Nanoemulsion strategy of pioglitazone for the treatment of skin inflammatory diseases.

Pioglitazone (PGZ) is a peroxisome proliferator-activated receptor agonist. Its role in the inflammatory response modulation paves the way for additional therapeutic applications. The purpose of this study was to develop a pioglitazone nanoemulsion (PGZ-NE) in order to investigate its anti-inflammatory efficacy on the skin. To that end, an NE vehicle developed for skin delivery was optimized and characterized. The resulting PGZ-NE showed good anti-inflammatory efficacy by decreasing the expression of inflammatory cytokines IL-6, IL-1ß and TNF-α. The properties of the developed nanocarrier allowed achievement of a high permeation flux of PGZ through the skin as well as a high retained amount in the skin, likely due to the depot effect of ingredients, which assured a prolonged local action, with good skin tolerability among participating individuals. Consequently, these results suggest that PGZ-NE may be used as an alternative treatment for inflammatory skin diseases such as rosacea, atopic dermatitis or psoriasis.

Multifunctional Serine Protease Inhibitor-Coated Water-Soluble Gold Nanoparticles as a Novel Targeted Approach for the Treatment of Inflammatory Skin Diseases.

The overexpression and increased activity of the serine protease Kallikrein 5 (KLK5) is characteristic of inflammatory skin diseases such as Rosacea. The use of inhibitors of this enzyme-such as 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride (AEBSF·HCl) or the anti-human recombinant Kallikrein 5 (anti-KLK5) antibody-in the treatment of the disease has been limited due to their low bioavailability, for which their immobilization in drug delivery agents can contribute to making serine protease inhibitors clinically useful. In this work, we synthesized gold nanoparticles (GNP) coated with a mixture of hydroxyl- and carboxyl-terminated thiolates (GNP.OH/COOH), whose carboxyl groups were used to further functionalize the nanoparticles with the serine protease inhibitor AEBSF·HCl either electrostatically or covalently (GNP.COOH AEBSF and GNP.AEBSF, respectively), or with the anti-KLK5 antibody (GNP.antiKLK5). The synthesized and functionalized GNP were highly water-soluble, and they were extensively characterized using UV-vis absorption spectroscopy, Transmission Electron Microscopy (TEM), Dynamic Light Scattering (DLS), and Thermogravimetric Analysis (TGA). GNP.OH/COOH and their subsequent functionalizations effectively inhibited KLK5 in vitro. Internalization of fluorophore-coated GNP.OH/COOH in human keratinocytes (HaCaT cells) was proven using confocal fluorescence microscopy. Cell viability assays revealed that the cytotoxicity of free AEBSF is importantly decreased when it is incorporated in the nanoparticles, either ionically (GNP.COOH AEBSF) or, most importantly, covalently (GNP.AEBSF). The functionalized nanoparticles GNP.AEBSF and GNP.antiKLK5 inhibited intracellular KLK5 activity in HaCaT cells and diminished secretion of IL-8 under inflammatory conditions triggered by TLR-2 ligands. This study points to the great potential of these GNP as a new intracellular delivery strategy for both small drugs and antibodies in the treatment of skin diseases such as Rosacea.

Neoplastic Multifocal Skin Lesions: Biology, Etiology, and Targeted Therapies for Nonmelanoma Skin Cancers.

Neoplastic skin lesions are multifocal, diffuse skin infiltrations of particular relevance in the differential diagnosis of ulcerative, nodular, or crusting skin lesions. Nonmelanoma skin cancers (NMSCs), namely, basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and also actinic keratosis (AK), are the most common malignant tumors in humans. BCCs do not proliferate rapidly and most of the times do not metastasize, while SCCs are more infiltrative, metastatic, and destructive. AKs are precursor lesions of cutaneous SCCs. The classical therapy of NMSCs makes use of photodynamic therapy associated with chemotherapeutics. With improved understanding of the pathological mechanisms of tumor initiation, progression, and differentiation, a case is made towards the use of targeted chemotherapy with the intent to reduce the cytotoxicity of classical treatments. The present review aims to describe the current state of the art on the knowledge of NMSC, including its risks factors, oncogenes, and skin carcinogenesis, discussing the classical therapy against new therapeutic options.

Developing Transdermal Applications of Ketorolac Tromethamine Entrapped in Stimuli Sensitive Block Copolymer Hydrogels.

PURPOSE: In order to obtain dermal vehicles of ketorolac tromethamine (KT) for the local treatment of inflammation and restrict undesirable side effects of systemic levels hydrogels (HGs) of poloxamer and carbomer were developed. METHODS: KT poloxamer based HG (KT-P407-HG) and KT carbomer based HG (KT-C940-HG) were elaborated and characterized in terms of swelling, degradation, porosity, rheology, stability, in vitro release, ex vivo permeation and distribution skin layers. Finally, in vivo anti-inflammatory efficacy and skin tolerance were also assessed. RESULTS: HGs were transparent and kept stable after 3 months exhibiting biocompatible near neutral pH values. Rheological patterns fitted to Herschel-Bulkley for KT-C940-HG and Newton for KT-P407-HG due to its low viscosity at 25°C. Rapid release profiles were observed through first order kinetics. Following the surface the highest concentration of KT from C940-HG was found in the epidermis and the stratum corneum for P407-HG. Relevant anti-inflammatory efficacy of KT-P407-HG revealed enough ability to provide sufficient bioavailability KT to reach easily the site of action. The application of developed formulations in volunteers did not induce any visual skin irritation. CONCLUSIONS: KT-P407-HG was proposed as suitable formulation for anti-inflammatory local treatment without theoretical systemic side effect.

Amphotericin B releasing topical nanoemulsion for the treatment of candidiasis and aspergillosis.

The present study was designed to develop a nanoemulsion formulation of Amphotericin B (AmB) for the treatment of skin candidiasis and aspergillosis. Several ingredients were selected on the basis of AmB solubility and compatibility with skin. The formulation that exhibited the best properties was selected from the pseudo-ternary phase diagram. After physicochemical characterization its stability was assessed. Drug release and skin permeation studies were also accomplished. The antifungal efficacy and skin tolerability of developed AmB nanoemulsion was demonstrated. Finally, our results showed that the developed AmB formulation could provide an effective local antifungal effect without theoretical systemic absorption, based on its skin retention capacity, which might avoid related side effect. These results suggested that the nanoemulsion may be an optimal therapeutic alternative for the treatment of skin fungal infections with AmB.

Cytotoxic Evaluation of (2S)-5,7-Dihydroxy-6-prenylflavanone Derivatives Loaded PLGA Nanoparticles against MiaPaCa-2 Cells.

The search for new alternatives for the prevention and treatment of cancer is extremely important to minimize human mortality. Natural products are an alternative to chemical drugs, since they are a source of many potential compounds with anticancer properties. In the present study, the (2S)-5,7-dihydroxy-6-prenylflavanone (semi-systematic name), also called (2S)-5,7-dihydroxy-6-(3-methyl-2-buten-1-yl)-2-phenyl-2,3-dihydro-4H-1-Benzopyran-4-one (CAS Name registered) (1) was isolated from Eysenhardtia platycarpa leaves. This flavanone 1 was considered as the lead compound to generate new cytotoxic derivatives 1a, 1b, 1c and 1d. These compounds 1, 1a, 1b, 1c, and 1d were then loaded in nanosized drug delivery systems such as polymeric nanoparticles (NPs). Small homogeneous spherical shaped NPs were obtained. Cytotoxic activity of free compounds 1, 1a, 1b, 1c, and 1d and encapsulated in polymeric NPs (NPs1, NPs1a, NPs1b, NPs1c and NPs1d) were evaluated against the pancreatic cancer cell line MiaPaCa-2. The obtained results demonstrated that NPs1a and NPs1b exhibited optimal cytotoxicity, and an even higher improvement of the cytotoxic efficacy was exhibited with the encapsulation of 1a. Based on these results, NPs1a were proposed as promising anticancer agent candidates.

Development of Clotrimazole Multiple W/O/W Emulsions as Vehicles for Drug Delivery: Effects of Additives on Emulsion Stability.

Multiple emulsions have attracted considerable attention in recent years for application as potential delivery systems for different drugs. The aim of the present work is to design a new formulation containing clotrimazole (CLT) loaded into multiple emulsions by two-step emulsification method for transdermal delivery. Different ingredients and quantities like primary and secondary co-emulsifiers and the nature of oily phase were assayed in order to optimize the best system for good. Resulting formulations were characterized in terms of droplet size, conductivity, pH, entrapment efficiency, rheological behavior, and stability under various storage conditions for 180 days. pH values of multiple emulsions containing CLT ranged from 7.04 ± 0.03 to 6.23 ± 0.04. Droplet size increased when increasing concentration of sorbitan stearate. The addition of polysorbate 80 resulted in significant decrease of oil droplet size comparing with those prepared without this. CLT entrapment efficiency ranged between 85.64% and 97.47%. All formulations exhibited non-Newtonian pseudoplastic flow with some apparent thixotropic behavior. Cross and Herschel-Bulkley equations were the models that best fitted experimental data. In general, the addition of 1% polysorbate 80 resulted in a decrease of viscosity values. No signals of optical instability were observed, and physicochemical properties remained almost constant when samples were stored at room temperature after 180 days. On the contrary, samples stored at 40°C exhibited pronounced increase in conductivity values 24 h after elaboration and some of them were unstable after 180 days of storage. JMLP01 was proposed as an innovative and stable system to incorporate CLT as active pharmaceutical ingredient.

Melatonin Delivery: Transdermal and Transbuccal Evaluation in Different Vehicles.

PURPOSE: Melatonin (MLT) could be candidate drug for treatment of several diseases because of its high antioxidant and anticarcinogenic activity and its important biological roles. The aim of this study was to assess the influence of different vehicles on the permeation of MLT through buccal and skin tissues. METHODS: Formulations were characterized in terms of rheology, drug release and permeation through human skin as well as porcine buccal mucosa. Irradiation experiments were also performed. RESULTS: The lowest amount of MLT released was from oral adhesive paste Orabase® (OB) and the highest from the emulsion system Montanov® 68 (M68). Skin permeation revealed high pattern for Carbopol® 940 (C940) and M68, and poor for poloxamer 407 (P407) and Pluronic® lecithin organogel (PLO). Statistical differences of MLT remaining in skin between M68 vs C940 (p < 0.05) and M68 vs PLO (p < 0.05) were observed. Transmucosal results showed that sodium carboxymethylcellulose (NaCMC) was the best and OB the worst vehicle. P407 and PLO followed similar behaviour. Photostability studies revealed high percentage of degradation of MLT in solution which was also similar when was loaded in OB. The rest of formulations showed low rates of degradation. CONCLUSIONS: C940 or M68 and NaCMC can be proposed as formulations for a potential systemic effect of MLT by skin and buccal mucosa routes, respectively. However, if the intended objective is to obtain local action in the skin and buccal mucosa, the proposed formulations are M68 or P407 and PLO.

Design of pediatric oral formulations with a low proportion of methadone or phenobarbital for the treatment of neonatal abstinence syndrome.

CONTEXT: Elaboration of oral liquid formulations is the best alternative when no marketed forms are available for pediatrics. OBJECTIVE: The development, characterization and stability evaluation of methadone (MI, MII, MIII) and phenobarbital (PI, PII) can be used for the treatment of neonatal abstinence syndrome (NAS). MATERIAL AND METHODS: A standard operating procedure was established and parameters such as appearance, pH, rheological behavior and drug content were evaluated at three temperatures for 90 days. RESULTS AND DISCUSSION: Changes in color of phenobarbital made necessary the storage below 25 °C. pH did not change in methadone solutions and was able to maintain phenobarbital solubilized. Degradation data at 4 °C fitted to Plateau equation followed by one phase decay. MI was stable for 60 days at the three temperatures; MII for 90 days at 4 and 25 °C and 60 days at 40 °C; MIII for 60 days at 4 °C, 15 days at 25 °C and 7 days at 4 °C. PI was stable for 60 days at 4 °C and 30 days at 25 °C. PII was stable for 7 days at 4 and 25 °C. All solutions met microbial specifications. CONCLUSION: A correct dosage for the treatment of NAS was guaranteed.

Design and optimization of oleanolic/ursolic acid-loaded nanoplatforms for ocular anti-inflammatory applications.

Oleanolic acid (OA) and ursolic acid (UA) are ubiquitous pentacyclic triterpenes compounds in plants with great interest as anti-inflammatory therapeutics. The aim of this study was the design and optimization of polymeric nanoparticles (NPs) loaded with natural and synthetic mixtures (NM, SM) of these drugs for ophthalmic administration. A 2(3) + star central rotatable composite design was employed to perform the experiments. Results showed optimal and stable formulations with suitable physicochemical properties (mean diameter<225 nm), homogeneous distribution (polydispersity index∼0.1), negatively charged surface (∼-27 mV) and high entrapment efficiency (∼77%). Release and corneal permeation studies showed that NM release was faster than SM. Amounts of drug retained in the corneal tissue were also higher for NM. In vitro and in vivo tests showed no signs of irritation or toxicity and successful in vivo anti-inflammatory efficacy for both formulations, being NM-OA/UA NPs the most effective. From the clinical editor: Oleanolic acid (OA) and ursolic acid (UA) are compounds found in plants with anti-inflammatory properties. The authors in this paper designed nanoparticles (NPs) using poly(dl-lactide-coglycolide) acid (PLGA) loaded with these compounds for ophthalmic administration. Both in vitro and in vivo experiments showed no toxicity and significant anti-inflammatory efficacy. This may provide new drugs for ocular anti-inflammatory treatment.

Circadian rhythms on skin function of hairless rats: light and thermic influences.

Circadian rhythms are present in most functions of living beings. We have demonstrated the presence of circadian rhythms in skin variables (transepidermal water loss, TEWL; stratum corneum hydration, SCH; and skin temperature) in hairless rats under different environmental conditions of light and temperature. Circadian rhythms in TEWL and SCH showed mean amplitudes of about 20% and 14% around the mean, respectively, and appeared under light-dark cycles as well as under constant darkness. Environmental temperature was able to override TEWL, but not SCH rhythm, evidencing the dependency of TEWL on the temperature. Mean daily values of TEWL and SCH, and also the amplitude of TEWL rhythm, increased with the age of the animal. Under constant light, situation that induces arrhythmicity in rats, SCH and TEWL were inversely correlated. The results suggest the importance to take into account the functional skin rhythms in research in dermatological sciences.

Enhancing effect of glucose microspheres in the viability of human mesenchymal stem cell suspensions for clinical administration.

PURPOSE: A critical limiting factor of cell therapy is the short life of the stem cells. In this study, glucose containing alginate microspheres were developed and characterized to provide a sustained release system prolonging the viability of human mesenchymal stem cells (hMSCs) in a suspension for clinical application. METHODS: The glucose microspheres were satisfactorily elaborated with alginate by emulsification/internal gelation method. Particle size was evaluated by light diffraction and optical microscopy. Shape and surface texture by scanning electron microscopy (SEM). Zeta potential, infrared spectra and release studies were also conducted. Also, rheological properties and stability of hMSCs suspensions with microspheres were tested. The viability of hMSCs was determined by trypan blue dye exclusion staining. RESULTS: Microspheres of 86.62 µm, spherical shaped and -32.54 mV zeta potential with excellent stability, good encapsulation efficiency and providing an exponential release of glucose were obtained. hMSCs had better survival rate when they were packed with glucose microspheres. Microspheres maintained the aseptic conditions of the cell suspension without rheological, morphological or immunophenotypic disturbances on hMSCs. CONCLUSIONS: Developed microspheres were able to enhance the functionality of hMSC suspension. This strategy could be broadly applied to various therapeutic approaches in which prolonged viability of cells is necessary.

Baricitinib Lipid-Based Nanosystems as a Topical Alternative for Atopic Dermatitis Treatment.

Atopic dermatitis (AD) is a chronic autoimmune inflammatory skin disorder which causes a significant clinical problem due to its prevalence. The ongoing treatment for AD is aimed at improving the patient's quality of life. Additionally, glucocorticoids or immunosuppressants are being used in systemic therapy. Baricitinib (BNB) is a reversible Janus-associated kinase (JAK)-inhibitor; JAK is an important kinase involved in different immune responses. We aimed at developing and evaluating new topical liposomal formulations loaded with BNB for the treatment of flare ups. Three liposomal formulations were elaborated using POPC (1-palmitoyl-2-oleoyl-glycero-3-phosphocholine), CHOL (Cholesterol) and CER (Ceramide) in different proportions: (i) POPC, (ii) POPC:CHOL (8:2, mol/mol) and (iii) POPC:CHOL:CER (3.6:2.4:4.0 mol/mol/mol). They were physiochemically characterized over time. In addition, an in vitro release study, ex vivo permeation and retention studies in altered human skin (AHS) were also performed. Histological analysis was used to study the tolerance of the formulations on the skin. Lastly, the HET-CAM test was also performed to evaluate the irritancy capacity of the formulations, and the modified Draize test was performed to evaluate the erythema and edema capacity of the formulations on the altered skin. All liposomes showed good physicochemical properties and were stable for at least one month. POPC:CHOL:CER had the highest flux and permeation, and the retention in the skin was equal to that of POPC:CHOL. The formulations exhibited no harmful or irritating effects, and the histological examination revealed no changes in structure. The three liposomes have shown promising results for the aim of the study.

Release profile and transscleral permeation of triamcinolone acetonide loaded nanostructured lipid carriers (TA-NLC): in vitro and ex vivo studies.

Nanostructured lipid carriers (NLC) have been developed for sustained release of triamcinolone acetonide (TA), a corticosteroid commonly indicated for macular edema, neovascularization, and other ocular inflammatory disorders. TA-NLC were prepared by high-pressure homogenization and characterized for in vitro release by dialysis bag. Ex vivo permeation profile was assessed using rabbit sclera isolated and mounted in Franz diffusion cells. TA-NLC were placed in episcleral donor compartment and choroidal side was perfused with HEPES buffer. Tissue sections underwent drug wash-out, following analysis by validated RP-HPLC of drug content and perfused fractions collected over 24 hours. Drug release followed one-order kinetics and permeability studies confirmed that TA is able to diffuse across rabbit sclera in sustained profile, following zero-order kinetics. Strong tissue binding was observed, providing a drug depot. These findings are of potential use when designing future TA therapy strategies for ocular diseases of posterior segment.

Nano-engineering of ketorolac tromethamine platforms for ocular treatment of inflammatory disorders.

Aim: The development and optimization of Ketorolac tromethamine-loaded polylactic-co-glycolic acid nanoparticles (KT-NPs) for the treatment of inflammatory processes of the eye. Materials & methods: KT-NPs were developed by factorial design and characterized by assessing their physicochemical properties. Biopharmaceutical behavior studies, ocular tolerance, anti-inflammatory efficacy and bioavailability tests were performed on pigs. Results: Optimized KT-NPs of 112 nm, narrow distribution with encapsulation efficiency near 100% were obtained. KT release followed the Weibull model and there was significantly greater retention in the cornea and sclera than in the commercial reference. KT-NPs showed no signs of ocular irritancy and similar anti-inflammatory efficacy to the commercial reference. Conclusion: KT-NPs were a suitable alternative for the treatment of inflammatory disorders of the anterior and posterior segments of the eye as an alternative to conventional topical formulations.

Carprofen Permeation Test through Porcine Ex Vivo Mucous Membranes and Ophthalmic Tissues for Tolerability Assessments: Validation and Histological Study.

Carprofen (CP), a non-steroidal anti-inflammatory drug (NSAID), is profusely used in veterinary medicine for its analgesic and anti-inflammatory activity. Some undesirable effects are associated with its systemic administration. Alternative local routes are especially useful to facilitate its administration in animals. The main aim of this paper is to validate the suitability of ex vivo permeation experiments of CP with porcine mucous membranes (buccal, sublingual and vaginal) and ophthalmic tissues (cornea, sclera and conjunctiva) intended to be representative of naïve in vivo conditions. Chromatographic analysis of CP in membrane-permeated samples and drug-retained have been validated following standard bioanalytical guidelines. Then, recovery levels of drugs in tissue samples were assessed with aqueous phosphate buffered saline (PBS) buffer to preserve the histological integrity. Finally, as a proof of concept, a series of CP permeation tests in vertical Franz diffusion cells has been performed to evaluate permeation flux and permeability constants in all tissues, followed by a histological study for critical evaluation. Furthermore, synthetic tissue retention-like samples were prepared to verify the value of this experimental study. Results show linear relationships with good determination coefficient (R2 > 0.998 and R2 > 0.999) in the range of 0.78 to 6.25 mg/mL and 3.125 mg/mL to 100 mg/mL, respectively. Low limits of quantification around 0.40 µg/mL were allowed to follow permeation levels until a minimum of 0.40% of the locally-applied dose. This method showed a good accuracy and precision with values lower than 2%. After the recovery technique, reproducible values below 30% were achieved in all tissues, suggesting it is a non-damaging method with low efficiency that requires the use of further solvents to enhance the extraction percentages. After permeation and histology tests, no relevant peak interferences were detected, and no cell or tissue damage was found in any tissue. In conclusion, results demonstrate the suitability of this test to quantify the distribution of CP with good histological tolerability.

Study of Melatonin as Preventive Agent of Gastrointestinal Damage Induced by Sodium Diclofenac.

Safety profile of nonsteroidal anti-inflammatory drugs (NSAIDs) has been widely studied and both therapeutic and side effects at the gastric and cardiovascular level have been generally associated with the inhibitory effect of isoform 1 (COX-1) and 2 (COX-2) cyclooxygenase enzymes. Now there are evidences of the involvement of multiple cellular pathways in the NSAIDs-mediated-gastrointestinal (GI) damage related to enterocyte redox state. In a previous review we summarized the key role of melatonin (MLT), as an antioxidant, in the inhibition of inflammation pathways mediated by oxidative stress in several diseases, which makes us wonder if MLT could minimize GI NSAIDs side effects. So, the aim of this work is to study the effect of MLT as preventive agent of GI injury caused by NSAIDs. With this objective sodium diclofenac (SD) was administered alone and together with MLT in two experimental models, ex vivo studies in pig intestine, using Franz cells, and in vivo studies in mice where stomach and intestine were studied. The histological evaluation of pig intestine samples showed that SD induced the villi alteration, which was prevented by MLT. In vivo experiments showed that SD altered the mice stomach mucosa and induced tissue damage that was prevented by MLT. The evaluation by quantitative reverse transcription PCR (RT-qPCR) of two biochemical markers, COX-2 and iNOS, showed an increase of both molecules in less injured tissues, suggesting that MLT promotes tissue healing by improving redox state and by increasing iNOS/NO that under non-oxidative condition is responsible for the maintenance of GI-epithelium integrity, increasing blood flow and promoting angiogenesis and that in presence of MLT, COX-2 may be responsible for wound healing in enterocyte. Therefore, we found that MLT may be a preventive agent of GI damages induced by NSAIDs.

Melatonin nanogel promotes skin healing response in burn wounds of rats.

Aim: Development of a melatonin nanogel intended for wound healing (WH) application. Materials & methods: The main components of the nanogel were poloxamer 407, chitosan and hyaluronic acid. The nanogel was characterized by the assessment of physical interactions, swelling, wettability, rheological properties and internal structure. The drug release, antimicrobial efficacy against different strains and biocompatibility with human keratinocytes were also tested. Finally, the WH efficacy was evaluated in rats. Results: The nanogel showed optimal physicochemical properties and an internal network of interconnected channels from which melatonin was released following first order kinetics. Antimicrobial activity was similar to commercial reference material and it promoted epidermis growth with evident wound contraction. Conclusion: Melatonin nanogel can be proposed as a promising system for WH.

Endogenous Antioxidant Cocktail Loaded Hydrogel for Topical Wound Healing of Burns.

The main goal of this work is the study of the skin wound healing efficacy of an antioxidant cocktail consisting of vitamins A, D, E and the endogenous pineal hormone melatonin (MLT), with all of these loaded into a thermosensitive hydrogel delivery system. The resulting formulation was characterized by scanning electron microscopy. The antioxidant efficacy and microbiological activity against Gram positive and Gram negative strains were also assayed. The skin healing efficacy was tested using an in vivo model which included histological evaluation. Furthermore, atomic force microscopy was employed to evaluate the wound healing efficacy of rat skin burns through the determination of its elasticity at the nanoscale using force spectroscopy analysis. The resulting hydrogel exhibited sol state at low temperature and turned into a gel at 30 ± 0.2 °C. The hydrogel containing the antioxidant cocktail showed higher scavenging activity than the hydrogel containing vitamins or MLT, separately. The formulation showed optimal antimicrobial activity. It was comparable to a commercial reference. It was also evidenced that the hydrogel containing the antioxidant cocktail exhibited the strongest healing process in the skin burns of rats, similar to the assayed commercial reference containing silver sulfadiazine. Histological studies confirmed the observed results. Finally, atomic force microscopy demonstrated a similar distribution of Young's modulus values between burned skin treated with the commercial reference and burned skin treated with hydrogel containing the antioxidant cocktail, and all these with healthy skin. The use of an antioxidant cocktail of vitamins and MLT might be a promising treatment for skin wounds for future clinical studies.

Nanostructured lipid carriers loaded with Halobetasol propionate for topical treatment of inflammation: Development, characterization, biopharmaceutical behavior and therapeutic efficacy of gel dosage forms.

The aim of this research was the development and characterization of three gel dosage forms of Halobetasol propionate loaded lipid nanoparticles (HB-NLC) for the treatment of inflammatory skin diseases. A Pluronic gel (Pl-HB-NLC), a Carbopol gel (Cb-HB-NLC) and a Cremigel (Cg-HB-NLC), were characterized for stability, swelling, degradation, porosity and rheology. The biopharmaceutical behavior of in vitro release and ex vivo permeation, along with microbiological stability were also evaluated. Tolerance and therapeutic efficacy were determined in vivo. The gels proved to have eudermic pH and to be effective to improve HB-NLC stability for more than 6 months. In vitro drug release profiles were adjusted to a first order (Pl-HB-NLC, Cg-HB-NLC) and hyperbola (Cb-HB-NLC) kinetic models, revealing sustained drug release. Ex vivo biopharmaceutical behavior showed slow drug penetration through skin, delaying the drug entrance into systemic circulation. The formulations were effective in reducing inflammation with a lower drug dose in comparison with existing treatments, obtaining the fastest effect when using Pl-HB-NLC. After application of the formulations in volunteers, no irritation, redness or edema reactions were detected, plus, an enhancement of the biomechanical properties of the skin was evidenciated. Therefore, the results indicate that these formulations are a suitable alternative to current treatments.