Formulation and performance evaluation of emulgel platform for combined skin delivery of curcumin and propolis.

The environment can modify the physiology and body protective function of the skin. Propolis (PRP) and curcumin (CUR) possess important antioxidant and antimicrobial properties, and they can be administered in a combined way and using photodynamic therapy (PDT). Emulgels can control drug release due to the physicochemical properties of the gel and the emulsion. They constitute a good strategy for achieving an improved platform for the combined delivery of PRP and CUR. There are no other studies of emulgels composed of PRP and CUR and their performance as antimicrobial and skin healing using or not PDT. This study aimed to investigate the effect of Carbopol 934 P (C934P), 974 P (C974P) or polycarbophil (PC) on physicochemical stability, antioxidant activity, drug release profile, antimicrobial activity, and ex vivo skin permeation and retention of emulgels containing PRP and CUR. Formulations containing C974P or PC displayed improved stability and antioxidant activity. They displayed activity against Staphylococcus aureus and modified (extended) drug release, governed mainly by non-Fickian anomalous transport. C974P and PC resulted in improved emulgels for combined CUR and PRP delivery, allowing the drugs to cross the stratum corneum, and permeate the epidermis, reaching the dermis. The selected emulgels are candidates for further studies to prove their action and benefits to skin health.

Emulgels Containing Propolis and Curcumin: The Effect of Type of Vegetable Oil, Poly(Acrylic Acid) and Bioactive Agent on Physicochemical Stability, Mechanical and Rheological Properties.

Emulgels are obtained by the entrapment of an organic phase within a three-dimensional network built by hydrophilic molecules. Polymers based on cross-linked poly(acrylic acid) have been utilized as gel matrices, improving adhesiveness, rheological and mechanical performance. Propolis (PRP) produced by Apis mellifera L. bees displays a wide range of biological activities. Together with curcumin (CUR), they may show synergic anti-inflammatory, antioxidant and antimicrobial action on skin disorders. This work investigated the effect of vegetable oils (sweet almond, andiroba, and passion fruit) with regard to the physicochemical properties of emulgels composed of Carbopol 934P®, Carbopol 974P®, or polycarbophil aiming the CUR and PRP delivery. Physicochemical stability enabled the selection of systems containing passion fruit or andiroba oil. Mechanical and rheological characteristics provided rational comprehension of how vegetable oils and bioactive agents affect the structure of emulsion gels. All formulations exhibited high physiochemical stability and properties dependent on the polymer type, oil, and bioactive agent. Formulations displayed pseudoplastic, thixotropic and viscoelastic properties. Emulgels containing andiroba oil were the most stable systems. Carbopol 934P® or polycarbophil presence resulted in formulations with improved smoothness and mechanical properties. Systems containing andiroba oil and one of these two polymers are promising for further investigations as topical delivery systems of CUR and/or PRP on the skin and mucous membranes.

Development and in vitro evaluation of buccal mucoadhesive films for photodynamic inactivation of Candida albicans.

Candidiasis is one of the most common diseases that occur in the oral cavity, caused mainly by the species Candida albicans. Methylene blue (MB) has a potential for microbial photoinactivation and can cause the destruction of fungi when applied in Photodynamic Therapy (PDT). Mucoadhesive films are increasingly being studied as a platform for drug application due to their advantages when compared to other pharmaceutical forms. The aim of this work was to develop mucoadhesive buccal film containing poloxamer 407 (P407), alcohol polyvinyl (PVA) and polyvinylpyrrolidone (PVP) for the release of MB aiming the photoinactivation of Candida albicans in buccal infections. Different amounts of P407 were added to the binary polymeric blends composed PVA and PVP. Formulations were characterized as morphology, thickness, density, bending strength, mechanical properties, water vapor transmission, disintegration time, mucoadhesion, DSC, ATR-FTIR, in vitro drug release profile and photodynamic inactivation. The films displayed physicochemical characteristics dependent of polymeric composition, mucoadhesive properties, fast MB release and were effective in photo inactivate the local growth of Candida albicans isolates. The formulation containing the lowest PVA and P407 amounts displayed the best performance. Therefore, data obtained from the film system show its potentially useful role as a platform for buccal MB delivery in photoinactivation of C. albicans, showing its potential for in vivo evaluation.

Emulgels Containing Carbopol 934P and Different Vegetable Oils for Topical Propolis Delivery: Bioadhesion, Drug Release Profile, and Ex Vivo Skin Permeation Studies.

Topical administration can enable a more efficient therapy based on the improved bioavailability and patient compliance. Wounds and infections can lead to modifications of skin physiology and body protective function. Propolis (PRP) is utilized for skin protection and treatment. However, PRP extracts do not show suitable rheological characteristics and can cause irritation, pain, ulceration, and healing difficulties when they are administered on the harmed skin. Emulgels composed of Carbopol 934P (C934P) and different vegetable oils have been proposed for propolis extract release and may be a good strategy for topical delivery. The aim of this study was to investigate the bioadhesive properties, PRP release profile, skin permeation, and retention, by Franz's diffusion cell and photoacoustic spectroscopy (PS), of these emulgels. Formulations were composed of C934P and passion fruit oil (PF), sweet almond oil (SA), or andiroba oil (AO). PRP or by-product extracts were added to the systems, drug release profile was investigated, and porcine ear skin was utilized for analyses of bioadhesive properties, skin permeation, and retention. All formulations displayed similar bioadhesive force (0.05-0.07 N); PRP release was modified (prolonged), dependent on formulation composition, and mainly governed by diffusion. PS and analysis using diffusion cell showed that the systems could provide dermal permeation and retention, which was more effective for formulations containing AO. Considering the importance of propolis for many skin therapies, the emulgels containing AO for PRP delivery are worthy of biological studies and further clinical evaluation.

Propolis extract has bioactivity on the wall and cell membrane of Candida albicans.

ETHNOPHARMACOLOGICAL RELEVANCE: The use of natural products such as propolis extract (PE) is a promising alternative when topically administered to replace conventional antifungals, mostly due to its therapeutic applications, ease of access and low toxicity. However, despite being the subject of several mycology studies, they focus primarily on exploiting their antimicrobial activity, lacking information on the mechanisms of action of PE on Candida spp., characterizing its antifungal potential. AIM OF THE STUDY: To elucidate the bioactivity of PE on the cellular structure of Candida albicans. MATERIALS AND METHODS: A total of seven C. albicans clinical isolates plus a reference strain of C. albicans ATCC 90028 were used in this study. The PE was characterized and its effect on C. albicans was determined by susceptibility and growth kinetics assays; interference on C. albicans germination and filamentation; evaluation of the integrity of the C. albicans cell wall and membrane, as well as its mutagenic potential. RESULTS: The PE presented strong inhibitory activity, which showed its greatest antifungal activity at 12 h with dose and time dependent fungistatic characteristics, effectively inhibiting and interfering on C. albicans filamentation. In addition, PE caused membrane and cell wall damage with intracellular content extravasation. Moreover, PE was not mutagenic. CONCLUSIONS: The bioactivity of PE is mainly related to the loss of integrity membrane as well as the integrity of the cell wall and consequent increase in permeability, without mutagenic effects.

Design and characterization of an organogel system containing ascorbic acid microparticles produced with propolis by-product.

This study aimed to prepare and characterize organogels containing microparticles of ascorbic acid (AA) obtained from propolis by-product. The formulations F1 (5% of microparticles) and F2 (10% of microparticles) were evaluated regarding rheological and textural properties, antioxidant and radical scavenging activity, in vitro release and cellular studies. The organogels showed plastic flow behavior and rheopexy. The textural parameters were within acceptable values for semisolid formulations. The antioxidant capacity of organogels F1 and F2 by the DPPH assay demonstrated IC50 ranging from 1523.59 to 1166.97 µg/mL, respectively. For the FRAP assay, the values found were 842.88 and 956.14 µmol of FSE/g formulation, respectively. Good scavenging activity against nitrogen species was observed. The concentration of 63 µg/mL did not present toxicity on HaCaT and HFF-1 cells. In vitro release profile of AA from organogels showed a slow pattern of drug release, mainly for F2. Therefore, the proposed organogel containing AA microparticles with propolis by-product matrix represents a promising platform for topical drug delivery with antioxidant effect.

Design of a nanostructured mucoadhesive system containing curcumin for buccal application: from physicochemical to biological aspects.

Mucoadhesive nanostructured systems comprising poloxamer 407 and Carbopol 974P® have already demonstrated good mucoadhesion, as well as improved mechanical and rheological properties. Curcumin displays excellent biological activity, mainly in oral squamous cancer; however, its physicochemical characteristics hinder its application. Therefore, the aim of this study was to develop nanostructured formulations containing curcumin for oral cancer therapy. The photophysical interactions between curcumin and the formulations were elucidated by incorporation kinetics and location studies. They revealed that the drug was quickly incorporated and located in the hydrophobic portion of nanometer-sized polymeric micelles. Moreover, the systems displayed plastic behavior with rheopexy characteristics at 37 °C, viscoelastic properties and a gelation temperature of 36 °C, which ensures increased retention after application in the oral cavity. The mucoadhesion results confirmed the previous findings with the nanostructured systems showing a residence time of 20 min in porcine oral mucosa under flow system conditions. Curcumin was released after 8 h and could permeate through the porcine oral mucosa. Cytotoxicity testing revealed that the formulations were selective to cancer cells over healthy cells. Therefore, these systems could improve the physicochemical characteristics of curcumin by providing improved release and permeation, while selectivity targeting cancer cells.

Thermal Magnetic Field Activated Propolis Release From Liquid Crystalline System Based on Magnetic Nanoparticles.

Intra-periodontal pocket drug delivery systems, such as liquid crystalline systems, are widely utilized improving the drug release control and the therapy. Propolis is used in the treatment of periodontal diseases, reducing the inflammatory and infectious conditions. Iron oxide magnetic nanoparticles (MNPs) can improve the treatment when an alternating external magnetic field (AEMF) is applied, increasing the local temperature. The aim of this study was to develop a liquid crystalline system containing MNPs for intra-periodontal pocket propolis release. MNPs were prepared using iron salts and the morphological, size, thermal, x-ray diffraction, magnetometry, and Mössbauer spectroscopy analyses were performed. Cytotoxicity studies using Artemia salina and fibroblasts were also accomplished. The systems were prepared using polyoxyethylene (10) oleyl ether, isopropyl myristate, purified water, and characterized by polarized optical microscopy, rheometry, and in vitro drug release profile using a periodontal pocket simulator apparatus. The antifungal activity of the systems was investigated against Candida spp. using an AEMF. MNPs displayed nanometric size, were monodisperse, and they displayed very low cytotoxicity. Microscopically homogeneous formulations were obtained displaying important physicochemical and biological properties. The system displayed prolonged release of propolis and important in vitro fungicide activity, which was increased when the AEMF was applied, indicating a potentially alternative therapy for the treatment of the periodontal disease.

Development of a microparticulate system containing Brazilian propolis by-product and gelatine for ascorbic acid delivery: evaluation of intestinal cell viability and radical scavenging activity.

The use of propolis by-product (PBP) microparticles (MP) as delivery systems can be a promising tool to surpass drawbacks related to low stability of ascorbic acid (AA). The objective of this study was to develop and characterize MP prepared with PBP containing AA. The MP was characterized regarding morphology, particle size, polydispersity index (PDI), association efficiency (AE), drug loading (DL), infrared and Raman spectroscopy as well as antioxidant and radical scavenging activity, in vitro release, and cellular studies. MP was shown to be spherical with some agglomeration. Its particle size was 1654 ± 0.210 nm with a PDI of 0.7. The AE and DL were, respectively, 100.30 ± 2.66% and 13.16 ± 0.59. Spectroscopic studies indicated a possible interaction between the PBP and AA. 2,2-Diphenyl-1-picrylhydrazyl (DPPH˙), 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) and ferric reducing antioxidant power (FRAP) assays demonstrated that the MP containing AA have an excellent antioxidant capacity as well as a considerable scavenging activity against reactive oxygen and nitrogen species. The in vitro release profile showed a slow pattern of drug release of AA from MP. Viability studies with intestinal cells revealed that MP did not present toxicity in Caco-2 and HT29-MTX. Moreover, AA could permeate Caco-2 monolayers and triple co-culture substantially at the end of 8 h, opposite to the MP. Therefore, the proposed MP formulation represents a promising platform for oral delivery of AA with a local effect on intestines.

Correction: Development of a microparticulate system containing Brazilian propolis by-product and gelatine for ascorbic acid delivery: evaluation of intestinal cell viability and radical scavenging activity.

Correction for 'Development of a microparticulate system containing Brazilian propolis by-product and gelatine for ascorbic acid delivery: evaluation of intestinal cell viability and radical scavenging activity' by Lizziane Maria Belloto de Francisco et al., Food Funct., 2018, DOI: 10.1039/c8fo00863a.

Iron oxide magnetic nanoparticles as antimicrobials for therapeutics.

The use of iron oxide magnetic nanoparticles (IMNP) in medical and pharmaceutical areas dates to the beginning of the 1970s, as carriers. Some other uses to these nanoparticles are in vitro separation, magnetic resonance imaging and drug targeting agent. Many preparations containing IMNP have been described and used in drug delivery, hyperthermia, in vitro separation, tissue repair, cellular therapy, for magnetic separation, magnetic resonance imaging, as spoilers for magnetic resonance spectroscopy, and more recently as sensors for metabolites and other biomolecules. The use of these nanostructures as antibacterial agents has also been reported, which could kill some bacteria species causing no damage to the human host cells. Recently, they have been used as hyperthermia agents to treat infections or cancer, which are more susceptible than the healthy host's cells. Engineering designs, physiochemical characteristics, biomedical applications of IMNP, toxicity and magnetic nanotoxicology have been discussed. However, the application of IMNP as antimicrobials is very important. Thus, this review explores the therapeutic activities of IMNP and their use as antimicrobial agents. These nanoparticles can be efficient for the treatment of microbial infections, probably acting as membrane permeability enhancer, damaging the cell wall or by generating reactive oxygen species.

Nanostructured lipid systems modified with waste material of propolis for wound healing: Design, in vitro and in vivo evaluation.

Propolis, a natural compound that can accelerate the wound healing process, is mainly used as ethanolic extract. The extractive solution may also be obtained from the propolis by-product (BP), transforming this waste material into a pharmaceutical active ingredient. Even if propolis does not show toxicity, when used as an extract over harmed skin or mucosa, the present ethanol content may be harmful to the tissue recovering, besides hindering the drug release. This study describes the development of solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) as topical propolis delivery systems and the investigation of their in vitro and in vivo activities. The extracts were evaluated to guarantee their quality, and the lipid dispersions were characterized with respect to morphology (cryo-TEM), size and diffractometry (X-ray) properties. The occlusive capacity of formulations was also evaluated by an in vitro technique, which determines the occlusion factor. The drug entrapment efficiency (EE), as well as the in vitro drug release profile from the nanoparticulate systems was investigated as well. The size analysis performed through 90days was favorable to a topical administration and the polydispersity index, though not ideal in all cases due to the high content of resins and gums from the extracts, were relatively stable for the SLN. The propolis extract contributes to the occlusive potential of the formulations. The human immortalized keratinocytes presented good cell viability when tested with both extracts (propolis and BP) freely or entrapped in the systems. SLN modified with propolis material provided an acceleration of the in vivo wound healing process.

Waste Material of Propolis as a Film Forming Agent Intended to Modify the Metronidazole Release: Preparation and Characterization.

Metronidazole is an antimicrobial agent utilized for the treatment of protozoa and anaerobic bacteria infections. Many times, it is necessary to modify the metronidazole release, and the development of modified release systems may be suggested. In this study, we are able to investigate the use of the residue normally thrown out from the preparation of propolis extracts (BP) as strategy to modify the metronidazole release. We prepared films containing polymeric adjuvant (gelatin or ethylcellulose) and metronidazole, by solvent casting method. Density, mechanical properties, water vapor permeability (WVP), moisture uptake capacity (MUC), thermogravimetry, differential scanning calorimetry, Fourier transform infrared spectroscopy (FT-IR), and in vitro metronidazole release were investigated. Thickness and density of the preparations indicated that the compounds were homogeneously dispersed throughout. Mechanical properties were influenced by film composition. Films containing gelatin showed higher resistance to stress while those containing ethylcellulose presented greater flexibility. The greater the adjuvant concentrations lower the resistance to rupture and the elasticity, but higher MUC and WVP of formulations. FT-IR tests suggested interactions between BP and the adjuvants. Films were capable to protect the metronidazole and changed its release profile. BP films are of great practical importance constituting a novel strategy to modify the metronidazole release.

Pharmaceutical films made from the waste material from the preparation of propolis extracts: development and characterization

abstract This study investigated the development and characterized the physicochemical properties of films obtained from by-products (BP) from the preparation of propolis extracts. Films were produced in the presence and absence of a polymeric adjuvant (gelatin or ethylcellulose) and propylene glycol by a solvent casting method. Density, surface topography by scanning electron microscopy, mechanical properties (folding endurance, tensile strength and percentage elongation), water vapour permeability (WVP), moisture uptake capacity, thermogravimetry, differential scanning calorimetry and Fourier transform infrared spectroscopy (FTIR) were determined. The films were a transparent, light greenish-yellow colour, with a uniform surface, and were flexible and easy to handle. The thickness and density of the preparations indicated that the compounds were homogeneously dispersed throughout the film. Mechanical properties were influenced by the film composition; films containing gelatin were more resistant to stress, while those containing ethylcellulose were more flexible. Increasing the adjuvant concentration decreased the elasticity and the rupture resistance, but increased the moisture uptake capacity and WVP of the formulations. BP was thermally stable as were the films. FTIR tests suggested interactions between BP and the adjuvants. This work could contribute to the utilization of BP to prepare films for food and pharmaceutical uses.

resumo Este estudo investigou o desenvolvimento e as características físico-químicas de filmes obtidos com o resíduo (BP), normalmente descartado, advindo da preparação de extratos de própolis. Os filmes foram produzidos com e sem adjuvantes poliméricos (gelatina ou etilcelulose) e propilenoglicol, pelo método de evaporação de solvente. Foram determinadas a densidade, a topografia de superfície usando microscopia eletrônica de varredura, as propriedades mecânicas (resistência à dobra, tensão e elongação), transmissão de vapor de água (WVP), capacidade de absorção de umidade, termogravimetria, calorimetria exploratória diferencial e espectroscopia de infravermelho com transformada de Fourier (FTIR). Os filmes demonstraram coloração verde-amarelada, transparência, uniformidade de superfície, homogeneidade, flexibilidade e fácil manuseio. A espessura e a densidade das preparações indicaram que os compostos estavam dispersos de forma homogênea. As propriedades mecânicas foram influenciadas pela composição dos filmes e aqueles que continham gelatina apresentaram-se mais resistentes enquanto os compostos por etilcelulose demonstraram maior flexibilidade. Com o aumento da concentração polimérica, a resistência e a elasticidade diminuíam, porém aumentou a capacidade de absorção de água e a WVP das formulações. BP apresentou estabilidade térmica assim como os filmes. Os testes de FTIR sugeriram interações entre o BP e os adjuvantes utilizados. Este trabalho pôde contribuir com a utilização de BP na preparação de filmes para uso alimentício e farmacêutico.