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Pharmaceutical Research
Journal Prestige (SJR): 1.077
Citation Impact (citeScore): 3
Number of Followers: 145  
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 1573-904X - ISSN (Online) 0724-8741
Published by Springer-Verlag Homepage  [2351 journals]
  • Evaluation of Antiproliferative Activity, Safety and Biodistribution of
           Oxaliplatin and 5-Fluorouracil Loaded Lactoferrin Nanoparticles for the
           Management of Colon Adenocarcinoma: an In Vitro and an In Vivo Study
    • Authors: Farhan Ahmed; Sonali Kumari; Anand Kumar Kondapi
      Abstract: Purpose Colon adenocarcinoma is the most common form of gastro intestinal tract cancer, predominantly in ageing population. Chemotherapy with 5-Fluorouracil and oxaliplatin is an indispensable treatment regimen, nevertheless having limitation of systemic toxicity and lower therapeutic index. The present study is based on evaluation of anti-proliferative potential, pharmacokinetics parameters, safety profile, biodistribution and efficacy of 5-FU/oxaliplatin loaded lactoferrin nanoparticles in cell lines and wistar rats in order to overcome the above limitation. Methods Nanoparticles were prepared by Water-in-oil process. The anti-proliferative efficacy and mode of cellular entry was evaluated in COLO-205 cells. The pharmacokinetics and biodistribution analysis were performed in healthy rats while efficacy and safety assay were performed in ACF induced rats. Results 5-FU and oxaliplatin loaded nanoparticles shows enhanced antiproliferative activity as compare to free drugs in COLO-205 cells. Lactoferrin nanoparticles also improve the pharmacokinetics profile, safety parameters and efficacy of 5-FU and Oxaliplatin. Conclusion Lactoferrin nanoparticles demonstrated an attractive drug delivery module to manage the colon adenocarcinoma as it has improved the antiproliferative activity of 5-FU and Oxaliplatin against colon adenocarcinoma cells. Moreover, it also improves the pharmacokinetic profile and safety parameters of the same drug in wistar rat.
      PubDate: 2018-07-16
      DOI: 10.1007/s11095-018-2457-7
      Issue No: Vol. 35, No. 9 (2018)
  • Barriers to Effective Drug Treatment for Brain Metastases: A
           Multifactorial Problem in the Delivery of Precision Medicine
    • Authors: Minjee Kim; Sani H. Kizilbash; Janice K. Laramy; Gautham Gampa; Karen E. Parrish; Jann N. Sarkaria; William F. Elmquist
      Abstract: The treatment of metastatic lesions in the brain represents a serious unmet medical need in the field of neuro-oncology. Even though many effective compounds have demonstrated success in treating peripheral (non-CNS) tumors with targeted agents, one aspect of this lack of success in the brain may be related to poor delivery of otherwise effective compounds. Many factors can influence the brain delivery of these agents, but one key barrier is a heterogeneously “leaky” BBB that expresses efflux transporters that limit the BBB permeability for many targeted agents. Future success in therapeutics for brain metastases must take into account the adequate delivery of “active, free drug” to the target, and may include combinations of targeted drugs that are appropriate to address each individual patient’s tumor type. This review discusses some issues that are pertinent to precision medicine for brain metastases, using specific examples of tumor types that have a high incidence of brain metastases.
      PubDate: 2018-07-12
      DOI: 10.1007/s11095-018-2455-9
      Issue No: Vol. 35, No. 9 (2018)
  • 3D Printing in Pharmaceutical and Medical Applications – Recent
           Achievements and Challenges
    • Authors: Witold Jamróz; Joanna Szafraniec; Mateusz Kurek; Renata Jachowicz
      Abstract: Growing demand for customized pharmaceutics and medical devices makes the impact of additive manufacturing increased rapidly in recent years. The 3D printing has become one of the most revolutionary and powerful tool serving as a technology of precise manufacturing of individually developed dosage forms, tissue engineering and disease modeling. The current achievements include multifunctional drug delivery systems with accelerated release characteristic, adjustable and personalized dosage forms, implants and phantoms corresponding to specific patient anatomy as well as cell-based materials for regenerative medicine. This review summarizes the newest achievements and challenges of additive manufacturing in the field of pharmaceutical and biomedical research that have been published since 2015. Currently developed techniques of 3D printing are briefly described while comprehensive analysis of extrusion-based methods as the most intensively investigated is provided. The issue of printlets attributes, i.e. shape and size is described with regard to personalized dosage forms and medical devices manufacturing. The undeniable benefits of 3D printing are highlighted, however a critical view resulting from the limitations and challenges of the additive manufacturing is also included. The regulatory issue is pointed as well.
      PubDate: 2018-07-11
      DOI: 10.1007/s11095-018-2454-x
      Issue No: Vol. 35, No. 9 (2018)
  • Effect of Tumor Relevant Acidic Environment in the Interaction of a N
           -hydroxyindole-2-Carboxylic Derivative with the Phospholipid Bilayer
    • Authors: Daniela Monti; Silvia Tampucci; Erica Zucchetti; Carlotta Granchi; Filippo Minutolo; Anna Maria Piras
      Abstract: Purpose The inhibitors of the human isoform 5 of lactate dehydrogenase (hLDH5) have attracted growing interest as efficient anti-cancer agents. In the present paper, the interactions between an efficient hLDH5 inhibitor (N-hydroxyindole-2-carboxylic derivative) and lipid bilayers based on dipalmitoylphosphatidylcholine (DPPC) were investigated. Additionally, since interstitial acidification plays a key role in tumor pathogenesis and tumor drug therapy, the effect of acidic pH was assessed and correlated to DPPC/drug interaction. Methods Four different techniques were used: differential scanning calorimetry, dynamic light scattering, UV-VIS second derivative spectrometry and attenuated total reflection Fourier transformed infrared spectroscopy. Results All techniques concur in highlighting a structural change of lipid assembly, susceptible both to pH change and to the presence of the antitumor compound. Lipid vesicles appeared more compact at the lower pH, since the thermal pre-transition from the lamellar gel phase to the ripple gel phase was absent at pH 7.4 and the infrared analysis revealed a stronger acyl chain packing as well as a different hydration degree. Drug interaction was mainly detected in the lipid region including the ester linkages and the first portion of the acyl chains. Furthermore, a lower drug partitioning was recorded at pH 6.6. Conclusions The investigated antitumor agent possesses a stable negative charge at the investigated pH values, thus the lower interaction at the acidic pH is mainly ascribable to an environmental effect on lipid assembly. Therefore, drug efficacy under tumor acid conditions may be hampered by the observed lipid membrane constraints, and suggest for the development of suitable prodrugs.
      PubDate: 2018-07-09
      DOI: 10.1007/s11095-018-2449-7
      Issue No: Vol. 35, No. 9 (2018)
  • Safety Assessment of Formulation Vehicles Following Intravitreal
           Administration in Rabbits
    • Authors: Shirley A. Aguirre; Hovhannes J. Gukasyan; Husam S. Younis; Wenhu Huang
      Abstract: Purpose Evaluate 21 formulation vehicles administered to rabbits after intravitreal injection for tolerability and safety. Methods Forty-two Dutch Belted rabbits were anesthetized, and the eyes received a single intravitreal injection of the excipient formulation. Clinical signs and ocular irritation responses were recorded twice daily for 7 days and microscopic evaluation of the eyes, optic nerve, and eyelids was completed at 1-week post treatment. Results Saline (≥ 300 mOsm and ≤ 592 mOsm at pH 7.0 or 300 mOsm at pH 8.0) and 10 formulation excipients; (10% w/v PEG 3350 at pH 7.4, 1% polysorbate 21 at pH 7.4, PVA at pH 7.0, 0.2% polysorbate 80 at pH 7.2, 0.2% Pluronic F108® at pH 7.3, 2%, 100 mM sodium sulfate at pH 3.2, 2 mM sodium glycocholate at pH 7.4, and 275 mM D-mannitol pH 7.0 in sterile water, and 100 mM sodium phosphate in combination with 0.9% NaCl 300 mOsm and 0.01% or 0.05% polysorbate 80 at pH 7.4) considered as formulation vehicles for intravitreal injectables, were well-tolerated in rabbits. Clinical signs were transient and microscopic changes were not observed. Conclusions Of the 21 formulation vehicles evaluated, 10 formulation vehicles were well-tolerated in rabbits and feasible candidates for future investigations.
      PubDate: 2018-07-09
      DOI: 10.1007/s11095-018-2450-1
      Issue No: Vol. 35, No. 9 (2018)
  • A Multiscale Physiologically-Based Pharmacokinetic Model for Doxorubicin
           to Explore its Mechanisms of Cytotoxicity and Cardiotoxicity in Human
           Physiological Contexts
    • Authors: Hua He; Can Liu; Yun Wu; Xinyuan Zhang; Jianghong Fan; Yanguang Cao
      Abstract: Purpose The mechanisms underlying doxorubicin cytotoxicity and cardiotoxicity were broadly explored but remain incompletely understood. A multiscale physiologically-based pharmacokinetic (PBPK) model was developed to assess doxorubicin dispositions at levels of system, tissue interstitial, cell, and cellular organelles. This model was adopted to explore the mechanisms-of-action/toxicity of doxorubicin in humans. Methods The PBPK model was developed by analyzing data from mice and the model was verified by scaling up to predict doxorubicin multiscale dispositions in rats and humans. The multiscale dispositions of doxorubicin in human heart and tumors were explicitly simulated to elucidate the potential mechanisms of its cytotoxicity and cardiotoxicity. Results The developed PBPK model was able to adequately describe doxorubicin dispositions in mice, rats and humans. In humans, prolonged infusion, a dosing regimen with less cardiotoxicity, was predicted with substantially reduced free doxorubicin concentrations at human heart interstitium, which were lower than the concentrations associated with oxidative stress. However, prolonged infusion did not reduce doxorubicin-DNA adduct at tumor nucleus, consistent with clinical observations that prolonged infusion did not compromise anti-tumor effect, indicating that one primary anti-tumor mechanism was DNA torsion. Conclusions A multiscale PBPK model for doxorubicin was developed and further applied to explore its cytotoxic and cardiotoxic mechanisms.
      PubDate: 2018-07-09
      DOI: 10.1007/s11095-018-2456-8
      Issue No: Vol. 35, No. 9 (2018)
  • Development of a Virosomal RSV Vaccine Containing 3D-PHAD® Adjuvant:
           Formulation, Composition, and Long-Term Stability
    • Authors: J. Lederhofer; J. van Lent; F. Bhoelan; Z. Karneva; A. de Haan; J.C. Wilschut; T. Stegmann
      Abstract: Purpose Characterization of virosomes, in late stage preclinical development as vaccines for Respiratory Syncytial Virus (RSV), with a membrane-incorporated synthetic monophosphoryl lipid A, 3D-PHAD® adjuvant. Methods Virosomes were initially formed by contacting a lipid film containing 3D-PHAD® with viral membranes solubilized with the short chain phospholipid DCPC, followed by dialysis, later by adding solubilized 3D-PHAD to viral membranes, or to preformed virosomes from DMSO. Results Virosomes formed from lipid films contained the membrane glycoproteins G and F, at similar F to G ratios but lower concentrations than in virus, and the added lipids, but only a fraction of the 3D-PHAD®. By single particle tracking (SPT), the virosome size distribution resembled that seen by cryo-electron microscopy, but dynamic light scattering showed much larger particles. These differences were caused by small virosome aggregates. Measured by SPT, virosomes were stable for 300 days. 3DPHAD ® incorporation in virosomes could be enhanced by providing the adjuvant from DCPC solubilized stock, but also by adding DMSO dissolved adjuvant to pre-formed virosomes. Virosomes with 0.1 mg/mg of 3D-PHAD®/viral protein from DMSO induced antibody titers similar to those by virosomes containing 0.2 mg/mg of DCPC-solubilized 3D-PHAD®. Conclusions Stable 3D-PHAD® adjuvanted RSV virosomes can be formulated.
      PubDate: 2018-07-03
      DOI: 10.1007/s11095-018-2453-y
      Issue No: Vol. 35, No. 9 (2018)
  • Combined Used of Rheology and LF-NMR for the Characterization of
           PVP-Alginates Gels Containing Liposomes
    • Authors: Giulia Fanesi; Michela Abrami; Francesca Zecchin; Irina Giassi; Elena Dal Ferro; Anja Boisen; Gabriele Grassi; Paolo Bertoncin; Mario Grassi; Paolo Marizza
      Abstract: Purpose This paper is based on the characterization of the rheological and Low Field NMR (LF-NMR) properties of an interpenetrated hydrogel made up by poly(N-vinyl-2-pyrrolidone) and sodium alginate. The final aim is to use the hydrogel as a delivery matrix for liposomes, widely used tools in the drug delivery field. Methods Rheology, LF-NMR, TEM, cryo-TEM, confocal laser scanning microscopy and release test were employed to characterize the interpenetrated hydrogel. Different theoretical approaches such as Flory, Chui, Scherer and Schurz theories were used to interpret the experimental results. Results We found that the crosslinking mechanisms of the two polymers produced an anti-synergistic effect on the final mechanical properties of the interpenetrated hydrogel. Instead of creating a continuous network, alginate formed isolated, cross-linked, clusters embedded in a continuous network of poly(N-vinyl-2-pyrrolidone). Additionally, gel structure significantly influenced liposome delivery. Conclusions The rheological and LF-NMR characterization were confirmed and supported by the independent techniques TEM, cryo-TEM and release tests Thus, our findings reiterate the potentiality of both rheology and LF-NMR for the characterisation of soft materials such as interpenetrated polymeric networks.
      PubDate: 2018-07-02
      DOI: 10.1007/s11095-018-2427-0
      Issue No: Vol. 35, No. 9 (2018)
  • Naïve Bayesian Models for Vero Cell Cytotoxicity
    • Authors: Alexander L. Perryman; Jimmy S. Patel; Riccardo Russo; Eric Singleton; Nancy Connell; Sean Ekins; Joel S. Freundlich
      Abstract: Purpose To advance translational research of potential therapeutic small molecules against infectious microbes, the compounds must display a relative lack of mammalian cell cytotoxicity. Vero cell cytotoxicity (CC50) is a common initial assay for this metric. We explored the development of naïve Bayesian models that can enhance the probability of identifying non-cytotoxic compounds. Methods Vero cell cytotoxicity assays were identified in PubChem, reformatted, and curated to create a training set with 8741 unique small molecules. These data were used to develop Bayesian classifiers, which were assessed with internal cross-validation, external tests with a set of 193 compounds from our laboratory, and independent validation with an additional diverse set of 1609 unique compounds from PubChem. Results Evaluation with independent, external test and validation sets indicated that cytotoxicity Bayesian models constructed with the ECFP_6 descriptor were more accurate than those that used FCFP_6 fingerprints. The best cytotoxicity Bayesian model displayed predictive power in external evaluations, according to conventional and chance-corrected statistics, as well as enrichment factors. Conclusions The results from external tests demonstrate that our novel cytotoxicity Bayesian model displays sufficient predictive power to help guide translational research. To assist the chemical tool and drug discovery communities, our curated training set is being distributed as part of the Supplementary Material. Graphical Naive Bayesian models have been trained with publically available data and offer a useful tool for chemical biology and drug discovery to select for small molecules with a high probability of exhibiting acceptably low Vero cell cytotoxicity.
      PubDate: 2018-06-29
      DOI: 10.1007/s11095-018-2439-9
      Issue No: Vol. 35, No. 9 (2018)
  • First Infusion Reactions are Mediated by FcγRIIIb and Neutrophils
    • Authors: Felix Weber; Daniel Breustedt; Sonja Schlicht; Claas A. Meyer; Jens Niewoehner; Martin Ebeling; Per-Ola Freskgard; Peter Bruenker; Thomas Singer; Michael Reth; Antonio Iglesias
      Abstract: Purpose Administration of therapeutic monoclonal antibodies (mAbs) is frequently accompanied by severe first infusion reactions (FIR). The mechanism driving FIR is still unclear. This study aimed to investigate the cellular and molecular mechanisms causing FIR in humanized mouse models and their potential for evaluating FIR risk in patients. Methods Mice humanized for Fc gamma receptors (FcγRs) were generated by recombination-mediated genomic replacement. Body temperature, cytokine release and reactive oxygen species (ROS) were measured to assess FIR to mAbs. Results Infusion of human mAb specific for mouse transferrin receptor (HamTfR) into FcγR-humanized mice, produced marked transient hypothermia accompanied by an increase in inflammatory cytokines KC and MIP-2, and ROS. FIR were dependent on administration route and Fc-triggered effector functions mediated by neutrophils. Human neutrophils also induced FIR in wild type mice infused with HamTfR. Specific knock-in mice demonstrated that human FcγRIIIb on neutrophils was both necessary and sufficient to cause FIR. FcγRIIIb-mediated FIR was abolished by depleting neutrophils or blocking FcγRIIIb with CD11b antibodies. Conclusions Human FcγRIIIb and neutrophils are primarily responsible for triggering FIR. Clinical strategies to prevent FIR in patients should focus on this pathway and may include transient depletion of neutrophils or blocking FcγRIIIb with specific mAbs.
      PubDate: 2018-06-27
      DOI: 10.1007/s11095-018-2448-8
      Issue No: Vol. 35, No. 9 (2018)
  • Use of Cyclodextrin as a Novel Agent in the SEC-HPLC Mobile Phase to
           Mitigate the Interactions of Proteins or Peptide or their Impurities with
           the Residual Silanols of Commercial SEC-HPLC Columns with Improved
           Separation and Resolution
    • Authors: Indu Javeri; Kaliappanadar Nellaiappan; Charles McNemar; Kirill Yakovlevsky; Amina Soukrati; Phanindra Velisetty; Bijay Misra
      Abstract: Purpose Accurate quantification of the intact proteins, antibodies or peptides and their impurities without interaction to silanols of HPLC column. Methods Hydroxypropyl ß Cyclodextrin (HPCD) is added in the mobile phase at different concentrations. Different commercial SEC-HPLC columns and biologics with a molecular weight ranging from 5.8 kDa to 150kDa were assessed with and without cyclodextrin. Results Addition of non-ionic sugars such as Hydroxypropyl ß Cyclodextrin in the mobile phase, resulted improved peak performance such as theoretical plates, peak resolution, peak width, peak height, and improved quantification of aggregates in biologics such as antibodies Humira and Actemra, and peptides such as insulin. There is an increase in peak height, reduced retention time, increased plate and reduced peak width with increasing concentration of cyclodextrin studied. Discussion High ionic strength, basic amino acids such as arginine, organic solvents (with a concentration low enough not to precipitate protein), sodium perchlorate and ion pairing agents in the mobile phase used for separation of peptides, proteins and antibodies to prevent silanol interaction. These commonly used solutions are not always successful, as they not only interact with the biologic, but are sometimes, not compatible. The non-ionic cyclodextrin itself does not cause protein aggregation but prevents the nonspecific binding or interaction of protein itself and thereby allowing for improved resolution, and accurate quantification of aggregates in antibodies, and peptides. The data on the separation in presence of cyclodextrin in the mobile phase showed higher peak resolution, improved peak shape, accurate apparent molecular weight, improved efficiency, and less peak tailing for biological products. Conclusion Hydroxypropyl ß Cyclodextrin in the mobile phase, resulted improved SEC-HPLC resolution, and quantitation of aggregates in biologics by preventing the interaction of biologics to silanol of the commercial SEC-HPLC columns.
      PubDate: 2018-06-26
      DOI: 10.1007/s11095-018-2446-x
      Issue No: Vol. 35, No. 9 (2018)
  • Continuous Single-Step Wet Granulation with Integrated in-Barrel-Drying
    • Authors: Adrian Schmidt; Hans de Waard; Peter Kleinebudde; Markus Krumme
      Abstract: Purpose It was investigated if continuous wet granulation and drying could be combined in a twin-screw granulator with the aim to provide (pre-)dried granules in a single-step process, i.e. in-barrel-drying. Methods To have a consistent and robust material propulsion mechanism, a twin-screw granulator was divided into two compartments. One compartment was operated at lower temperature to granulate and to pre-heat the material, while another compartment was operated at very high temperature to evaporate the granulation liquid as rapidly as possible. Design of experiments was used to investigate the in-barrel-drying process in detail. The process was further investigated for twin-screw wet granulation with API suspension feed, and compared against traditional fluidised-bed drying. Granule and compact properties were evaluated to study the process impact on the product quality. Results In-barrel-drying was demonstrated as feasible and yielded completely dried and granulated material at specific settings. The evaporation zone temperature and the processed mass of water were identified as key parameters to balance the evaporation capacity of the process and the material throughput. Granules and compacts showed an acceptable product quality. Conclusions In-barrel-drying can be used to condense the wet granulation and drying process steps into one piece of equipment, thereby limiting or even omitting downstream drying process steps.
      PubDate: 2018-06-25
      DOI: 10.1007/s11095-018-2451-0
      Issue No: Vol. 35, No. 8 (2018)
  • Preclinical Development of Cell-Based Products: a European Regulatory
           Science Perspective
    • Authors: James W. McBlane; Parvinder Phul; Michaela Sharpe
      Abstract: Purpose This article describes preclinical development of cell-based medicinal products for European markets and discusses European regulatory mechanisms open to developers to aid successful product development. Cell-based medicinal products are diverse, including cells that are autologous or allogeneic, have been genetically modified, or not, or expanded ex vivo, and applied systemically or to an anatomical site different to that of their origin; comments applicable to one product may not be applicable to others, so bespoke development is needed, for all elements - quality, preclinical and clinical. Methods After establishing how the product is produced, proof of potential for therapeutic efficacy, and then safety, of the product need to be determined. This includes understanding biodistribution, persistence and toxicity, including potential for malignant transformation. These elements need to be considered in the context of the intended clinical development. Results This article describes regulatory mechanisms available to developers to support product development that aim to resolve scientific issues prior to marketing authorization application, to enable patients to have faster access to the product than would otherwise be the case. Conclusions Developers are encouraged to be aware of both the scientific issues and regulatory mechanisms to ensure patients can be supplied with these products.
      PubDate: 2018-06-25
      DOI: 10.1007/s11095-018-2437-y
      Issue No: Vol. 35, No. 8 (2018)
  • Local Application of Pyrophosphorylated Simvastatin Prevents Experimental
    • Authors: Xiaobei Wang; Zhenshan Jia; Yosif Almoshari; Subodh M. Lele; Richard A. Reinhardt; Dong Wang
      Abstract: Purpose Simvastatin (SIM), a HMG-CoA reductase inhibitor widely prescribed for hypercholesterolemia, has been reported to ameliorate inflammation and promote osteogenesis. Its clinical applications on these potential secondary indications, however, have been hampered by its lack of osteotropicity and poor water solubility. To address this challenge, we propose to design and evaluate the therapeutic efficacy of a novel simvastatin prodrug with better water solubility and bone affinity. Method The prodrug (SIM-PPi) was synthesized by directly conjugating a SIM trimer to a pyrophosphate (PPi). It was characterized and evaluated in vitro for its water solubility, osteotropicity, toxicity, anti-inflammatory and osteoinductive properties. It was then tested for anti-inflammatory and osteoinductive properties in vivo by three weekly injections into gingiva of a ligature-induced experimental periodontitis rat model. Results In vitro studies showed that SIM-PPi has greatly improved water-solubility of SIM and shows strong binding to hydroxyapatite (HA). In macrophage culture, SIM-PPi inhibited LPS-induced pro-inflammatory cytokines (IL-1β, IL-6). In osteoblast culture, it was found to significantly increase alkaline phosphatase (ALP) activity with accelerated mineral deposition, confirming the osteogenic potential of SIM-PPi. When tested in vivo on an experimental periodontal bone-loss model, SIM-PPi exhibited a superior prophylactic effect compared to dose equivalent SIM in reducing inflammatory cells and in preserving alveolar bone structure, as shown in the histological and micro-CT data. Conclusion SIM-PPi may have the potential to be further developed for better clinical management of bone loss associated with periodontitis.
      PubDate: 2018-06-25
      DOI: 10.1007/s11095-018-2444-z
      Issue No: Vol. 35, No. 8 (2018)
  • Chemotherapeutic Delivery from a Self-Assembling Peptide Nanofiber
           Hydrogel for the Management of Glioblastoma
    • Authors: Christina Karavasili; Emmanuel Panteris; Ioannis S. Vizirianakis; Sotirios Koutsopoulos; Dimitrios G. Fatouros
      Abstract: Purpose Localized chemotherapy has gained significant impetus for the management of malignant brain tumors. In the present study, we appraised the versatility of an in-situ gel forming self-assembling peptide, ac-(RADA)4-CONH2, as a biocompatible delivery depot of the chemotherapeutic drug doxorubicin (DOX) and the anticancer agent curcumin (CUR), respectively. Methods The morphology and mechanical properties of ac-(RADA)4-CONH2 were assessed with scanning electron microscopy (SEM) and rheological studies. The in vitro drug release from ac-(RADA)4-CONH2 was monitored in phosphate-buffered saline pH 7.4. Distribution of the fluorescent actives within the peptide matrix was visualized with confocal laser scanning microscopy (CLSM). The in vitro biological performance of the ac-(RADA)4-CONH2-DOX and ac-(RADA)4-CONH2-CUR was evaluated on the human glioblastoma U-87 MG cell line. Results SEM studies revealed that the ac-(RADA)4-CONH2 hydrogel contains an entangled nanofiber network. Rheology studies showed that the more hydrophobic CUR resulted in a stiffer hydrogel compared with ac-(RADA)4-CONH2 and ac-(RADA)4-CONH2-DOX, due to the interaction of CUR with the hydrophobic domains of the peptide nanofibers as confirmed by CLSM. In vitro release studies showed a complete DOX release from ac-(RADA)4-CONH2 within 4 days and a prolonged release for ac-(RADA)4-CONH2-CUR over 20 days. An increased cellular uptake and a higher cytotoxic effect were observed for ac-(RADA)4-CONH2-DOX, compared with DOX solution. Higher levels of early apoptosis were observed for the cells treated with the ac-(RADA)4-CONH2-CUR, compared to CUR solution. Conclusions The current findings highlight the potential utility of the in-situ depot forming ac-(RADA)4-CONH2 hydrogel for the local delivery of both water soluble and insoluble chemotherapeutic drugs.
      PubDate: 2018-06-25
      DOI: 10.1007/s11095-018-2442-1
      Issue No: Vol. 35, No. 8 (2018)
  • Development of a Clinically Relevant Dissolution Method for Metaxalone
           Immediate Release Formulations Based on an IVIVC Model
    • Authors: Lucija Vuletić; M. Zahirul I. Khan; Drago Špoljarić; Maja Radić; Biserka Cetina-Čižmek; Jelena Filipović-Grčić
      Abstract: Purpose The aim of the present work was to classify metaxalone according to the Biopharmaceutics Classification System (BCS), to develop a clinically relevant dissolution method that can be used to predict the oral absorption of metaxalone and to establish an in vitro-in vivo correlation (IVIVC). Methods Solubility of the drug was studied in different pH media and permeability studies were performed using a Caco-2 cell model. The in vitro dissolution and in vivo disposition of metaxalone from 3 different immediate release (IR) tablet formulations were investigated using USP 2 apparatus and a single dose, four-way, crossover bioequivalence study in healthy humans along with an oral solution of the drug, respectively. An IVIVC was established by using a direct, differential based method. Results Metaxalone has been confirmed as a Class II drug according to BCS. Bioavailability studies performed in humans demonstrated that dissolution was the rate limiting step for bioavailability of the drug and one of the test products had significantly improved bioavailability compared to the marketed product Skelaxin®. An IVIVC model was developed that demonstrated an acceptable internal predictability. Conclusion The IVIVC demonstrated that formulation factors play a significant role in dissolution and absorption of metaxalone. A pH 4.5 dissolution medium containing 0.5% NaCl with 0.2% SLS (USP apparatus 2 at 50 rpm) is clinically relevant to predict bioavailability of the drug and is superior to the USP method in terms of the Quality by Design (QbD) concept.
      PubDate: 2018-06-22
      DOI: 10.1007/s11095-018-2434-1
      Issue No: Vol. 35, No. 8 (2018)
  • A Semi-Physiologically Based Pharmacokinetic Model Describing the Altered
           Metabolism of Midazolam Due to Inflammation in Mice
    • Authors: Ninad Varkhede; Nita Patel; William Chang; Kenneth Ruterbories; M. Laird Forrest
      Abstract: Purpose To investigate influence of inflammation on metabolism and pharmacokinetics (PK) of midazolam (MDZ) and construct a semi-physiologically based pharmacokinetic (PBPK) model to predict PK in mice with inflammatory disease. Methods Glucose-6-phosphate isomerase (GPI)-mediated inflammation was used as a preclinical model of arthritis in DBA/1 mice. CYP3A substrate MDZ was selected to study changes in metabolism and PK during the inflammation. The semi-PBPK model was constructed using mouse physiological parameters, liver microsome metabolism, and healthy animal PK data. In addition, serum cytokine, and liver-CYP (cytochrome P450 enzymes) mRNA levels were examined. Results The in vitro metabolite formation rate was suppressed in liver microsomes prepared from the GPI-treated mice as compared to the healthy mice. Further, clearance of MDZ was reduced during inflammation as compared to the healthy group. Finally, the semi-PBPK model was used to predict PK of MDZ after GPI-mediated inflammation. IL-6 and TNF-α levels were elevated and liver-cyp3a11 mRNA was reduced after GPI treatment. Conclusion The semi-PBPK model successfully predicted PK parameters of MDZ in the disease state. The model may be applied to predict PK of other drugs under disease conditions using healthy animal PK and liver microsomal data as inputs.
      PubDate: 2018-06-21
      DOI: 10.1007/s11095-018-2447-9
      Issue No: Vol. 35, No. 8 (2018)
  • Ranking Itraconazole Formulations Based on the Flux through Artificial
           Lipophilic Membrane
    • Authors: Konstantin Tsinman; Oksana Tsinman; Ram Lingamaneni; Saijie Zhu; Bernd Riebesehl; Arnaud Grandeury; Michael Juhnke; Bernard Van Eerdenbrugh
      Abstract: Purpose The goal of the study was to evaluate a miniaturized dissolution-permeation apparatus (μFLUX™ apparatus) for its ability to benchmark several itraconazole (ITZ) formulations for which in vivo PK data was available in the literature. Method Untreated and micronized powders of ITZ and various enabling formulations of ITZ (commercial Sporanox® solid dispersion, a Soluplus®-based solid dispersion and a nanosuspension) were introduced to the donor compartment of μFLUX™ apparatus. Donor and acceptor chambers were divided from each other by a lipophilic membrane. In addition to the flux evaluations, changes in solid state as a function of time were investigated to gain further insight into the flux changes observed over time for the solid dispersion formulations. Results Initial flux values from Sporanox®, the nanosuspension and the micronized ITZ showed ratios of 52/4/1 with a decreasing flux from nanosuspension and both solid dispersions after 2.5–3 h. Although the initial flux from the Soluplus® formulation was 2.2 times lower than the one observed for Sporanox®, the decrease in flux observed was milder and became ~ 2 times higher than Sporanox® after approximately 2.5 h. The total amounts of ITZ in the receiver compartment after 240 min showed the same rank order as the rodent AUCs of these formulations reported in literature. Conclusions It was demonstrated that in vitro flux measurements using lipophilic artificial membranes could correctly reproduce the rank order of PK results for ITZ formulations. The drop in flux over time for solid dispersions could be backed by experimental indications of crystallization.
      PubDate: 2018-06-20
      DOI: 10.1007/s11095-018-2440-3
      Issue No: Vol. 35, No. 8 (2018)
  • Fampridine is a Substrate and Inhibitor of Human OCT2, but not of Human
           MATE1, or MATE2K
    • Authors: Guangqing Xiao; Christopher Rowbottom; Carri Boiselle; Liang-Shang Gan
      Abstract: Purpose The renal clearance of fampridine (Fampyra®, or Ampyra®) significantly exceeds the glomerular filtration rate, suggesting active renal secretion is likely the major elimination pathway. The goal of this study was to identify the renal transporters that are involved in the renal active secretion, and elucidate the active renal secretion mechanism of fampridine. Methods The uptake of fampridine to HEK-293 cells overexpressing human OCT2, MATE1 or MATE2K was determined in the absence and presence of Cimetidine, the prototypical inhibitor of the transporters. The inhibition potential of fampridine on the renal transporters was evaluated by determining the uptake of TEA and Metformin, the probe substrates of the transporters of OCT2 and MATEs, respectively, in the absence or presence of fampridine. Results Significant time- and concentration-dependent uptake of fampridine by human OCT2 was observed. The Km and Vmax were determined as 51.0 ± 17.1 μM and 1107 ± 136 pmole/min/106 cells, respectively. Fampridine also inhibited OCT2 mediated uptake of Metformin with estimated IC50 of 66.8 μM. In contrast, there was not significant uptake of fampridine by human MATE1 or MATE2K, and fampridine did not inhibit MATE1 or MATE2K mediated uptake of TEA. Conclusion The studies indicated fampridine is a substrate and inhibitor of OCT2, but not MATE1 or MATE2K. Results from the study suggested the active renal secretion of fampridine is mediated by human OCT2 but not MATE1 or MATE2K. To our knowledge, fampridine is the first reported substrate specific to OCT2 but not to MATE1 or MATE2K.
      PubDate: 2018-06-18
      DOI: 10.1007/s11095-018-2445-y
      Issue No: Vol. 35, No. 8 (2018)
  • Investigation into the Emerging Role of the Basic Amino Acid L-Lysine in
           Enhancing Solubility and Permeability of BCS Class II and BCS Class IV
    • Authors: Hamdy Abdelkader; Zeinab Fathalla
      Abstract: Background The search for a simple and scalable approach that can improve the two key biopharmaceutical processes (solubility and permeability) for BCS Class II and BCS Class IV has still been unmet need. Purpose In this study, L-lysine was investigated as a potential excipient to tackle problems with solubility and permeability. Bendazac (Class II); quercetin and rutin (Class IV) were employed. Methods Drugs-lysine complexes in 1:1 M ratios were prepared by co-precipitation and co-grinding; characterized for solubility, partition coefficient, DSC, FTIR, SEM, dissolution rate and permeability. Chemical stability of quercetin-lysine and rutin-lysine was studied by assessing antioxidant capacity using Trolox and CUPRAC assays. Results and Conclusion Drugs-lysine salt/complexes were confirmed. Solubility enhancement factors ranged from 68- to 433-fold increases and dissolution rates were also significantly enhanced by up to 6-times, compared with drugs alone. With the exception of rutin-lysine, Papp for bendazac-lysine and quercetin-lysine enhanced by 2.3- to 4-fold. Papp for quercetin (Class IV) benefited more than bendazac (Class II) when complexed with lysine. This study warrants the use of L-lysine as a promising excipient for enhanced solubility and permeability of Class II and Class IV, providing that the solubility of the drug is ensured at ‘the door step’ of absorption sites.
      PubDate: 2018-06-18
      DOI: 10.1007/s11095-018-2443-0
      Issue No: Vol. 35, No. 8 (2018)
School of Mathematical and Computer Sciences
Heriot-Watt University
Edinburgh, EH14 4AS, UK
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