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The objective of these in vitro studies was to investigate the impact of the encapsulation of three cannabis-based terpenes, namely β-myrcene (MC), β-caryophyllene (CPh), and nerolidol (NL), on their potential efficacy in pain management. Terpene-encapsulated poly(ethylene glycol)-poly(lactic-co-glycolic acid) nanoparticles (PEG-PLGA NPs) were prepared by an emulsion-solvent evaporation method. The terpene-loaded NPs were examined in HEK293 cells that express the nociceptive transient receptor potential vanilloid-1 (TRPV1), an ion channel involved in pain perception. TRPV1 activation was assessed by monitoring calcium influx kinetics over 1 h in cells pre-treated with the fluorescent indicator Fluo-4. In addition, the fluorescence intensity changes induced by the NPs in living cells were also explored by a fluorescence microscope. Furthermore, the cytotoxicity of the terpene-loaded NPs was evaluated by the 3-(4,5-dimethylthiazol-2-yl)-3,5-diphenyl tetrazolium bromide (MTT) proliferation assay. The terpene-loaded NPs had a diameter in the range of 250-350 nm and a zeta potential of approximately -20 mV. The encapsulation efficiency was 18.5%, 51.3%, and 60.3% for MC, NL, and CPh NPs, respectively. The nano-formulations significantly increased the fluorescence intensity in comparison with free terpenes. Furthermore, combinations of terpene-loaded NPs produced significantly higher calcium responses when compared to combinations of free terpenes. Similar findings were shown by the fluorescence images. In conclusion, the terpene-PLGA NPs can be promising therapeutics for more effective pain management.

Background: Actually, no drugs provide therapeutic benefit to approximately one-third of depressed patients. Depression is predicted to become the first global disease by 2030. So, new therapeutic ...

The editorial team greatly appreciates the reviewers who have dedicated their considerable time and expertise to the journal’s rigorous editorial process over the past 12 months, regardless of whether the papers are finally published or not [...]

Neurodegenerative diseases, like Alzheimer´s and Parkinson´s disease, are a group of disorders that have in common their increasingly high prevalence along with the shortage of effective treatments. In addition, the scientific community faces the challenge of getting the drugs used in these treatments to cross the blood-brain barrier (BBB) and reach the brain in sufficient concentration to be able to exert its effect. Hence, researchers across multiple disciplines are working together in order to improve the ability of therapeutics to penetrate the BBB. In this sense, the use of nanomedicine, nanoscale structures for drug delivery, exhibits a really high therapeutic potential in the field of neurodegenerative diseases therapy. Since there is new evidence that neuroinflammation produced by reactive microglia contributes to the activation and pathogenesis of neurological disorders, many investigations focus on the identification of new targets whose inhibition can reduce, totally or partially, microglial activation. This review analyzes a wide variety of compounds as possible candidates to achieve this target, from compounds with a natural origin to anti-diabetics, antidepressants, antibiotics and hormones. We also discuss the different strategies to enhance the capacity of these compounds to cross the BBB. Although this review focuses on PLGA nanoparticles as one of the most versatile drug delivery nanosystems, we also describe other strategies, such as direct intranasal administration (nose-tobrain), novel viral vectors and novel implanted catheters.

The cannabinoid substances contained in the Cannabis sativa plant have been shown to have great potential in a wide variety of therapeutic applications. However, its neuroprotective capacity has been the most widely studied in diseases such as Alzheimer's, Parkinson's, Huntington's, multiple sclerosis and amyotrophic lateral sclerosis. Knowing the problems of formulating these substances in different dosage forms and their side effects, the present paper addresses different alternatives offered by the use of nanotechnology to transport these drugs in suitable platforms, as well as the different methodologies and materials used for this purpose.

Terpenes derived from different varieties of Cannabis sativa have shown potentially useful pharmacological activities, including the ability to bind to transient receptor potential (TRP) channels. Beta-myrcene (MC), beta-caryophyllene (CPh), and nerolidol (NL) are among the most abundant and studied terpenes found in cannabis. Despite the potential pharmacological effectiveness of these terpenes, their volatile and hydrophobic nature, and associated poor solubility and low bioavailability limit their suitability as pharmaceutical agents. To address these limitations, the current study sought to design poly(DL-lactide-co-glycolide) (PLGA) based nanoparticles (NPs) that encapsulate MC, CPh, and NL. First, several preparation methods and formulations were tested to develop MC-loaded PLGA NPs. The NPs produced had a mean diameter between 200–350 nm, a narrow size distribution, and a negative zeta potential in the range of -25 to -30 mV. Optimal NPs were produced using emulsion-solvent evaporation, purified and collected by ultra-filtration, and freeze-dried in the presence of trehalose 5% (w/w), achieving the highest encapsulation efficiency (EE%: ∼8%). Utilizing the optimized formulation and preparation method, PEG-PLGA NPs encapsulating MC, CPh, or NL were also fabricated and characterized. The encapsulation capacities of CPh (EE%: 64.9 %) and NL (EE%: 55.7 %) PEG-PLGA NPs were approximately 3-fold that of MC NPs (EE%: 18.1 %). In conclusion, these three terpenes were successfully encapsulated in PLGA-based NPs. The nanosystems developed herein can be proposed as promising therapeutic tools for the enhanced delivery of cannabis-derived terpenes.

Nanoplatforms can optimize the efficacy and safety of chemotherapy, and thus cancer therapy. However, new approaches are encouraged in developing new nanomedicines against malignant cells. In this work, a reproducible methodology is described to prepare Δ(9)-tetrahidrocannabinol (Δ(9)-THC)-loaded poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles against lung cancer. The nanoformulation is further improved by surface functionalization with the biodegradable polymers chitosan and poly(ethylene glycol) (PEG) in order to optimize the biological fate and antitumor effect. Mean nanoparticle size (≈ 290 nm) increased upon coating with PEG, CS, and PEG-CS up to ≈ 590 nm, ≈ 745 nm, and ≈ 790 nm, respectively. Surface electrical charge was controlled by the type of polymeric coating onto the PLGA particles. Drug entrapment efficiencies (≈ 95%) were not affected by any of the polymeric coatings. On the opposite, the characteristic sustained (biphasic) Δ(9)-THC release from the particles can be accelerated or slowed down when using PEG or chitosan, respectively. Blood compatibility studies demonstrated the adequate in vivo safety margin of all of the PLGA-based nanoformulations, while protein adsorption investigations postulated the protective role of PEGylation against opsonization and plasma clearance. Cell viability studies comparing the activity of the nanoformulations against human A-549 and murine LL2 lung adenocarcinoma cells, and human embryo lung fibroblastic MRC-5 cells revealed a statistically significant selective cytotoxic effect toward the lung cancer cell lines. In addition, cytotoxicity assays in A-549 cells demonstrated the more intense anticancer activity of Δ(9)-THC-loaded PEGylated PLGA nanoparticles. These promising results were confirmed by in vivo studies in LL2 lung tumor-bearing immunocompetent C57BL/6 mice.

This article aimed to produce, characterize and evaluate different surface-modified naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone (CB13) loaded poly(lactic-co-glycolic acid) nanoparticles in order to improve their oral absorption and in vivo biodistribution. Plain and surface-modified PLGA nanoparticles were successfully prepared using a nanoprecipitation method. Chitosan, Eudragit RS, lecithin and vitamin E were used as surface modifying agents. The NPs were evaluated in terms of mean diameter and size distribution, zeta potential, morphology, drug loading, drug release profiles, mucoadhesive properties, in vitro cell viability and uptake and in vivo biodistribution. Mean particle size distributions in the range of 253-344 nm, spherical shape and controlled zeta potential values were observed depending on the additive employed. High values of entrapment efficiency were obtained for all the formulations. Lecithin and vitamin E modified particles showed higher release rates when compared to the rest of formulations. A clear improvement in ex vivo mucoadhesion properties was observed in the case of chitosan- and Eudragit RS-modified nanoparticles. Chitosan-poly(lactic-co-glycolic acid) nanoparticles showed the highest uptake values on Caco-2 cells. Biodistribution assays proved that most of the particles were accumulated in liver and spleen. An important goal has been achieved in this investigation: CB13, a highly lipophilic drug with low water solubility, can reach the interior of cells more efficiently when it is included in these surface-modified polymeric carriers.

Neuropathic pain, resistant to opiates and other drugs, is a chronic/persistent state with a complex treatment and often poor efficacy. In this scenario, cannabinoids are increasingly regarded as a genuine alternative. In this paper, and in an experimental animal model of neuropathic pain, we studied the efficacy of three kinds of PLGA nanoparticles containing synthetic cannabinoid CB13: (i) plain nanoparticles (PLGA); (ii) particles coated with PEG chains (PLGA+PEG) and (iii) particles possessing hydrophilic surfaces obtained by covalently binding PEG chains (PLGA-PEG). The optimized formulation, CB13-PLGA-PEG, showed high drug loading (13%) and small size (

In the present work, a promising formulation of an inhaled powder based on tobramycin-loaded microparticles has been reported. Biodegradable microparticles with controlled diameters in the range of 1-5 μm and narrow size distribution were synthesized by Flow Focusing® technology. Particles production was planned and optimized with the aid of a well-established mathematic model. Close agreements between theoretical an experimental sizes were obtained. To deliver a high payload of tobramycin to the lungs, the influence of surfactant concentration, polymer-drug ratio and initial drug concentration were investigated. For chosen formulations, drug delivery profiles were also studied. In some cases, it was found a controlled drug delivery for more than ten days, which could represent an important advance in the treatment of chronic lung infections. Other particles factors affecting deposit of an aerosol in the lung were also studied, such as surface charge and density.

Nanoparticulate-based drug carriers have been developed to overcome the problems of conventional anticancer pharmacotherapy, i.e., the little specificity and low accumulation of the drug into the tumor interstitium, and the extensive biodistribution leading to severe toxicity. Unfortunately, conventional nanoparticles have been demonstrated to merely accumulate the loaded drug into organs associated to the reticuloendothelial system, e.g., the liver. Recently, drug delivery strategies involving the use of nanoplatforms surface decorated with unique biomolecules have demonstrated their potential in concentrating the chemotherapy agent specifically into the malignant cells. This review will be focused on the analysis of the current state of the art and future perspectives of such passive and active targeting strategies based on the enhanced permeability and retention effect and on a ligand-mediated transport, respectively. Special attention will be given to the use of these surface functionalized nanocarriers to overcome multi-drug resistances in cancer cells.

Lysosomal storage diseases (LSDs) comprise a group of rare inherited chronic syndromes that cause deficiency of specific native enzymes within the lysosomes. The macromolecular compounds that are usually catabolized by lysosomal enzymes are accumulated within these organelles, causing progressive damage to tissues, skeleton and organs and, in several cases, the central nervous system (CNS). The damage caused by substrate accumulation finally results in physical deterioration, functional impairment and potential death. Up to date, the most promising therapy for most LSDs is enzyme-replacement therapy (ERT), which provides patients with the corresponding active enzyme. However, these enzymes do not have enough stability in blood, the treatment must be therefore periodically administrated by i.v. infusion under medical supervision, and immunogenicity issues are frequent. In addition, affected areas within the CNS, where the blood-brain barrier (BBB) is a major obstacle, cannot be reached by the enzymes. Nanotechnology can provide useful carriers to successfully protect and preserve enzymes, and transport them through the BBB towards brain locations. Several strategies based on targeting specific receptors on the BBB have led to nanoparticles that successfully carry sensitive molecules to the brain. Then, the main LSDs are described and a thorough review of nanotechnology strategies for brain delivery studied up to date is presented.

An in vivo preclinical study has been made of the oral absorption of morphine (CAS 57-27-2) from a new sustained release formulation (morphine-Eudragit® L complex, MEC), which had shown good sustained release properties in in vitro dissolution studies. The absorption of morphine from capsules filled with morphine hydrochloride trihydrate (MHT) or MEC was compared in fasted and fed dogs. Mean plasma morphine concentrations obtained after administration of MHT and MEC to fasted dogs were similar, and no statistically significant differences were found in the pharmacokinetic parameters of morphine (C max , T max and area under the plasma morphine concentration versus time curve from time zero to the last time with a detectable concentration of morphine). When MHT and MEC were administered to fed animals, mean plasma morphine concentrations were again similar for both formulations, without statistically significant differences in the pharmacokinetic parameters of morphine. These results contrast with those obtained in vitro , and indicate the limited usefulness of in vitro assays for this kind of sustained release formulations in which pH and ionic strength are important factors for drug release from the polymeric structure. The plasma morphine concentrations obtained in fed dogs were generally lower than in fasted dogs, though they were detectable for a longer time, until 10 h after dosing, in contrast to up to 6 h in fasted dogs. It is postulated that the apparently prolonged absorption of morphine in fed dogs may be due to the enterohepatic recycling of the drug (excreted in bile as glucuronide, hydrolysed back to the parent compound in the intestine, and then reabsorbed) as a consequence of gallbladder emptying induced by food.

This review aims to summarize present approaches employed in delivering drugs to the central nervous system. Changes in blood-brain barrier (BBB) function have been reported in several neurological disorders. A brief description of the blood brain barrier and the main pathologies related to this barrier disfunction are described. Treatments for these disorders are based on several available strategies for delivering drugs into the brain, through circumvention of the BBB, as disruption of the BBB, prodrugs, molecular Trojan horses, among others. Particular attention will be placed on nanocarriers and more specifically on polymeric nanoparticles, which are presented as the most promising strategy for CNS delivery, helping drugs to be targeted more efficiently to the brain. This also allows attacking previously untreatable disorders such as brain tumors and other neurodegenerative diseases. New strategies and technologies commercialized by different pharmaceutical companies are also included.

10 páginas, 6 figuras, 4 tablas., Paramagnetic particles offer an extensive improvement in the magnetic separation or purification of a wide variety of protein molecules. Most commercial paramagnetic particles are synthesized by laborious and costly procedures. A straightforward production of paramagnetic microparticles with homogeneous and selectable sizes using flow focusing (FF) technology is described in this work. The development of an initial formulation of a stable iron oxide suspension compatible with the FF requirements is also reported. The obtained particles, below 10 microns in diameter and presenting smooth and reactive surface, were codified with an organic fluorophore and showed excellent properties for covalent attachment of biomolecules such as proteins and its subsequent recognition by flow cytometry. Furthermore, particles with suitable magnetite content resulted as well-suited for commercial magnet separators for these purposes., This work was funded by the Spanish Ministerio de Ciencia y Tecnología (Project nos. DPI2002-04305-C02-02 and DPI2000-0392-P4-03), Consejería de Innovación de la Junta de Andalucía (Projects nos. 830446 and TEP-1190), and Corporación Tecnológica de Andalucía e Ingeniatrics Tecnologías S.L. L. M.-Banderas, A. R.-Gil and R. G.-Prieto are grateful for financial support from the Spanish Ministerio de Ciencia y Tecnología, University of Sevilla-El Monte Foundation, and Consejería de Innovación de la Junta de Andalucía grants for researcher formation.

The present work is a review of classical and recently developed methods for drop production in micro- and nanoencapsulation processes. Most of the methods and technologies used in microencapsulation processes require the formation of drops as a previous step. The drop formation step is very influential for the subsequent microparticle size and size distribution. These parameters, together with the microparticle structure, usually determine the application. The most important methods and technologies used to generate drops are briefly described. These have been divided into three large groups as a function of their production rate and capacity for drop-size control. A comparative review is com- pleted, reporting the main advantages and disadvantages of the key technologies.

In the present work, two methods for the preparation of lidocaine-loaded PLGA microparticles are compared. The differences between the polymeric particles obtained by solvent evaporation (SEVM) or flow focusing (FF) were studied by means of scanning electron microscopy and surface thermodynamics determinations. A detailed investigation of the capabilities of the polymer particles to load this drug is described. The physical state of the drug in the polymeric particles and the existence of interactions between both entities were studied by differential scanning calorimetry. The main factors determining the lidocaine incorporation and the release kinetics were the synthesis procedure followed, the amount of drug dissolved in the organic phase during the synthesis routine, the type of polymer (molecular weight and end chemical groups) and the size and the hydrophobic/hydrophilic properties of the particles. The FF technology allowed higher drug incorporations and slower release kinetics. The release studies showed a biphasic profile probably due to diffusion-cum-degradation mediated processes.

This work aims at developing and optimizing a valuable oral delivery carrier for the cannabinoid derivative CB13, which presents a high therapeutic potential in chronic pain states that respond poorly to conventional analgesics, but also shows highly unfavorable physicochemical properties. CB13-loaded lipid nanoparticles (LNP) formulations were developed through solvent-emulsion evaporation and optimized in terms of physicochemical properties, long-term stability, integrity under gastric simulated conditions and in vitro interaction with NIH 3T3, HEK 293T and Caco-2 cells. An optimized formulation of LNP containing CB13 was obtained from a wide range of conditions assayed and analyzed. The selection of the lipid core, production conditions and the inclusion of lecithin proved to be key factors for the final properties of encapsulation, integrity and performance of the carriers. The LNP formulation proposed proved to be a promising carrier for the oral delivery of CB13, a cannabinoid with high therapeutic potential in chronic pain states that currently lack a valid oral treatment.

The cannabinoid derivative 1-naphthalenyl[4-(pentyloxy)-1-naphthalenyl]methanone (CB13) has an important therapeutic potential as analgesic in chronic pain states that respond poorly to conventional drugs. However, the incidence of its mild-to-moderate and dose-dependent adverse effects, as well as its pharmacokinetic profile, actually holds back its use in humans. Thus, the use of a suitable carrier system for oral delivery of CB13 becomes an attractive strategy to develop a valuable therapy. Polymeric poly(lactic-co-glycolic) acid (PLGA) and lipid nanoparticles (LNPs) are widely studied delivery vehicles that improve the bioavailability of lipophilic compounds and present special interest in oral delivery. Their surface can be modified to improve the adhesion of particles to the oral mucosa and increase their circulation time in blood with additives such as chitosan (CS) and polyethylene glycol (PEG), which can be feasibly incorporated onto these particles in a post-production step. In this work, CS- and PEG-modified polymeric PLGA and LNPs were successfully obtained and comparatively evaluated under the same experimental conditions as oral carriers for CB13. All the formulations presented adequate blood compatibility and absence of cytotoxicity in Caco-2 cells. Coating with CS led to a higher interaction with Caco-2 cells and a limited uptake in THP1 cells, while coating with PEG led to a limited uptake in Caco-2 cells and strongly prevented THP1 cells uptake. The performance of each formulation is discussed as a comparison of the potential of these carriers as oral delivery systems of CB13.

Didanosine, a nucleoside analog used in the treatment of acquired immuno deficiency syndrome (AIDS), has been incorporated into directly compressed monolythic matrices whose excipients were mixtures at different ratios of a methacrylic resin (Eudragit RSPM) and an ethylcellulose (Ethocel 100), both water-insoluble and pH-independent polymers. Technological characterization (drug particle morphology, mean weight, diameter, thickness and hardness of tablets) was carried out and in vitro drug release behaviour was measured using the USP basket apparatus. The effect of varying the Eudragit–Ethocel ratio, as well as the drug–polymeric matrix ratio, was evaluated. The results showed the suitability of Eudragit–Ethocel mixtures as matrix-forming material for didanosine sustained release formulations. Combination of the moderate swelling properties of Eudragit RSPM with the plastic properties of the more hydrophobic Ethocel 100 allowed suitable modulation of didanosine release.

The objective of this work is to develop a nanoplatform that can potentiate the oral administration of Δ9-tetrahidrocannabinol, a highly lipophilic active agent with very promising antiproliferative and antiemetic activities. To that aim, colloidal carriers based on the biodegradable and biocompatible poly( d,l -lactide-co-glycolide) were investigated. Such delivery systems were prepared by nanoprecipitation, and nanoparticle engineering further involved surface modification with a poly(ethylene glycol), chitosan, or poly(ethylene glycol)-chitosan shells to assure the greatest uptake by intestinal cells and to minimize protein adsorption. Characterization of the nanoplatforms included particle geometry (size and shape), electrophoretic properties (surface charge). Δ9-tetrahydrocannabinol vehiculization capabilities (loading and release), blood compatibility, and cellular uptake and cytotoxicity. Results were satisfactorily used to define the optimum engineering conditions to formulate surface modified nanoparticles for the efficient oral administration of Δ9-tetrahydrocannabinol. To the best of our knowledge, this is the first time that biocompatible polymeric nanoparticles have been formulated for Δ9-tetrahydrocannabinoldelivery.

Naltrexone hydrochloride, an opioid antagonist used as an adjunct to the maintenance of the opioid-free state for detoxified individuals, was introduced into the polymeric structure of Eudragit L30D, ananionic copolymer based on polymethacrylic acid and ethylacrylate. From the results of a preclinical study, this complexation technique can be considered as a useful tool in the design of oral controlled-release systems (naltrexone-Eudragit L) capable of inducing long-lasting effects in-vivo. The biopharmaceutical characterization of the naltrexone-Eudragit L complex in comparison with naltrexone hydrochloride using the mouse hot-plate model has been previously carried out. The results showed a longer effect, an enhancement of 23.47% of the area under the curve of the inhibition of analgesic activity vs time, and a delay of 51.80% in the t1/2 value induced by the complex, compared with those induced by conventional naltrexone. In this study, a regimen of chronic administration of naltrexone-Eudragit L was established. Thus, in an 8-day treatment (4 doses in alternate days) this oral controlled-release system effectively antagonized the analgesic effect of morphine for 8 h, whereas naltrexone hydrochloride has to be administered over 16 days (8 doses in alternate days) to induce the same effect. In the 16-day schedule the complex-induced antagonism lasted over 14 h after administration.

Polymeric complexes based on the interaction between Eudragit® L and naltrexone hydrochloride were elaborated. A preformulation study of the drug was designed to address the following points: (a) the development of two alternative methods (high performance liquid chromatography (HPLC) and UV spectrophotometry) for the analysis and quantifying of naltrexone; (b) the determination of the aqueous solubility of naltrexone hydrochloride; and (c) the characterization of naltrexone hydrochloride from the following points of view: morphological (scanning electronic microscopy, SEM), thermal (differential scanning calorimetry, DSC and hot stage-microscopy, HSM) and spectroscopical (1H- and 13C-nuclear magnetic resonance, NMR). Furthemore, some of these thechniques were used for the physical and chemical characterization of naltrexone polymeric complexes. An interaction by means of hydrogen bonds between the polymer and naltrexone was demonstrated using NMR spectroscopic techniques. The in vitro release of naltrexone-Eudragit® L complex using a pH gradient technique was studied. A significant reduction in the release rate of drug from the complex used as naltrexone controlled release system as well as a very high efficiency in the dissolution process have been found.

The paper reports a study of the capability of the percolation theory to explain the influence of several formulation factors over the release behavior of carteolot hydrochloride inert matrix systems. For this purpose, previously prepared matrix systems have been employed. The characterization of these matrices by means of “classical theories” has been reported in previous papers. Similar percolation thresholds have been found (52.7%, 56.2% v/v for the insoluble phase and 48.2% to 51.2% v/v for the soluble phase), even with changing formulation factors such as nature and percentage of polymer, type of wetting liquid and nature, and percentage of filler. This fact suggests an advantage for the application of percolation theory to the rationalization of pharmaceutical dosage form design. From the obtained results, the characterization of a multicomponent system on the basis of percolation theory seems to be rather general. On the other hand, the relatively high percolation thresholh obtained can be ...

Lipid nanoparticles (LNPs) are a promising carrier for all administration routes due to their safety, small size, and high loading of lipophilic compounds. Among the LNP production techniques, the easy scale-up, lack of organic solvents, and short production times of the high-pressure homogenization technique (HPH) make this method stand out. In this study, a statistical analysis was applied to the production of LNP by HPH. Spherical LNPs with mean size ranging from 65 nm to 11.623 μm, negative zeta potential under –30 mV, and smooth surface were produced. Manageable equations based on commonly used parameters in the pharmaceutical field were obtained. The lipid to emulsifier ratio (R L/S) was proved to statistically explain the influence of oil phase and surfactant concentration on final nanoparticles size. Besides, the homogenization pressure was found to ultimately determine LNP size for a given R L/S, while the number of passes applied mainly determined polydispersion. α-Tocopherol was used as a model drug to illustrate release properties of LNP as a function of particle size, which was optimized by the regression models. This study is intended as a first step to optimize production conditions prior to LNP production at both laboratory and industrial scale from an eminently practical approach, based on parameters extensively used in formulation.

The efficiency of a new controlled release oral system containing morphine hydrochloride elaborated by introducing the drug into the polymeric structure of Eudragit® L30D is evaluated. Its in vitro dissolution behaviour and its effectiveness using the tail flick test model of pain in rats are investigated. A significant reduction in the drug release rate from the morphine-Eudragit® L30D complex as well as a very high efficiency in the dissolution process have been found. The tested morphine complex has an analgesic effect in rats. This effect is very clear from 30 min to 8 h. At 12 h the effect remains clear but with a lower level of statistical significance. Furthermore, there are no significative differences between the different doses tested.

One of the handicaps for the application of the principles of percolation theory in pharmaceutical systems is the fact that this theory has been developed for binary systems. The aim of this work is to study for the first time the existence and behaviour of the percolation thresholds in ternary pharmaceutical tablets. For this purpose, mixtures containing three substances with very different hydrophilicity and water-solubility—KCl, polyvinylpyrrolidone cross-linked (PVP-CL) and Eudragit® RS-PM—were prepared and compressed. The bulk and tapped densities of the mixtures as well as the hardness and in-vitro release behaviour of the tablets have been studied. The KCl percolation threshold has been estimated in the range 0.26–0.31 of total porosity. A range where PVP-CL percolates can be defined between 10 and 30% v/v. This influences the hardness of the tablet. On the other hand, the existence of a ‘combined percolation threshold’ of the sum of all the hydrophilic substances, i.e. KCl and PVP-CL, has been found at 35% v/v approximately. This fact is in agreement with previous results.

In this paper, the morphological and surface characteristics of lactose and coated lactose particles are investigated, continuing with the use of SEM descriptors and fractal dimensions to characterize powder particles. The coating materials were different acrylic polymers of the Eudragit® type. The size parameters of lactose and coated lactoses indicated that the particle forms deviated from irregular or acicular forms. Shape factor data of coated substances obtained demonstrated that these particles presented regular contours. This fact signifies that lactose particles without coating treatment present irregular profiles with patent edges implying poor flow properties. The aspect ratio values of coated lactoses were close to unity and smaller than that showed by lactose. It is concluded that the polymer particles are placed on the irregularities of lactose particles, smoothing the roughness of the excipient surface. The fractal dimensions calculated from the slope of Richardson plots were 1.11 for lactose and 1.04, 1.05 and 1.08 for coated lactoses. These results are consistent with the shape parameters and flow properties. Some interesting relationships between SEM descriptors and a number of rheological properties have been found.

In the present paper, a simple, direct, accurate and sensitive HPLC method applied over combinations of dextromethorphan, diphenhydramine, phenylephrine, phenylpropanolamine and pseudoephedrine is presented. The use of alumina particles bonded with polybutadiene as stationary phase allows the use of an alkaline mobile phase which provides an important improvement of the assay.

A simple, fast, and reversed-phase high-performance liquid chromatographic (RP-HPLC) method has been developed and validated for determining of a cannabinoid derivate, which displays potent antihyperalgesic activity, 1-naphthalenyl[4-(pentyloxy)-1-naphthalenyl]methanone (CB13) into PLGA nanoparticles. Separation was achieved in a C18 column using a mobile phase consisting of two solvents: solvent A, consisting of acetonitrile : water : acetic acid (75 : 23.7 : 1.3 v/v), and solvent B, consisting of acetonitrile. An isocratic method (70 : 30 v/v), with a flow rate of 1.000 mL/min, and a diode array detector were used. The developed method was precise, accurate, and linear over the concentration range of analysis with a limit of detection and a limit of quantification of 0.5 and 1.25 μg/mL, respectively. The developed method was applied to the analysis of CB13 in nanoparticles samples obtained by three different procedures (SEV, FF, and NPP) in terms of encapsulation efficiency and drug release. Nanoparticles size and size distribution were also evaluated founding that NPP method presented the most lowest particle sizes with narrow-size distribution (≈320 nm) and slightly negative zeta potential (≈−25 mV) which presumes a suitable procedure for the synthesis of PLGA-CB13 nanoparticles for oral administration.

Coprecipitates of morphine were prepared by using EudragitR L30D as a carrier in order to obtain controlled release dosage systems. Differential Scanning Calorimetry and IR, 1H- and 13C-NMR spectroscopies were applied in order to explain the mechanism of this interaction. The results obtained indicated that there was an intermolecular association between the polymer and the drug consisting in two different hydrogen bonds interactions. The proposed reaction involves coprecipitates having morphine contents greater than 50%.

Inert matrix tablets of carteolol hydrochloride were prepared using 50% of Eudragit® RS as a supporting material and a series of fillers: Emcompress®, mannitol, polyethylene glycol 6000 and lactose. Two liquids were used to wet the drug-excipient mixtures: Eudragit® L 12.5% and isopropanol-acetone 6:4 mixture. The affinity of carteolol hydrochloride to the matrix forming material Eudragit® RS (expressed as a Kaff value) was calculated: the higher the pH value, the greater was the value of the Kaff obtained. Each component of the formulations as well as its presence in the matrix systems was identified by differential scanning calorimetry (DSC). The thermal analysis suggested that no drug-excipient interaction occurs during the preparation process. Finally, the dissolution profiles were studied applying three different kinetic models (zero-order, first-order and Higuchi equation). Controlled release profiles were obtained in all the inert matrix compressed tablets studied with the unique exception of lactose used as a filler. The mechanism of release from the matrices was shown to be diffusion-controlled. The dissolution behavior was found to display a biphasic profile in the case of the lots prepared with Eudragit® L 12.5% as wetting liquid of the formulations. Higuchi release rate constants were also calculated.

A specific HPLC method was applied to study the evolution of the concentrations of thimerosal (thiomersal), thiosalicylic acid and 2,2'-di(thiosalicylic) acid over a period of 3 months. The mechanism of degradation of thimerosal in pharmaceutical formulations has been proposed. The protective effect of tromethamine has been also evaluated. It has been found that tromethamine does not exert its effect on the initial reaction of thimerosal decomposition but on the degradation of its initial decomposition products.

A high-performance liquid chromatographic (HPLC) assay has been developed for thimerosal and some of its degradation products: thiosalicylic and 2,2′-dithiosalicylic acids. Using this method, the influence of formulation factors as: isotonic agent, initial concentration, addition of tromethamine, pH and container material, over thimerosal stability was studied.

Due to a very poor specificity, many chemotherapy agents generate a low antitumor effect and important severe side effects. Poly(D,L-lactide-co-glycolide) (PLGA)-based nanomedicines are under investigation to assure a very efficient anticancer activity in chemotherapy. In this work, we analyze the major applications of this FDA-approved biodegradable polymer in the formulation of nanomedicines against cancer. Despite conventional PLGA colloids could be only used to target tumors located into the mononuclear phagocyte system (MPS), special strategies are under intensive research to enhance the accumulation of anticancer drugs into any given tumor site. These are passive targeting (through the enhanced permeability and retention effect, so-called EPR effect), drug delivery through stimuli-sensitive colloids, and ligand-mediated targeting. We further discuss unique approaches of PLGA colloids in oral chemotherapy, drug delivery to brain tumors, and multi-drug resistance of cancer cells.

In the present study, a novel synthesis technique based on the flow focusing (FF) technology is investigated for the preparation of green fluorescent protein (GFP)-loaded poly(D,L-lactide-co-glycolide) (PLGA) microparticles. To our knowledge, this novel technique has never been applied to the formulation of proteins in polymeric systems. A simple, specific and rapid reversed-phase HPLC (RP-HPLC) method was validated for the determination of GFP in PLGA microparticles with the best chromatographic peak resolution, reduced run time and low cost of analysis. In order to achieve the finest GFP-loaded polymeric particles, experimental parameters mainly associated to the FF device were studied (liquid flow rate and pressure of the focusing air). Very high GFP encapsulation values (>90%) were obtained by this technique, and the electrokinetic characterization of these systems suggested that this protein was incorporated into the polymeric matrix. This study is intended to offer information on which to base the development of high molecular weight protein-loaded polymeric delivery systems prepared by FF.

An in vivo preclinical study has been made of the oral absorption of morphine (CAS 57-27-2) from a new sustained release formulation (morphine-Eudragit L complex, MEC), which had shown good sustained release properties in in vitro dissolution studies. The absorption of morphine from capsules filled with morphine hydrochloride trihydrate (MHT) or MEC was compared in fasted and fed dogs. Mean plasma morphine concentrations obtained after administration of MHT and MEC to fasted dogs were similar, and no statistically significant differences were found in the pharmacokinetic parameters of morphine (Cmax, Tmax and area under the plasma morphine concentration versus time curve from time zero to the last time with a detectable concentration of morphine). When MHT and MEC were administered to fed animals, mean plasma morphine concentrations were again similar for both formulations, without statistically significant differences in the pharmacokinetic parameters of morphine. These results contrast with those obtained in vitro, and indicate the limited usefulness of in vitro assays for this kind of sustained release formulations in which pH and ionic strength are important factors for drug release from the polymeric structure. The plasma morphine concentrations obtained in fed dogs were generally lower than in fasted dogs, though they were detectable for a longer time, until 10 h after dosing, in contrast to up to 6 h in fasted dogs. It is postulated that the apparently prolonged absorption of morphine in fed dogs may be due to the enterohepatic recycling of the drug (excreted in bile as glucuronide, hydrolysed back to the parent compound in the intestine, and then reabsorbed) as a consequence of gallbladder emptying induced by food.

In this paper, a new pharmaceutical formulation for the administration of morphine has been developed. This system is based on a polymeric complex previously characterized. After the studies performed, it has been selected the following formulation: 62.5% of morphine complex, 15% of free morphine and 22.5% of Eudragit ® RS. The morphine formulation proposed has been characterized by means of the study of the influence of several parameters such as pH, ionic strength, mean particle diameter of the components and total morphine dose by means of the tablet dimensions. This assayed formulation is able to provide a specific in vitro release profile that will be no influenced by possible variations in the GIT conditions. Moreover, this formulation can reproduce the same biopharmaceutical behaviour in an independent manner of the mean diameter particle of the components and the dimension of the tablet produced with several doses inside a wide interval of doses.

The purpose of this research was to perform the design and in vitro evaluation of alginate beads containing 5-ASA in order to achieve an oral system that protects the drug until it reaches the colon. Alginate beads were prepared by the well-known ionic gelation reaction (Ca2+). The influence of the incorporation of several polymers (Eudragit FS 30D, Eudragit S100, and chitosan) in the initial formulation was studied. In all formulations, entrapment efficiencies of the drug higher than 70% were obtained. The scanning electron microscopy (SEM) study of beads showed homogeneous sizes and shapes in all cases. Finally, the release behavior of these polymeric beads were also studied and compared. The results indicated that Eudragit FS 30D (26%) showed the most favorable dissolution behavior in terms of achieving a controlled release of 5-ASA. To determine the mechanism of drug release from these beads, the Korsmeyer equation was applied. Qt/Qinfinity

A new oral drug delivery system for colon targeting has been developed based on enteric-coated matrix tablets which suitably exploits both pH-sensitive and time-dependent functions. Matrix-tablets were prepared by direct compression of mixtures of hydroxyethylcellulose (HEC), a hydrophilic swellable polymer, with the inert insoluble ethylcellulose (EC) or micro-crystalline cellulose (MCC) polymers, in which theophylline, selected as model drug, was dispersed. Eudragit S100, a methacrylic acid copolymer soluble at pH 7, was used as pH-sensitive coating polymer. The influence of varying the cellulose-derivative combinations and their relative ratios as well as the level of the coating polymer was investigated. Surface morphology of the tablets was monitored by SEM analysis before and after the release test. The results of release studies, performed according to the USP basket method using a sequence of dissolution media simulating the gastrointestinal physiological pH variation, indicated that the Eudragit S100 enteric-coated matrix tablets were successful in achieving gastric resistance and timed-release of the drug, assuring an adequate lag time for the intended colonic targeting, followed by a controlled-release phase. The enteric-coating level emerged as the critical factor in determining the duration of the lag-phase, whereas the release rate mainly depended on the matrix composition. Formulations with higher HEC content showed a faster drug release rate than those with greater content in inert polymer and the MCC-HEC combinations were more effective than the corresponding EC-HEC ones. The best results were given by the 27% coated 1:0.3:0.7 (w/w) drug/MCC/HEC tablets, which, after a 260 min lag time, regularly released the drug, achieving about 90% of release after 10 h.

The purpose of this research was to perform a granulometrical and flow properties study of a morphine polymeric complex and determine the influence of 3 variables—particle size of complex, pH value, and ionic strength of the dissolution medium—on the dissolution behavior. The morphineEudragit L complex was produced in aqueous medium from morphine hydrochloride saturated solution and Eudragit L 30D diluted until 12% wt/vol and partially neutralized (40%). To determine the rheological behavior of the complex, several rheological tests were developed: bulk and tapped densities, Hausner ratio, angle of repose, and flow rate. The results corresponding to the technological study suggest that the 100- to 250-µm fraction can be considered as free flowing powder. In relation to the dissolution behavior of the complex, the results indicate that the ionic strength has been detected as the most influencing factor when values below physiological conditions are used. In conclusion, no technological problems for the production of further solid dosage forms are expected. Furthermore, no changes in the dissolution profiles of the complex have been detected when ionic strength values are inside the physiological range.

Inert matrices of didanosine (ddI) were elaborated as controlled release dosage forms, using two different types of polymers: Eudragit® RS-PM, an anionic acrylic acid copolymer, and Ethocel® 100 Premium, an ethylcellulose. A preformulation study of the drug was designed to address the following points: (a) the development of two alternative methods (high performance liquid chromatography ( HPLC ) and UV spectrophotometry) for the analysis and quantifying of ddI; (b) the determination of the aqueous solubility of ddI; and (c) the characterization of ddI from the following points of view: morphological (scanning electronic microscopy (SEM)) and thermal (differential scanning calorimetry (DSC)). Furthermore, some of these techniques were used for the characterization of those components which will be included in the oral controlled release system to be developed. The in vitro release of ddI matrices was studied at pH 7.4, because of the instability of ddI at pH values lower than 3 units. A significant reduction in the release rate of drug from both ddI controlled release systems was found. Furthermore, Ethocel® 100 Premium showed a minor efficiency in the dissolution process, with a reduction of more than double in the final dissolution efficiency (DE) value. This parameter and the fit factors (f1 and f2) have been compared for the characterization of dissolution profiles.

Statistical experimental design was applied to evaluate the influence of some process and formulation variables and possible interactions among such variables, on didanosine release from directly-compressed matrix tablets based on blends of two insoluble polymers, Eudragit RS-PM and Ethocel 100, with the final goal of drug release behavior optimization. The considered responses were the percent of drug released at three determined times, the dissolution efficiency at 6 h and the time to dissolve 10% of drug. Four independent variables were considered: tablet compression force, ratio between the polymers and their particle size, and drug content. The preliminary screening step, carried out by means of a 12-run asymmetric screening matrix according to a D-optimal design strategy, allowed evaluation of the effects of different levels of each variable. The drug content and the polymers ratio had the most important effect on drug release, which, moreover, was favored by greater polymers particle size; on the contrary the compression force did not have a significant effect. The Doehlert design was then applied for a response-surface study, in order to study in depth the effects of the most important variables. The desirability function was used to simultaneously optimize the five considered responses, each having a different target. This procedure allowed selection, in the studied experimental domain, of the best formulation conditions to optimize drug release rate. The experimental values obtained from the optimized formulation highly agreed with the predicted values. The results demonstrated the reliability of the model in the preparation of extended-release matrix tablets with predictable drug release profiles.

Naltrexone, a long-acting, orally effective, opioid antagonist which blocks opioid effects as well as the development of physical dependence, would appear to be a drug ideally suited to addiction treatment. An optimal dosage regimen is critical for the treatment patient compliance in ambulatory opiate detoxification programs. The ideal dosage regimen would be an oral controlled-release system of naltrexone that allowed once-a-day administration providing stable plasma levels. A naltrexone-Eudragit L complex was produced in aqueous medium from naltrexone hydrochloride solution and Eudragit L30D (30% w/v) previously diluted (6% w/v) and partially neutralized. The antagonistic activity of naltrexone-Eudragit L on morphine-induced thermal antinociception, in comparison with conventional naltrexone, was evaluated, using the mouse hot-plate model. Mice were administered 10 mg kg−1 morphine subcutaneously, 10 min before test, and the antagonist products, either naltrexone-Eudragit L or naltrexone hydrochloride, were administered orally at 0.5, 1, 2, 4, 6, 8, 10, 12, 14 and 16 h before the test. The results showed that the antagonism induced by naltrexone-Eudragit L was effective until 12 h after drug administration, while that induced by naltrexone hydrochloride disappeared 10 h after its administration. A 23.47% increase of the area under curve was obtained when naltrexone-Eudragit L was administered, compared with that induced by conventional naltrexone. The time taken to decrease the inhibition of analgesic activity to 50% was delayed by 51.80%. This complexation technique can be considered as a useful tool in the design of oral controlled-release systems capable of inducing a long-lasting effect in-vivo.

Lucía Martín-Banderas,1 Josefa Álvarez-Fuentes,1 Matilde Durán-Lobato,1 José Prados,2 Consolación Melguizo,2 Mercedes Fernández-Arévalo,1 Mª Ángeles Holgado11Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Seville, Seville, Spain; 2Institute of Biopathology and Regenerative Medicine (IBIMER), School of Medicine, University of Granada, Granada, SpainAbstract: CB13 (1-Naphthalenyl[4-(pentyloxy)-1-naphthalenyl]methanone)-loaded poly(lactic-co-glycolic acid nanoparticles (NPs) were produced by nanoprecipitation and tested for their in vitro release behavior and in vitro cytotoxicity assays. The effects of several formulation parameters such as polymer type, surfactant concentration, and initial drug amount were studied. NPs had a particle size 90–300 nm in diameter. Results obtained show that the main influence on particle size was the type of polymer employed during the particle production: the greater the hydrophobicity, the smaller the particle size. In terms of encapsulation efficiency (%), high values were achieved (~68%–90%) for all formulations prepared due to the poor solubility of CB13 in the external aqueous phase. Moreover, an inverse relationship between release rate and NP size was found. On the other hand, low molecular weight and low lactide content resulted in a less hydrophobic polymer with increased rates of water absorption, hydrolysis, and erosion. NPs showed no cytotoxicity and may be considered to be appropriate for drug-delivery purposes.Keywords: neuropathic pain, CB13, nanoprecipitation

Eudragit® L 30D was used as a carrier to prepare carteolol polymeric complexes in order to obtain controlled release dosage forms. The polyanionic form of the polymer, neutralized at different degrees, reacts readily with carteolol hydrochloride to give water-insoluble complexes. Carteolol complexes were characterized by differential scanning calorimetry, IR, 1H- and 13C-NMR spectroscopy. In fact, results indicated that there were intermolecular associations between the polymer and the drug consisting in ammonium salt interactions. Maximum carteolol content was found to be 22% in the complexes.

The release behaviour of carteolol hydrochloride matrix tablets was investigated as a function of filler nature (Emcompress®, mannitol, PEG 6000 and lactose), type of wetting liquid (Eudragit ® L 12.5% and isopropanol-acetone mixture 6:4) and mode of filler incorporation. The values of the technological parameters suggest that hardness was the most significantly affected by the three formulation factors considered. The strongest influence over the technological parameters was exerted by the mode of filler incorporation. The kinetic data conformed with the Higuchi square root equation, except for the lots containing mannitol and isopropanol-acetone mixture that conformed to a first-order plot. The lot containing Emcompress® and isopropanol-acetone mixture displayed acceptable linearity with both plots. Therefore, a non-linear regression procedure and reduced time method were used to define with precision the kinetic model followed by this formulation. Release parameters such as the Higuchi rate constant, ts0 and dissolution efficiency were calculated. Lots containing mannitol presented more rapid release rates due to the high solubility of this filler. On the other hand, the use of PEG 6000 as diluent significantly decreased drug release. The influence of technological parameters on the release of these systems was also examined, an inverse relationship between hardness and dissolution efficiency being found.