0000000000009416
AUTHOR
Amparo Nácher
Sorbitol-penetration enhancer containing vesicles loaded with baicalin for the protection and regeneration of skin injured by oxidative stress and UV radiation.
Abstract Aiming at improving the protective effects of baicalin on the skin, new highly-biocompatible penetration enhancer containing vesicles (PEVs) were developed by modifying the base formulation of transfersomes with sorbitol, thus obtaining sorbitol-PEVs. An extensive evaluation of the physico-chemical features of both transfersomes and sorbitol-PEVs was carried out. Transfersomes were mainly close-packed, multi-compartment vesicles, while sorbitol-PEVs appeared mostly as single, spherical, unilamellar vesicles. All the vesicles were small in size (∼128 nm) and negatively charged (∼−67 mV), without significant differences between the formulations. The in vitro delivery of baicalin to i…
Erratum: Mangas-Sanjuán, V.; et al. Assessment of the Inter-Batch Variability of Microstructure Parameters in Topical Semisolids and Impact on the Demonstration of Equivalence. Pharmaceutics 2019, 11, 503
Demonstration of similar microstructure is essential for demonstrating the equivalence of generic topical products since the microstructure of semisolids may affect the drug release. The objective of this study was to compare the microstructure-defining physical parameters of different batches of a reference ointment containing calcipotriol and betamethasone (Daivobet 50 µg/0.5 mg/g) in order to define the acceptance range that allows concluding equivalence between these batches. Being batches of the same reference product, they are expected to be clinically equivalent and possess similar microstructure. The 90% confidence intervals for the test/reference ratio of these physical parameters …
Development of antibiotic loaded biodegradable matrices to prevent superficial infections associated to total knee arthroplasty.
Abstract Development of a pharmaceutical form for the superficial infections related with arthroplasties would be helpful for clinical practice. In this context, we set out to evaluate ciprofloxacin and gentamicin elution from systems based on chitosan. Films and semisolid hydrogels containing chitosan alone (2%) or in combination with gelatin (6%) or different proportions (from 12% to 36%) of tetrakis-(hydroxymethyl)-phosphonium-chloride (THPC) were tested as delivery systems. Different antibiotic doses were assayed (0.5 mg/cm2,1 mg/cm2 and 2 mg/cm2). Antibiotic release was studied for each formulation. In vitro cytocompatibility studies and a simulation exercise for bioactivity evaluation…
Impact of nutritional status on the oral bioavailability of leucine administered to rats as part of a standard enteral diet.
Summary Background To investigate the absorption and relative bioavailability of leucine administered orally as part of an enteral diet in well and malnourished animals. Methods Two groups – RN (regular nutrition) and PCR (protein-calorie restricted) – were fed with different diets for 23–25 days. Rats from each group were assigned randomly to one of three treatments (water, T-Diet Plus Standard ® (problem) or Isosource ST ® (reference)) administered in single ( N = 76) or multiple ( N = 39) doses. Blood samples were assayed for leucine content. Area under the curve (AUC) was calculated by non-compartmental analysis. Log-transformed AUC(s) were statistically compared by analysis of varian…
Polymeric nanospheres as strategy to increase the amount of triclosan retained in the skin: passive diffusion vs. iontophoresis
The aim of this study was to evaluate the passive and iontophoretic permeation of triclosan in human skin using a triclosan solution and triclosan-loaded cationic nanospheres in order to determine which of the two strategies is more effective in allowing the deposition of triclosan within the skin. Triclosan-loaded nanospheres were prepared by the emulsification-solvent displacement technique using aminoalkyl methacrylate (Eudragit® RL 100) as polymer matrix. Nanospheres of 261.0 ± 15.1 nm with a positive surface charge (Ψz = 26.0 ± 3.2 mV) were obtained. Drug loading was 62.0 ± 1.7%. Results demonstrated that the amount of triclosan retained within the skin was significantly greater (8.5-f…
Nutriosomes: Prebiotic delivery systems combining phospholipids, a soluble dextrin and curcumin to counteract intestinal oxidative stress and inflammation
Nutriosomes, new phospholipid nanovesicles specifically designed for intestinal protection were developed by simultaneously loading a water-soluble dextrin (Nutriose® FM06) and a natural antioxidant (curcumin). Nutriosomes were easily fabricated in a one-step, organic solvent-free procedure. The stability and delivery performances of the vesicles were improved by adding hydroxypropyl methylcellulose. All the vesicles were small in size (mean diameter ∼168 nm), negatively charged (zeta potential ∼-38 mV, irrespective of their composition), and self-assembled predominantly in unilamellar vesicles stabilized by the presence of Nutriose®, which was located in both the inter-lamellar and inter-v…
Mangiferin glycethosomes as a new potential adjuvant for the treatment of psoriasis
[EN] Mangiferin, a natural compound isolated from Mangifera indica L, was incorporated in glycerosomes, ethosomes and alternatively in glycerol-ethanol phospholipid vesicles (glycethosomes). Actually, only glycethosomes were able to stably incorporate the mangiferin that was loaded at increasing concentrations (2, 4, 6, 8 mg/mL). The morphology, size distribution, rheological properties, surface charge and entrapment efficiency of prepared vesicles were deeply measured. All vesicles were mainly spherical, oligolamellar, small in size (similar to 145 nm) and negatively charged (similar to-40 mV), as confirmed by cryo-TEM observation and dynamic laser light scattering measurements. The higher…
Bifunctional viscous nanovesicles co-loaded with resveratrol and gallic acid for skin protection against microbial and oxidative injuries.
Resveratrol and gallic acid were co-loaded in phospholipid vesicles aiming at protecting the skin from external injuries, such as oxidative stress and microbial infections. Liposomes were prepared using biocompatible phospholipids dispersed in water. To improve vesicle stability and applicability, the phospholipids and the phenols were dispersed in water/propylene glycol or water/glycerol, thus obtaining PEVs and glycerosomes, respectively. The vesicles were characterized by size, morphology, physical stability, and their therapeutic efficacy was investigated in vitro. The vesicles were spherical, unilamellar and small in size: liposomes and glycerosomes were around 70nm in diameter, while …
Exploring the co-loading of lidocaine chemical forms in surfactant/phospholipid vesicles for improved skin delivery
Abstract Objectives The present study was aimed at targeting the skin to deliver lidocaine loaded in surfactant/phospholipid vesicles tailored for improved local delivery. The influence of different formulation parameters was explored to maximise drug efficacy. Methods The vesicles were prepared using a mixture of soy lipids (Phospholipon 50) and a surfactant with penetration-enhancing properties (Oramix CG110, Labrasol, Labrafac PG or Labrafac CC), and loaded with lidocaine. The formulations were analysed in detail by cryo-TEM, SAXS, Turbiscan Lab, and tested in permeation experiments through new born pig skin, as a function of the chemical form and concentration of lidocaine (i.e. free ba…
Enhancement of nortriptyline penetration through human epidermis: influence of chemical enhancers and iontophoresis.
Abstract Different known percutaneous chemical enhancers and iontophoresis have been tested in-vitro to study their ability to increase transdermal absorption of nortriptyline hydrochloride (20 mg mL−1). The chemicals 1-dodecanol, Span 20, Azone, (R)-(+)-limonene or isopropyl myristate were used as an overnight pretreatment at 5% (w/w) in ethanol. Furthermore, isopropyl myristate (20%, w/w) and propylene glycol (15%, w/w) were tested in the same vehicle. Iontophoresis was applied directly to the nortriptyline hydrochloride donor solution for three different concentrations (20, 2 and 0.5 mgmL−1). The chemical enhancers slightly increased the nortriptyline transdermal flux but iontophoresis w…
Levofloxacin effect on erlotinib absorption. Evaluation of the interaction in undernutrition situations through population pharmacokinetic analysis in rats
The main objective of this study was to develop a pharmacokinetic model in order to describe the intestinal absorption of erlotinib in rat and to quantify the interaction of levofloxacin on this process in well- and under-nourished rats. Absorption studies were performed in male Wistar rats. Concentration-time profiles in proximal and distal intestine were analysed through non-linear mixed effect modelling using the NONMEM software version 7.3. Simulations were performed in order to explore the influence of covariates on the apparent absorption rate constant. A passive absorption and an active secretion process best-described erlotinib absorption from lumen to enterocyte. The developed mode…
Hydroxypropylmethylcellulose films for the ophthalmic delivery of diclofenac sodium
Abstract Objectives The aim of this study was to prepare diclofenac/hydroxypropylmethylcellulose (HPMC) and diclofenac-loaded nanoparticles/HPMC films as potential systems for ocular delivery. Methods Two different concentration of the polymer were used: 1.5 and 2.0% w/v. Chitosan–hyaluronic acid nanoparticles were prepared by the ionotropic gelation technique. Nanoparticles were characterized by transmission electron microscopy, dynamic light scattering, drug encapsulation efficiency and rheological studies. In-vitro drug studies and corneal penetration release studies were carried out. Drug release mechanism was finally evaluated by fitting the Ritger and Peppas equation to data. In addit…
Fabrication of quercetin and curcumin bionanovesicles for the prevention and rapid regeneration of full-thickness skin defects on mice
In the present work biocompatible quercetin and curcumin nanovesicles were developed as a novel approach to prevent and restore skin tissue defects on chronic cutaneous pathologies. Stable and suitable quercetin- and curcumin-loaded phospholipid vesicles, namely liposomes and penetration enhancer-containing vesicles (PEVs), were prepared. Vesicles were made from a highly biocompatible mixture of phospholipids and alternatively a natural polyphenol, quercetin or curcumin. Liposomes were obtained by adding water, while PEVs by adding polyethylene glycol 400 and Oramix®CG110 to the water phase. Transmission electron microscopy, cryogenic-transmission electron microscopy and small- and wide-ang…
Influence of gamma-aminobutyric acid on baclofen intestinal absorption.
Since previous studies suggested that baclofen absorption in the rat middle intestine was inhibited by beta-alanine and therefore mediated, at least in part, by the beta-aminoacid carrier, we focused our new studies on the analysis of the possible inhibition of the drug by a gamma-aminoacid model compound, gamma-aminobutyric acid (GABA). A rat jejunum in situ study was undertaken in order to evaluate the effect of GABA on baclofen absorption and to establish the inhibition model. Assays using isotonic perfusion solutions of 0.5 mM baclofen with starting GABA concentrations ranging from 0 to 100 mM are reported. The results show that the absorption rate pseudoconstants of the drug decrease a…
Labetalol absorption kinetics: Rat small intestine and colon studies
Labetalol is a widely used drug for the management of hypertension, which is preferably administered by the oral route despite its low bioavailability. The objective of this study is to ascertain the mechanisms underlying its absorption as an approach to help in predicting the influence of dosage changes, possible drug-drug and drug-fruit juice interactions. Perfusion experiments have been performed in rats in two sites of absorption: the intestine and the colon. The nonlinearity of the process has been established by means of the assay of a wide range of concentrations (2-2000 microM). Fitting of the concentration versus time data allows the estimation of passive diffusion constant in the …
Evidence of competitive inhibition for the intestinal absorption of baclofen by phenylalanine
Abstract Previous studies showed that the absorption of the antispastic drug baclofen, in the rat middle intestine, is inhibited by β-alanine, γ-aminobutyric acid (GABA) and leucine. It was concluded that baclofen intestinal transport was mediated, at least in part, by the β-, γ- and α-amino acid carriers. We therefore focused our next studies on the analysis of the possible inhibition of drug absorption by an aromatic α-amino acid model compound, phenylalanine. An in situ study in the rat small intestine was undertaken in order to evaluate the effect of phenylalanine on baclofen absorption and to establish the inhibition model. Assays using isotonic perfusion solutions of 0.5 mM baclofen w…
Intestinal absorption pathway of gamma-aminobutyric acid in rat small intestine.
Intestinal absorption of gamma-aminobutyric acid (GABA), as a model compound for gamma-aminoacids, has not been extensively studied from the kinetic viewpoint. Since data from our laboratory suggested that some competition arises between intestinal absorption of beta-alanine and GABA and since our intent was to maintain the aqueous stagnant diffusion layer in order to approach absorption tests to in vivo physiological conditions, a rat jejunum in situ study was undertaken in order to gain an insight into the mechanism of GABA absorption. In the present paper, results from assays using isotonic perfusion solutions with starting GABA concentrations ranging from 1 to 50 mM are reported. They s…
Nonlinear intestinal absorption kinetics of cefuroxime axetil in rats.
Cefuroxime is commercially available for parenteral administration as a sodium salt and for oral administration as cefuroxime axetil, the 1-(acetoxy)ethyl ester of the drug. Cefuroxime axetil is a prodrug of cefuroxime and has little, if any, antibacterial activity until hydrolyzed in vivo to cefuroxime. In this study, the absorption of cefuroxime axetil in the small intestines of anesthetized rats was investigated in situ, by perfusion at four concentrations (11.8, 5, 118 and 200 microM). Oral absorption of cefuroxime axetil can apparently be described as a specialized transport mechanism which obeys Michaelis-Menten kinetics. Parameters characterizing absorption of prodrug in free solutio…
Inhibition of skin inflammation by baicalin ultradeformable vesicles.
The topical efficacy of baicalin, a natural flavonoid isolated from Scutellaria baicalensis Georgi, which has several beneficial properties, such as antioxidative, antiviral, anti-inflammatory and antiproliferative, is hindered by its poor aqueous solubility and low skin permeability. Therefore, its incorporation into appropriate phospholipid vesicles could be a useful tool to improve its local activity. To this purpose, baicalin at increasing concentrations up to saturation, was incorporated in ultradeformable vesicles, which were small in size (∼67nm), monodispersed (PI<0.19) and biocompatible, regardless of the concentration of baicalin, as confirmed by in vitro studies using fibroblasts…
Formulation of liposomes loading lentisk oil to ameliorate topical delivery, attenuate oxidative stress damage and improve cell migration in scratch assay
[EN] Pistacia lentiscus L. is a sclerophyllous shrub capable of growing under harsh climatic conditions especially in the Mediterranean Basin. Different products can be obtained from this plant, such as essential oil, mastic gum or even fixed oil. The last is well known for its flavor which is mainly exploited in the food industry. Additionally, it has been traditionally used in the treatment of skin diseases, but, at the moment, any suitable formulation for skin delivery has been formulated and its biological effects was not deeply confirmed. Given that, in the present study, the lentisk oil has been formulated in liposomes at different concentrations (10, 20, 30 mg/ml) and their physicoch…
Baicalin and berberine ultradeformable vesicles as potential adjuvant in vitiligo therapy.
0.5-1% of the world's population is affected by vitiligo, a disease characterized by a gradual depigmentation of the skin. Baicalin and berberine are natural compounds with beneficial activities, such as antioxidant, anti-inflammatory and proliferative effects. These polyphenols could be useful for the treatment of vitiligo symptoms, and their efficacy can be improved by loading in suitable carriers. The aim of this work was to formulate and characterize baicalin or berberine loaded ultradeformable vesicles, and demonstrate their potential as adjuvants in the treatment of vitiligo. The vesicles were produced using a previously reported simple, scalable method. Their morphology, size distrib…
Nanodesign of new self-assembling core-shell gellan-transfersomes loading baicalin and in vivo evaluation of repair response in skin
Gellan nanohydrogel and phospholipid vesicles were combined to incorporate baicalin in new self-assembling core-shell gellan-transfersomes obtained by an easy, scalable method. The vesicles were small in size (~107 nm) and monodispersed (P.I. ≤ 0.24), forming a viscous system (~24 mPa/s) as compared to transfersomes (~1.6 mPa/s), as confirmed by rheological studies. Gellan was anchored to the bilayer domains through cholesterol, and the polymer chains were distributed onto the outer surface of the bilayer, thus forming a core-shell structure, as suggested by SAXS analyses. The optimal carrier ability of core-shell gellan-transfersomes was established by the high deposition of baicalin in th…
Eco-scalable baicalin loaded vesicles developed by combining phospholipid with ethanol, glycerol, and propylene glycol to enhance skin permeation and protection.
Abstract A new class of biocompatible and scalable phospholipid vesicles was developed, aiming at improving the efficacy of baicalin on the skin. Phosphatidylcholine and baicalin (a natural polyphenol) were hydrated in two steps with a mixture of ethanol, glycerol, and propylene glycol at different ratios, and a low amount of water (4%). Hence, water was almost completely replaced by the co-solvents, which were never used before as predominant dispersing medium of phospholipid vesicles. The vesicles appeared three-dimensionally structured, forming a network that conferred a high viscosity to the dispersions. The vesicles were unilamellar, small in size (∼100 nm), and stable during 12 months…
Use of nonlinear mixed effect modeling for the intestinal absorption data: application to ritonavir in the rat.
The aim of this study is to investigate in situ the mechanisms involved in the gastrointestinal absorption of ritonavir in the rat, as an animal model for preclinical studies of anti-HIV agents in vivo. Four ritonavir solutions (40, 27, 13 and 7 microM) in the presence of 1% dimethylsulfoxide (DMSO) were perfused in the small intestine of anaesthetised rats. Effects of DMSO on the intestinal permeability were investigated using solutions containing antipyrine 1.33 mM and ritonavir 7 microM with and without 1% of DMSO. Antipyrine and ritonavir transport was not modified in the presence of 1% of DMSO. The population pharmacokinetic parameters of the ritonavir intestinal transport were obtaine…
Assessment of the Inter-Batch Variability of Microstructure Parameters in Topical Semisolids and Impact on the Demonstration of Equivalence
Demonstration of similar microstructure is essential for demonstrating the equivalence of generic topical products since the microstructure of semisolids may affect the drug release. The objective of this study was to compare the microstructure-defining physical parameters of different batches of a reference ointment containing calcipotriol and betamethasone (Daivobet 50 µ
In Situ Study of the Effect of Naringin, Talinolol and Protein-Energy Undernutrition on Intestinal Absorption of Saquinavir in Rats
To study the potential interactions of naringin (NAR), talinolol (TAL) and protein-energy undernutrition (PEU) in the absorption process of saquinavir (SQV), perfusion experiments were performed in the small intestine of rats at different SQV concentrations. The results obtained demonstrated that SQV intestinal absorption was described by simultaneous passive diffusion (kdif = 3.44 hr) and saturable absorption (Vma = 127.31 lM ⁄ hr; Kma =1 0.50lM) together with a capacity-limited efflux (Vms = 270.53 lM ⁄ hr; Kms =2 3.44lM). The competitive inhibition constants of NAR on the SQV input and efflux processes were (IC50)a =3 .98l Ma nd(IC50)s = 5.00 lM, respectively. NAR significantly decreased…
Bioavailability and pharmacokinetic model for ritonavir in the rat.
The aim of this study is to investigate in vivo the oral bioavailability of ritonavir and to evaluate the pharmacokinetic model that best describes the plasma concentration behavior after oral and intravenous administration. Male Wistar rats were intravenously administered at 3 mg dose of pure ritonavir and oral administered at 4.6 +/- 2.5 mg of diluted Norvir. Blood samples were taken by means of the jugular vein for a 24 h period of time. An analytical high-performance liquid chromatography (HPLC) technique was developed in order to quantify ritonavir plasma concentrations. A nonlinear modeling approach was used to estimate the pharmacokinetic parameters of interest. Results showed that a…
Mangiferin nanoemulsions in treatment of inflammatory disorders and skin regeneration
Abstract In this paper mangiferin nanoemulsions were developed using hyaluronic acid of different molecular weight, in absence or presence of Transcutol-P. An extensive study was carried out on the physico-chemical properties of nanoemulsions. Nanosizer and transmission electron microscopy showed oil droplets average size 296 nm with monodisperses distribution (PI ≤ 0.30). The zeta potential was highly negative (−30 mV). FTIR analysis confirms the existence of physical interactions among compounds. Rheological measurements allowed to conclude that all formulations present a pseudoplastic behavior (s ∼ 0.4) in presence of the biopolymer. Moreover, mangiferin release depends on the molecular …
Population modelling to describe pharmacokinetics of amiodarone in rats: Relevance of plasma protein and tissue depot binding
The objective of this paper was to characterize the disposition phase of AM in rats, after different high doses and modalities of i.v. administration. Three fitting programs, WINNONLIN, ADAPT II and NONMEM were employed. The two-stage fitting methods led to different results, none of which can adequately explain amiodarone's behaviour, although a great amount of data per subject is available. The non-linear mixed effect modelling approach allows satisfactory estimation of population pharmacokinetic parameters, and their respective variability. The best model to define the AM pharmacokinetic profile is a two-compartment model, with saturable and dynamic plasma protein binding and linear tiss…
Glycerosomes: Use of hydrogenated soy phosphatidylcholine mixture and its effect on vesicle features and diclofenac skin penetration.
In this work, diclofenac was encapsulated, as sodium salt, in glycerosomes containing 10, 20 or 30% of glycerol in the water phase with the aim to ameliorate its topical efficacy. Taking into account previous findings, glycerosome formulation was modified, in terms of economic suitability, using a cheap and commercially available mixture of hydrogenated soy phosphatidylcholine (P90H). P90H glycerosomes were spherical and multilamellar; photon correlation spectroscopy showed that obtained vesicles were ∼131nm, slightly larger and more polydispersed than those made with dipalmitoylphosphatidylcholine (DPPC) but, surprisingly, they were able to ameliorate the local delivery of diclofenac, whic…
N-Succinyl-chitosan systems for 5-aminosalicylic acid colon delivery: In vivo study with TNBS-induced colitis model in rats
5-Aminosalicylic acid (5-ASA) loaded N-Succinyl-chitosan (SucCH) microparticle and freeze-dried system were prepared as potential delivery systems to the colon. Physicochemical characterization and in vitro release and swelling studies were previously assessed and showed that the two formulations appeared to be good candidates to deliver the drug to the colon. In this work the effectiveness of these two systems in the treatment of inflammatory bowel disease was evaluated. In vitro mucoadhesive studies showed excellent mucoadhesive properties of both the systems to the inflamed colonic mucosa. Experimental colitis was induced by rectal instillation of 2,4,6-trinitrobenzene sulfonic acid (TNB…
Profile of P-glycoprotein distribution in the rat and its possible influence on the salbutamol intestinal absorption process.
8 pages, 2 figures, 2 tables.--PMID: 15124220 [PubMed]
Relationship between rheological properties, in vitro release and in vivo equivalency of topical formulations of diclofenac.
Determination of bioequivalence remains a challenge in generic topical drug development. To support pharmacokinetic studies, strategies to demonstrate microstructure sameness of the products being compared include in vitro evaluations, such as the comparison of rheological properties, droplet size and in vitro release rates. Nevertheless, defining the appropriate acceptance range to consider equivalence between test and reference formulation is complex. To shed more light into this issue, in vitro release and rheological properties were compared to in vivo bioequivalence data (systemic blood measurements within a clinical trial) after topical application of a single dose. Test and reference…
The influence of active secretion processes on intestinal absorption of salbutamol in the rat.
Abstract Salbutamol was perfused in the small intestine of rat using a standard rat gut ‘in situ’ preparation: (1) in inhibitor-free solution at seven different concentrations (0.15, 0.29, 1.20, 5.0, 9.0, 13.0 and 18.0 mM); (2) at a 0.29 mM concentration – thought to be close to the allometric dose in man – in the presence of a non-specific enzyme inhibitor, sodium azide (0.3, 3.0 and 6.0 mM); and (3) at 0.29 mM in the presence of a selective secretion inhibitor, verapamil (10.0 and 20.0 mM). In free solution, the mixed-order rate constants, k ′ a , of salbutamol increase as the solute concentration increases until an apparent asymptotic value is reached. This could be due to the saturation…
Impact of nutritional status on the pharmacokinetics of erlotinib in rats
Malnourishment is a complex condition in which physiopathological changes take place in multiple systems as a result of energy, protein and nutrient deficiency. The purpose of this study was to evaluate, using an experimental animal model, the impact of nutritional status on the pharmacokinetic profile of erlotinib, a reversible, highly selective, human epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor. Two groups of rats -WN (well-nourished) and UN (undernourished) - were fed with different diets for 23-26 days. Rats were assigned randomly to one of three erlotinib treatments (n = 42) consisting of a single dose administered intravenously (i.v.), via oral solution or v…
A preclinical study to model taurine pharmokinetics in the undernourished rat
AbstractMalnutrition is a common feature of chronic and acute diseases, often associated with a poor prognosis, including worsening of clinical outcome, owing, among other factors, to dysfunction of the most internal organs and systems affecting the absorption, metabolism and elimination of drugs and nutrients. Taurine is involved in numerous biological processes and is required in increased amounts in response to pathological conditions. The aim of this study was to describe the behaviour of taurine in well-nourished (WN) rats and to analyse the influence of protein–energy undernutrition on the pharmacokinetic (PK) parameters of taurine, using a PK model. Wistar rats were randomly distribu…
Design, characterization and in vitro evaluation of 5-aminosalicylic acid loaded N-succinyl-chitosan microparticles for colon specific delivery
The objective of this study was to prepare NS-chitosan microparticles for the delivery of 5-aminosalicylic acid (5-ASA) to the colon. Microparticles can spread out over a large area of colon allowing a more effective local efficacy of 5-ASA. N-Succinyl-chitosan was chosen as carrier system because of its excellent pharmaceutical properties in colon drug targeting such as poor solubility in acid environment, biocompatibility, mucoadhesive properties, and low toxicity. It was prepared by introducing succinic group into chitosan N-terminals of the glucosamine units. 5-ASA loaded NS-chitosan microparticles were prepared using spray-drying. As a control, a matrix obtained by freeze-drying techni…
Investigation of Different Iontophoretic Currents Profiles for Short-Term Applications in Cosmetics.
[EN] This study aimed at investigating the effect of electrical current profile upon the iontophoretic transport of (i) ascorbic acid (AA) and (ii) ellagic acid (EA), into porcine skin in vitro, and the impact of the physicochemical properties of both actives on their mechanism of transport when formulated in cosmetic compositions. The experiments were performed using a proprietary iontophoretic device containing a roller to apply the formulation. Three current profiles were tested: (i) galvanic direct current (DC), (ii) square unipolar pulse current (SPC), and (iii) galvanic direct current (DC) + pulse current (PC). The skin samples were collected at different sampling points, extracted an…
The dopamine uptake inhibitor 3 alpha-[bis(4'-fluorophenyl)metoxy]-tropane reduces cocaine-induced early-gene expression, locomotor activity, and conditioned reward.
Benztropine (BZT) analogs, a family of high-affinity dopamine transporter ligands, are molecules that exhibit pharmacological and behavioral characteristics predictive of significant therapeutic potential in cocaine addiction. Here, we examined in mice the effects of 3 alpha-[bis(4'-fluorophenyl)metoxy]-tropane (AHN-1055) on motor activity, conditioned place preference (CPP) and c-Fos expression in the striatum. AHN-1055 produced mild attenuation of spontaneous locomotor activity at a low dose (1 mg/kg) and weak stimulation at a higher dose (10 mg/kg). In parallel, the BZT analog significantly increased c-Fos expression in the dorsolateral caudoputamen at the high dose, whereas producing ma…
Pharmacokinetic models for the saturable absorption of cefuroxime axetil and saturable elimination of cefuroxime.
Since oligopeptidic drugs such as beta-lactam antibiotics share the same carriers in humans and animals, the absorption and elimination kinetics of cefuroxime (C) were investigated in rats. Plasma C concentrations were measured by liquid chromatography. Pharmacokinetics and bioavailability of C in the rat were examined after intravenous (i.v.) administration at three doses (1.78, 8.9 and 17.8mg) of cefuroxime sodium and oral administration at two doses (2.02 and 8.9mg) of cefuroxime axetil (CA). Preliminary fits using data from intravenous administration of C showed that the drug disposition kinetics were clearly nonlinear, with an increase in plasma clearance as the intravenous dose increa…
Alternative Methods to Animal Testing in Safety Evaluation of Cosmetic Products
Abstract This chapter reviews alternative methods recommended for animal testing in various toxicological areas. An alternative model to achieve complete animal replacement for acute toxicity testing is not possible. Skin corrosion/irritation alternative methods have been validated and accepted. For eye irritation testing, no single method is able to replace the Draize rabbit eye test. Skin sensitization methods imply refinement and reduction of numbers of animals. An in vitro dermal absorption test could be an alternative to in vivo testing. There are no generally accepted alternative methods to replace the usual repeated-dose toxicity in vivo assays. To determine the genotoxic and mutagen…
Evidence of competitive inhibition of methotrexate absorption by leucovorin calcium in rat small intestine
Abstract The effect of leucovorin calcium on the intestinal absorption of methotrexate in rat small intestine was investigated using an in situ rat gut technique. First, the kinetic absorption in situ parameters for methotrexate in solution were obtained: V m =21.54 (±2.22) μ M/h; K m =10.51 (±1.08) μ M; k a =0.26 (±0.03) h −1 and AIC=−188.63. The inhibitory effect of leucovorin calcium in methotrexate intestinal absorption has been investigated by perfusing of 10 μ M methotrexate isotonic solutions containing increasing concentrations of leucovorin calcium (10–500 μ M), and the remaining concentrations of both compounds were measured. A competitive inhibition of methotrexate absorption was…
Intestinal transport of cefuroxime axetil in rats: absorption and hydrolysis processes.
Studies were performed using three cefuroxime axetil solutions (11.8, 118 and 200 microM) in three selected intestinal segments and one cefuroxime axetil solution (118 microM) in colon of anaesthetized rats. First-order absorption rate pseudoconstants, k(ap) and effective permeability coefficients, P(eff), were calculated in each set. Absorption of cefuroxime axetil can apparently be described as a carrier-mediated transport, which obeys Michaelis-Menten and first order kinetics in the proximal segment of the small intestine and a passive diffusion mechanism in the mean and distal segments. The absorption kinetic parameters for cefuroxime axetil were obtained: Vm=0.613 (0.440) microM min-1;…
Development of novel diolein–niosomes for cutaneous delivery of tretinoin: Influence of formulation and in vitro assessment
Abstract This work describes innovative niosomes, composed of diolein alone or in association with the hydrophilic penetration enhancer Labrasol ® , as carriers for cutaneous drug delivery. The model drug was tretinoin and conventional, and Labrasol ® containing liposomes was used as controls to evaluate the influence of vesicle composition and the role of Labrasol ® on vesicle physico-chemical properties and performance as skin delivery system. Vesicles, prepared by the thin film hydration technique, were characterized in terms of size distribution, morphology, zeta potential, structure, incorporation efficiency, and rheological properties. The influence of carrier composition on tretinoin…
Pharmacokinetics and absolute bioavailability of oral cefuroxime axetil in the rat.
The objectives of this study were to determine the oral bioavailability of cefuroxime (C) and to evaluate the pharmacokinetic model that best describes the plasma concentration behaviour following single intravenous (IV), intraperitoneal (IP) and oral single doses. The same dose of C was administered by IV, IP and oral routes to three separate groups of rats (2.02 mg of cefuroxime axetil (CA) by the oral route or 1.78 mg of cefuroxime sodium (CNa) by IV and IP route). A two-compartment open model without lag time can predict the C disposition kinetics. The influence of the administration route on the pharmacokinetic parameters and AUC values was investigated by means of a one-way analysis o…
A novel ultradeformable liposomes of Naringin for anti-inflammatory therapy
[EN] Ultradeformable liposomes were formulated using naringin (NA), a flavanone glycoside, at different concentrations (3, 6 and 9 mg/mL). Nanovesicles were small size (similar to 100 nm), regardless of the NA concentration used, and monodisperse (PI<0.30). All formulations showed a high entrapment efficiency (similar to 88%) and a highly negative zeta potential (around -30 mV). The selected formulations were highly biocompatible as confirmed by in vitro studies using 3T3 fibroblasts. In vitro assay showed that the amounts (%) of NA accumulated in the epidermis (similar to 10%) could explain the anti-inflammatory properties of ultradeformable liposomes. In vivo studies confirmed the higher …
Modelling intestinal absorption of salbutamol sulphate in rats
The objective was to develop a semiphysiological population pharmacokinetic model that describes the complex salbutamol sulphate absorption in rat small intestine. In situ techniques were used to characterize the salbutamol sulphate absorption at different concentrations (range: 0.15-18 mM). Salbutamol sulphate at concentration of 0.29 mM was administered in presence of verapamil (10 and 20 mM), grapefruit juice and sodium azide (NaN3) (0.3, 3 and 6 mM). Different pharmacokinetic models were fitted to the dataset using NONMEM. Parametric and non-parametric bootstrap analyses were employed as internal model evaluation techniques. The validated model suggested instantaneous equilibrium betwee…
Oleuropein multicompartment nanovesicles enriched with collagen as a natural strategy for the treatment of skin wounds connected with oxidative stress.
Aim: Collagen-enriched transfersomes, glycerosomes and glytransfersomes were specifically tailored for skin delivery of oleuropein. Methods: Vesicles were prepared by direct sonication and their main physicochemical and technological properties were measured. Biocompatibility, protective effect and promotion of the healing of a wounded cell monolayer were tested in vitro using fibroblasts. Results: Vesicles were mainly multicompartment, small (∼108 nm), slightly polydispersed (approximately 0.27) and negatively charged (~-49 mV). Oleuropein was incorporated in high amounts (approximately 87%) and vesicles were stable during four months of storage. In vitro studies confirmed the low toxicit…
Innovative strategies to treat skin wounds with mangiferin: fabrication of transferosomes modified with glycols and mucin
Aim: The moisturizing properties of glycerol, the penetration enhancing capability of propylene glycol and the bioadhesive properties of mucin were combined to improve the carrier capabilities of transfersomes and the efficacy of mangiferin in the treatment of skin lesions. Materials & methods: Mangiferin was incorporated in transfersomes and glycoltransfersomes, which were also modified with mucin. The physico–chemical features were assessed, along with the efficacy against oxidative stress and skin wounds in vitro and in vivo. Results: Glycoltransfersomes promoted the deposition of mangiferin in epidermis and dermis, protected fibroblasts from oxidative stress and stimulated their pr…
Development of curcumin loaded sodium hyaluronate immobilized vesicles (hyalurosomes) and their potential on skin inflammation and wound restoring.
In the present work new highly biocompatible nanovesicles were developed using polyanion sodium hyaluronate to form polymer immobilized vesicles, so called hyalurosomes. Curcumin, at high concentration was loaded into hyalurosomes and physico-chemical properties and in vitro/in vivo performances of the formulations were compared to those of liposomes having the same lipid and drug content. Vesicles were prepared by direct addition of dispersion containing the polysaccharide sodium hyaluronate and the polyphenol curcumin to a commercial mixture of soy phospholipids, thus avoiding the use of organic solvents. An extensive study was carried out on the physico-chemical features and properties o…
Impact of Undernutrition on the Pharmacokinetics and Pharmacodynamics of Anticancer Drugs: A Literature Review
The etiology of undernourishment in cancer patients is multifactorial: tumor-related mechanisms (such as obstruction, metabolic abnormalities, and functionality changes) in addition to the influence of anticancer therapies, which can induce or worsen undernutrition. The evident role of undernutrition in cancer treatment outcomes suggests the need of considering nutritional status when evaluating anticancer drugs. In order to merge the available data and offer researchers and clinicians a global view of this phenomenon, the present manuscript reviews on a drug-by-drug basis the undernutrition-related pharmacokinetic and pharmacodynamic aspects of anticancer treatments. This review notes inte…
Co-loading of finasteride and baicalin in phospholipid vesicles tailored for the treatment of hair disorders
[EN] Hair loss affects a large number of people worldwide and it has a negative impact on the quality of life. Despite the availability of different drugs for the treatment of hair disorders, therapeutic options are still limited and scarcely effective. An innovative strategy to improve the efficacy of alopecia treatment is presented in this work. Finasteride, the only oral synthetic drug approved by Unites States Federal Drug Administration, was loaded in phospholipid vesicles. In addition, baicalin was co-loaded as an adjuvant. Their effect on hair growth was evaluatedin vitroandin vivo. Liposomes, hyalurosomes, glycerosomes and glycerol-hyalurosomes were manufactured by using a simple me…
Interaction of Taurine on Baclofen Intestinal Absorption: A Nonlinear Mathematical Treatment using Differential Equations to Describe Kinetic Inhibition Models
Previous studies showed that the in situ absorption of baclofen in rat jejunum was inhibited by beta-alanine, a nonessential amino acid, and therefore mediated, at least in part, by some beta-amino acid carrier. In this paper a similar study was undertaken using taurine, a sulfonic beta-amino acid, in order to evaluate its effect and to establish a general inhibition model. To achieve this goal, remaining concentrations of inhibitor were also measured and incorporated into the model. Previously, kinetic absorption in situ parameters for taurine in free solution were obtained: Vm = 27.73 +/- 9.99 mM h-1, K(m) = 8.06 +/- 2.82 mM, Ka (passive difussion component) = 0.40 +/- 0.28 h-1. Isotonic …
Influence of leucine on intestinal baclofen absorption as a model compound of neutral α-aminoacids
The inhibitory effect of the essential alpha-aminoacid L-leucine on the intestinal absorption of the antispastic drug baclofen was examined by means of an in situ rat gut perfusion technique. When 0.5 mM baclofen solutions were perfused in the presence of increasing concentrations of the aminoacid (5-100 mM), the apparent absorption rate constant of the drug decreased as the initial leucine concentration increased. Higher leucine concentrations however did not completely abolish the absorption of the drug (at 100 mM of leucine, only 76% inhibition was observed). The interaction can be mathematically described as a complete competitive inhibition with a second component, K = 0.35 (+/- 0.08)h…
Fabrication of polyelectrolyte multilayered vesicles as inhalable dry powder for lung administration of rifampicin
A polyelectrolyte complex based on chitosan and carrageenan was used to coat rifampicin-loaded vesicles and obtain a dry powder for inhalation by spray-drying. The polymer complexation on vesicle surface stabilized them and improved their adhesion on airways and epithelia cells. Uncoated liposomes were small in size, negatively charged and able to incorporate large amounts of rifampicin (70%). Coated vesicles were still able to load adequate amounts of drug (∼70%) but the coating process produced larger particles (1 μm) that were positively charged and with a spherical shape. Aerosol performances, evaluated using the next-generation impactor, showed that coated vesicles reached the 50% of f…