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Nanostructured systems of thymol for dermatological and topical treatments

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Universitat de Barcelona. Facultat de Farmàcia i Ciències de l'Alimentació

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[eng] The skin is major organ of the human body, and its function is to protect the internal tissue from environmental changes, maintains the body temperature and avoid penetration of contaminants. Therefore, the skin barrier is highly impermeant and it the major challenge for most of compound to be administered dermally. Moreover, the skin possesses resident microbiota, which perform several roles in the skin functionality, more specifically, maintain the sebum levels, the acid pH and protect the skin against other pathogenic microorganism. The healthy skin is a result of an equilibrium of resident microbiota. Their unbalanced proliferation may lead to skin disorders such as infection and inflammation, either caused by internal disfunction or external contaminants. Antimicrobial actives from natural source, such as plant material, are a promoting approach for the treatment of skin infection, should be considered to avoid antibiotic class of drug, which along the treatment normally lead to microbial resistance.
Natural products are the most favourable active types, since they may not develop side effects, and in the case of antimicrobial agents, they are unlikely to lead to microbial resistance, as most of the antibiotic class of drugs. Plant material are suitable choices, due to their high content of antioxidant compounds, which most of them are phenolic aromatic molecules, which normally possess antimicrobial and anti-inflammatory activities, the key treatment requirement for skin infections.
Thymol (TH), is a multifunctional monoterpene of aromatic phenolic structure, found naturally occurring in plant extracts or on its white crystalline synthetic form. The effects of TH are largely attributed to its antioxidant properties, via free radical scavenging thus enhancing endogenous antioxidant activities and chelation of metal ions.
Nanostructured systems, such as polymeric and lipid nanoparticles, may contribute as a novelty approach for management of skin diseases. Nanotechnology offers several advantages to improve active compounds bioavailability after topical administration, since small particle diameters tend to penetrate the deep skin, withdraw the drug in a controlled manner and be mainly retained in the deeper layers. Moreover, they constitute an excellent potential candidate in skin disorders, especially for acne treatment, due to their ability to penetrate inside the follicle and provide for long-term release of actives inside the lesions.
According to the above, the main objective of this work was the development and characterization of polymeric and lipid nanostructured systems containing TH for the treatment of skin infections, mainly focused to the acne. The study consisted of varied surface composition of the nanosystem, in other to enhance the therapeutic efficacy of this novel approach.
 
Polymeric and lipid nanoparticles of thymol provided suitable physicochemical morphometry, sustained release, and slow-rate penetration of TH into the hair follicle, being highly retained inside the skin. The therapeutical efficacy was achieved with good results as antimicrobial activity against Cutibacterium acnes and minor effect towards Staphylococcus epidermis, the major resident of the healthy skin microbiota. Moreover, the development of surface-modified polymeric NPs with thymol performed enhanced in vitro anti-inflammatory, antioxidant, and wound healing activities in human keratinocyte cells (HaCaT). Moreover, semi-solid formulations with the nanosystem incorporated had proven to diminish the trans-epidermal water loss due to the film-forming developed on the skin surface. Sebum reduction activity was also recorded in oily skin, presenting outstanding results.
To conclude, nanostructured systems of thymol provided good antimicrobial activity for acne treatment without affecting the healthy skin microbiota. The surface-modification of TH-NPs had proven to be suitable to be used as anti-inflammatory, antioxidant, and wound healing agents, constituting a promising therapy for treating acne infection and associated inflammation. According to the results obtained, the nanostructured systems of thymol and the semi-solid formulations which they were incorporated, demonstrated an outstanding strategy for skin disorders, being considered a novelty approach as a natural treatment of acne. These formulations could be useful for daily application as a complement with other cosmetic and personal hygiene products, for prevention or treatment of also other microbial skin infections.

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[spa] La piel es el órgano principal del cuerpo humano, y su función es proteger el tejido interno de los cambios ambientales, mantiene la temperatura corporal y evita la penetración de contaminantes. Además, la piel pose microbiota residente, que desempeña diversas funciones como mantener los niveles de sebo, regular el pH y proteger la piel contra otros microorganismos patógenos. La piel sana es el resultado de un equilibrio del microbiota residente. Su proliferación desequilibrada puede provocar trastornos de la piel como infecciones e inflamación.
Los productos naturales son los tipos activos más favorables, ya que no desarrollan efectos secundarios o resistencia microbiana, como ocurre con los antibióticos. El timol (TH), es un monoterpeno multifuncional, que se encuentra de forma natural en extractos de plantas o en su forma sintética cristalina blanca. Los efectos de la TH se atribuyen en gran medida a sus propiedades antioxidantes.
Los sistemas nanoestructurados, como las nanopartículas poliméricas y lipídicas, pueden contribuir como un enfoque novedoso para el manejo de enfermedades de la piel. La nanotecnología ofrece varias ventajas para mejorar la penetración en la piel profunda, liberación controlada del activo y capacidad de retenerse en las capas más profundas.
El objetivo principal de este trabajo fue el desarrollo y caracterización de sistemas nanoestructurados poliméricos y lipídicos que contienen TH para el tratamiento de infecciones cutáneas. La eficacia terapéutica se logró con buenos resultados como actividad antimicrobiana contra Cutibacterium acnes y efecto menor contra Staphylococcus epidermis, el principal residente de la microbiota cutánea sana. Además, la modificación de la superficie de las nanopartículas ha potencializado los efectos antiinflamatorias, antioxidantes y cicatrizantes realizadas in vitro en células de queratinocitos humanos (HaCaT). Además, las formulaciones han demostrado disminuyen la pérdida de agua trans-epidérmica actividad reductora del sebo.
Para concluir, los sistemas nanoestructurados de timol proporcionaron una buena actividad antimicrobiana para el tratamiento del acné sin afectar el microbiota de la piel sana, como también adecuada para su uso como agentes antiinflamatorios, antioxidantes y cicatrizantes, lo que constituye una terapia prometedora para tratar la infección por acné y la inflamación asociada. De acuerdo con los resultados obtenidos, los sistemas nanoestructurados de timol se consideran un enfoque novedoso como tratamiento natural del acné.

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Tesis Doctorals - Facultat - Farmàcia i Ciències de l'Alimentació

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Nanostructured systems of thymol for dermatological and topical treatments