Understanding mucus modulation behavior of chitosan oligomers and dextran sulfate combining light scattering and calorimetric observations.

This study reports the fundamental understanding of mucus-modulatory strategies combining charged biopolymers with distinct molecular weights and surface charges. Here, key biophysical evidence supports that low-molecular-weight (Mw) polycation chitosan oligosaccharides (COSs) and high-Mw polyanion dextran sulfate (DS) exhibit distinct thermodynamic signatures upon interaction with mucin (MUC), the main protein of mucus. While the COS â†’ MUC microcalorimetric titrations released ~14 kcal/mol and ~60 kcal/mol, the DS â†’ MUC titrations released ~1200 and ~1450 kcal/mol at pH of 4.5 and 6.8, respectively. The MPT-2 titrations of COS â†’ MUC and DS â†’ MUC indicated a greater zeta potential variation at pH = 4.5 (relative variation = 815 % and 351 %, respectively) than at pH = 6.8 (relative variation = 282 % and 136 %, respectively). Further, the resultant binary (COS-MUC) and ternary (COS-DS-MUC) complexes showed opposite behavior (aggregation and charge inversion events) according to the pH environment. Most importantly, the results indicate that electrostatics could not be the driving force that governs COS-MUC interactions. To account for this finding, we proposed a two-level abstraction model. Macro features emerge collectively from individual interactions occurring at the molecular level. Therefore, to understand the outcomes of mucus modulatory strategy based on charged biopolymers it is necessary to integrate both visions into the same picture.

Development of a Mucoadhesive Liquid Crystal System for the Administration of Rifampicin Applicable in Tuberculosis Therapy.

Since 1966, rifampicin (RIF) has been considered one of the most potent drugs in the treatment of tuberculosis (TB), which is caused by infection with M. tuberculosis (Mtb). New nanostructured formulations for RIF delivery and alternative routes of administration have been studied as potential forms of treatment. This study evaluates a liquid crystal system for RIF delivery, using alternative drug delivery routes. The systems developed are composed of surfactant, oleylamine, and soy phosphatidylcholine. With the aid of polarized light microscopy, it was possible to determine that the developed systems had a hexagonal mesophase. All systems developed showed non-Newtonian pseudoplasticity and a high degree of thixotropy. Liquid crystal systems with RIF showed an increase in elastic potential, indicating greater mu-coadhesiveness. The evaluation of mucoadhesive forces revealed an increase in the mucoadhesive potential in the presence of mucus, indicating the presence of satisfactory mucoadhesive forces. The 9DR and 10DR liquid crystal systems, when submitted to Differential Scanning Calorimetry analysis, remained structured even at temperatures above 100 °C, showing excellent stability. The developed liquid crystal systems showed a tolerable degree of cytotoxicity and bactericidal potential, for example, the 9DR system demonstrated a reduction in bacterial load after the third day and reached zero CFU on the seventh day of the test. The developed systems were also evaluated in the preclinical model of Mtb-infected mice, using the nasal, sublingual, and cutaneous route for the delivery of RIF associated with a nanostructured liquid crystal system as a possible tool in the treatment of TB.

Lipid Nanocarriers for Hyperproliferative Skin Diseases.

Hyperproliferative skin diseases (HSD) are a group of diseases that include cancers, pre-cancerous lesions and diseases of unknown etiology that present different skin manifestations in terms of the degree and distribution of the injuries. Anti-proliferative agents used to treat these diseases are so diverse, including 5-aminolevulinic acid, 5-fluorouracil, imiquimod, methotrexate, paclitaxel, podophyllotoxin, realgar, and corticosteroids in general. These drugs usually have low aqueous solubility, which consequently decreases skin permeation. Thus, their incorporation in lipid nanocarriers has been proposed with the main objective to increase the effectiveness of topical treatment and reduce side effects. This manuscript aims to describe the advantages of using lipid nanoparticles and liposomes that can be used to load diversity of chemically different drugs for the treatment of HSD.

Validation of an innovative analytical method for simultaneous quantification of alpha-cyano-4-hydroxycinnamic acid and the monoclonal antibody cetuximab using HPLC from PLGA-based nanoparticles.

Accumulating evidence has been suggesting that combining two or more anticancer drugs can provide additive or synergistic effects, improving therapeutic efficacy and delaying resistance. Nowadays, advances in nanotechnology-based delivery systems have enabled the association of different drugs into a single carrier and provided therapeutic gains to the proposed regimen. However, a new strategy also requires innovative analytical approaches that assess loading capacity, biological performance, and also comprehend the mechanisms of action. Alpha-cyano-4-hydroxycinnamic acid (CHC) and the monoclonal antibody (mAb) cetuximab (CTX) are explored worldwide for their therapeutic benefits against multiple cancer cells. The present work aims to develop and validate a new method for simultaneous quantification of CHC and CTX in nanoparticulate systems by using reverse phase high-performance liquid chromatography (RP-HPLC) with ultraviolet (UV) detection for CHC, and fluorescence detection for CTX. This method was designed following the guidelines of the International Conference on Harmonization ICH Q2 (R1) and the Food and Drug Administration (FDA) - Guidance for Bioanalytical Method Validation. Chromatographic separation was performed on a C18 column with the mobile phase composed by water, 0.1 % (v/v) trifluoroacetic acid (TFA) and acetonitrile (ACN)-0.1 % TFA on gradient mode at a flow rate of 0.6 mL/min. The performance of the present method was evaluated by system suitability; therefore, linearity, accuracy, precision, detection, limit of detection / limit of quantification, and robustness were also highlighted. Specificity was demonstrated by the chromatographic analyses of CHC and CTX, subjected to several informative stress conditions. The developed method was also successfully used for the first time to quantify the CHC and CTX content in poly(lactic-co-glycolic acid)-based nanoparticles. In conclusion, this new and rapid method presented acceptable analytical performance and can be helpful to simultaneously quantify CHC and CTX in future studies applied to anticancer therapy.

Natural membranes of Hevea brasiliensis latex as delivery system for Casearia sylvestris leaf components

ABSTRACT Natural latex from Hevea brasiliensis (Wild. ex A.Juss) Müll.Arg., Euphorbiaceae, showed angiogenic action and Casearia sylvestris Sw., Salicaceae, leaf derivatives presented anti-inflammatory and wound healing activities. Therefore, an association of these effects was interesting for wound healing applications. The aims of this study were the development of membranes of natural latex incorporated with C. sylvestris leaf derivatives (ethanolic extract, diterpene concentrated fraction and casearin J), their chemical and physical characterization, and the evaluation of in vitro skin permeation and retention of C. sylvestris bioactive secondary metabolites (diterpenes and phenolic compounds). The membranes were developed mixing hydroethanolic solutions of C. sylvestris derivatives with latex and drying them in a desiccator. They were characterized by infrared spectroscopy, scanning electron microscopy, water vapor permeability and mechanical resistance assays, demonstrating that all membranes were permeable, resistant and homogeneous in surfaces. The permeation and retention assays demonstrated dermal penetration of phenolic compounds for ethanolic extract membrane and of casearin-like clerodane diterpenes for all membranes, indicating that these membranes have great potential for therapeutical application as a topical system for C. sylvestris components releasing.

Nanostructured Lipid Carriers as a Strategy to Improve the In Vitro Schistosomiasis Activity of Praziquantel.

Praziquantel (PZQ) is a pyrazinoisoquinoline anthelmintic that was discovered in 1972 by Bayer Germany. Currently, due to its efficacy, PZQ is the drug of choice against all species of Schistosoma. Although widely used, PZQ exhibits low and erratic bioavailability because of its poor water solubility. Nanostructured lipid carriers (NLC), second-generation solid lipid nanoparticles, were developed in the 1990s to improve the bioavailability of poorly water soluble drugs. The aim of this study was to investigate nanostructured lipid carriers as a strategy to improve the efficacy of PZQ in S. mansoni treatment. We prepared NLC2 and NLC4 by adding seventy percent glycerol monostearate (GMS) as the solid lipid, 30% oleic acid (OA) as the liquid lipid and two surfactant systems containing either soybean phosphatidylcholine/poloxamer (PC/P-407) or phosphatidylcholine/Tween 60 (PC/T60), respectively. The carriers were characterized by nuclear magnetic resonance, differential scanning calorimetry, thermogravimetric analysis and Fourier transform-infrared spectroscopy. The safety profile was evaluated using red cell hemolysis and in vitro cytotoxicity assays. The results showed that the encapsulation of PZQ in NLC2 or NLC4 improved the safety profile of the drug. Treatment efficacy was evaluated on the S. mansoni BH strain. PZQ-NLC2 and PZQ-NLC4 demonstrated an improved efficacy in comparison with free PZQ. The results showed that the intestinal transport of free PZQ and PZQ-NLC2 was similar. However, we observed that the concentration of PZQ absorbed was smaller when PZQ was loaded in NLC4. The difference between the amounts of absorbed PZQ could indicate that the presence of T60 in the nanoparticles (NLC4) increased the rigid lipid matrix, prolonging release of the drug. Both systems showed considerable in vitro activity against S. mansoni, suggesting that these systems may be a promising platform for the administration of PZQ for treating schistosomiasis.

Mucoadhesive Amphiphilic Methacrylic Copolymer-Functionalized Poly(ε-caprolactone) Nanocapsules for Nose-to-Brain Delivery of Olanzapine.

Nose-to-brain drug delivery has been proposed to overcome the low absorption of drugs in central nervous system due to the absence of brain-blood barrier in the olfactory nerve pathway. However, the presence of a mucus layer and quick clearance limit the use of this route. Herein, amphiphilic methacrylic copolymer-functionalized poly(ε-caprolactone) nanocapsules were proposed as a mucoadhesive system to deliver olanzapine after intranasal administration. In vitro evaluations showed that these nanocapsules were able to interact with mucin (up to 17% of increment in particle size and 30% of reduction of particle concentration) and nasal mucosa (2-fold higher force for detaching), as well as to increase the retention of olanzapine (about 40%) on the nasal mucosa after continuous wash. The olanzapine-loaded amphiphilic methacrylic copolymer-functionalized PCL nanocapsules enhanced the amount of drug in the brain of rats (1.5-fold higher compared to the drug solution). In accordance with this finding, this formulation improved the prepulse inhibition impairment induced by apomorphine, which is considered as an operational measure of pre-attentive sensorimotor gating impairment present in schizophrenia. Besides, nanoencapsulated olanzapine did not affect the nasal mucosa integrity after repeated doses. These data evidenced that the designed nanocapsules are a promising mucoadhesive system for nose-to-brain delivery of drugs.

Zidovudine-poly(L-lactic acid) solid dispersions with improved intestinal permeability prepared by supercritical antisolvent process.

A supercritical antisolvent (SAS) process for obtaining zidovudine-poly(L-lactic acid) (PLLA) solid dispersions (SDs) was used to attain a better intestinal permeation of this drug. A 3(2) factorial design was used, having as independent variables the ratio 3'-azido-2'3'-dideoxythymidine (AZT)-PLLA and temperature/pressure conditions, as dependent variables the process yield and particle macroscopic morphology. AZT-PLLA production batches were carried out by the SAS process, and the resulting products evaluated via scanning electron microscope, X-ray diffraction, differential scanning calorimetry, and Fourier transform infrared analyses. From the nine possible combinations of tests performed experimentally, only one combination did not produced a solid. The L3 batch of SD, produced with 1:2 (AZT-PLLA) ratio, resulted in a 91.54% yield, with 40% AZT content. Intestinal permeability studies using the AZT-PLLA from L3 batch led to an AZT permeability of approximately 9.87%, which was higher than that of pure AZT (∼3.84%). AZT remained in crystalline form, whereas PLLA remained in semicrystalline form. AZT release is controlled by a diffusion mechanism. It has been demonstrated that it is possible to use PLLA carrier and SAS process to obtain SD, in a single step.

Surfactant systems for nasal zidovudine delivery: structural, rheological and mucoadhesive properties.

OBJECTIVES: Zidovudine is the antiretroviral drug most frequently used for the treatment of AIDS. Although its effectiveness is recognized, it undergoes extensive first-pass metabolism and exhibits poor oral bioavailability. The nasal route is an option for enhanced therapeutic efficacy and to reduce the extent of the first-pass effect. There are some mechanisms that limit intranasal absorption, such as mucociliary clearance, which rapidly removes the formulation from the nasal cavity. To improve the nasal residence time of zidovudine on the nasal mucosa, we aimed to develop a mucoadhesive surfactant system for zidovudine nasal administration. METHODS: Systems composed of PPG-5-CETETH-20 as surfactant, oleic acid and water were characterized by polarized light microscopy, small-angle X-ray scattering and rheological measurements. Mucoadhesion was investigated by phase behaviour studies, rheological synergism and mucoadhesive strength determination. KEY FINDINGS: Results indicate that the original formulations were microemulsions that displayed phase transition to a lamellar phase when brought into contact with aqueous nasal simulated mucus. The phase transition was accompanied by an increase in system elasticity and, irrespective of phase behaviour, all the systems showed a good mucoadhesive force. Thus, a viscous and mucoadhesive liquid crystalline matrix could be formed when the formulations were in contact with simulated mucus, which may prolong the residence time of zidovudine in the nasal cavity. CONCLUSIONS: These findings indicate a potentially useful system for nasal administration of zidovudine.

Development and in vitro evaluation of surfactant systems for controlled release of zidovudine.

The development of a controlled-release dosage form of zidovudine (AZT) is of crucial importance, in view of the pharmacokinetics of its toxic activity. A suitable drug delivery system could increase AZT bioavailability, reducing its dose-dependent side effects. In this study, systems composed of polyoxypropylene (5) polyoxyethylene (20) cetyl alcohol as surfactant (S), oleic acid as oil phase (O), and water (W) were developed, as possible AZT control release systems. They were characterized by polarized light microscopy (PLM), SAXS, and rheological analysis, followed by in vitro release assay. PLM and SAXS results indicated that the mixtures of S/O/W in the proportions 55/35/10 and 55/25/20 formed microemulsion (ME) systems, while 55/20/25 formed lamellar phase. The incorporation of AZT in these systems was greater than in water or oil; moreover, AZT incorporation did not significantly change the phase behavior of the mixtures. MEs behave as Newtonian fluids in flow rheological analysis and the lamellar phase as a pseudoplastic fluid. The release profile indicated that AZT could be released in a controlled manner, since an exponential pattern governs AZT diffusion, as demonstrated by the Weibull mathematical model. These systems are potential carriers for AZT and could have advantages over conventional pharmaceutical forms.

Semisolid systems containing propolis for the treatment of periodontal disease: in vitro release kinetics, syringeability, rheological, textural, and mucoadhesive properties.

Formulations containing poloxamer 407 (P407), carbopol 934P (C934P), and propolis extract (PE) were designed for the treatment of periodontal disease. Gelation temperature, in vitro drug release, rheology, hardness, compressibility, adhesiveness, mucoadhesion, and syringeability of formulations were determined. Propolis release from formulations was controlled by the phenomenon of relaxation of polymer chains. Formulations exhibited pseudoplastic flow and low degrees of thixotropy or rheopexy. In most samples, increasing the concentration of C934P content significantly increased storage modulus (G'), loss modulus (G''), and dynamic viscosity (eta'), at 5 degrees C, G'' exceeded G'. At 25 and 37 degrees C, eta' of each formulation depended on the oscillatory frequency. Formulations showed thermoresponsive behavior, existing as a liquid at room temperature and gel at 34-37 degrees C. Increasing the C934P content or temperature significantly increased formulation hardness, compressibility, and adhesiveness. The greatest mucoadhesion was noted in the formulation containing 15% P407 (w/w) and 0.25% C934P (w/w). The work of syringeability values of all formulations were similar and very desirable with regard to ease of administration. The data obtained in these formulations indicate a potentially useful role in the treatment of periodontitis and suggest they are worthy of clinical evaluation.