Naringenin: A potential flavonoid phytochemical for cancer therapy.

Naringenin is an important phytochemical which belongs to the flavanone group of polyphenols, and is found mainly in citrus fruits like grapefruits and others such as tomatoes and cherries plus medicinal plants derived food. Available evidence demonstrates that naringenin, as herbal medicine, has important pharmacological properties, including anti-inflammatory, antioxidant, neuroprotective, hepatoprotective, and anti-cancer activities. Collected data from in vitro and in vivo studies show the inactivation of carcinogens after treatment with pure naringenin, naringenin-loaded nanoparticles, and also naringenin in combination with anti-cancer agents in various malignancies, such as colon cancer, lung neoplasms, breast cancer, leukemia and lymphoma, pancreatic cancer, prostate tumors, oral squamous cell carcinoma, liver cancer, brain tumors, skin cancer, cervical and ovarian cancer, bladder neoplasms, gastric cancer, and osteosarcoma. Naringenin inhibits cancer progression through multiple mechanisms, like apoptosis induction, cell cycle arrest, angiogenesis hindrance, and modification of various signaling pathways including Wnt/ß-catenin, PI3K/Akt, NF-ĸB, and TGF-ß pathways. In this review, we demonstrate that naringenin is a natural product with potential for the treatment of different types of cancer, whether it is used alone, in combination with other agents, or in the form of the naringenin-loaded nanocarrier, after proper technological encapsulation.

Methyl-ß-cyclodextrin Inclusion Complex with ß-Caryophyllene: Preparation, Characterization, and Improvement of Pharmacological Activities.

ß-Caryophyllene (BCP) is a sesquiterpene that shows high potential in pharmacological applications. However, these have been drastically limited by the respective volatility and poor water solubility. The present study investigates the formation of inclusion complexes between BCP and methyl-ß-cyclodextrin (MßCD) and shows that these complexes promote a significant improvement of the anti-inflammatory, gastric protection, and antioxidant activities relative to neat BCP. It is shown that the solubility of BCP is significantly increased through complexation in phase solubility studies. Inclusion complexes with MßCD in solid state were prepared by three different methods, kneading, rotary evaporation, and lyophilization, with the latter confirmed by differential scanning calorimetry, Fourier transformed infrared spectroscopy, scanning electron microscopy, 1H NMR spectroscopy, and molecular dynamics studies. This study provides for the first time a full characterization of inclusion complexes between BCP and MßCD and highlights the impact of complex formation upon pharmacological activity.

Novel serine-based gemini surfactants as chemical permeation enhancers of local anesthetics: A comprehensive study on structure-activity relationships, molecular dynamics and dermal delivery.

This work aims at studying the efficacy of a series of novel biocompatible, serine-based surfactants as chemical permeation enhancers for two different local anesthetics, tetracaine and ropivacaine, combining an experimental and computational approach. The surfactants consist of gemini molecules structurally related, but with variations in headgroup charge (nonionic vs. cationic) and in the hydrocarbon chain lengths (main and spacer chains). In vitro permeation and molecular dynamics studies combined with cytotoxicity profiles were performed to investigate the permeation of both drugs, probe skin integrity, and rationalize the interactions at molecular level. Results show that these enhancers do not have significant deleterious effects on the skin structure and do not cause relevant changes on cell viability. Permeation across the skin is clearly improved using some of the selected serine-based gemini surfactants, namely the cationic ones with long alkyl chains and shorter spacer. This is noteworthy in the case of ropivacaine hydrochloride, which is not easily administered through the stratum corneum. Molecular dynamics results provide a mechanistic view of the surfactant action on lipid membranes that essentially corroborate the experimental observations. Overall, this study suggests the viability of these serine-based surfactants as suitable and promising delivery agents in pharmaceutical formulations.

Transport properties in aqueous ethambutol dihydrochloride.

Mutual diffusion coefficients, densities and viscosities are reported for aqueous solutions of ethambutol as its dihydrochloride (EMBDHC) at finite concentrations and at 298.15K. From these experimental results and by using the appropriate models (Stokes-Einstein and Hartley), the hydrodynamic radii Rh, the diffusion coefficient at infinitesimal concentration D(0) and the thermodynamic factors, FT, have been estimated, permitting us to have a better understanding of the transport behavior of ethambutol dihydrochloride in solution. Elucidation of lack of any possible drug-drug interactions in these systems was obtained by complementary (1)H nuclear magnetic resonance (NMR) spectroscopy data.

Lysine-based surfactants as chemical permeation enhancers for dermal delivery of local anesthetics.

The aim of this study is to investigate the efficacy of new, biocompatible, lysine-based surfactants as chemical permeation enhancers for two different local anesthetics, tetracaine and ropivacaine hydrochloride, topically administered. Results show that this class of surfactants strongly influences permeation, especially in the case of the hydrophilic and ionized drug, ropivacaine hydrochloride, that is not easily administered through the stratum corneum. It is also seen that the selected permeation enhancers do not have significant deleterious effects on the skin structure. A cytotoxicity profile for each compound was established from cytotoxicity studies. Molecular dynamics simulation results provided a rationale for the experimental observations, introducing a mechanistic view of the action of the surfactants molecules upon lipid membranes.

Effect of cyclodextrins and pH on the permeation of tetracaine: supramolecular assemblies and release behavior.

This work provides a new insight on fundamental principles of the interaction mechanism between two forms of tetracaine - a potent local anesthetic - both in neutral (TC) and ionized (TC(+)) states, with beta- (ß-CD) and hydroxypropyl-beta-cyclodextrin (HP-ß-CD), and how such interactions affect the transport of tetracaine, at different concentrations, across a model membrane. The kinetics and mechanism of TC release from HPMC gels is also evaluated giving an insight on the role of cyclodextrin on the tetracaine transport. HPLC, fluorescence and NMR spectroscopies provided solid physicochemical knowledge of these systems and in vitro studies were performed to obtain relevant data on the transport and mechanism parameters. HPLC and fluorescence spectroscopy data revealed that tetracaine interacts with both cyclodextrins on a 1:1 stoichiometry but it is observed that neutral tetracaine forms more stables complexes (ca. 1050 M(-1) for both cyclodextrins) than in its ionized form (628 and 337 M(-1) for ß-CD and HP-ß-CD respectively). Despite of that, no host-guest interactions take place as seen by ROESY. This study clearly demonstrates that both forms of tetracaine are successfully released from the formulations at a controlled rate, following a Super-Case transport mechanism and the transport of tetracaine can be tuned by using cyclodextrins.

Mass transport techniques as a tool for a better understanding of the structure of L-Dopa in aqueous solutions.

Mutual diffusion coefficients, D, densities, ρ, and viscosities, η, are reported for aqueous solutions of L-3,4-dihydroxyphenylalanine (L-Dopa) at 298.15K and 310.15K at concentrations from (0.00025 to 0.0075) moldm(-3). The aim of this study is to contribute to a better understanding of the structure of these systems and the thermodynamic behaviour of L-Dopa in solution. Thus, from these experimental data it was possible to estimate some parameters, such as the hydrodynamic radius, Rh, apparent molar volumes, ϕV, and diffusion coefficients at infinitesimal concentration, D(0), essential for a better understanding of disperse systems. From the measured diffusion coefficients, activity coefficients, γ, for aqueous L-Dopa solutions were also estimated by using Nernst-Hartley equation. The effect of the viscosity on the estimated hydrodynamic radius was also studied.

Effect of HP-ß-cyclodextrin in the diffusion behaviour of hydrocortisone in aqueous solutions at T=298.15 K.

Binary (D) and ternary (D(11), D(22), D(12) and D(21)) mutual diffusion coefficients determined by the Taylor dispersion method are reported for two aqueous systems, pure hydrocortisone (HC/H(2)O) and HC plus HP-ß-cyclodextrin (HC/HP-ßCD/H(2)O), at T=298.15 K. From these data, some thermodynamic information as well as conclusions about the influence of that carbohydrate in the diffusion of this drug are given.

Calculations of Diffusion Coefficients of Iron Salts in Aqueous Solutions at 298.15 K: A Useful Tool for the Knowledge of the Structure of these Systems.

Diffusion coefficients, thermodynamic and mobility factors of iron salts in aqueous solutions are estimated from Onsager-Fuoss model. The influence of the ion size parameter a, "mean distance of closest approach of ions", determined from different approaches, on the variation of diffusion coefficients with concentration, is also discussed. The aim of this work is to have a better understanding of the structure of these systems and of the thermodynamic behaviour of iron salts in aqueous media.

Solid dispersions of imidazolidinedione by PEG and PVP polymers with potential antischistosomal activities.

Solid dispersions have been used as a strategy to improve the solubility, dissolution rate, and bioavailability of poor water-soluble drugs. The increase of the dissolution rate presented by (5Z)-3-(4-chloro-benzyl)-5-(4-nitro-benzylidene)-imidazolidine-2,4-dione (LPSF/FZ4) from the solid dispersions is related to the existence of intermolecular interactions of hydrogen bond type (>N-H···O<) between the amide group (>N-H) of the LPSF/FZ4 and the ether group (-O-) of the polyethyleneglycol polymer, or the carbonyl (C=O) of the polyvinylpyrrolidone polymer (PVP). The intensity of these interactions is directly reflected in the morphology acquired by LPSF/FZ4 in these systems, where a new solid phase, in the form of amorphous aggregates of irregular size, was identified through scanning electron microscopy and confirmed in the characterizations achieved using X-ray diffraction and thermal analysis of DSC. The solid dispersions with the polymer PVP, in higher concentrations, were revealed to be the best option to be used in the formulations of LPSF/FZ4 in both theoretical and experimental studies.

A comprehensive development strategy in buccal drug delivery.

This work combines several methods in an integrated strategy to develop a matrix for buccal administration. For this purpose, tablets containing selected mucoadhesive polymers loaded with a model drug (omeprazole), free or in a complexed form with cyclodextrins, and in the absence and presence of alkali agents were subjected to a battery of tests. Mucoadhesion studies, including simple factorial analysis, in vitro release studies with both model-dependent and model-independent analysis, and permeation studies were performed. Mucoadhesive profiles indicated that the presence of the drug decreases the mucoadhesion profile, probably due its hydrophobic character. In tablets loaded with the drug complexed with ß-cyclodextrin or methyl-ß-cyclodextrin, better results were obtained with the methylated derivative. This effect was attributed to the fact that in the case of ß-cyclodextrin, more hydroxyl groups are available to interact with the mucoadhesive polymers, thus decreasing the mucoadhesion performance. The same result was observed in presence of the alkali agent (L: -arginine), in this case due to the excessive hydrophilic character of L: -arginine. Drug release from tablets was also evaluated, and results suggested that the dissolution profile with best characteristics was observed in the matrix loaded with omeprazole complexed with methyl-ß-cyclodextrin in the presence of L: -arginine. Several mathematical models were applied to the dissolution curves, indicating that the release of the drug, in free or in complexed state, from the mucoadhesive matrices followed a super case II transport, as established on the basis of the Korsmeyer-Peppas function. The feasibility of drug buccal administration was assessed by permeation experiments on porcine buccal mucosa. The amount of drug permeated from mucoadhesive tablets presented a maximum value for the system containing drug complexed with the methylated cyclodextrin derivative in presence of L: -arginine. According to these results, the system containing the selected polymer mixture and the drug complexed with methyl-ß-cyclodextrin in presence of L: -arginine showed a great potential as a buccal drug delivery formulation, in which a good compromise among mucoadhesion, dissolution, and permeation properties was achieved.

Cyclodextrin multicomponent complexation and controlled release delivery strategies to optimize the oral bioavailability of vinpocetine.

In the present work, to maintain a suitable blood level of vinpocetine (VP) for a long period of time, VP-cyclodextrin-tartaric acid multicomponent complexes were prepared and formulated in hydroxypropylmethylcellulose matrix tablets. In vitro and in vivo performances of these formulations were investigated over a VP immediate release dosage form. Solubility studies were performed to evaluate the drug pH solubilization profile and to assess the effect of multicomponent complexation on VP solubility. The drug release process was investigated using United States Pharmacopeia apparatus 3 and a comparative oral pharmacokinetic study was subsequently undertaken in rabbits. Solubility studies denoted the pH-solubility dependence of VP and solubility improvement attained by complexation. Dissolution results showed controlled and almost complete release behavior of VP over a 12-h period from complex hydroxypropylmethylcellulose-based formulations. A clear difference between the pharmacokinetic patterns of VP immediate release and VP complex-based formulations was revealed. The area under the plasma concentration-time curve after oral administration of complex-based formulations was 2.1-2.9 times higher than that for VP immediate release formulation. Furthermore, significant differences found for mean residence time, elimination half-life, and elimination rate constant values corroborated prolonged release of VP from complex-based formulations. These results suggest that the oral bioavailability of VP was significantly improved by both multicomponent complexation and controlled release delivery strategies.

Solid-state characterization and dissolution profiles of the inclusion complexes of omeprazole with native and chemically modified beta-cyclodextrin.

The aim of this work was to investigate the formation of the inclusion complex between omeprazole (OME), a benzimidazolic derivative and a methylated cyclodextrin, methyl-beta-cyclodextrin (MbetaCD), with an average degree of substitution of 0.5. Inclusion complex between OME and beta-cyclodextrin (betaCD), a natural cyclodextrin, was used as reference. In aqueous media, apparent stability constants (K(s)), which describe the extent of formation of the complexes, have been determined by UV spectroscopy and 1H NMR experiments. The stoichiometry of the complexes was found to be 1:1 mol:mol OME:cyclodextrin (CD) and the value of K(s) was higher for OME:MbetaCD than for OME:betaCD inclusion complexes. Solid binary systems of OME and CDs were prepared by different techniques, namely kneading, spray-drying and freeze-drying. The formation and physicochemical characterization of solid inclusion complexes were investigated by differential scanning calorimetry (DSC), Fourier transform-infrared (FTIR), X-ray diffractometry (XRD) and scanning electron microscopy (SEM). The results show that freeze-drying method produces true inclusion complexes between OME and both CDs. In contrast, crystalline drug was detectable in kneaded and spray-drying products. The dissolution of OME from the binary systems was studied to select the most appropriate system for the development of a buccal drug delivery formulation. It was concluded that the preparation technique played an important role in the dissolution behaviour of the drug and the inclusion complex between OME and MbetaCD obtained by spray-drying and freeze-drying allowed better performances.

Interaction of omeprazole with a methylated derivative of beta-cyclodextrin: phase solubility, NMR spectroscopy and molecular simulation.

PURPOSE: Cyclodextrins are known to be good solubility enhancers for several drugs, improving bioavailability when incorporated in pharmaceutical formulations. In this work we intend to assess and characterize the formation of inclusion complexes between omeprazole (OME) and a methylated derivative of beta-cyclodextrin, methyl-beta-cyclodextrin (MbetaCD). A comparison with results obtained from the most commonly used natural cyclodextrin, beta-cyclodextrin (betaCD) is also presented in most cases. MATERIALS AND METHODS: The interaction of OME with the mentioned cyclodextrins in aqueous solutions was studied by phase solubility studies, 1D (1)H and 2D rotating frame nuclear overhauser effect NMR spectroscopy (ROESY) and Molecular Dynamics. RESULTS: The solubility of OME was significantly increased by formation of inclusion complexes with each cyclodextrin. Phase solubility studies and continuous variation plots revealed that OME forms an inclusion complex in a stoichiometry of 1:1 with both cyclodextrins. (1)H NMR and ROESY spectra of the inclusion complexes indicated that the benzimidazole moiety is included within the cyclodextrins cavities. Molecular dynamics showed that OME is more deeply included in the MbetaCD than in betaCD cavity, in agreement with a larger apparent stability constant (K (S)) obtained for the inclusion complex with MbetaCD. CONCLUSIONS: MbetaCD proved to be an efficient enhancer of OME solubility, thus possessing characteristics for being an useful excipient in pharmaceutical formulations of this drug.

In vitro controlled release of vinpocetine-cyclodextrin-tartaric acid multicomponent complexes from HPMC swellable tablets.

The objective of this study was to investigate the effect of multicomponent complexation (MCC) of vinpocetine (VP), a poorly soluble base-type drug, with beta-cyclodextrin (betaCD), sulfobutylether beta-cyclodextrin (SBEbetaCD), tartaric acid (TA), polyvinylpyrrolidone (PVP) and hydroxypropylmethylcellulose (HPMC), on the design of controlled release hydrophilic HPMC tablets and to evaluate their in vitro release profiles by a pH gradient method. Multicomponent complexation led to enhanced dissolution properties of VP both in simulated gastric and intestinal fluids, and became possible the development of HPMC tablet formulations with more independent pH dissolution profiles. Drug release process was investigated experimentally using USP apparatus 3 and by means of model-independent parameters. Responses studied included similarity of dissolution profiles, time for 60% of the drug to dissolve (T(60%)), percent of VP released after 7 h (PD(7 h)) and the dissolution efficiency parameter at 12 h (DE(12 h)). Influence of multicomponent complexation was proved to increase the release of VP from HPMC tablets and superior PD(7 h) and DE(12 h) values were obtained in formulations containing VP-CD-TA complexes. Results supported the use of HPMC matrices to provide a useful tool in retarding the release of VP and that dissolution characteristics of the drug may be modulated by multicomponent complexation in these delivery systems, suggesting an improvement on VP bioavailability.

Multicomponent complex formation between vinpocetine, cyclodextrins, tartaric acid and water-soluble polymers monitored by NMR and solubility studies.

This work deals with multicomponent complex formation of vinpocetine (VP) with beta-cyclodextrin (betaCD), sulfobutyl ether beta-cyclodextrin (SBEbetaCD) and tartaric acid (TA), in the presence or absence of water-soluble polymers, in aqueous solution. Complexation was monitored by phase-solubility and proton nuclear magnetic resonance ((1)H NMR) studies. TA demonstrated a synergistic effect on VP solubility, and in the complexation efficiency of betaCD and SBEbetaCD. Additionally, water-soluble polymers increased even more the complexation efficiency of the CDs that was reflected by a 2.1-2.5 increase on K(C) values for VP-CD-TA-polymer multicomponent complexes. SBEbetaCD was more effective in VP solubilization, as K(C) values of VP-SBEbetaCD-TA multicomponent complexes were notably higher than in corresponding betaCD complexes. The large chemical shift displacements from protons located in the interior of the hydrophobic CD cavities (i.e., H-3 and H-5) coupled with significant chemical shift displacements of VP aromatic protons suggested that this moiety was included in the cavity of both betaCD and SBEbetaCD. Two-dimensional rotating frame nuclear Overhauser effect spectroscopy (ROESY) experiments were carried out in order to obtain information about the multicomponent complex geometry in solution. Inspection of ROESY spectra allowed the establishment of spatial proximities between all aromatic protons of VP and the internal protons of the CDs, confirming that the aromatic moiety of VP is included in CD cavities being deeply inserted in SBEbetaCD multicomponent complexes, since additional interactions with the sulfobutyl side chains were evidenced.

Physicochemical investigation of the effects of water-soluble polymers on vinpocetine complexation with beta-cyclodextrin and its sulfobutyl ether derivative in solution and solid state.

The studies reported in this work aimed to elucidate the inclusion complex formation of vinpocetine (VP), a poorly water-soluble base type drug, with beta-cyclodextrin (betaCD) and its sulfobutyl ether derivative (sulfobutyl ether beta-cyclodextrin (SBEbetaCD)), with or without water-soluble polymers (PVP and HPMC), by thoroughly investigating their interactions in solution and solid state. Phase solubility studies were carried out to evaluate the solubilizing power of both cyclodextrins (CDs), in association with water-soluble polymers, towards VP and to determine the apparent stability constants (Kc) of the complexes. SBEbetaCD showed higher solubilizing efficacy toward VP than the parent betaCD due to its greater solubility and complexing abilities, what was reflected in higher Kc values. Improvement in Kc values for ternary complexes clearly proves the benefit on the addition of water-soluble polymers to promote higher complexation efficiency. VP-CDs (1:1) binary and ternary systems were prepared by physical mixing, kneading, co-evaporation, and lyophilization methods. In the solid state, drug-carrier interactions were studied by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), X-ray diffractometry (XRD) and Fourier-transform infrared spectroscopy. The results of these analysis suggested the formation of new solid phases, some of them in amorphous state, allowing to the conclusion of strong evidences of binary and ternary inclusion complex formation between VP, CD and water-soluble polymers, particularly for co-evaporated and lyophilized binary and ternary products.

Multimodal molecular encapsulation of nicardipine hydrochloride by beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin and triacetyl-beta-cyclodextrin in solution. Structural studies by 1H NMR and ROESY experiments.

Proton nuclear magnetic resonance spectroscopy (1H NMR), which has become an important tool for in vitro study of cyclodextrin (CD) complexes, was used to study and structurally characterize the inclusion compounds formed in solution between nicardipine hydrochloride (NC) and beta-cyclodextrin (betaCD), hydroxypropyl-beta-cyclodextrin (HPbetaCD) and triacetyl-beta-cyclodextrin (TAbetaCD). The large variation of chemical shifts from protons located around the interior of the hydrophobic cavity (i.e. H-3, H-5 and H-6) coupled with minimal variation of shifts from protons located on the outer sphere of the betaCD (i.e. H-1, H-2 and H-4) provided clear evidence of inclusion complexation. In the presence of the different CDs, the aromatic protons of NC were the most affected, suggesting a strong involvement of the phenyl groups in the inclusion mechanism. The application of continuous variation method indicated the presence of complexes with a 1:1 host/guest stoichiometry for all the studied CDs. Two-dimensional rotating frame nuclear Overhauser effect spectroscopy (ROESY) experiments were carried out to further support the proposed inclusion mode. Inspection of the ROESY spectra allowed the establishment of spatial proximities between several aromatic hydrogens of the guest and the CD protons, indicating that the inclusion occurs by accommodation of the two aromatic groups of NC. All the experimental data were further rationalized to elaborate possible three-dimensional geometric models of inclusion complexes. From the aforementioned observations, we concluded there is no preference for inclusion of a particular aromatic ring. Instead, two types of 1:1 complexes with different inclusion structures may exist simultaneously in solution, being alternatively included through the wider side of the cavity, i.e. the so-called multimodal inclusion occurs in the interaction of NC with the different CDs.

Physicochemical characterization and in vitro dissolution behavior of nicardipine-cyclodextrins inclusion compounds.

Inclusion complexation between nicardipine hydrochloride (NC), a calcium-channel antagonist, and beta-cyclodextrin (beta-CD) or hydroxypropyl-beta-cyclodextrin (HPbetaCD) was evaluated in aqueous environment and in solid state. The phase solubility profiles with both cyclodextrins (CDs) were classified as A(L)-type, indicating the formation of 1:1 stoichiometric inclusion complexes. Stability constants (Ks) were calculated from the phase solubility diagrams and were found to be pH dependent. More stable NC:CDs complexes were formed in alkaline medium in which the drug is in its non-ionized form. Binary systems of NC with CDs, prepared experimentally by different techniques (kneading, evaporation, freeze-drying and spray-drying), were investigated by differential scanning calorimetry, Fourier transformation-infrared spectroscopy, X-ray diffractometry and scanning electron microscopy. From this analysis, evaporation, freeze-drying and spray-drying were found to produce inclusion complexes. In contrast, crystalline drug was still clearly detectable in the kneaded products. The dissolution profiles of the obtained powders were studied in order to define the most appropriate CD and preparation method to originate inclusion complexes, which will be used in the development of a new controlled release formulation of NC. Both the preparation and nature of carrier played an important role in the dissolution performance of the system. However, independently of the preparation technique, all the combinations with HPbetaCD were more effective in achieving the enhancement of the NC dissolution rate, yielding better performances than the corresponding ones with betaCD.