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European Journal of Pharmaceutical Sciences
Journal Prestige (SJR): 1.016
Citation Impact (citeScore): 4
Number of Followers: 185  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0928-0987 - ISSN (Online) 1879-0720
Published by Elsevier Homepage  [3206 journals]
  • Tuning mPEG-PLA/vitamin E-TPGS-based mixed micelles for combined
           celecoxib/honokiol therapy for breast cancer
    • Abstract: Publication date: Available online 24 February 2020Source: European Journal of Pharmaceutical SciencesAuthor(s): Jiahui Sun, Jing Li, Qi Liu, Min Jiang, Mengjia Yang, Siwen Zhan, Tong Qiu, Kaiyong He, Xueqiong ZhangThis study aimed to develop, evaluate, and optimize the mPEG-PLA/vitamin E-TPGS mixed micelle drug delivery system to encapsulate celecoxib (CXB) and honokiol (HNK) for intravenous treatment of breast cancer. To this end, we formulated CXB-loaded mPEG-PLA/vitamin E-TPGS (PV-CXB) and HNK-loaded mPEG-PLA/vitamin E-TPGS (PV-HNK) mixed micelles and analyzed their characteristics. The 4T1 cell line was used for cytotoxicity determination and cellular uptake experiments, and for establishing a 4T1-bearing mouse model for histopathology, immunofluorescence, terminal deoxynucleotidyl transferase-mediated nick end labeling, and Western blot analysis. The synergistic effects of PV-CXB and PV-HNK combination therapy were investigated in vitro and in vivo using the coefficient of drug interaction values. The mean size of PV-CXB and PV-HNK prepared with optimal formulation was approximately 50 nm, with a spherical shape. PV-CXB and PV-HNK combination therapy exhibited cytotoxicity in 4T1 cells in vitro. However, the toxicity of PV-CXB and PV-HNK combination therapy was not apparent in normal tissues (heart, liver, spleen, lung, and kidney) in vivo and reduced the expression of collagen fibers in tumor tissues. Moreover, the combination therapy reduced the expression of tumor growth biomarkers (Foxp3, CD4, Gr-1, CD11b, CD31, Ki67, FoxM1, and VEGF). In addition, the tumor cell apoptosis rate reached 45.71 ± 0.62 %. The combined treatment with PV-CXB and PV-HNK showed synergistic effect both in vitro and in vivo. Thus, the PV-CXB and PV-HNK drug delivery system could be used as a potential combination therapy for breast cancer.G AImage, graphical abstract
       
  • Amorphous Solid Dispersions Containing Residual Crystallinity: Influence
           of Seed Properties and Polymer Adsorption on Dissolution Performance
    • Abstract: Publication date: Available online 21 February 2020Source: European Journal of Pharmaceutical SciencesAuthor(s): Dana E. Moseson, Andrew S. Parker, Stephen P. Beaudoin, Lynne S. TaylorThe solubility advantage of amorphous solid dispersions (ASDs) is contingent upon supersaturation being generated and maintained. If crystals are present within an ASD, these crystals directly result in lost solubility advantage, and may also seed crystal growth leading to desupersaturation. The goal of this study was to evaluate the impact of residual crystals on ASD supersaturation profiles. Indomethacin-copovidone (PVPVA) ASDs with different levels of residual crystallinity were manufactured by hot melt extrusion (HME). PVPVA at 5 and 50 µg/mL was found to be a highly effective nucleation and crystal growth inhibitor of indomethacin at high supersaturation. Evidence of polymer adsorption onto indomethacin crystals was observed by atomic force microscopy and scanning electron microscopy. HME ASDs containing 0-25% residual crystallinity demonstrated lost solubility advantage, along with minimal desupersaturation during non-sink dissolution testing. While bulk seeds did not properly represent the impact of residual crystals, extensive polymer adsorption onto residual seed crystals resulted in poisoned crystal growth, limiting the potential dissolution performance consequences. Several risk factors related to the presence of residual crystallinity were identified: polymeric crystal growth inhibition effectiveness, seed properties, and supersaturation conditions.Graphical Image, graphical abstract
       
  • Updating the portfolio of physicochemical descriptors related to
           permeability in the Beyond the Rule of 5 chemical space
    • Abstract: Publication date: Available online 20 February 2020Source: European Journal of Pharmaceutical SciencesAuthor(s): Giuseppe Ermondi, Maura Vallaro, Gilles Goetz, Marina Shalaeva, Giulia CaronBeyond rule of 5 (bRo5) molecules are attracting significant interest in modern drug discovery mostly because many novel targets require large and more flexible structures.The main aim of this paper is the identification of ad hoc bRo5 physicochemical descriptors of ionization, lipophilicity, polarity and chameleonicity and their measurement. We used different methods to collect ionization (pKa measures and log k’80 PLRP-S trends), lipophilicity (in octanol/water, in apolar systems and in biomimetic environments), polarity (Δlog Poct-tol, EPSA and Δlog KWIAM) and chameleonicity (ChameLogD) descriptors for 26 bRo5 drugs. A second aim was to check the relationship between physicochemical descriptors and permeability for a subset of compounds for which solid permeability values are reported in the literature.Results showed that the physicochemical profile in the bRo5 chemical space is often experimentally accessible, albeit more tools are required to overcome limitations of individual methods. For the investigated compounds, permeability is governed by Δlog Poct-tol and preliminary data support that chameleonicity could also have an impact.Graphical abstractImage, graphical abstract
       
  • Pluronic micelles with suppressing doxorubicin efflux and detoxification
           for efficiently reversing breast cancer resistance
    • Abstract: Publication date: Available online 20 February 2020Source: European Journal of Pharmaceutical SciencesAuthor(s): Xu Cheng, Xiaodong Lv, Jiaxi Xu, Yan Zheng, Xin Wang, Rupei TangThe antitumor activity of doxorubicin (DOX) is often limited owing to the occurrence of multidrug resistance (MDR) during treatment. Herein, we developed hybrid polymeric micelles, which consisted of pluronic F127 as long-circulating helper in blood, and phenylboronic ester-grafted pluronic P123 (PHE) as efflux and detoxification regulator to efficiently deliver DOX and reverse MDR in vivo. Hybrid F127/PHE micelles exhibited higher stability and drug encapsulation (∼80%) than simple F127/P123 micelles due to its lower CMC, and displayed in vitro drug release in a hydrogen peroxide (H2O2)-sensitive manner. Besides, DOX-loaded hybrid micelles (F127/PHE-DOX) possessed higher cell-killing ability and induce more apoptotic in MDR-cells than other groups, which was probably because it not only could greatly increase intracellular drug concentration by inhibiting P-gp mediated drug efflux, but also promote reactive oxygen species (ROS) generation by decreasing glutathione (GSH) levels. Besides, in vivo evaluation indicated that F127/PHE-DOX could well accumulate at tumor regions and exhibit the strongest tumor growth inhibition (TGI 87.87%) accompanied with low side effects. As a result, F127/PHE micelles had great potentials as a platform for anticancer drugs delivery and tumor MDR reversal in clinical application.Graphical Image, graphical abstract
       
  • Evaluation of cell and hemocompatibility of Cucurbiturils
    • Abstract: Publication date: Available online 19 February 2020Source: European Journal of Pharmaceutical SciencesAuthor(s): Sarah Fink, Kirsten Reddersen, Cornelia Wiegand, Peter Elsner, Uta-Christina HiplerBackground: Cucurbiturils (CB) are pumpkin-shaped macrocyclic molecules consisting of methylen-bridged glycoluril units. Because of their complexing characteristics, they can be used as drug containers for medical purposes. For future biomedical and dermal application of CB, the investigation of cell compatibility is essential. Little is known about the influence of CB on eukaryotic cells, especially on dermal keratinocytes. The structurally related cyclodextrins are known to induce cell death by apoptosis in HaCaT keratinocytes as well as hemolysis in erythrocytes.Objective: To examine cytotoxic effects of different CB.Methods: Different cytotoxicity tests were performed on HaCaT keratinocytes and erythrocytes incubated with CB[5], CB[6] and CB[7].Results: CB[5] and CB[6] did not lead to cytotoxic reactions at high concentrations up to 30 mg/mL whereas incubation with CB[7] triggered apoptosis at a concentration of 3,75 mg/mL. None of the investigated CB caused hemolytic effects on erythrocytes.Conclusion: These results confirm the high potential of CB as host-complexes for biomedical and dermal applications.Graphical abstractImage, graphical abstract
       
  • Design and Characterization of Chitosan/Citrate Films as Carrier for Oral
           Macromolecule Delivery
    • Abstract: Publication date: Available online 19 February 2020Source: European Journal of Pharmaceutical SciencesAuthor(s): Yousif H-E.Y. Ibrahim, Géza Regdon, Katalin Kristó, András Kelemen, Mohamed E. Adam, Elnazeer I. Hamedelniel, Tamás SoványThe oral delivery of biopharmaceuticals requires the including of absorption enhancer, protease inhibitor and a suitable carrier system. The aim of the present work was to formulate and characterize chitosan solutions/films incorporating citric acid (CA) as potential excipient in comparison to the well-known acetic acid (AA)-based films as a reference. Films were made by the solvent casting method with/without glycerol (G), propylene glycol (PG) and polyethylene glycol (PEG-400) as plasticizers. The minimum film forming temperature (MFFT) of the prepared solutions, film thickness, hardness/deformation, mucoadhesivity, moisture content, FT-IR spectra and surface free energy (SFE) were investigated. Chitosan has been reported as a safe and effective paracellular absorption enhancer for hydrophilic macromolecules, therefore there would be more rationale for incorporating CA as a solubility enhancer, a permeation enhancer and an enzyme inhibitor. CA shows good cross-linking, an ideal plasticizing property and increases both tensile strength and mucoadhesivity, thus its incorporation simplifies the formulation while improving effectiveness. We concluded that CA (3.5, 4 and 5 w/v %)-based chitosan solution could be used as a novel coating/subcoating polymer for oral macromolecule delivery, or as oral mucoadhesive films.Graphical abstractImage, graphical abstract
       
  • Correlation between the conformational crossover of carbamazepine and its
           polymorphic transition in supercritical CO2: On the way to polymorph
           control
    • Abstract: Publication date: Available online 19 February 2020Source: European Journal of Pharmaceutical SciencesAuthor(s): Roman D. Oparin, Maria V. Kurskaya, Michael A. Krestyaninov, Abdenacer Idrissi, Michael G. KiselevIn this paper we have established a correlation between the conformation crossover of carbamazepine and associated polymorph transformation. This was achieved by using a combination of quantum chemical calculations and in situ IR spectroscopy for performing a conformational analysis of carbamazepine molecules in its saturated solution in scCO2 being in permanent contact with the carbamazepine solid form. Using quantum calculations, we determined two carbamazepine conformers, whose spectral signatures were then found in experimental IR spectra. Further analysis of the IR spectra allowed us to quantify the distribution of these conformations in supercritical CO2. We found that this distribution can be changed by heating from 40°C to 110°C along two isochores at 1.1 and 1.3 of the critical CO2 density. Using in situ Raman spectroscopy we proved that the appearing conformational crossover correlates with the polymorphic transformation of the carbamazepine solid form. Moreover, this transformation was proved by the results of IR diffuse reflection spectroscopy.Graphical abstractImage, graphical abstract
       
  • Evaluation Of Self-Emulsifying Drug Delivery Systems For Oral Insulin
           Delivery Using An In Vitro Model Simulating The Intestinal Proteolysis
    • Abstract: Publication date: Available online 19 February 2020Source: European Journal of Pharmaceutical SciencesAuthor(s): Jingying Liu, Cosima Hirschberg, Mathias Fanø, Huiling Mu, Anette MüllertzThe gentle preparation and the functionalization potential of self-emulsifying drug delivery systems (SEDDS) make them an interesting formulation strategy for oral administration of peptide and protein (p/p) drugs.A series of Kolliphor® RH40 (RH40) and Labrasol® (LAB) glycerides-based SEDDS containing either long-chain (LC) or medium-chain (MC) were formulated and characterized with regard to their rheological behavior, as well as the size distribution and zeta potential of formed emulsions. Insulin, in order to be incorporated in SEDDS, was complexed with soybean phosphatidylcholine before loading. The ability of different SEDDS to protect incorporated insulin against enzymatic hydrolysis was evaluated by an in vitro model simulating the intestinal proteolysis. SEDDS were incubated in simulated intestinal fluids in the presence of α-Chymotrypsin, and HPLC was used to quantify the remaining insulin. Principal component analysis (PCA) was applied to identify the relations between different excipients and properties of SEDDS that describe SEDDS protective effect on insulin during proteolysis.The RH40-SEDDS behaved Newtonian in the presence of ethanol (EtOH) and non-Newtonian when EtOH is absent, which generated emulsion with droplets between 30 to 300 nm. The LAB-SEDDS always behaved Newtonian and generated polydisperse emulsions with broad size distribution (190-4000 nm). During the vitro proteolysis, insulin can be effectively protected against proteolysis (e.g.> 60% remaining insulin after 60 min proteolysis). According to PCA analysis, insulin was better protected in MC-SEDDS compared to LC-SEDDS, and better in LAB-SEDDS compared to RH40-SEDDS. Monoacyl phosphatidylcholine and Capmul® MCM C8 were recognized as excipients favored for SEDDS protection on insulin. However, viscosity and the addition of EtOH played insignificant roles in the percentage of remaining insulin after proteolysis.In summary, an in vitro proteolysis model with increased physiological relevance was applied to enable the optimal design of SEDDS for oral p/p drug delivery.Graphical abstractImage, graphical abstract
       
  • Hyaluronan molecular weight: effects on dissolution time of dissolving
           microneedles in the skin and on immunogenicity of antigen
    • Abstract: Publication date: Available online 18 February 2020Source: European Journal of Pharmaceutical SciencesAuthor(s): Mara Leone, Stefan Romeijn, Bram Slütter, Conor O’ Mahony, Gideon Kersten, Joke A. BouwstraBiomaterials used as matrix for dissolving microneedles (dMNs) may affect the manufacturing process as well as the potency of the active pharmaceutical ingredient, e.g. the immunogenicity of incorporated vaccine antigens. The aim of this study was to investigate the effect of the molecular weight of hyaluronan, a polymer widely used in the fabrication of dMNs, ranging in molecular weight from 4.8 kDa to 1.8 MDa, on the dissolution of microneedles in the skin in time as well as the antibody response in mice and T-cell activation in vitro. Hyaluronan molecular weight (HA-MWs) did not affect antibody responses (when lower than 150 kDa) nor CD4+ T-cell responses against model antigen ovalbumin. However, the HA-MWs had an effect on the fabrication of dMNs. The 1.8 MDa HA was not suitable for the fabrication of dMNs. Similarly, the 4.8 kDa HA generated dMN arrays less robust compared to the other HA-MWs requiring optimization of the drying conditions. Finally, higher HA-MWs led to longer application time of dMN arrays for a complete dissolution of microneedles into the skin. Specifically, we identified 20 kDa HA as the optimal HA-MW for the fabrication of dMNs as with this MW the dMNs are robust and dissolve fast in the skin without affecting immunogenicity.Graphical Image, graphical abstract
       
  • Exposure to Sub-Inhibitory Ciprofloxacin and Nitrofurantoin Concentrations
           Increases recA Gene Expression in Uropathogenic Escherichia coli: The Role
           of RecA protein as a Drug Target
    • Abstract: Publication date: Available online 17 February 2020Source: European Journal of Pharmaceutical SciencesAuthor(s): Ághata Cardoso da Silva Ribeiro, Willames Marcos Brasileiro da Silva Martins, Adilson Aderito da Silva, Ana Cristina Gales, Daniela Gonçales Galasse Rando, Luciene Andrade da Rocha MinariniSub-inhibitory concentrations (sub-MIC) of antimicrobial agents can lead to genetic changes in bacteria, modulating the expression of genes related to bacterial stress and leading to drug resistance. Herein we describe the impact of sub-MIC of ciprofloxacin and nitrofurantoin on three uropathogenic Escherichia coli strains. Disk-diffusion assays with different antimicrobial agents were tested to detect phenotype alterations, and quantitative real-time PCR (qRT-PCR) was performed to analyze the expression of ompF and recA genes. Significant reduction on the susceptibility to ciprofloxacin and nitrofurantoin was detected on disk diffusion test. The qRT-PCR results revealed a 1.2 to 4.7 increase in recA expression in all E. coli studied, while the ompF expression varied. Because RecA was pointed as an important component to the development of drug resistance, molecular docking studies were performed with three experimentally known inhibitors of this enzyme. These studies aimed to understand the inhibitory binding mode of such compounds. The results confirmed the ADP/ATP binding site as a potential site of inhibitor recognition and a binding mode based on π-stacking interactions with Tyr103 and hydrogen bonds with Tyr264. These findings can be useful for guiding the search and design of new antimicrobial agents, mainly concerning the treatment of infections with resistant bacterial strains.GRAPHICAL ABSTRACTImage, graphical abstract
       
  • Preparation and Characterization of a New Solid Form of Praziquantel, an
           Essential Anthelmintic Drug. Praziquantel Racemic Monohydrate
    • Abstract: Publication date: Available online 13 February 2020Source: European Journal of Pharmaceutical SciencesAuthor(s): Duvernis Salazar-Rojas, Rubén M. Maggio, Teodoro S. KaufmanPraziquantel (PZQ) is a highly effective low-cost anthelmintic agent used as the first-choice treatment against schistosomiasis. The low solubility of the active is a major drawback for pharmaceutical formulation. A valid approach of the pharmaceutical industry for the improvement of the pharmacotechnical features of the active principles (such as solubility, processability, stability, among others), is the preparation of new solid forms, such as salts, polymorph, and pseudo-polymorph.Herein we report the preparation and characterization of a new solid form PZQ. The PZQ monohydrate (PZQ-MH) was prepared by a solventless procedure from the commercial racemate and the product was characterized at the solid-state employing optical digital microscopy, thermal methods (melting point, differential scanning calorimetry and thermogravimetric analysis), as weel as and mid-infrared and near infrared spectroscopies. The chemical structure and content of water were full assessed by 1H nuclear magnetic resonance (NMR) in solution. The amount of water in PZQ-was also determined by different approaches, including thermogravimetric analysis and the loss on drying test. Solid-state 13C NMR (ssNMR) and X-ray powder diffraction (XRPD) completed the structural characterization of the new monohydrate.PZQ-MH showed a crystalline behaviour during XRPD experiments and showed relevant differences in spectroscopic, calorimetric, ssNMR and XRPD signals when it was compared with the known crystal (Form A) and amorphous forms of PZQ. The determination of the intrinsic dissolution rate (IDR) of PZQ-MH was carried out as a functional characterization, observing that the new form had slightly higher IDR than Form A.Graphical Image, graphical abstract
       
  • Raloxifene Potentiates The Effect Of Fluoxetine Against Maximal
           Electroshock Induced Seizures In Mice
    • Abstract: Publication date: Available online 13 February 2020Source: European Journal of Pharmaceutical SciencesAuthor(s): Faheem Hyder Pottoo, Nahida Tabassum, Md. Noushad Javed, Shah Nigar, Shrestha Sharma, Md. Abul Barkat, Harshita, Md. Sabir Alam, Mohammad Azam Ansari, George E. Barreto, Ghulam Md AshrafThe evidence to guide clinicians regarding rationale polytherapy with current antiepileptic drugs (AEDs) is lacking, and current practice recommendations are largely empirical.  The excessive drug loading with combinatorial therapies of existing AEDs are associated with escalated neurotoxicity, and that emergence of pharmacoresistant seizures couldn't be averted. In pursuit of judicious selection of novel AEDs in combinatorial therapies with mechanism based evidences, standardized dose of raloxifene, fluoxetine, bromocriptine and their low dose combinations, were experimentally tested for their impact on maximal electroshock (MES) induced tonic hind limb extension (THLE) in mice. Hippocampal neuropeptide Y (NPY) levels, oxidative stress and histopathological studies were undertaken. The results suggest the potentiating effect of 4mg/kg raloxifene on 14mg/kg fluoxetine against MES induced THLE, as otherwise monotherapy with 4mg/kg raloxifene was unable to produce an effect. The results also depicted better efficacy than carbamazepine (20 mg/kg), standard AED. Most profoundly, MES-induced significant (P
       
  • QUANTITATIVE FTA USING MONTE CARLO ANALYSES IN A PHARMACEUTICAL PLANT
    • Abstract: Publication date: Available online 13 February 2020Source: European Journal of Pharmaceutical SciencesAuthor(s): Mayre Aparecida Borges da Costa, Amanda Lemette T. Brandão, Jorge G.F. Santos, José Carlos Pinto, Márcio NeleThe evaluation of faults in a multipurpose pharmaceutical pilot plant used for production of polymer particles was performed, integrating traditional Fault Tree Analyses (FTA) and Monte Carlo procedures and employing tools of the quality risk management methodology for production of medicines. The plant was divided into four basic processes: (i) receipt and sampling of materials; (ii) treatment of purified water; (iii) reaction; and (iv) lyophilization and purification. For each process, the most critical failure was selected, and the FTA was built. Selection of basic events considered the most important effects on the final quality of the medicine. Then, the FTA was reduced to basic events using Boolean algebra. The quantitative assessment was made by assigning failure rate values for each event. The reliability data of the failure rates were based on the literature that deals with similar processes. The frequencies for each fault were determined through Monte Carlo simulations, considering that fault probability distributions followed the exponential distribution. When failure rate (ʎ) data are available, the quality management can establish a prediction of plant behavior over a period. This scenario is consistent and coherent with practices of pharmaceutical sites, since occurrence of high rates of failure must be corrected immediately in order to preserve the safety of the operation.Graphical Image, graphical abstract
       
  • Investigation of drug partition kinetics to fat in simulated fed state
           gastric conditions based on drug properties.
    • Abstract: Publication date: Available online 12 February 2020Source: European Journal of Pharmaceutical SciencesAuthor(s): Fotios Baxevanis, Panagiota Zarmpi, Jesse Kuiper, Nikoletta FotakiThe presence of fat in the gastric environment can affect the pharmacokinetic behavior of drugs with mechanisms which have not been yet fully understood. The objective of the current study was to assess the drug partition to the lipid part of the fed gastric content under different emulsification conditions, using in vitro discriminating setups. The model drugs used in the study were selected on the basis of different physicochemical properties (lipophilicity, ionization, molecular weight and aqueous solubility) and different food effect observed in in vivo human studies. Fed State Simulated Gastric Fluid prepared with skimmed milk (FeSSGFsk) and anhydrous milk fat were used as surrogates for the aqueous and fat portions of the fed gastric environment respectively. An optimized biphasic model was developed so as to predict the differences in partition rate constants to fat, for model drugs of a wide range of the properties mentioned above. The experimental data and the use of statistical analysis revealed that molecular weight, molecular weight and log D pH 5 interaction and negative food effect act as negative factors to the rate constants of fat partition, while absence of food effect and logD pH 5 interaction with aqueous solubility affect the rate constants of partition to fat favorably.Graphical abstractImage, graphical abstract
       
  • Polymer/lipid interplay in altering in vitro supersaturation and plasma
           concentration of a model poorly soluble drug
    • Abstract: Publication date: Available online 12 February 2020Source: European Journal of Pharmaceutical SciencesAuthor(s): Rui Peng, Jiahao Huang, Li He, Lina Zhao, Cuitong Wang, Wei Wei, Tongchao Xia, Yifei Mao, Yinghui Wen, Ling Wang, Junyi YangSupersaturation drug delivery system (SDDS) based on amorphous solid dispersion (ASD) is a widely used strategy to improve oral absorption of poorly water-soluble drugs by achieving a supersaturated state where drug concentration is significantly higher than drug solubility. However, dissolved drugs tend to recrystallize in gastrointestinal (GI) tract if without effective stabilizing excipients. In this paper, well-recognized polymer (polyvinylpyrrolidone, PVP) and lipid (phosphatidylcholine, PC) excipients are combined as ASD carrier, aiming at investigating the effects on evolution of in vitro supersaturation and in vivo plasma concentration of a model poorly soluble drug indomethacin (IND). Fundamental aspects including polymer/lipid composition ratio, drug loading (DL) degree and administration dose were investigated. The in vitro dissolution profiles of ASDs were assessed by supersaturation degree, duration, maximum achievable drug concentration and dose-normalized efficiency, and correlated with in vivo pharmacokinetic data. Results showed that both in vitro and in vivo concentration-time profiles of IND were significantly varying with abovementioned factors. Solution viscosity, solid-state properties and morphology of ASDs were related to the results. This study revealed fundamental mechanisms of PVP/PC mixture effect on IND supersaturation and oral bioavailability, demonstrating that polymer/lipid mixture could be used as a promising carrier to alter supersaturation profile and oral bioavailability of SDDS products.Graphical abstractThe combination polyvinylpyrrolidone (PVP)/phosphatidylcholine (PC) as a carrier for indomethacin: the adjustment of in vitro supersaturation induced by PVP/PC complex successfully transformed into varied oral bioavailability profiles with good in vitro-in vivo correlation.Image, graphical abstract
       
  • Investigation of semi-solid formulations for 3D printing of drugs after
           prolonged storage to mimic real-life applications
    • Abstract: Publication date: Available online 12 February 2020Source: European Journal of Pharmaceutical SciencesAuthor(s): Ilias El Aita, Jörg Breitkreutz, Julian QuodbachThe implementation of tailor-made dosage forms is currently one of the biggest challenges in the health sector. Over the last years, different approaches have been introduced to provide an individual and precise dispensing of the appropriate dose of an active pharmaceutical ingredient (API). A more recent approach, which has been intensively researched in the last years, is 3D-printing of medicines.The aim of this work was to develop printing formulations free of organic solvents for a pressure-assisted microsyringe printing method (PAM), which should also be printable over several days of storage. Furthermore, the printed dosage forms should provide a sustained release of the incorporated API. A mixture of polyvinyl acetate/polyvinylpyrrolidone copolymer (PVAc-PVP), hydroxypropyl methylcellulose (HPMC) and highly dispersed silicon dioxide (SiO2) was found to be a feasible polymer matrix to achieve a sustained drug release. Levetiracetam (LEV) was used as model drug.The printed formulations were analyzed regarding mass variation, friability and thickness. Furthermore, the dissolution behavior of freshly printed tablets and tablets printed from stored printing formulations were investigated. The dissolution profiles indicate that the dissolution of LEV could be modified by varying the amount of HPMC and by changing the infill design of tablets. Tablet-like geometries with an infill design of 0.35 mm and 5 % HPMC released 50 % of the incorporated drug after 4 h, while for tablets with a higher HPMC amount the release was decreased (10 % HPMC: 5.5 h; 15 % HPMC: 8 h). All printed tablets exhibit a friability < 0.5 %, indicating that PAM printing is suitable for the manufacturing of tablets with a high structural integrity. Furthermore, this study demonstrates the ability of producing tablets with a uniform content and mass using PAM printing.Graphical abstractImage, graphical abstract
       
  • Rheumatoid arthritis downregulates the drug transporter OATP1B1:
           fluvastatin as a probe.
    • Abstract: Publication date: Available online 11 February 2020Source: European Journal of Pharmaceutical SciencesAuthor(s): Juciene Aparecida Caris, Jhohann Richard de Lima Benzi, Flávio Falcão Lima de Souza, Renê Donizeti Ribeiro de Oliveira, Eduardo Antônio Donadi, Vera Lucia LanchoteAims: Rheumatoid arthritis (RA) is a long term autoimmune inflammatory disease characterized by high autoantibody production and cytokine release, especially IL-6 and TNF-α. Some clinical studies have shown the effect of RA on CYP metabolism. However, the effect of RA on the drug transporter OATP1B1 remains a gap.Methods: Patients with RA under pharmacological treatment (n=10) and healthy volunteers (n=15) treated for seven consecutive days with racemic fluvastatin (20, 40, or 80 mg/24 h) were investigated. Serial blood samples were collected during the last dose interval. All participants were assessed for cytokine profile and CYP2C9 genotype.Results: Patients with RA showed increased plasma concentrations of IFN-γ and TNF-α up to two and four times, respectively, when compared to healthy volunteers, whereas CYP2C9 activity based on genotype was considered normal or slightly reduced for both investigated groups. When compared to healthy volunteers, patients with RA presented higher values (median and 25th–75th percentiles) of normalized AUC for 20 mg dose (250 [114–405] vs. 96.7 [78.1–131] ng⋅h⋅mL−1 for (−)-3S,5R-fluvastatin and 163 [96.9–325] vs. 83.1 [61.7–107] ng⋅h⋅mL−1 for (+)-3R,5S-fluvastatin) and lower values of CL/F (40.9 [24.5–89.1] vs. 103 [75.9–128] L⋅h−1 for (−)-3S,5R-fluvastatin and 61.4 [30.6–103] vs. 120 [93.0–162] L⋅h−1 for (+)-3R,5S-fluvastatin) and V/F (73.0 [28.5–117] vs. 143 [108–221] L for (−)-3S,5R-fluvastatin and 93.9 [32.7–116] vs. 153 [122–234] L for (+)-3R,5S-fluvastatin) for both enantiomers.Conclusion: The lower values of CL/F and V/F for both fluvastatin enantiomers in RA patients suggest that the inflammatory disease downregulates the sinusoidal drug transporter OATP1B1, the rate-determining step in the hepatic clearance of fluvastatin.Graphical Image, graphical abstract
       
  • Comparison of free software platforms for the calculation of the 90%
           confidence interval of f2 similarity factor by bootstrap analysis
    • Abstract: Publication date: Available online 10 February 2020Source: European Journal of Pharmaceutical SciencesAuthor(s): L. Noce, L. Gwaza, V. Mangas-Sanjuan, A. Garcia-ArietaIntroductionThe calculation of the 90% confidence interval of f2 based on the bootstrap methodology has been proposed and accepted by the main regulatory authorities when the dissolution data shows excessive variability. Different free software platforms allow the calculation of the 90% CI of f2 by means of bootstrapping. Their use in regulatory submissions is growing, but divergent results have been observed between the available software platforms. Therefore, the objective of this work is to analyze the characteristics of these software platforms and evaluate their results.Methods and MaterialsHighly variable in vitro dissolution data from two products were selected. Three different similarity factors, f2, E(f2) and bc-f2, and their corresponding 90% confidence intervals were calculated with three free software platforms, Pheq_bootstrap, Bootf2bca and DDSolver, and computed by four different approaches, normal approximation, bootstrap-t-CI, percentile CI, and bias corrected and accelerated CI.Resultsall three platforms report the same f2 value, 49.66 upon comparison of products 1 and 3 and 54.87 for products 2 and 3 (no truncation rule). Bootf2bca and Pheq_bootstrap provided the same f2 and E(f2) also under other truncation rules (EMA or FDA), which are not implemented in DDSolver. Pheq_bootstrap allowed the calculation of bc-f2. The conclusion of similarity is based on a bootstrap percentile CI of E(f2) and f2 in Pheq_bootstrap and DDSolver, respectively. Bootf2bca provides all four 90% CI.DiscussionBootf2bca or Pheq_bootstrap should be considered for the estimation of the 90% CI of the f2 similarity factor when dissolution profiles show high variability.Graphical abstractImage, graphical abstract
       
  • Development of a Minimal Physiologically-Based Pharmacokinetic/
           Pharmacodynamic Model to Characterize Target Cell Depletion and Cytokine
           Release for T Cell-Redirecting Bispecific Agents in Humans
    • Abstract: Publication date: Available online 10 February 2020Source: European Journal of Pharmaceutical SciencesAuthor(s): Xiling Jiang, Xi Chen, Pharavee Jaiprasart, Thomas J. Carpenter, Rebecca Zhou, Weirong WangT cell-redirecting bispecific antibodies (bsAbs) are highly potent tumor-killing molecules. Following bsAb mediated engagement with target cells, T cells get activated and kill target cells while inducing cytokine release, which at higher levels may lead to life-threatening cytokine release syndrome (CRS). Clinical evidence suggests that CRS can be mitigated by implementing a stepwise dosing strategy. Here, we developed a mechanism-based minimal physiologically-based pharmacokinetic/pharmacodynamic (mPBPK/PD) model using reported preclinical and clinical data from blinatumomab. The mPBPK/PD model reasonably captured blinatumomab PK and B cell depletion profiles in blood and in various tissue sites of action (i.e., red marrow perivascular niche, spleen, and lymph nodes) in patients with non-Hodgkin's lymphoma (NHL) and acute lymphoblastic leukemia (ALL). Using interleukin 6 (IL-6) as an example, our model quantitatively characterized the mitigation of cytokine release by a blinatumomab 5-15-60 µg/m2/day stepwise dosing regimen comparing to a 60 µg/m2/day flat dose in NHL patients. Furthermore, by only modifying the system parameters specific for ALL patients, the mPBPK/PD model successfully predicted the mitigation of IL-6 release by a blinatumomab 5-15 µg/m2/day stepwise dosing regimen comparing to a 15 µg/m2/day flat dose. Our work provided a case example to show how mPBPK/PD model can be used to support the discovery and clinical development of T cell-redirecting bsAbs.Graphical abstractImage, graphical abstract
       
  • In vitro and in vivo activities of multi-target phtalimido-thiazoles on
           Schistosomiasis mansoni.
    • Abstract: Publication date: Available online 10 February 2020Source: European Journal of Pharmaceutical SciencesAuthor(s): Carlos André Laranjeira Miranda Filho, Miria de Oliveira Barbosa, Arsênio Rodrigues Oliveira, Edna Farias Santiago, Veruska Cintia Alexandrino de Souza, Jéssica Paula Lucena, Camila Juliet Barbosa Fernandes, Ignes Regina dos Santos, Renata Lins Carneiro Leão, Fabio André Brayner dos Santos, Luiz Carlos Alves, Valéria Rego Alves Pereira, Roni Evêncio de Araújo, Ana Cristina Lima Leite, Sheilla Andrade de OliveiraSchistosomicidal activity of six phthalimido-thiazoles derivatives with substitutions at the position three of the thiazole ring were analyzed in an experimental model. The substituents biphenyl (2i) and 2- naphthyl (2j) at a concentration of 80 µg/mL caused 100% mortality of the parasite in culture after 24 hours and 48 hours respectively. An evaluation of ultrastructural parasites showed damage in the tegument, formation of bubbles and partial destruction of the tubercles. The in vivo anti-parasitic activity with the derivate 2i was performed by administering it orally and intraperitoneally in a 400mg/kg/5days regimen. Decreases in the number of eggs in the gut (45.1%) and a reduction of the percentage of mature (23.7%) and increased unviable (53.8%) eggs were observed. Our results also showed a reduction in the number of recovered worms after treatment with 2i (oral administration: 81, 25%). The results demonstrated that the prototypes which were tested had a significant anti-schistosomal effect against S. mansoni, suggesting that these derivatives are promising candidates for further research into the chemotherapy of schistosomiasis.Graphical Image, graphical abstract
       
  • Vaccinomics to Design a Novel Single Chimeric Subunit Vaccine for
           Broad-Spectrum Immunological Applications targeting Nosocomial
           Enterobacteriaceae Pathogens
    • Abstract: Publication date: Available online 5 February 2020Source: European Journal of Pharmaceutical SciencesAuthor(s): Saba Ismail, Sajjad Ahmad, Syed Sikander AzamHealthcare associated infections (HAIs) are major cause of elevated mortality, morbidity, and high healthcare costs. Development of a vaccine targeting these pathogens could benefit in reducing HAIs count and excessive use of antibiotics. This work aimed to design a multi-epitope based prophylactic/ therapeutic vaccine directing against carbapenem resistant Enterobacter cloacae and other leading nosocomial members of Enterobacteriaceae group. Based on subtractive proteomics and immunoinformatics in-depth investigation of E. cloacae reference proteome, we prioritize four targets: outer membrane usher protein-lpfC, putative outer membrane protein A-OmpA, putative outer membrane protein-FimD, and arginine transporter fulfilling criteria of vaccine candidacy. A multi-epitope peptide vaccine construct is then formulated comprising predicted epitopes with potential to evoke both innate and adaptive immunity and B-subunit of cholera toxin as an adjuvant. The construct is modelled, loop refined, improved for stability via disulfide engineering and optimized for codon usage as per Escherichia coli expression system to ensure its maximum expression. Cross-conservation analysis carried out to evaluate broad-spectrum applicability by providing cross protection against nosocomial pathogens. A blind docking method is applied further to predict predominant binding mode of the construct with TLR4 innate immune receptor, followed by molecular dynamics simulation protocol to probe complex dynamics and exposed topology of the construct epitopes for recognition and immune processing by the host. Towards the end, binding free energies of the vaccine construct-TLR4 receptor were estimated to test docking predictions and affirm complex stability. We believe these findings to be highly useful for vaccinologists in making a highly effective vaccine for E. cloacae specifically, and other notorious Enterobacteriaceae nosocomial pathogens in general.Graphical abstractImage, graphical abstract
       
  • Strategic photosafety screening system consisting of in chemico
           photoreactivity and in vitro skin exposure for quinolone derivatives
    • Abstract: Publication date: Available online 5 February 2020Source: European Journal of Pharmaceutical SciencesAuthor(s): Yosuke Iyama, Hideyuki Sato, Yoshiki Seto, Satomi OnoueThe main objective of this study was to verify the applicable domain of a proposed photosafety screening system, consisting of a reactive oxygen species (ROS) assay and in vitro skin permeation test, for dermally-applied chemicals. Quinolones (QNLs) were selected as test compounds, including enoxacin, flumequine, moxifloxacin, nalidixic acid, orbifloxacin, and oxolinic acid. The ROS assay and in vitro skin permeation test were employed to evaluate photoreactivity and skin deposition of QNLs, respectively. All QNLs exhibited significant ROS generation on exposure to simulated sunlight; in particular, enoxacin was indicative of potent photoreactivity compared with the other 5 QNLs. Steady-state concentration values of flumequine and nalidixic acid were calculated to be 5.0 and 8.2 μg/mL, respectively, and higher than those of the other QNLs. Based on the photoreactivity and skin exposure of QNLs, the phototoxic risk was ranked, and the predicted phototoxic risk by the proposed system was mostly in agreement with observed in vivo phototoxicity, suggesting the applicability of the proposed strategy to photosafety assessment of QNLs. The proposed screening would be efficacious to predict phototoxic risk of dermally-applied chemicals.Graphical abstractImage, graphical abstract
       
  • Determination of glycation levels in Erwinia chrysanthemi asparaginase
           Drug Product by liquid chromatography – mass spectrometry
    • Abstract: Publication date: Available online 4 February 2020Source: European Journal of Pharmaceutical SciencesAuthor(s): Patrick Kanda, Thomas T. MinshullErwinase (Erwinia chrysanthemi L-asparaginase) Drug Product (DP) is a freeze-dried formulation with a three-year shelf life at 2-8 o C, and an established safety, stability and efficacy profile over the more than three decades of clinical use. Seven Erwinase® DP batches, released over a 7-year period, were screened by reversed-phase liquid chromatography coupled to time-of-flight mass spectrometry for glycation levels. This modification is a known and natural consequence of exposure of Erwinase Drug Product to glucose excipients in stabilizing formulations. Although glycation is detected in current release and stability methods, glycation, including the conditions under which this reaction occurs, has not been previously characterised in detail. We have found that glycation levels of different DP lots generally correlated with age, when they were stored at low temperature. This suggests that the glycation reaction continues over time within the Drug Product formulation in the lyophilised state, even under low temperature (+2 - 8°C) conditions. We were also able to examine glycation levels of one DP lot, Lot D, held under long term stability at 3 different temperatures over a 5-year period. The 2 samples held at -20° C and -80° C, were glycated to levels of 12% and 17%, respectively. However, the DP Lot D sample held at +2 – 8o C in this time period was found to be glycated to a level of 35.6%, with multiple glycations of individual subunits observed. For analytical reference materials, it is important to keep parameters such as glycation levels as constant as possible, to avoid a ‘moving target’ with respect to comparisons with release and stability testing. These data suggest that storage of DP as reference standards at a lower temperature (e.g., -20° C) can significantly reduce levels of glycation over the longer time periods required for analytical reference standards.Graphical abstractImage, graphical abstract
       
  • Levan-based Hydrogels for Controlled Release of Amphotericin B for Dermal
           Local Antifungal Therapy of Candidiasis
    • Abstract: Publication date: Available online 4 February 2020Source: European Journal of Pharmaceutical SciencesAuthor(s): Tuba Demirci, Merve Erginer Hasköylü, Mehmet Sayip Eroğlu, Jürgen Hemberger, Ebru Toksoy ÖnerHydrogels from Halomonas levan polysaccharide were prepared at different crosslinking densities. Swelling results demonstrated pH dependent rather than temperature dependent swelling of the hydrogel and the highest swelling value was achieved at basic conditions with a swelling ratio of 9.1 ± 0.1 which is the highest reported for levan based hydrogels. SEM images show a porous network architecture, which indicates a large surface area of the hydrogels. Rheological analyses showed the viscoelastic behavior of the hydrogels. Biocompatibility of the hydrogels was confirmed by cell culture experiments. For drug release experiments Amphotericin B (AmB) was used. 51% of the loaded AmB was released into the PBS buffer and the released AmB had a significant antifungal activity against Candida albicans.Graphical abstractImage, graphical abstract
       
  • Nano-elastic liposomes as multidrug carrier of sodium stibogluconate and
           ketoconazole: A potential new approach for the topical treatment of
           cutaneous leishmaniasis
    • Abstract: Publication date: Available online 4 February 2020Source: European Journal of Pharmaceutical SciencesAuthor(s): M. Junaid Dar, Sidra Khalid, Sanjay Varikuti, Abhay R. Satoskar, Gul Majid KhanThe present study evaluates the efficacy of sodium stibogluconate (SSG) co-loaded with ketoconazole (KTZ) in nano-elastic liposomes (NELs) for the topical treatment of cutaneous leishmaniasis (CL). SSG-KTZ co-loaded NELs were developed and assessed for various physicochemical properties and anti-leishmanial potential. The optimized nano-vesicles have an average size of 212.8 ± 3.1 nm and entrapment efficiency of 61.2 ± 2.9%. SSG-KTZ co-loaded NELs displayed 5.37-fold higher skin permeation of SSG as compared to drug solution. SSG and KTZ displayed a synergistic interaction and flow cytometry revealed enhanced killing of DsRed Leishmania mexicana in infected macrophages. In-vitro and in-vivo anti-leishmanial studies indicated a 10.67-fold lower IC50 value and a 35.33-fold reduced parasitic burden as compared with plain SSG solution, respectively. SSG-KTZ co-loaded NELs were found to be a promising approach for the topical treatment of CL.Graphical-abstractImage, graphical abstract
       
  • Novel multiparticulate pH triggered delayed release chronotherapeutic drug
           delivery of celecoxib-β-cyclodextrin inclusion complexes by using
           Box-Behnken design
    • Abstract: Publication date: Available online 2 February 2020Source: European Journal of Pharmaceutical SciencesAuthor(s): Irsah Maqbool, Muhammad Akhtar, Rabbiya Ahmad, Hadia Sadaquat, Sobia Noreen, Amna Batool, Sajid Ullah KhanThis study aimed to prepare novel colon targeted celecoxib-β-cyclodextrin (CXB-β-CD) inclusion complex loaded eudragit S 100 (ES100) microparticles for chronotherapy of rheumatoid arthritis (RA) which is an innovative approach, never reported before, for the fabrication of CXB-β-CD complex in the form of microparticles and its colon targeting. CXB was complexed with β-cyclodextrin by kneading technique and we evaluated the effect of β-CD on saturation solubility of CXB. Microparticles were developed by oil-in-oil emulsion solvent evaporation technique and formulation variables (polymer conc, surfactant conc and stirring speed) were optimized by using three-factor three-level Box-Behnken design. SEM imaging revealed smooth, uniform and spherical shape microparticles. There was 7.3 fold increases in saturation solubility of CXB-β-CD inclusion complex in distilled water as compared to pure CXB. Particle size was in the range of 50.42 µm to 238.38 µm with entrapment efficiency of 68.47% to 91.65%. Biphasic drug release pattern was found i.e initially delayed release in stomach and small intestine followed by fast release at colonic pH. Response variable results achieved from optimized formulation were very close to the response values suggested by BBD signifying the actual reliability and robustness of BBD in the fabrication of colon targeted CXB-β-CD microparticles. The comparison of CXB-β-CD optimized formulation with optimized formulation containing pure CXB showed increase in drug release due to enhancement of water solubility of CXB-β-CD inclusion complex. So, it can be concluded that CXB-β-CD loaded ES100 microparticles can be successfully fabricated with enhanced solubility for the chronotherapy of rheumatoid arthritis.Graphocal AbImage, graphical abstract
       
  • Insight into the colonic disposition of celecoxib in humans
    • Abstract: Publication date: Available online 31 January 2020Source: European Journal of Pharmaceutical SciencesAuthor(s): Glenn Lemmens, Joachim Brouwers, Jan Snoeys, Patrick Augustijns, Tim VanuytselABSTRACTAlthough the effect of NSAIDs such as celecoxib on the progression of colorectal polyps has been established, it is currently unknown how sufficiently high concentrations of celecoxib are reached in colonic tissue. Indeed, the lipophilic and poorly soluble celecoxib is orally dosed as an immediate release capsule without any colon-targeting delivery strategy. In the present study, we aimed to distinguish between plasma and gut driven caecal tissue accumulation of celecoxib in healthy volunteers. After developing a protocol to reliably collect colonic biopsies and contents, the disposition of celecoxib was assessed in plasma, caecal tissue and caecal contents collected after intake of a celecoxib capsule (200mg; Celebrex®) with 240mL of tap water. During a first colonoscopy (1.0-2.5h after drug intake), plasma concentrations of celecoxib and its carboxy metabolite were increasing, while caecal tissue concentrations were relatively low. As no celecoxib was present in caecal contents, tissue accumulation was clearly plasma driven. During a second colonoscopy (6.0-7.5h after drug intake), tissue concentrations of the drug and its metabolite were substantially higher despite decreasing plasma concentrations. As a high amount of celecoxib was found in the caecal contents, the increased tissue accumulation most likely resulted from direct uptake of celecoxib from the gut. These data demonstrate that incomplete small intestinal absorption of the poorly soluble drug celecoxib enables gut driven drug accumulation in caecal tissue, which is, most likely, critical for the role of this NSAID in the prevention of colorectal cancer.Graphical Image, graphical abstract
       
  • Platelet lysate-loaded PLGA nanoparticles in a thermo-responsive hydrogel
           intended for the treatment of wounds
    • Abstract: Publication date: Available online 31 January 2020Source: European Journal of Pharmaceutical SciencesAuthor(s): Sergio Alberto Bernal-Chávez, Sergio Alcalá-Alcalá, Doris Cerecedo, Adriana Ganem-RonderoA thermo-responsive hydrogel of Pluronic F-127, containing PLGA nanoparticles loaded with a platelet lysate for wound treatment, was prepared. A high rate of incorporation of the lysate (about 80%) in the nanoparticles was achieved by the double emulsion-solvent evaporation method. The nanoparticles were characterized by measuring their size (about 318 nm), polydispersity index (0.29) and Z potential (-17.6), as well as by infrared and calorimetric techniques, and determining their stability as a function of time. It was found through measures of transepidermal water loss that the hydrogel containing the nanoparticles was capable of providing a semi-occlusive environment, necessary for the recovery of a wound. The inclusion of lysate in nanoparticles and this in turn in the hydrogel allowed a gradual release, which would avoid contact of the total dose with the biological medium. Studies with fibroblasts and in vivo in mice showed that the hydrogel containing nanoparticles with platelet lysate promoted faster tissue regeneration than the lysate in its free form, so this system is presented as a good alternative for the treatment of wounds.Graphical abstractImage, graphical abstract
       
  • Development of a nattokinase–polysialic acid complex for advanced
           tumor treatment
    • Abstract: Publication date: Available online 28 January 2020Source: European Journal of Pharmaceutical SciencesAuthor(s): Yanmei Kou, Rui Feng, Jiepeng Chen, Lili Duan, Siyu Wang, Yawei Hu, Ning Zhang, Tianyue Wang, Yihui Deng, Yanzhi SongCancer-associated thrombus (CAT) impedes delivery of nanoparticles to tumor sites and also inhibits the ability of immune cells to detect and attack these tumors, particularly in advanced tumors with old thrombi. Nattokinase (NK) is an extract from a popular Japanese food, natto, which consists of boiled soybeans fermented with bacteria. Nattokinase exerts strong fibrinolytic and thrombolytic activities and can unblock blood vessels. To deliver NK to thrombus sites in tumors, we modified the surface of NK with polysialic acid (PSA), which formed complexes via electrostatic interactions, resulting in NK–PSA. Particle size and zeta potential of NK–PSA were evaluated, and differential scanning calorimetry, Fourier-transform infrared spectroscopy, and morphological analyses of NK–PSA were performed. To determine the efficacy of the NK–PSA complex on delivery of nanoparticulate drugs, sialic acid-modified doxorubicin liposomes (DOX-SAL) were used as a model drug. In vivo pharmacokinetic and tissue distribution analyses showed that the blood clearance rate of DOX-SAL was significantly enhanced by NK–PSA, and NK–PSA increased accumulation of 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindotricarbocyanine iodide (DiR) labeled SAL (DiR-SAL) in tumors. Analysis of anti-tumor efficacy showed that the combination of NK–PSA and DOX-SAL enhanced anti-tumor activity. These results suggested that NK–PSA combined with DOX-SAL may be an effective strategy to clear CAT and increase the ability of nanoparticles and immune cells to reach tumors.Graphical abstractImage, graphical abstract
       
  • Systematic external evaluation of published population pharmacokinetic
           models for tacrolimus in adult liver transplant recipients
    • Abstract: Publication date: Available online 27 January 2020Source: European Journal of Pharmaceutical SciencesAuthor(s): Xiaojun Cai, Ruidong Li, Changcheng Sheng, Yifeng Tao, Quanbao Zhang, Xiaofei Zhang, Juan Li, Conghuan Shen, Xiaoyan Qiu, Zhengxin Wang, Zheng JiaoBackground: Diverse tacrolimus population pharmacokinetic (popPK) models in adult liver transplant recipients have been established to describe the PK characteristics of tacrolimus in the last two decades. However, their extrapolated predictive performance remains unclear. Therefore, in this study, we aimed to evaluate their external predictability and identify their potential influencing factors.Methods: The external predictability of each selected popPK model was evaluated using an independent dataset of 84 patients with 572 trough concentrations prospectively collected from Huashan Hospital. Prediction- and simulation-based diagnostics and Bayesian forecasting were conducted to evaluate model predictability. Furthermore, the effect of model structure on the predictive performance was investigated.Results: Sixteen published popPK models were assessed. In prediction-based diagnostics, the prediction error within ± 30% was below 50% in all the published models. The simulation-based normalised prediction distribution error test and prediction- and variability-corrected visual predictive check indicated large discrepancies between the observations and simulations in most of the models. Bayesian forecasting showed improvement in model predictability with two to three prior observations. Additionally, the predictive performance of the nonlinear Michaelis–Menten model was superior to that of linear one- and two-compartment models with first-order elimination, indicating the underlying nonlinear kinetics of tacrolimus in liver transplant recipients, which was consistent with the findings in adult kidney transplant recipients.Conclusions: The published models performed inadequately in prediction- and simulation-based diagnostics. Bayesian forecasting may improve the predictive performance of the models. Furthermore, nonlinear kinetics of tacrolimus may be mainly caused by the properties of the drug itself, and incorporating nonlinear kinetics may be considered to improve model predictability.Graphical abstractImage, graphical abstract
       
  • Gold nanoparticles promote a multimodal synergistic cancer therapy
           strategy by co-delivery of thermo-chemo-radio therapy
    • Abstract: Publication date: Available online 25 January 2020Source: European Journal of Pharmaceutical SciencesAuthor(s): Zahra Alamzadeh, Jaber Beik, Mehraban Mirrahimi, Ali Shakeri-Zadeh, Fatemeh Ebrahimi, Ali Komeili, Behafarid Ghalandari, Habib Ghaznavi, S. Kamran Kamrava, Christos MoustakisMultimodal cancer therapy has become a new trend in clinical oncology due to potential generation of synergistic therapeutic effects. Herein, we propose a multifunctional nanoplatform comprising alginate hydrogel co-loaded with cisplatin and gold nanoparticles (abbreviated as ACA) for triple combination of photothermal therapy, chemotherapy and radiotherapy (thermo-chemo-radio therapy). The therapeutic potential of ACA was assessed in combination with 532 nm laser and 6 MV X-ray against KB human mouth epidermal carcinoma cells. The results demonstrated that tri-modal thermo-chemo-radio therapy using ACA induced a superior anticancer efficacy than mono- or bi-modality treatments. The intracellular reactive oxygen species (ROS) level in KB cells treated with tri-modal therapy was increased by 4.4-fold compared to untreated cells. The gene expression analysis demonstrated the up-regulation of Bax pro-apoptotic factor (by 4.5-fold) and the down-regulation of Bcl-2 anti-apoptotic factor (by 0.3-fold). The massive cell injury and the appearance of morphological characteristics of apoptosis were also evident in the micrograph of KB cells caused by thermo-chemo-radio therapy. Therefore, ACA nanocomplex can be offered as a promising platform to combine photothermal therapy, chemotherapy and radiotherapy, thereby affording an opportunity for combating chemo- and radio-resistant tumors.Graphical abstractImage, graphical abstract
       
  • Synergistic Effects of Binary Oil Mixtures on the Solubility of Sunscreen
           UV Absorbers
    • Abstract: Publication date: Available online 24 January 2020Source: European Journal of Pharmaceutical SciencesAuthor(s): Bernd Herzog, Ansgar Schäfer, Katja Quass, Jochen GiesingerSunscreens for the photoprotection of human skin often are prepared as emulsions, containing organic UV-absorber molecules dissolved in the oil phase. The solubility of such oil-soluble UV-absorbers can be a limiting factor when aiming for high protection against UV-radiation. Possible synergistic effects of combinations of oil components toward UV-absorber solubility are therefore of great interest. Since a multitude of different combinations of oil components are possible, it would be desirable to predict synergistic effects by computational methods. As a model system, the solubility of a hydroxyphenyl triazine type UV-absorber was studied in several binary oil mixtures, experimentally and also by using a computational procedure based on density functional theory (DFT) and the continuum solvation model COSMO-RS. We have found good agreement of experimental and computational results. Computational methods may thus be employed to predict synergistic behaviour of solubility for systems containing two or more solvents.Graphical abstractImage, graphical abstract
       
  • Towards In Vitro In Vivo Correlation for Modified Release Subcutaneously
           Administered Insulins
    • Abstract: Publication date: Available online 24 January 2020Source: European Journal of Pharmaceutical SciencesAuthor(s): Frederik Bock, Eva Lin, Claus Larsen, Henrik Jensen, Kasper Huus, Susan Weng Larsen, Jesper ØstergaardTherapeutic proteins and peptides are mainly administrated by subcutaneous injection. In vitro release testing of subcutaneous injectables performed using methods that take the structure and environment of the subcutaneous tissue into account may improve predictability of the in vivo behavior and thereby facilitate establishment of in vitro in vivo correlations. The aim of the study was to develop a biopredictive flow-through in vitro release method with a gel-type matrix for subcutaneously administered formulations and to explore the possibility of establishing a level A in vitro in vivo correlation for selected insulin products. A novel gel-based flow-through method with the incorporation of an injection step was used to assess selected commercial insulin formulations with different duration of action (Actrapid®, Mixtard® 30, Insulatard®, Lantus®). The in vitro release method provided the correct rank ordering in relation to the in vivo performance. For the modified release insulins Insulatard® and Lantus®, an in vitro in vivo correlation using non-linear time scaling was established based on the in vitro release data and in vivo subcutaneous absorption data of the 125I-labeled insulins taken from literature. Predicted absorption profiles were constructed using the in vitro in vivo correlation and subsequently converted into simulated plasma profiles. The approach taken may be of wider utility in characterizing injectables for subcutaneous administration.Graphical Image, graphical abstract
       
  • Current trends in theranostics for Rheumatoid Arthritis
    • Abstract: Publication date: Available online 24 January 2020Source: European Journal of Pharmaceutical SciencesAuthor(s): Yamini Madav, Kalyani Barve, Bala PrabhakarThe very complexity of Rheumatoid Arthritis (RA) makes its prognosis and management challenging. The manifestations pertaining to RA emerge in the late stage of the disease when the damage to bone and cartilage has already occurred. Therefore early diagnosis of RA becomes critical in order to avoid further complications and disabilities. In such a scenario, theranostics can be an ideal solution to tackle the barriers to disease management in RA patients. Nanotechnology has paved the way for emerging theranostics to achieve better targetability and high performance. The shortcomings of current diagnostic techniques and pharmacological treatment are addressed in this review. The article also summarizes the laboratory studies that have reported promising theranostic entities for RA diagnosis, treatment and discusses the outcomes of each. Novel platforms combined with newer techniques have found application in the theranostics of RA. These platforms include gold nanorods, nanoshells, nanowhiskers, magnetic nanoparticles, solid and mesoporous silica nanoparticles, etc. Photodynamic, chemo-photo responsive, magnetic field based imaging and simultaneous stimulation have been reported for the release of therapeutic moieties from these nanoplatform. Theranostics can also assist clinicians in determining the respondents and non-respondents to biological response modifiers and other treatments available for RA. This not only plays an important role in selecting the suitable therapy for every patient but also in monitoring the progress of treatment in the patient. The advantages of theranostics over current diagnosis and treatment for RA are tremendous. Hence it holds great opportunities for progress and enhancement of RA disease management.Graphical abstractImage, graphical abstract
       
  • Selected papers of the “12th Central European Symposium on
           Pharmaceutical Technology and Regulatory Affairs”
    • Abstract: Publication date: Available online 23 January 2020Source: European Journal of Pharmaceutical SciencesAuthor(s): Ildikó Csóka, Géza Regdon, Tamás Sovány, Rok Dreu
       
  • Chromatographic HILIC indexes to characterize the lipophilicity of
           zwitterions
    • Abstract: Publication date: Available online 23 January 2020Source: European Journal of Pharmaceutical SciencesAuthor(s): Maura Vallaro, Giuseppe Ermondi, Giulia CaronReverse phase high pressure liquid chromatography (RP-HPLC) is widely employed in drug discovery for lipophilicity measurements. Hydrophilic interaction liquid chromatography (HILIC) may represent a good alternative to RP-HPLC in the determination of the lipophilicity of hydrophilic compounds like zwitterions. In this paper three different HILIC stationary phases (ZIC®-HILIC, ZIC®-pHILIC and ZIC®-cHILIC) and two different mobile phases (80%ACN/20%buffer and 90%ACN/10%buffer) were combined to set-up six chromatographic systems. A computational tool named Block Relevance (BR) analysis was firstly used to deconvolute the balance of intermolecular forces governing retention in the six systems. Then the lipophilicity profiles (log k vs pH) of ten model ampholytes were determined. Results support that the lipophilicity of zwitterions at any pH can be successfully determined with a ZIC®-cHILIC stationary phase and an 80%ACN/20%buffer mobile phase. To extend the dataset and confirm results, a second series of zwitterionic drugs was also analysed.Graphical abstractImage, graphical abstract
       
  • Benznidazole Self-Emulsifying Delivery System: A Novel Alternative Dosage
           Form For Chagas Disease Treatment
    • Abstract: Publication date: Available online 22 January 2020Source: European Journal of Pharmaceutical SciencesAuthor(s): Ana Lia MAZZETI, Liliam Teixeira OLIVEIRA, Karolina R. GONÇALVES, Géssica C. SCHAUN, Vanessa Carla Furtado MOSQUEIRA, Maria Terezinha BAHIABenznidazole (BZ) tablets are a unique form of treatment available for treating Chagas disease. Development of a liquid formulation containing BZ easy to administer orally for the treatment of paediatric patients, particularly for newborns is urgently required, with the same efficacy, safety and suitable biopharmaceutical properties as BZ tablets. Self-emulsifying drug delivery systems (SEDDS) may improve bioavailability of drugs such as BZ, which have poor water solubility and low permeability. In this context, the aim of this work was to develop a liquid BZ-SEDDS formulation as an alternative to tablets and to evaluate its cytotoxicity in different host cell lines and its efficacy in experimental Trypanosoma cruzi infection in mice. The optimized SEDDS formulation (25 mg/ml of BZ) induced no cytotoxicity in H9c2, HepG2 and Caco2 cells in vitro at 25 μM level. BZ-SEDDS and free-BZ showed similar in vitro trypanocidal activity in H9c2 cells infected by T. cruzi Y strain, with IC50 values of 2.10 ± 0.41 μM and 1.29 ± 0.01 μM for BZ and BZ-SEDDS, respectively. A follow up of efficacy in an acute model of infected mice resulted in the same percentage of cure (57%) for both free-BZ and BZ-SEDDS- groups according to established parameters. Furthermore, no additional in vivo toxicity was observed in animals treated with BZ-SEDDS. Taken together, in vitro and in vivo data of BZ-SEDDS showed that the incorporation of BZ into SEDDS does not alter its potency, efficacy and safety. Thus, BZ-SEDDS can be a more practical and personalized orally administered liquid dosage form compared to suspension of crushed BZ-tablets to treat newborn and young children by emulsifying SEDDS in different aqueous liquids with advantage of dosing flexibility.Graphical Image, graphical abstract
       
  • Development of Human Respiratory Airway Models: A Review
    • Abstract: Publication date: Available online 21 January 2020Source: European Journal of Pharmaceutical SciencesAuthor(s): Kaveh Ahookhosh, Oveis Pourmehran, Habib Aminfar, Mousa Mohammadpourfard, Mohammad Mohsen SarafrazPulmonary drug delivery has gained great interest as an important subject of research over the past decades given the lung diseases which are affecting millions of people suffer from these diseases. Drug delivery into the respiratory system is influenced by many anatomical and physiological factors such as lung morphometry, breathing patterns, fluid dynamics, particle properties, etc. The respiratory airway structure is one of these parameters which greatly influences the deposition pattern of inhaled drug particles. There have been a wide variety of major morphometric studies, conducted using cadavers to increase an understanding of the respiratory airway anatomy and provide important information for developing realistic airway models. Casting as one of the first methods, was utilized for morphometric studies providing a hollow model for in vitro investigations. The above-mentioned morphometric data were utilized to describe the first idealized airway model as a simple symmetric description of the branching airways, later followed by more realistic asymmetric models. However, even these asymmetric airway models were not good enough to reflect the anatomical complexities of the human respiratory airway and contained several major limitations which made them inefficient. Further attempts alongside with the progress of technology led to introduction of the stochastic and image-based models which provided more realistic and efficient tools for numerical and experimental investigations. The main objective of this study is to provide a comprehensive review about the development of different perspectives of the respiratory airway modeling over the past decades. The following sections will present useful information about anatomy of the human respiratory tract, and different viewpoints of the respiratory airway modeling, including their historical routes, strengths, and deficiencies.Graphical abstractGraphical abstract for this article
       
  • An example of how to establish the thermodynamic stability relationship
           between two polymorphs of a compound highly prone to solvate formation
    • Abstract: Publication date: Available online 15 January 2020Source: European Journal of Pharmaceutical SciencesAuthor(s): Norbert Nagel, Bruno Baumgartner, Harald BerchtoldUpon transition from research to development, a new chemical entity, which acts upon the Kv1.5-potassium channel and blocks potassium flow in the atrium of the human heart, has been subjected to a crystallization screen. The sodium salt of an anthranilic acid amide with a heteroarylsulfonyl side chain forms solvates from all tested organic solvents. Solvent-free crystalline phases can only be obtained by drying certain solvates under suitable conditions. Two well crystalline solvent-free phases can be obtained this way. Three different methods were applied to determine their thermodynamic stability relationship from melting, solution and eutectic melting data. The different approaches are discussed and compared with respect to their accuracy and limitations.Graphical abstractImage, graphical abstract
       
  • Development and validation of a Level A in-vitro in-vivo correlation for
           tofacitinib modified-release tablets using extrudable core system osmotic
           delivery technology
    • Abstract: Publication date: Available online 19 December 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Joseph Kushner, Manisha Lambaal, Thomas Stock, Ronnie Wang, Mary Anne Nemeth, Christine Alvey, Raymond Chen, Vincent DeMatteo, Andrew BlanchardPurposeTo determine if a validated Level A in-vitro in-vivo correlation (IVIVC) could be achieved with the extrudable core system (ECS) osmotic tablet platform. Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis.MethodsFast-, medium-, and slow-release modified-release formulations of 11 mg tofacitinib ECS tablets, and one formulation of 22 mg tofacitinib ECS tablet, were manufactured. In vitro dissolution of the tofacitinib ECS tablets was performed using USP Apparatus 2 (paddles) and in vivo pharmacokinetic (PK) data were obtained from a Phase 1 study in healthy volunteers. A 5 mg immediate-release formulation tablet was included to support deconvolution of the tofacitinib ECS PK tablet data to obtain the in vivo absorption profiles. A linear, piecewise correlation and a simple linear correlation were used to build and validate two IVIVC models.ResultsThe prediction errors (PEs) for the linear, piecewise correlation met the Food and Drug Administration's criteria for establishing a Level A IVIVC, with a maximum absolute individual internal PE of 4.6%, a maximum absolute average internal PE of 3.9%, and a maximum absolute external PE of 8.4% obtained.ConclusionsThis study demonstrates that the tofacitinib ECS osmotic tablet platform can achieve a Level A IVIVC, similar to other osmotic delivery systems.Graphical abstractImage, graphical abstract
       
  • Quality and Equivalence of Topical Products: A Critical Appraisal
    • Abstract: Publication date: Available online 15 October 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Margarida Miranda, Catarina Cardoso, Carla VitorinoThe approval of topical generic products is essentially governed by clinical endpoint studies. Is this the most efficient approach to document bioequivalence in these particular dosage forms? This issue has sparkled multiple discussions among different stakeholders – academia, industry and several regulatory agencies – in the active pursuit for new and robust surrogate methodologies.This mini review attempts to critically discuss this topic in light of the recently issued European regulatory requirements within the proposed modular framework for bioequivalence assessment.Graphical Image, graphical abstract
       
 
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