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European Journal of Pharmaceutical Sciences
Journal Prestige (SJR): 1.016
Citation Impact (citeScore): 4
Number of Followers: 126  
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0928-0987
Published by Elsevier Homepage  [3162 journals]
  • Impact of PCL nanofiber mat structural properties on hydrophilic drug
           release and antibacterial activity on periodontal pathogens
    • Abstract: Publication date: Available online 12 July 2018Source: European Journal of Pharmaceutical SciencesAuthor(s): Špela Zupančič, Liis Preem, Julijana Kristl, Marta Putrinš, Tanel Tenson, Petra Kocbek, Karin Kogermann Electrospinning enables to design and manufacture novel drug delivery systems capable of advancing the local antibacterial therapy. In this study, two hydrophilic drugs – metronidazole and ciprofloxacin hydrochloride – were loaded both individually and in combination into hydrophobic polycaprolactone (PCL) matrix using electrospinning. We aimed to develop prolonged release drug delivery systems suitable for the treatment of periodontal diseases and understand how different rarely studied structural features, such as nanofiber mat thickness, surface area, wettability, together with intrinsic properties, like solid state and localization of incorporated drugs in nanofibers, affect the drug release. Furthermore, the safety of nanofiber mats was assessed in vitro on fibroblasts, and their antibacterial activity was tested on selected strains of periodontopathogenic bacteria. The results showed that the structural properties of nanofiber mat are crucial in particular drug-polymer combinations, affecting the drug release and consequently the antibacterial activity. The hydrophobicity of a PCL nanofiber mat and its thickness are the key characteristics in prolonged hydrophilic drug release, but only when wetting is the rate-limiting step for the drug release. Combination of drugs showed beneficial effects by inhibiting the growth of all tested pathogenic bacterial strains important in periodontal diseases.Graphical abstractUnlabelled Image
  • Development of novel gastroretentive salbutamol sulfate-loaded sodium
           alginate-pectin bubble beads prepared by co-axial needle air-injection
           method and in vivo clinical evaluation by ultrasound studies
    • Abstract: Publication date: Available online 12 July 2018Source: European Journal of Pharmaceutical SciencesAuthor(s): Pooja Devi, Sandeep Rathor, Pratibha Sharma, Jyotsna Sen, Harmeet Kaur, Jasbir Singh In the present study, the salbutamol sulfate-loaded sodium alginate-pectin (SS-loaded SA-PEC) bubble beads have been optimized and evaluated for drug loading, in vitro drug release, in vivo floating behavior in the stomach, etc. Nine batches (F1–F9) of bubble beads with different SA and PEC contents were prepared by novel co-axial needle air-injection method and related to the percent drug loading efficiency (%DLE) and percent drug release at 4 h (%R4h) as response factors. The multivariate analysis has shown the effect of SA/PEC ratio, total polymer content, as well as their interaction on %DLE and %R4h. In the quantitative modeling, the satisfactory adjustment of the linear models (along with interaction terms) with the experimental data for both %DLE and %R4h has confirmed the findings of the multivariate analysis. The optimized SS-loaded SA-PEC bubble beads based on various 2D (contours), 3D, desirability, and overlay plots has exhibited %DLE of 87.35 ± 2.48% (n = 3 and error = 2.94%) and %R4h of 85.79 ± 2.98% (n = 3 and error = 0.25%). The in vitro drug release studies have shown almost complete (≥85%) SS release from all the batches within 4–6 h in simulated gastric fluid (SGF) pH 1.2. The in vivo clinical findings by ultrasound studies have shown excellent floatation (>6 h) behavior of bubble beads in the upper gastrointestinal tract (GIT) and efficient stomach-specific gastroretention.Graphical abstractUnlabelled Image
  • Spectroscopic characterization of tablet properties in a continuous powder
           blending and tableting process
    • Abstract: Publication date: Available online 12 July 2018Source: European Journal of Pharmaceutical SciencesAuthor(s): Brigitta Nagy, Attila Farkas, Krisztina Magyar, Balázs Démuth, Zsombor Kristóf Nagy, György Marosi By the advent of continuous pharmaceutical manufacturing, fast and accurate characterization of product quality has become of a major interest. Although it also promotes the real-time release testing approach, so far mainly content uniformity studies were performed by near-infrared (NIR) spectroscopy. This paper proposes the simultaneous application of NIR and Raman spectroscopy to nondestructively analyze the critical quality attributes of continuously produced tablets in a real-time release testing procedure. A face-centered composite design was applied to determine the impact of lubrication and compression force on the properties of a tablet formulation containing caffeine, glucose-monohydrate and magnesium stearate and to provide a systematic comparison of the applicability of spectroscopic methods. Quantitative methods were developed to evaluate different lubrication approaches in a continuous blending and tableting line. The simultaneous application of NIR and Raman spectroscopy revealed that NIR spectroscopy is more suitable to follow the changes of compression force, while Raman spectroscopy could be successfully applied for the detection of overlubrication. The presented approach can be a part of a comprehensive real-time release strategy, where NIR and Raman spectroscopy provide complementary information about multiple critical quality attributes, such as content uniformity, tablet hardness, friability and dissolution.Graphical abstractUnlabelled Image
  • Unique laser coding technology to fight falsified medicines
    • Abstract: Publication date: Available online 12 July 2018Source: European Journal of Pharmaceutical SciencesAuthor(s): K. Ludasi, T. Sovány, O. Laczkovich, B. Hopp, T. Smausz, G. Regdon Based on WHO statistics, counterfeit medicines represent 10% of the global drug trade. According to Directive 2011/62/EU as regards the prevention of falsified medicines from entering into the legal supply chain, a unique identification should be put on each box of drugs to be able to track and trace them. The objective of this study is to develop a technology to mark an individual traceability code directly on the surface of the tablet. By using this technique, anyone with a camera-enabled phone and a suitable application installed should be able to authenticate these drugs. By marking the medicine's surface, patients could be protected from fake drugs.The aim of the present work was to study how different types of lasers affect the film coating of the tablet during the laser marking intervention.To sum up, the present findings may contribute to efficient and reliable laser marking solutions in the unique identification procedure. Based on our measurement results, it can be stated that the excimer UV laser is clearly the most suitable marking instrument for anti-counterfeiting coding on solid coated tablet form as this caused the least amount of chemical degradation of the polymer film.Graphical abstractUnlabelled Image
  • Lyophilized tablets for focal delivery of fluconazole and itraconazole
           through vaginal mucosa, rational design and in vitro evaluation
    • Abstract: Publication date: 15 September 2018Source: European Journal of Pharmaceutical Sciences, Volume 122Author(s): Maria José de Jesús Valle, Paula Coutinho, Maximiano Prata Ribeiro, Amparo Sánchez Navarro The present work deals with the rational design and in vitro evaluation of vaginal tablets for focal delivery of fluconazole (FLZ) and itraconazol (ITZ). Drug loaded liposomes with and without d-alpha-tocopheryl polyethylene glycol 1000 succinate (vit E TPGS) were prepared by direct sonication of the components and mixed with albumin to obtain albusomes. Tablets were obtained by direct compression of the lyophilized cake. The influence of vit E TPGS on size, zeta potential and entrapment efficiency (EE%) of liposomes and albusomes was evaluated. Tablet swelling and drug release were studied by in vitro assays. Vit E TPGS neither affected the zeta potential nor the EE% of liposomes and albusomes, but affected the liposomes size and the tablet disintegration time. A rapid erosion was observed for the tablets with the highest content of vitamin, while a slow swelling for those lacking the vitamin (swelling index = 57.76 ± 13.51%). A faster drug release profile was obtained for the former compared to the latter. The in vitro assay showed that FLZ diffused and solved in the vaginal fluid simulant while ITZ remained into the albusomes, which slowly released ITZ-albumin complex and ITZ-loaded liposomes, both suitable carriers for drug transport to deeper vaginal endothelium.Graphical abstractUnlabelled Image
  • Pharmacokinetics of pericyte involvement in small-molecular drug transport
           across the blood-brain barrier
    • Abstract: Publication date: 15 September 2018Source: European Journal of Pharmaceutical Sciences, Volume 122Author(s): Nebojsa Mihajlica, Christer Betsholtz, Margareta Hammarlund-Udenaes Pericytes are perivascular cells that play important roles in the regulation of the blood-brain barrier (BBB) properties. Pericyte-deficiency causes compromised BBB integrity and increase in permeability to different macromolecules mainly by upregulated transcytosis. The aim of the present study was to investigate pericyte involvement in the extent of small-molecular drug transport across the BBB. This was performed with five compounds: diazepam, digoxin, levofloxacin, oxycodone and paliperidone. Compounds were administered at low doses via subcutaneous injections as a cassette (simultaneously) to pericyte-deficient Pdgfbret/ret mice and corresponding WT controls. Total drug partitioning across the BBB was calculated as the ratio of total drug exposures in brain tissue and plasma (Kp,brain). In addition, equilibrium dialysis experiments were performed to estimate unbound drug fractions in brain (fu,brain) and plasma (fu,plasma). This enabled estimation of unbound drug partitioning coefficients (Kp,uu,brain). The results indicated slight tendencies towards increase of total brain exposures in Pdgfbret/ret mice as reflected in Kp,brain values, which were within the 2-fold limit. Part of these differences could be explained by differences in plasma protein binding. No difference was found in brain tissue binding. The combined in vivo and in vitro data resulted in no differences in BBB transport in pericyte-deficiency, as described by similar Kp,uu,brain values in Pdgfbret/ret and control mice. In conclusion, these findings imply no influence of pericytes on the extent of BBB transport of small-molecular drugs, and suggest preserved BBB features relevant for handling of this type of molecules irrespective of pericyte presence at the brain endothelium.Graphical abstractUnlabelled Image
  • Mesoporous silica nanoparticles facilitating the dissolution of poorly
           soluble drugs in orodispersible films
    • Abstract: Publication date: 15 September 2018Source: European Journal of Pharmaceutical Sciences, Volume 122Author(s): Didem Ṣen Karaman, Giorgia Patrignani, Emil Rosqvist, Jan-Henrik Smått, Aleksandra Orłowska, Rawand Mustafa, Maren Preis, Jessica M. Rosenholm Orodispersible films (ODF) are immediately dissolving/disintegrating intraoral dosage forms, presented as substitutes of conventional tablets or capsules to ease problems associated with swallowing. Efforts have been made to be able to exploit ODFs as dosage forms for poorly soluble drugs. In the last two decades, mesoporous silica nanoparticles (MSNs) have been extensively used in drug delivery applications to overcome solubility problems of drugs. The tunable features of MSNs make them suitable candidates as drug carriers and solubility enhancers. In this study, the feasibility of MSNs as a carrier of poorly soluble drugs, using prednisolone as a model drug, in ODFs was investigated. Our results revealed that the increased amount of MSNs in ODFs leads to shortening of the disintegration time of the films. Drug content investigations showed that low dose ODFs with prednisolone incorporation efficiencies higher than 80% could be produced. Furthermore, the prednisolone release profile from ODFs can be tuned with the incorporation of MSNs as drug carrier (MSNpred). The MSNpred incorporated ODFs yield with immediate release of drug from the ODF, whereby 90% of the prednisolone content could be released in the first minutes. By modifying the MSNpred design with copolymer surface coating, prednisolone (cop-MSNpred) release can be modulated into a two-step sustained release profile. To sum up, the MSNs platform does not only provide careful low dose incorporation into ODF with high efficiency, but it also aids in tuning the drug release profiles from ODFs.Graphical abstractUnlabelled Image
  • Design and characterization of loratadine nanosuspension prepared by
           ultrasonic-assisted precipitation
    • Abstract: Publication date: 15 September 2018Source: European Journal of Pharmaceutical Sciences, Volume 122Author(s): Areen Alshweiat, Gábor Katona, Ildikó Csóka, Rita Ambrus Nanoparticle engineering is a well-defined technique employed as a novel and effective method in drug design and delivery. It is widely used to control particle size, as well as the morphological and physicochemical properties of active pharmaceutical ingredients. Furthermore, it serves as a method of pre-dispersion preparation for various dosage form developments. Nanotechnology produces nanomaterials with enhanced properties in terms of solubility, dissolution and permeability. In this work, ultrasonic-assisted precipitation was employed to produce nanosuspensions of poorly water-soluble loratadine, using different stabilizers. The objective of our study was attempting to prepare solid nanoparticles of loratadine to be used as a possible intermediate for designing various dosage forms. The effects of the type(s) and concentration(s) of stabilizer(s) on mean particle size were assessed. Optimal process parameters required to produce homogeneous nanoparticles with particle size below 500 nm and polydispersity less than 0.3 were determined both for precipitation and ultrasonication. Pre-dispersions were evaluated for their particle size, polydispersity index and zeta potential. Freeze-drying was employed to produce dry nanoparticles. Particle size, particle size distribution and zeta potential of the dried nanoparticles were measured after reconstitution in water. Besides thermal analysis using DSC and structural analyses (XRPD and FT-IR), the morphological characteristics and dissolution behaviors were also investigated. The selected freeze-dried nanoparticles had a mean particle size range of 353–441 nm, a polydispersity index ranging between 0.167 and 0.229 and a zeta potential between −25.7 and −20.7 mV. These results suggest that material and process parameters were successfully optimized. DSC and XRPD spectra confirmed interactions between the formulation's components during freeze-drying. The solid nanoparticles showed 30–42% of cumulative release after 10 min compared to less than 1% of dissolution characterizing loratadine without pre-processing. This study demonstrates that preparing dried loratadine nanoparticles suitable for designing effective drug preparations is a feasible approach.Graphical abstractUnlabelled Image
  • Microstructural characterization of papaverine-loaded HPC/PVA gels, films
           and nanofibers
    • Abstract: Publication date: 15 September 2018Source: European Journal of Pharmaceutical Sciences, Volume 122Author(s): Adrienn Kazsoki, Attila Domján, Károly Süvegh, Romána Zelkó Papaverine hydrochloride loaded gels, films and electrospun fibers were prepared for buccal drug delivery with the aim of improving the oral bioavailability of the crystalline drug, which can be achieved by the increased solubility and by the circumvention of the intensive first pass metabolism. The water soluble hydroxypropyl cellulose (HPC) was chosen as a mucoadhesive polymer. In order to improve the electrospinnability of HPC, the similarly mucoadhesive poly(vinyl alcohol) (PVA) was used. Since the drying of gels is of decisive role in either the formation of drug-loaded cast films or electrospun fibers, a real time ortho-positronium (o-Ps) tracking of gels was applied in order to obtain information about the supramolecular changes of the drying-induced gel-film transition. An anomalous increase of o-Ps lifetime value in the gel-film transition region was observed which refers to the remaining intramolecularly bound water in the drug-loaded polymeric gel matrix. The latter could provide information about the characteristics of polymer-water interactions in the phase transition, consequently the storage stability of the formulated solid system.Graphical abstractUnlabelled Image
  • Melatonin vitamin C-based nanovesicles for treatment of androgenic
           alopecia: Design, characterization and clinical appraisal
    • Abstract: Publication date: 15 September 2018Source: European Journal of Pharmaceutical Sciences, Volume 122Author(s): Shymaa Hatem, Maha Nasr, Noha H. Moftah, Maha H. Ragai, Ahmed S. Geneidi, Seham A. Elkheshen The present study aimed to develop vitamin C based nanovesicles (aspasomes) loaded with the antioxidant melatonin, as a novel cosmeceutical to be used for clinical treatment of androgenic alopecia (AGA). Aspasomes were assessed regarding their particle size, charge, drug entrapment, anti-oxidant potential, physical stability, in vitro release, surface morphology, and ex-vivo skin deposition. Clinically, melatonin aspasomes were tested on AGA patients, and assessed by evaluating the degree of improvement through conduction of hair pull test, histometric analysis and dermoscopic evaluation. Results revealed that melatonin aspasomes showed favorable pharmaceutical properties in addition to clinically promising results compared to melatonin solution, manifested by increased hair thickness, density and decreased hair loss, with photographic improvement in most patients. Therefore, melatonin vitamin C-based aspasomes were clinically auspicious in the treatment of AGA, hence, paving the way for their further exploration in other oxidative-dependent dermatological diseases.Graphical abstractUnlabelled Image
  • I-131 doping of silver nanoparticles platform for tumor theranosis guided
           drug delivery
    • Abstract: Publication date: 15 September 2018Source: European Journal of Pharmaceutical Sciences, Volume 122Author(s): Tamer M. Sakr, O.M. Khowessah, M.A. Motaleb, A. Abd El-Bary, M.T. El-Kolaly, Mohamed M. Swidan Nanotechnology may be applied in medicine where the utilization of nanoparticles (≤100 nm) for the delivery and targeting of theranostic agents is at the forefront of projects in cancer nano-science. This study points a novel one step synthesis approach to build up polyethylene glycol capped silver nanoparticles doped with I-131 radionuclide (131I-doped Ag-PEG NPs). The formula was prepared with average hydrodynamic size 21 nm, zeta potential – 25 mV, radiolabeling yield 98 ± 0.76%, and showed good in-vitro stability in saline and mice serum. The in-vitro cytotoxicity study of cold Ag-PEG NPs formula as a drug carrier vehicle showed no cytotoxic effect on normal cells (WI-38 cells) at a concentration below 3 μL/104 cells. The in-vivo biodistribution pattern of 131I-doped Ag-PEG NPs in solid tumor bearing mice showed high radioactivity accumulation in tumor tissues with maximum uptake of 35.43 ± 1.12 and 63.8 ± 1.3% ID/g at 60 and 15 min post intravenous (I.V.) and intratumoral injection (I.T.), respectively. Great potential of T/NT ratios were obtained throughout the experimental time points with maximum ratios 45.23 ± 0.65 and 92.46 ± 1.02 at 60 and 15 min post I.V. and I.T. injection, respectively. Thus, 131I-doped Ag-PEG NPs formulation could be displayed as a great potential tumor nano-sized theranostic probe.Graphical abstractUnlabelled Image
  • Synthesis of thiolated, PEGylated and POZylated silica nanoparticles and
           evaluation of their retention on rat intestinal mucosa in vitro
    • Abstract: Publication date: 15 September 2018Source: European Journal of Pharmaceutical Sciences, Volume 122Author(s): Twana Mohammed M. Ways, Wing Man Lau, Keng Wooi Ng, Vitaliy V. Khutoryanskiy In this study, we synthesised thiolated silica nanoparticles using 3-mercaptopropyltrimethoxysilane and functionalised them with either 5 kDa methoxy polyethylene glycol maleimide (PEG) or 5 kDa alkyne-terminated poly(2-ethyl-2-oxazoline) (POZ). The main objectives of this study are to investigate the effects of pH on the size and ξ-potential of these nanoparticles and evaluate their mucoadhesive properties ex vivo using rat intestinal mucosa. The sizes of thiolated, PEGylated and POZylated silica nanoparticles were 53 ± 1, 68 ± 1 and 59 ± 1 nm, respectively. The size of both thiolated and POZylated nanoparticles significantly increased at pH ≤ 2, whereas no size change was observed at pH 2.5–9 for both these two types of nanoparticles. On the other hand, the size of PEGylated nanoparticles did not change over the studied pH range (1.5–9). Moreover, thiolated nanoparticles were more mucoadhesive in the rat small intestine than both PEGylated and POZylated nanoparticles. After 12 cycles of washing (with a total of 20 mL of phosphate buffer solution pH 6.8), a significantly greater amount of thiolated nanoparticles remained on the intestinal mucosa than FITC-dextran (non-mucoadhesive polymer, p 
  • Phytosome complexed with chitosan for gingerol delivery in the treatment
           of respiratory infection: In vitro and in vivo evaluation
    • Abstract: Publication date: 15 September 2018Source: European Journal of Pharmaceutical Sciences, Volume 122Author(s): Rudra Pratap Singh, H.V. Gangadharappa, K. Mruthunjaya Respiratory infection is a viral spreading disease and a common issue, particularly in kids. The treatments are available but have so many limitations because the drawback of this disease is more morbidity and mortality in the severely immune compromised. Even, the phyto-constituent antibacterial drug Gingerol was selected to treat respiratory infection but it exhibits low bioavailability profile, less aqueous-solubility issue and most important is rapidly eliminated from the body. To overcome these problems, novel drug delivery (nanoparticle) based phytosome complexed with chitosan approach was implemented. In this research work, the phytosome (GP) was prepared by blending of gingerol with soya lecithin in organic solvent using anti-solvent precipitation technique and it was further loaded in the aqueous solution of chitosan to formulate the phytosome complexed with chitosan (GLPC). To optimize the formulations of gingerol, it was characterized for percentage yield, percentage entrapment efficiency, drug loading and particle size, physical compatibility studies etc. which demonstrated the confirmation of complex of GLPC with soya lecithin and chitosan. The % entrapment efficiency and % drug loading of GLPC was found (86.02 ± 0.18%, 08.26 ± 0.72%) and of GP (84.36 ± 0.42%, 08.05 ± 0.03%), respectively. The average particle size and zeta potential of GLPC and GP were 254.01 ± 0.05 nm (−13.11 mV), and 431.21 ± 0.90 nm (−17.53 mV), respectively which confirm the inhibition of particle aggregation by using chitosan in complex. The in vitro release rate of GP (86.03 ± 0.06%) was slower than GLPC (88.93 ± 0.33%) in pH 7.4 phosphate buffer up to 24 h by diffusion process (Korsmeyer Peppas model). The optimized GLPC and GP were shown irregular particle shapes & spherical and oval structures with smooth surface by SEM analysis. Furthermore, GLPC has shown the potent in vitro antioxidant activity, susceptible antibacterial activity and effective anti-inflammatory activity as compared to GP against stress, microbial infection and inflammation which were causable reason for the respiratory infections. GLPC has improved the significant bioavailability and also correlated the hematological values on rabbit blood against the incubation of microorganisms. Thus, the prepared nanoparticle based approach to deliver the gingerol, has the combined effect of chitosan and phytosome which shown better sustained-release profile and also prolonging the oral absorption rate of gingerol with effective antibacterial activity to treat respiratory infection.Graphical abstractUnlabelled Image
  • Inhibition of multidrug resistance-associated protein 2 (MRP2) activity by
           the contraceptive nomegestrol acetate in HepG2 and Caco-2 cells
    • Abstract: Publication date: 15 September 2018Source: European Journal of Pharmaceutical Sciences, Volume 122Author(s): Guillermo Nicolás Tocchetti, Camila Juliana Domínguez, Felipe Zecchinati, Maite Rocío Arana, María Laura Ruiz, Silvina Stella Maris Villanueva, Aldo Domingo Mottino, Johanna Weiss, Juan Pablo Rigalli Multidrug resistance-associated protein 2 (MRP2) plays a key role in hepatic and intestinal disposition of endo- and xenobiotics. Several therapeutic agents modulate MRP2 activity resulting in pharmacological interactions. Nomegestrol acetate (NMGA) is a progestogen increasingly used in contraceptive formulations. The aim of this work was to evaluate the effect of NMGA on MRP2 activity in HepG2 and Caco-2 cells as models of human hepatocytes and enterocytes, respectively. NMGA (5, 50 and 500 nM; 48 h) decreased MRP2-mediated transport of 2,4-dinitrophenyl-S-glutathione in HepG2 cells, with no effect on MRP2 protein expression. Acute exposure (1 h) to the same concentrations of NMGA failed to affect MRP2 activity, ruling out an inhibitory action directly induced by the drug. In contrast, acute incubation with a lysate of HepG2 cells pre-treated with NMGA, containing potential metabolites, reproduced MRP2 inhibition. Preincubation of lysates with sulfatase but not with β-glucuronidase abolished the inhibitory action, strongly suggesting participation of NMGA sulfated derivatives. Western blot studies in plasma vs. intracellular membrane fractions ruled out internalization of MRP2 to be responsible for the impairment of transport activity. MRP2-mediated transport of 5(6)-carboxy-2′,7′-dichlorofluorescein was not affected in Caco-2 cells incubated for 48 h with either 5, 50 or 500 nM NMGA. Conversely, acute exposure (1 h) of Caco-2 cells to NMGA-treated HepG2 lysates decreased MRP2 activity, being this effect also prevented by pre-treatment of the lysates with sulfatase. Taken together, these findings demonstrate an inhibitory effect of NMGA sulfated metabolites on hepatic and intestinal MRP2 function. Extrapolated to the in vivo situation, they suggest the possibility of pharmacological interactions with coadministered drugs.Graphical Unlabelled Image
  • Fast dissolving drug delivery membrane based on the ultra-thin shell of
           electrospun core-shell nanofibers
    • Abstract: Publication date: 15 September 2018Source: European Journal of Pharmaceutical Sciences, Volume 122Author(s): Jiao-Jiao Li, Yao-Yao Yang, Deng-Guang Yu, Qing Du, Xiang-Liang Yang Structural nanocomposites that provide fast dissolving drug release profiles are highly in demand in pharmaceutics. In this study, a poorly water-soluble drug such as quercetin or tamoxifen citrate (TC) was selected as a model active pharmaceutical ingredient. Core-shell nanofibers with ultra-thin shells were designed and prepared using modified coaxial electrospinning. Polyvinylpyrrolidone (PVP) K90 or Polycaprolactone (PCL) was selected as core. The drugs and PVP K10 were selected as shell. All types of solutions can be used as the shell fluids in modified coaxial process regardless of their electrospinnability, which means the increasing functional ingredients and unspinnable matrix can be processed. Evaluations via SEM and TEM demonstrated that the core-shell nanofibers had linear morphology with a shell thickness smaller than 100 nm. XRD and FTIR results showed that the model drug was distributed in the polymeric matrix amorphously and that PVP K10 had good compatibility with quercetin or TC. In vitro dissolution tests suggested that the core-shell nanofibers with ultra-thin shells released the loaded cargoes in the dissolution media within 1 min. The present investigation paved a new way for implementing the modified coaxial processes, which can be utilized to fabricate structural nanocomposites with ultra-thin shells for enhancing the fast dissolution of poorly water-soluble drugs.Graphical abstractUnlabelled Image
  • UV filter entrapment in mesoporous silica hydrogel for skin protection
           against UVA with minimization of percutaneous absorption
    • Abstract: Publication date: 15 September 2018Source: European Journal of Pharmaceutical Sciences, Volume 122Author(s): Yu-Chih Lin, Chwan-Fwu Lin, Ahmed Alalaiwe, Pei-Wen Wang, Yi-Ping Fang, Jia-You Fang The UVA absorbers such as avobenzone are widely used for sunlight protection; however, they show a significant skin penetration. The aim of the present study was to formulate UVA absorbers into mesoporous silicas (MSs) for enhanced UVA protection with reduced percutaneous absorption. Two MSs prepared with different structure-directing agents (Pluronic P123 as single MS and combined Pluronic P123-Pluronic F68 as hybrid MS) were synthesized in this study. The hybrid MS exhibited higher specific surface area (853 m2/g) than the single MS (764 m2/g). The particle sizes of single MS and hybrid MS were about 1 and 1.5 μm, respectively. The adsorbed avobenzone had greatly decreased crystallinity compared with free avobenzone. The in vitro photoprotection determined by UVA/UVB ratio showed that the MS-loaded avobenzone in hydrogel endowed a synergistic effect on UVA protection compared to the free avobenzone. The skin absorption test using Franz diffusion cell indicated that the skin permeation of avobenzone and oxybenzone from MSs in semisolid preparations was one-third to one-half of those from free control. This effect was observed by using both pig skin and UVA-damaged nude mouse skin as the penetration barriers. Topical application of hybrid MS on nude mouse skin before UVA irradiation had prevented the increased transepidermal water loss (TEWL), furrow formation, keratinocyte apoptosis, and neutrophil infiltration. Our findings conclude that MSs containing avobenzone or oxybenzone effectively ameliorated UVA-induced skin disruption and reduced the possible toxicity elicited by percutaneous penetration.Graphical abstractUnlabelled Image
  • Dexamethasone-diclofenac loaded polylactide nanoparticles: Preparation,
           release and anti-inflammatory activity
    • Abstract: Publication date: 15 September 2018Source: European Journal of Pharmaceutical Sciences, Volume 122Author(s): Mohyeddin Assali, Ramzi Shawahna, Safa' Dayyeh, Mays Shareef, Imad-Aldin Alhimony Inflammation is a nonspecific response of tissues to diverse stimuli and/or insults associated with the release of various mediators that induce pain, fever, and general sense of illness. Such responses can be reduced by the administration of non-steroidal or steroidal anti-inflammatory drugs. These anti-inflammatory drugs are associated with various side effect. However, the combination of non-steroidal anti-inflammatory drugs (NSAIDs) with glucocorticoids provides a synergistic anti-inflammatory and pain relief with less side effects. In this study, we aimed to synthesize a novel twin-drug of Dexamethasone-Diclofenac formulated into polylactide (PLA) nanoparticles to improve their solubility and provide a sustained release system. The twin-drug was synthesized through an esterification reaction which was then encapsulated into PLA nanoparticles. The hydrolysis of the synthesized twin-drug and drug release from PLA nanoparticles were studied in vitro with and without esterase enzyme. The anti-inflammatory activity was studied in BALB/c mice. After the successful synthesis of the twin-drug, its water solubility was improved by its encapsulation into PLA nanoparticles with a loading capacity of 66%. The in vitro release showed a sustained release profile of the twin-drug up to 52 h. The esterase hydrolysis showed a rapid release with a maximum hydrolysis after 1.5 h. Moreover, the anti-inflammatory activity exhibited a synergistic effect with a higher percentage of inhibition for the TNF-α level in comparison to the parent drugs after 6 h treatment. In conclusion, the prepared nano twin-drug is a novel therapy that showed a sustained release profile with an excellent anti-inflammatory activity.Graphical abstractUnlabelled Image
  • Population pharmacokinetics of valproic acid in epileptic children:
           Effects of clinical and genetic factors
    • Abstract: Publication date: 15 September 2018Source: European Journal of Pharmaceutical Sciences, Volume 122Author(s): Shansen Xu, Yanan Chen, Mingming Zhao, Yingjie Guo, Zhanyou Wang, Limei Zhao Valproic acid (VPA) is a first-line anti-epileptic drug that is used in the treatment of generalized and partial seizures. Gene variants had been proved to influence the pharmacokinetics (PK) of VPA and contribute to its inter-individual variability (IIV). The aim of this study was to systematically investigate the effects of candidate gene variants (CYPs, UGTs, ABC transporters, and nuclear receptors) on VPA PK in Chinese children with epilepsy. A total of 1065 VPA serum trough concentrations at steady state were collected from 264 epileptic pediatric patients aged 3 months to 16 years. The population pharmacokinetic (PPK) model was developed using a nonlinear mixed effects modelling (NONMEM) approach.For the final PPK model, the oral clearance (CL/F) of VPA was estimated to be 0.259 L/h with IIV of 13.3%. The estimates generated by NONMEM indicated that the VPA CL/F was significantly influenced by patient body weight (increased by an exponent of 0.662), co-administration with carbamazepine (increased CL/F by 22%), and daily dose of VPA (increased by an exponent of 0.22). CL/F in patients with the LEPR rs1137101 variant (668 AG and GG genotypes) was much lower than in patients with the AA genotype (17.8% and 22.6% lower, respectively). However, none of the CYPs or UGTs gene variants was found to influence the PK of VPA in this study. Evaluation by bootstrap and normalized prediction distribution error (NPDE) showed that the final model was stable. The predictive performance was evaluated by goodness-of-fit (GOF) plots and visual predictive checks (VPC), and the results indicated satisfactory precision. Our model suggests a correlation between VPA CL/F and LEPR rs1137101 variants, which might be beneficial in the context of individual dose optimization.Graphical abstractUnlabelled Image
  • Initial Risk Assessment as part of the Quality by Design in peptide drug
           containing formulation development
    • Abstract: Publication date: 15 September 2018Source: European Journal of Pharmaceutical Sciences, Volume 122Author(s): E. Pallagi, R. Ismail, T.L. Paál, I. Csóka Risk Assessment (RA) is the key element of the Quality by Design (QbD) approach recommended by the pharmaceutical regulatory bodies. This research paper aimed to implement the regulatory requirements, the QbD thinking and the RA from the first steps of the oral peptide formulation development. The authors intended to give a general recommendation about the application possibilities of this methodology, to demonstrate the risk factors and the required decision points. Later, this paper presents a concrete development in practice. This case study shows the QbD and RA based early phase development of the GLP 1 analog, Liraglutide, an antidiabetic peptide drug mainly used in the treatment of type 2 Diabetes Mellitus. The objective here was to design Liraglutide encapsulated polymeric nanoparticles for oral delivery and the progress of their RA based development is presented. In this case, the particle size, the encapsulation efficiency, and the drug loading were found as the most critical quality attributes, the polymer concentration, the drug concentration, the w2/o ratio, the stabilizer concentration and polymer type were identified by the criticality rating as having the greatest impact on the product quality among the critical material attributes, finally the sonication time and sonication power were selected as the most critical elements of the production process. The results showed the importance of the risk factor-focused development in the oral peptide pharmaceutical formulations, and underlined the importance of the profound planning phase even in such cases. The formulation of an oral peptide delivery system is associated with several risks, but their priority ranking helps to focus on the resources (human, financial, time) related to the final product quality aimed at.Graphical abstractUnlabelled Image
  • Interspecies comparison of putative ligand binding sites of human, rat and
           mouse P-glycoprotein
    • Abstract: Publication date: 15 September 2018Source: European Journal of Pharmaceutical Sciences, Volume 122Author(s): Sankalp Jain, Melanie Grandits, Gerhard F. Ecker Prior to the clinical phases of testing, safety, efficacy and pharmacokinetic profiles of lead compounds are evaluated in animal studies. These tests are primarily performed in rodents, such as mouse and rats. In order to reduce the number of animal experiments, computational models that predict the outcome of these studies and thus aid in prioritization of preclinical candidates are heavily needed. However, although computational models for human off-target interactions with decent quality are available, they cannot easily be transferred to rodents due to lack of respective data. In this study, we assess the transferability of human P-glycoprotein activity data for development of in silico models to predict in vivo effects in rats and mouse using a structure-based approach. P-glycoprotein (P-gp) is an ATP-dependent efflux transporter that transports xenobiotic compounds such as toxins and drugs out of cells and has a broad substrate and inhibitor specificity. Being mostly expressed at barriers, it influences the bioavailability of drugs and thus contributes also to toxicity. Comparison of the binding site interaction profiles of human, rat and mouse P-gp derived from docking studies with a set of common inhibitors suggests that the inhibitors share potentially similar binding modes. These findings encourage the use of in vitro human P-gp data for predicting in vivo effects in rodents and thus contributes to the 3Rs (Replace, Reduce and Refine) of animal experiments.Graphical abstractUnlabelled Image
  • Pharmacokinetic and pharmaceutical properties of a novel
           buprenorphine/naloxone sublingual tablet for opioid substitution therapy
           versus conventional buprenorphine/naloxone sublingual tablet in healthy
    • Abstract: Publication date: 15 September 2018Source: European Journal of Pharmaceutical Sciences, Volume 122Author(s): Martin Jönsson, Gill Mundin, Michael Sumner PurposeA novel sublingual buprenorphine/naloxone rapidly-dissolving tablet (BNX-RDT) for opioid substitution therapy has been developed for improved bioavailability, rapid disintegration and improved taste masking. We compared the bioavailability and pharmaceutical properties of BNX-RDT with conventional buprenorphine/naloxone sublingual tablets (BNX).MethodsFasting, open-label, randomized, single-dose, two-cohort crossover study in healthy volunteers under naltrexone block. Cohort 1 (high-dose, N = 64) received BNX-RDT 11.4/2.9 mg and BNX 16/4 mg. Cohort 2 (low-dose, N = 61) received BNX-RDT 2.9/0.71 mg and BNX 4/1 mg. Plasma samples were collected over 72 h. Relative systemic exposures of buprenorphine and naloxone were assessed using standard statistical models for bioequivalence analysis. Pharmaceutical assessments included dissolve time, taste and mouthfeel assessments, and overall preference.ResultsBNX-RDT 11.4/2.9 mg provided equivalent buprenorphine and naloxone exposure to BNX 16/4 mg. BNX-RDT 2.9/0.71 mg provided ~20% lower buprenorphine and 35% lower naloxone exposure compared with BNX 4/1 mg. The comparison of BNX-RDT 2.9/0.71 mg with BNX 4/1 mg did not fully meet equivalence criteria. BNX-RDT was associated with improved dose proportionality across strengths compared with BNX (post hoc analysis), resulting in lower exposure from BNX-RDT relative to BNX at the lower strength. Median perceived dissolve times were significantly shorter for BNX-RDT than BNX at high (8.5 versus 16.2 min) and low (7.6 versus 9.1 min) doses. Taste and mouthfeel were rated significantly more pleasant than BNX, with ~78% of subjects preferring BNX-RDT.ConclusionBNX-RDT provided improved buprenorphine absorption compared to a conventional sublingual tablet, with shorter dissolve times and improved taste and mouthfeel, resulting in a high preference for the novel formulation.Graphical abstractUnlabelled Image
  • Investigation of molecular mobility of pressure-sensitive-adhesive in
           oxybutynin patch in vitro and in vivo: Effect of sorbitan monooleate on
           drug release and patch mechanical property
    • Abstract: Publication date: 15 September 2018Source: European Journal of Pharmaceutical Sciences, Volume 122Author(s): Wei Wang, Chao Liu, Zheng Luo, Xiaocao Wan, Liang Fang The aim of present study was to develop an oxybutynin (OXY) transdermal patch with good permeation behavior and mechanical property. Special attention was paid to the effect of chemical enhancer on the molecular mobility of pressure sensitive adhesive (PSA) at molecular level. PSAs and permeation enhancers were investigated through in vitro experiment using rat skin. The optimized formulation was evaluated through pharmacokinetic study using rat. In addition, the molecular mechanism of sorbitan monooleate (Span® 80) in the improvement of PSA molecular mobility was investigated using FT-IR, molecular dynamics simulation, DSC and rheological study. As a result, the optimized formulation using amide PSA demonstrated good adhesion property. And the AUC0-t and Cmax of optimized patch were 6435.8 ± 747.8 h ∗ ng/mL and 127.8 ± 18.0 ng/mL, respectively, which had no significant difference with commercial product. Furthermore, the improvement of the PSA mobility by Span® 80 rather than the decrease of interaction between drug and PSA was the main factor that enhanced the release of OXY from patch. In conclusion, a drug-in-adhesive OXY patch was developed, and the effect of PSA molecular mobility increase on the enhancement of drug skin permeation was proposed at molecular level.Graphical abstractUnlabelled Image
  • Understanding effects of process parameters and forced feeding on die
    • Abstract: Publication date: 15 September 2018Source: European Journal of Pharmaceutical Sciences, Volume 122Author(s): Hui Ping Goh, Paul Wan Sia Heng, Celine Valeria Liew Die filling is a critical step during pharmaceutical tablet production and is still not well understood due to the rather complex interplay between particle attributes, die orifice diameter and fill energetics. While shoe-die filling models have been used to simulate die filling conditions, they typically lack the sophistication of the actual production-scale, feeder-based die filling conditions. The relationship between tableting process parameters and filling into die orifices of different diameters by powders of different flowabilities requires critical examination and understanding. In this study, a special die filling contraption was designed and custom-made to simulate the effects of gravity, suction and feeder paddle assistance as present in modern rotary tablet presses. Die fill performance was studied using powders with different flow properties. Suction impact was greatest on die fill, in particular, for small orifice diameters and less permeable powders. Effect of paddle velocity on die fill was greater for compressible powders and larger orifice diameters. In comparison to suction and paddle velocity, forced feeding did not significantly affect die fill performance. Relationship between process parameters and die fill performance was found to be highly dependent on the material and orifice diameter.Graphical abstractUnlabelled Image
  • Charged cyclic hexapeptides: Updating molecular descriptors for
           permeability purposes
    • Abstract: Publication date: 15 September 2018Source: European Journal of Pharmaceutical Sciences, Volume 122Author(s): G. Ermondi, M. Vallaro, M.P. Camacho-Leal, T. Potter, S. Visentin, G. Caron Three polar cyclic hexapeptides differently charged at physiological pH (1 = neutral, 2 = anionic, 3 = cationic) were synthesized and their cell permeability measured. Lipophilicity in octanol/water didn't account for the higher permeability of the cationic derivative but three chromatographic indexes (log KwIAM, log k′ HILIC and log k′ c-HILIC) were more efficient to this respect. NMR amide chemical shift temperature coefficients (ΔδNH/ΔT) were used to explore the IMHB network of the backbone. MD simulations in different environments (water, chloroform and DMPC lipid bilayer) highlighted that the charged amino group of the lysine moiety of 3 is not involved in the formation of any IMHB in water whereas a different behavior is registered in chloroform and DMPC lipid bilayer. Overall this paper highlights how a combination of experimental and computational approaches could help in comparing permeability and physicochemical properties of neutral and charged cyclic peptides.Graphical abstractUnlabelled Image
  • Design and characterization of emulsified spray dried alginate
           microparticles as a carrier for the dually acting drug roflumilast
    • Abstract: Publication date: 15 September 2018Source: European Journal of Pharmaceutical Sciences, Volume 122Author(s): Azza A. Mahmoud, Nermeen A. Elkasabgy, Abdelfattah A. Abdelkhalek Roflumilast is a selective inhibitor of phosphodiesterase-4 isoenzyme in lung cells. Having psychiatric adverse reactions when administered orally affects negatively the patients' adherence to the drug. This work aimed to prepare emulsified spray dried alginate microparticles for the pulmonary delivery of roflumilast. Sodium alginate was used as microparticle-forming material, isopropyl myristate as an oil, Tween®80 as surfactant and calcium beta-glycerophosphate as cross-linking agent to enhance the mechanical properties of the particles. The prepared particles were evaluated for their encapsulation efficiency, particle size and in-vitro drug release. From the studied carriers, beta-cyclodextrin (CD) was the best regarding giving formulation with smaller particle size and more sustained drug release. The inhalation profile of CD-based microparticles was investigated using Anderson cascade impactor. The aerosolization profile of CD-based microparticles suggested their efficiency to deliver the drug deep in the lung. The CD-based microparticles possessed more inhibitory effects on the viability of A549 cells and on the pro-inflammatory cytokines (TNF-α, IL-6 and IL-10) compared to the pure drug. Hence, CD-based microparticles could regulate the tumorigenesis besides tumor-associated inflammation. Finally, CD-based microparticles showed more sustained bronchodilatation properties in healthy human volunteers when compared to Ventolin®HFA. CD-based microparticles proved to be a promising carrier for inhaled roflumilast in human.Graphical abstractUnlabelled Image
  • Liposils: An effective strategy for stabilizing Paclitaxel loaded
           liposomes by surface coating with silica
    • Abstract: Publication date: 15 September 2018Source: European Journal of Pharmaceutical Sciences, Volume 122Author(s): Subhash G. Ingle, Rohan V. Pai, Jasmin D. Monpara, Pradeep R. Vavia The present work aims at improving stability of paclitaxel (PTX) loaded liposomes by its coating with silica on the surface by a modified sol-gel method. Effect of various components of liposomes such as phosphatidylcholine to cholesterol ratio (PC:CH), PTX and stearylamine on entrapment efficiency (% EE) and particle size were systematically investigated and optimized using central composite design on Design-Expert®. The optimized liposomes were utilized as a template for silica coating to prepare surface coated PTX liposils. Physical stability of liposomes and liposils was evaluated with Triton X-100 and the results indicated that liposils were much more stable as compared to liposomes and the same has been reiterated in stability study performed over 6 months. In vitro cytotoxicity study on B16F10 tumor cells showed cytotoxicity of PTX liposils was not significantly different than PTX liposomes, whereas both were less cytotoxic as compared to the commercial Taxol®. In vivo pharmacokinetics on rats, exhibited increased T1/2 of liposils when compared to liposomes and Taxol®, thus releasing the drug over a longer duration. The enhanced physicochemical stability as well as controlled release of PTX in liposils developed in this study could be an effective alternative to Taxol® and PTX liposomes.Graphical abstractUnlabelled Image
  • Multivalent targeting and killing of HER2 overexpressing breast carcinoma
           cells with methotrexate-encapsulated tetra-specific non-overlapping
           variable domain heavy chain anti-HER2 antibody-PEG-liposomes: In vitro
    • Abstract: Publication date: 15 September 2018Source: European Journal of Pharmaceutical Sciences, Volume 122Author(s): Shahryar Khoshtinat Nikkhoi, Fatemeh Rahbarizadeh, Davoud Ahmadvand, Seyed Moein Moghimi The variable domain of the heavy chain antibodies (VHHs) is the smallest (15 kDa) intact single domain antigen-binding fragment. VHHs often exhibit sub-nanomolar affinity for their designated targets and therefore are receiving increasing attention in molecular targeting and nanomedicine engineering. We cloned and expressed four non-overlapping anti-HER2 VHHs in a prokaryotic expression system that yielded disulfide-bonded VHHs. Purified VHHs, before and after thiolation, were characterized by Western blot and their functionality against the ecto-domain of HER2 receptor was confirmed by ELISA and flow cytometry. Thiolated VHHs were conjugated to the reactive maleimide-PEG2000-distearoylphosphatidylethanolamine incorporated into the bilayer of small unilamellar vesicles. We show high target-binding avidity and efficient cytotoxicity of optimized tetra-specific multivalent methatoraxate-loaded VHH-PEG-liposomes (55–60 VHH/vesicle) in HER2 over-expressing breast carcinoma cell lines compared with the best performing monoclonal VHH conjugated vesicles of identical VHH surface density. The VHH expression and production methodology as well as the synergistic effect of the four non-overlapping VHHs in HER2 binding provides an efficient approach for design and engineering of anti-cancer nanomedicines and their future applications within the context of personalized and precision therapies and diagnostics are discussed.Graphical abstractUnlabelled Image
  • Antiparasitic activity of new gibbilimbol analogues and SAR analysis
           through efficiency and statistical methods
    • Abstract: Publication date: 15 September 2018Source: European Journal of Pharmaceutical Sciences, Volume 122Author(s): Marina T. Varela, Maiara M. Romaneli, Marta L. Lima, Samanta E.T. Borborema, Andre G. Tempone, João P.S. Fernandes Chagas' disease and leishmaniasis are parasitic infections enrolled among the neglected tropical diseases, which urge for new treatments. In the search for new chemical entities as prototypes, gibbilimbols A/B have shown antiparasitic activity against Trypanosoma cruzi and Leishmania infantum, and then a set of analogues (LINS03 series) of this natural product were synthesized and evaluated in vitro against the parasites. In the present paper we reported five new compounds with activity against these protozoan parasites, and quite low cytotoxicity. Moreover, the interference of plasma membrane permeability of these analogues were also evaluated. We found that [(4-methoxyphenyl)methyl]octylamine (4) was noteworthy due to its high activity against the amastigote form of both parasites (IC50 1.3–5.8 μM) and good selectivity index. In order to unveil the SAR for this chemotype, we also presented a group efficiency analysis and PCA and HCA study, which indicated that the methoxyl provides good activity with lower cytotoxicity to mammalian cells. The results from SAR analyses suggest different mechanisms of action between the neutral and basic compounds. In summary, the analogues represent important activity against these parasites and must be prototypes for further exploitation.Graphical abstractUnlabelled Image
  • Optimization of nanostructured lipid carriers for Zidovudine delivery
           using a microwave-assisted production method
    • Abstract: Publication date: 15 September 2018Source: European Journal of Pharmaceutical Sciences, Volume 122Author(s): S.M.T. Cavalcanti, C. Nunes, S.A. Costa Lima, J.L. Soares-Sobrinho, S. Reis An adapted methodology for obtaining lipid nanoparticles that only uses the microwave reactor in the synthesis process was developed. The method has the following features: one-pot, one-step, fast, practical, economical, safe, readiness of scaling-up, lack of organic solvents and production of nanoparticles with low polydispersity index (PDI) (below 0.3).This new method was applied for the development of nanostructured lipid carriers (NLC) loaded with a hydrophilic drug, the antiretroviral agent zidovudine (AZT). The aim of the present work was to develop, evaluate and compare optimized NLC formulations produced by two different methods – hot ultrasonication and microwave-assisted method. The development and optimization of the NLC formulations were supported by a Quality by Design (QbD) approach.All formulations were physicochemically characterized by the same parameters. The optimized formulations presented a suitable profile for oral administration (particle size between 100 and 300 nm, PDI −20 mV). Furthermore, the morphologies assessed by TEM showed spherical shape and confirmed the results obtained by DLS. Both AZT loaded formulations were physically stable for at least 45 days and non-toxic on Jurkat T cells. Drug release studies showed a controlled release of AZT under gastric and plasma-simulated conditions.Graphical abstractUnlabelled Image
  • Rapid Bioavailability and Disposition protocol: A novel higher throughput
           approach to assess pharmacokinetics and steady-state brain distribution
           with reduced animal usage
    • Abstract: Publication date: 15 September 2018Source: European Journal of Pharmaceutical Sciences, Volume 122Author(s): Tingting Fu, Ruina Gao, Paul Scott-Stevens, Yan Chen, Chalmers Zhang, Jianfei Wang, Scott Summerfield, Houfu Liu, Jasminder Sahi Besides routine pharmacokinetic (PK) parameters, unbound brain-to-blood concentration ratio (Kp,uu) is an index particularly crucial in drug discovery for central nervous system (CNS) indications. Despite advantages of Kp,uu from steady state after constant intravenous (i.v.) infusion compared with one- or multiple time points after transient dosing, it is seldom obtained for compound optimization in early phase of CNS drug discovery due to requirement of prerequisite PK data to inform the study design. Here, we designed a novel rat in vivo PK protocol, dubbed as Rapid Bioavailability and Disposition (RBD), which combined oral (p.o.) dosing and i.v. infusion to obtain steady-state brain penetration, along with blood clearance, oral exposure and oral bioavailability for each discovery compound, within a 24 hour in-life experiment and only a few (e.g., 3) animals. Protocol validity was verified through simulations with a range of PK parameters in compartmental models as well as data comparison for nine compounds with distinct PK profiles. PK parameters (Kp,brain, CLb and oral AUC) measured from the RBD protocol for all compounds, were within two-fold and/or statistically similar to those derived from conventional i.v./p.o. crossover PK studies. Our data clearly indicates that the RBD protocol offers reliable and reproducible data over a wide range of PK properties, with reduced turnaround time and animal usage.Graphical abstractUnlabelled Image
  • Material distributions and functional structures in probiotic
    • Abstract: Publication date: 15 September 2018Source: European Journal of Pharmaceutical Sciences, Volume 122Author(s): Li Wu, Wei Qin, Yuanzhi He, Weifeng Zhu, Xiaohong Ren, Peter York, Tiqiao Xiao, Xianzhen Yin, Jiwen Zhang Smart microstructure design of dosage forms such as microcapsules that protect the microorganism, can improve probiotics survival from gastric pH challenges and prolong their shelf life. In this study, synchrotron radiation X-ray microcomputed tomography (SR-μCT) was applied to quantitatively reveal the material distributions and functional structures of bifidobacterium and lactobacillus microcapsules. The shell layer, middle protective layer, and the microorganisms as particles in the center layer were extracted and visualized. All the microorganisms were encapsulated by the shell completely, which prevents them from being destroyed by external environments. However, the non-uniform thickness of the shell and typical defects in the microcapsules were observed. The quantitative analysis and characterization of internal microstructures provide evidence of the need for further improvement in formulations and processing technologies for the structured system to deliver living microorganisms.Graphical abstractUnlabelled Image
  • Bioequivalence of topical generic products. Part 2. Paving the way to a
           tailored regulatory system
    • Abstract: Publication date: 15 September 2018Source: European Journal of Pharmaceutical Sciences, Volume 122Author(s): Margarida Miranda, João José Sousa, Francisco Veiga, Catarina Cardoso, Carla Vitorino Hitherto, for the approval of a topical generic drug product, the majority of the regulatory agencies require clinical endpoint studies to prove its therapeutic equivalence in relation to a reference product. Pharmacodynamic studies are also available to support bioequivalence, however, these are solely applicable for corticosteroids. The first strategy is considered the “gold standard”, since it can be applied to all drug products. Nevertheless, the high variability intrinsic to topical drug delivery makes this analysis relatively insensitive, costly, time-consuming, besides requiring a large number of subjects. There are, however, alternative methods capable of providing a more rigorous analysis and requiring a lower cost. Amongst them, in vitro methods have sparked considerable attention, not only in the academic field, but also in the pharmaceutical industry and regulatory agencies.In this context, this review attempts to discuss the main regulatory constraints and the recent advances in the regulatory science of topical generic drugs bioequivalence assessment. Initiatives, such as the Strawman decision tree and the topical drug classification system are specially referred, since these highlight the importance of establishing a broader concept of pharmaceutical equivalence for topical generic drugs, similar to the one already set for orally administered conventional dosage forms, such as tablets and capsules.Finally, the FDA Product-Specific Guidances for Generic Drug Development released for topical products in recent years and particular European Public Assessment Reports are presented and discussed, to illustrate the change of paradigm which is occurring in this regulatory field.Graphical abstractUnlabelled Image
  • Dermal flurbiprofen nanosuspensions: Optimization with design of
           experiment approach and in vitro evaluation
    • Abstract: Publication date: 15 September 2018Source: European Journal of Pharmaceutical Sciences, Volume 122Author(s): Ayse N. Oktay, Alptug Karakucuk, Sibel Ilbasmis-Tamer, Nevin Celebi Flurbiprofen (FB) is the one of the non-steroidal anti-inflammatory drugs (NSAIDs) which has low water solubility and dissolution. Nanosuspensions are promising drug delivery systems consisting pure drug particles to overcome poor water solubility issues. Recently, design of experiment (DoE) approaches have often been used to develop new formulations include nanosuspensions. The main objective of this study was to prepare FB nanosuspensions in existence of Plantacare 2000 (PL) as stabilizer using DoE approach to evaluate the critical formulation attributes (CFAs) and critical process parameters (CPPs). Particle size, particle size distribution and zeta potential values were selected as dependent variables and FB%, FB: PL and homogenization cycles were independent variables. Both 23 and 33 factorial designs were used to achieve optimum nanosuspension formulation. The final nanosuspension was freeze-dried and then crystalline state, morphological and thermal properties were investigated using X-ray diffraction, scanning electron microscopy and differential scanning calorimetry, respectively. The saturation solubility studies of nanosuspensions were conducted in comparison with the coarse powder and the physical mixture. The in vitro permeation of nanosuspension and FB solution were determined through dialysis membrane and rat skin. The particle size, polydispersity index and zeta potential values were found to range 665 nm–700 nm, 0.200–0.300 and approximately −30 mV, respectively. Nanosuspensions were obtained with spherical shape and no polymorphic or crystalline state change were observed. The saturation solubility of FB was 5.3 fold increased in nanosuspension formulation. Permeability of FB nanosuspension was higher than FB solution in rat skin. It was concluded that the DoE approach is a useful tool to prepare FB nanosuspensions and nanosuspensions benefit to improve water solubility and dermal permeation of Biopharmaceutical Classification System (BCS) Class II drugs.Graphical abstractUnlabelled Image
  • Acute and chronic escitalopram alter EEG gamma oscillations differently:
           relevance to therapeutic effects
    • Abstract: Publication date: 30 August 2018Source: European Journal of Pharmaceutical Sciences, Volume 121Author(s): Noémi Papp, Szilvia Vas, Emese Bogáthy, Zita Kátai, Diána Kostyalik, György Bagdy Brain oscillations in the gamma frequency band of the electroencephalogram (EEG) have been implicated in several sensory and cognitive processes, and have also been associated with numerous neuropsychiatric disorders, including depression. The widely prescribed selective serotonin reuptake inhibitors (SSRIs), similarly to other antidepressants, are known to produce markedly different effects on sleep and behavioral measures with acute and chronic administration. Although there are studies examining the acute effect of escitalopram on slower (30 Hz) in different sleep-wake stages, particularly comparing the acute and chronic effects of the drug concerning gamma oscillations. Our aim was to investigate, how escitalopram affects gamma power in different sleep-wake stages, and to discover possible differential effects between acute and chronic treatment. EEG-equipped Wistar rats were treated with escitalopram or vehicle acutely (10 mg/kg, i.p.) or chronically (10 mg/kg/day for 21 days, osmotic minipumps) and frontoparietal EEG, electromyogram and motor activity were recorded during the first 3 h of passive phase. We found that acute and chronic escitalopram treatment affected gamma oscillations differently. While acute escitalopram caused a reduction in gamma power during rapid eye movement sleep (REMS) and intermediate stage of sleep (IS), chronic treatment caused an elevation in gamma power during non-REMS stages, namely in light and deep slow-wave sleep (SWS-1 and SWS-2, respectively) and in IS. However, gamma activity during active and passive wakefulness (AW and PW, respectively) was not influenced by either acute or chronic dosing of escitalopram. Furthermore, we found that in drug-free (vehicle-treated) rats, a relatively high gamma power was present during wakefulness and REMS, while a much lower power was measured during non-REMS stages. These findings indicate that acute and chronic administration of escitalopram alter gamma activity differently, moreover, in a sleep-wake stage dependent manner that may be related to differential therapeutic and/or side effects.Graphical abstractUnlabelled Image
  • Application of hydroxypropyl methylcellulose as a protective agent against
           magnesium stearate induced crystallization of amorphous itraconazole
    • Abstract: Publication date: 30 August 2018Source: European Journal of Pharmaceutical Sciences, Volume 121Author(s): B. Démuth, D.L. Galata, A. Balogh, E. Szabó, B. Nagy, A. Farkas, E. Hirsch, H. Pataki, T. Vigh, J. Mensch, G. Verreck, Z.K. Nagy, G. Marosi Itraconazole is a fungicide drug which has low bioavailability due to its poor water solubility. Amorphous solid dispersion (ASD) is a tool that has the potential to greatly increase the dissolution rate and extent of compounds. In this work, the dissolution of tablets containing the ASD of itraconazole with either hydroxypropyl methylcellulose (HPMC) or vinylpyrrolidone-vinyl acetate copolymer (PVPVA) was compared in order to find a formulation which can prevent the drug from the precipitation caused by magnesium stearate. Formulations containing the PVPVA-based ASD with HPMC included in various forms could reach 90% dissolution in 2 h, while HPMC-based ASDs could release 100% of the drug. However, HPMC-based ASD had remarkably poor grindability and low bulk density, which limited its processability and applicability. The latter issue could be resolved by roller compacting the ASD, which significantly increases the bulk density and the flowability of the powder blends used for tableting. This roller compaction step might be a base for the industrial application of HPMC-based, electrospun ASDs.Graphical abstractUnlabelled Image
  • Semisolid self-microemulsifying drug delivery systems (SMEDDSs): Effects
           on pharmacokinetics of acyclovir in rats
    • Abstract: Publication date: 30 August 2018Source: European Journal of Pharmaceutical Sciences, Volume 121Author(s): Ljiljana Djekic, Jovana Janković, Aleksandar Rašković, Marija Primorac Semisolid self-microemulsifying drug delivery system (SMEDDS) with optimized drug loading capacity, stability, dispersibility in aqueous media and in vitro drug release profile, was evaluated in vivo regarding effects on pharmacokinetics of acyclovir, an antiviral with low bioavailability (BA) and short half-life (t1/2). Additional goal of this study was evaluation of safety of this semisolid SMEDDS consisted of medium chain length triglycerides (oil) (10% w/w), macrogolglycerol hydroxystearate (surfactant) (56.25% w/w), polyglyceryl-3-dioleate (cosurfactant) (6.25% w/w), glycerol (cosolvent) (20% w/w), macrogol 8000 (viscosity modifier) (7.5% w/w), and acyclovir (2.5 mg/ml). The study was performed on fully mature white male Wistar rats. The pharmacokinetics of acyclovir was monitored in three groups (1–3) of animals after administration of drug solution (intravenously (IV)), drug suspension (orally) and semisolid SMEDDS (orally), respectively. The determined pharmacokinetic parameters were: maximum concentration of acyclovir in serum (Cmax), time taken to reach Cmax (Tmax), areas under time-concentration curves (AUC0–t and AUC0–∞), terminal elimination rate constant (kel), t1/2, volume of distribution (Vd), mean residence time (MRT), clearance (Cl), zero concentration (C0), steady state volume of distribution (Vss), and BA. Additionally, for safety evaluation, animals were treated orally with aqueous solution of acyclovir, drug-free semisolid SMEDDS and acyclovir-loaded semisolid SMEDDS, during 21 days (groups 4–7). Serum samples of sacrificed animals were used for biochemical analysis of enzymatic activity of alanine transaminase (ALT) and aspartate transaminase (AST), urea, creatinine, and uric acid. Acyclovir administered by semisolid SMEDDS reached twice higher Cmax (0.92 ± 0.21 μg/ml) and has significantly shorter Tmax (14 ± 10.84 min) compared to the suspension of acyclovir (Cmax 0.29 ± 0.09 μg/ml and Tmax 26.00 ± 5.48 min). BA of the drug was significantly increased by semisolid SMEDDS, while the analysis of biochemical parameters excluded damage on function of liver and kidneys caused by the investigated drug delivery system.Graphical abstractUnlabelled Image
  • Melt-electrospinning as a method to improve the dissolution and physical
           stability of a poorly water-soluble drug
    • Abstract: Publication date: 30 August 2018Source: European Journal of Pharmaceutical Sciences, Volume 121Author(s): Kristian Semjonov, Andres Lust, Karin Kogermann, Ivo Laidmäe, Sirkka Liisa Maunu, Sami-Pekka Hirvonen, Jouko Yliruusi, Gunnar Nurk, Enn Lust, Jyrki Heinämäki The present study introduces a modified melt-electrospinning (MES) method for fabricating the melt-electrospun fibers (MSFs) of a poorly water-soluble drug and carrier polymer. The MES of poorly water-soluble model drug indomethacin (IND) and hydrophilic carrier polymer, Soluplus® (SOL) were prepared at a 1:3 drug-polymer weight ratio. Water was used as an external plasticizer to regulate a MES processing temperature and to improve fiber formation. The fiber size, surface morphology, physical solid state, drug-polymer (carrier) interactions, thermal and chemical stability and dissolution behavior of MSFs were investigated. Solid state nuclear magnetic resonance spectroscopy (NMR) was used to measure T1(1H), and the domain size of IND in MSFs (25–100 nm) was calculated from these results. Solid-state and thermal analysis confirmed the presence of amorphous solid dispersions of IND and SOL. IND was found to be chemically stable during an entire MES process. Only small drug content variability of different MSF batches was detected with high performace liquid chromatography (HPLC). Given findings were verified with the liquid NMR spectroscopy. The dissolution of MSFs was significantly faster than that of physical mixtures (PMs) or pure drug. The enhanced dissolution of MSFs was caused by high surface area, amorphous state of the drug and solubilizing properties of the carrier polymer (SOL).Graphical abstractUnlabelled Image
  • Development of probiotic-loaded microcapsules for local delivery: Physical
           properties, cell release and growth
    • Abstract: Publication date: 30 August 2018Source: European Journal of Pharmaceutical Sciences, Volume 121Author(s): Janja Mirtič, Tomaž Rijavec, Špela Zupančič, Alenka Zvonar Pobirk, Aleš Lapanje, Julijana Kristl The delivery of probiotics to different sites of action within the human body might help to prevent and treat several diseases. Here, we describe a microcapsule-based system for delivery of probiotic bacteria, as vegetative cells or spores, which promotes their prolonged survival and efficient revival, and successful colonisation of the target surface. This system is proposed for local delivery into periodontal pockets. Encapsulation of the probiotic bacteria was based on alginate crosslinking with calcium ions. This was performed by prilling the polymer dispersion supplemented with the probiotic using membrane vibration technology, followed by chitosan coating by polyelectrolyte complexation. The microcapsules were 120–150 μm in diameter, and were dried by lyophilisation. The chitosan coating increased the specific surface area and improved the bioadhesion potential, with no negative impact on viability and growth kinetics of the probiotic bacteria. Chitosan represents a barrier, which promotes sustained release of the probiotic bacteria. Vegetative bacteria were encapsulated at 2 × 108 CFU/g dry microcapsules, which represented ~5% of the prepared microcapsules, with stable viability for at least 2 months. Encapsulation of bacterial spores was greater, at 2 × 1010 CFU/g dry microcapsules, achieving 100% of microcapsules with incorporated revivable spores.Graphical abstractUnlabelled Image
  • Construction and biological evaluation of different self-assembled
           nanoarchitectures of FZU-03,010
    • Abstract: Publication date: 30 August 2018Source: European Journal of Pharmaceutical Sciences, Volume 121Author(s): Tingting Lv, Liang Xu, Guolin Wu, Cailong Li, Yibo Wen, Tao Zhang, Yu Gao, Haijun Chen Chemotherapy is currently one of the promising therapeutic methods for non-small-cell lung cancer (NSCLC), but the emergence of multidrug resistance (MDR) is the greatest obstacle to efficient drug delivery for successful chemotherapy. Nanotechnology-based drug delivery holds great promise to promote intracellular drug delivery to reverse MDR. In this work, we used our previously synthesized ursolic acid (UA) derivative, FZU-03,010 (F3), to prepare nanodrugs of F3 with different architectures and study the role of the structure on the physiochemical properties and the biological effects against A549 and its PTX-resistant A549/PTX lung cancer cells. Using different preparation methods, amphiphilic F3 could self-assemble into different structures such as nanoaggregates (F3-NA), vesicles (F3-VC), or nanoparticles (F3-NP) with different physiochemical properties. The self-assembled nanodrugs could be utilized for the entrapment of fluorophores and showed different cellular uptake efficiencies. The cytotoxicity results demonstrated that compared with UA, F3-NA and F3-NP could suppress A549 and A549/PTX cells viability more potently at lower concentration. In addition, F3-NA and F3-NP could induce G1 cell cycle arrest, cell apoptosis and caspase-3 activation more efficiently than that of UA. Furthermore, F3-NA and F3-NP could effectively inhibit PI3K/Akt pathway and decrease the expression of Bcl-2 and the cell cycle-dependent kinase inhibitors p-ERK1/2 and Cyclin D1 in both A549 and A549/PTX cells. In conclusion, our results suggest that the UA derivative F3 is more potent in inhibiting cancer cell proliferation, and F3-NA and F3-NP have the potential to be developed as a therapeutic agent for resistant NSCLC cells.Graphical Unlabelled Image
  • Human intestinal fluid factors affecting intestinal drug permeation in
    • Abstract: Publication date: 30 August 2018Source: European Journal of Pharmaceutical Sciences, Volume 121Author(s): Danny Riethorst, Joachim Brouwers, Jens Motmans, Patrick Augustijns Intestinal permeability assessment is an important aspect of drug development, which strongly depends on the solvent system used in the intestinal donor compartment. For this purpose, human intestinal fluids (HIF) can be considered as the golden standard. A recent study demonstrated a reduced apparent permeation across rat intestinal tissue from fed versus fasted state HIF for 9 out of 16 compounds tested. Commercially available fed and fasted state simulated fluids (FeSSIF and FaSSIF) reproduced this food effect for only 3 out of 16 compounds. To elucidate this observed difference, the current study assessed the impact of relevant intestinal fluid factors (bile salt, phospholipids, cholesterol, free fatty acids (FFA), monoacylglycerides (MAG)) and 2-factor interactions at a fixed pH of 6.5 on drug permeation across both rat tissue (Ussing chambers setup) and an artificial membrane (dialysis setup). Four representative compounds were selected for the permeation experiments: for propranolol and indomethacin, a food-induced permeation reduction was previously seen in both HIF and SIF; for metoprolol and darunavir, a reduction was only seen in HIF. Using a fractional 25–1 design of experiments (DoE) approach, 16 SIF combinations were defined as donor media for permeation studies.In the Ussing chambers (rat tissue), FFA and MAG reduced the permeation for all 4 compounds. Only for propranolol and indomethacin, permeation was further reduced by bile salts and phospholipids. This explains why the use of FeSSIF vs FaSSIF, lacking FFA and MAG, predicted a negative food effect for propranolol and indomethacin but not for metoprolol and darunavir. In the dialysis set-up using an artificial membrane, significantly higher permeation rates compared to the Ussing chambers were observed. Under those conditions, FFA and MAG no longer reduced permeation, while bile salts and phospholipids still did. This may indicate that lipidic structures can provide depot release in the case of a dynamic equilibrium between free and entrapped drug.Graphical abstractUnlabelled Image
  • Application of composite dissolving microneedles with high drug loading
           ratio for rapid local anesthesia
    • Abstract: Publication date: 30 August 2018Source: European Journal of Pharmaceutical Sciences, Volume 121Author(s): Haohui Zhan, Fengsen Ma, Yingcong Huang, Jie Zhang, Xiayun Jiang, Yongchang Qian We report a type of dissolving microneedles (DMNs) which was made of composite matrix materials of hydroxypropyl methyl cellulose (HPMC) and poly(methylvinylether‑co‑maleic anhydride) (PMVE/MA copolymer, Gantrez S-97), and was successfully loaded with lidocaine hydrochloride. The weight of lidocaine hydrochloride loaded in the microneedles tip was 70% of the weight of the whole tip. The content was 3.43 ± 0.12 mg in weight, which was determined by high performance liquid chromatography (HPLC). The results for mechanical test showed that these microneedles were able to penetrate into the skin of the experimental animals, that was proved using organic staining, texture analyzer and histological examination. The fracture force of the microneedles was 5.442 ± 0.412 N, which was much higher than the one required for the skin penetration. The DMNs with lidocaine hydrochloride could be dissolved inside of the rat skin in 5 min. The onset time would be faster (in
  • Platinated graphene oxide: A nanoplatform for efficient gene-chemo
           combination cancer therapy
    • Abstract: Publication date: 30 August 2018Source: European Journal of Pharmaceutical Sciences, Volume 121Author(s): Peng Liu, Shengfeng Wang, Xuanjun Liu, Jinsong Ding, Wenhu Zhou Cisplatin (CisPt) is one of the most effective antitumor drugs against a wide range of solid cancers, and recent studies have indicated that combination of CisPt and RNA interference (RNAi) agents would effectively enhance therapeutic index, while the development of simple yet robust dual-delivery systems still remains a challenge. Here, we demonstrated that platinated graphene oxide is an excellent platform to achieve such goal. Nano-Graphene oxide (NGO) was easily platinated by CisPt, and the resulting CisPt/NGO was characterized by several aspects. As a proof-of-concept, an antisense microRNA-21 (Anti-miR-21) was employed as a potential RNAi agent. While most previous work functionalized NGO with cationic polymers for gene delivery, we demonstrated that platinated NGO is a potent carrier to load Anti-miR-21 with improved capacity and adsorption stability. With Anti-miR-21 loading, the system displayed significantly enhanced cytotoxicity to cancer cells, suggesting a synergistic effect. Finally, the underlying mechanism of the improved efficacy was explored, which can be ascribed to the cell apoptosis induced by Anti-miR-21 for gene silencing. This work demonstrated platinated graphene oxide as an effective nanocarrier to co-deliver CisPt and gene therapy for the treatment of cancer.Graphical abstractAfter platination, nano-graphene oxide becomes a better platform to load gene therapy, through which a facile yet robust dual-delivery system was developed, and synergistic cancer therapy was demonstrated.Unlabelled Image
  • Comparative behavior between sunscreens based on free or encapsulated UV
           filters in term of skin penetration, retention and photo-stability
    • Abstract: Publication date: 30 August 2018Source: European Journal of Pharmaceutical Sciences, Volume 121Author(s): Arianna C. Cozzi, Paola Perugini, Samuel Gourion-Arsiquaud BackgroundThe growing incidence of photodamaging effects caused by UV radiation (e.g. sunburn, skin cancer) has increased the attention from health authorities which recommend the topical application of sunscreens to prevent these skin damages. The economic stakes for those companies involved in this international market are to develop new UV filters and innovative technologies to provide the most efficient, flexible and robust sunscreen products. Today the development of innovative and competitive sunscreen products is a complex formulation challenge. Indeed, the current sunscreens must protect against skin damages, while also being safe for the skin and being sensory and visually pleasant for the customers when applied on the skin. Organic UV filters, while proposing great advantages, also present the risk to penetrate the stratum corneum and diffuse into underlying structures with unknown consequences; moreover, their photo-stability are noted thorny outcomes in sunscreen development and subsequent performance. In recent years, the evaluation of the interaction between skin and sunscreen in terms of penetration after topical application has been considered from European authority but still its testing as their photo-stability assessment are not mandatory in most countries.ObjectiveThis study, based on in-vitro approaches, was performed to evaluate and compare the retention and the penetration of organic UV filters in free or encapsulated form inside the skin as well as their respective photo-stability.MethodsSunscreen formulation with a combination of Avobenzone and Octocrylene in “free form” and a formulation using the same UV filters but encapsulated in a sol-gel silica capsule, were analyzed and compared by FTIR Imaging Spectroscopy. Tape stripping method was used to investigate the penetration of these UV filters inside the stratum corneum. Their photo-stabilities were evaluated by spectroscopic measurements (FTIR, UV/Vis) and standard measurements were calculated: AUC (Area Under the Curve) and SPF (Sun Protection Factor).ResultWith traditional formulation, the organic UV filters penetrated significantly into the stratum corneum while the same UV filters combined with encapsulation technology remained on the skin surface. The encapsulation technology also improved significantly their stability.ConclusionEncapsulation technology is a promising strategy to improve the efficacy of sunscreen product using organic UV filters and to reduce safety problem. On the other hand, this study highlighted the pertinence of the FTIR Spectroscopy to test, compare and investigate sunscreen formulations.Graphical abstractUnlabelled Image
  • Resolution and evaluation of 3-chlorophenyl-3-hydroxypropionylhydroxamic
           acid as antivirulence agent with excellent eradication efficacy in
           Helicobacter pylori infected mice
    • Abstract: Publication date: 30 August 2018Source: European Journal of Pharmaceutical Sciences, Volume 121Author(s): Qi Liu, Wei-Wei Ni, Zhen Li, Cai-Fu Bai, Dan-Dan Tan, Chang-Jun Pu, Dong Zhou, Qing-Peng Tian, Ni Luo, Kai-Li Tan, Le Dai, Yuan Yan, Yong Pei, Xian-Hui Li, Zhu-Ping Xiao, Hai-Liang Zhu The continuing emergence of drug-resistant Helicobacter pylori (HP) drives the ongoing need for the development of new and effective anti-HP drugs. Urease inhibitor has now gained strong interest as an alternative approach for HP infections. 3-Chlorophenyl-3-hydroxypropionylhydroxamic acid (CPH), a novel urease inhibitor identified in our group, shows impressive potency, which was optically separated for a further exploration. Here, we report in vitro/in vivo pharmacological evaluation of (±)-CPHs and the enantiomers. The raceme and the individual enantiomers significantly suppress gastritis at 32 mg/kg b.i.d dose with lower toxicity to mammalian cells (with CC50s ≥ 3.16 mM) and mice (LD50s ≥ 2338 mg/kg) than the clinically used agent acetohydroxamic acid. Furthermore, a significant increase of eradication of HP is observed for the combination of (±)-CPHs or the enantiomers with an antimicrobial. These studies revealed that CPH is a promising candidate for an alternative treatment of HP-dependent conditions by targeting virulence factor urease, and CPH may be used as a raceme.Graphical abstractUnlabelled Image
  • Pharmacokinetics and disposition of miltefosine in healthy mice and
           hamsters experimentally infected with Leishmania infantum
    • Abstract: Publication date: 30 August 2018Source: European Journal of Pharmaceutical Sciences, Volume 121Author(s): M. Dolores Jiménez-Antón, Estefanía García-Calvo, Cristina Gutiérrez, Mª.D. Escribano, Nour Kayali, José L. Luque-García, Ana Isabel Olías-Molero, María J. Corral, Maria P. Costi, Juan J. Torrado, José Mª. Alunda Miltefosine is the only currently available oral drug for treatment of leishmaniasis. However, information on the pharmacokinetics (PK) of miltefosine is relatively scarce in animals. PK parameters and disposition of the molecule was determined in healthy NMRI mice and Syrian hamsters infected and treated with different miltefosine doses and regimens. Long half-life of the molecule was confirmed and differential pattern of accumulation of the drug was observed in analyzed organs in mice and hamster. Long treatment schedules produced miltefosine levels over IC50 value against L. infantum intracellular amastigotes for at least 24 days in spleen and liver of infected hamsters. The observed differential pattern of organ accumulation of the drug in mice and hamster supports the relevance of both species for translational research on chemotherapy of leishmaniasis.Graphical abstractUnlabelled Image
  • Beta-glucan-loaded nanofiber dressing improves wound healing in diabetic
    • Abstract: Publication date: 30 August 2018Source: European Journal of Pharmaceutical Sciences, Volume 121Author(s): Jostein Grip, Rolf Einar Engstad, Ingrid Skjæveland, Nataša Škalko-Basnet, Johan Isaksson, Purusotam Basnet, Ann Mari Holsæter The increased prevalence of chronic wounds requires novel treatment options. The aim of this study was to develop a beta-glucan (βG)-loaded nanofiber wound dressing. Nanofibers were prepared using the needle-free Nanospider™ technology, an electrospinning method which enables the production of nanofibers at an industrial scale. The βG was selected as active ingredient based on its confirmed wound healing potential in both animals and humans. Hydroxypropyl methylcellulose (HPMC) and polyethylene oxide (PEO) were included as copolymers. Rheological profiles of spinning solutions containing HPMC, PEO, βG, ethanol and water, were optimized. The nanofiber formation was confirmed by Field Emission Scanning Electron Microscopy (FE-SEM), and both nanofibers with (βG-nanofibers) or without βG (NoβG-nanofibers) were evaluated by their swelling index and FT-IR spectroscopy. The formulations, active ingredient and excipients were tested for their possible in vitro toxicity in keratinocytes. Finally, the wound healing potential of the nanofibers was tested in externally induced excisional wounds in male diabetic db/db mice. Three different doses of βG-nanofibers and the βG-free, NoβG-nanofibers, were evaluated for their in vivo wound healing efficacy. All nanofiber-treatments provided improved wound healing as compared to the negative control (water). All βG-nanofiber treated groups exhibited significantly improved wound healing as compared to the NoβG-nanofiber treated group, indicating the potential of βG-nanofibers as wound dressing.Graphical abstractUnlabelled Image
  • Pharmacology study of a chimeric decoy receptor trap fusion protein on
           retina neovascularization by dual blockage of VEGF and FGF-2
    • Abstract: Publication date: 30 August 2018Source: European Journal of Pharmaceutical Sciences, Volume 121Author(s): Jing Jiang, Ke Xu, Ling Wang, Wei Xin, Guorui Zhao, Min Huang, Shenjun Li, Xuejing Luan, Jianmin Fang BackgroundClinical anti-vascular epithelial growth factor (VEGF) therapy trials faced a major challenge due to upregulated expression of other pro-angiogenic factors, such as fibroblast growth factor-2 (FGF-2). RC28, a novel recombinant dual decoy receptor IgG1 Fc-fusion protein, can block VEGFA and FGF-2 simultaneously. It is designed for the treatment of neovascular age-related macular degeneration and other pathological ocular neovascularization. The present study investigated the prevention efficacy of RC28 on choroidal neovascularization (CNV) in a monkey model and compared to the other mono VEGF antagonists; biodistribution and pharmacokinetics performance were also investigated.MethodsELISA and endothelial cell proliferation, migration, and tubule formation assay evaluated the bioactivity of RC28 in vitro, and an initial comparison was made among the mono target antagonists, Bevacizumab (Avastin), Ranibizumab (Lucentis), Aflibercept (EYLEA), Conbercept (KH902), and Ranibizumab (Lucentis). Laser-induced CNV in monkeys, and both VEGF and FGF-2 serum levels were detected in animals before and after the CNV model were induced. RC28 prevention efficacy was compared to other VEGF antagonists on CNV with respect to the incidence of CNV and several ophthalmic examinations. Ocular and systemic levels of RC28 were analyzed by 89Zr-labeled RC28 after single intravitreal administration for the biodistribution and pharmacokinetic profiles.ResultsRC28 is a unique fusion protein with high affinity to both VEGF and FGF-2, and beneficial to in vitro and in vivo bioactivity. The in vivo pharmacological studies demonstrated that the incidence of CNV formation was largely reduced in RC28 treatment groups with a low dosage as compared to other VEGF antagonist control groups. Furthermore, traces of RC28 were detected as dispersing from eyeballs to the liver after 20 days, and a prolonged half-time pharmacokinetic profile was exhibited.Graphical abstractUnlabelled Image
  • Penehyclidine hydrochloride regulates mitochondrial dynamics and apoptosis
           through p38MAPK and JNK signal pathways and provides cardioprotection in
           rats with myocardial ischemia–reperfusion injury
    • Abstract: Publication date: 30 August 2018Source: European Journal of Pharmaceutical Sciences, Volume 121Author(s): Min Feng, Lirui Wang, Siyuan Chang, Pu Yuan AimThe potential mechanism of penehyclidine hydrochloride (PHC) against myocardial ischemia–reperfusion (I/R) injury has not been fully elucidated. The aim of the present study was to reveal whether mitochondrial dynamics, apoptosis, and MAPKs were involved in the cardioprotective effect of this drug on myocardial I/R injury.MethodsNinety healthy adult male Wistar rats were separately pretreated with normal saline (0.9%); PHC; and signal pathway blockers of MAPKs, Drp1, and Bcl-2. Coronary artery ligation and subsequent reperfusion were performed to induce myocardial I/R injury. Echocardiography was performed. Myocardial enzymes and oxidative stress markers were detected. Myocardial cell apoptotic rates and infarct sizes were measured. Mitochondrial function was evaluated. Expression levels of MAPKs, mitochondria regulatory proteins (Drp1, Mfn1/2), and apoptosis-related proteins (Bcl-2, Bax) were determined.ResultsPHC pretreatment improved myocardial abnormalities (dysfunction, injury, infarct size, and apoptotic rate), mitochondrial abnormalities (dysfunction and fission), and excessive oxidative stress and inhibited the activities of p38MAPK and JNK signal pathways in rats with myocardial I/R injury (P 
  • Intestinal permeability determinants of norfloxacin in Ussing chamber
    • Abstract: Publication date: 30 August 2018Source: European Journal of Pharmaceutical Sciences, Volume 121Author(s): Cassiana Mendes, Gabriela C. Meirelles, Marcos A.S. Silva, Gilles Ponchel Recently, many efforts are taken to identify the intestinal uptake and efflux transporters since they are responsible for the absorption of many drugs as their interactions. Norfloxacin (NFX) is a fluoroquinolone that presents low solubility and low permeability, and as a consequence, low bioavailability. In this context, the aim of this study is evaluate for the first time the intestinal permeability mechanisms of NFX by Ussing chamber model. The low permeation of NFX at low temperature, where the efflux pumps are not active, reveals that NFX permeation is transporter-dependent. The permeation study at different level of intestine demonstrated that NFX passage is in the decrescent order: ileum > jejunum > duodenum > colon, probably attributed to transporters that are expressed differently along the intestinal tract. NFX intestinal flow was evaluated in the presence of many inhibitors and substrates to identify the uptake and efflux transporters implicate in NFX permeability mechanism. It could be observed that BCRP and MRPs are involved in the NFX efflux and PEPT1, PMAT and OCT in the NFX uptake transport. Furthermore, this work revealed that NFX has itself an affinity for OCTN and OATP, demonstrating that NFX could inhibit these transporters and influence the absorption of other drugs. The updated description of NFX intestinal permeability factors could contribute to the development of rational pharmaceutical formulations that could circumvent the efflux problems and consequently improve NFX biopharmaceutical properties and avoid drug-drug interactions.Graphical abstractUnlabelled Image
  • Acyclovir lipid nanocapsules gel for oromucosal delivery: A preclinical
           evidence of efficacy in the chicken pouch membrane model
    • Abstract: Publication date: 30 August 2018Source: European Journal of Pharmaceutical Sciences, Volume 121Author(s): Darine Abozaid, Alyaa Ramadan, Heba Barakat, Nawal Khalafallah The study aimed to develop a patient-friendly acyclovir gel with improved efficacy in viral mouth infections, in response to patients' need for an intraoral acyclovir product. Acyclovir was loaded in lipid nanocapsules in gel form, and formulae were evaluated for oromucosal delivery. Lipid nanocapsules were prepared by the phase inversion method. Formulae were optimized to achieve maximum acyclovir entrapment and minimum acyclovir precipitation. Colloidal properties, and pharmaceutical performance indicators were assessed. Drug-loaded lipid nanocapsules were in the nanorange (39–120 nm), PdI (0.03–0.2), negative zeta potential, and entrapment efficiency (33–64%). Acyclovir (0.3% w/w) lipid nanocapsules gels were prepared using hydroxyethylcellulose (3% w/w). Resulting gel attributes were considered suitable.Lipid nanocapsules gels (0.3% w/w) showed enhanced Ex vivo acyclovir permeation across, and comparable retention in chicken pouch membrane compared to the 5% marketed cream despite lower drug content. The data provides basis for future exploration of lipid nanocapsules as carrier for transmucosal delivery of acyclovir; the enhanced acyclovir retention in chicken pouch membrane, compared to controls, suggests suitability of lipid nanocapsules for drug delivery to the viral lesion within the buccal membrane.Graphical abstractUnlabelled Image
  • Modified equation for particle bonding area and strength with inclusion of
           powder fragmentation propensity
    • Abstract: Publication date: 30 August 2018Source: European Journal of Pharmaceutical Sciences, Volume 121Author(s): Dejan Lamešić, Odon Planinšek, Ilija German Ilić The paper considers a novel, modified equation for evaluation of relationship between tablet tensile strength, bonding area and bonding strength with inclusion of fragmentation as particle deformation mechanism. Four types of lactose particles for direct compression were assessed for their micromeritic and mechanical properties (compressibility and compactibility), with particular focus on fragmentation behaviour, bonding area and bonding strength. Compressibility properties were assessed using three established models. Walker and Kuentz-Leuenberger models distinguished lactose plastic properties more effectively in contrast to the Heckel model. Spherical agglomerates of lactose were most prone to fragmentation as determined with the fragmentation propensity coefficient and the number of interparticulate bonds. Fragmentation, together with plastic deformation were found to be the governing factors for tablet tensile strength in α-lactose samples, while high bonding force primarily controlled the tablet tensile strength of anhydrous lactose. Tensile strength of all lactose tablets showed best correlation to the ratio of fragmentation propensity and Walker compressibility coefficient, which is proposed as better deformation index, intended to describe the overall deformation properties of lactose more precisely. A novel expression for determining bonding area is proposed, established on the enhanced deformation index, which includes both plastic deformation and fragmentation as bond formation mechanisms.Graphical Unlabelled Image
  • Study of the influence of substrate and spectrophotometer characteristics
           on the in vitro measurement of sunscreens efficiency
    • Abstract: Publication date: 30 August 2018Source: European Journal of Pharmaceutical Sciences, Volume 121Author(s): C. Couteau, A. Philippe, M.-A. Vibet, E. Paparis, L. Coiffard All the methods used for the in vitro measurement of the SPF, the universal indicator of sunscreens efficiency, rely on a spectrophotometric analysis. What can vary about the experimental protocol used is mainly the substrate and the type of spectrophotometer chosen. We decided to work with polymethylmetacrylate plates that we analyzed using two spectrophotometers equipped with integrating spheres, the UV1000S and the UV2000 apparatus. Two marketed products were such tested, after spreading 2 mg/cm2 on the plates, using one apparatus after another. We applied a non-parametric Wilcoxon test for paired data to the measures realized on 10 plates (as we systematically used the 2 apparatus), in order to compare the series of measures obtained with the two machines. This way, we were able to show a significant difference between the SPF values respectively obtained with the UV1000S and the UV2000 spectrophotometers. This difference could be explained by the decrease of the stray light in the case of the UV2000 apparatus.Graphical abstractUnlabelled Image
  • Dissolving polymeric microneedle arrays for enhanced site-specific
           acyclovir delivery
    • Abstract: Publication date: 30 August 2018Source: European Journal of Pharmaceutical Sciences, Volume 121Author(s): Boonnada Pamornpathomkul, Tanasait Ngawhirunpat, Ismaiel A. Tekko, Lalitkumar Vora, Helen O. McCarthy, Ryan F. Donnelly Acyclovir is widely indicated for the treatment of herpes labialis (cold sores), typically caused by the herpes simplex virus type 1 (HSV-1). However, topical acyclovir has poor efficacy, due to its low skin permeability. The purpose of this study was, therefore, to evaluate the ability of dissolving polymeric microneedle (MN) arrays to improve the local delivery of acyclovir. Acyclovir-loaded dissolving MN arrays (0.49 cm2) were formulated from aqueous blends of Gantrez® S-97 with 361 needles per array (589 ± 9.29 μm height). MN penetrated excised neonatal porcine skin, showing sufficient mechanical strength to resist compression and maintained their appearance after application of a 0.089 N per needle force for 30 s. Dissolution of the needles was observed within 15 min after application to skin and the needles had completely dissolved at 2 h in vitro. In vitro skin permeation studies revealed that the percentage of total acyclovir loading which permeated the skin over a 24 h period using MNs was approximately 45 times higher than that of a commercial cream formulation (Lipsore®). The accumulation of acyclovir at the basal epidermis, the target site of the herpes simplex virus, using MNs was a total of 21.5 μg/cm3in vitro, which is approximately 5 times greater than the 99% inhibition of viral cytopathic effect (ID99) required for HSV infections. This level was also 16 times higher than that obtained using the cream formulation. An in vivo study showed that the use of acyclovir-loaded dissolving MN arrays successfully provided intradermal delivery of acyclovir over a 48 h period and the drug levels in the skin delivered using MN arrays (45.09 ± 13.28 μg/cm3) were superior to those generated by the cream formulation (4.55 ± 1.37 μg/cm3). Accordingly, acyclovir-loaded dissolving MN arrays could be a promising approach for effective local delivery of acyclovir.Graphical abstractUnlabelled Image
  • Repurposing of sodium valproate in colon cancer associated with diabetes
           mellitus: Role of HDAC inhibition
    • Abstract: Publication date: 30 August 2018Source: European Journal of Pharmaceutical Sciences, Volume 121Author(s): Mayur M. Patel, Bhoomika M. Patel Background and purposeDiabetic patients are at greater risk for colon cancer. Histone deacetylases (HDACs) serve as common target for both. The key objective of the study was to evaluate the effect of sodium valproate in type 2 diabetes mellitus associated colon cancer.Experimental approachHigh fat diet and streptozotocin were used to induce type 2 diabetes. Following this, after diabetes confirmation, colon cancer was induced using 1,2 dimethylhydrazine (25 mg/kg, s.c.) once weekly from 7th week to 20th weeks. Sodium valproate (200 mg/kg) treatment was given from 20th to 24th week. At the end of 24 weeks, several enzymatic and biochemical parameters, were estimated. MTT, clonogenic and scratch wound healing assay were carried out in HCT-15 cell line.Key resultsHyperglycemia, hyperinsulinemia, increase in cytokines (TNF-α and IL-1β) and carcinoembryonic antigen and presence of proliferating cells was seen in disease control animals which was prevented by sodium valproate treatment. Overexpression of relative HDAC2 mRNA levels was found in diseased control animals, which was reduced by sodium valproate treatment. IC50 of sodium valproate was found to be 3.40 mM and 3.73 mM at 48 h and 72 h respectively on HCT-15 cell line. Sodium valproate also dose dependently prevented colony formation and cell migration.Conclusion and implicationsSodium valproate can be considered for repurposing in colon cancer associated with diabetes mellitus.Graphical abstractUnlabelled Image
  • Evaluating prodrug characteristics of a novel anticoagulant fusion protein
           neorudin, a prodrug targeting release of hirudin variant 2-Lys47 at the
           thrombosis site, by means of in vitro pharmacokinetics
    • Abstract: Publication date: 30 August 2018Source: European Journal of Pharmaceutical Sciences, Volume 121Author(s): Xiaona Dong, Ruolan Gu, Xiaoxia Zhu, Hui Gan, Jianglin Liu, Jide Jin, Zhiyun Meng, Guifang Dou Recombinant neorudin (EPR-hirudin, EH), a low-bleeding anticoagulant fusion protein, is an inactive prodrug designed to be converted to the active metabolite, hirudin variant 2-Lys47 (HV2), locally at the thrombus site by FXa and/or FXIa, following activation of the coagulation system. Our aim was to evaluate the prodrug characteristics of EH by comparing the biotransformation of EH and HV2 in biological matrices, including rat blood, liver, and kidney homogenates, demonstrating the cleavage of EH to HV2 by FXa and FXIa, and comparing the conversion of EH to HV2 between fresh whole blood and whole-blood clot homogenate, using ultra-performance liquid chromatography-mass spectrometry (UPLC-MS/MS). Both EH and HV2 were stable in blood and unstable in the liver and kidney homogenates. Eight EH metabolites and eight HV2 metabolites identified as N-terminal fragments were found in the liver and kidney. C-terminal proteolysis is therefore the major metabolic pathway, with serine/cysteine carboxypeptidases and metallocarboxypeptidases being responsible for the degradation of EH and HV2 in the liver and kidney, respectively. EH was cleaved to release HV2 by FXIa. Higher levels of HV2 were produced from EH in the whole-blood clot homogenate, in which the coagulation system was activated compared with those in fresh whole blood. In conclusion, the metabolism of EH and HV2 shares the same cleavage pattern, and EH is transformed into HV2 when the coagulation system is activated, where FXIa is a specific enzyme. Our in vitro study revealed the anticipated prodrug characteristics of EH newly designed as an inactive prodrug of hirudin.Graphical abstractUnlabelled Image
  • Do new N-substituted 3-amino-4-phenyl-5-oxo-pyrazolinecarboxamide
           derivatives exhibit antitubercular potential'
    • Abstract: Publication date: 30 August 2018Source: European Journal of Pharmaceutical Sciences, Volume 121Author(s): Marta Swatko-Ossor, Katarzyna Klimek, Anna Belcarz, Agnieszka Anna Kaczor, Monika Pitucha, Grazyna Ginalska As a continuation of previous tests concerning new N-substituted 3-amino-4-phenyl-5-oxo-pyrazolinecarboxamide derivatives (R3, R4 and R8) of notable antibacterial activity, their antitubercular potential against different mycobacterial strains was estimated. Tests performed on virulent (reference and clinical) strains of Mycobacterium bovis and Mycobacterium tuberculosis revealed the highest therapeutic potential of R8 derivative: MIC within the range 7.8–15.6 μg/ml and TI (therapeutic index) within the range 46.5–93. Moreover, the synergistic interaction was found between R3, R4 and R8 derivatives and rifampicin, one of the front-line antitubercular drugs. R8/rifampicin mixture in concentrations effective in inhibition of Mycobacterium tuberculosis strain was non-cytotoxic against GMK cells, displaying cell viability approximately 88–97% when compared to control. Molecular docking study enabled to conclude that enoyl acyl carrier protein reductase (InhA) can be considered as a potential molecular target of tested pyrazole derivatives. Although further modifications of chemical structure of the investigated pyrazole derivatives is required, in order to increase their antitubercular efficacy and therapeutic safety, these compounds, in particular R8 compound, can be promising for the treatment of human and bovine tuberculosis.Graphical abstractUnlabelled Image
  • Characterization of solution stress degradation products of aliskiren and
           prediction of their physicochemical and ADMET properties
    • Abstract: Publication date: 30 August 2018Source: European Journal of Pharmaceutical Sciences, Volume 121Author(s): Bhoopendra Singh Kushwah, Jugal Gupta, Dilip Kumar Singh, Moolchand Kurmi, Archana Sahu, Saranjit Singh Forced degradation studies on aliskiren were carried out according to ICH and WHO guidelines. Six degradation products were formed in total in the solution state. Their separation among themselves and from the drug was successfully achieved on a C-18 column utilizing acetonitrile and phosphate buffer (pH 3.0) in the mobile phase, which was run in a gradient mode. To characterize them, a complete mass fragmentation pathway of the drug was first established with the help of MS/TOF and MSn data. This was followed by LC-MS/TOF studies on the degradation products. Some of the degradation products were also isolated and subjected to 1D (1H, 13C and DEPT-135) and 2D (COSY, HSQC and HMBC) NMR studies for confirmation of their structures. An interesting observation was hydrolysis followed by cyclization in case of three degradation products. Also, acetonitrile was found to react with aliskiren, leading to formation of a pseudo degradation product. Additionally, comparative ADMET properties of the drug and degradation products were established using ADMET Predictor™.Graphical abstractUnlabelled Image
  • Effect of formulation and process variables on lipid based sustained
           release tablets via continuous twin screw granulation: A comparative study
    • Abstract: Publication date: 30 August 2018Source: European Journal of Pharmaceutical Sciences, Volume 121Author(s): Venkata Raman Kallakunta, Roshan Tiwari, Sandeep Sarabu, Suresh Bandari, Michael A. Repka The current study's aim is to prepare lipid based sustained release tablets via a twin-screw granulation technique and compare those dosage forms with conventional techniques, namely wet granulation and direct compression. The granules were successfully manufactured in a single-step, continuous twin-screw granulation process with a low proportion of binder (Klucel™ EF, HPC SSL) using Compritol® 888 ATO, Precirol® ATO 5 and Geleol™ as sustained release agents. The granules prepared showed good flow characteristics and compaction properties. DSC and XRD studies were conducted to characterize the granules prepared via a twin-screw granulation method and the results demonstrated the crystalline nature of lipids within the granules. FTIR data indicated that there were no interactions with the formulation components investigated. The formulations developed by all three methods were compressed into tablets with a mechanical strength of 14–16 KP. The tablets formulated were characterized for physicochemical properties, in vitro drug release studies, water uptake and erosion studies. These results showed that the drug was not completely released after 24 h for tablets developed by the wet granulation process using all three lipids. The tablets prepared by the direct compression method demonstrated a burst release within 8 to 10 h from Precirol ATO 5® and Geleol™ formulations compared to Compritol® 888 ATO. However, tablets prepared using twin-screw granulation exhibited sustained release of the drug over 24 h and the water uptake and erosion results were in accordance with dissolution data. Stability data for 45 days at accelerated conditions (40 °C/75% RH) showed similar release profiles with ƒ2 values above 50 for all of the twin screw granulation formulations, indicating the suitability of the process for formulating sustained release tablets. These findings of a single-step, continuous twin-screw granulation process are novel and demonstrate new opportunities for development of sustained release tablets.Graphical abstractUnlabelled Image
  • The effect of size and polymer architecture of
           doxorubicin–poly(ethylene) glycol conjugate nanocarriers on breast duct
           retention, potency and toxicity
    • Abstract: Publication date: 30 August 2018Source: European Journal of Pharmaceutical Sciences, Volume 121Author(s): Zichao Gu, Dayuan Gao, Firas Al-Zubaydi, Shike Li, Yashveer Singh, Kristia Rivera, Jennifer Holloway, Zoltan Szekely, Susan Love, Patrick J. Sinko Although systemic administration of chemotherapeutic agents is routinely used for treating invasive breast cancer, the only therapeutic options for ductal carcinoma in situ (DCIS) are surgery and radiation. Treating DCIS by delivering drugs locally to the affected milk duct offers significant advantages over systemic administration, including reduced systemic and breast toxicities, as well as a greatly reduced need for surgery and radiation. In this study, mammary gland retention and toxicity of intraductally administered poly(ethylene) glycol-doxorubicin (PEG-DOX) polymeric conjugate nanocarriers of varying molecular sizes and architectures were investigated. Nanocarriers were formed by conjugating one or more copies of doxorubicin to PEG polymers, of varying molecular weights (5, 10, 20, and 40 kDa) and architectures (linear, four-arm and eight-arm). Cytotoxicity against MCF7 cells, a human breast cancer cell line, was assessed, and IC50 values were calculated. The nanocarriers were intraductally administered into the mammary glands of female retired breeder Sprague-Dawley rats. Whole body images were captured using in vivo optical imaging, and changes in ductal structure as well local inflammation were monitored. Fluorescence intensities were monitored, over time, to evaluate nanocarrier mammary gland retention half-lives (t1/2). The IC50 values of PEG-DOX nanocarriers against MCF7 cells were 40 kDa PEG-(DOX)4 (1.23 μM) 
  • Novel therapeutic drug identification and gene correlation for fatty liver
           disease using high-content screening: Proof of concept
    • Abstract: Publication date: 30 August 2018Source: European Journal of Pharmaceutical Sciences, Volume 121Author(s): Wei-Jia Luo, Ting-Yu Cheng, Keng-Ieng Wong, Woei-horng Fang, Keng-Mao Liao, Yun-Ting Hsieh, Kang-Yi Su Non-alcoholic fatty liver disease (NAFLD) is a problem in obese people caused by increasing intake of high-calorie food such as fructose implicated in the elevated prevalence. It is necessary to identify novel drugs to develop effective therapies. In this study, we combined LOPAC® (The Library of Pharmacologically Active Compounds) and High-Content screening to identify compounds that significantly reduced intracellular lipid droplets (LD) after high fat medium (HFM) treatment. Among 1280 compounds, we identified 239 compounds that reduced LD by>50%. Of these, 17 maintained cell viability. Nine of them were selected for validation using normal primary hepatocytes, of which five compounds showed dose-dependent efficacy. Whole genome transcriptomic network analysis was performed to construct the underlying regulatory network. There were 831 (711 up-regulated and 120 down-regulated genes) and 3480 (2009 up-regulated and 1471 down-regulated genes) genes that showed a significant change (>2-fold; p 
  • Ocular irritation and cyclosporine A distribution in the eye tissues after
           administration of Solid Lipid Microparticles in the rabbit model
    • Abstract: Publication date: 30 August 2018Source: European Journal of Pharmaceutical Sciences, Volume 121Author(s): Eliza Wolska, Małgorzata Sznitowska, Juliusz Chorążewicz, Oliwia Szerkus, Aleksandra Radwańska, Michał J. Markuszewski, Roman Kaliszan, Krystyna Raczyńska The aim of this study was to investigate the in vivo effect of Solid Lipid Microparticles (SLM), proposed for topical ocular administration of cyclosporine, on the rabbit eye.SLM carrier is an aqueous dispersion of lipid microparticles (20% w/w) with a size up to 15 μm. Cyclosporine was dissolved in the formulation in the concentration of 0.5 or 2.0% (w/w). Ocular tolerance of microsphere dispersion was assessed in rabbit model by the Draize eye test (SLM was compared with emulsion and oily solution), and cyclosporine distribution in ocular tissues was evaluated after multiple application of tested formulations (SLM dispersions, emulsions and oily solution) for 7 days.Good tolerance of cyclosporine-SLM formulation was demonstrated in the rabbit model. Concentration of cyclosporine in the precorneal tissues, such as cornea and conjunctiva, was much higher than the therapeutic value (8.4 ng/mg and 3.2 ng/mg, respectively). After SLM administration, the cyclosporine concentrations determined in the anterior ocular tissues, were also significantly higher compared to those obtained after the application of other tested carriers (emulsions and oily solution).The obtained results prove that the recognized SLM dispersions are safe formulations for ophthalmic use. It can be concluded that lipid microparticles are highly promising for an efficient ophthalmic drug delivery, when compared to other conventional dosage forms.Graphical abstractUnlabelled Image
  • New insights in the in vitro characterisation and molecular modelling of
           the P-glycoprotein inhibitory promiscuity
    • Abstract: Publication date: 30 August 2018Source: European Journal of Pharmaceutical Sciences, Volume 121Author(s): Giovanni Bocci, Amélie Moreau, Philippe Vayer, Claire Denizot, Olivier Fardel, Yannick Parmentier The presence of several binding sites for both substrates and inhibitors is yet a poorly explored thematic concerning the assessment of the drug-drug interactions risk due to interactions of multiple drugs with the human transport protein P-glycoprotein (P-gp or MDR1, gene ABCB1). In this study we measured the inhibitory behaviour of a set of known drugs towards P-gp by using three different probe substrates (digoxin, Hoechst 33,342 and rhodamine 123). A structure-based model was built to unravel the different substrates binding sites and to rationalize the cases where drugs were not inhibiting all the substrates. A separate set of experiments was used to validate the model and confirmed its suitability to either detect the substrate-dependent P-gp inhibition and to anticipate proper substrates for in vitro experiments case by case. The modelling strategy described can be applied for either design safer drugs (P-gp as antitarget) or to target specific sub-site inhibitors towards other drugs (P-gp as target).Graphical abstractUnlabelled Image
  • Pharmacodynamic and pharmacokinetic characteristics of YMR-65, a tubulin
           inhibitor, in tumor-bearing mice
    • Abstract: Publication date: 30 August 2018Source: European Journal of Pharmaceutical Sciences, Volume 121Author(s): Ali Fan, Jiali Wei, Mengru Yang, Qing Zhang, Yaliang Zhang, Qingwang Liu, Ning Li, Di Zhao, Yang Lu, Junxiu Li, Jie Zhao, Shuhua Deng, Bingjie Zhang, Hailiang Zhu, Xijing Chen YMR-65​, 5-(5-bromo-1-methyl-1H-indol-3-yl)-3-(3-methoxyphenyl)-4, 5-dihydro-1H-pyrazole-1-carboxamide, is a potential tubulin inhibitor exhibiting good anticancer activity. In our study, we illustrated the biological activities in HepG2 cells and the pharmacodynamic and pharmacokinetic profiles were evaluated in murine H22 hepatoma-bearing mice. Molecular docking assay and colchicine competition assay indicated that YMR-65 could bind tightly to the colchicine binding site of tubulin. Further investigation demonstrated that YMR-65 arrested cells in the G2/M phase of cell cycle and induced apoptosis in HepG2 cells. Compared with control group, the tumor growth inhibition determined by final relative volume of tumor/the initial tumor volume were 32.57%, 24.00% and 34.95%, respectively, for YMR-65 (10 mg/kg), YMR-65 (20 mg/kg) and CA4P (10 m/kg) groups. Besides there were no obvious body change or tissue damage (enhanced by histopathology study). YMR-65 administration at 10 and 20 mg/kg in H22 tumor-bearing mice resulted in 1.87- and 1.80-fold longer half time (t1/2) and 0.36- and 0.78-fold lower area under concentration-time curve (AUC0–∞) in plasma in contrast with normal mice at 10 mg/kg. Furthermore, YMR-65 showed a wide distribution to various tissues or tumor and the highest distribution index (the ratio of AUCtissue or tumor/AUCplasma) was found in tumor, which implied that it might accumulate in tumor after administration. In brief, our results indicated that YMR-65 was a promising candidate with high antitumor efficacy and low tissue damage.Graphical abstractUnlabelled Image
  • Human and rat precision-cut intestinal slices as ex vivo models to study
           bile acid uptake by the apical sodium-dependent bile acid transporter
    • Abstract: Publication date: 30 August 2018Source: European Journal of Pharmaceutical Sciences, Volume 121Author(s): Ming Li, Ivan Vokral, Bernard Evers, Inge A.M. de Graaf, Marina H. de Jager, Geny M.M. Groothuis The apical sodium-dependent bile acid transporter (ASBT) is the primary transporter for the uptake of bile acids in the small intestine. It is localized on the apical membrane of the ileal enterocytes and is known for its high capacity and affinity for taurocholic acid in vitro. However, less is known about its activity towards taurocholic acid and other bile acids in vivo due to the lack of a suitable model. The aim of this study was to validate precision-cut intestinal slices (PCIS) of rat and human intestine as ex vivo model to study the activity of ASBT-mediated transport, and subsequently to study regional and interspecies differences in ASBT function. PCIS maintain the natural cell polarization and communication, expression of transporters and metabolizing enzymes. Therefore this model is expected to be more relevant to the in vivo situation than in vitro cell culture models. PCIS of human and rat ileum were prepared and incubated with 0.04–2.00 mM taurocholic acid, deoxycholic acid and cholic acid, respectively at 4 and 37 °C. In this study, the respective contribution of active uptake appeared to be higher for taurocholic acid whereas the passive diffusion was higher for deoxycholic acid and cholic acid. Furthermore, the rank order of calculated (apparent) Km and Vmax for these bile acids is in line with literature reports. The active uptake of taurocholic acid in rat PCIS could be inhibited partly by simvastatin and fluvastatin and was fully inhibited by the specific inhibitor GSK2299027B, supporting the involvement of rat ASBT as uptake transporter. In both species, the ASBT-mediated active uptake of bile acids was observed only in the ileum whereas only passive diffusion was observed in the jejunum and colon. In addition, ASBT activity was higher in the human ileum compared to the rat ileum. In the future rat and human PCIS can be used to study the uptake of new ASBT substrates and as a screening method for potential ASBT inhibitors.Graphical abstractUnlabelled Image
  • Topical delivery of anthramycin II. Influence of binary and ternary
           solvent systems
    • Abstract: Publication date: 30 August 2018Source: European Journal of Pharmaceutical Sciences, Volume 121Author(s): Tasnuva Haque, Khondaker Miraz Rahman, David E. Thurston, Jonathan Hadgraft, Majella E. Lane Anthramycin (ANT) is a member of the pyrolobenzodiazepine family and is a potent cytotoxic agent. Previously, we reported the topical delivery of ANT from a range of solvents that may also act as skin penetration enhancers (SPEs). The skin penetration and uptake was monitored for simple solutions of ANT in propylene glycol (PG), dipropylene glycol (DiPG), Transcutol P (TC), isopropyl myristate (IPM), propylene glycol monocaprylate (PGMC) and propylene glycol monolaurate (PGML). The amounts of PG, DiPG and TC that were taken up by, and that penetrated the skin were also measured, with a clear dependence of ANT penetration on the rate and extent of PG and TC permeation. The present work investigates ANT skin delivery from a range of binary and ternary systems to determine any potential improvement in skin uptake compared with earlier results for the neat solvents. Following miscibility and stability studies a total of eight formulations were taken forward for evaluation in human skin in vitro. Binary systems of PG and water did not result in any skin permeation of ANT. Combining PG with either PGMC or PGML did promote skin penetration of ANT but no significant improvement was evident compared with PG alone. More complex ternary systems based on PG, DiPG, PGMC, PGML and water also did not show significant improvements on ANT permeation, compared with single solvents. Total skin penetration and retention of ANT ranged from 1 to 6% across all formulations studied. Where ANT was delivered to the receptor phase there were also high amounts of PG permeation with>50% and ~35% PG present for the binary systems and ternary vehicles, respectively. These findings along with our previous paper confirm PG as a suitable solvent / SPE for ANT either alone or in combination with PGML or PGMC. The results also underline the necessity for empirical testing to determine whether or not a vehicle is acting as a SPE for a specific active in a topical formulation.Graphical abstractUnlabelled Image
  • Preparation of 99mTc-levetiracetam intranasal microemulsion as the first
           radiotracer for SPECT imaging of the Synaptic Vesicle Protein SV2A
    • Abstract: Publication date: 30 August 2018Source: European Journal of Pharmaceutical Sciences, Volume 121Author(s): Hassan M. Rashed, Rehab N. Shamma, Hanan A. El-Sabagh Selective receptors imaging using gamma emitting radiopharmaceuticals allows accurate diagnosis and follow up of many brain related disorders. Levetiracetam, a selective SV2A receptor antiepileptic, was successfully radiolabeled using 99mTc. Different conditions affecting the labelling process were studied and optimum radiochemical yield of 89.8% was obtained. 99mTc-levetiracetam was effectively formulated and characterized as microemulsion with particle size of 16.34 ± 5.58 nm and polydispersity index of 0.382 ± 0.05. Parallel biodistribution studies were performed comparing brain targeting efficiency of I.V 99mTc-levetiracetam solution, I.N 99mTc-levetiracetam solution and I.N 99mTc-levetiracetam microemulsion. Brain radioactivity uptake and brain/blood uptake ratio for I.N 99mTc-levetiracetam microemulsion were higher than the other two routes at all time intervals. Such results present intranasal 99mTc-levetiracetam microemulsion as the first SPECT tracer for imaging SV2A receptor.Graphical abstractUnlabelled Image
  • Polymer-lipid hybrid nanoparticles as enhanced indomethacin delivery
    • Abstract: Publication date: 30 August 2018Source: European Journal of Pharmaceutical Sciences, Volume 121Author(s): Annalisa Dalmoro, Sabrina Bochicchio, Shamil F. Nasibullin, Paolo Bertoncin, Gaetano Lamberti, Anna Angela Barba, Rouslan I. Moustafine Non-steroidal anti-inflammatory drugs (NSAIDs), i.e. indomethacin used for rheumatoid arthritis and non-rheumatoid inflammatory diseases, are known for their injurious actions on the gastrointestinal (GI) tract. Mucosal damage can be avoided by using nanoscale systems composed by a combination of liposomes and biodegradable natural polymer, i.e. chitosan, for enhancing drug activity.Aim of this study was to prepare chitosan-lipid hybrid delivery systems for indomethacin dosage through a novel continuous method based on microfluidic principles. The drop-wise conventional method was also applied in order to investigate the effect of the two polymeric coverage processes on the nanostructures features and their interactions with indomethacin. Thermal-physical properties, mucoadhesiveness, drug entrapment efficiency, in vitro release behavior in simulated GI fluids and stability in stocking conditions were assayed and compared, respectively, for the uncoated and chitosan-coated nanoliposomes prepared by the two introduced methods.The prepared chitosan-lipid hybrid structures, with nanometric size, have shown high indomethacin loading (about 10%) and drug encapsulation efficiency up to 99%. TEM investigation has highlighted that the developed novel simil-microfluidic method is able to put a polymeric layer, surrounding indomethacin loaded nanoliposomes, thicker and smoother than that achievable by the drop-wise method, improving their storage stability. Finally, double pH tests have confirmed that the chitosan-lipid hybrid nanostructures have a gastro retentive behavior in simulated gastric and intestinal fluids thus can be used as delivery systems for the oral-controlled release of indomethacin.Based on the present results, the simil-microfluidic method, working with large volumes, in a rapid manner, without the use of drastic conditions and with a precise control over the covering process, seems to be the most promising method for the production of suitable indomethacin delivery system, with a great potential in industrial manufacturing.Graphical abstractUnlabelled Image
  • Comparison of dissolution time profiles: No similarity but where is the
    • Abstract: Publication date: 30 August 2018Source: European Journal of Pharmaceutical Sciences, Volume 121Author(s): Stefan Horkovics-Kovats The similarity of the dissolution time profiles is routinely determined by various statistical methods, e.g. by calculating the f2 similarity factor, by calculating the multivariate statistical distance or determining the confidence interval of f2 metrics using the bootstrapping method. If the similarity of the dissolution profiles is not achieved, these methods provide no information about the possible causes of the differences in the final dosage forms. In this article it is shown that after introduction of summary parameters into the disintegration-dissolution model (DDM), such as intrinsic lifetime distribution of particles, saturation state function, drug load of the system and applying population data analysis, differences on the level of intrinsic lifetime distributions of particles of active pharmaceutical ingredient in immediately release formulations are identified. The identification of these differences provides important clues to target development of generic formulations or helps to explain possible differences in the in vivo behavior of products.Graphical abstractUnlabelled Image
  • Confocal Raman microspectroscopy as an alternative to differential
           scanning calorimetry to detect the impact of emulsifiers and formulations
           on stratum corneum lipid conformation
    • Abstract: Publication date: 30 August 2018Source: European Journal of Pharmaceutical Sciences, Volume 121Author(s): Ziwei Zhang, Dominique Jasmin Lunter The purpose of this study was to investigate the impact of emulsifiers and formulations on stratum corneum (SC) lipid conformation and evaluate confocal Raman microspectroscopy (CRM) as an alternative method to differential scanning calorimetry (DSC) in this research context. To this end, four different formulations were used: three conventional creams that contained ionic and/or non-ionic emulsifiers and one surfactants-free emulsion stabilized by a polymeric emulsifier. Additionally, all emulsifiers were tested in aqueous solutions/dispersions in the respective concentrations as present in the formulations. In this study, emulsifiers and formulations were applied onto excised porcine skin during incubation in Franz diffusion cells. Subsequently, SC was isolated, dried and subjected to CRM and DSC measurement to analyse lipid structural changes after treatment. In CRM measurement, 1080 cm−1/(1130 cm−1 + 1070 cm−1) peak ratio, which represents the C-C skeleton vibration and trans-gauche conformation order of lipids, was investigated. Various emulsifiers and formulations showed different impact on SC lipid conformation. Specifically, cetearyl alcohol and sodium cetearyl sulfate mixture dispersion showed the strongest ability among all studied emulsifiers, followed by glycerol monostearate, polyoxyethylene-20-glycerol monostearate as well as their mixture. Polysorbate 60, cetyl stearyl alcohol and their mixture did not affect SC lipid structure. The results of CRM and DSC correlated very well, indicating CRM, as an alternative to DSC, can be a reliable method to investigate SC lipid conformation.Graphical abstractUnlabelled Image
  • Safer anti-inflammatory therapy through dual COX-2/5-LOX inhibitors: A
           structure-based approach
    • Abstract: Publication date: 30 August 2018Source: European Journal of Pharmaceutical Sciences, Volume 121Author(s): Jaismy Jacob P, S.L. Manju, K.R. Ethiraj, Geetha Elias Inflammatory mediators of the arachidonic acid cascade from cyclooxygenase (COX) and lipoxygenase (LOX) pathways are primarily responsible for many diseases in human beings. Chronic inflammation is associated with the pathogenesis and progression of cancer, arthritis, autoimmune, cardiovascular and neurological diseases. Traditional non-steroidal anti-inflammatory agents (tNSAIDs) inhibit cyclooxygenase pathway non-selectively and produce gastric mucosal damage due to COX-1 inhibition and allergic reactions and bronchospasm resulting from increased leukotriene levels. ‘Coxibs’ which are selective COX-2 inhibitors cause adverse cardiovascular events. Inhibition of any of these biosynthetic pathways could switch the metabolism to the other, which can lead to fatal side effects. Hence, there is undoubtedly an urgent need for new anti-inflammatory agents having dual mechanism that prevent release of both prostaglandins and leukotrienes. Though several molecules have been synthesized with this objective, their unfavourable toxicity profile prevented them from being used in clinics. Here, this integrative review attempts to identify the promising pharmacophore that serves as dual inhibitors of COX-2/5-LOX enzymes with improved safety profile. A better acquaintance of structural features that balance safety and efficacy of dual inhibitors would be a different approach to the process of understanding and interpreting the designing of novel anti-inflammatory agents.Graphical abstractUnlabelled Image
  • CD44 targeted PLGA nanomedicines for cancer chemotherapy
    • Abstract: Publication date: 30 August 2018Source: European Journal of Pharmaceutical Sciences, Volume 121Author(s): Ankit Saneja, Divya Arora, Robin Kumar, Ravindra Dhar Dubey, Amulya K. Panda, Prem N. Gupta In recent years scientific community has drawn a great deal of attention towards understanding the enigma of cluster of differentiation-44 (CD44) in order to deliver therapeutic agents more selectively towards tumor tissues. Moreover, its over-expression in variety of solid tumors has attracted drug delivery researchers to target this receptor with nanomedicines. Conventional nanomedicines based on biodegradable polymers such as poly(lactide-co-glycolide) (PLGA) are often associated with insufficient cellular uptake by cancer cells, due to lack of active targeting moiety on their surface. Therefore, to address this limitation, CD44 targeted PLGA nanomedicines has gained considerable interest for enhancing the efficacy of chemotherapeutic agents. In this review, we have elaborately discussed the recent progress in the design and synthesis of CD44 targeted PLGA nanomedicines used to improve tumor-targeted drug delivery. We have also discussed strategies based on co-targeting of CD44 with other targeting moieties such as folic acid, human epidermal growth factor 2 (HER2), monoclonal antibodies using PLGA based nanomedicines.
  • Functionalized extracellular vesicles as advanced therapeutic nanodelivery
    • Abstract: Publication date: 30 August 2018Source: European Journal of Pharmaceutical Sciences, Volume 121Author(s): Mei Lu, Haonan Xing, Zhe Xun, Tianzhi Yang, Xiaoyun Zhao, Cuifang Cai, Dongkai Wang, Pingtian Ding Extracellular vesicles (EVs) are membrane enclosed vesicles that are shed by almost all cell types, and play a fundamental role in cell-to-cell communication. The discovery that EVs are capable of functionally transporting nucleic acid- and protein-based cargoes between cells, rapidly promotes the idea of employing them as drug delivery systems. These endogenous vesicles indeed hold tremendous promise for therapeutic delivery. However, issues associated with exogenously administered EVs, including rapid clearance by the immune system, apparent lack of targeting cell specificity, and insufficient cytoplasmic delivery efficiency, may limit their therapeutic applicability. In this review, we discuss recent research avenues in EV-based therapeutic nanodelivery systems. Furthermore, we narrow our focus on the development of modification strategies to enhance the delivery properties of EVs, and elaborate on how to rationally harness these functionalized vesicles for therapeutic delivery.Graphical abstractUnlabelled Image
  • Critical comparison of shake-flask, potentiometric and chromatographic
           methods for lipophilicity evaluation (log P o/w) of neutral, acidic,
           basic, amphoteric, and zwitterionic drugs
    • Abstract: Publication date: Available online 10 July 2018Source: European Journal of Pharmaceutical SciencesAuthor(s): Adriana Port, Magda Bordas, Raquel Enrech, Rosalia Pascual, Martí Rosés, Clara Ràfols, Xavier Subirats, Elisabeth Bosch In the present study three different procedures have been compared for the determination of the lipophilicity of the unionized species (log Po/w) of neutral, acidic, basic, amphoteric, and zwitterionic drugs. Shake-flask, potentiometric and chromatographic approaches have been assayed in a set of 66 representative compounds in different phases of advanced development. An excellent equivalence has been found between log Po/w values obtained by shake-flask and potentiometry, while the chromatographic approach is less accurate but very convenient for screening purposes when a high-throughput is required. In the case of zwitterionic and amphoteric compounds, either for shake-flask and chromatographic methods, the pH has to be accurately selected in order to ensure the compound to be in its neutral form.Graphical abstractUnlabelled Image
  • Gastric fluid composition in a paediatric population: Age-dependent
           changes relevant for gastrointestinal drug disposition
    • Abstract: Publication date: Available online 10 July 2018Source: European Journal of Pharmaceutical SciencesAuthor(s): Jens Van Den Abeele, Maissa Rayyan, Ilse Hoffman, Els Van de Vijver, Wei Zhu, Patrick Augustijns This work aimed to (i) expand the dataset on gastric fluid composition in the paediatric population (0–18 years old) and (ii) improve our understanding of age-dependent changes in gastric fluid characteristics involved in gastrointestinal drug disposition. For this purpose, gastric fluids from preterm neonates, term neonates, infants, children and adolescents were collected during routine medical procedures. Gastric fluid constituents relevant for gastrointestinal drug disposition were characterized i.e., pH, osmolality and bile salts (concentration + composition). Differences in gastric fluid composition compared to adults were most prominent in neonates. In this context, the fact that neonates are rarely fasted due to frequent feedings should be taken into account during paediatric drug product development. It remains to be explored to what extent the observed variability and differences in gastric fluid characteristics within and between age groups translates to variability and/or differences in oral drug disposition.Graphical abstractUnlabelled Image
  • A high-sensitivity HPLC-ELSD method for HPMC-AS quantification and its
           application in elucidating the release mechanism of HPMC-AS based
           amorphous solid dispersions
    • Abstract: Publication date: Available online 10 July 2018Source: European Journal of Pharmaceutical SciencesAuthor(s): Shan Wang, Chengyu Liu, Yuejie Chen, Zhen Zhang, Alan Zhu, Feng Qian Hydroxypropyl methylcellulose acetate succinate (HPMC-AS) is one of the most widely used polymers used in amorphous solid dispersions (ASD) for solubility and bioavailability enhancement of poorly water-soluble drugs. Once released from ASDs, HPMC-AS was often found to be highly effective in maintaining drug supersaturation, and this capability is dependent on the concentration and substitution types of this pH-dependent polymer. Therefore, accurate quantification of different grades of HPMC-AS allows us to better understand the release and supersaturation mechanisms of HPMC-AS based ASDs. Since previously reported analytical methods were unable to quantify HPMC-AS in a complex medium with enough sensitivity, we hereby developed a high-sensitivity HPLC-ELSD (evaporative light scattering detector) method with satisfactory specificity, linearity, accuracy and precision, to quantify HPMC-AS down to 20 μg/mL in dissolution media, with the presence of various commonly used pharmaceutical excipients. With the assistance of this method, we compared the intrinsic dissolution rates (IDR) of both the drug and the polymer of posaconazole ASDs based on different types of HPMC-AS. We observed that: 1) For ASDs that were spray dried and uniformly mixed, drug and polymer released simultaneously into the medium with practically identical IDRs slower than the IDR of pure HPMC-AS; 2) For ASDs that were heterogeneously mixed, IDRs of the drug and polymer were significantly slower or faster than the IDRs of the drug and polymer of the uniform ASDs, respectively. In summary, the high sensitivity HPLC-ELSD method established here can be readily applied to quantify HPMC-AS in various dissolution media, thus helps to reveal the release kinetics and mechanisms of different HPMC-AS based ASDs.Graphical abstractUnlabelled Image
  • Aggressive conditions during primary drying as a contemporary approach to
           optimise freeze-drying cycles of biopharmaceuticals
    • Abstract: Publication date: Available online 10 July 2018Source: European Journal of Pharmaceutical SciencesAuthor(s): Maja Bjelošević, Katarina Bolko Seljak, Uroš Trstenjak, Manca Logar, Boris Brus, Pegi Ahlin Grabnar Freeze-drying is the method of choice to dry formulations with biopharmaceutical drugs, to enhance protein stability. This is usually done below the glass transition temperature of maximally freeze-concentrated solutions (Tg′), to avoid protein aggregation, preserve protein activity, and obtain pharmaceutically ‘elegant’ cakes. Unfortunately, this is a lengthy and energy-consuming process. However, it was recently shown that drying above Tg′ or even above the collapse temperature (Tc) is not necessarily detrimental for stability of biopharmaceuticals, and hence provides an attractive option for freeze-drying cycle optimisation. The goal of the present study was to optimise the freeze-drying cycle for a model IgG monoclonal antibody (20 mg/mL) in sucrose and sucrose/glycine formulations, by reducing primary drying time. To study the impact of shelf temperature (Ts) and chamber pressure on product temperature (Tp), one conventional and five aggressive cycles were tested. Aggressive conditions during primary drying were achieved by increasing Ts from −20 °C (conventional cycle) to 30 °C, with chamber pressure set to 0.1 mbar, 0.2 mbar or 0.3 mbar. These combinations of Ts and chamber pressure resulted in Tp well above Tg′, and in some cases, even above Tc, without causing macrocollapse. Other critical quality attributes of the products were also within the expected ranges, such as reconstitution time and residual water content. Physical stability was tested using size exclusion chromatography, dynamic light scattering, and micro-flow imaging. All of the lyophilised samples were exposed to stress and the intended storage conditions, with no impacts on the product seen. These data show that implementation of aggressive conditions for the investigated formulations is possible and can significantly contribute to the reduction of primary drying times by up to 54% (from 48 to 22 h) in comparison to conventional freeze-drying.Graphical abstractUnlabelled Image
  • Surface functionalized dendrimers as controlled-release delivery
           nanosystems for tumor targeting
    • Abstract: Publication date: Available online 9 July 2018Source: European Journal of Pharmaceutical SciencesAuthor(s): Maryam Ghaffari, Gholamreza Dehghan, Fereydoon Abedi-Gaballu, Soheila Kashanian, Behzad Baradaran, Jafar Ezzati Nazhad Dolatabadi, Dusan Losic Dendrimers are nano-sized and three-dimensional macromolecules with well-defined globular architecture and are widely used in various aspects such as drug and gene delivery owing to multivalent and host-guest entrapment properties. However, dendrimers like other nanomaterials have some disadvantages for example rapid clearance by reticuloendothelial system, toxicity due to interaction of amine terminated group with cell membrane, low transfection efficiency and lack of controlled release behavior, which reduce their therapeutic efficiency. To solve these problems, surface functionalization of dendrimers can be carried out. Surface functionalization not only mitigates this obstacle but also renders excessive specificity to dendrimer to improve efficiency of cancer therapy. Specific properties in cancer cell compared to normal cells such as overexpression of various receptors and difference in biological condition like pH, temperature and redox of tumor environment can be an appropriate strategy to increase site-specific targeting efficiency. Therefore, in this article we focus on numerous functionalization strategies, which are used in the modification of dendrimers through attachment of lipid, amino acid, protein/peptide, aptamer, vitamin, antibody. Moreover, increased biocompatibility, site-specific delivery based on various ligands, enhanced transfection efficiency, sustained and controlled release behavior based on stimuli responsiveness are benefits of functionalized dendrimer which we discuss in this review. Overall, these functionalized dendrimers can open a new horizon in the field of targeted drug and gene delivery.Graphical abstractUnlabelled Image
  • pH-permeability profiles for drug substances: Experimental detection,
           comparison with human intestinal absorption and modelling
    • Abstract: Publication date: Available online 6 July 2018Source: European Journal of Pharmaceutical SciencesAuthor(s): Mare Oja, Uko Maran The influence of pH on human intestinal absorption is frequently not considered in early drug discovery studies in the modelling and subsequent prediction of intestinal absorption for drug candidates. To bridge this gap, in this study, experimental membrane permeability data were measured for current and former drug substances with a parallel artificial membrane permeability assay (PAMPA) at different pH values (3, 5, 7.4 and 9). The presented data are in good agreement with human intestinal absorption, showing a clear influence of pH on the efficiency of intestinal absorption. For the measured data, simple and general quantitative structure-activity relationships (QSARs) were developed for each pH that makes it possible to predict the pH profiles for passive membrane permeability (i.e., a pH-permeability profile), and these predictions coincide well with the experimental data. QSARs are also proposed for the data series of highest and intrinsic membrane permeability. The molecular descriptors in the models were analysed and mechanistically related to the interaction pattern of permeability in membranes. In addition to the regression models, classification models are also proposed. All models were successfully validated and blind tested with external data. The models are available in the QsarDB repository ( abstractUnlabelled Image
  • Population, basicity and partition of short-lived conformers.
           Characterization of baclofen and pregabalin, the biaxial, doubly rotating
           drug molecules
    • Abstract: Publication date: Available online 5 July 2018Source: European Journal of Pharmaceutical SciencesAuthor(s): Tamás Pálla, Gergő Tóth, Márta Kraszni, Arash Mirzahosseini, Béla Noszál Populations, protonation constants and octanol-water partition coefficients were determined and assigned specifically to fast interconverting individual conformers, exemplified in baclofen and pregabalin, the GABA-related drug molecules of biaxial, double rotations. Rotamer statuses along both axes in water and octanol were elucidated from 1H NMR vicinal coupling constants. Conformer abundances were obtained by the appropriate combination of the rotamer populations in the two adjacent moieties in the molecule. The bulky aromatic group in baclofen versus the aliphatic side chain of pregabalin explains why baclofen exists mainly in trans-trans conformeric form, throughout the pH range, unlike pregabalin that has no any highly dominant form. Characteristically enough, for pregabalin, the lipophilicity of the conformers is primarily influenced by the conformation state. Conformers in gauche state are of higher lipophilicity. The conformers of the two compounds were ranked by their membrane-influx and –outflow propensities.Graphical abstractUnlabelled Image
  • A novel biocompatible NiII tethered moiety as a glucose uptake agent and a
           hit against methicillin-resistant Staphylococcus aureus
    • Abstract: Publication date: Available online 5 July 2018Source: European Journal of Pharmaceutical SciencesAuthor(s): Manasa Kongot, Neeraj Dohare, Vishal Singh, Nitin Kumar Singhal, Rajan Patel, Amit Kumar In the efforts to develop a biocompatible transition metal complex as a drug alike for some of the prevailing non-communicable diseases (NCDs) and communicable diseases (CDs), a novel binuclear NiII compound [{NiII(hpdbal-sbdt)}2] (2) has been synthesized by the reaction of Ni(OAc)2.4H2O and H2hpdbal-sbdt (1) [1 is a dibasic tridentate ONS2− donor Schiff base ligand obtained by the condensation of 2-hydroxy-5-(phenyldiazenyl)benzaldehyde (Hhpdbal) and S-benzyldithiocarbazate (Hsbdt)]. Both ligand 1 and compound 2 were structurally characterized in the solid and solution state using various spectroscopic techniques like ATIR, 1H NMR, 13C NMR, TGA, FESEM, EDS and CHNS analysis. The antidiabetic activity of H2hpdbal-sbdt (1) and [{NiII(hpdbal-sbdt)}2] (2) were assessed using 2-NBDG uptake assay. The assay results showed 85% and 95% of fluorescent glucose uptake by insulin resistant HePG2 cells treated with compounds 1 and 2 respectively. The 2-NBDG uptake by the cells treated with the compound 2 was observed to be comparable to the standard antidiabetic drug metformin. Compounds 1 and 2 were also tested against five bacterial and two fungi strains in order to evaluate pathogen killing activity. Compound 2 showed significant inhibitory action towards the methicillin-resistant Staphylococcus aureus (MRSA) strain with an MIC value of 2 μg/mL whereas the ligand 1 was found to be inactive. Furthermore, the interactive nature of compound 2 with a model serum carrier protein bovine serum albumin (BSA) was studied using a multi-spectroscopic approach which provided an insight into the nature and extent of binding, conformational changes and the quenching of amino acid residues of the protein.Graphical abstractUnlabelled Image
  • Study on process parameters and optimization of microencapsulation based
           on phase separation
    • Abstract: Publication date: Available online 5 July 2018Source: European Journal of Pharmaceutical SciencesAuthor(s): M. Lengyel, E. Balogh, D. Szerőczei, Cs. Dobó-Nagy, Zs. Pápay, V. Stömmer, I. Klebovich, I. Antal As surfactants are capable of influencing the droplet formation, our study primarily aims the investigation of the effect of a nonionic surfactant e.g. Polysorbate 80 on the formation of microspheres on the course of vibrating nozzle method with coacervation. The experiments also concern the impact of the different process parameters (e.g. vibration frequency, feed rate and voltage) on the shape and size distribution of microspheres characterized by laser diffraction size determination completed with particle image analysis. The calcium-alginate microspheres were processed using freeze-drying to ensure solid state with better drug carrier capability.Addition of isomalt was advantageous in the formation of freeze-dried microspheres at low alginate concentration, which was explained by micro-CT analysis of the constructed particle structure. The internal three-dimensional network of calcium alginate demonstrated a more cancellous architecture ameliorating the roundness of microparticles.Graphical abstractUnlabelled Image
  • Functionalized Graphene Oxide as a nanocarrier of new Copper (II)
           complexes for targeted therapy on nasopharyngeal carcinoma
    • Abstract: Publication date: Available online 4 July 2018Source: European Journal of Pharmaceutical SciencesAuthor(s): Guo Li, Yanfang Yang, Rui Zhou, Fayan Meng, Xuehua Li Cancer cell targeted therapy using a biocompatible targeted drug delivery system can increase the therapeutic effects of cellular cancer therapy. Here, we report a Folic Acid (FA) and polyethyleneimine (PEI) functionalized Graphene Oxide (GO) nanocarrier, FA-PEI-GO, used to deliver two new Copper complexes into the folate-receptor-positive nasopharyngeal carcinoma cell line. GO was prepared by modified Hummers method and then decorated by PEI and FA. Afterwards, the material was characterized by the X-ray photoelectron spectra (XPS), Fourier transform infrared spectroscopy (FT-IR), scanning electron microscope (SEM), and atomic force microscope (AFM). Copper complexes were synthesized by a hydrothermal method and then characterized by single crystal X-ray diffraction analysis. Cytotoxicity assessment of the complexes illustrated that the IC50 values against the nasopharyngeal carcinoma cell lines, HNE-1 and CNE-2, were, respectively, 17.7 ± 1.2, 13.2 ± 1.9, 6.7 ± 0.8, 2.9 ± 0.7 μM. Flow cytometry findings suggested that both complexes were capable of decreasing cancer cell viability through causing late-stage cell apoptosis. The obtained targeted drug delivery systems had good biocompatibility and stability. Compared with Cis-Dichlorodiamineplatinum (CDDP), the non-specific antitumor drug normally used in chemotherapy, one of the obtained agents had similar therapeutic effect while the other had significantly higher activity, suggesting future possible application of this new targeted therapy against nasopharyngeal carcinoma.Graphical abstractUnlabelled Image
  • Preclinical pharmacokinetics of benznidazole-loaded interpolyelectrolyte
           complex-based delivery systems
    • Abstract: Publication date: Available online 3 July 2018Source: European Journal of Pharmaceutical SciencesAuthor(s): Mónica Cristina García, María Laura Guzman, Martín A. Himelfarb, Nicolás J. Litterio, María Eugenia Olivera, Alvaro Jimenez-Kairuz Benznidazole (BZ), first-line drug for Chagas treatment, is available as immediate-release tablets. High frequency of administration, long-term therapy, and side effects of BZ conspire against treatment adherence, and negatively impact in therapeutic success. We have developed BZ-loaded interpolyelectrolyte complexes (IPECs) composed of polymethacrylates (EE-EL-BZ) or polysaccharides (Ch-AA-BZ) for controlled BZ release. This work aimed to evaluate their preclinical pharmacokinetics compared to Abarax® (reference treatment) and to correlate them with the in vitro BZ release. A randomization schedule with a 3 × 2 cross-over design was used. Each healthy dog received a single oral dose of 100 mg of BZ from EE-EL-BZ, Ch-AA-BZ or Abarax®. BZ quantification was performed in plasma by a validated HPLC-UV method. Moreover, in silico simulations using the pharmacokinetic software PK Solutions 2.0™ were calculated for the multiple-dose administration at two dose regimens: 100 mg of BZ administered every 12 and 24 h. Also, the relationship between in vitro dissolution and in vivo plasma BZ concentration profiles in a single step was model for IVIVC analysis. BZ was rapidly absorbed from all formulations. The Cmax value for Ch-AA-BZ was 32% higher than reference (p 
  • Concentration-dependent plasma protein binding: Expect the unexpected
    • Abstract: Publication date: Available online 3 July 2018Source: European Journal of Pharmaceutical SciencesAuthor(s): Roger L. Nation, Ursula Theuretzbacher, Brian T. Tsuji, International Society of Anti-Infective Pharmacology (ISAP) The unbound fraction of a drug in plasma can profoundly influence both its pharmacokinetics and pharmacodynamics. For most drugs, the unbound fraction is relatively constant across the clinically relevant range of concentrations in a given individual. Nonlinear plasma protein binding involving saturation of binding sites results in increasing unbound fraction as the concentration of the drug increases, a phenomenon that is consistent with the law of mass action and is well recognized. Not widely appreciated is that some drugs undergo atypical concentration-dependent binding to plasma proteins, whereby the unbound fraction decreases with increasing concentration. In this article we review the drugs for which atypical nonlinear plasma protein binding has been reported. For each drug, the evidence for the phenomenon is presented and the proposed mechanism discussed. Also reviewed are the potential implications of atypical nonlinearity in plasma protein binding. Highlighted is the importance of understanding the relationship between unbound fraction and plasma drug concentration during the preclinical and early clinical stages of drug development, and during the routine clinical use of a drug especially if therapeutic drug monitoring is used to assist in optimization of the dosing regimen. The lesson is that the unexpected concentration-dependent behavior that has been observed for a number of drugs should be expected to occur for some other drugs.Graphical abstractUnlabelled Image
  • Right filter-selection for phase separation in equilibrium solubility
    • Abstract: Publication date: Available online 30 June 2018Source: European Journal of Pharmaceutical SciencesAuthor(s): Gergely Völgyi, Dóra Csicsák, Krisztina Takács-Novák The phase separation is a crucial step in equilibrium solubility measurements. In the standardized protocol of saturation shake-flask method, sedimentation is proposed as the safest technique. However filtration is widely used in pharma practice. In this paper the effect of the filtration on the measured equilibrium solubility results is presented. The equilibrium solubility values of four model compounds, namely diclofenac sodium, hydrochlorothiazide, papaverine hydrochloride and progesterone were determined at various pH values using the saturation shake-flask method. Two phase separation techniques (sedimentation and filtration) were applied for the separation of the solid from the saturated solution. Four membrane filters, polyvinylidene fluoride (PVDF), polyether sulfone (PES), polytetrafluoroethylene (PTFE) and nylon, as well as an analytical filter paper were investigated. The results obtained by filtration were compared with those measured by sedimentation and the distortion effect of the filter (DEF) on solubility results was expressed in %. The results showed that the filter material type is able to remarkably influence the results in solubility measurements. In several cases, the significant adsorption to the filter caused high inaccuracy in the measured concentration value, more over in some cases failed to work at all. As a main conclusion of this work, if the step of filtration is inevitable, the adsorption to the filter can be mitigated with the appropriate filter type selection what needs some experiences and knowledge about the acid-base chemistry and polar/apolar nature of the sample.Graphical abstractUnlabelled Image
  • Toxicology study for magnetic injection of prednisolone into the rat
    • Abstract: Publication date: Available online 19 June 2018Source: European Journal of Pharmaceutical SciencesAuthor(s): M. Shimoji, B. Ramaswamy, M.I. Shukoor, P. Benhal, A. Broda, S. Kulkarni, P. Malik, B. McCaffrey, J.-F. Lafond, A. Nacev, I.N. Weinberg, B. Shapiro, D.A. Depireux This paper investigates the safety of a novel ‘magnetic injection’ method of delivering therapy to the cochlea, in a rodent model. In this method of administration, a magnetic field is employed to actively transport drug-eluting superparamagnetic iron-oxide core nanoparticles into the cochlea, where they then release their drug payload (we delivered the steroid prednisolone). Our study design and selection of control groups was based on published regulatory guidance for safety studies that involve local drug delivery. We tested for both single and multiple delivery doses to the cochlea, and found that magnetic delivery did not harm hearing. There was no statistical difference in hearing between magnetically treated ears versus ears that received intra-tympanic steroid (a mimic of a standard-of-care for sudden sensorineural hearing loss), both 2 and 30 days after treatment. Since our treatment is local to the ear, the levels of steroid and iron circulating systemically after our treatment were low, below mass-spectrometry detection limits for the steroid and no different from normal for iron. No adverse findings were observed in ear tissue histopathology or in animal gross behavior. At 2 and 30 days after treatment, inflammatory changes examined in the ear were limited to the middle ear, were very mild in severity, and by day 90 there was ongoing and almost complete reversibility of these changes. There were no ear tissue scarring or hemorrhage trends associated with magnetic delivery. In summary, after conducting a pre-clinical safety study, no adverse safety issues were observed.Graphical abstractUnlabelled Image
  • Inner ear drug delivery: Recent advances, challenges, and perspective
    • Abstract: Publication date: Available online 21 May 2018Source: European Journal of Pharmaceutical SciencesAuthor(s): Jinsong Hao, S. Kevin Li Effective and safe treatment of auditory and vestibular diseases has become increasingly dependent on inner ear drug delivery systems. This review highlights recent advances in inner ear drug delivery research and technologies. The focus is on strategies to overcome delivery barriers and to improve drug residence and targeting, with special attention to in vivo animal and human studies. The research in gene and stem cell delivery to the inner ear is briefly reviewed. Newly developed research tools to address experimental challenges and safety issues are discussed. Local drug delivery to the inner ear with non-invasive or minimally invasive approaches still remains challenging. Nanocarrier-based systems with sustained and targeted delivery properties may be promising for future clinical applications. Precisely controlled intratympanic and intracochlear administration with minimized trauma to the delicate inner ear represents the future perspective in inner ear drug research and development. Trans-oval window delivery may be promising as it allows direct delivery of drugs to the vestibule for vestibular disorders while avoiding the undesired effects due to drug distribution to the cochlea.Graphical abstractUnlabelled Image
  • Hybrid Ear Cubes for local controlled dexamethasone delivery to
           the inner ear
    • Abstract: Publication date: Available online 1 May 2018Source: European Journal of Pharmaceutical SciencesAuthor(s): M. Gehrke, J. Verin, D. Gnansia, G. Tourrel, M. Risoud, C. Vincent, F. Siepmann, J. Siepmann A new type of miniaturized implants for local controlled drug delivery to the inner ear is proposed: Hybrid Ear Cubes. They are composed of two main parts: (i) a cylinder, which is placed into a tiny hole (
  • Mitochondria-targeting nanomedicine: An effective and potent strategy
           against aminoglycosides-induced ototoxicity
    • Abstract: Publication date: Available online 21 April 2018Source: European Journal of Pharmaceutical SciencesAuthor(s): Shuang Zhou, Yanhui Sun, Xiao Kuang, Shanshan Hou, YinXian Yang, Zhenjie Wang, Hongzhuo Liu We report a proof-of-concept for the development of mitochondria-targeting nanoparticles (NPs) loaded with geranylgeranylacetone (GGA) to protect against a wide range of gentamicin-induced ototoxicity symptoms in a zebrafish model. The polymeric NPs were functionalized with a mitochondrial-homing peptide (d‑Arg‑Dmt‑Orn‑Phe‑NH2) and exhibited greater mitochondrial uptake and lower gentamicin uptake in hair cells via mechanotransduction (MET) channels and tuned machinery in the hair bundle than the ordinary NPs did. Blockade of MET channels rapidly reversed this effect, indicating the reversible responses of hair cells to the targeting NPs were mediated by MET channels. Pretreatment of hair cells with mitochondria-targeting GGA-loaded NPs exhibited a superior acute or chronic protective efficacy against subsequent exposure to gentamicin compared with unmodified formulations. Mitochondrial delivery regulating the death pathway of hair cells appeared to cause the therapeutic failure of untargeted NPs. Thus, peptide-directed mitochondria-targeting NPs may represent a novel therapeutic strategy for mitochondrial dysfunction-linked diseases.Graphical abstractUnlabelled Image
  • Is oval window transport a royal gate for nanoparticle delivery to
           vestibule in the inner ear'
    • Abstract: Publication date: Available online 28 February 2018Source: European Journal of Pharmaceutical SciencesAuthor(s): Shan Ding, Shibao Xie, Weiquan Chen, Lu Wen, Junyi Wang, Fan Yang, Gang Chen Drug delivery to the inner ear by nanomedicine strategies has emerged as an effective therapeutic approach for the management of inner ear diseases including hearing and balance disorders. It is well accepted that substance enters the perilymph from the middle ear through the round window membrane (RWM), but the passage through the oval window (OW) has long been neglected. Up to now, researchers still know little about the pathway via which nanoparticles (NPs) enter the inner ear or how they reach the inner ear following local applications. Herein, we engineered fluorescence traceable chitosan (CS) NPs, investigated the NP distribution within cochlear and vestibular organs, and assessed the availability of RWM and OW pathways to NP transport. Intriguingly, there were high levels of CS NPs in vestibular hair cells, dark cells and supporting cells, but negligible ones in cochlear hair cells and epithelial cells after intratympanic administration. However, the NPs were visualized in two cell models, L929 and HEI-OC1 cell lines, and in the hair cells of cochlear explants after co-incubation in vitro. These combined studies implied that CS NPs might enter the vestibule directly through the OW and then preferentially accumulated in the cells of vestibular organs. Thus, in vivo studies were carried out and clearly revealed that CS NPs entered the inner ear through both the RWM and OW, but the latter played a governing role in delivering NPs to the vestibule with vivid fluorescence signals in the thin bone of the stapes footplate. Overall, these findings firstly suggested that the OW, as a royal gate, afforded a convenient access to facilitate CS NPs transport into inner ear, casting a new light on future clinical applications of NPs in the effective treatment of vestibular disorders by minimizing the risk of hearing loss associated with cochlear hair cell pathology.Graphical abstractUnlabelled Image
  • Evaluation of a transtympanic delivery system in Mus musculus for
           extended release steroids
    • Abstract: Publication date: Available online 10 January 2018Source: European Journal of Pharmaceutical SciencesAuthor(s): Nathan H. Dormer, Jennifer Nelson-Brantley, Hinrich Staecker, Cory J. Berkland ObjectiveThe current investigation evaluated a novel extended release delivery system for treating inner ear diseases. The platform technology consists of a film forming agent (FFA) and microsphere component to localize and extend drug delivery within the ear.Study designStudies evaluated dissolution kinetics of microspheres with multiple encapsulates, testing of a variety of FFAs, and ability to localize to the round window membrane in mice in vivo.SettingStudies were completed at Orbis Biosciences and The University of Kansas Medical Center.SubjectsIn conjunction with in vitro characterization, an infrared dye-containing microsphere formulation was evaluated for round window membrane (RWM) localization and general tolerability in C57/BL6 Mus musculus for 35 days. Methods: In vitro characterization was performed using upright diffusion cells on cellulose acetate membranes, with drug content quantified by high performance liquid chromatography. Mus musculus dosing of infrared dye-containing microspheres was performed under anesthesia with a 27 GA needle and 2.0 μL injection volumeResultsIn vitro dissolution demonstrates the ability of the FFA with microsphere platform to release steroids, proteins, peptides, and nucleic acids for at least one month, while necroscopy shows the ability of the FFA with dye-loaded microspheres to remain localized to Mus musculus RWM for the same period of time, with favorable tolerability. Conclusions: Combining FFA and microsphere for localized drug delivery may enable cost-effective, extended release local delivery to the inner ear of new and existing small molecules, proteins, peptides, and nucleic acids.Graphical abstractUnlabelled Image
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