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Journal Cover Pharmaceutical Research
  [SJR: 1.189]   [H-I: 163]   [142 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 1573-904X - ISSN (Online) 0724-8741
   Published by Springer-Verlag Homepage  [2350 journals]
  • Improving Viscosity and Stability of a Highly Concentrated Monoclonal
           Antibody Solution with Concentrated Proline
    • Authors: Jessica J. Hung; Barton J. Dear; Aileen K. Dinin; Ameya U. Borwankar; Sumarth K. Mehta; Thomas T. Truskett; Keith P. Johnston
      Abstract: Purpose To explain the effects of the osmolyte proline on the protein-protein interactions (PPI), viscosity and stability of highly concentrated antibody solutions in contrast to other neutral osmolytes. Methods The viscosity of ~225 mg/mL mAb solutions was measured with proline, glycine and trehalose as a function of pH and co-solute concentration up to 1.3 M. The stability was assessed via turbidity as well as size exclusion chromatography after 4 weeks storage at 40°C. The PPI strength was assessed qualitatively via the high concentration diffusion rate by dynamic light scattering. Results Increasing proline significantly reduced the mAb viscosity and increased the colloidal stability at pH 6, but not at pH 5 further from the mAb pI. In contrast, glycine and trehalose did not improve the viscosity nor stability. The normalized diffusion coefficient at high concentration, which is inversely proportional to the attractive PPI strength, increased with proline concentration but decreased with increasing glycine. Conclusions Proline demonstrated greater efficacy for improving mAb viscosity and stability in contrast to glycine and trehalose due to its amphipathic structure and partial charge on the pyrrolidine side chain. These properties likely allow proline to screen the attractive electrostatic and hydrophobic interactions that promote self-association and high viscosities. Binary proline-histidine formulations also demonstrated greater viscosity reduction effects than histidine alone at the same total co-solute concentration, while maintaining a lower total solution osmolarity.
      PubDate: 2018-04-30
      DOI: 10.1007/s11095-018-2398-1
      Issue No: Vol. 35, No. 7 (2018)
  • Population Pharmacokinetic Modeling to Describe the Total Plasma and Free
           Brain Levels of Fluconazole in Healthy and Cryptococcus neoformans
           Infected Rats: How Does the Infection Impact the Drug’s Levels on
    • Authors: Izabel Almeida Alves; Keli Jaqueline Staudt; Fernando Olinto Carreño; Graziela de Araujo Lock; Carolina de Miranda Silva; Stela Maris Kuze Rates; Teresa Dalla Costa; Bibiana Verlindo De Araujo
      Abstract: Purpose The present work aimed to evaluate the influence of experimental meningitis caused by C. neoformans on total plasma and free brain concentrations of fluconazole (FLC) in Wistar rats. Method The infection was induced by the administration of 100 μL of inoculum (1.105 CFU) through the tail vein. Free drug in the brain was assessed by microdialisys (μD). Blood and μD samples were collected at pre-determined time points up to 12 h after intravenous administration of FLC (20 mg/kg) to healthy and infected rats. The concentration-time profiles were analyzed by non-compartmental and population pharmacokinetics approaches. Results A two-compartmental popPK model was able to simultaneously describe plasma and free drug concentrations in the brain for both groups investigated. Analysis of plasma and μD samples showed a better FLC distribution on the brain of infected than healthy animals (1.04 ± 0.31 vs 0.69 ± 0.14, respectively). The probability of target attainment was calculated by Monte Carlo simulations based on the developed popPK model for 125 mg/kg dose for rats and 400–2000 mg for humans. Conclusions FLC showed a limited use in monotherapy to the treatment of criptoccocosis in rats and humans to value of MIC >8 μg/mL.
      PubDate: 2018-04-27
      DOI: 10.1007/s11095-018-2402-9
      Issue No: Vol. 35, No. 7 (2018)
  • The Preservation of Lyophilized Human Growth Hormone Activity: how Do
           Buffers and Sugars Interact'
    • Authors: Andrea Arsiccio; Roberto Pisano
      Abstract: Purpose One of the most common classes of excipients used in protein formulations are buffers. The aim of this work is to investigate the effect of buffers on protein stabilization given by sugars during freeze drying. Methods Molecular Dynamics simulations of human growth hormone (hGH) in the presence of sucrose and trehalose were performed, and the impact of phosphate and citrate buffers on their protective action was analyzed. Results We found that buffers broke the hydrogen bonding network formed by excipients, and the consequences of this disruption of structure ordering were different in sucrose-based or trehalose-based formulations. More specifically, we observed that buffers increased protein recovery in the presence of excipients, such as sucrose, that exert their action mainly by preferential exclusion. By contrast, the opposite effect was sometimes noted in the case of excipients, such as trehalose, whose protective action is related to the formation of a highly structured matrix. Conclusions We found that buffers have important properties, other than the control of pH, that can contribute to the overall stability of proteins. Some of these properties are related to their interaction with the other components of the formulation.
      PubDate: 2018-04-26
      DOI: 10.1007/s11095-018-2410-9
      Issue No: Vol. 35, No. 7 (2018)
  • Assessment of Complement Activation by Nanoparticles: Development of a SPR
           Based Method and Comparison with Current High Throughput Methods
    • Authors: Jean-Baptiste Coty; Magali Noiray; Christine Vauthier
      Abstract: Purpose A Surface Plasmon Resonance chip (SPR) was developed to study the activation of complement system triggered by nanomaterials in contact with human serum, which is an important concern today to warrant safety of nanomedicines. Methods The developed chip was tested for its specificity in complex medium and its longevity of use. It was then employed to assess the release of complement fragments upon incubation of nanoparticles in serum. A comparison was made with other current methods assessing complement activation (μC-IE, ELISA). Results The SPR chip was found to give a consistent response for C3a release upon activation by nanoparticles. Results were similar to those obtained by μC-IE. However, ELISA detection of iC3b fragments showed an explained high non-specific background. The impact of sample preparation preceding the analysis was assessed with the newly develop SPR method. The removal of nanoparticles before analysis showed an important modification in the obtained response, possibly leading to false negative results. Conclusion The SPR chip developed in this work allows for an automated assessment of complement activation triggered by nanoparticles with possibility of multiplexed analysis. The design of the chip proved to give consistent results of complement activation by nanoparticles.
      PubDate: 2018-04-26
      DOI: 10.1007/s11095-018-2406-5
      Issue No: Vol. 35, No. 7 (2018)
  • Is the Fractional Laser Still Effective in Assisting Cutaneous
           Macromolecule Delivery in Barrier-Deficient Skin' Psoriasis and Atopic
           Dermatitis as the Disease Models
    • Authors: Woan-Ruoh Lee; Shing-Chuan Shen; Calvin T. Sung; Pei-Ying Liu; Jia-You Fang
      Abstract: Purpose Most of the investigations into laser-assisted skin permeation have used the intact skin as the permeation barrier. Whether the laser is effective in improving cutaneous delivery via barrier-defective skin is still unclear. Methods In this study, ablative (Er:YAG) and non-ablative (Er:glass) lasers were examined for the penetration of peptide and siRNA upon topical application on in vitro skin with a healthy or disrupted barrier. Results An enhanced peptide flux (6.9 fold) was detected after tape stripping of the pig stratum corneum (SC). A further increase of flux to 11.7 fold was obtained after Er:YAG laser irradiation of the SC-stripped skin. However, the application of Er:glass modality did not further raise the flux via the SC-stripped skin. A similar trend was observed in the case of psoriasiform skin. Conversely, the flux was enhanced 3.7 and 2.6 fold after treatment with the Er:YAG and the Er:glass laser on the atopic dermatitis (AD)-like skin. The 3-D skin structure captured by confocal microscopy proved the distribution of peptide and siRNA through the microchannels and into the surrounding tissue. Conclusions The fractional laser was valid for ameliorating macromolecule permeation into barrier-disrupted skin although the enhancement level was lower than that of normal skin.
      PubDate: 2018-04-26
      DOI: 10.1007/s11095-018-2413-6
      Issue No: Vol. 35, No. 7 (2018)
  • Dual Receptor Targeting Cell Penetrating Peptide Modified Liposome for
           Glioma and Breast Cancer Postoperative Recurrence Therapy
    • Authors: Yue Qiu; Qianwen Yu; Yayuan Liu; Jiajing Tang; Xuhui Wang; Zhengze Lu; Zhuping Xu; Qin He
      Abstract: Purpose Cell penetrating peptides (CPPs) were widely used as motifs for drug delivery to tumor. In former study, an RGD reverse sequence dGR was used to develop active-targeting liposome R8dGR-Lip, which showed well penetrating ability and treatment efficiency on glioma model. However, recurrence after tumor resection caused by post-operative residual cancer cells was a huge obstacle in tumor treatment. In consideration of the effective anti-cancer effect of PTX-R8dGR-Lip when treating glioma in former study, we decide to evaluate its pharmacodynamics on tumor resection models, which were more invasive and resistant. Method In vitro, the effectiveness of PTX-R8dGR-Lip in reducing tumor initiating cell (TIC) was investigated using mammosphere formation. In vivo, the inhibition efficiency of PTX-R8dGR-Lip on C6 glioma recurrence and 4 T1 breast cancer recurrence model were evaluated, including tumor bioluminescence imaging, survival rate and immumohistochemical staining, etc.. Results C6 mammosphere formation rate of PTX-R8dGR-Lip group was 48.06 ± 2.72%, and 4 T1 mammosphere formation rate of PTX-R8dGR-Lip group was 39.51 ± 4.02% when PBS group was set as 100%. C6 and 4 T1 bioluminescent tumor resected model were established, then effectiveness of different PTX-loaded preparations were evaluated on these two models. PTX-R8dGR-Lip could obviously inhibit tumor recurrence, prolong survival rate and reduce tumor tissue invasion. Conclusion PTX-R8dGR-Lip could reduce post-operative recurrence rate, prolong survival time, and decrease the proliferation of residual cancer cells through regulating the expression of recurrence-related cytokines.
      PubDate: 2018-04-26
      DOI: 10.1007/s11095-018-2399-0
      Issue No: Vol. 35, No. 7 (2018)
  • Development of Fast-Dissolving Amorphous Solid Dispersion of Itraconazole
           by Melt Extrusion of its Mixture with Weak Organic Carboxylic Acid and
    • Authors: Tapan Parikh; Abu T. M. Serajuddin
      Abstract: Purpose The purpose of this study was to explore the feasibility of developing amorphous solid dispersion (ASD) by inducing acid-base interaction at an elevated temperature using hot melt extrusion. Methods Itraconazole and glutaric acid, which do not form salt with each other, were selected as, respectively, model basic drug and weak organic acid. A 1:4:1w/w mixture of itraconazole, glutaric acid and a polymer, Kollidon®VA64, was melt extruded at 95°C. The ground extrudate was characterized by DSC and PXRD and then tested for dissolution at pH 1.2, followed by a change in pH to 5.5. Results Despite the high melting point of 168°C, itraconazole dissolved in glutaric acid at around the melting temperature of acid (~98°C), and physically stable ASD was produced when the formulation was extruded at 95°C. Capsules containing 100-mg equivalent of itraconazole dissolved rapidly at pH 1.2 producing highly supersaturated solution. When the pH was changed from 1.2 to 5.5, very fine suspensions, facilitated by the presence of Kollidon®VA64, was formed. Conclusions Physically stable ASD of itraconazole with high drug load was prepared by interaction with glutaric acid in a hot melt extruder. This may be used as a platform technology for the development ASD of most poorly water-soluble basic drugs.
      PubDate: 2018-04-25
      DOI: 10.1007/s11095-018-2407-4
      Issue No: Vol. 35, No. 7 (2018)
  • Characterization of the PEGylated Functional Upstream Domain Peptide
           (PEG-FUD): a Potent Fibronectin Assembly Inhibitor with Potential as an
           Anti-Fibrotic Therapeutic
    • Authors: Pawel Zbyszynski; Bianca R. Tomasini-Johansson; Donna M. Peters; Glen S. Kwon
      Abstract: Purpose To develop PEGylated variants of pUR4/FUD (FUD), a fibronectin assembly inhibitor, using 10 kDa, 20 kDa, and 40 kDa PEGs to evaluate their binding affinity and inhibitory potency. Methods The FUD peptide was recombinantly expressed, purified, and PEGylated at the N-terminus using 10 kDa, 20 kDa, and 40 kDa methoxy-PEG aldehyde. The PEGylates were purified and fractionated using ion-exchange chromatography. The molecular weight and degree of PEGylation of each conjugate was verified using MALDI-TOF. The binding affinity of each PEG-FUD conjugate was studied using isothermal titration colorimetry (ITC) and their inhibitory potency was characterized by a cell-based matrix assembly in vitro assay. Results The 10 kDa, 20 kDa, and 40 kDa PEG-FUD conjugates were synthesized and isolated in good purity as determined by HPLC analysis. Their molecular weight was consistent with attachment of a single PEG molecule to one FUD peptide. The binding affinity (Kd) and the fibronectin fibrillogenesis inhibitory potency (IC50) of all PEG-FUD conjugates remained nanomolar and unaffected by the addition of PEG. Conclusions Retention of FUD fibronectin binding activity following PEGylation with three different PEG sizes suggest that PEG-FUD holds promise as an effective anti-fibrotic with therapeutic potential and a candidate for further pharmacokinetic and biodistribution studies.
      PubDate: 2018-04-24
      DOI: 10.1007/s11095-018-2412-7
      Issue No: Vol. 35, No. 7 (2018)
  • Physical Stability of Amorphous Solid Dispersions: a Physicochemical
           Perspective with Thermodynamic, Kinetic and Environmental Aspects
    • Authors: Xia Lin; Yang Hu; Lei Liu; Lili Su; Na Li; Jing Yu; Bo Tang; Ziyi Yang
      Abstract: Purpose Amorphous solid dispersions (ASDs) have been widely used in the pharmaceutical industry for solubility enhancementof poorly water-soluble drugs. The physical stability, however, remainsone of the most challenging issues for the formulation development.Many factors can affect the physical stability via different mechanisms, and therefore an in-depth understanding on these factors isrequired. Methods In this review, we intend to summarize the physical stability of ASDsfrom a physicochemical perspective whereby factors that can influence the physical stability areclassified into thermodynamic, kinetic and environmental aspects. Results The drug-polymer miscibility and solubility are consideredas the main thermodynamicfactors which may determine the spontaneity of the occurrence of the physical instabilityof ASDs. Glass-transition temperature,molecular mobility, manufacturing process,physical stabilityof amorphous drugs, and drug-polymerinteractionsareconsideredas the kinetic factors which areassociated with the kinetic stability of ASDs on aging. Storage conditions including temperature and humidity could significantly affect the thermodynamicand kineticstabilityof ASDs. Conclusion When designing amorphous solid dispersions, it isrecommended that these thermodynamic, kinetic and environmental aspects should be completely investigatedand compared to establish rationale formulations for amorphous solid dispersions with high physical stability.
      PubDate: 2018-04-23
      DOI: 10.1007/s11095-018-2408-3
      Issue No: Vol. 35, No. 6 (2018)
  • Notch-1 siRNA and Methotrexate towards a Multifunctional Approach in
           Rhematoid Arthritis Management: a Nanomedicine Approach
    • Authors: Guang Zhao; Haifei Zhang
      Abstract: ABSTRACT Purpose Rheumatoid arthritis (RA) is a chronic inflammatory disease and Notch pathway plays a pivotal role in synoviocytes involved in progression of RA. Methods Herein, we have designed a self-assembled polymeric micelles based on polycaprolactone-polyethylene glycol (PCL-PEG) and polyethylenimine-polyethylene glycol (PEI-PEG) was prepared and loaded with methotrexate and Notch-1 siRNA for the effective treatment of rheumatoid arthritis. Results The MTX/siRNA-loaded polymeric micelles (siM-PM) showed appreciable cellular uptake in Raw264.7 cells which were activated with LPS and did not exhibit any toxicity to Raw264.7 and HUVEC cells. The AUC of siM-PM was 4-fold higher compared to that of free MTX while t1/2 was 6 fold for siM-PM compared to that of free drug indicating the superior pharmacokinetic parameters. Importantly, siM-PM significantly reduced the paw thickness and slowed the disease progression remarkably, indicating that siM-PM is very effective in recovering the edema in arthritic animals. Importantly, 2-fold decrease in arthritic score was observed in siM-PM treated group at the end of day 24. The data clearly reveals anti-inflammatory effect of combinational nanoparticle due to the sequence specific downregulation of Notch-1 expression in the RA clinical models. Conclusions Overall, nanomedicine-based delivery of MTX and siRNA could overcome the side effects of small molecules and could improve the therapeutic effect of siRNA in rheumatoid arthritis.
      PubDate: 2018-04-20
      DOI: 10.1007/s11095-018-2401-x
      Issue No: Vol. 35, No. 6 (2018)
  • Immediate Release 3D-Printed Tablets Produced Via Fused Deposition
           Modeling of a Thermo-Sensitive Drug
    • Authors: Wiebke Kempin; Vanessa Domsta; Georg Grathoff; Iris Brecht; Beatrice Semmling; Susan Tillmann; Werner Weitschies; Anne Seidlitz
      Abstract: Purpose Dissolution speeds of tablets printed via Fused Deposition Modeling (FDM) so far are significantly lower compared to powder or granule pressed immediate release tablets. The aim of this work was to print an actual immediate release tablet by choosing suitable polymers and printing designs, also taking into account lower processing temperatures (below 100°C) owing to the used model drug pantoprazole sodium. Methods Five different pharmaceutical grade polymers polyvinylpyrrolidone (PVP K12), polyethylene glycol 6000 (PEG 6000), Kollidon® VA64, polyethylene glycol 20,000 (PEG 20,000) and poloxamer 407 were successfully hot-melt-extruded to drug loaded filaments and printed to tablets at the required low temperatures. Results Tablets with the polymers PEG 6000 and PVP K12 and with a proportion of 10% pantoprazole sodium (w/w) demonstrated a fast drug release that was completed within 29 min or 10 min, respectively. By reducing the infill rate of PVP tablets to 50% and thereby increase the tablet porosity it was even possible to reduce the mean time for total drug release to only 3 min. Conclusions The knowledge acquired through this work might be very beneficial for future FDM applications in the field of immediate release tablets especially with respect to thermo-sensitive drugs.
      PubDate: 2018-04-20
      DOI: 10.1007/s11095-018-2405-6
      Issue No: Vol. 35, No. 6 (2018)
  • Adsorption and Leachable Contamination of Flucloxacillin, Cyclosporin and
           Amiodarone Following Delivery Through an Intravenous Administration Set
    • Authors: Zachary Woodward; Peter Brooks; Bernadette Morris-Smith; Marianne Wallis; Steven M. Ogbourne
      Abstract: Purpose Interactions between a pharmaceutical drug and its delivery device can result in changes in drug concentration and leachable contamination. Flucloxacillin, amiodarone and cyclosporin were investigated for drug concentration changes and leachable contamination after delivery through an intravenous administration set. Methods Flucloxacillin, amiodarone and cyclosporin were delivered through an intravenous administration set and the eluate analysed by HPLC-UV and HPLC-MS. Results The average recovery of flucloxacillin was 99.7% and no leachable compounds were identified. The average recovery of cyclosporin was 96.1%, which contrasts previous findings that have reported up to 50% loss of cyclosporin. This is likely due to the use of DEHP-free administration sets in this study, as adsorption of cyclosporin is linearly related to DEHP content. The average recovery of amiodarone was 91.5%. 5-hydroxymethylfurfural was identified in the amiodarone solution following delivery through the administration set as well as the 5% glucose solution used for delivery. Conclusions Drug/administration set interactions may modify pharmaceuticals during delivery. In this study, only 90% of the amiodarone was delivered through a generic administration set. Given the growing use of generic administration sets in hospital settings, validation of the suitability of their use is required to ensure patient safety and expected levels of efficacy.
      PubDate: 2018-04-19
      DOI: 10.1007/s11095-018-2409-2
      Issue No: Vol. 35, No. 6 (2018)
  • A Pharmacometric Analysis of Patient-Reported Outcomes in Breast Cancer
           Patients Through Item Response Theory
    • Authors: Emilie Schindler; Lena E. Friberg; Bertram L. Lum; Bei Wang; Angelica Quartino; Chunze Li; Sandhya Girish; Jin Y. Jin; Mats O. Karlsson
      Abstract: Purpose An item response theory (IRT) pharmacometric framework is presented to characterize Functional Assessment of Cancer Therapy-Breast (FACT-B) data in locally-advanced or metastatic breast cancer patients treated with ado-trastuzumab emtansine (T-DM1) or capecitabine-plus-lapatinib. Methods In the IRT model, four latent well-being variables, based on FACT-B general subscales, were used to describe the physical, social/family, emotional and functional well-being. Each breast cancer subscale item was reassigned to one of the other subscales. Longitudinal changes in FACT-B responses and covariate effects were investigated. Results The IRT model could describe both item-level and subscale-level FACT-B data. Non-Asian patients showed better baseline social/family and functional well-being than Asian patients. Moreover, patients with Eastern Cooperative Oncology Group performance status of 0 had better baseline physical and functional well-being. Well-being was described as initially increasing or decreasing before reaching a steady-state, which varied substantially between patients and subscales. T-DM1 exposure was not related to any of the latent variables. Physical well-being worsening was identified in capecitabine-plus-lapatinib-treated patients, whereas T-DM1-treated patients typically stayed stable. Conclusion The developed framework provides a thorough description of FACT-B longitudinal data. It acknowledges the multi-dimensional nature of the questionnaire and allows covariate and exposure effects to be evaluated on responses.
      PubDate: 2018-04-19
      DOI: 10.1007/s11095-018-2403-8
      Issue No: Vol. 35, No. 6 (2018)
  • Reversion of Multidrug Resistance by Co-Encapsulation of Doxorubicin and
           Metformin in Poly(lactide-co-glycolide)-d-α-tocopheryl Polyethylene
           Glycol 1000 Succinate Nanoparticles
    • Authors: Vahid Shafiei-Irannejad; Nasser Samadi; Roya Salehi; Bahman Yousefi; Mahdi Rahimi; Abolfazl Akbarzadeh; Nosratollah Zarghami
      Abstract: Purpose P-glycoprotein (P-gp) mediated multidrug resistance (MDR) has been recognized as the main obstacle against successful cancer treatment. To address this problem, co-encapsulated doxorubicin (DOX) and metformin (Met) in a biodegradable polymer composed of poly(lactide-co-glycolide) (PLGA) and D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) was prepared. We reported in our previous study that Met inhibits P-gp in DOX resistant breast cancer (MCF-7/DOX) cells. TPGS is a bioactive compound which has also been shown to inhibit P-gp, further to its pharmaceutical advantages. Methods The DOX/Met loaded PLGA-TPGS nanoparticles (NPs) were prepared by double emulsion method and characterized for their surface morphology, size and size distribution, and encapsulation efficiencies of drugs in NPs. Results All NPs were found to be spherical-shaped with the size distribution below 100 nm and encapsulation efficiencies were 42.26 ± 2.14% for DOX and 7.04 ± 0.52% for Met. Dual drug loaded NPs showed higher cytotoxicity and apoptosis in MCF-7/DOX cells in comparison to corresponding free drugs. The higher cytotoxicity of dual drug loaded NPs was attributed to the enhanced intracellular drug accumulation due to enhanced cellular uptake and reduced drug efflux which was obtained by combined effects of Met and TPGS in reducing cellular ATP content and inhibiting P-gp. Conclusion Simultaneous delivery of DOX and Met via PLGA-TPGS NPs would be a promising approach to overcome MDR in breast cancer chemotherapy.
      PubDate: 2018-04-18
      DOI: 10.1007/s11095-018-2404-7
      Issue No: Vol. 35, No. 6 (2018)
  • Assessment of Forces in Intradermal Injection Devices: Hydrodynamic Versus
           Human Factors
    • Authors: Stijn Verwulgen; Koen Beyers; Timothi Van Mulder; Thomas Peeters; Steven Truijen; Francis Dams; Vanessa Vankerckhoven
      Abstract: Purpose The force that has to be exerted on the plunger for administering a given amount of fluid in a given time, has an important influence on comfort for the subject and usability for the administrator in intradermal drug delivery. The purpose of this study is to model those forces that are subject-independent, by linking needle and syringe geometry to the force required for ejecting a given fluid at a given ejection rate. Material and Methods We extend the well-known Hagen-Poiseuille formula to predict pressure drop induced by a fluid passing through a cylindrical body. The model investigates the relation between the pressure drop in needles and the theoretic Hagen-Poiseuille prediction and is validated in fifteen needles from 26G up to 33G suited for intradermal drug delivery. We also provide a method to assess forces exerted by operators in real world conditions. Results The model is highly linear in each individual needle with R-square values ranging from 75% up to 99.9%. Ten out of fifteen needles exhibit R-square values above 99%. A proof-of-concept for force assessment is provided by logging forces in operators in real life conditions. Conclusions The force assessment method and the model can be used to pinpoint needle geometry for intradermal injection devices, tuning comfort for subjects and usability for operators.
      PubDate: 2018-04-18
      DOI: 10.1007/s11095-018-2397-2
      Issue No: Vol. 35, No. 6 (2018)
  • Activity of Indatuximab Ravtansine against Triple-Negative Breast Cancer
           in Preclinical Tumor Models
    • Authors: Kurt Schönfeld; Peter Herbener; Chantal Zuber; Thomas Häder; Katrin Bernöster; Christoph Uherek; Jörg Schüttrumpf
      Abstract: Purpose Triple-negative breast cancer (TNBC) is related with a poor prognosis as patients do hardly benefit from approved therapies. CD138 (Syndecan-1) is upregulated on human breast cancers. Indatuximab ravtansine (BT062) is an antibody-drug-conjugate that specifically targets CD138-expressing cells and has previously shown clinical activity in multiple myeloma. Here we show indatuximab ravtansine as a potential mono- and combination therapy for TNBC. Methods The effects of indatuximab ravtansine were assessed in vitro in SK-BR-3 and T47D breast cancer cell lines. The in vivo effects of indatuximab ravtansine alone and in combination with docetaxel or paclitaxel were assessed in MAXF401, MAXF1384 and MAXF1322 xenograft TNBC models. Results CD138+ SK-BR-3 and T47D cells were highly sensitive to indatuximab ravtansine. The high CD138-expressing MAXF401 xenograft model demonstrated strong inhibition of tumor growth with 4 mg/kg indatuximab ravtansine. High doses of indatuximab ravtansine (8 mg/kg), docetaxel and the combination of both led to complete remission. In the low CD138-expressing MAXF1384 xenograft model, only combination of indatuximab ravtansine and docetaxel demonstrated a significant efficacy. In the MAXF1322 xenograft model, indatuximab ravtansine alone and in combination with paclitaxel elicited complete remission. Conclusions These data demonstrate potential use of indatuximab ravtansine in combination with docetaxel or paclitaxel for CD138-positive TNBC.
      PubDate: 2018-04-17
      DOI: 10.1007/s11095-018-2400-y
      Issue No: Vol. 35, No. 6 (2018)
  • Tacrolimus Loaded PEG-Cholecalciferol Based Micelles for Treatment of
           Ocular Inflammation
    • Authors: Shallu Kutlehria; Imran Vhora; Arvind Bagde; Nusrat Chowdhury; Gautam Behl; Ketan Patel; Mandip Singh
      Abstract: Purpose Poor corneal permeability, nasolacrimal drainage and requirement of chronic administration are major drawbacks of existing therapies for ocular inflammation. Hence, we designed topical micelles of PEG2000 conjugated with cholecalciferol (PEGCCF). Methods Integrin targeted tacrolimus loaded PEGCCF micelles (TTM) were prepared by solvent diffusion evaporation method and characterized for particle size, osmolality, encapsulation efficiency and drug loading. Therapeutic potential of TTM was evaluated in benzalkonium chloride induced ocular inflammation model in BALB/c mice. Corneal flourescein staining and histopathological analysis of corneal sections was performed. Results TTM had a particle size of 45.3 ± 5.3 nm, encapsulation efficiency (88.7 ± 0.9%w/w) and osmolality of 292–296 mOsmol/Kg. TTM significantly reduced the corneal fluorescence as compared to tacrolimus suspension (TACS). H&E staining showed that TTM could restore corneal epithelial thickness, reduce stromal edema (p < 0.05) and decrease number of inflammatory cells (p < 0.01) compared with TACS. Immunohistochemistry analysis demonstrated lower expression of Ki67 + ve cells (p < 0.05) and IL-6 throughout the cornea against TACS (p < 0.01) and the control (p < 0.001). Conclusions TTM is an innovative delivery system for improving ocular inflammation due to a) integrin targeting b) PEGCCF in the form of carrier and c) anti-inflammatory and synergistic effect (due to Pgp inhibition) with TAC.
      PubDate: 2018-04-16
      DOI: 10.1007/s11095-018-2376-7
      Issue No: Vol. 35, No. 6 (2018)
  • In-Situ Molecular Vapor Composition Measurements During Lyophilization
    • Authors: Evan T. Liechty; Andrew D. Strongrich; Ehab M. Moussa; Elizabeth Topp; Alina A. Alexeenko
      Abstract: Purpose Monitoring process conditions during lyophilization is essential to ensuring product quality for lyophilized pharmaceutical products. Residual gas analysis has been applied previously in lyophilization applications for leak detection, determination of endpoint in primary and secondary drying, monitoring sterilization processes, and measuring complex solvents. The purpose of this study is to investigate the temporal evolution of the process gas for various formulations during lyophilization to better understand the relative extraction rates of various molecular compounds over the course of primary drying. Methods In this study, residual gas analysis is used to monitor molecular composition of gases in the product chamber during lyophilization of aqueous formulations typical for pharmaceuticals. Residual gas analysis is also used in the determination of the primary drying endpoint and compared to the results obtained using the comparative pressure measurement technique. Results The dynamics of solvent vapors, those species dissolved therein, and the ballast gas (the gas supplied to maintain a set-point pressure in the product chamber) are observed throughout the course of lyophilization. In addition to water vapor and nitrogen, the two most abundant gases for all considered aqueous formulations are oxygen and carbon dioxide. In particular, it is observed that the relative concentrations of carbon dioxide and oxygen vary depending on the formulation, an observation which stems from the varying solubility of these species. This result has implications on product shelf life and stability during the lyophilization process. Conclusions Chamber process gas composition during lyophilization is quantified for several representative formulations using residual gas analysis. The advantages of the technique lie in its ability to measure the relative concentration of various species during the lyophilization process. This feature gives residual gas analysis utility in a host of applications from endpoint determination to quality assurance. In contrast to other methods, residual gas analysis is able to determine oxygen and water vapor content in the process gas. These compounds have been shown to directly influence product shelf life. With these results, residual gas analysis technique presents a potential new method for real-time lyophilization process control and improved understanding of formulation and processing effects for lyophilized pharmaceutical products.
      PubDate: 2018-04-11
      DOI: 10.1007/s11095-018-2395-4
      Issue No: Vol. 35, No. 6 (2018)
  • Efficacious Cefazolin Prophylactic Dose for Morbidly Obese Women
           Undergoing Bariatric Surgery Based on Evidence from Subcutaneous
           Microdialysis and Populational Pharmacokinetic Modeling
    • Authors: Eduardo Celia Palma; Nelson Guardiola Meinhardt; Airton Tetelbom Stein; Isabela Heineck; Maria Isabel Fischer; BibianaVerlindo de Araújo; Teresa Dalla Costa
      Abstract: Purpose To determine the efficacious cefazolin prophylactic dose for bariatric surgery using free subcutaneous concentrations accessed by microdialysis after 2 g or 3 g i.v. bolus dosing to morbidly obese women and POPPK modeling. Methods A POPPK model with variable plasma and subcutaneous tissue protein binding was developed to simultaneously describe plasma and tissue data sets. The outcomes was predicted for common surgical site infection (SSI) bacteria over 3, 4, 5 and 6 h periods postdose, as probability of target attainment (PTA) using Monte Carlo simulation. Results CFZ 2 g warrant up to 5 h SSI prophylaxis for bacteria with MICs ≤1 mg/L such as Escherichia coli and Staphylococcus aureus. For species such as Klebsiella pneumoniae, which present MIC distribution frequency of 2 mg/L, the maintenance of PTA ≥ 90% occurs with a 3 g dose for surgeries lasting up to 5 h, and 2 g dose provide an adequate response up to 4 h (PTA of 89%). Conclusions Effectiveness of CFZ 2 g is similar to 3 g against bacteria with a MIC up to 2 mg/L, especially if the surgery does not last for more than 4 h.
      PubDate: 2018-04-11
      DOI: 10.1007/s11095-018-2394-5
      Issue No: Vol. 35, No. 6 (2018)
  • Tissue Distribution and Gender-Specific Protein Expression of Cytochrome
           P450 in five Mouse Genotypes with a Background of FVB
    • Authors: Jiamei M. Chen; Qisong S. Zhang; Xiaoyan Y. Li; Xia Gong; Yanjiao J. Ruan; Sijing J. Zeng; Linlin L. Lu; Xiaoxiao X. Qi; Ying Wang; Ming Hu; Lijun J. Zhu; Zhongqiu Q. Liu
      Abstract: Purpose To systematically investigate tissue distribution and gender-specific protein expression of Cytochrome P450 (Cyps) in five mouse genotypes with a background of Friend virus B (FVB). Methods The Cyps were extracted from the tissue S9 fractions of the main metabolic organs and then absolutely quantified by applying the UHPLC-MS/MS method. Results The liver had the highest expression of Cyps, followed by the small intestine and kidney. In the liver, Cyp1a2, Cyp2c29, Cyp2c39, Cyp2d22, Cyp2e1, and Cyp3a11 were the main isoforms. Cyp1a2 and Cyp2c29 were male-specific, while Cyp2c39 was female-specific. Compared with the expression in Wild-type (WT) FVB mice, the expression of Cyp1a2, Cyp1b1, Cyp2d22, and Cyp3a25 significantly decreased in female efflux transporter (ET) knockout mice. In the small intestine, Cyp2c29 and Cyp3a11 were the major isoforms. Knockout of ET didn’t alter the expression levels of most Cyps. However, female ET knockout mice presented higher Cyp2c29 expression than WT FVB mice. The Cyp7a1 expression was markedly decreased in ET knockout mice except Bcrp1−/− mice. In the kidney, Cyp2e1 was the main isoform and exhibited male specificity. Knockout of ET slightly affected the protein expression of Cyps in the brain, heart, lung, spleen and stomach. Conclusions A comprehensive understanding of the distribution characteristics and gender-specific expression of Cyps in major metabolic organs of WT and ET knockout FVB mice should contribute to a better understanding of drug efficacy and toxicity, and drug-drug interactions.
      PubDate: 2018-04-10
      DOI: 10.1007/s11095-018-2389-2
      Issue No: Vol. 35, No. 6 (2018)
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Heriot-Watt University
Edinburgh, EH14 4AS, UK
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