Marcos Luciano Bruschi

Mucoadhesive drug delivery systems

Drug actions can be improved by developing new drug delivery systems, such as the mucoadhesive system. These systems remain in close contact with the absorption tissue, the mucous membrane, releasing the drug at the action site leading to a bioavailability increase and both local and systemic effects. Mucoadhesion is currently explained by six theories: electronic, adsorption, wettability, diffusion, fracture and mechanical. Several in vitro and in vivo methodologies are proposed for studying its mechanisms. However, mucoadhesion is not yet well understood. The aim of this study was to review the mechanisms and theories involved in mucoadhesion, as well as to describe the most-used methodologies and polymers in mucoadhesive drug delivery systems.

Rheological, mechanical and mucoadhesive properties of thermoresponsive, bioadhesive binary mixtures composed of poloxamer 407 and carbopol 974P designed as platforms for implantable drug delivery systems for use in the oral cavity

This study described the formulation and characterisation of the viscoelastic, mechanical and mucoadhesive properties of thermoresponsive, binary polymeric systems composed of poloxamer (P407) and poly(acrylic acid, C974P) that were designed for use as a drug delivery platform within the oral cavity. Monopolymeric and binary polymeric formulations were prepared containing 10, 15 and 20% (w/w) poloxamer (407) and 0.10-0.25% (w/w) poly(acrylic acid, 934P). The flow rheological and viscoelastic properties of the formulations were determined using controlled stress and oscillatory rheometry, respectively, the latter as a function of temperature. The mechanical and mucoadhesive properties (namely the force required to break the bond between the formulation and a pre-hydrated mucin disc) were determined using compression and tensile analysis, respectively. Binary systems composed of 10% (w/w) P407 and C934P were elastoviscous, were easily deformed under stress and did not exhibit mucoadhesion. Formulations containing 15 or 20% (w/w) Pluronic P407 and C934P exhibited a sol-gel temperature T(sol/gel), were viscoelastic and offered high elasticity and resistance to deformation at 37 degrees C. Conversely these formulations were elastoviscous and easily deformed at temperatures below the sol-gel transition temperature. The sol-gel transition temperatures of systems containing 15% (w/w) P407 were unaffected by the presence of C934P; however, increasing the concentration of C934P decreased the T(sol/gel) in formulations containing 20% (w/w) P407. Rheological synergy between P407 and C934P at 37 degrees C was observed and was accredited to secondary interactions between these polymers, in addition to hydrophobic interactions between P407 micelles. Importantly, formulations composed of 20% (w/w) P407 and C934P exhibited pronounced mucoadhesive properties. The ease of administration (below the T(sol/gel)) in conjunction with the viscoelastic (notably high elasticity) and mucoadhesive properties (at body temperature) render the formulations composed of 20% (w/w) P407 and C934P as potentially useful platforms for mucoadhesive, controlled topical drug delivery within the oral cavity.

Oral bioadhesive drug delivery systems.

The oral mucosal cavity is a feasible, safe, and very attractive site for drug delivery with good acceptance by users. The mucosa is relatively permeable and robust, shows short recovery times after stress or damage, is tolerant to potential allergens, and has a rich blood supply. Moreover, oral mucosal drug delivery bypasses the first-pass effect and avoids presystemic elimination in the gastrointestinal tract. Bioadhesive systems provide intimate contact between a dosage form and the absorbing tissue, which may result in high concentration in a local area and hence high drug flux through the absorbing tissue. The efficacy of oral bioadhesive drug delivery systems is affected by the biological environment and the properties of the polymer and the drug. In the present paper, we review systematically some relevant citations regarding the environment, strategies for oral drug delivery and evaluation, and utilization of the main polymers.

Antifungal Activity of Brazilian Propolis Microparticles against Yeasts Isolated from Vulvovaginal Candidiasis

Propolis, a resinous compound produced by Apis mellifera L. bees, is known to possess a variety of biological activities and is applied in the therapy of various infectious diseases. The aim of this study was to evaluate the in vitro antifungal activity of propolis ethanol extract (PE) and propolis microparticles (PMs) obtained from a sample of Brazilian propolis against clinical yeast isolates of importance in the vulvovaginal candidiasis (VVC). PE was used to prepare the microparticles. Yeast isolates (n = 89), obtained from vaginal exudates of patients with VVC, were exposed to the PE and the PMs. Moreover, the main antifungal drugs used in the treatment of VVC (Fluconazole, Voriconazole, Itraconazole, Ketoconazole, Miconazole and Amphotericin B) were also tested. Minimum inhibitory concentration (MIC) was determined according to the standard broth microdilution method. Some Candida albicans isolates showed resistance or dose-dependent susceptibility for the azolic drugs and Amphotericin B. Non-C. albicans isolates showed more resistance and dose-dependent susceptibility for the azolic drugs than C. albicans. However, all of them were sensitive or dose-dependent susceptible for Amphotericin B. All yeasts were inhibited by PE and PMs, with small variation, independent of the species of yeast. The overall results provided important information for the potential application of PMs in the therapy of VVC and the possible prevention of the occurrence of new symptomatic episodes.

Vaginal mucoadhesive drug delivery systems

Background: The vaginal mucosal cavity is a feasible, safe, very attractive site for drug delivery and highly dynamic with respect to absorption of drugs, their metabolism and their elimination. Compared with other mucosal application sites, the vagina has the following advantages as, a fall in the incidence and severity of gastrointestinal side effects, avoidance of the inconvenience caused by pain, tissue damage and risk of infections which are associated with parenteral routes, ease of self-insertion and removal of the dosage form is possible. In addition, a prolonged contact of a delivery system with the vaginal mucosa may be achieved more easily than at other absorption sites like rectum or intestinal mucosa. Mucoadhesive systems provide intimate contact between a dosage form and the vaginal mucosa, which may result in high concentration in a local area and hence high drug flux through the vaginal mucosa. The efficacy of vaginal mucoadhesive drug delivery systems (DDS) is affected by the biological environment and the properties of the polymer and the drug. Objective: This article reviews systematically some relevant citations regarding the environment, strategies for vaginal drug delivery, evaluation, and utilization of the main polymers. Conclusion: We provide a review of several vaginal mucoadhesive DDS currently in developmental stages or available in the market, immunization via the vagina and special emphasis on the challenges and difficulties associated with delivery of drugs via the vaginal route.

Preparation and Antimicrobial Activity of Gelatin Microparticles Containing Propolis Against Oral Pathogens

ABSTRACT Gelatin microparticles containing propolis ethanolic extractive solution were prepared by spray-drying technique. Particles with regular morphology, mean diameter ranging of 2.27 μm to 2.48 μm, and good entrapment efficiency for propolis were obtained. The in vitro antimicrobial activity of microparticles was evaluated against microorganisms of oral importance (Enterococcus faecalis, Streptococcus salivarius, Streptococcus sanguinis, Streptococcus mitis, Streptococcus mutans, Streptococcus sobrinus, Candida albicans, and Lactobacillus casei). The utilized techniques were diffusion in agar and determination of minimum inhibitory concentration. The choice of the method to evaluate the antimicrobial activity of microparticles showed be very important. The microparticles displayed activity against all tested strains of similar way to the propolis, showing greater activity against the strains of E. salivarius, S. sanguinis, S. mitis, and C. albicans.

Antifungal Activity of Propolis Extract Against Yeasts Isolated from Vaginal Exudates

OBJECTIVE The objective of this study was to evaluate the in vitro antifungal activity of propolis extract against yeasts Candida albicans and Candida non-albicans isolated from vaginal exudates, in comparison with nystatin. DESIGN Ninety-seven (97) vaginal yeasts strains were evaluated. These strains were obtained from different clinical conditions, isolated and stored at the Sector of Medical Mycology of the State University of Maringá (Paraná, Brazil). The assays of susceptibility to nystatin and propolis extracts (PE) were conducted through microdilution in broth (National Committee for Clinical Laboratory Standards-NCCLS, M-27A Document of 1997). RESULTS All the yeasts tested were inhibited by low concentrations of PE (maximum of 393.19 mug/mL of the total flavonoid content), including an isolate resistant to nystatin, regardless of the clinical conditions of the women and the species of yeast isolated. CONCLUSIONS The PE showed an outstanding performance against the tested vaginal yeast strains, and could be included among the novel therapeutic options for the treatment of vulvovaginal candidiasis.

Preparation and characterization of mucoadhesive thermoresponsive systems containing propolis for the treatment of vulvovaginal candidiasis

This work describes the preparation and characterization of mucoadhesive thermoresponsive systems consisted of poloxamer 407 (P407), Carbopol® 934P (C934P), and propolis to treat vulvovaginal candidiasis (VVC). Systems were obtained with different percentages of P407 and C934P to deliver propolis, a potent drug against VVC. Temperature of gelation, hardness, compressibility, adhesiveness, elasticity, cohesiveness, mucoadhesion, rheology (continuous flow and oscillatory), in vitro drug release, and antimicrobial activity were evaluated. Increasing the polymer content or temperature and the drug presence significantly increased mechanical properties of formulations. These exhibited pseudoplastic flow and low degrees of thixotropy. In most samples, increasing the C934P content significantly changed the oscillatory rheological properties. Formulations showed thermoresponsive behavior, existing as a liquid at room temperature and gel at 34°C-37°C. Propolis release from formulations was controlled by phenomenon of relaxation of polymer chains or displayed anomalous behavior, dependent of concentration of each polymer. The in vitro antimicrobial activity of preparations was evaluated against microorganisms of vaginal importance (Candida albicans, Candida glabrata, Candida parapsilosis, Candida tropicalis, and Saccharomyces cerevisiae), displaying activity against all yeast tested. The data obtained for these systems indicate a potentially useful role in the treatment of VVC and suggest they are worthy of clinical evaluation.

Application of an HPLC method for analysis of propolis extract

Abstract Propolis obtained from honeybee hives has been widely used in medicine, cosmetics, and industry due to its versatile biological activities (antioxidant, antimicrobial, fungicidal, antiviral, antiulcer, immunostimulating, and cytostatic). These activities are mainly attributed to the presence of flavonoids in propolis, which points out the interest in quantifying these constituents in propolis preparations, as well as validation of analytical methodologies. High‐performance liquid chromatography (HPLC) methods have been reported to quantify isolated flavonoids or these compounds in complex biological matrices, such as herbal raw materials and extractive preparations. An efficient, precise, and reliable method was developed for quantification of propolis extractive solution using HPLC with UV detection. The chromatograms were obtained from various gradient elution systems (GES) tested in order to establish the ideal conditions for the analysis of propolis extractive solution, using methanol and water:acetonitrile (97.5:2.5, v/v) as mobile phase. Gradient reversed phase chromatography was performed using a stainless steel column (250 × 4.6 mm i.d., 5 µm) filled with Chromsep RP 18 (Varian), column temperature at 30.0 ± 0.1°C and detection at 310 nm. The main validation parameters of the method were also determined. The method showed linearity for chrysin in the range 0.24–2.4 µg mL−1 with good correlation coefficients (0.9975). Precision and accuracy were determined. The obtained results demonstrate the efficiency of the proposed method. The analytical procedure is reliable and offers advantages in terms of speed and cost of reagents.

Rheological, mucoadhesive and textural properties of thermoresponsive polymer blends for biomedical applications.

The development of binary polymeric mixtures (polymer blends) containing bioadhesive and thermoresponsive polymers can provide new materials for biomedical applications, with higher contact, increased adhesion, prolonged residence time, protection, and in determined cases, secured absorption of an active agent from the site of application. Mixtures were prepared using a wide range of poloxamer 407 and Carbopol 971P(®) amounts. The rheological (flow and oscillatory), sol-gel transition temperature, mechanical (hardness, compressibility, adhesiveness, cohesiveness and elasticity), softness, and mucoadhesive properties of formulations were investigated. Moreover, the interaction between the different proportions of polymers was also analyzed. Continuous shear and oscillatory rheometry identified the plastic flow with various degrees of thixotropy, besides the viscoelastic behavior of formulations. The determination of gelation temperature displayed values ranged from 27.17 to 41.09°C. It was also found that low carbomer concentrations were enough to provide positive interaction parameter. However, the highest values were obtained for the polymeric blends with higher concentration of poloxamer 407. The mucoadhesion and softness index were greater in preparations containing 20% (w/w) poloxamer 407. The rheological, mechanical and mucoadhesive properties of the polymeric blends can be manipulated by changing the concentrations of the polymers and they suggest the blends are worthy of biomedical applications.