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The BBB is a protective entity that prevents external substances from reaching the CNS but it also hinders the delivery of drugs into the brain when they are needed. The main objective of this work was to improve a previously proposed in vitro cell-based model by using a more physiological cell line (hCMEC/D3) to predict the main pharmacokinetic parameters that describe the access and distribution of drugs in the CNS: Kpuu,brain, fu,plasma, fu,brain and Vu,brain. The hCMEC/D3 permeability of seven drugs was studied in transwell systems under different conditions (standard, modified with albumin and modified with brain homogenate). From the permeability coefficients of those experiments, the parameters mentioned above were calculated and four linear IVIVCs were established. The best ones were those that relate the in vitro and in vivo Vu,brain and fu,brain (r2 = 0.961 and r2 = 0.940) which represent the binding rate of a substance to the brain tissue, evidencing the importance of using brain homogenate to mimic brain tissue when an in vitro brain permeability assay is done. This methodology could be a high-throughput screening tool in drug development to select the CNS promising drugs in three different in vitro BBB models (hCMEC/D3, MDCK and MDCK-MDR1).

Finding predictive dissolution tests and valid IVIVCs are essential activities in generic industry, as they can be used as substitutes of human bioequivalence studies. IVIVCs can be developed by two different strategies: a one-step approach or a two-step approach. The objectives of this work were to compare different deconvolution and convolution methods used in the development of two-step level A IVIVCs and to study if the relationship between the in vitro dissolution rate and the in vivo dissolution rate should guide the decision between using a two-step approach or a one-step approach during the development of a new IVIVC. When the in vitro and the in vivo dissolution rates had a linear relationship, valid and biopredictive two-step IVIVCs were obtained, although there was not a combination of deconvolution and convolution methods that could be named as the best one, as long as all the prediction errors for any combination were within the limits. It was not possible to obtain a valid two-step IVIVC when the relationship between dissolution rates was non-linear, but the one-step approach was able to overcome this fact and it gave valid IVIVCs regardless of whether the relationship between dissolution rates was linear or non-linear.

Dysphagia is a very common problem suffered by elderly patients. The use of thickeners during administration in these patients helps to prevent difficulties with swallowing larger solid dosage forms. However, there are several indications when the thickeners may influence disintegration and dissolution processes of solid dosage forms, potentially affecting therapeutic efficacy. In this paper the effects of a commonly used thickener on tablet disintegration, dissolution and subsequent absorption of 6 formulated drugs frequently used in elderly patients (Aspirin, Atenolol, Acenocumarol, Candesartan, Ramipril and Valsartan) in two different administration conditions (intact tablet and crushed tablet) are reported. Disintegration times were determined using a modified disintegration test device. The presence of thickener leads to a pseudoplastic behavior with clearly increased viscosity values. The thickener was also shown to significantly affect the release processes (dissolution and disintegration), but not the permeability of the studied drugs. When tablets are crushed the effect of the thickener on drug dissolution is avoided. Consequently, crushing the tablets would be a recommendation for these drugs if the use of a thickener is necessary in patients with dysphagia.

The aim of the present paper is to study the effect of common excipients on the permeability of atenolol (as drug absorbed mainly by passive diffusion) and rhodamine (as P-glycoprotein substrate). The apparent permeability was measured by an in situ perfusion method in Wistar rats using the closed loop Doluisio's method. Permeability values were characterized in the absence and presence of 18 commonly used excipients. Excipient concentrations were selected based on the amounts in oral immediate release dosage forms, which failed the test during the human bioequivalence studies. Atenolol was studied with and without excipients in the whole small intestine, whereas rhodamine was tested in three different intestinal segments to account for the differential expression of P-glycoprotein, and it was further on tested in the ileum, in the presence of excipients. Atenolol presented higher permeability values when it was administered with colloidal silica, croscarmellose, hydroxypropyl methylcellulose (HPMC), magnesium stearate, MgCO3, poly(ethylene glycol) 400, poly(vinylpyrrolidone), sorbitol, starch, and TiO2 rhodamine showed higher permeability values when it was administered with croscarmellose and HPMC. On the one hand, the mechanisms of action were not discernible with the proposed experiments. On the other hand, commercial formulations do not present a single excipient but several, which can counteract their effects. The in situ perfusion technique can be useful for a preliminary screening and risk analysis, while the in vivo pharmacokinetic results would be needed to define conclusive effects.

Controlled release (CR) dosage forms comprise a wide range of technologies, which modify the drug pharmacokinetic (PK) profile by avoiding the immediate release (IR) of the active pharmaceutical ingredient (API). They are particularly of interest in chronic diseases, for narrow therapeutic index drugs or for targeting a particular gastrointestinal tract (GI) segment.Diffusion and dissolution limited controlled release systems are described in terms of release kinetics and formulation strategies with e xamples marketed or under development. Additionally, the physiological variables affecting the release (such as fluid pH, volume and composition, physical forces, and transit times) and the in vitro dissolution techniques currently available are reviewed.Selection of the appropriate release mechanism is not a straightforward process, as it requires a balance based on the desired target, the API properties and the technological challenges of the dosage form structure. Diffusion, dissolution or a combination of both could be adequate without an absolute superiority of one mechanism over the other. The combination of in vivo predictive dissolution systems, with mathematical modeling of the release mechanism and its correlation with formulation composition could help to design prototype candidates, with enhanced probabilities of success in human clinical trials.

In December 2019, a new virus called SARS-CoV-2 appeared, and the disease it produced was named COVID-19. After the pandemic situation was declared by the World Health Organization in March 2020, an increasing worsening of the mental health of the population, especially healthcare professionals, became apparent. To determine the psychosocial impact of the pandemic on healthcare professionals in Spain, a longitudinal study was conducted at two time points separated by 5 weeks (n time 1 = 169; n time 2 = 65). Participants completed an online questionnaire assessing depression, anxiety, and stress (Depression Anxiety Stress Scale, DASS-21), burnout (Maslach Burnout Inventory—MBI), resilience (Brief Resilience Scale—BRS), and health-related quality of life (SF-36 Health Questionnaire). The results showed high levels of depression, anxiety, stress, and burnout, as well as moderate levels of resilience and low levels of quality of life at the first assessment. Resilience was negatively related to negative experiences, and positively related to the quality of life, also at the first assessment. Overall, there was an improvement in the mental health of healthcare professionals when comparing the two assessments. In this improvement, having COVID-19 in the first assessment had a positive effect on perceived mental health in the second assessment.

One of the main obstacles in neurological disease treatment is the presence of the blood–brain barrier. New predictive high-throughput screening tools are essential to avoid costly failures in the advanced phases of development and to contribute to the 3 Rs policy. The objective of this work was to jointly develop a new in vitro system coupled with a physiological-based pharmacokinetic (PBPK) model able to predict brain concentration levels of different drugs in rats. Data from in vitro tests with three different cells lines (MDCK, MDCK-MDR1 and hCMEC/D3) were used together with PK parameters and three scaling factors for adjusting the model predictions to the brain and plasma profiles of six model drugs. Later, preliminary quantitative structure–property relationships (QSPRs) were constructed between the scaling factors and the lipophilicity of drugs. The predictability of the model was evaluated by internal validation. It was concluded that the PBPK model, incorporating the barrier resistance to transport, the disposition within the brain and the drug–brain binding combined with MDCK data, provided the best predictions for passive diffusion and carrier-mediated transported drugs, while in the other cell lines, active transport influence can bias predictions.

In the last few decades, controlled release formulations have gained an extraordinary interest [...]

Mesoporous silica microparticles functionalized with lactose for the specific release of essential oil components (EOCs) in the small intestine are presented. In vitro and in vivo intestinal models were applied to validate the microparticles (M41-EOC-L), in which the presence of lactase acts as the triggering stimulus for the controlled release of EOCs. Among the different microdevices prepared (containing thymol, eugenol and cinnamaldehyde), the one loaded with cinnamaldehyde showed the most significant Caco-2 cell viability reduction. On the other hand, interaction of the particles with enterocyte-like monolayers showed a reduction of EOCs permeability when protected into the designed microdevices. Then, a microdevice loaded with cinnamaldehyde was applied in the in vivo model of Wistar rat. The results showed a reduction in cinnamaldehyde plasma levels and an increase in its concentration in the lumen of the gastrointestinal tract (GIT). The absence of payload release in the stomach, the progressive release throughout the intestine and the prolonged stay of the payload in the GIT-lumen increased the bioavailability of the encapsulated compound at the site of the desired action. These innovative results, based on the specific intestinal controlled delivery, suggest that the M41-payload-L could be a potential hybrid microdevice for the protection and administration of bioactive molecules in the small intestine and colon., Ministerio de Ciencia, Innovación y Universidades (Spanish Government) )the Agencia Estatal de Investigación (AEI) and European Union (projects RTI2018-100910-B-C41 and RTI2018-101599-B-C22-AR (MCIU/AEI/ FEDER, EU)), Ministerio de Universidades (Spanish Government) (BG20/00020, A.B. Beatriz Galindo contract), Agencia Estatal de Investigación and European Union through FEDER (Fondo Europeo de Desarrollo Regional, AEI/FEDER EU, project SAF2016-78756), Conselleria de Innovación, Universidades, Ciencia y Sociedad Digital, Generalitat Valenciana (project PROMETEO 2018/024 and E.P-R. predoctoral grant ACIF/2016/023)

Excipients are necessary to develop oral dosage forms of any Active Pharmaceutical Ingredient (API). Traditionally, excipients have been considered inactive and inert substances, but, over the years, numerous studies have contradicted this belief. This review focuses on the effect of excipients on the physiological variables affecting oral absorption along the different segments of the gastrointestinal tract. The effect of excipients on the segmental absorption variables are illustrated with examples to help understand the complexity of predicting their in vivo effects.The effects of excipients on disintegration, solubility and dissolution, transit time, and absorption are analyzed in the context of the different gastrointestinal segments and the physiological factors affecting release and membrane permeation. The experimental techniques used to study excipient effects and their human predictive ability are reviewed.The observed effects of excipient in oral absorption process have been characterized in the past, mainly

[EN] The main objective of this investigation was to develop an in vitro-in vivo correlation (IVIVC) for immediate release candesartan cilexetil formulations by designing an in vitro dissolution test to be used as development tool. The IVIVC could be used to reduce failures in future bioequivalence studies. Data from two bioequivalence studies were scaled and combined to obtain the dataset for the IVIVC. Two-step and one-step approaches were used to develop the IVIVC. Experimental solubility and permeability data confirmed candesartan cilexetil. Biopharmaceutic Classification System (BCS) class II candesartan average plasma profiles were deconvoluted by the Loo-Riegelman method to obtain the oral fractions absorbed. Fractions dissolved were obtained in several conditions in USP II and IV apparatus and the results were compared calculating the f(2)similarity factor. Levy plot was constructed to estimate the time scaling factor and to make both processes, dissolution and absorption, superimposable. The in vitro dissolution experiment that reflected more accurately the in vivo behavior of the products of candesartan cilexetil employed the USP IV apparatus and a three-step pH buffer change, from 1.2 to 4.5 and 6.8, with 0.2% of Tween 20. This new model was able to predict the in vivo differences in dissolution and it could be used as a risk-analysis tool for formulation selection in future bioequivalence trials., This research was funded by the Agencia Estatal de Investigacion and the European Union, through FEDER (Fondo Europeo de Desarrollo Regional), grant number SAF2016-78756 (AEI/FEDER, EU). Barbara Sanchez-Dengra received a grant from the Ministry of Science, Innovation and Universities of Spain, grant number FPU17/00530.

[EN] In recent decades, the versatility of mesoporous silica particles and their relevance to develop controlled release systems have been demonstrated. Within them, gated materials able to modulate payload delivery represent great advantages. However, the role played by the porous matrix in this kind of systems is scarce. In this work, different mesoporous silica materials (MCM-41, MCM-48, SBA-15 and UVM-7) are functionalized with oleic acid as a molecular gate. All systems are fully characterized and their ability to confine the entrapped cargo and release it in the presence of bile salts is validated with release assays and in vitro digestion experiments. The cargo release profile of each synthesized support is studied, paying attention to the inorganic scaffold. Obtained release profiles fit to Korsmeyer-Peppas model, which explains the differences among the studied supports. Based on the results, UVM-7 material was the most appropriate system for duodenal delivery and was tested in an in vivo model of the Wistar rat. Payload confinement and its complete release after gastric emptying is achieved, establishing the possible use of mesoporous silica particles as protection and direct release agents into the duodenum and, hence, demonstrating that these systems could serve as an alternative to the administration methods employed until now., This research was funded by the Spanish Government (projects RTI2018-100910-B-C41 and RTI2018-101599-B-C22-AR (MCUI/FEDER, EU)) and the Generalitat Valenciana (project PROMETEO/2018/024 and ACIF/2016/023 grant).

The purpose of this work is to explore the predictive ability of the biopharmaceutics classification system (BCS) biowaiver based on the dissolution methods for two pravastatin test products, where one of them showed bioequivalence (BE) while the other test failed (non-bioequivalence, or NBE), and to explore the reasons for the BE failure. Experimental solubility and permeability data confirmed that pravastatin is a BCS class III compound. The permeability experiments confirmed that the NBE formulation significantly increased pravastatin permeability, and could explain its higher absorption rate and higher Cmax. This finding highlights the relevance of requiring similar excipients for BCS class III drugs. The BCS-based biowaiver dissolution tests at pH 1.2, 4.5, and 6.8, with the paddle apparatus at 50 rpm in 900 mL media, were not able to detect differences in pravastatin products, although the NBE formulation exhibited a more rapid dissolution at earlier sampling times. Dissolution tests conducted in 500 mL did not achieve complete dissolution, and both formulations were dissimilar because the amount dissolved at 15 min was less than 85%. The difference was less than 10% at pH 1.2 and 4.5, while at pH 6.8 f2, results reflected the Cmax rank order.

Aims Unavailability and lack of appropriate, effective and safe formulations are common problems in paediatric therapeutics. Key factors such as swallowing abilities, organoleptic preferences and dosage requirements determine the need for optimization of formulations. The provisional Biopharmaceutics Classification System (BCS) can be used in paediatric formulation design as a risk analysis and optimization tool. The objective of this study was to classify six neglected tropical disease drugs following a provisional paediatric BCS (pBCS) classification adapted to three paediatric subpopulations (neonates, infants and children). Methods Albendazole, benznidazole, ivermectin, nifurtimox, praziquantel and proguanil were selected from the 5th edition of the Model List of Essential Medicines for Children from the World Health Organization. Paediatric drug solubility classification was based on dose number calculation. Provisional permeability classification was based on log P comparison versus metoprolol log P value, assuming passive diffusion absorption mechanisms and no changes in passive membrane permeability between paediatric patients and adults. pBCS classes were estimated for each drug, according to different doses and volumes adapted for each age stage and were compared to the adult classification. Results All six drugs were classified into provisional pBCS in the three paediatric subpopulations. Three drugs maintained the same classification as for adults, ivermectin and benznidazole changed solubility class from low to high in neonates and proguanil changed from low to high solubility in all age stages. Conclusion Provisional pBCS classification of these six drugs shows potential changes in the limiting factors in oral absorption in paediatrics, depending on age stage, compared to the adult population. This valuable information will aid the optimization of paediatric dosing and formulations and can identify bioinequivalence risks when comparing different formulations and paediatric populations.

[EN] Colon targeted drug delivery is highly relevant not only to treat colonic local diseases but also for systemic therapies. Mesoporous silica nanoparticles (MSNs) have been demonstrated as useful systems for controlled drug release given their biocompatibility and the possibility of designing gated systems able to release cargo only upon the presence of certain stimuli. We report herein the preparation of three gated MSNs able to deliver their cargo triggered by different stimuli (redox ambient (S1), enzymatic hydrolysis (S2), and a surfactant or being in contact with cell membrane (S3)) and their performance in solution and in vitro with Caco-2 cells. Safranin O dye was used as a model drug to track cargo fate. Studies of cargo permeability in Caco-2 monolayers demonstrated that intracellular safranin O levels were significantly higher in Caco-2 monolayers when using MSNs compared to those of free dye. Internalization assays indicated that S2 nanoparticles were taken up by cells via endocytosis. S2 nanoparticles were selected for in vivo tests in rats. For in vivo assays, capsules were filled with S2 nanoparticles and coated with Eudragit FS 30 D to target colon. The enteric coated capsule containing the MSNs was able to deliver S2 nanoparticles in colon tissue (first step), and then nanoparticles were able to deliver safranin O inside the colonic cells after the enzymatic stimuli (second step). This resulted in high levels of safranin O in colonic tissue combined with low dye levels in plasma and body tissues. The results suggested that this combination of enzyme-responsive gated MSNs and enteric coated capsules may improve the absorption of drugs in colon to treat local diseases with a reduction of systemic effects., The authors acknowledge the financial support from the Spanish Government (Projects MAT2015-64139-C4-1-R, SAF2016-78756 and AGL2015-70235-C2-2-R) and the Generalitat Valenciana (Project GVA/2014/13).

The purpose of this study was to predict in vivo performance of three oral products of Etoricoxib (Arcoxia® as reference and two generic formulations in development) by conducting in vivo predictive dissolution with GIS (Gastro Intestinal Simulator) and computational analysis. Those predictions were compared with the results from previous bioequivalence (BE) human studies. Product dissolution studies were performed using a computer-controlled multicompartmental dissolution device (GIS) equipped with three dissolution chambers, representing stomach, duodenum, and jejunum, with integrated transit times and secretion rates. The measured dissolved amounts were modelled in each compartment with a set of differential equations representing transit, dissolution, and precipitation processes. The observed drug concentration by in vitro dissolution studies were directly convoluted with permeability and disposition parameters from literature to generate the predicted plasma concentrations. The GIS was able to detect the dissolution differences among reference and generic formulations in the gastric chamber where the drug solubility is high (pH 2) while the USP 2 standard dissolution test at pH 2 did not show any difference. Therefore, the current study confirms the importance of multicompartmental dissolution testing for weak bases as observed for other case examples but also the impact of excipients on duodenal and jejunal in vivo behavior.

Traditionally, the colon is considered a secondary intestinal segment in the drug absorption process. However, in many cases the role of colonic drug permeability cannot be overlooked. The purpose of this research was to compare colon permeability data obtained using two different rat perfusion methods the single-pass intestinal perfusion (SPIP) approach and the closed-loop (Doluisio) perfusion model. A list of 14 structurally diverse model drugs was constructed, and their rat colon permeability was studied using the two methods. The two sets of results were compared to each other, and were evaluated vs. in-vitro, ex-vivo, and in-vivo literature values. The SPIP and the Doluisio results exhibited good correlation between them (R2=0.81). The best correlation of both sets was obtained with transport studies across Caco-2 monolayers (R2∼0.9), as well as the sigmoidal fit vs. human fraction of dose absorbed (Fabs) data. On the other hand, Ussing chambers data, as well as lipophilicity (Log P) data, resulted in weak correlation to the in-situ results. In conclusion, the single-pass intestinal perfusion (SPIP) and the Doluisio (closed-loop) perfusion models were found to be equally convenient and useful for obtaining validated colon permeability values, although more human colonic Fabs data are needed for a better understanding of colonic drug permeability and absorption.

The Caco-2 cellular monolayer is a widely accepted in vitro model to predict human permeability but suffering from several and critical limitations. Therefore, some alternative cell cultures to mimic the human intestinal epithelium, as closely as possible, have been developed to achieve more physiological conditions, as the Caco-2/HT29-MTX coculture and the triple Caco-2/HT29-MTX/Raji B models. In this work the permeability of 12 model drugs of different Biopharmaceutical Classification System (BCS) characteristics, in the coculture and triple coculture models was assessed. Additionally, the utility of both models to classify compounds according to the BCS criteria was scrutinized. The obtained results suggested that the coculture of Caco-2/HT29-MTX and the triple coculture of Caco-2/HT29-MTX/Raji B were useful models to predict intestinal permeability and to classify the drugs in high or low permeability according to BCS. Moreover, to study thoroughly the transport mechanism of a specific drug, using a more complex model than Caco-2 monocultures is more suitable because coculture and triple coculture are more physiological models, so the results obtained with them will be closer to those obtained in the human intestine.

Intestinal drug permeability is position dependent and pertains to a specific point along the intestinal membrane, and the resulted segmental-dependent permeability phenomenon has been recognized as a critical factor in the overall absorption of drug following oral administration. The aim of this research was to compare segmental-dependent permeability data obtained from two different rat intestinal perfusion approaches: the single-pass intestinal perfusion (SPIP) model and the closed-loop (Doluisio) rat perfusion method. The rat intestinal permeability of 12 model drugs with different permeability characteristics (low, moderate, and high, as well as passively and actively absorbed) was assessed in three small intestinal regions: the upper jejunum, mid-small intestine, and the terminal ileum, using both the SPIP and the Doluisio experimental methods. Excellent correlation was evident between the two approaches, especially in the upper jejunum ( R 2 = 0.95). Significant regional-dependent permeability was found in half of drugs studied, illustrating the importance and relevance of segmental-dependent intestinal permeability. Despite the differences between the two methods, highly comparable results were obtained by both methods, especially in the medium-high P eff range. In conclusion, the SPIP and the Doluisio method are both equally useful in obtaining crucial segmental-dependent intestinal permeability data.

[EN] Silica mesoporous microparticles loaded with both rhodamine B fluorophore (S1) or hydrocortisone (S2), and capped with an olsalazine derivative, are prepared and fully characterized. Suspensions of Si and S2 in water at an acidic and a neutral pH show negligible dye/drug release, yet a notable delivery took place when the reducing agent sodium dithionite is added because of hydrolysis of an azo bond in the capping ensemble. Additionally, olsalazine fragmentation induced 5-aminosalicylic acid (5-ASA) release. In vitro digestion models show that S1 and S2 solids are suitable systems to specifically release a pharmaceutical agent in the colon. In vivo pharmacokinetic studies in rats show a preferential rhodamine B release from Si in the colon. Moreover, a model of ulcerative colitis is induced in rats by oral administration of 2,4,6-trinitrobenzenesulfonic acid (TNBS) solutions, which was also used to prove the efficacy of S2 for colitis treatment. The specific delivery of hydrocortisone and 5-ASA from S2 material to the colon tissue in injured rats markedly lowers the colon/body weight ratio and the clinical activity score. Histological studies showed a remarkable reduction in inflammation, as well as an intensive regeneration of the affected tissues., We thank the Generalitat Valenciana (Project PROMETE02018/024) and the Spanish Government (Projects AGL2015-70235-C2-2-R and MAT2015-64139-C4-1-R (MINECO/FEDER)) for support. A.H.T. thanks the Spanish MEC for his FPU fellowship. The authors also thank the support of the Electron Microscopy Service at the UPV. The SCSIE (of the Universitat de Valencia) is also gratefully acknowledged for all the equipment used. NMR spectra were measured at the U26 facility of ICTS "NANBIOSIS" at the Universitat de Valencia.

Introduction: There is no consensus on administering hyperosmolar formulations by mouth to neonates. In 1976, the Committee on Nutrition of the American Academy of Pediatrics published a recommendation of not administer formulations with an osmolarity higher than 400 mOsm/L due to the possible damage to intestine and relationship with necrotizing enterocolitis. Since this recommendation, exists a general trend of reducing osmolality of oral formulations without considering the pharmacokinetics of absorption of the drugs. The objective of this study was to characterize the permeability values of drugs formulated at different osmolalities by using a well-established rat intestinal perfusion model and to measure the osmolality of the most used formulations in our neonatology unit. Methods: For the osmolality measurement study, most common used oral drugs were selected (compounded formulations and drug products). Osmolality of three dilutions (1:1, 1:4 and 1:8) were measured using a cryoscopic descent osmometer. Atenolol, caffeine, furosemide, hydrocortisone and paracetamol were selected for the permeability study. Three suspensions were elaborated of each drug (150 mOsm/kg, 300 mOsm/kg and 1500 mOsm/kg). Permeability values and absorption rate coefficients were determined in complete small intestine using in situ "closed loop" perfusion method. Results: The formulations that resulted to be hyperosmolar ( > 400 mOsm/kg) were 86% (70% of these proved to be above 1500 mOsm/kg). The permeability study shown that the osmolality is inversely proportional to the apparent permeability of the drug in the studied drugs. The permeability values obtained with hyperosmolar samples were lower compared to 150 mOsm/kg or 300 mOsm/kg. Conclusions: Osmolality parameter is of particular relevance in oral drug administration in neonate because the risk of damaging the gastrointestinal tract and because of the risk that modifying osmolality also modifies its permeability, resulting in a potential change in bioavailability.

The objective was using the Essential Medicines List for children by the World Health Organization (WHO) to create a pediatric biopharmaceutics classification system (pBCS) of the oral drugs included in the Essential Medicines List by the World Health Organization and to compare our results with the BCS for adults (aBCS). Several methods to estimate the oral drug dose in different pediatric groups were used to calculate dose number (Do) and solubility (high/low). The estimation of the gastrointestinal water volume was adapted to each pediatric group. Provisional permeability classification was done by comparison of each drug lipophilicity versus metoprolol as the model drug of high permeability. As a result, 24.5% of the included drugs moved from the favorable to unfavorable class (i.e., from high to low solubility). Observed changes point out potential differences in product performance in pediatrics compared to adults, due to changes in the limiting factors for absorption. BCS Class Changes 1 to 2 or 3 to 4 are indicative of drugs that could be more sensitive to the choice of appropriate excipient in the development process. Validating a pBCS for each age group would provide a valuable tool to apply in specific pediatric formulation design by reducing time and costs and avoiding unnecessary pediatric experiments restricted due to ethical reasons. Additionally, pBCS could minimize the associated risks to the use of adult medicines or pharmaceutical compound formulations.

[EN] Hydrogels are widely studied as drug delivery system. In this work we propose the employment of tetrakis (hydroxymethyl)phosphonium chloride as crosslinking agent to obtain covalent hydrogels based on chitosan. These hydrogels are obtained by Mannich reaction between the amino groups of chitosan with the hydroxymethyl groups of the crosslinker molecule. They show a pH sensitive second order swelling kinetic, have low toxicity, are biocompatible, mucoadhesive and allow a modified release of the encapsulated drug, camptothecin, for 48 h. This antitumor drug has been studied as a drug of interest to develop oral chemotherapy administration strategies. According to the obtained results, oral administration of camptothecin through hydrogels would provide low concentrations of drug at the absorption site, avoiding carrier saturation and reducing its intestinal toxicity., Authors acknowledge partial financial support to project SAF2016-78756 from MINECO (Spanish Ministry of economy, industry and competitivity). Mayte Martinez-Martínez received a grant from the Ministry of Education and Science of Spain (FPU13-01105).

[EN] Nanohydrogels based on natural polymers, such as polysaccharides, are gaining interest as vehicles for therapeutic agents, as they can modify the pharmacokinetics and pharmacodynamics of the carried drugs. In this work, hyaluronan-riboflavin nanohydrogels were tested in vivo in healthy rats highlighting their lack of toxicity, even at high doses, and their different biodistribution with respect to that of native hyaluronan. They were also exploited as carriers of a hydrophobic model drug, the anti-inflammatory piroxicam, that was physically embedded within the nanohydrogels by an autoclave treatment. The nanoformulation was tested by intravenous administration showing an improvement of the pharmacokinetic parameters of the molecule. The obtained results indicate that hyaluronan-based self-assembled nanohydrogels are suitable systems for low-soluble drug administration, by increasing the dose as well as the circulation time of poorly available therapeutic agents., Financial support from University Sapienza Progetti di Ricerca: grant RP116154C2EF9AC8 and grant RM11715C1743EE89 are acknowledged. Isabel Gonzalez-Alvarez, Marta Gonzalez-Alvarez and Marival Bermejo acknowledge partial financial support to project SAF2016-78756 from MINECO (Spanish Ministry of economy, industry and competitivity). Mayte Martinez-Martínez received a grant from the Ministry of Education and Science of Spain (FPU13-01105).

[EN] Colonic Drug Delivery Systems (CDDS) are especially advantageous for local treatment of inflammatory bowel diseases (IBD). Site-targeted drug release allows to obtain a high drug concentration in injured tissues and less systemic adverse effects, as consequence of less/null drug absorption in small intestine. This review focused on the reported contributions in the last four years to improve the effectiveness of treatments of inflammatory bowel diseases. The work concludes that there has been an increase in the development of CDDS in which pH, specific enzymes, reactive oxygen species (ROS), or a combination of all of these triggers the release. These delivery systems demonstrated a therapeutic improvement with fewer adverse effects. Future perspectives to the treatment of this disease include the elucidation of molecular basis of IBD diseases in order to design more specific treatments, and the performance of more in vivo assays to validate the specificity and stability of the obtained systems., The authors want to thank the Spanish Government (project RTI2018-100910-B-C41 (MCUI/AEI/FEDER, UE)) and the Generalitat Valenciana (project PROMETEO/2018/024) for support. This work was also supported by the project "MODELOS IN VITRO DE EVALUACION BIOFARMACEUTICA" SAF2016-78756(AEI/FEDER, EU) funded by Agencia Estatal Investigacion and European Union, through FEDER (Fondo Europeo de Desarrollo Regional).

Lack of age-appropriate commercially drug products availability is a common problem in pediatric therapeutics; this population needs improved and safer drug delivery. In addition, biopharmaceutic aspects, dosage requirements, and swallowing abilities demand pediatric forms different to adult formulations. The objective of this study was to evaluate the authorization availability from United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) of oral essential medicines for children and analyze its age-appropriateness for oral administration in children. All oral drugs from 7th List of Essential Medicines for Children by World Health Organization (WHO) were selected. Availability of commercial drug products was collected from OrangeBook, Spanish drug product catalogue, British electronic Medicines Compendium, and the International Vademecum. Tablets, effervescent tablets, and capsules were considered as not age-appropriate forms. Liquid forms, powder for oral suspension, mini tablets, granules, and soluble films were considered as age-appropriate forms due to their flexibility. More than 80% of the studied drugs possess a commercial authorization in oral forms in both EMA and FDA. Nevertheless, around 50% of these formulations are not age-appropriate for most pediatric groups. This study shows the lack of age-appropriate medicines for children. More efforts are needed to improve development and approval of pediatric medicines.

Seven novel Copper(II) complexes, namely [Cu(Am4DHotaz)(H2O)2](ClO4) (1), [Cu(Am4DHotaz)(NO3)(MeOH)]·H2O (2), [Cu(Am4Motaz)2(H2O)](ClO4)2·0.83H2O (3), [Cu(Am4Motaz)2(NO3)]NO3·MeOH (4), [Cu(Am4Eotaz)2(NO3)]3(NO3)3·2H2O (5), [Cu(Am4Eotaz)2(ClO4)](ClO4) (6) and [Cu(Am4Eotaz)(ClO4)(H2O)](ClO4) (6a) (HAm4DHotaz = N′-(4-oxothiazolidin-2-ylidene)pyridine-2-carbohydrazonamide, Am4Motaz = N′-(3-methyl-4-oxothiazolidin-2-ylidene)pyridine-2-carbohydrazonamide and Am4Eotaz = N′-(3-ethyl-4-oxothiazolidin-2-ylidene)pyridine-2-carbohydrazonamide), have been successfully synthesized and characterized by several physicochemical techniques and, for 1–6 complexes, single crystal X-ray diffraction. Having the structural data as a base, complexes 1, 2 and 3 exhibited square pyramidal to square pyramidal slightly distorted geometry, whereas 4, 5 and 6 an intermediate between square pyramidal and trigonal bipyramidal. The ability of complexes 1–6 to cleave DNA was assayed with the aid of gel electrophoresis on supercoiled pUC18-DNA. Except for [Cu(Am4Motaz)2(H2O)](ClO4)2·0.83H2O (3), the compounds were not able to perform DNA cleavage (data not shown). Since 3 has been shown to behave as a nuclease, its interaction with DNA was studied by means of thermal denaturation and viscosimetry measurements.

Atenolol is a drug widely used for the treatment of hypertension. However, the great drawback it presents is a low bioavailability after oral administration. To obtain formulations that allow to improve the bioavailability of this drug is a challenge for the pharmaceutical technology. The objective of this work was to increase the rate and extent of intestinal absorption of atenolol as model of a low permeability drug, developing a double technology strategy. To increase atenolol permeability an ion pair with brilliant blue was designed and the sustained release achieved through encapsulation in polymeric nanoparticles (NPs). The in vitro release studies showed a pH-dependent release from NPs, (particle size 437.30 ± 8.92) with a suitable release profile of drug (atenolol) and counter ion (brilliant blue) under intestinal conditions. Moreover, with the in vivo assays, a significant increase (2-fold) of atenolol bioavailability after administering the ion-pair NPs by oral route was observed. In conclusion, the combination of ion-pair plus polymeric NPs have proved to be a simple and very useful approach to achieve a controlled release and to increase the bioavailability of a low permeability charged drugs.

The purpose of this work was to describe the closed loop in situ perfusion method in rats and to compare the difficulties and advantages with other methods proposed by regulatory agencies for BCS classification and finally to illustrate its application to evaluate the permeability of digoxin at relevant clinical concentrations. Digoxin was evaluated at two concentration levels: 1.0 μg/ml (with and without sodium azide 65.0 μg/ml) and 6.0 μg/ml. These concentrations correspond to the ratio of the highest dose strength (0.25 mg) and the highest single dose administered (1.5 mg) and the 250 ml of water. In situ closed loop perfusion studies in rats were performed in the whole small intestine and also in duodenum, jejunum and ileum segments to evaluate the relevance of P-gp secretion in the overall permeability. A kinetic modelling approach involving passive permeation and efflux transport mechanism allowed the estimation of the passive diffusional component and the Michaelis-menten parameters. The estimated Km value demonstrated that at clinical luminal concentrations the efflux process is not saturated and then it could be inhibited by other drugs, excipients or food components leading to the already reported clinical drug-drug and drug-food interations. The present data confirms from a mechanistic point of view these interactions.

Giardia intestinalis infection causes enterocytes damage and loss of brush border of the epithelial cells of the intestine that leads to shortening of microvilli and altered epithelial barrier function. This pathology results in aqueous diarrhoea, steatorrhea, nausea, abdominal pain, vomiting and weight loss. However, most infections are asymptomatic. The main consequence of Giardia colonization is nutrients malabsorption. Several families of drugs with good efficacy are used for Giardia treatment, but sometime dosing regimens are suboptimal and emerging resistance begins to question their clinical value. Moreover, some of these drugs can cause side effects that result in patient discomfort and low adherence to the treatment. This paper reviews the drugs currently used for the treatment against Giardia: the mechanism of action, the efficacy, the normal dosing, side effects and in vitro and clinical studies. In addition, new therapies against Giardia such as those based on phytochemicals, Lactobacillus and nanotechnology are collected in this paper, trying to find the ideal treatment for this disease with maximum efficacy and minimum adverse effects.

Oral controlled release (CR) formulations have many benefits and have become a valuable resource for the local and systemic administration of drugs. The most important characteristic of these pharmaceutical products is that drug absorption occurs mainly in the colon. Therefore, this review analyses the physiological and physicochemical features that may affect an orally administered CR product, as well as the different strategies to develop a CR dosage form and the methods used to evaluate the formulation efficacy. The models available to study the intestinal permeability and their applicability to colonic permeability determinations are also discussed.

The purpose of this investigation was to develop an exploratory two-step level A IVIVC for three telmisartan oral immediate release formulations, the reference product Micardis, and two generic formulations (X1 and X2). Correlation was validated with a third test formulation, Y1. Experimental solubility and permeability data were obtained to confirm that telmisartan is a class II compound under the Biopharmaceutic Classification System. Bioequivalence (BE) studies plasma profiles were combined using a previously published reference scaling procedure. X2 demonstrated in vivo BE, while X1 and Y1 failed to show BE due to the lower boundary of the 90% confidence interval for Cmax being outside the acceptance limits. Average plasma profiles were deconvoluted by the Loo-Riegelman method to obtain the oral fractions absorbed ( fa). Fractions dissolved ( fdiss) were obtained in several conditions in USP II and USP IV apparatus, and later, the results were compared in order to find the most biopredictive model, calculating the f2 similarity factor. The apparatus and conditions showing the same rank order than in vivo data were selected for further refinement of conditions. A Levy plot was constructed to estimate the time scaling factor and to make both processes, dissolution and absorption, superimposable. The in vitro dissolution experiment that reflected more accurately the in vivo behavior of the different formulations of telmisartan employed the USP IV dissolution apparatus and a dissolution environment with a flow rate of 8 mL/min and a three-step pH change, from 1.2 to 4.5 and 6.8, with a 0.05% of Tween 80. Thus, these conditions gave rise to a biopredictive dissolution test. This new model is able to predict the formulation differences in dissolution that were previously observed in vivo, which could be used as a risk-analysis tool for formulation selection in future bioequivalence trials.

[EN] Magnetic mesoporous silica microparticles were loaded with safranin O (S1) and with hydrocortisone (S2) and the outer surface functionalized with a bulky azo derivative bearing urea moieties. Aqueous suspensions of both solids at pH 7.4 showed negligible payload release whereas a marked delivery was observed in the presence of sodium dithionite due to the rupture of the azo bonds. Besides, a moderate cargo release was observed at acidic pH due to the hydrolysis of the urea bonds that linked the azo derivative onto the external surface of the inorganic scaffolds. In vitro digestion models showed that S1 and S2 microparticles could be used for the controlled release of payload in the reducing colon environment (in which azoreductase enzymes are present). On the other hand, in vivo pharmacokinetic studies in rats showed that safranine O release from S1 microparticles was concentrated in colon. The performance of S2 microparticles for the treatment of colitis in rats (induced by oral administration of a 2,4,6-trinitrobenzenesulfonic acid solution) was tested. The controlled release of hydrocortisone from S2 in the colon of injured rats induced marked reduction in colon/body weight ratio and in clinical activity score. Also, histological studies showed a marked decrease in inflammation followed by intensive regeneration and almost normal mucosal structure of the individuals treated with S2. Besides, the use of a magnetic belt increased the therapeutic performances of S2 due to an enhanced retention time of the particles in the colon., We thank the Spanish Government (projects MAT2015-64139-C4-1-R and AGL2015-70235-C2-2-R (MINECO/FEDER)) and the Generalitat Valenciana (project PROMETEOII/2014/047) for support. AHT thanks to the Spanish MEC for his FPU grant. The authors also thank the Electron Microscopy Service at the Universitat Politecnica de Valencia for support. SCSIE (Universitat de Valencia) is also gratefully acknowledged for all the equipment employed. NMR was registered at the U26 facility of ICTS "NANBIOSIS" at the Universitat de Valencia. The authors thanks Dr. L. A. Villaescusa for his helpful discussion about the 1H NMR analysis of the composition of loaded and functionalized supports.

[EN] In this work, 6-phosphogluconic trisodium salt (6-PG(-)Na(+)) is introduced as a new aqueous and nontoxic cross-linking agent to obtain ionic hydrogels. Here, it is shown the formation of hydrogels based on chitosan cross-linked with 6-PG(-)Na(+). This formulation is obtained by ionic interaction of cationic groups of polymer with anionic groups of the cross linker. These hydrogels are nontoxic, do not cause dermal irritation, are easy to extend, and have an adequate adhesion force to be applied as polymeric film over the skin. This AWN formulation exhibits a first order release kinetic and can be applied as drug vehicle for topical administration or as wound dressing for wound healing. The primary goal of this communication is to report the identification and utility of 6-phosphogluconic trisodium salt (6-PG(-)Na(+)) as a nontoxic cross-linker applicable for cationic polymers., The authors acknowledge partial financial support to project SAF2016-78756 from MINECO (Spanish Ministry of economy, industry and competitiveness). Maria Teresa Martinez Martinez received a grant from the Ministry of Education and Science of Spain (FPU13-01105). The product was patented in Spain in 2016 by authors of this paper. Patent application 201631463.

[EN] Magnetic micro-sized mesoporous silica particles were used for the preparation of a gated material able to release an entrapped cargo in the presence of an azo-reducing agent and, to some extent, at acidic pH. The magnetic mesoporous microparticles were loaded with safranin O and the external surface was functionalized with an azo derivative 1 (bearing a carbamate linkage) yielding solid S1. Aqueous suspensions of S1 at pH 7.4 showed negligible safranin O release due to the presence of the bulky azo derivative attached onto the external surface of the inorganic scaffold. However, in the presence of sodium dithionite (azoreductive agent), a remarkable safranin O delivery was observed. At acidic pH, a certain safranin O release from S1 was also found. The pH-triggered safranin O delivery was ascribed to the acid-induced hydrolysis of the carbamate moiety that linked the bulky azo derivatives onto the mesoporous inorganic magnetic support. The controlled release behavior of S1 was also tested using a model that simulated the gastro intestinal tract., We thank the Spanish Government (projects MAT2015-64139-C4-1-R and AGL2015-70235C2-2-R (MINECO/FEDER)) and the Generalitat Valenciana (project PROMETEOII/2014/047) for support. AHT thanks to the Spanish MEC for his FPU grant. The authors also thank the Electron Microscopy Service at the Universitat Politecnica de Valencia for support. SCSIE (Universitat de Valencia) is also gratefully acknowledged for all the equipment employed. NMR was registered at the U26 facility of ICTS "NANBIOSIS" at the Universitat de Valencia. The authors thanks L.A. Villaescusa for his helpful discussion about the 1H-NMR analysis of the composition of loaded and functionalized supports.

The effective rat intestinal permeability (P eff ) was deconvolved using a biophysical model based on parameterized paracellular, aqueous boundary layer, transcellular permeabilities, and the villus-fold surface area expansion factor. Four types of rat intestinal perfusion data were considered: single-pass intestinal perfusion (SPIP) in the jejunum (n = 40), and colon (n = 15), closed-loop (Doluisio type) in the small intestine (n = 78), and colon (n = 74). Moreover, in vitro Caco-2 permeability values were used to predict rat in vivo values in the rat data studied. Comparable number of molecules permeate via paracellular water channels as by the lipoidal transcellular route in the SPIP method, although in the closed-loop method, the paracellular route appears dominant in the colon. The aqueous boundary layer thickness in the small intestine is comparable to that found in unstirred in vitro monolayer assays; it is thinner in the colon. The mucosal surface area in anaesthetized rats is 0.96–1.4 times the smooth cylinder calculated value in the colon, and it is 3.1–3.6 times in the small intestine. The paracellular permeability of the intestine appeared to be greater in rat than human, with the colon showing more leakiness (higher P para ) than the small intestine. Based on log intrinsic permeability values, the correlations between the in vitro and in vivo models ranged from r2 0.82 to 0.92. The SPIP-Doluisio method comparison indicated identical log permeability selectivity trend with negligible bias.

The purpose of this work is to investigate the discriminatory power of the Biopharmaceutics Classification System (BCS)-biowaiver in vitro methodology, i.e., to investigate if a BCS-biowaiver approach would have detected the Cmax differences observed between two zolpidem tablets and to identify the cause of the in vivo difference. Several dissolution conditions were tested with three zolpidem formulations: the reference (Stilnox), a bioequivalent formulation (BE), and a nonbioequivalent formulation (N-BE). Zolpidem is highly soluble at pH 1.2, 4.5, and 6.8. Its permeability in Caco-2 cells is higher than that of metoprolol and its transport mechanism is passive diffusion. None of the excipients (alone or in combination) showed any effect on permeability. All formulations dissolved more than 85% in 15 min in the paddle apparatus at 50 rpm in all dissolution media. However, at 30 rpm the nonbioequivalent formulation exhibited a slower dissolution rate. A slower gastric emptying rate was also observed in rats for the nonbioequivalent formulation. A slower disintegration and dissolution or a delay in gastric emptying might explain the Cmax infra-bioavailability for a highly permeable drug with short half-life. The BCS-biowaiver approach would have declared bioequivalence, although the in vivo study was not conclusive but detected a 14% mean difference in Cmax that precluded the bioequivalence demonstration. Nonetheless, these findings suggest that a slower dissolution rate is more discriminatory and that rotation speeds higher than 50 rpm should not be used in BCS-biowaivers, even if a coning effect occurs.

New organometallic gold(III) and platinum(II) complexes containing iminophosphorane ligands are described. Most of them are more cytotoxic to a number of human cancer cell lines than cisplatin. Cationic Pt(II) derivatives 4 and 5, which differ only in the anion, Hg2Cl6(2-) or PF6(-) respectively, display almost identical IC50 values in the sub-micromolar range (25-335-fold more active than cisplatin on these cell lines). The gold compounds induced mainly caspase-independent cell death, as previously reported for related cycloaurated compounds containing IM ligands. Cycloplatinated compounds 3, 4, and 5 can also activate alternative caspase-independent mechanisms of death. However, at short incubation times cell death seems to be mainly caspase dependent, suggesting that the main mechanism of cell death for these compounds is apoptosis. Mercury-free compound 5 does not interact with plasmid (pBR322) DNA or with calf thymus DNA. Permeability studies of 5 by two different assays, in vitro Caco-2 monolayers and a rat perfusion model, have revealed a high permeability profile for this compound (comparable to that of metoprolol or caffeine) and an estimated oral fraction absorbed of 100%, which potentially makes it a good candidate for oral administration.