, Sherif S. Abdel Mageed, Abdulla M. A. Mahmoud, Elsayed A. El-Ghany and Ahmed S. Geneidi
Pharmaceutics 2023, 15(2), 490; https://doi.org/10.3390/pharmaceutics15020490 - 01 Feb 2023
Cited by 2 | Viewed by 1877
Abstract
Lipid nanocapsules (LNCs) are promising for transdermal drug delivery due to their higher permeability-enhancing effects compared to polymeric nanoparticles. Lavender oil is an essential oil consisting of several terpenes (primarily linalool and linalyl acetate) known for their profound permeation-enhancing action. In the present [...] Read more.
Lipid nanocapsules (LNCs) are promising for transdermal drug delivery due to their higher permeability-enhancing effects compared to polymeric nanoparticles. Lavender oil is an essential oil consisting of several terpenes (primarily linalool and linalyl acetate) known for their profound permeation-enhancing action. In the present work, we successfully encapsulated asenapine maleate (a second-generation antipsychotic that is highly metabolized by the liver, reducing its oral bioavailability) into biocompatible LNCs for transdermal application using a novel oily phase, i.e., lavender oil (LO-LNCs). A comparative study was conducted to determine the effects of different oily phases (i.e., Miglyol® 812, Labrafil® M1944CS, and Labrafac™ PG) on the LNCs. Surfactant types (Kolliphor® HS15, Kolliphor® EL and Tween80) and oil:surfactant ratios were studied. Blank and asenapine-loaded LNCs were optimized for particle size, polydispersity index, zeta potential, drug content and ex vivo skin permeation. Lavender oil and Labrafil® showed smaller vesicular sizes, while LO-LNCs increased the permeation of ASP across rat skin. In vivo pharmacokinetics revealed that LO-LNCs could increase the ASP Cmax via transdermal application by fourfold compared to oral suspension. They increased the bioavailability of ASP by up to 52% and provided sustained release for three days. The pharmacokinetic profile of the LO-LNCs was compared to ASP-loaded invasomes (discussed in a previous study) to emphasize LNCs’ transdermal delivery behavior. Full article
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Review

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24 pages, 3430 KiB  
Review
An Overview of Nanoemulgels for Bioavailability Enhancement in Inflammatory Conditions via Topical Delivery
by Diwya Kumar Lal, Bhavna Kumar, Abdulaziz S. Saeedan and Mohd Nazam Ansari
Pharmaceutics 2023, 15(4), 1187; https://doi.org/10.3390/pharmaceutics15041187 - 07 Apr 2023
Cited by 6 | Viewed by 2796
Abstract
The anti-inflammatory drugs that are generally available possess the disadvantage of hydrophobicity, which leads to poor permeability and erratic bioavailability. Nanoemulgels (NEGs) are novel drug delivery systems that aim to improve the solubility and permeability of drugs across the biological membrane. The nano-sized [...] Read more.
The anti-inflammatory drugs that are generally available possess the disadvantage of hydrophobicity, which leads to poor permeability and erratic bioavailability. Nanoemulgels (NEGs) are novel drug delivery systems that aim to improve the solubility and permeability of drugs across the biological membrane. The nano-sized droplets in the nanoemulsion enhance the permeation of the formulation, along with surfactants and co-surfactants that act as permeation enhancers and can further improve permeability. The hydrogel component of NEG helps to increase the viscosity and spreadability of the formulation, making it ideal for topical application. Moreover, oils that have anti-inflammatory properties, such as eucalyptus oil, emu oil and clove oil, are used as oil phases in the preparation of the nanoemulsion, which shows a synergistic effect with active moiety and enhances its overall therapeutic profile. This leads to the creation of hydrophobic drugs that possess enhanced pharmacokinetic and pharmacodynamic properties, and simultaneously avoid systemic side effects in individuals with external inflammatory disorders. The nanoemulsion’s effective spreadability, ease of application, non-invasive administration, and subsequent ability to achieve patient compliance make it more suitable for topical application in the combat of many inflammatory disorders, such as dermatitis, psoriasis, rheumatoid arthritis, osteoarthritis and so on. Although the large-scale practical application of NEG is limited due to problems regarding its scalability and thermodynamic instability, which arise from the use of high-energy approaches during the production of the nanoemulsion, these can be resolved by the advancement of an alternative nanoemulsification technique. Considering the potential advantages and long-term benefits of NEGs, the authors of this paper have compiled a review that elaborates the potential significance of utilizing nanoemulgels in a topical delivery system for anti-inflammatory drugs. Full article
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24 pages, 2245 KiB  
Review
Can Essential Oils/Botanical Agents Smart-Nanoformulations Be the Winning Cards against Psoriasis?
by Mohamed Ashraf, Hossam S. El-Sawy, Ghada M. El Zaafarany and Mona M. A. Abdel-Mottaleb
Pharmaceutics 2023, 15(3), 750; https://doi.org/10.3390/pharmaceutics15030750 - 23 Feb 2023
Cited by 2 | Viewed by 3272
Abstract
Although psoriasis remains one of the most devastating inflammatory disorders due to its huge negative impact on patients’ quality of life, new “green” treatment approaches still need to be fully explored. The purpose of this review article is to focus on the utilization [...] Read more.
Although psoriasis remains one of the most devastating inflammatory disorders due to its huge negative impact on patients’ quality of life, new “green” treatment approaches still need to be fully explored. The purpose of this review article is to focus on the utilization of different essential oils and active constituents of herbal botanical origin for the treatment of psoriasis that proved efficacious via both in vitro and in vivo models. The applications of nanotechnology-based formulations which displayed great potential in augmenting the permeation and delivery of these agents is also addressed. Numerous studies have been found which assessed the potential activity of natural botanical agents to overcome psoriasis. Nano-architecture delivery is applied in order to maximize the benefits of their activity, improve properties, and increase patient compliance. This field of natural innovative formulations can be a promising tool to optimize remediation of psoriasis while minimizing adverse effects. Full article
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