Joana Marto

Starch-based Pickering emulsions for topical drug delivery: A QbD approach.

Pickering emulsions are stabilized by solid particles instead of surfactants and have been widely investigated in pharmaceutical and cosmetic fields since they present less adverse effects than the classical emulsions. A quality by design (QbD) approach was applied to the production of w/o emulsions stabilized by starch. A screening design was conducted to identify the critical variables of the formula and the process affecting the critical quality properties of the emulsion (droplet size distribution). The optimization was made by establishing the Design Space, adjusting the concentration of starch and the quantity of the internal aqueous phase. The emulsion production process was, in turn, adjusted by varying the time and speed of stirring, to ensure quality and minimum variability. The stability was also investigated, demonstrating that an increase in starch concentration improves the stability of the emulsion. Rheological and mechanical studies indicated that the viscosity of the emulsions was enhanced by the addition of starch and, to a higher extent, by the presence of different lipids. The developed formulations was considered non-irritant, by an in vitro assay using human cells from skin (Df and HaCat) with the cell viability higher than 90% and, with self-preserving properties. Finally, the QbD approach successfully built quality in Pickering emulsions, allowing the development of hydrophilic drug-loaded emulsions stabilized by starch with desired organoleptic and structural characteristics. The results obtained suggest that these systems are a promising vehicle to be used in products for topical administration.

Pickering emulsions: challenges and opportunities in topical delivery

ABSTRACT Introduction: Topical drug delivery is a challenging area with many advantages such as avoidance of first passage effect, stabilization of blood concentrations and attainment of local therapeutic effect with fewer side effects. Despite all these advantages, topical drug delivery remains limited to few molecules, since skin acts as a barrier to the delivery of many therapeutic molecules. To overcome this obstacle, a favored strategy relies on selecting suitable vehicles for dermatologic therapy, such as emulsions, gels and, more recently, nanoparticulate systems. Areas covered: Particle-stabilized emulsions, also known as Pickering emulsions, have garnered interest in recent years. Although most of the investigation on Pickering emulsions has been based on model systems with inorganic or organic solid particles, recent advances have been made regarding the application of nanocarriers, protein-based particles or cyclodextrins for this purpose. This review reports the latest advances in Pickering emulsions technical challenges, and discusses the potential benefits and drawbacks of using these formulations for topical pharmaceutical and cosmetic applications as an alternative to conventional surfactant-based systems. Expert opinion: Pickering emulsions appear as a multifunctional dosage form with endless advantages. A great deal of progress is expected in this area, which might represent a renewed vision for the pharmaceutical and cosmetic industry.

A Quality by design (QbD) approach on starch-based nanocapsules: A promising platform for topical drug delivery.

Exploring novel applications for approved excipients with a history of safe use in therapeutics is a smart strategy to obtain improved pharmaceutical products. The present study aimed at developing a novel starch-based nanoparticulate carrier system (StNC) for topical delivery of lipophilic bioactive molecules. The role of the different factors that affect the particle size distribution and zeta potential of StNC prepared by the emulsification-solvent evaporation method was assessed using a quality by design approach. An optimal formulation was selected and fully characterized in terms of molecular interactions (DSC and FTIR), morphology (TEM and AFM), as well as in vitro and in vivo biological properties, including biological sensitivity/irritation studies performed in human volunteers. Results show the surfactant and lipid contents play a major role in StNC particle size distribution. In addition, all tested formulations presented a zeta potential of ca. +33.6±6.7 mV, indicating a good physical stability, while revealing an excellent compromise between stability, safety and cosmeticity, evidencing that StNC are suitable nanocarriers for topical use. Finally, the design planning methodology has clearly shown its usefulness for optimizing the formulation, being also crucial for the understanding of StNC formation process. The StNC proved to be a promising formulation strategy and a potential nanocarrier for topical lipophilic bioactive molecules.

Melatonin-based pickering emulsion for skin's photoprotection

Abstract Context: Based on its antioxidant activity, melatonin was recently found to have a protection effect against photocarcinogenesis. Objective: This work aimed to develop an innovative sunscreen formulation based on the Pickering emulsions concept, stabilized by physical UV filters, modified starch and natural oils associated to melatonin as a key strategy for prevention against UV-induced skin damage. Materials and methods: For this purpose, melatonin was incorporated in Pickering emulsions that were characterized using physicochemical, in vitro and in vivo testing. Physicochemical studies included physical and chemical stability by a thorough pharmaceutical control. The possible protective effects of melatonin against UV-induced cell damage in HaCaT cell lines were investigated in vitro. The safety assessment and the in vivo biological properties of the final formulations, including Human Repeat Insult Patch Test and sunscreen water resistance tests were also evaluated. Results and discussion: These studies demonstrated that melatonin sunscreen Pickering emulsion was beneficial and presented a powerful protection against UVB-induced damage in HaCat cells, including inhibition of apoptosis. The inclusion of zinc oxide, titanium dioxide, green coffee oil and starch ensured a high SPF (50+) against UVA and UVB. Conclusion: The combination of melatonin, multifunctional solid particles and green coffee oil, contributed to achieve a stable, effective and innovative sunscreen with a meaningful synergistic protection against oxidative stress.

Design of novel starch-based Pickering emulsions as platforms for skin photoprotection

Green coffee oil and modified starch were recently found to have an enhanced protection effect against UV radiation. Therefore, this work aimed to develop an innovative sunscreen formulation based on Pickering emulsions concept, i.e., surfactant-free emulsions stabilized by physical UV filters associated natural oils as a key strategy for prevention against UV-induced skin damage. The Pickering emulsions of different compositions were characterized in terms of pH, mechanical, physical and microbiological stability by a thorough pharmaceutical control. In addition, the sun protection factor (SPF) as well as the in vitro and in vivo biological properties of the final formulations, including Episkin®, HRIPT and sunscreen water resistance. Formulation studies demonstrated the addition of physical UV filters was beneficial, leading to the inclusion of ZnO and TiO2 to ensure a high SPF against UVA and UVB, respectively. Although starch particles presented no intrinsic photoprotection properties, they proved to be a SPF promoter by a synergistic effect. Green coffee oil was the selected natural oil due to the highest SPF, when compared to other natural oils tested. Besides the excellent sunscreen activity confirmed by in vitro and in vivo results, the final formulations proved to be also suitable for topical use according to the rheological assessment and stability throughout the study period (3months). In conclusion, the combination of three multifunctional solid particles and green coffee oil, contributed to achieve a stable and effective innovative sunscreen with a wide range of UV radiation protection.

Ethosomes for enhanced skin delivery of griseofulvin

Griseofulvin (GRF) is an important antifungal drug with low bioavailability and, for this reason, a topical formulation with a targeted action and minimal systemic effects, appears to be a preferable solution. GRF poor solubility has limited the development of topical formulations and their release to the market. The aim of this work was to prepare a new GRF formulation for topical application using lipid-based nanosystems; to study its permeation and penetration, cell viability and to evaluate its therapeutic action. Ethosomal systems composed of soy bean phosphatidylcholine, ethanol and water were prepared for incorporating GRF. After the characterization of the vesicles in terms of size, charge and penetrability, permeation through newborn pig using Franz diffusion cells was conducted. Cell viability at different concentrations of the chosen formulation was determined. At last, skin adapted agar diffusion test was performed to assess the therapeutic efficacy of the formulation. GRF vesicles had mean size of 130nm. Permeation and penetration assays revealed that GRF-loaded ethosomes have an adequate profile to be used in a topical formulation since drug retention in the stratum corneum was achieved. Cell viability tests proved this formulation presented no cytotoxicity to HaCaT cells for concentrations below 50μg/mL. The skin diffusion test evidenced the potential of developed formulation to target skin dermatophytes. The results obtained in this study contribute to a new perspective in topical treatment of fungal infections.

Topical gels of etofenamate: in vitro and in vivo evaluation

Abstract Non-steroid anti-inflammatory drugs (NSAIDs), such as etofenamate, are among the most prescribed drugs used for their analgesic, anti-rheumatic, antipyretic and anti-inflammatory properties. Topical formulations have the main advantage of targeted delivery. However, drugs must overcome the skin due to its role as a physical and chemical barrier against the penetration of chemicals and microorganisms. This barrier must be altered to allow the permeation of drugs at a suitable rate to the desired site of activity. Permeation modulators can intercalate the skin outer layers causing structure disruption, opening an energetically favourable route for the drug to diffuse through. The aim of this work was the development of hydroalcoholic gels containing 5.0% (w/w) of etofenamate for topical administration with anti-inflammatory activity and enhanced drug delivery. The physical and chemical characterization, in vitro release and permeation studies and in vivo anti-inflammatory activity were assessed. The gel with 30% ethanol showed in vivo anti-inflammatory activity with suitable physical chemical and microbiologic characteristics. In vitro release and permeation studies revealed that the different amounts of ethanol used influenced the release profiles of etofenamate. Moreover, it was demonstrated that this formulation is an adequate vehicle for the etofenamate skin permeation.

Chitosan Nanoparticles as a Mucoadhesive Drug Delivery System for Ocular Administration

Pharmaceutical approaches based on nanotechnologies and the development of eye drops composed of the mucoadhesive polymers chitosan and hyaluronic acid are emerging strategies for the efficient treatment of ocular diseases. These innovative nanoparticulate systems aim to increase drugs’ bioavailability at the ocular surface. For the successful development of these systems, the evaluation of mucoahesiveness (the interaction between the ocular delivery system and mucins present on the eye) is of utmost importance. In this context, the aim of the present work was to investigate the mucoadhesivity of a novel nanoparticle eye drop formulation containing an antibiotic (ceftazidime) intended to treat eye infections. Eye drop formulations comprised a polymer (hydroxypropyl) methyl cellulose (HPMC) 0.75% (w/v) in an isotonic solution incorporating chitosan/sodium tripolyphosphate (TPP)-hyaluronic acid-based nanoparticles containing ceftazidime. The viscosity of the nanoparticles, and the gels incorporating the nanoparticles were characterized in contact with mucin at different mass ratios, allowing the calculation of the rheological synergism parameter (∆η). Results showed that at different nanoparticle eye formulation:mucin weight ratios, a minimum in viscosity occurred which resulted in a negative rheological synergism. Additionally, the results highlighted the mucoadhesivity of the novel ocular formulation and its ability to interact with the ocular surface, thus increasing the drug residence time in the eye. Moreover, the in vitro release and permeation studies showed a prolonged drug release profile from the chitosan/TPP-hyaluronic acid nanoparticles gel formulation. Furthermore, the gel formulations were not cytotoxic on ARPE-19 and HEK293T cell lines, evaluated by the metabolic and membrane integrity tests. The formulation was stable and the drug active, as shown by microbiological studies. In conclusion, chitosan/TPP-hyaluronic acid nanoparticle eye drop formulations are a promising platform for ocular drug delivery with enhanced mucoadhesive properties.

Mometasone furoate hydrogel for scalp use: in vitro and in vivo evaluation

Abstract Dermatological inflammatory diseases often affect the scalp and the eyebrows. Common dosage forms available on the market for those situations are lotions; however, the presence of hair limits their use. Gels, for their consistency and adhesiveness, are a suitable alternative to the lotions in these situations. The aim of this study was to develop a new stable gel containing mometasone furoate (MF), with anti-inflammatory activity and a controlled delivery, to improve topical treatment of scalp dermatitis. Pharmaceutical development, physical and chemical characterization, stability, in vitro release and permeation studies and in vivo anti-inflammatory activity were performed. The gel presented an acidic pH and an apparent viscosity of 35 Pa.s. The microbiological analysis showed that the results were within the established specification limits. The release and the permeation profiles suggest that the drug is mainly retained in the upper skin layers. MF gel was tested in an animal model of cutaneous inflammation and presented similar anti-inflammatory activity compared to a commercially available MF dosage form. The gel was chemically, physically and microbiologically stable. The results suggest that the developed hydrogel formulation containing MF can be of actual value for improving the clinical effectiveness in the treatment of scalp dermatitis.

Starch nanocapsules containing a novel neutrophil elastase inhibitor with improved pharmaceutical performance

Graphical abstract Figure. No caption available. HighlightsER143‐loaded StNC proved as a strategy to improve ER143 pharmaceutical performance.ER143‐loaded StNC showed an improved anti‐inflammatory effect.A QbD approach was successfully applied to obtain ER143‐loaded StNC. &NA; Psoriasis and atopic dermatitis patients show an excessive amount of elastase in peripheral blood neutrophils due to an imbalance between this proteolytic enzyme and its endogenous inhibitors, the search for new human neutrophil elastase (HNE) inhibitors are required. The HNE is an attractive therapeutic target and inhibitors with new molecular architectures have been extensively investigated. In this context a promising novel synthetic human neutrophil elastase inhibitor (ER143) was associated to a starch‐based nanoparticulate system (StNC) with improved pharmaceutical performance, using a quality by design approach to support product development and optimization. The resulting formulation was characterized in terms of and in vitro release, permeation and retention studies in newborn pig skin, using Franz diffusion cells revealing the StNC have the ability to control the drug release rate and contribute to a high skin retention and/or permeation profiles. The anti‐inflammatory activity accessed in vivo using the croton oil‐induced ear inflammation model in mice showed that erythema and edema were attenuated in 98% following local application. These observations suggest the association of ER143 to the StNC promotes a deeper skin penetration and retention, also confirming StNC as a potential topical delivery system.