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European Journal of Pharmaceutical Sciences
Journal Prestige (SJR): 1.016
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  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0928-0987
Published by Elsevier Homepage  [3181 journals]
  • Comparative biocompatibility and antimicrobial studies of sorbic acid
    • Abstract: Publication date: Available online 20 November 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Dániel Nemes, Renátó Kovács, Fruzsina Nagy, Zoltán Tóth, Pál Herczegh, Anikó Borbás, Viktor Kelemen, Walter P. Pfliegler, István Rebenku, Péter B. Hajdu, Pálma Fehér, Zoltán Ujhelyi, Ferenc Fenyvesi, Judit Váradi, Miklós Vecsernyés, Ildikó Bácskay Nowadays, the sorbates are the third largest group of antimicrobial preservatives in food and pharmaceutical industries, following the parabens and benzoates whose safety is questioned by recent publications. A disadvantage of sorbates is their pH dependence, as their antimicrobial effect is greatly reduced in alkaline environment. The main, widely used sorbate derivatives are sorbic acid and potassium sorbate, no sorbic acid esters are involved in current industrial application. We aimed to test whether the esters of sorbic acid are capable to extend the antimicrobial spectrum of the original molecule while maintaining its advantageous biocompatibility profile. A comparative biocompatibility study of different derivatives (sorbic acid, potassium sorbate, isopropyl sorbate and ethyl sorbate) was carried out. In vitro cell viability assays of MTT (2-(4,5-dimethyl-2-thiazolyl)-3,5-diphenyl-2H-tetrazolium bromide), Neutral Red (3-amino-7-dimethylamino-2-methylphenazine hydrochloride) and flow cytometry with propidium iodide and annexin were performed on Caco-2 cells. In case of in vivo toxicity study, Galleria mellonella larvae were injected with different concentrations of the test compounds. Time-kill tests were executed on reference strains of C. albicans, E. coli, and S. aureus. According to the MTT-assay, the IC50 values were the following: ethyl sorbate, sorbic acid 0.75% w/w, while Neutral Red values were>0.75% w/w for the esters and potassium sorbate and 0.66% w/w for sorbic acid. Flow cytometry results indicated the higher cell damage in case of isopropyl sorbate. However, the cytotoxic results of isopropyl sorbate, in vivo toxicity study on Galleria mellonella larvae did not show significant mortality. It was found, that the antimicrobial properties of isopropyl sorbate were outstanding compared to sorbic acid and potassium sorbate. These results indicate, that the use of sorbate esters can be advantageous, hence, further toxicity studies are needed to prove their safety.Graphical abstractImage, graphical abstract
  • Low-dose docetaxel enhances the anti-tumour efficacy of a human umbilical
           vein endothelial cell vaccine
    • Abstract: Publication date: Available online 19 November 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Ling Zhou, Meiyu Lu, Weilan Zhong, Junhou Yang, Yancun Yin, Minjing Li, Defang Li, Shumin Zhang, Maolei Xu Our previous studies have indicated that human umbilical vein endothelial cell (HUVEC) vaccination appears to be a potentially promising anti-angiogenesis therapy, but the modest therapeutic anti-tumour efficiency limits its clinical use. This highlights the importance of identifying more potent therapeutic HUVEC vaccine strategies for clinical testing. In the present study, the immune-modulating doses of docetaxel (DOC) was combined with 1 × 106 viable HUVECs as a means to enhance the therapeutic anti-tumour efficiency of the HUVEC vaccine. Our results demonstrated that 5 mg/kg DOC administrated prior to HUVEC vaccine could most effectively assist HUVEC vaccine to display a remarkable suppression of tumour growth and metastasis as wells as a prolongation of survival time in a therapeutic procedure. CD31 immunohistochemical analysis of the excised tumours confirmed a significant reduction in vessel density after treatment with the HUVEC vaccine with 5 mg/kg DOC. Additionally, an increased HUVEC-specific antibody level, activated CTLs and an elevated IFN-γ level in cultured splenocytes were revealed after treatment with HUVEC vaccine with 5 mg/kg DOC. Finally, 5 mg/kg DOC coupled with the HUVEC vaccine led to induction of significant increases in CD8+ T cells and decrease in Tregs in the tumour microenvironment. Taken together, all the results verified that 5 mg/kg DOC could assist HUVEC vaccine to elicit strong HUVEC specific humoral and cellular responses, which could facilitate the HUVEC vaccine-mediated inhibition of cancer growth and metastasis. These findings provide the immunological rationale for the combined use of immune-modulating doses of DOC and HUVEC vaccines in patients with cancer.Graphical abstractImage, graphical abstract
  • 3-Bromopyruvate as a potent covalently reversible inhibitor of New Delhi
           metallo-β-lactamase-1 (NDM-1)
    • Abstract: Publication date: Available online 18 November 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Peng-Wei Kang, Jian-Peng Su, Le-Yun Sun, Han Gao, Ke-Wu YangABSTRACTThe bacteria, harboring metallo-β-lactamases (MβLs), become resistant on most β-lactam antibiotics, specifically New Delhi metallo-β-lactamase-1 (NDM-1), which hydrolyzes almost all β-lactam antibiotics leading to bacterial multiple-drug resistance. It is highly desirable to develop effective NDM-1 inhibitors in reviving the efficacy of existing antibiotics. Here, we report a potent covalently reversible scaffold, 3-Bromopyruvate (3BP) to target the NDM-1 in vitro and in vivo. Enzymatic kinetic studies revealed that 3BP is capable of inhibiting the B1 and B2 MβLs and exhibited the best inhibition on NDM-1 with an IC50 of 2.57 μM, also, it was found to be a dose- and time-dependent inhibitor. The study of inhibition mechanism suggested that 3BP reversibly inactivate NDM-1, and may form a dynamic reversible covalent bond with cysteine at active site of the enzyme. Besides, 3BP effectively restored the activity of five β-lactam antibiotics on three clinical strains expressing NDM-1, resulting in 2-8-fold reduction in MIC. Moreover, the toxicity evaluation of 3BP against L929 mouse fibroblastic cells indicated that 3BP had low cytotoxicity, implying it may be used as lead molecule for future drug candidate.Table Of ContentImage, graphical abstract
  • Immunoinformatics Design of a Novel Multi-Epitope Peptide Vaccine to
           Combat Multi-Drug Resistant Infections caused by Vibrio vulnificus
    • Abstract: Publication date: Available online 18 November 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Ghulam Abbas, Iqra Zafar, Sajjad Ahmad, Syed Sikander Azam Multi-drug resistant Vibrio vulnificus is a Gram-negative bacillus responsible for diseases, such as: sepsis, septicemia, gastroenteritis, and fatal necrotizing fasciitis in humans. The treatment and prevention of V. vulnificus infections are challenging because of resistance to antibiotics and the non-availability of a licensed vaccine. Considering this, an in-silico based approach comprising subtractive proteomics, immunoinformatics, molecular docking, and dynamics simulation studies is applied herein to identify potential epitope vaccine candidates for the mentioned pathogen. Two potential vaccine candidates: vibC and flgL are filtered based on essentiality, outer membrane localization, virulence, antigenic, pathway mapping, and cellular protein-protein network analysis. Using immunoinformatic tools, 9-mer B-cell derived T-cell antigenic epitopes are predicted for the said shortlisted two proteins that are demonstrating excellent affinity for predominant HLA allele (DRB1*0101) in human population. Screened peptides are used further in multi-epitope peptide designing and linked to an adjuvant to enhance the immunogenic properties of the designed construct. Furthermore, the construct was docked blindly to TLR4 immune receptor, and analyzed in conformational dynamics simulation to decipher the complex affinity and understand time dependent behavior, respectively. We expect this designed in silico construct to be useful for vaccinologists to evaluate its immune protective efficacy in in vivo animal models.Graphical Image, graphical abstract
  • Lipid-Based Nanocarriers for delivery of Small interfering RNA for
           therapeutic use
    • Abstract: Publication date: Available online 17 November 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Deepti Parashar, Vinoth Rajendran, Ravi Shukla, Dr. Sistla Ramakrishna Small interfering RNAs (siRNAs) indicate the unprecedented versatility in silencing disease-causing genes. However, the therapeutic use of siRNA is limited by its inherent instability in serum and immunogenicity. Thus, to realize their full therapeutic potential, there is a growing need to develop an efficient siRNA delivery system that targets it towards the localized symptomatic sites. Consequently, nanosized lipid carriers have been utilized for the targeted delivery of therapeutic agents to improve their efficacy in clinical studies. In this review, we attempt to elaborate on the current improvements of chemically diverse lipid carriers for the delivery of siRNAs-based drugs across a wide range of diseases. Finally, we discuss the patents and clinical status of siRNA in lipid formulations, which continue to expand for years to come.Graphical Image, graphical abstract
  • Pharmacokinetic profile of N-acetylcysteine amide and its main metabolite
           in mice using new analytical method
    • Abstract: Publication date: Available online 16 November 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Rui He, Wenyi Zheng, Tobias Ginman, Hakan Ottosson, Svante Norgren, Ying Zhao, Moustapha Hassan N-acetylcysteine amide (NACA) is the amide derivative of N-acetylcysteine (NAC) that is rapidly converted to NAC after systemic administration. It has emerged as a promising thiol antioxidant for multiple indications; however, the pharmacokinetic property is yet unclear due to lack of an accurate quantification method. The present investigation aimed to develop an analytical method for simultaneous quantification of NACA and NAC in plasma. A new reagent (2-(methylsulfonyl)-5-phenyl-1,3,4-oxadiazole, MPOZ) was introduced for thiol stabilization during sample processing and storage. Further, we utilized tris (2-carboxyethyl) phosphine (TCEP) to reduce the oxidized forms of NACA and NAC. After derivatization, NACA-MPOZ and NAC-MPOZ were quantified using liquid chromatography–mass spectrometry (LC-MS). The new method was validated and found to have high specificity, linearity, accuracy, precision, and recovery for the quantification of NACA and NAC in plasma. Furthermore, the formed derivatives of NACA and NAC were stable for 48 h under different conditions. The method was utilized in pharmacokinetic study which showed that the bioavailability of NACA is significantly higher than NAC (67% and 15%, respectively). The pharmacokinetic of NACA obeyed a two-compartment open model. The glutathione (GSH)-replenishing capacity was found to be three to four-fold higher after the administration of NACA compared to that observed after the administration of NAC. In conclusion, the present method is simple, robust and reproducible, and can be utilized in both experimental and clinical studies. NACA might be considered as a prodrug for NAC. Furthermore, this is the first report describing the pharmacokinetics and bioavailability of NACA in mouse.Graphical Image, graphical abstract
  • Essential role of STAT-3 dependent NF-κB activation on IL-6-mediated
           downregulation of hepatic transporters
    • Abstract: Publication date: Available online 15 November 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Walaa A. Abualsunun, Cigdem Sahin, Carolyn L. Cummins, Micheline Piquette-Miller IL-6 markedly decreases the expression of numerous hepatic transporters. We previously demonstrated that IL-6-mediated downregulation of transporters occurs through STAT3, with partial involvement of PXR. However, while IL-6-mediated induction of STAT3 occurs rapidly, repression of transporter expression is not observed until 6 hours post-treatment. This temporal mismatch suggested that the downregulation of transporters following IL-6 at 6 hours might require additional signaling downstream of STAT3. Since NF-κB has been implicated in endotoxin-mediated downregulation of transporters, we hypothesized that NF-κB may be similarly involved in suppressing transporter expression following IL-6. Our objective was to investigate whether IL-6-mediated changes in transporter expression occur through STAT3-dependent NF-κB activation, and whether PXR is involved. PXR null (-/-) or wild type (+/+) mice were pre-dosed with the NF-κB inhibitor PHA408 or vehicle 30 minutes prior to receiving a single dose of IL-6 or saline. Mice were euthanized after 6 hours and transporter expression was analyzed using qRT-PCR. IL-6 imposed downregulation of Abcb1a, Abcb1b, Abcc3, Abcg2 and Cyp3a11 in both PXR (+/+) and PXR (-/-) mice, while downregulation of Abcb11, Abcc2, Slc10a1, and Slco2b1 was only significant in PXR (+/+) mice. PHA408 pretreatment fully inhibited NF-κB activation in PXR (+/+) but only partially inhibited NF-κB in PXR (-/-). Inhibition of NF-κB attenuated IL-6-mediated changes in transporters in PXR (+/+) mice. Transient transfection assays did not detect significant activation of human or mouse PXR by PHA408. Our findings suggest that IL-6 imposes significant downregulation of numerous ABC and SLC transporters in the liver via collaborative STAT3/NF-κB activation. Since drug transporters play an integral role in the pharmacokinetics of numerous clinically relevant drugs, understanding the signaling pathways involved in transporter regulation during inflammation will contribute to a better understanding of drug-disease interactions.Graphical abstractImage, graphical abstract
  • The impact of dopamine D2-like agonist/antagonist on [18F]VAT PET
           measurement of VAChT in the brain of nonhuman primates
    • Abstract: Publication date: Available online 15 November 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Hui Liu, Zonghua Luo, Jiwei Gu, Yi Su, Hubert Flores, Stanley M. Parsons, Yun Zhou, Joel S. Perlmutter, Zhude Tu Vesicular acetylcholine transporter (VAChT) is a promising target for a PET measure of cholinergic deficits which contribute to cognitive impairments. Dopamine D2-like agonists and antagonists are frequently used in the elderly and could alter cholinergic function and VAChT level. Therefore, pretreatment with dopamine D2-like drugs may interfere with PET measures using [18F]VAT, a specific VAChT radioligand. Herein, we investigated the impact of dopaminergic D2-like antagonist/agonist on VAChT level in the brain of macaques using [18F]VAT PET. PET imaging studies were carried out on macaques at baseline or pretreatment conditions. For pretreatment, animals were injected using a VAChT inhibitor (-)-vesamicol, a D2-like antagonist (-)-eticlopride, and a D2-like agonist (-)-quinpirole, separately. (-)-Vesamicol was injected at escalating doses of 0.025, 0.05, 0.125, 0.25 and 0.35 mg/kg; (-)-eticlopride was injected at escalating doses of 0.01, 0.10 and 0.30 mg/kg; (-)-quinpirole was injected at escalating doses of 0.20, 0.30, and 0.50 mg/kg. PET data showed [18F]VAT uptake declined in a dose-dependent manner by (-)-vesamicol pretreatment, demonstrating [18F]VAT uptake is sensitive to reflect the availability of VAChT binding sites. Furthermore, (-)-eticlopride increased [18F]VAT striatal uptake in a dose-dependent manner, while (-)-quinpirole decreased its uptake, suggesting striatal VAChT levels can be regulated by D2-like drug administration. Our findings confirmed [18F]VAT offers a reliable tool to in vivo assess the availability of VAChT binding sites. More importantly, PET with [18F]VAT successfully quantified the impact of dopaminergic D2-like drugs on striatal VAChT level, suggesting [18F]VAT has great potential for investigating the interaction between dopaminergic and cholinergic systems in vivo.Graphical abstractImage, graphical abstract
  • Drug-drug interaction between crizotinib and entecavir via renal secretory
           transporter OCT2
    • Abstract: Publication date: Available online 15 November 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Wenying Shu, Lei Ma, Xiaoye Hu, Meimei Zhang, Wensheng Chen, Wen Ma, Jianing Huang, Jia Li Both entecavir and crizotinib are substrates of organic cation transporter 2 (OCT2). The aim of present study was to investigate the mechanisms of drug interactions between these two drugs. Kinetic analysis of entecavir on crizotinib uptake was conduct. Plasma concentration of crizotinib in rats and lung cancer patients, uptake of crizotinib in kidney slices and OCT2 transfected cells, were determined by LC-MS/MS. The clinical pharmacokinetic interactions and impact on adverse reaction of crizotinib in lung cancer patients were investigated. Steady-state through concentration of crizotinib was measured. The crizotinib-related adverse reactions were recorded in lung cancer patients with and without entecavir. Entecavir and 1-methyl-4-phenylpyridinium iodide significantly inhibited the uptake of crizotinib in kidney slices. Kinetic constants for crizotinib uptake by OCT2 were Km 1.16±0.26 µM, Vmax 12.05±0.53 µmol/min mg-1 protein and Ki 9.711 nM. Entecavir can inhibit crizotinib transport by OCT2 in kidney. Co-administration of entecavir significantly reduced the elimination of crizotinib in rats. In lung cancer patients, the steady-state AUCss of crizotinib increased approximately 1.2 fold (p0.001). Co-medication of entecavir significantly (p
  • Tableting of hot-melt coated paracetamol granules: Material tableting
           properties and quality characteristics of the obtained tablets
    • Abstract: Publication date: 15 January 2020Source: European Journal of Pharmaceutical Sciences, Volume 142Author(s): Ana Milanovic, Ivana Aleksic, Svetlana Ibric, Jelena Parojcic, Sandra Cvijic Hot-melt coating (HMC) has been recognized as a promising technique in the production of solid dosage forms e.g., HMC of granules can be applied prior to compression in order to obtain modified drug release or taste masking. However, tableting properties of HMC granules have not been studied yet. In this work, we explored the influence of the lipid coating on granules tableting properties, and assessed quality attributes of the obtained tablets. Paracetamol granules, previously coated with the lipid excipient Precirol® ATO 5 using a hot-melt coating technique in modified fluidized-bed system, were evaluated in terms of work of compression, elastic recovery, tablets tensile strength, detachment stress and ejection stress. Regarding the product quality, tablets content uniformity, friability, disintegration time and drug release properties were tested. Our results demonstrated that tablets made of coated granules exhibited more pronounced elastic behaviour, and increased tensile strength in comparison to tablets made of uncoated granules, suggesting that lipid coating promotes elastic deformation and forms lipid matrix within the tablets. Additionally, low detachment and ejection stresses for tablets made of HMC granules indicated no need to add lubricant prior to tableting process. Evaluation of tablets properties revealed that tablets friability was not influenced by the presence of lipid coating on the compressed granules. However, formation of lipid matrix within the tablets made of HMC granules resulted in prolonged tablet disintegration time, and sustained drug release. Moreover, the performance of lipid matrix tablets, in terms of drug dissolution rate, was relatively insensitive to compression pressure variations in 104–173 MPa range. The obtained results indicate that tableting of HMC granules is a promising technique to obtain sustained release lipid matrix tablets of suitable pharmaceutical-technical properties.Graphical abstractImage, graphical abstract
  • Enhancement of intestinal absorption of coenzyme Q10 using emulsions
           containing oleyl polyethylene acetic acids
    • Abstract: Publication date: Available online 13 November 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Yuki Sato, Sayaka Yokoyama, Yoshiaki Yamaki, Yuta Nishimura, Mami Miyashita, Shingo Maruyama, Yoh Takekuma, Mitsuru Sugawara Emulsions have often been prepared to improve absorption of lipophilic compounds that have poor solubility. Coenzyme Q10 (CoQ10) is a lipophilic compound that has been used as an anti-aging supplement. We focused on oleyl polyethyleneoxy acetic acid, an oxa acid derivative, to prepare emulsions of CoQ10 with the expectation of application to oral pharmaceutics. Oxa acids were purified and classified into four groups based on the average length of the ethylene oxide chain. The emulsion that were prepared using the four oxa acid groups were administered to rats and the plasma concentration profiles of CoQ10 were analyzed. The absorption of CoQ10 was improved in all emulsion groups compared with that in the powder group. The emulsion using oxa acid (n=9.0) greatly increased the plasma concentration of CoQ10. Absorption was also improved by using emulsions containing larger percentage of oxa acids (6%, 15% and 23%) to compared with the same oxa acid (n=9.0). The effects of oxa acids on cell viability were almost the same as those of conventional surfactants such as polyoxyethylene (20) sorbitan monooleate (Tween 80). The results showed that oxa acids are useful to prepare emulsions for oral administration and that the absorption of CoQ10 using oxa acids is significantly improved by using our formulations.Graphical abstractImage, graphical abstract
  • Strain and sex differences in drug hydrolase activities in rodent livers
    • Abstract: Publication date: Available online 11 November 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Fumiya Kisui, Tatsuki Fukami, Masataka Nakano, Miki Nakajima Carboxylesterase (CES) 1, CES2, and arylacetamide deacetylase (AADAC) are the major drug hydrolases in humans, and they have different substrate preferences. Because rodents are widely used in preclinical studies, we aimed to clarify the extent of the species, strain, and sex differences in hydrolase activity in rats and mice. Hydrolase activities for 24 compounds were evaluated in Fischer 344, Sprague-Dawley, and Wistar-Imamichi rat liver microsomes (RLM) and Balb/c, C3H/He, C57BL/6J, and ddY mouse liver microsomes (MLM) by comparing the results with the activities in human liver microsomes (HLM). Imidapril hydrolase activities in RLM from all strains were substantially higher than those in MLM and HLM, whereas oseltamivir was hardly hydrolyzed in rodents, although both are specific substrates of CES1 in humans. In rats, males tended to show higher hydrolase activities for most human CES1 substrates than females. Hydrolase activities for irinotecan and procaine, which are CES2 substrates in humans, tended to be higher in RLM and MLM than in HLM. Rifamycins, substrates of human AADAC, were not hydrolyzed in RLM and MLM. The results of this study provide important information about the species, strain, and sex differences in hydrolase activities in rats and mice.Graphical abstractImage, graphical abstract
  • Improved stability of polyclonal antibodies: A case study with
           lyophilization-conserved antibodies raised against epitopes from the
           malaria parasite Plasmodium falciparum
    • Abstract: Publication date: 15 January 2020Source: European Journal of Pharmaceutical Sciences, Volume 142Author(s): Nina Simon, Christine Sperber, Cornelia Voigtländer, Julia Born, Daniel F. Gilbert, Stefan Seyferth, Geoffrey Lee, Barbara Kappes, Oliver Friedrich Antibodies can be produced as polyclonal (pAb) or monoclonal (mAb) liquid formulations with limited shelf-life. For pAbs, unlike mAbs, only little is known about excipients and lyophilization affecting antibody stability upon reconstitution. We used a model pAb directed against Plasmodium falciparum (Pf) pyridoxal 5′-phosphate synthase 2 (Pdx2) to systemically study effects of bulking agents (amino acids, phosphate buffers, salt solutions), sugar(alcohols), surfactants and protein additions (bovine serum albumin, BSA) in liquid pAb formulations (isolated or in combinations) on the activity to detect the antigen in Pf extracts by Western blots. Repeated freeze-thaw cycles (20x) and extended room temperature storage markedly compromised pAb stability, the former being ameliorated by addition of cryoprotectants (glycerol, sucrose). Lyophilization of pure liquid pAb formulation markedly decreased antibody reactivity upon reconstitution which was not preserved by most bulking agents tested (e.g., histidine, arginine, acetate). Among the tested salt solutions (NaCl, Ringer, PBS), phosphate buffered saline had the largest lyoprotective potential, alongside sucrose, but not trehalose or maltitol. Among combinations of excipients, PBS, sucrose, low concentration BSA and Tween potently preserved PfPdx2 stability. Results for PBS were transferable to PfEnolase pAb, indicating that some of the formulations investigated here might be a low-cost solution for more general applicability to pAbs.Graphical abstractImage, graphical abstract
  • A novel method to purify adenovirus based on increasing salt
           concentrations in buffer
    • Abstract: Publication date: 1 January 2020Source: European Journal of Pharmaceutical Sciences, Volume 141Author(s): Jinhu Ma, Chao Su, Xilei Wang, Yongheng Shu, Shichuan Hu, Chengzhi Zhao, Yueting Kuang, Yanwei Chen, Yuhua Li, Yuquan Wei, Ping Cheng With the rapid development of gene therapy, gene-based medicine with adenovirus as vectors has become a new method for disease treatment. However, there are still enormous challenges in the large-scale production of adenoviruses for clinical use. Recent reports show that ion-exchange chromatography (IEC) is an effective tool for the isolation and purification of adenovirus. However, during the separation and purification, host cell protein and DNA, as well as serum from the culture medium, can non-specifically occupy numerous binding sites of the chromatography packings, thereby reducing the binding between the adenovirus and packing media. We here report a novel method for highly efficient purification of adenoviruses by increasing the salt concentrations of the samples to be ultrafiltrated by tangential flow filtration, the diafiltration buffer, and the samples for IEC purification. This method could significantly remove a large amount of serum proteins and host cell proteins, increase the amount of sample loaded on the IEC column, and improve the binding of the adenovirus samples to the packing media. A purity of> 95% could be obtained after one chromatography operation, and the number of purification steps and the amount of used packing media were reduced. The method is simple, economical, and efficient, and has excellent applications.Graphical Image, graphical abstract
  • Maturation of midazolam clearance in critically ill children with severe
           bronchiolitis: A population pharmacokinetic analysis
    • Abstract: Publication date: 1 January 2020Source: European Journal of Pharmaceutical Sciences, Volume 141Author(s): Mojca Kerec Kos, Mirjana Miksić, Marija Jovanović, Robert Roškar, Štefan Grosek, Iztok Grabnar PurposeThe aim of the present study was to develop a population pharmacokinetic model of midazolam, and to evaluate the influence of maturation process and other variability factors in critically ill children with severe acute bronchiolitis, who received a long-term intravenous infusion of midazolam.MethodsIn the study were included 49 critically ill children of both genders (from 0 to 130 weeks of age) with severe acute bronchiolitis hospitalised in intensive care units. Nonlinear mixed effects modelling approach was applied for data analyses and simulations.ResultsThe final model is a two-compartment model that includes the effects of body weight using allometric scaling with fixed exponents and maturation of clearance. For a typical subject, scaled to the adult body weight of 70 kg, population pharmacokinetic values were estimated at 8.52 L/h for clearance (when maturation function was 1), 25.5 L/h for intercompartmental clearance, and 5.71 L and 39.8 L for the volume of the central and peripheral compartment, respectively. Based on the final model, maturation reaches 50% of the adult clearance in 45.9 weeks of postmenstrual age. The influence of gender, ABCB1 genotype and biochemical parameters on midazolam clearance was not detected. Results of simulations indicate the need for reduced dosing in certain groups of patients in order to maintain plasma concentrations of midazolam within recommended values.ConclusionsThe developed population pharmacokinetic model can contribute to the dosing optimisation of midazolam, especially in critically ill children as it includes the influence of size and maturation of clearance, which are important parameters for achieving the desired plasma concentrations of midazolam.Graphical abstractImage, graphical abstract
  • Convection enhanced delivery of anti-angiogenic and cytotoxic agents in
           combination therapy against brain tumour
    • Abstract: Publication date: 1 January 2020Source: European Journal of Pharmaceutical Sciences, Volume 141Author(s): Wenbo Zhan Convection enhanced delivery is an effective alternative to routine delivery methods to overcome the blood brain barrier. However, its treatment efficacy remains disappointing in clinic owing to the rapid drug elimination in tumour tissue. In this study, multiphysics modelling is employed to investigate the combination delivery of anti-angiogenic and cytotoxic drugs from the perspective of intratumoural transport. Simulations are based on a 3-D realistic brain tumour model that is reconstructed from patient magnetic resonance images. The tumour microvasculature is targeted by bevacizumab, and six cytotoxic drugs are included, as doxorubicin, carmustine, cisplatin, fluorouracil, methotrexate and paclitaxel. The treatment efficacy is evaluated in terms of the distribution volume where the drug concentration is above the corresponding LD90. Results demonstrate that the infusion of bevacizumab can slightly improve interstitial fluid flow, but is significantly efficient in reducing the fluid loss from the blood circulatory system to inhibit the concentration dilution. As the transport of bevacizumab is dominated by convection, its spatial distribution and anti-angiogenic effectiveness present high sensitivity to the directional interstitial fluid flow. Infusing bevacizumab could enhance the delivery outcomes of all the six drugs, however, the degree of enhancement differs. The delivery of doxorubicin can be improved most, whereas, the impacts on methotrexate and paclitaxel are limited. Fluorouracil could cover the comparable distribution volume as paclitaxel in the combination therapy for effective cell killing. Results obtain in this study could be a guide for the design of this co-delivery treatment.Graphical Image, graphical abstract
  • Discovery of M2 channel blockers targeting the drug-resistant double
           mutants M2-S31N/L26I and M2-S31N/V27A from the influenza A viruses
    • Abstract: Publication date: 1 January 2020Source: European Journal of Pharmaceutical Sciences, Volume 141Author(s): Rami Musharrafieh, Chunlong Ma, Jun Wang Influenza virus infections are a persistent threat to human health due to seasonal outbreaks and sporadic pandemics. Amantadine and rimantadine are FDA-approved influenza antiviral drugs and work by inhibiting the viral M2 proton channel. However, the therapeutic potential for the antiviral amantadine/rimantadine was curtailed by the emergence of drug-resistant mutations in its target protein M2. In this study, we identified four amantadine-resistant M2 mutants among avian and human influenza A H5N1 strains circulating between 2002 and 2019: the single S31N and V27A mutants, and the S31N/L26I and S31N/V27A double mutants. Herein, utilizing two-electrode voltage clamp (TEVC) assays, we screened a panel of structurally diverse M2 inhibitors against these single and double mutant channels. Three compounds 6, 7, and 15 were found to significantly block all three M2 mutants: M2-S31N, M2-S31N/L26I, and M2-S31N/V27A. Using recombinant viruses generated from reverse genetics, we further showed that these compounds also inhibited the replication of recombinant viruses harboring either the single S31N or double S31N/L26I and S31N/V27A mutants. This work represents the first example in developing antivirals by targeting the drug-resistant double mutants of M2 proton channels.Graphical abstractImage, graphical abstract
  • The effects of scopolamine on the survival time and microcirculation of
           septic shock rats
    • Abstract: Publication date: 1 January 2020Source: European Journal of Pharmaceutical Sciences, Volume 141Author(s): Linlin Song, Rai Chu, Zhongping Cao Introduction: Shock has been established as a disorder of the microcirculation. Despite various treatments, the mortality rate of infectious shocks remains 30–50%. The study was designed to explore the effects of scopolamine on the survival time, microcirculation and inflammatory cytokine secretion in rats with septic shock.Methods: SD rats were randomly divided into seven groups: a sham group, a control group, a saline group and four scopolamine group. The rat septic shock model was induced by cecal ligation, perforation and drainage, while the operation in the sham group involved opening and closing the abdominal cavity. The survival time was recorded to determine a suitable dose for the subsequent experiments. The microcirculation of the terminal ileum was observed. The concentrations of IL-10, IL-6 and TNF-α in the plasma and lungs were detected by ELISA, and the wet-dry ratio of the lung was calculated.Results: Compared to the control and saline group, the septic shock rats treated in the scopolamine group had a longer survival time, a lower reduction in arteriolar blood flow, and a decreased change in the average diameter of arterioles and venules. The rat wet–dry lung ratio was less in the sham, control and scopolamine groups compared to the saline group. The plasma and lung cytokine concentrations of the rats belonging to the scopolamine group were less than those of the control and saline groups; however, all of the cytokine concentrations were higher than those of the sham group.Conclusions: Scopolamine reduced the plasma and lung concentrations of specific cytokines, improved the function of the microcirculation and prolonged the survival time of rats with septic shock.Graphical abstractImage, graphical abstract
  • Novel radiopharmaceutical (Technetium-99m)-(DOTA-NHS-ester)-Methionine as
           a SPECT-CT tumor imaging agent
    • Abstract: Publication date: 1 January 2020Source: European Journal of Pharmaceutical Sciences, Volume 141Author(s): Paria Mojarrad, Saeedeh Zamani, Mohammad Seyedhamzeh, Farnoor Davachi Omoomi, Naeim Karimpourfard, Shahin Hadadian, Seyed Esmadeil Sadat Ebrahimi, Morteza Pirali Hamedani, Jafar Farzaneh, Mehdi Shafiee Ardestani Breast cancer is the most common type of cancer in women worldwide. There have been many efforts for early breast cancer detection and among them molecular imaging have been extremely of high importance. Single-photon emission computed tomography (SPECT/CT) is a kind of imaging technique able to reveal crucial information with using radiopharmaceuticals.In this study, Technetium-99m-(DOTA-NHS-ester)-Methionine radiopharmaceutical was synthesized. Between 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid mono-N-hydroxysuccinimide ester (DOTA-HNS ester) (MACROCYCLICS, DOTA-NHS ester, Plano, Texas, USA) and methionine(marker) were conjugated. The DOTA-HNS ester-Methionine was labeled with Technetium-99m (Inter-Medical, Technetium-99m, Bergamo, Italy). The synthesized radiopharmaceutical was used in SPECT/CT imaging for breast cancer diagnosis. For radiopharmaceutical evaluation, MTT assay for cellular toxicity, biodistribution, cellular uptake and radiochemical purity were employed.Technetium-99m-(DOTA-NHS-ester)-Methionine radiochemical had less cellular toxicity in human embryonic kidney cells 293 cell line (HEK293). Cellular uptake was indicated higher percent with use of Methionine as a marker, and radiochemical purity was high.Based on the results Technetium-99m-(DOTA-NHS-ester)-Methionine radiochem may be a better option for early detection of breast cancer. Further study is recommended to confirm these findings in clinical practice.Graphical abstractImage, graphical abstract
  • Continuous drying of a protein-type drug using scaled-up fiber formation
           with HP-β-CD matrix resulting in a directly compressible powder for
    • Abstract: Publication date: 1 January 2020Source: European Journal of Pharmaceutical Sciences, Volume 141Author(s): Panna Vass, Zsombor K. Nagy, Rita Kóczián, Csaba Fehér, Balázs Démuth, Edina Szabó, Sune K. Andersen, Tamás Vigh, Geert Verreck, István Csontos, György Marosi, Edit Hirsch The goals of this work were to evaluate if high-speed electrospinning can be used as a gentle and continuous drying technology to produce protein-containing cyclodextrin-based fibers from an aqueous solution and to convert the produced protein-cyclodextrin fibers into a directly compressible powder. A 400 mL/h feeding rate was used during the electrospinning experiments, corresponding to a ~270 g/h production rate of the dried material. The produced fibers were collected in a cyclone. The fibers were found grindable without secondary drying, and the ground powder was mixed with tableting excipients and was successfully tableted by direct compression. The model protein-type drug (β-galactosidase) remained stable during each of the processing steps (electrospinning, grinding, tableting) and after 6 months of storage at room temperature in the tablets. The obtained results demonstrate that high speed electrospinning can be a gentle alternative to traditional drying methods used for protein-type drugs, and that tablet formulation is achievable from the electrospun material prepared this way.Graphical abstractImage, graphical abstract
  • Mucoadhesive buccal films based on a graft co-polymer – A
           mucin-retentive hydrogel scaffold
    • Abstract: Publication date: Available online 7 November 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Julia F. Alopaeus, Marie Hellfritzsch, Tobias Gutowski, Regina Scherließ, Andreia Almeida, Bruno Sarmento, Nataša Škalko-Basnet, Ingunn Tho From a patient-centric perspective, oromucosal drug delivery is highly attractive due to the ease of administration without the need of swallowing, and improved patient safety. The aim of the presented work was to prepare a buccal film using a self-forming micellar drug solubiliser as the film matrix, combining it with a mucoadhesive polymer for an enhanced retention on the buccal mucosa. Specifically, we propose the use of a graft copolymer (Soluplus®), as a solubiliser and film former, supplemented with polymers with more hydrophilic properties and known mucoadhesive properties; hydroxypropyl methylcellulose (HPMC) or modified hydroxypropyl pea starch (Lycoat®). The film was manufactured by the solvent casting method. The resulting dual polymer film containing HPMC exhibited resistance to erosion and mucoadhesive properties superior to the control films of single polymers. In an in vitro oral cavity model, these properties were shown to correlate with increased residence time on simulated oral mucosa. Furthermore, all films containing the graft co-polymer showed similar permeability characteristics of furosemide towards buccal TR146 epithelial cells. This work illustrated that it is possible to manufacture dry, solid, dual polymer films containing an advanced drug delivery system with a cheap and simple method. The combination of a graft co-polymer with a mucoadhesive polymer transform into drug solubilising micelles in a mucin-retentive hydrogel scaffold with longer retention time on buccal mucosa for safe and enhanced advanced formulation.Graphical abstractImage, graphical abstract
  • Investigation of drug-polymer miscibility, biorelevant dissolution, and
           bioavailability improvement of Dolutegravir-Polyvinyl
           caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer solid
    • Abstract: Publication date: Available online 6 November 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Dani Lakshman, Mohith Chegireddy, Geeta K. Hanegave, K. Navya Sree, Naveen Kumar, Shaila A. Lewis, Swapnil J. DengaleGraphical Image, graphical abstract
  • Development of doxycycline hyclate suppositories and pharmacokinetic study
           in rabbits
    • Abstract: Publication date: Available online 6 November 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Ana Paula Christ, Pauline Trindade Biscaino, Rebeca Lino Lourenço, Alieni Bitencourt de Souza, Estevan Sonego Zimmermann, Andréa Inês Horn Adams Doxycycline hiclate is a broad spectrum antibiotic widely used in human and veterinary medicine. The inability to perform the parenteral administration of drugs and the lack of oral preparations can be mentioned as difficulties in the treatment of animals in the domestic environment. In this scenario, the aim of this study was to investigate the bioavailability of the drug by rectal route, to propose a potential suppository formulation containing 25 mg of doxycycline as an alternative to the available injectable formulations. Hydrophilic and lipophilic suppositories were prepared, in polyethylene glycol (S-PEG) or cocoa butter (S-CBT), respectively. The suppositories were prepared and evaluated concerning visual characteristics, content, average weight, melting range, content uniformity and in vitro release. A stability study was performed and the two most stable formulations were submitted to a pharmacokinetic study in rabbits. The bioavailability of the suppositories was compared to the data of the intravenous (i.v.) formulation. PEG suppository showed 49.13% bioavailability and CBT 51.43% with Cmax equal to 2.06 ± 2.96 µg.mL−1 and 1.54 ± 0.28 µg.mL−1, respectively. The data obtained suggest that rectal administration may become another method of administration of doxycycline in the treatment of bacterial infections.Graphical abstractImage, graphical abstract
  • Target delivery selective CSF-1R inhibitor to tumor-associated macrophages
           via erythrocyte-cancer cell hybrid membrane camouflaged pH-responsive
           copolymer micelle for cancer immunotherapy
    • Abstract: Publication date: Available online 5 November 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Yuchi Wang, Zhiyong Luan, Chaoyue Zhao, Chunhua Bai, Kangjuan Yang Tumor-associated macrophages (TAMs) is a promising therapeutic target for cancer immunotherapy, while TAMs targeting therapy using nano-sized drug delivery system (NDDS) is a great challenge. To overcome these drawbacks, a novel erythrocyte-cancer cell hybrid membrane camouflaged pH-responsive copolymer micelle (dextran-grafted-poly (histidine) copolymer) was prepared to target deliver a selective CSF-1R inhibitor: BLZ-945 (shorten as DH@ECm) to TAMs for TAMs depletion. The prepared DH@ECm possessed favorable particle size (∼190 nm) preferable immune camouflage and tumor homologies targeting characteristic when it was intravenously administrated into blood system. In tumor acidic microenvironment, DH@ECm possessed pH-responsive characteristic and unique “membrane escape effect” to facilitate recognition and internalization by TAMs via dextran-CD206 receptor specific interaction (about 3.9 fold than free drug), followed by TAMs depletion in vitro. For in vivo studies, DH@ECm could reverse tumor immune-microenvironment with the elevation of CD8+ T cells and possess sufficient tumor immunotherapy (inhibition rate: 64.5%). All the in vitro and in vivo studies demonstrated the therapeutical potential of DH@ECm for tumor immunotherapy.Graphical abstractImage, graphical abstract
  • Nanomaterials for direct and indirect immunomodulation: A review of
    • Abstract: Publication date: Available online 5 November 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Jana Kubackova, Jarmila Zbytovska, Ondrej Holas The potential of nanotechnology has been explored throughout fields of medicine and found its application also in immunology. Given the crucial defence role and disseminated character of the immune system, the idea of using its strength in treatment has always been very attractive.Immunomodulation is an optimisation of the immune response both in terms of immunosuppression in autoimmune disorders and immunostimulation in vaccination or cancer immunotherapy. For these purposes, a wide range of nanomaterials has been investigated to influence the immune system directly by their composition itself or indirectly as intact carriers of the active.This review attempts to refer to nanomaterials and drug delivery systems utilised to modulate the immune response. It lists various structural types of nanoparticles discussing their composition and interplay with the immune system. Throughout the literature, both novel and traditional nanoparticles were utilised. The most progressive ones extend beyond the delivery of a single substance moving towards combined drug delivery systems and stimuli-responsive formulations.Graphical Image, graphical abstract
  • Screening of kinase inhibitors downregulating PD-L1 expression via on/in
           cell quantitative immunoblots.
    • Abstract: Publication date: Available online 15 October 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Yongli Xie, Jiwei Ding, Xiangling Cui, Meng Wu, Chenchao Huang, Rongyu Zhang, Jing Wang, Xiaoyu Li, Shan Cen, Jinming ZhouABSTRACTThe interaction of programmed death-1 (PD-1) and it's ligands (PD-L1) is an important immune checkpoint and blockade of PD-1/PD-L1 axis with antibodies against PD-L1 showed promising anti-tumor activity in clinical practice. However, only a small percentage of patients can benefit from PD-L1 mAbs. Small molecular kinase inhibitors have been widely used as antitumor drugs for many years, and several kinase inhibitors were recently reported to inhibit the expression of PD-L1. However, the connections between PD-L1 expression and kinase inhibitors were not thoroughly elucidated. Herein, we set up a novel and robust screening system to identify small molecular compounds which downregulate the PD-L1 level of tumor cell based on Odyssey on/in cell quantitative immunoblots technology. A collected kinase inhibitor library was screened and 14 hits were further confirmed by western blot and flow cytometry. System biological analysis and further bio-assay identified a synergy combination between KU-60019 and Vacquinol-1 in downregulation of PD-L1. Taken together, the work established a novel method to screen the PD-L1 down-regulators using kinase inhibitors library, thus providing new clues for the application of kinase inhibitors in cancer immunotherapy.Graphical Image, 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 Vitorino The 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
  • Synergistic Antibacterial Actions of Graphene Oxide and Antibiotics
           towards Bacteria and the Toxicological Effects of Graphene Oxide on Human
           Epidermal Keratinocytes
    • Abstract: Publication date: Available online 15 October 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Thiruchelvi Pulingam, Kwai Lin Thong, Jimmy Nelson Appaturi, Nurul Izza Nordin, Ignatius Julian Dinshaw, Chin Wei Lai, Dr. Bey Fen Leo Graphene oxide (GO) has displayed antibacterial activity that has been investigated in the past, however, information on synergistic activity of GO with conventional antibiotics is still lacking. The objectives of the study were to determine the combinatorial actions of GO and antibiotics against Gram-positive and Gram-negative bacteria and the toxicological effects of GO towards human epidermal keratinocytes (HaCaT). Interactions at molecular level between GO and antibiotics were analyzed using Attenuated Total Reflectance-Fourier-transform infrared spectroscopy (ATR-FTIR). Changes in the antibacterial activity of antibiotics towards bacteria through the addition of GO was investigated. Toxicity of GO towards HaCaT cells were examined as skin cells play a role as the first line of defense of the human body. The ATR-FTIR characterizations of GO and antibiotics showed adsorption of tested antibiotics onto GO. The combinatorial antibacterial activity of GO and antibiotics were found to increase when compared to GO or antibiotic alone. This was attributed to the ability of GO to disrupt bacterial membrane to allow for better adsorption of antibiotics. Cytotoxicity of GO was found to be dose-dependent towards HaCaT cell line, it is found to impose negligible toxic effects against the skin cells at concentration below 100 μg/mL.Graphical Image, graphical abstract
  • Thermodynamics and solute-solvent interactions of lovastatin in an aqueous
           arginine solution
    • Abstract: Publication date: 1 January 2020Source: European Journal of Pharmaceutical Sciences, Volume 141Author(s): N.F. Zolkiflee, M.M.R. Meor Mohd Affandi, A.B.A. Majeed Lovastatin (LVS) is an effective therapeutic and prophylactic agent in several cardiovascular disorders. However, it has low bioavailability. This study investigated solute-solvent and solute-cosolute interactions and assessed thermodynamic parameters that contributed to LVS solubility enhancement in the presence of arginine (ARG) as a hydrotropic agent. The electrolytic conductance of LVS-ARG binary system was measured at temperatures from 298.15 K to 313.15 K. Conductometric parameters such as limiting molar conductance was evaluated. Additionally, thermodynamic parameters (ΔG0, ΔH0, ΔS0 and ES) involved in the association process of the solute in the aqueous solution of ARG solution were determined systematically. Solubility markedly improved 43-fold in the LVS-ARG complex compared to LVS alone. The analysed data from values of molar conductance and activation energy suggested favourable solubilisation, with a stronger solute-solvent interaction between LVS-ARG in water at higher temperatures. ARG and LVS complexation caused by strong molecular interactions was confirmed by spectral results. Hence, the addition of ARG as a co-solute was proven to enhance LVS solubility in water. The obtained data will ultimately enable the development of desired highly soluble, more efficient and safer LVS preparations.Graphical abstractImage, graphical abstract
  • Inhaled rapamycin solid lipid nano particles for the treatment of
    • Abstract: Publication date: Available online 5 November 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Emelie Landh, Lyn M. Moir, Larissa Gomes dos Reis, Daniela Traini, Paul M. Young, Hui Xin Ong Lymphangioleiomyomatosis (LAM) is a rare lung disease characterized by uncontrolled growth of smooth muscle -like cells in the lungs that can spread via the lymphatic system to other parts of the body. The current treatment for LAM, oral rapamycin, is limited by its low oral bioavailability and side effects. This study aims to develop an inhaled formulation of rapamycin solid lipid nanoparticles (Rapa-SLNs) to avoid first-pass metabolism, increase in-vivo half-life and facilitate entry into the lymphatic system through the lungs. Rapa-SLNs were manufactured using a hot evaporation technique and freeze-dried overnight with 5% (w/v) mannitol and before being assessed further for particle characteristics and in vitro aerosol performance and release. The formulation's ability to penetrate through bronchial epithelial layer was evaluated using a Calu-3 cell model, while its ability to interfere with the LAM intracellular cascade was evaluated using Mouse Embryonic fibroblast (MEF) cells deficient for the tuberous sclerosis complex 2 (TSC2) and compared with rapamycin solution. Results showed that the Rapa- SLNs had the appropriate size (237.5 ± 1.8 nm), charge (-11.2), in-vitro aerosol performance (MMAD =5.4 ± 0.4 μm) and sustained release profile suitable for entry into the lymphatic system via the pulmonary route. Additionally, the nanoparticles were transported at a faster rate across the bronchial epithelial layer compared to free rapamycin solution. The formulation also showed similar mTOR (mammalian target of Rapamycin) inhibition properties compared to raw rapamycin, and was able to significantly decrease the amount of proliferation in TSC2 negative MEF cells. This formulation is therefore a promising alternative treatment for LAM patients, as it could potentially reduce problems associated with low bioavailability and side effects of current oral treatment.Graphical abstractImage, graphical abstract
  • In vivo antitumour properties of tribenzyltin carboxylates in a 4T1 murine
           metastatic mammary tumour model: Enhanced efficacy by PLGA nanoparticles
    • Abstract: Publication date: Available online 5 November 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Theebaa Anasamy, Chin Fei Chee, Lik Voon Kiew, Lip Yong Chung This study reports the in vivo performance of two tribenzyltin carboxylate complexes, tri(4-fluorobenzyl)tin[(N,N-diisopropylcarbamothioyl)sulfanyl]acetate (C1) and tribenzyltin isonicotinate (C9), in their native form as well as in a poly(lactic-co-glycolic acid) (PLGA)-based nanoformulation, to assess their potential to be translated into clinically useful agents. In a 4T1 murine metastatic mammary tumour model, single intravenous administration of C1 (2.7 mg/kg) and C9 (2.1 mg/kg; 2.1 mg/kg C9 is equivalent to 2.7 mg/kg C1) induced greater tumour growth delay than cisplatin and doxorubicin at equivalent doses, while a double-dose regimen demonstrated a much greater tumour growth delay than the single-dose treated groups. To improve the efficacy of the complexes in vivo, C1 and C9 were further integrated into PLGA nanoparticles to yield nanosized PLGA-C1 (183.7 ± 0.8 nm) and PLGA-C9 (163.2 ± 1.2 nm), respectively. Single intravenous administration of PLGA-C1 (2.7 mg C1 equivalent/kg) and PLGA-C9 (2.1 mg C9 equivalent/kg) induced greater tumour growth delay (33% reduction in the area under curve compared to that of free C1 and C9). Multiple-dose administration of PLGA-C1 (5.4 mg C1 equivalent/kg) and PLGA-C9 (4.2 mg C9 equivalent/kg) induced tumour growth suppression at the end of the study (21.7 and 34.6% reduction relative to the size on day 1 for the double-dose regimen; 73.5 and 79.0% reduction relative to the size on day 1 for the triple-dose regimen, respectively). Such tumour growth suppression was not observed in mice receiving multiple-dose regimens of free C1 and C9. Histopathological analysis revealed that metastasis to the lung and liver was inhibited in mice receiving PLGA-C1 and PLGA-C9. The current study has demonstrated the improved in vivo antitumour efficacies of C1 and C9 compared with conventional chemotherapy drugs and the enhancement of the efficacies of these agents via a robust PLGA-based nanoformulation and multiple-drug administration approach.Graphical abstractImage, graphical abstract
  • Dissolution behavior of various drugs in different FaSSIF versions
    • Abstract: Publication date: Available online 5 November 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Lukas Klumpp, Mathew Leigh, Jennifer Dressman Biorelevant media have proven to be useful in predicting the performance of poorly soluble drugs in the gastrointestinal tract. Several versions of fasted state simulated intestinal fluids have been published and compared with respect to their physical chemical properties and solubilization of drugs. However, to date there have been no reports in the literature comparing dissolution of poorly soluble drugs in these media. In this study eleven BCS Class II compounds (five nonionized compounds, three weak bases and three weak acids) were investigated with respect to their thermodynamic solubility and dissolution behavior in three biorelevant media simulating conditions in the small intestine (FaSSIF V1, FaSSIF V2 and FaSSIF V3). It was shown that the maximum percentage release of drugs from their commercial formulations can differ from the results for the thermodynamic solubility of the pure drug; these differences can be largely attributed to API presentation, composition of the formulation and manufacturing effects.The results were additionally compared with data for solubility in HIF taken from the literature in order to determine which version of FaSSIF most closely corresponds to the physiological conditions. The different versions of FaSSIF are able to achieve solubility results similar to those in HIF, with closest results generally achieved in FaSSIF V1. The magnitude of solubility/dissolution differences among the three FaSSIF versions is dependent on the drug's characteristics. In the case of weakly basic compounds, the differences among the FaSSIF versions are minor. For weakly acidic compounds the behavior in the different versions is primarily pH dependent and influenced by the lipid composition of the FaSSIF only to a minor extent. The differences in solubility and dissolution of the nonionized compounds among the three versions of FaSSIF becomes apparent above a log P value of 2.5, with larger differences among the versions at high log P values.Graphical Image, graphical abstract
  • Development and characterization of mucoadhesive-thermoresponsive gels for
           the treatment of oral mucosa diseases
    • Abstract: Publication date: Available online 1 November 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Cinzia Pagano, Stefano Giovagnoli, Luana Perioli, Maria Cristina Tiralti, Maurizio Ricci IntroductionThe mucositis is an inflammatory, erosive and ulcerative process of the oral mucosa. It is usually caused by radiation, chemotherapy, infections, diabetes, smoking and it is characterized by severe pain and difficulty eating and can have a very serious impact on quality of life. A suitable treatment must ensure pain control and mechanical protection to promote mucosal healing. The purpose of this work was to study an in-situ gelling formulation to be sprayed onto the damaged oral mucosa by self-administration. The formulation must be able to quickly form a film when applied in the oral cavity.Methodsmany batches were prepared mixing a thermosensitive polymer (poloxamer PF127 or P123) with mucoadhesive polymers polyvinylpyrrolidone (PVP), sodium carboxymethyl cellulose (NaCMC), Carbopol 971P, chitosan (CS). By an experimental design three suitable formulations were identified and loaded with the model drug benzydamine hydrochloride. The hydrogel based on 25.50% PF127, 0.20% PVP and 0.35% CS maintained its original properties (gelling, rheological and mucoadhesive) after loading and showing a sustained drug release.Conclusionsthe selected hydrogel showed to be suitable for the treatment of mucositis, able to reduce the number of daily administration and to protect the damaged mucosa from mechanical and chemical solicitations.Graphical abstractImage, graphical abstract
  • Microstructure and biopharmaceutical performances of curcumin-loaded
           low-energy nanoemulsions containing eucalyptol and pinene: terpenes’
           role overcome penetration enhancement effect'
    • Abstract: Publication date: Available online 1 November 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Ines Nikolic, Evgenia Mitsou, Ivana Pantelic, Danijela Randjelovic, Bojan Markovic, Vassiliki Papadimitriou, Aristotelis Xenakis, Dominique Jasmin Lunter, Ana Žugic, Snezana Savic The objective of this work was to develop low-energy nanoemulsions for enhanced dermal delivery of curcumin, using monoterpene compounds eucalyptol (EUC) and pinene (PIN) as chemical penetration enhancers.Spontaneous emulsification was the preparation method. All formulations contained 10% of the oil phase (medium-chain triglycerides (MCT), or their mixture with EUC or PIN. Formulations were stabilized by the combination of polysorbate 80 and soybean lecithin (surfactant-to-oil-ratio=1). Concentration of curcumin was set to 3 mg/ml.Average droplet diameter of all tested formulations ranged from 102nm to 132nm, but the ones containing monoterpenes had significantly smaller size compared to the MCT formulation. Such finding was profoundly studied through electron paramagnetic resonance spectroscopy, which proved that the presence of monoterpenes modified the nanoemulsions’ interfacial environment, resulting in droplet size reduction. The release study of curcumin (using Franz cells) demonstrated that the cumulative amount released after 6h of the experiment was 10.1±0.2% for the MCT nanoemulsions, 13.9±0.1% and 14.0±0.2% for PIN and EUC formulations, respectively. In vivo tape stripping revealed their performances in delivering curcumin into the skin, indicating the following order: EUC>MCT>PIN. The formulation with EUC was clearly the most successful, giving the highest cumulative amount of curcumin that penetrated per surface unit: 34.24±5.68 µg/cm2. The MCT formulation followed (30.62±2.61 µg/cm2) and, finally, the one with PIN (21.61±0.11 µg/cm2). These results corelated with curcumin's solubility in the chosen oils: 4.18±0.02 mg/ml for EUC, 1.67±0.04 mg/ml for MCT and 0.21±0.01 mg/ml for PIN. Probably, higher solubility in the oil phase of the nanoemulsion promoted curcumin's solubility in the superficial skin layers, providing enhanced penetration.Graphical Image, graphical abstract
  • Investigation of MDR1-overexpressing cell lines to derive a quantitative
           prediction approach for brain disposition using in vitro efflux activities
    • Abstract: Publication date: Available online 1 November 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Sho Sato, Kimio Tohyama, Yohei Kosugi MDR1-overexpressing Lilly Laboratories cell porcine kidney 1 cells (LLC-PK1-MDR1) and Madin-Darby canine kidney cells (MDCK-MDR1) are widely used in drug discovery to evaluate the in vivo relevance of MDR1-mediated efflux. However, as the in vitro efflux ratio (ER) of these cell lines are variable among research facilities, the in vitro ER of these cell lines that would affect quantitative predictivity of brain disposition has not been fully clarified. The aim of this study was to examine the effect of ER on the quantitative predictivity of brain disposition toward compounds with MDR1 and/or breast cancer resistant protein (BCRP) liabilities. Test compounds including internal molecules and five typical substrates of MDR1 and/or BCRP were assessed via an in vitro transporter assay to determine the corrected flux ratio (CFR) and an in vivo animal study using wild-type (WT) and Mdr1a (-/-)/Bcrp(-/-) (dual KO) rats. To assess the in vivo ER for MDR1, the two cell lines LLC-PK1-MDR1 and MDCK-MDR1 were used. After intravenously administering 29 test compounds to rats, the Kp,brain ratio (ratio of Kp,brain,WT to Kp,brain,dual KO), which is considered to be the unbound plasma-to-brain ratio (Kp,uu,brain) that does not require correction for protein binding in both plasma and brain, was determined by measuring their concentrations in the plasma and brain. The Kp,brain ratio of these compounds was predicted by fitting scaling factor that was extrapolated from the in vitro to in vivo ER for MDR1 and BCRP, defined as α and β, respectively. Kp,brain ratio values of 83% and 68% of compounds were predicted by using MDCK-MDR1 and LLC-PK1-MDR1, respectively, within a 2-fold range of the actual corresponding values. The α predicted from CFRs of MDCK-MDR1 was 47-fold smaller than that of LLC-PK1-MDR1; however, a dramatic change in β was not observed. This result appears to be consistent with the data of in vitro transport activity of MDR1, which was estimated to be ∼28-fold higher in MDCK-MDR1 than in LLC-PK1-MDR1 by correlation analysis with CFR. Through this study, we revealed that 1) brain disposition in rats was well-predicted by considering the in vitro efflux activities for both MDR1 and BCRP, and 2) MDCK-MDR1 was the superior cell line for the quantitative prediction of brain disposition.Graphical abstractImage, graphical abstract
  • The influence of gastric motility on the intraluminal behavior of
    • Abstract: Publication date: Available online 1 November 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Marlies Braeckmans, Joachim Brouwers, Imke Masuy, Cécile Servais, Jan Tack, Patrick Augustijns In fasting conditions, the gastrointestinal system contracts according to the interdigestive migrating motor complex (MMC), in which phases of quiescence (MMC phase I) alternate phases of medium (MMC phase II) to very strong (MMC phase III) contractions. The time of drug intake relative to this cyclic motility pattern may cause variations in formulation behavior. To explore this hypothesis, a cross-over study was performed in healthy volunteers with an immediate release tablet of fosamprenavir (Telzir) which was administered in either MMC phase I or MMC phase II, as determined by high-resolution manometry. In the intestinal tract, fosamprenavir is rapidly hydrolyzed to the active compound amprenavir by alkaline phosphatases. Drug concentrations of both prodrug and drug were determined in the stomach and duodenum and linked to simultaneously assessed systemic concentrations. In 5 out of 6 healthy volunteers, the gastric release of fosamprenavir and the systemic uptake of amprenavir were affected by the MMC phase in which the tablet was administered. The intragastric disintegration of the tablet was faster and less variable after administration in MMC phase II, resulting in faster and less variable uptake of amprenavir in the systemic circulation. Mean plasma tmax values were 157 (± 72.0) and 73.3 (± 27.3) min after administration in MMC phase I and MMC phase II, respectively. The study clearly identified the time of oral drug intake relative to the interdigestive motility pattern as a possible source of variation in gastrointestinal drug behavior and absorption.Graphical Image, graphical abstract
  • Safety, tolerability, and pharmacokinetics of adamgammadex sodium, a novel
           agent to reverse the action of rocuronium and vecuronium, in healthy
    • Abstract: Publication date: Available online 31 October 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): YingYing Jiang, YuJun Zhang, ShunJu Xiang, WenLing Zhao, Jin Liu, WenSheng Zhang Neuromuscular blockers (NMBs) selectively block neuromuscular transmission at the N2-nicotinic receptor on motor neurons to paralyze skeletal muscles, and are mainly used to facilitate tracheal intubation and surgical procedures. Rapid reversal is necessary in clinical practice to avoid profound block and reduce recovery time. Adamgammadex sodium is a modified γ-cyclodextrin derivative consisting of a lipophilic core and a hydrophilic outer end that forms an inactive tight inclusion complex with free molecules of rocuronium and vecuronium. In preclinical study, adamgammadex produced a concentration-dependent reversion effect of neuromuscular blockade induced by rocuronium in beagle dogs. Furthermore, adamgammadex had a less potential side effects than sugammadex and other clinical used neuromuscular block antagonists. In this study, the objective was to assess the safety, tolerability, and pharmacokinetics of single intravenous injection of adamgammadex in healthy volunteers. Approved by the China Food and Drug Administration, 52 healthy volunteers (half male and half female) were enrolled in this single-center, randomized, double-blind placebo-controlled study. No serious adverse effects were happened in this study. The overall frequency of adverse effects in adamgammadex was similar for that in placebo, and there was no specific adverse effect in adamgammadex. All of the volunteers bearing the adverse effects were recovered to normal without any treatment or intervention. In pharmacokinetic study, the value of half-time, Tmax, and clearance were not changed significantly, and the Cmax and AUC0-∞ increased with a similar ratio of the escalating doses. For dose proportionality analysis of adamgammadex, the estimate of slope was close to 1, and it was not significantly different from 1 after doses (AUC0-∞, 0.9965 [90%CI, 0.9468, 1.046]; Cmax, 0.9462 [90%CI, 0.8800, 1.012]). Therefore, adamgammadex exposure in plasma increased in a dose- proportional manner. The urinary route is a significant excretory pathway for adamgammadex, and it is mostly completed at 8 h. All the results in this study showed that adamgammadex may be a novel safe neuromuscular blockade reversal agent.Graphical abstractImage, graphical abstract
  • Role of P-glycoprotein in the brain disposition of seletalisib: Evaluation
           of the potential for drug-drug interactions
    • Abstract: Publication date: Available online 31 October 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Jean-Marie Nicolas, Hugues Chanteux, Johan Nicolaï, Frédéric Brouta, Delphine Viot, Marie-Luce Rosseels, Eric Gillent, Pierre Bonnaillie, François-Xavier Mathy, Jeff Long, Eric Helmer Seletalisib is an orally bioavailable selective inhibitor of phosphoinositide 3-kinase delta (PI3Kδ) in clinical development for the treatment of immune-mediated inflammatory diseases. The present study investigated the role of P-gp in seletalisib disposition, especially brain distribution, and the associated risks of interactions. Seletalisib was found to be actively transported by rodent and human P-gp in vitro (transfected LLC-PK1 cells; Km of ca. 20 µM), with minimal or no affinity for the other tested transporters. A distribution study in knockout rats (single oral dosing at 750 mg kg−1) showed that P-gp restricts the brain disposition of seletalisib while having minimal effect on its intestinal absorption. Restricted brain penetration was also observed in cynomolgus monkeys (single oral dosing at 30 mg kg−1) using brain microdialysis and cerebrospinal fluid sampling (Kp,uu of 0.09 and 0.24, respectively). These findings opened the question of potential pharmacokinetic interaction between seletalisib and P-gp inhibitors. In vitro, CsA inhibited the active transport of seletalisib with an IC50 of 0.13 µM. In rats, co-administration of high doses of CsA (bolus iv followed by continuous infusion) increased the brain distribution of seletalisib (single oral dosing at 5 mg kg−1). The observed data were found aligned with those predicted by in vitro-in vivo extrapolation. Based on the same extrapolation method combined with literature data, only very few P-gp inhibitors (i.e. CsA, quinine, quinidine) were predicted to increase the brain disposition of seletalisib in the clinical setting (maximal 3-fold changes).Graphical Image, graphical abstract
  • Antimicrobial peptides conjugated with fatty acids on the side chain of
           D-amino acid promises antimicrobial potency against multidrug-resistant
    • Abstract: Publication date: Available online 30 October 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Chao Zhong, Ningyi Zhu, Yuewen Zhu, Tianqi Liu, Sanhu Gou, Junqiu Xie, Jia Yao, Jingman Ni With the alarming burden of antibiotic resistance, antimicrobial peptides (AMPs) seem to be novel antimicrobial alternatives for infection treatment due to their rapid broad-spectrum antimicrobial activity and low tendency for bacterial resistance. To obtain promising AMPs, a series of new peptides were designed and synthesized by conjugating various lengths of fatty acid chains onto the side chain of the position 4 or 7 D-amino acid of Ano-D4,7 (analogue of anoplin with D-amino acid substitutions at positions 4 and 7). The new peptides exhibited excellent antimicrobial activity against a range of bacteria, especially multidrug-resistant bacteria in contrast to conventional antibiotics. Moreover, the new peptides conjugated with fatty acid chains ranging from 8 to 12 carbons in length presented preferable antimicrobial selectivity and anti-biofilm activity. Additionally, the new peptides also exerted high stability to trypsin, serum, salts and different pH environments. Most notably, the new peptides showed a low tendency to develop bacterial resistance and they displayed optimal antimicrobial activity against the obtained resistant strains. Furthermore, the results from the outer/inner membrane permeabilization and cytoplasmic membrane depolarization assays and flow cytometry and scanning electron microscopy analyses demonstrated that the new peptides exert antimicrobial effects by typical non-receptor-mediated membrane mechanisms, as well as intracellular targets characterized by gel retardation and reactive oxygen species (ROS) generation assays. Furthermore, the new peptides presented remarkable in vivo antimicrobial potency, anti-inflammatory activity, and endotoxin neutralization. Collectively, the conjugation of fatty acids to the side chains of D-amino acids is a potential strategy for designing hopeful antimicrobial alternatives to tackle the risk of bacterial resistance.Graphical Image, graphical abstract
  • Nanoemulsions and thermosensitive nanoemulgels of phenytoin and
           fosphenytoin for intranasal administration: formulation development and in
           vitro characterization
    • Abstract: Publication date: Available online 28 October 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Patrícia C. Pires, Diana Peixoto, Isaura Teixeira, Márcio Rodrigues, Gilberto Alves, Adriana O. Santos Phenytoin is a low solubility anticonvulsant drug. It has, nonetheless, other possible therapeutic indications, such as neuropathic pain, including trigeminal neuralgia, or wound healing. Its use has decreased due to side effects, but nasal/intranasal administration could significantly increase drug safety and efficacy.The aim of this work was to develop and study nanoemulsions and thermosensitive nanoemulgels of phenytoin and fosphenytoin, in combination, for intranasal administration, with immediate and sustained release profiles.Nanoemulsions were prepared by adding the aqueous phase, containing gelling polymers in the case of nanoemulgels, to emulsion preconcentrates, followed, in the optimized procedure, by premix membrane emulsification. Formulation design and optimization was guided by drug strength, rheological behavior, osmolality, mean droplet size and polydispersity.Fosphenytoin interfered significantly with Carbopol but not with Pluronic's gelation, and allowed to achieve drug strengths equivalent to 22 or 27 mg/g of phenytoin in lead nanoemulsions, and 16.7 mg/g of phenytoin in the lead nanoemulgel. The final selected low viscosity nanoemulsions had an immediate or prolonged fosphenytoin release profile, depending of anhydrous phase proportion (10% or 40%, respectively). The thermosensitive nanoemulgel, with 10% anhydrous phase, showed prolonged drug release. Future studies will establish whether they are more suited for topical effects or therapeutic brain delivery.Graphical abstractImage, graphical abstract
  • Using CETSA assay and a mathematical model to reveal dual Bcl-2/Mcl-1
           inhibition and on-target mechanism for ABT-199 and S1
    • Abstract: Publication date: Available online 25 October 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Zongwei Guo, Ting Song, Zuguang Xue, Peng Liu, Minhang Zhang, Xiaodong Zhang, Zhichao Zhang Deepening understanding of how Bcl-2 family proteins protect cancer cells from apoptosis has driven the development of ‘BH3 mimetic’ drugs that target various anti-apoptotic Bcl-2-like proteins by mimicking their natural inhibitors, the BH3-only proteins. The proof of target engagement and an on-target mechanism validation are critical for evaluating drug development potential. To evaluate target engagement of BH3 mimetics in cells, we measured binding potency of ABT-199, A-1210477 and ABT-737 to Bcl-2 and Mcl-1 proteins by using a dose-response cellular thermal shift assay (CETSA), similar affinity rank-order and selectivity were obtained in comparison with in vitro binding assays. A proof of direct target engagement for S1 and AT-101 was obtained through CETSA assay. By using a previously established mathematical model, we simulated individual death response of various cancer cell lines to ABT-199, S1 or AT-101 in comparison with experimental data. A positive correlation between model predictions and experimental data for ABT-199 and S1 showed that dual Bcl-2 and Mcl-1 target engagement underlies their anticancer efficacy. In contrast, an off-target effect was determined for AT-101.Graphical abstractImage, graphical abstract
  • Preparation and evaluation of novel multi-channel orally disintegrating
    • Abstract: Publication date: Available online 25 October 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Jiaojiao Yu, Xiaosong Shan, Shichao Chen, Xinli Sun, Pengjin Song, Ruidong Zhao, Liandong Hu In this study, novel orally disintegrating tablets (ODTs) with multi-channel structure were designed to provide a rapid disintegration and subsequently drug dissolution. The ODTs were prepared using conventional wet compression through perforating channels with a special multi-channel mold. A modified sieve method was used in disintegration test as a quick screening tool during formulation evaluation. Moreover, physical properties, in vitro and in vivo disintegration time, dissolution rate and mouthfeel were also evaluated. The results demonstrated that developed multi-channel ODTs had good physical parameters, in vitro/in vivo correlation (IVIVC) of disintegration time and acceptable mouthfeel and dissolution. It also revealed that the presence of channels could accelerate the disintegration of ODTs because the channels could shorten the distance of water penetration and increased the specific surface area, resulting in a significant reduction in disintegration time. Above all, the introduction of novel multi-channel ODTs provided an alternative preparation method for ODTs and achieved good disintegration characteristics.Graphical Image, graphical abstract
  • Pharmacological potential of novel agonists for FFAR4 on islet and
           enteroendocrine cell function and glucose homeostasis
    • Abstract: Publication date: Available online 25 October 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): A.G. McCloskey, M.G. Miskelly, P.R. Flatt, A.M. McKillop BackgroundTo investigate the metabolic effects of FFAR4-selective agonists on islet and enteroendocrine cell hormone release and the combined therapeutic effectiveness with DPP-IV inhibitors.MethodsInsulinotropic activity and specificity of FFAR4 agonists were determined in clonal pancreatic BRIN-BD11 cells. Expression of FFAR4 was assessed by qPCR and western blotting following agonist treatment in BRIN-BD11 cells and by immunohistochemistry in mouse islets. Acute in-vivo effects of agonists was investigated after intraperitoneal (i.p.) or oral administration in lean and HFF-obese diabetic mice.ResultsGSK137647 (10-11-10-4 M) and Compound-A (10-10-10-4 M) stimulated insulin secretion at 5.6mM (p
  • In vitro glucuronidation of 7-hydroxycoumarin derivatives in intestine and
           liver microsomes of Beagle dogs
    • Abstract: Publication date: Available online 25 October 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Risto O. Juvonen, Aki T. Heikkinen, Olli Kärkkäinen, Rabia Jehangir, Juhani Huuskonen, Johanna Troberg, Hannu Raunio, Olli T. Pentikäinen, Moshe Finel Beagle dog is a standard animal model for evaluating nonclinical pharmacokinetics of new drug candidates. Glucuronidation in intestine and liver is an important first-pass drug metabolic pathway, especially for phenolic compounds. This study evaluated the glucuronidation characteristics of several 7-hydroxycoumarin derivatives in beagle dog's intestine and liver in vitro. To this end, glucuronidation rates of 7-hydroxycoumarin (compound 1), 7-hydroxy-4-trifluoromethylcoumarin (2), 6-methoxy-7-hydroxycoumarin (3), 7-hydroxy-3-(4-tolyl)coumarin (4), 3-(4-fluorophenyl)coumarin (5), 7-hydroxy-3-(4-hydroxyphenyl)coumarin (6), 7-hydroxy-3-(4-methoxyphenyl)coumarin (7), and 7-hydroxy-3-(1H-1,2,4-tirazole)coumarin (8) were determined in dog's intestine and liver microsomes, as well as recombinant dog UGT1A enzymes. The glucuronidation rates of 1, 2 and 3 were 3–10 times higher in liver than in small intestine microsomes, whereas glucuronidation rates of 5, 6, 7 and 8 were similar in microsomes from both tissues. In the colon, glucuronidation of 1 and 2 was 3–5 times faster than in small intestine. dUGT1A11 glucuronidated efficiently all the substrates and was more efficient catalyst for 8 than any other dUGT1A. Other active enzymes were dUGT1A2 that glucuronidated efficiently 2, 3, 4, 5, 6 and 7, while dUGT1A10 glucuronidated efficiently 1, 2, 3, 4, 5 and 7. Kinetic analyses revealed that the compounds’ Km values varied between 1.1 (dUGT1A10 and 2) and 250 µM (dUGT1A7 and 4). The results further strengthen the concept that dog intestine has high capacity for glucuronidation, and that different dUGT1As mediate glucuronidation with distinct substrates selectivity in dog and human.Graphical abstractImage, graphical abstract
  • The mechanism of solifenacin release from a pH-responsive ion-complex oral
           suspension in the fasted upper gastrointestinal lumen
    • Abstract: Publication date: Available online 25 October 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Yosuke Yamamoto, Harumi Kumagai, Moe Haneda, Maria Vertzoni, Niels Ouwerkerk, Daisuke Murayama, Yoshifumi Katakawa, Kei Motonaga, Christos Reppas, Tomokazu Tajiri The main objective of this study was to investigate the mechanism of solifenacin release from a pH-responsive ion-complex oral resinate suspension under conditions simulating the environment in the upper gastrointestinal lumen. A secondary objective was to propose an appropriate in vitro test for evaluating the quality of orally administered solifenacin suspensions. The mechanism of solifenacin release from polacrilin potassium resin (Amberlite® IRP88) was investigated using biorelevant media and compendial setups (USP Apparatus 2 and USP Apparatus 4) and using newer, recently validated in vitro methodologies [biorelevant gastrointestinal transfer (BioGIT) system]. We evaluated the impact of particle size and concentration of the resin; thickener concentration (carbomer homopolymer, type B); and pH, cationic strength, agitation intensity and level of simulation of contents in the upper gastrointestinal lumen. Data suggested that solifenacin release from the resinate was determined by resin particle size, medium pH, cationic strength (when the conditions in the upper small intestine are simulated) and the level of simulation of contents in the upper small intestine. The interaction of solifenacin with taurocholic acid/lecithin aggregates was significant, but unlikely to affect the degree of solifenacin absorption, as a BCS Class I compound. Under acidic conditions, solifenacin was dissociated and released from the pH-responsive resin rapidly. Under conditions simulating the contents of the upper small intestine, solifenacin was replaced by cations from the testing media and diffused through the resin matrix. All three in vitro systems with or without a pH gradient are useful in distinguishing solifenacin release characteristics from resinate suspensions with different particle sizes. Because of this drug release mechanism, USP Apparatus 2 with fixed pH media demonstrated equivalent or slightly higher discriminative sensitivity than the other setups and appears to be appropriate for product quality control.Graphical abstractImage, graphical abstract
  • CNS penetration and pharmacodynamics of the CHK1 inhibitor prexasertib in
           a mouse Group 3 medulloblastoma model
    • Abstract: Publication date: Available online 25 October 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Olivia Campagne, Abigail Davis, Anil R. Maharaj, Bo Zhong, Jennifer Stripay, Dana Farmer, Martine F. Roussel, Clinton F. Stewart Prexasertib (LY2606368) is a potent and selective small molecule inhibitor of cell-cycle checkpoint CHK1 and CHK2 protein kinases and is currently under clinical evaluation for treatment of pediatric malignancies. As a candidate therapy for pediatric Group 3 medulloblastoma (G3MB), prexasertib CNS penetration was evaluated in mice using cerebral microdialysis and pharmacokinetic modeling. A plasma pharmacokinetic study with a population-based design was performed in CD1 nude mice bearing G3MB orthotopically implanted in the brain and receiving a single dose of prexasertib (10 mg/kg, subcutaneously) to characterize prexasertib disposition and to establish a limited plasma sampling model for the microdialysis studies. The microdialysis studies were performed in both non-tumor bearing mice and in mice bearing G3MB receiving 10 mg/kg prexasertib subcutaneously, for up to 24 hours post-dose. Plasma and extracellular fluid (ECF) concentrations were quantified using validated LC MS/MS methods, and analyzed using a population pharmacokinetic model. Model-derived prexasertib tumor/ECF to plasma partition coefficient Kp,uu (ratio of tumor/brain ECF to unbound plasma AUC0-24h) was significantly greater in G3MB tumor-bearing mice (0.17 ± 0.08) compared to non-tumor bearing mice (0.09 ± 0.04, p=0.04). A pharmacodynamic study was then performed in mice bearing G3MB (20 mg/kg, IV) to evaluate prexasertib-induced target engagement after a single dose. Phosphorylated CHK1 serine 345 (pCHK1 S345), phosphorylated Histone 2A variant (γ-H2AX), and cleaved caspase-3 were quantified in mouse G3MB tumor tissues by immunohistochemistry at different time points up to 24 hours post-dose. The induction of pCHK1 S345 and γ-H2AX peaked at 2 hours after the dose and was elevated above baseline for at least 6 hours, reflecting relevant CHK1 inhibition and DNA damage. Cleaved caspase-3 levels increased at 24 hours suggesting initiation of cell apoptosis. Adequate unbound prexasertib exposure reached the brain tumor site relative to target engagement in G3MB tumor bearing mice at a clinically relevant dosage. These results support further preclinical and clinical development of prexasertib to treat children with medulloblastoma.
  • GMP manufacturing of Vvax001, a therapeutic anti-HPV vaccine based on
           recombinant viral particles
    • Abstract: Publication date: Available online 25 October 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Annelies Jorritsma-Smit, Coba J. van Zanten, Jolande Schoemaker, Janneke J.M. Meulenberg, Daan J. Touw, Jos G.W. Kosterink, Hans W. Nijman, Toos Daemen, Derk P. Allersma Therapeutic vaccination is being explored as a treatment strategy for the treatment of patients with primary or metastatic tumours. We developed a vaccine targeted to Human papillomavirus (HPV)-induced tumours based on recombinant Semliki Forest virus (rSFV) encoding a fusion protein of the E6 and E7 proteins of HPV type 16. To enable a phase I clinical trial with this vaccine, Vvax001, a Good Manufacturing Practice (GMP)-compliant manufacturing process was set up and clinical material was produced.Upstream production of the clinical material resulted in viral titers from 2.4 × 107 to 1.3 × 109 infectious particles/ mL in the harvest. The total volume of 6.0 liter crude virus was purified in 13 consecutive downstream purification runs. The mean titer after purification was 4.0 × 108 infectious particles/ mL and the mean recovery was 19%. Finally, clinical material was filled at a target concentration of 1.25 × 108 infectious particles/mL. Release testing included tests for viral titer and virus identity, biological activity, sterility, bacterial endotoxins, adventitious viruses and absence of replication competent virus. The product complied with all specifications and was released for use as an investigational medicinal product.This is the first GMP production process developed for a SFV-based therapeutic vaccine. The vaccine, Vvax001 is targeted to HPV and has shown promising results in preclinical studies. The GMP-produced Vvax001 material met the quality criteria and was of sufficient quantity to enable assessment of its immunogenicity, safety and efficacy in a clinical setting.Graphical Image, graphical abstract
  • A study to evaluate herb-drug interaction underlying mechanisms: an
           investigation of ginsenosides attenuating the effect of warfarin on
           cardiovascular diseases
    • Abstract: Publication date: Available online 25 October 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Juan-Fang Lin, Lu-Lu Fan, Bo-Wen Li, Rui-Rui Zhao, Long-Guang Jiang, Bing-Chen Zhang, Yu-Sheng Lu, Jing-Wei Shao Warfarin and ginseng have been widely used in the treatment of cardiovascular diseases. However, the clinical safety and effectiveness of herb-drug combination treatment are still controversial. Therefore, it is very essential to probe the interaction between warfarin and ginseng. In this study, in vitro and in vivo study was carried out to demonstrate that whether there is an interaction between warfarin and ginsenosides (GS), which is the main component of ginseng. In vitro study showed that the adhesion ability of endothelial cells to matrigel/platelets was enhanced due to the up-regulating the expression of intercellular adhesion molecule (ICAM-1) and vascular cell adhesion molecule (VCAM-1) proteins by treatment of warfarin+GS combination compared to warfarin/GS treatment alone. Moreover, GS could weaken the anticoagulation effect of warfarin in hyperlipemia rats owning to the increased expression levels of coagulation factors and hepatic cytochrome P450 enzymes in plasma after long-term co-administration of warfarin with GS. The results of both in vitro and in vivo study demonstrated that there is a serious interaction between warfarin and ginseng, which may deteriorate atherosclerosis and thrombosis after combined use of warfarin and GS.Graphical abstrcatImage, graphical abstract
  • Characterization of microcrystalline cellulose spheres and prediction of
           hopper flow based on a μ(I)-rheology model.
    • Abstract: Publication date: Available online 24 October 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Johan Remmelgas, Abdoulaye Fall, Srdjan Sasic, Henrik Ström, Pirjo Tajarobi, Håkan Wikström, Mariagrazia Marucci, Catherine Boissier The objective of this study was to characterize the rheology of a pharmaceutical material in the context of the µ(I)-rheology model and to use this model to predict powder flow in a manufacturing operation that is relevant to pharmaceutical manufacturing. The rheology of microcrystalline cellulose spheres was therefore characterized in terms of the μ(I)-rheology model using a modified Malvern Kinexus rheometer. As an example of an important problem in pharmaceutical manufacturing, the flow of these particles from a hopper was studied experimentally and numerically using a continuum Navier-Stokes solver based on the Volume-Of-Fluid (VOF) interface-capturing numerical method. The work shows that the rheology of this typical pharmaceutical material can be measured using a modified annular shear rheometer and that the results can be interpreted in terms of the μ(I)-rheology model. It is demonstrated that both the simulation results and the experimental data show a constant hopper discharge rate. It is noted that the model can suffer from ill-posedness and it is shown how an increasingly fine grid resolution can result in predictions that are not entirely physically realistic. This shortcoming of the numerical framework implies that caution is required when making a one-to-one comparison with experimental data.Graphical abstractImage, graphical abstract
    • Abstract: Publication date: Available online 24 October 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Daniela Pacheco dos Santos Haupenthal, Fernando Milanez Dias, Rubya Pereira Zaccaron, Gustavo de Bem Silveira, Maria Eduarda Anastácio Borges Corrêa, Carolini Mendes, Laura de Roch Casagrande, Ricardo Aurino Pinho, Thiago Antonio Moretti de Andrade, Paulo Emilio Feuser, Marcos Marques da Silva Paula, Paulo Cesar Lock Silveira The repair process consists of molecular and cellular events that can be accelerated by specific therapies. Considering this, the objective of this study was to evaluate the effects of ibuprofen phonophoresis associated with gold nanoparticles in the animal model of traumatic muscle injury. Was used 80 male wistar rats divided into eight groups: Sham; Muscle injury (MI); MI + therapeutic pulsed ultrasound (TPU); MI + Ibuprofen (IBU); MI + GNPs; MI + TPU+ IBU; MI + TPU + GNPs and MI + TPU + IBU + GNPs. The lesion in the gastrocnemius was performed by a single direct trauma impact on the injured press. The animals were treated with pulsed ultrasound and the gel with gold nanoparticles and/or ibuprofen. The treatment was applied daily for 5 days and the first session was 12 hours after the muscle injury. The gastrocnemius muscle was surgically removed for analyzes biochemical, molecular and histological. In the analyzes only the MI + TPU + IBU + GNPs group showed a reduction in TNF-a and IL-1 levels, with a concomitant increase in the levels of anti-inflammatory cytokines. In the analysis of oxidative stress, only the MI + TPU + IBU + GNPs group presented a reversal of the condition when compared to the MI group. In the histological analysis, the MI group presented a large cell infiltrate and a centralized nucleus and only the MI + TPU + IBU + GNPs group showed a structural improvement, also in the pain results the MI + TPU + IBU + GNPs showed a significant difference in comparison to the MI group (p
  • Does the molecular mobility and flexibility of the saccharide ring affect
           the glass-forming ability of naproxen in binary mixtures'
    • Abstract: Publication date: Available online 23 October 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): A. Minecka, E. Kamińska, M. Tarnacka, K. Jurkiewicz, A. Talik, K. Wolnica, M. Dulski, A. Kasprzycka, P. Spychalska, G. Garbacz, K. Kamiński, M. PaluchABSTRACTIn this paper, we studied the impact of saccharides having a similar backbone but differing in the degree of freedom, local molecular mobility, flexibility of the ring and intermolecular interactions on the glass-forming ability (GFA) of naproxen (NAP) in binary mixtures. For this purpose, a series of methyl and acetyl derivatives of glucose (GLS) and anhydroglucose (anhGLS), as well as neat anhGLS have been used to produce homogeneous solid dispersions (SDs) of varying molar concentration of examined active pharmaceutical ingredient (API). Systematic measurements with the use of Differential Scanning Calorimetry (DSC) and Broadband Dielectric Spectroscopy (BDS) enabled us to determine the phase transitions, homogeneity and molecular mobility of the investigated binary mixtures as well as the impact of excipient on the crystallization tendency of NAP. It turned out that acetylated glucose (acGLS), being one of the mostmobileandflexible saccharides of all studied herein materials, is the best excipient enhancing the GFA of studied API. Although, it should be noted that upon storage at room temperature, we observed the recrystallization of NAP from binary mixtures. Interestingly, API always crystallized to the initial polymorphic form, as shown by X-ray diffraction (XRD) investigations. Finally, since additional measurements with the use of Fourier Transform Infrared (FTIR) Spectroscopy clearly indicated that there are no significant differences in the intermolecular interactions in the systems composed of NAP and all examined saccharides, one can postulate that the mobility and ring flexibility of the matrix have, in fact, the most important impact on the crystallization tendency of NAP upon cooling. Consequently, it seems that in some cases, more mobile/flexible matrices can be a much better choice to enhance the glass-forming ability of studied pharmaceutical.Graphical Image, graphical abstract
  • Incorporation of HPMCAS during loading of glibenclamide onto mesoporous
           silica improves dissolution and inhibits precipitation
    • Abstract: Publication date: Available online 23 October 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Daniel J. Price, Anita Nair, Johanna Becker-Baldus, Clemens Glaubitz, Martin Kuentz, Jennifer Dressman, Christoph Saal Mesoporous silica has emerged as an enabling formulation for poorly soluble active pharmaceutical ingredients (APIs). Unlike other formulations, mesoporous silica typically does not inhibit precipitation of supersaturated API therefore, a suitable precipitation inhibitor (PI) should be added to increase absorption from the gastrointestinal (GI) tract. However, there is limited research about optimal processes for combining PIs with silica formulations. Typically, the PI is added by simply blending the API-loaded silica mechanically with the selected PI. This has the drawback of an additional blending step and may also not be optimal with regard to release of drug and PI. By contrast, loading PI simultaneously with the API onto mesoporous silica, i.e. co-incorporation, is attractive from both a performance and practical perspective. The aim of this study was to demonstrate the utility of a co-incorporation approach for combining PIs with silica formulations, and to develop a mechanistic rationale for improvement of the performance of silica formulations using the co-incorporation approach. The results indicate that co-incorporating HPMCAS with glibenclamide onto silica significantly improved the extent and duration of drug supersaturation in single-medium and transfer dissolution experiments. Extensive spectroscopic characterization of the formulation revealed that the improved performance was related to the formation of drug-polymer interactions already in the solid state; the immobilization of API-loaded silica on HPMCAS plates, which prevents premature release and precipitation of API; and drug-polymer proximity on disintegration of the formulation, allowing for rapid onset of precipitation inhibition. The data suggests that co-incorporating the PI with the API is appealing for silica formulations from both a practical and formulation performance perspective.Graphical Image, graphical abstract
  • Role of Allopurinol and Febuxostat in the amelioration of dextran-induced
           colitis in rats
    • Abstract: Publication date: Available online 23 October 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Nageh Ahmed El-Mahdy, Dina Ali Saleh, Magdy Salah Amer, Sally El-Sayed Abu-Risha Ulcerative colitis is a chronic auto-inflammatory disorder confined to the colorectal region. It is challenging to find an absolute treatment and current therapy aims to ameliorate symptoms, decrease relapses and prevent prognosis of colorectal cancer. In the present study, we investigated the possible action of xanthine oxidase inhibitors in murine colitis model by measuring different indicative parameters and comparing the results to those of the reference sulfasalazine. Also, we compared the effects of combining sulfasalazine and allopurinol to each drug alone. Dextran Sodium Sulfate (DSS) is used in this study to induce ulcerative colitis in male wistar rats as it is known to be the closest model that mimics human ulcerative colitis. Allopurinol was given prior to colitis induction by four days and febuxostat for six days before induction with DSS (5% w/v) and continue to give them concomitantly during the induction.Il-1β, malondialdehyde, reduced glutathione (GSH), xanthine oxidase, and superoxide dismutase were measured in colonic tissue. We also measured concentrations of IL-1β, Il-6 and uric acid in serum.Allopurinol dose-dependently ameliorated biochemical injuries. Febuxostat has shown better results than allopurinol and sulfasalazine, and this is the first study to demonstrate this.Graphical abstractGraph representing the role of xanthine oxidase inhibitors (XOIs) in the amelioration of ulcerative colitis (UC).XOIs: xanthine oxidase inhibitors; UC: ulcerative colitis; DSS: Dextran sodium sulphate; IL-1β: interleukin-1β; IL-6: interleukin-6; SOD: superoxide dismutase; GSH: reduced glutathione; XO: xanthine oxidase enzyme; ROS: reactive oxygen species.Image, graphical abstract
  • Overcoming challenges in co-formulation of proteins with contradicting
           stability profiles - EPO plus G-CSF
    • Abstract: Publication date: Available online 23 October 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Dennis Krieg, Hristo Svilenov, Julian H. Gitter, Gerhard Winter The co-formulation of drugs is widely used for small molecules, e.g. fixed-dose-combinations of synergistic medicines in the treatment of infections, diabetes or neurodegenerative diseases. For protein drugs, only a few studies have been published to elucidate the challenges of stabilizing two proteins in one formulation. Here, we show a systematic study with the model proteins EPO and G-CSF, which differ significantly in their physicochemical properties. We apply several analytical methods to investigate the stability of the co-formulated proteins in the liquid and solid state. Forced degradation studies at elevated temperature indicate poor stability of the liquid co-formulations. Therefore, we use lyophilization as a stabilization strategy. Finally, we adopt an elegant approach, in which the proteins are lyophilized at pH 4.0 and reconstituted with buffer at pH 7.0 to obtain high monomer recovery and to preserve the protein structure of both EPO and G-CSF. After reconstitution, both proteins in co-formulation remain stable for the timespan until eventual application in patients. With this case study, we demonstrate how to overcome some challenges during the co-formulation of therapeutic proteins.Graphical Image, graphical abstract
  • Transient analysis of drug delivery from a toroidal membrane: Applications
           for medicated vaginal rings
    • Abstract: Publication date: Available online 23 October 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): LAURENT SIMON, JUAN OSPINA A mathematical construct is proposed to analyze drug released from matrix-type vaginal rings. This work is intended to support experimental studies and promote the fabrication of these devices. The transport of a dissolved drug through a toroidal membrane was predicted using diffusion equations and their solutions. This dynamic framework led to the estimation of the time elapsed before releasing 98% of the ethynodiol diacetate from the polymer. Closed-form expressions, easily adaptable to spreadsheet implementation, were developed to simulate the controlled delivery of levonorgestrel initially dispersed in a silicone vaginal ring. As the loading increased, a greater amount of medication was delivered. However, the fractional release decreased from 32.6% to 23.1% when the dosage changed from 4.137 g/cm3 to 8.274 mg/cm3. The expressions were further simplified for thin rings.Graphical abstractImage, graphical abstract
  • Stability of frozen 1% voriconazole eye-drops in both glass and innovative
    • Abstract: Publication date: Available online 23 October 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Marine Roche, Damien Lannoy, Florence Bourdon, Cécile Danel, Pierre Labalette, Christophe Berneron, Nicolas Simon, Pascal Odou PurposeTo assess the physico-chemical stability of Voriconazole Eye-Drops (VED), when stored frozen and refrigerated once thawed, in 3 containers: Amber glass with a Low-Density PolyEthylene (LDPE) eyedropper, and two types of LDPE bottles: one classical and one with an innovative insert that maintains sterility after opening (Novelia® from Nemera)Methods: Three batches of 1% VED (10 mL) were aseptically compounded from marketed injectable voriconazole (Vfend®) diluted in sterile water for injection. VEDs were stored for three months at -20°C in amber glass (n=32), classical LDPE (n=32) or innovative LDPE (n=31) bottles. Stability-indicating (HPLC-UV-DAD) and chiral chromatography methods were developed. The stability study was conducted according to GERPAC-SFPC guidelines. At each study time, the following parameters were controlled: visual aspect, voriconazole concentration, pH and osmolality. In addition, non-visible particle count, sterility and absence of racemisation (impurity D – (2S,3R)-voriconazole) were assessed at the beginning and end of the study.Results are expressed as mean ± standard deviation. Statistical analyses were performed using non-parametric tests (α < 5%) to compare containers.ResultsWhen stored frozen, concentration was between 95.2±1.4% and 103.6±1.3% of the initial concentration (C0) with no difference between the three containers (p=0.564; non-significant). Fifteen days after thawing, concentration was between 97.1±1.6% and 98.6±0.8% of C0 with no difference between containers (p=0.278 and 0.368 for VED thawed at room temperature and at 2-8°C, respectively). pH remained stable between each time. Osmolality was slightly higher in glass (533.17 ± 8.93 mOsm/Kg) than in plastic containers (522.17±3.31mOsm/Kg, classical LDPE; 517.5±12.42 mOsm/Kg, innovative LDPE) (p=0.022). Sterility was preserved. Degradation product areas increased slightly but remained below the limit of quantification. Impurity D was never detected.ConclusionWe have demonstrated that the ability of the innovative container Novelia® to maintain VED physicochemical and microbiological stability does not differ from that of amber glass and classical LDPE containers. Real life studies are required to find out if there is a potential difference between Novelia® and other containers in terms of sterility preservation.Graphical abstractImage, graphical abstract
  • Development, characterisation and nasal deposition of melatonin-loaded
           pectin/hypromellose microspheres
    • Abstract: Publication date: Available online 22 October 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Laura Nižić, Joanna Potaś, Katarzyna Winnicka, Marta Szekalska, Iva Erak, Matija Gretić, Mario Jug, Anita Hafner In this study, we present the development of spray-dried pectin/hypromellose microspheres as efficient melatonin carrier for targeted nasal delivery. Different pectin to hypromellose weight ratios in the spray-dried feed were employed (i.e. 1:0, 3:1, 1:1 and 1:3) in order to optimise microsphere physicochemical properties influencing overall powder behaviour prior, during and upon nasal delivery. All microspheres assured complete melatonin entrapment and increased dissolution rate in relation to pure melatonin powder. Among all combinations tested, combining pectin with hypromellose at 1:3 weight ratio resulted in the microspheres with the highest potential for melatonin nasal delivery as they assured highest swelling ability and most prominent mucoadhesive properties. Studies on deposition profile revealed adequate turbinate and olfactory deposition of microsphere/lactose monohydrate powder blend administered nasally using MIAT® device, complementing findings relevant for their therapeutic potential. In conclusion, developed microspheres bear the potential to ensure prolonged melatonin retention at the nasal mucosa, improved bioavailability and advanced therapeutic outcome.Graphical abstractImage, graphical abstract
  • Analgesic and antipruritic effects of oxymatrine sustained-release
           microgel cream in a mouse model of inflammatory itch and pain
    • Abstract: Publication date: Available online 22 October 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Tao Zhu, Dan Zhou, Zhe Zhang, Lina Long, Yujuan Liu, Qinghong Fan, Feifan Chen, Xueke Zhang, Yan Wu, Hekun Zeng, Alexei Verkhratsky, Jianhao Zhao, Hong Nie BackgroundAllergic contact dermatitis (ACD) is a highly prevalent inflammatory and immune skin disease accompanied with persistent pruritus and pain. Oxymatrine (OMT) exhibits antipruritic and anti-inflammatory effects in squaric acid dibutyl ester (SADBE) induced ACD mice model, but the need for frequent administration stipulated by short half-life and low bioavailability limits clinical application.ObjectiveTo evaluate the analgesic and antipruritic effects of OMT gel (OG), OMT sustained release microgel powder (OMP) and OMT sustained release microgel cream (OMC) in SADBE induced ACD mice, with subsequent study of the mechanism and side effects (irritation) of optimal dosage form.MethodOn day 11, the thickness of the right cheek skin of mice was measured and mice spontaneous behaviors were recorded for 1.5 hours. In the OMC experiment, hematoxylin-eosin and toluidine blue staining were performed on the cheek skin, and the irritation of OMC was tested on the back skin of rabbits. Blood analyzer was used to measure the counts of inflammatory cells in peripheral blood. The mRNA expressions of IL-1β, TNF-α, CXCR3, CXCL10, IL-6, IL-10, IL-17A and IL-31 in cheek skin, TRPA1 and TRPV1 channels in trigeminal ganglion (TG), IFN-γ in spleen and IL-17A in thymus were measured by RT-qPCR.ResultsOMC, OMP and OG significantly decreased wipes and scratching bouts, alleviated skin inflammation. OMC required less frequent administration and is easier to apply, while its antipruritic effect was stronger than the analgesic effect. OMC rescued the deficits in epidermal keratinization and inflammatory cell infiltration, decreased the leukocyte count in peripheral blood, had no irritation to the broken rabbit's skin. Furthermore, OMC significantly down-regulated the mRNA expression of IL-1β, TNF-α, CXCR3, CXCL10, IL-6, IL-10, IL-17A and IL-31 in cheek skin, TRPA1 and TRPV1 channels in TG, IFN-γ in thymus and IL-17A in spleen.ConclusionWe have demonstrated that OMC exhibits advanced analgesic, antipruritic and anti-inflammatory effects when compared with OG and OMP in ACD mice by regulating inflammation, chemokines, immune mediators and inhibiting the mRNA expression of TRPA1 and TRPV1. OMC has no irritation to the intact and damaged skin of rabbits.Graphical We first evaluate the analgesic and antipruritic effects of OMT gel (OG), OMT sustained release microgel powder (OMP) and OMT sustained release microgel cream (OMC) in SADBE induced ACD mice (Graphical not show), and then investigate the mechanism and irritation of optimal dosage form, OMC Image, graphical abstract.
  • Formulation and optimization of drug-loaded mesoporous silica
           nanoparticle-based tablets to improve the dissolution rate of the poorly
           water-soluble drug silymarin
    • Abstract: Publication date: Available online 21 October 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Ahmed H. Ibrahim, Jan-Henrik Smått, N. Prakirth Govardhanam, Hany M. Ibrahim, Hatem R. Ismael, Mohsen I. Afouna, Ahmed M. Samy, Jessica M. Rosenholm Porous carriers have been put forward as a promising alternative for stabilizing the amorphous state of loaded drugs, and thus significantly improving the dissolution rate of poorly soluble compounds. The purpose of this study was to enhance the saturation solubility, dissolution rate and drug loading of the poorly water-soluble drug silymarin via incorporation into mesoporous silica nanospheres within a lyophilized tablet to obtain a unique formulation. 32 full factorial design was applied to study the effect of both independent variables, polyvinyl alcohol (PVA) as stabilizer and binder and sucrose as cryoprotectant and disintegrant; and on the dependent variables that included the mean particle size (Y1), disintegration time (Y2), tablet strength (Y3) and % of drug release after 2 minutes, R2min,Y4. The drug-loaded mesoporous silica nanospheres and the optimized formula was evaluated by different characterization methods: scanning electron microscopy, transmission electron microscopy, differential scanning calorimetry, X-ray diffractometry and Fourier transform infrared spectroscopy; as well as drug content, saturation solubility and moisture content. The evaluation demonstrated that the loaded mesoporous silica nanospheres and the optimized formula are in amorphous state without any chemical interaction with the silica matrix or the stabilizer. Moreover, the drug was stably maintained in nanosize range with narrow particle size distribution. Furthermore, the optimized lyophilized tablets had highly porous structure, low friability (less than 1%), fast disintegration (less than 30 seconds), high tablet strength, low moisture content (less than 1%), remarkably increased dissolution rate and noticeable improvement in saturation solubility.Graphical abstractImage, graphical abstract
  • A dual system platform for drug metabolism: Nalbuphine as a model compound
    • Abstract: Publication date: Available online 21 October 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Ren-Jong Liang, Yin-Ning Shih, Yen-Lun Chen, Wei-Yang Liu, Wan-Ling Yang, Shih-Yu Lee, Hong-Jaan Wang Reaction phenotyping is a method commonly used for characterizing drug metabolism. It determines the drug metabolic pathways and ratios by measuring the metabolized fractions of individual enzymes. However, currently published results have focused on cytochrome P450 (CYP), while not considering phase II metabolism. Therefore, the morphinan analgesic, nalbuphine, primarily metabolized in the liver via CYPs and UDP-glucuronosyltransferases (UGTs), was selected as a model drug to establish a dual-phase platform to elucidate its comprehensive metabolic pathway. Enzyme kinetics was studied using 8 common recombinant (r)CYPs,10 rUGTs, and pooled human liver microsomes. The overall fraction of nalbuphine metabolized by each isozyme was evaluated by determining parent drug depletion. Finally, in vitro-in vivo correlation was validated in animal studies. Fluconazole, a specific UGT2B7 inhibitor, was administered orally to rats to determine the pharmacokinetic effects on nalbuphine and nalbuphine metabolites. Seventy-five percent and 25% of nalbuphine was metabolized by UGTs and CYPs, respectively. UGT2B7, UGT1A3, and UGT1A9 were primarily responsible for nalbuphine glucuronidation; only UGT2B7 produced nalbuphine-6-glucuronide. CYP2C9 and CYP2C19 were the two CYP isozymes that produced 3′-hydroxylnalbuphine and 4′-hydroxylnalbuphine. In vivo, the maximum serum concentration (Cmax) and area under the curve (AUC) of nalbuphine increased 12.4-fold and 13.2-fold, respectively, with fluconazole co-administration. A dual system platform for drug metabolism was successfully established in this study and was used to generate a complete metabolic scheme for nalbuphine. This platform has been verified by in vivo evaluations and can be utilized to study drugs that undergo multisystem metabolism.Graphical abstractImage, graphical abstract
  • Towards a Novel Continuous HME-Tableting Line: Process Development and
           Control Concept
    • Abstract: Publication date: Available online 21 October 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Stephan Sacher, Selma Celikovic, Jakob Rehrl, Johannes Poms, Martin Kirchengast, Julia Kruisz, Martin Sipek, Sharareh Salar-Behzadi, Hannes Berger, Gerald Stark, Martin Horn, Johannes G. Khinast The objective of this study was to develop a novel closed-loop controlled continuous tablet manufacturing line, which first uses hot melt extrusion (HME) to produce pellets based on API and a polymer matrix. Such systems can be used to make complex pharmaceutical formulations, e.g., amorphous solid dispersions of poorly soluble APIs. The pellets are then fed to a direct compaction (DC) line blended with an external phase and tableted continuously. Fully-automated processing requires advanced control strategies, e.g., for reacting to raw material variations and process events. While many tools have been proposed for in-line process monitoring and real-time data acquisition, establishing real-time automated feedback control based on in-process control strategies remains a challenge. Control loops were implemented to assess the critical quality attributes of intermediates and product and to coordinate the mass flow rate between the unit operations. Feedback control for the blend concentration, strand temperature and pellet thickness was accomplished via proportional integral derivative (PID) controllers. The tablet press hopper level was controlled using a model predictive controller. To control the mass flow rates in all unit operations, several concepts were developed, with the tablet press, the extruder or none assigned to be the master unit of the line, and compared via the simulation.Graphical abstractImage, graphical abstract
  • Molecular dynamics, viscoelastic properties and physical stability studies
           of a new amorphous dihydropyridine derivative with T-type calcium channel
           blocking activity
    • Abstract: Publication date: Available online 18 October 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Justyna Knapik-Kowalczuk, Miyase Gözde Gündüz, Krzysztof Chmiel, Karolina Jurkiewicz, Mateusz Kurek, Lidia Tajber, Renata Jachowicz, Marian Paluch One of the greatest problems of pre-clinical development of new chemical entities is their poor aqueous solubility. Herein, we focus our attention on MD20 – a novel calcium channel blocker that selectively blocks T-type calcium channel (Cav3.2) over L-type calcium channel (Cav1.2). To avoid future problems with limited solubility of this compound, an amorphous form of MD20 was obtained and thoroughly investigated by various experimental techniques. The thermal properties of both crystalline and amorphous MD20 were examined by differential scanning calorimetry and thermogravimetry. Dielectric spectroscopy studies of MD20 at T < Tg revealed that this compound possesses as many as four secondary relaxation processes. The molecular dynamics of the supercooled sample was investigated by dielectric and mechanical spectroscopies. In this paper, a comparison of the relaxation dynamics of supercooled MD20 obtained from both of these experimental techniques is presented. On the basis of the dielectric studies the time of physical stability of the investigated material (at T = 298 K) was predicted as 150 years. Finally, we have performed experimental long-term stability tests, which showed that amorphous MD20 did not reveal any sign of re-crystallization for at least 260 days.Graphical abstractImage, graphical abstract
  • Quantitative Characterization of Leachables Sinks in Biopharmaceutical
           Downstream Processing
    • Abstract: Publication date: Available online 18 October 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Kushal Paudel, Armin Hauk, Tanja Verena Maier, Roberto Menzel This article demonstrates, on a quantitative level, that leachables — potentially accumulated during a biopharmaceutical manufacturing process — will be significantly reduced/removed during four key downstream process steps: cell harvest using centrifugation or depth filtration, sterile filtration and virus filtration. Eight common leachables model compounds (LMCs) were spiked into typical feed solutions containing buffer and proteins and were analyzed post-processing in the supernatant or filtrates by HPLC-UV. The clearance rates were calculated as the quotient between the scavenged and initially spiked amount of each leachable. High clearance rates were found for hydrophobic LMCs for all investigated downstream operation steps. It is shown that the removal of cells and cell debris from a culture broth reduces the amount of LMCs almost completely after centrifugation or depth filtration. Also, sterilizing-grade and virus filtration provided a high scavenger effect to most of the LMCs. In contrast, only one hydrophilic acid was not significantly scavenged by the described operations. The possibility to include leachables sinks to a process qualification and risk mitigation concept is explained.Graphical Image, graphical abstract
  • Development of a W/O emulsion using ionic liquid strategy for transdermal
           delivery of anti – aging component α – lipoic acid: Mechanism of
           different ionic liquids on skin retention and efficacy evaluation
    • Abstract: Publication date: Available online 18 October 2019Source: European Journal of Pharmaceutical SciencesAuthor(s): Zhuang Zhou, Chao Liu, Xiaocao Wan, Liang Fang Skin aging affects personal image and health. α – lipoic acid (ALA), with excellent free radical scavenging capacity, was used in this research to prepare W/O emulsion. Considering the instability of ALA, ionic liquid strategy was adopted to heighten the solubility of ALA for dissolving in water phase. The mechanism of different ionic liquids (ILs) on skin retention of ALA was investigated by in vitro skin permeation experiment, emulsion quality characterization, rheological test, ATR – FTIR and molecular simulation. The results showed that ionic liquid strategy had a positive influence on the solubilization of ALA. Different ILs were different in skin retention and regulated by skin layers rather than drug release, in which ALA – triethanolamine (ALA – TEOA) presented the best affinity with both stratum corneum (SC) and viable epidermis and dermis (VED), while ALA – N – (2 – Hydroxyethyl) piperidine (ALA – HEPP) as well as ALA – N – (2 – hydroxyethyl) pyrrolidine (ALA – HEPR) showed affinity with either SC or VED respectively. Finally, the emulsion presented brilliant anti – aging efficacy. This study provided a new method of emulsion research and had great significance for the development of topical formulations.Graphical abstractImage, graphical abstract
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