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Journal Cover Pharmaceutical Research
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   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 1573-904X - ISSN (Online) 0724-8741
   Published by Springer-Verlag Homepage  [2352 journals]
  • Optimizing the Bioavailability of Subcutaneously Administered
           Biotherapeutics Through Mechanochemical Drivers
    • Authors: D. S. Collins; L. C. Kourtis; N. R. Thyagarajapuram; R. Sirkar; S. Kapur; M. W. Harrison; D. J. Bryan; G. B. Jones; J. M. Wright
      Pages: 2000 - 2011
      Abstract: The subcutaneous route offers myriad benefits for the administration of biotherapeutics in both acute and chronic diseases, including convenience, cost effectiveness and the potential for automation through closed-loop systems. Recent advances in parenteral administration devices and the use of additives which enhance drug dispersion have generated substantial additional interest in IV to SQ switching studies. Designing pre-clinical and clinical studies using SQ mediated delivery however requires deep understanding of complex inter-related physiologies and transport pathways governing the interstitial matrix, vascular system and lymphatic channels. This expert review will highlight key structural features which contribute to transport and biodistribution in the subcutaneous space and also assess the impact of drug formulations. Based on the rapidly growing interest in the SQ delivery route, a number of potential areas for future development are highlighted, which are likely to allow continued evolution and innovation in this important area.
      PubDate: 2017-10-01
      DOI: 10.1007/s11095-017-2229-9
      Issue No: Vol. 34, No. 10 (2017)
  • Scanning Electron Microscope Observations of Powder Sticking on Punches
           during a Limited Number ( N  < 5) of Compactions of Acetylsalicylic
    • Authors: Henrietta Tsosie; James Thomas; John Strong; Antonios Zavaliangos
      Pages: 2012 - 2024
      Abstract: Purpose To obtain quantitative information and mechanistic insight into the problem of sticking of acetylsalicylic acid tablets on a metallic punch. Methods Low voltage scanning electron microscopy was used to observe punch area coverage and morphology of adhered powder on a flat punch used for a limited number of compactions. Results Material accumulation in terms of area coverage of the punch per compaction cycle was determined at two pressures over five compactions. The distribution of the adhered material on the punch was non-uniform with more material left on the center of the punch. The sizes of the adhered particles range from 1 to 100 μm, with 50% of the punch surface coverage from particles of an equivalent diameter > 30 μm. Three types of adhered particles were identified after the first compaction: (a) fragments of initial particles with very high aspect ratio, (b) nearly equiaxed fragments with multiple cracks, (c) heavily deformed islands of low profile. Some preliminary ideas that explain these observations are presented and discussed. Conclusions The ability of SEM to provide quantitative information on sticking from few compactions presents an interesting possibility for a material sparing technique that provides insight on the propensity of sticking.
      PubDate: 2017-10-01
      DOI: 10.1007/s11095-017-2186-3
      Issue No: Vol. 34, No. 10 (2017)
  • Development of a Two-Dimensional Model for Predicting Transdermal
           Permeation with the Follicular Pathway: Demonstration with a Caffeine
    • Authors: Panayiotis Kattou; Guoping Lian; Stephen Glavin; Ian Sorrell; Tao Chen
      Pages: 2036 - 2048
      Abstract: Purpose The development of a new two-dimensional (2D) model to predict follicular permeation, with integration into a recently reported multi-scale model of transdermal permeation is presented. Methods The follicular pathway is modelled by diffusion in sebum. The mass transfer and partition properties of solutes in lipid, corneocytes, viable dermis, dermis and systemic circulation are calculated as reported previously [Pharm Res 33 (2016) 1602]. The mass transfer and partition properties in sebum are collected from existing literature. None of the model input parameters was fit to the clinical data with which the model prediction is compared. Results The integrated model has been applied to predict the published clinical data of transdermal permeation of caffeine. The relative importance of the follicular pathway is analysed. Good agreement of the model prediction with the clinical data has been obtained. The simulation confirms that for caffeine the follicular route is important; the maximum bioavailable concentration of caffeine in systemic circulation with open hair follicles is predicted to be 20% higher than that when hair follicles are blocked. Conclusions The follicular pathway contributes to not only short time fast penetration, but also the overall systemic bioavailability. With such in silico model, useful information can be obtained for caffeine disposition and localised delivery in lipid, corneocytes, viable dermis, dermis and the hair follicle. Such detailed information is difficult to obtain experimentally.
      PubDate: 2017-10-01
      DOI: 10.1007/s11095-017-2209-0
      Issue No: Vol. 34, No. 10 (2017)
  • Small Airway Absorption and Microdosimetry of Inhaled Corticosteroid
           Particles after Deposition
    • Authors: P. Worth Longest; Michael Hindle
      Pages: 2049 - 2065
      Abstract: Purpose To predict the cellular-level epithelial absorbed dose from deposited inhaled corticosteroid (ICS) particles in a model of an expanding and contracting small airway segment for different particle forms. Methods A computational fluid dynamics (CFD)-based model of drug dissolution, absorption and clearance occurring in the surface liquid of a representative small airway generation (G13) was developed and used to evaluate epithelial dose for the same deposited drug mass of conventional microparticles, nanoaggregates and a true nanoaerosol. The ICS medications considered were budesonide (BD) and fluticasone propionate (FP). Within G13, total epithelial absorption efficiency (AE) and dose uniformity (microdosimetry) were evaluated. Results Conventional microparticles resulted in very poor AE of FP (0.37%) and highly nonuniform epithelial absorption, such that <5% of cells received drug. Nanoaggregates improved AE of FP by a factor of 57-fold and improved dose delivery to reach approximately 40% of epithelial cells. True nanoaerosol resulted in near 100% AE for both drugs and more uniform drug delivery to all cells. Conclusions Current ICS therapies are absorbed by respiratory epithelial cells in a highly nonuniform manner that may partially explain poor clinical performance in the small airways. Both nanoaggregates and nanoaerosols can significantly improve ICS absorption efficiency and uniformity.
      PubDate: 2017-10-01
      DOI: 10.1007/s11095-017-2210-7
      Issue No: Vol. 34, No. 10 (2017)
  • Computational Analysis on Down-Regulated Images of Macrophage Scavenger
    • Authors: Byeongtaek Oh; Yugyung Lee; Mingui Fu; Chi H. Lee
      Pages: 2066 - 2074
      Abstract: Background Thiolated-graphene quantum dots (SH-GQDs) were developed and assessed for an efficient preventive means against atherosclerosis and potential toxicity through computational image analysis and animal model studies. Experiments Zebrafish (wild-type, wt) were used for evaluation of toxicity through the assessment of embryonic mortality, malformation and ROS generation. The amounts of SH-GQDs uptaken by mouse macrophage cells (Raw264.7) were analyzed using a flow cytometer. For the time-dependent cellular uptake study, Raw264.7 cells were treated with SH-GQDs (200 μg/ml) at specific time intervals (0.5, 1, 2, 5, 10 and 24 h). The efficacy of SH-GQDs on DiO-oxLDL efflux by Raw264.7 cells was evaluated (DiO, 3,3′-dioctadecyl-oxacarbocyanine) based on the percentage of positive cells containing DiO-oxLDL. TEER of human primary umbilical vein endothelial cells (hUVECs) were examined to assess the barrier function of the cell layers upon being treated with oxLDL. Results SH-GQDs significantly enhanced the efflux of oxLDL and down-regulated macrophage scavenger receptor (MSR) in Raw264.7. The ROS levels stimulated by oxidative stress were alleviated by SH-GQDs. oxLDL (10 μg/ml) significantly impaired the barrier function (TEER) of adherence junctions, which was recovered by SH-GQDs (10 μg/ml) (oxLDL: 67.2 ± 2.2 Ω-cm2 for 24 h; SH-GQDs: 114.6 ± 8.5 Ω-cm2 for 24 h). The mortality rate (46% for 1 mg/ml) of the zebra fish increased, as the concentrations and exposure duration of SH-GQDs increased. SH-GQDs exerted negligible side effects. Conclusion SH-GQDs have target specificity to macrophage scavenger receptor (MSR) and efficiently recovered the ROS levels and TEER. SH-GQDs did not induce endothelial cell layer disruption nor affected zebrafish larvae survival.
      PubDate: 2017-10-01
      DOI: 10.1007/s11095-017-2211-6
      Issue No: Vol. 34, No. 10 (2017)
  • Gentamicin-Loaded Polysaccharide Membranes for Prevention and Treatment of
           Post-operative Wound Infections in the Skeletal System
    • Authors: Urszula Cibor; Małgorzata Krok-Borkowicz; Monika Brzychczy-Włoch; Łucja Rumian; Krzysztof Pietryga; Dominika Kulig; Wojciech Chrzanowski; Elżbieta Pamuła
      Pages: 2075 - 2083
      Abstract: ABSTRACT Purpose To develop polysaccharide-based membranes that allow controlled and localized delivery of gentamicin for the treatment of post-operative bone infections. Methods Membranes made of gellan gum (GUM), sodium alginate (ALG), GUM and ALG crosslinked with calcium ions (GUM + Ca and ALG + Ca, respectively) as well as reference collagen (COL) were produced by freeze-drying. Mechanical properties, drug release, antimicrobial activity and cytocompatibility of the membranes were assessed. Results The most appropriate handling and mechanical properties (Young’s modulus, E = 92 ± 4 MPa and breaking force, F MAX  = 2.6 ± 0.1 N) had GUM + Ca membrane. In contrast, COL membrane showed F MAX  = 0.14 ± 0.02 N, E = 1.0 ± 0.3 MPa and was deemed to be unsuitable for antibiotic delivery. The pharmacokinetic data demonstrated a uniform and sustainable delivery of gentamicin from GUM + Ca (44.4 ± 1.3% within 3 weeks), while for COL, ALG and ALG + Ca membranes the most of the drug was released within 24 h (55.3 ± 1.9%, 52.5 ± 1.5% and 37.5 ± 1.8%, respectively). Antimicrobial activity against S. aureus and S. epidermidis was confirmed for all the membranes. GUM + Ca and COL membranes supported osteoblasts growth, whereas on ALG and ALG + Ca membranes cell growth was reduced. Conclusions GUM + Ca membrane holds promise for effective treatment of bone infections thanks to favorable pharmacokinetics, bactericidal activity, cytocompatibility and good mechanical properties.
      PubDate: 2017-10-01
      DOI: 10.1007/s11095-017-2212-5
      Issue No: Vol. 34, No. 10 (2017)
  • Anti-Tuberculosis Bacteriophage D29 Delivery with a Vibrating Mesh
           Nebulizer, Jet Nebulizer, and Soft Mist Inhaler
    • Authors: Nicholas B. Carrigy; Rachel Y. Chang; Sharon S. Y. Leung; Melissa Harrison; Zaritza Petrova; Welkin H. Pope; Graham F. Hatfull; Warwick J. Britton; Hak-Kim Chan; Dominic Sauvageau; Warren H. Finlay; Reinhard Vehring
      Pages: 2084 - 2096
      Abstract: Purpose To compare titer reduction and delivery rate of active anti-tuberculosis bacteriophage (phage) D29 with three inhalation devices. Methods Phage D29 lysate was amplified to a titer of 11.8 ± 0.3 log10(pfu/mL) and diluted 1:100 in isotonic saline. Filters captured the aerosolized saline D29 preparation emitted from three types of inhalation devices: 1) vibrating mesh nebulizer; 2) jet nebulizer; 3) soft mist inhaler. Full-plate plaque assays, performed in triplicate at multiple dilution levels with the surrogate host Mycobacterium smegmatis, were used to quantify phage titer. Results Respective titer reductions for the vibrating mesh nebulizer, jet nebulizer, and soft mist inhaler were 0.4 ± 0.1, 3.7 ± 0.1, and 0.6 ± 0.3 log10(pfu/mL). Active phage delivery rate was significantly greater (p < 0.01) for the vibrating mesh nebulizer (3.3x108 ± 0.8x108 pfu/min) than for the jet nebulizer (5.4x104 ± 1.3x104 pfu/min). The soft mist inhaler delivered 4.6x106 ± 2.0x106 pfu per 11.6 ± 1.6 μL ex-actuator dose. Conclusions Delivering active phage requires a prudent choice of inhalation device. The jet nebulizer was not a good choice for aerosolizing phage D29 under the tested conditions, due to substantial titer reduction likely occurring during droplet production. The vibrating mesh nebulizer is recommended for animal inhalation studies requiring large amounts of D29 aerosol, whereas the soft mist inhaler may be useful for self-administration of D29 aerosol.
      PubDate: 2017-10-01
      DOI: 10.1007/s11095-017-2213-4
      Issue No: Vol. 34, No. 10 (2017)
  • Galactosyl Pentadecene Reversibly Enhances Transdermal and Topical Drug
    • Authors: Monika Kopečná; Miloslav Macháček; Eva Prchalová; Petr Štěpánek; Pavel Drašar; Martin Kotora; Kateřina Vávrová
      Pages: 2097 - 2108
      Abstract: Purpose To study new skin penetration/permeation enhancers based on amphiphilic galactose derivatives. Methods Two series of alkyl and alkenyl galactosides were synthesized and evaluated for their enhancing effect on transdermal/topical delivery of theophylline (TH), hydrocortisone (HC) and cidofovir (CDV), reversibility of their effects on transepidermal water loss (TEWL) and skin impedance, interaction with the stratum corneum using infrared spectroscopy, and cytotoxicity on keratinocytes and fibroblasts. Results Initial evaluation identified 1-(α-d-galactopyranosyl)-(2E)-pentadec-2-ene A15 as a highly potent enhancer – it increased TH and HC flux through human skin 8.5 and 5 times, respectively. Compound A15 increased the epidermal concentration of a potent antiviral CDV 7 times over that reached by control and Span 20 (an established sugar-based enhancer). Infrared spectroscopy of human stratum corneum indicated interaction of A15 with skin barrier lipids but not proteins. These effects of A15 on the skin barrier were reversible (both TEWL and skin impedance returned to baseline values within 24 h after A15 had been removed from skin). In vitro toxicity of A15 on HaCaT keratinocytes and 3T3 fibroblasts was acceptable, with IC50 values over 60 μM. Conclusions Galactosyl pentadecene A15 is a potent enhancer with low toxicity and reversible action.
      PubDate: 2017-10-01
      DOI: 10.1007/s11095-017-2214-3
      Issue No: Vol. 34, No. 10 (2017)
  • Item Response Theory as an Efficient Tool to Describe a Heterogeneous
           Clinical Rating Scale in De Novo Idiopathic Parkinson’s Disease Patients
    • Authors: Simon Buatois; Sylvie Retout; Nicolas Frey; Sebastian Ueckert
      Pages: 2109 - 2118
      Abstract: Purpose This manuscript aims to precisely describe the natural disease progression of Parkinson’s disease (PD) patients and evaluate approaches to increase the drug effect detection power. Methods An item response theory (IRT) longitudinal model was built to describe the natural disease progression of 423 de novo PD patients followed during 48 months while taking into account the heterogeneous nature of the MDS-UPDRS. Clinical trial simulations were then used to compare drug effect detection power from IRT and sum of item scores based analysis under different analysis endpoints and drug effects. Results The IRT longitudinal model accurately describes the evolution of patients with and without PD medications while estimating different progression rates for the subscales. When comparing analysis methods, the IRT-based one consistently provided the highest power. Conclusion IRT is a powerful tool which enables to capture the heterogeneous nature of the MDS-UPDRS.
      PubDate: 2017-10-01
      DOI: 10.1007/s11095-017-2216-1
      Issue No: Vol. 34, No. 10 (2017)
  • Influence of Molecular size on the clearance of antibody fragments
    • Authors: Zhe Li; Ben-Fillippo Krippendorff; Dhaval K. Shah
      Pages: 2131 - 2141
      Abstract: Purpose To establish a continuous relationship between the size of various antibody fragments and their systemic clearance (CL) in mice. Methods Two different orthogonal approaches have been used to establish the relationship. First approach uses CL values estimated by non-compartmental analysis (NCA) to establish a correlation with protein size. The second approach simultaneously characterizes the PK data for all the proteins using a 2-compartment model to establish a relationship between protein size and pharmacokinetic (PK) parameters. Results Simple mathematical functions (e.g. sigmoidal, power law) were able to characterize the CL vs. protein size relationship generated using the investigated proteins. The relationship established in mouse was used to predict rat, rabbit, monkey, and human relationships using allometric scaling. The predicted relationships were found to capture the available spares data from each species reasonably well. Conclusions The CL vs. protein size relationship is important for establishing a robust quantitative structure-PK relationship (QSPKR) for protein therapeutics. The relationship presented here can help in a priori predicting plasma exposure of therapeutic proteins, and together with our previously established relationship between plasma and tissue concentrations of proteins, it can predict the tissue exposure of non-binding proteins simply based on molecular weight/radius and dose.
      PubDate: 2017-10-01
      DOI: 10.1007/s11095-017-2219-y
      Issue No: Vol. 34, No. 10 (2017)
  • Evaluation of the Crystallization Tendency of Commercially Available
           Amorphous Tacrolimus Formulations Exposed to Different Stress Conditions
    • Authors: Niraj S. Trasi; Hitesh S. Purohit; Lynne S. Taylor
      Pages: 2142 - 2155
      Abstract: Purpose Tacrolimus, an immunosuppressant, is a poorly water soluble compound whereby the commercially available capsule formulations contain the drug in amorphous form. The goal of this study was to evaluate the robustness of the innovator product and five generic formulations to crystallization following storage at stress conditions. Methods Products were purchased from a pharmacy and stored at 40°C/75% relative humidity (RH), open dish conditions. Crystallinity was determined using X-ray diffraction. The quantity of the ingredients in the formulations were determined using different approaches and the various factors that might cause instability in the formulations were studied. Results After 4 weeks of open dish storage at 40°C/75% RH, one of the generic formulations showed evidence of tacrolimus crystallization. Further investigations revealed batch-to-batch variations in crystallization tendency with the extent of crystallinity varying between 50 and 100% for different batches. Crystallization was also observed at lower storage temperatures (30°C) when the RH was maintained at 75%. It was found that crystallization could be induced in a model formulation by wet granulating an ethanolic solution of the drug with lactose and drying at 60–70°C followed by exposure to stress conditions. Conclusions It seems probable that the generic that was susceptible to crystallization contains amorphous drug physically mixed with polymeric excipients, rather than as an amorphous solid dispersion. This study highlights the importance of considering the manufacturing process on the stability of the resultant amorphous product.
      PubDate: 2017-10-01
      DOI: 10.1007/s11095-017-2221-4
      Issue No: Vol. 34, No. 10 (2017)
  • Hemodynamic Effects of Lipid-Based Oxygen Microbubbles via Rapid
           Intravenous Injection in Rodents
    • Authors: Katherine J. Black; Andrew T. Lock; Lindsay M. Thomson; Alexis R. Cole; Xiaoqi Tang; Brian D. Polizzotti; John N. Kheir
      Pages: 2156 - 2162
      Abstract: Purpose Low oxygen levels, or hypoxemia, is a common cause of morbidity and mortality in critically ill patients. Hypoxemia is typically addressed by increasing the fraction of inspired oxygen, the use of mechanical ventilation, or more invasive measures. Recently, the injection of oxygen gas directly into the bloodstream by packaging it within lipid-based oxygen microbubbles (LOMs) has been explored. The purpose of this work is to examine the acute hemodynamic effects of intravenous injections of LOMs. Methods LOMs composed of 1,2-distearoyl-sn-glycero-3-phosphocoline and cholesterol were manufactured using a process of shear homogenization under an oxygen headspace. A 5 mL aliquot of either PlasmaLyte A, or low (37%) or high (55%) concentration LOMs (n = 10 per group) was injected over a 1 min period into Sprague Dawley rats instrumented for measurement of cardiac index and pulmonary (PVR) and systemic (SVR) vascular resistance during a 60 min observation period. Hemodynamics were compared between groups by linear mixed modeling. Results Approximately 1011 LOMs with mean diameter 3.77 ± 1.19 μm were injected over the 1 min period. Relative to controls, rodents treated with high concentration LOMs exhibited a higher pulmonary artery pressure (20 ± 0.4 mmHg vs 18 ± 0.4 mmHg, P < 0.001) and higher PVR (0.31 ± 0.01 vs 0.23 ± 0.01 mmHg/mL*min*kg, P < 0.001. Despite a stable cardiac index (62.2 ± 3.5 vs 62.3 ± 3.4 mL/min*kg, P < 0.001), mean arterial blood pressure decreased significantly in LOM-treated animals (46 ± 2 vs 60 ± 2 mmHg, P < 0.001) due to a decrease in SVR. Injections with aged LOM emulsions (>48 h since manufacture) resulted in a higher incidence of hemodynamic collapse during the observation period (P = 0.02). Conclusions LOMs may be injected in quantities sufficient to deliver clinically meaningful volumes of oxygen but cause significant decrements in blood pressure and elevations in PVR.
      PubDate: 2017-10-01
      DOI: 10.1007/s11095-017-2222-3
      Issue No: Vol. 34, No. 10 (2017)
  • Chitooligosaccharides Modified Reduction-Sensitive Liposomes: Enhanced
           Cytoplasmic Drug Delivery and Osteosarcomas-Tumor Inhibition in Animal
    • Authors: Xuelei Yin; Yingying Chi; Chuanyou Guo; Shuaishuai Feng; Jinhu Liu; Kaoxiang Sun; Zimei Wu
      Pages: 2172 - 2184
      Abstract: ABSTRACT Purpose To investigate the potential of a reduction-sensitive and fusogenic liposomes, enabled by surface-coating with chotooligosaccharides (COS) via a disulfide linker, for tumor-targeted cytoplasmic drug delivery. Methods COS (MW2000-5000) were chemically tethered onto the liposomes through a disulfide linker (-SS-) to cholesterol (Chol). Doxorubicin (DOX) was actively loaded in the liposomes. Their reduction-sensitivities, cellular uptake, cytotoxicity, pharmacokinetics and antitumor efficacy were investigated. Results The Chol-SS-COS/DOX liposomes (100 nm) had zeta potential of 33.9 mV and high drug loading (13% w/w). The liposomes were stable with minimal drug leakage under physiological conditions but destabilized in the presence of reducing agents, dithiothreitol (DTT) or glutathione (GSH) at 10 mM, the cytosolic level. MTT assay revealed that the cationic Chol-SS-COS/DOX liposomes had higher cytotoxicity to MG63-osteosarcoma cells than non-reduction sensitive liposome (Chol-COS/DOX). Flow cytometry and confocal microscopy revealed that Chol-SS-COS/DOX internalized more efficiently than Chol-COS/DOX with more content to cytoplasm whereas Chol-COS/DOX located around the cell membrane. Chol-SS-COS/DOX preferentially internalized into MG63 cancer cell over LO2 normal liver cells. In rats both liposomes produced a prolonged half-life of DOX by 4 - 5.5 fold (p < 0.001) compared with the DOX solution. Chol-SS-COS/DOX exhibited strong inhibitory effect on tumor growth in MG63 cell-bearing nude mice (n = 6), and extended animal survival rate. Conclusions Reduction-responsive Chol-SS-COS liposomes may be an excellent platform for cytoplasmic delivery of anticancer drugs. Conjugation of liposomes with COS enhanced tumor cell uptake, antitumor effect and survival rate in animal models.
      PubDate: 2017-10-01
      DOI: 10.1007/s11095-017-2225-0
      Issue No: Vol. 34, No. 10 (2017)
  • Design, Preparation and Evaluation of HPMC-Based PAA or SA Freeze-Dried
           Scaffolds for Vaginal Delivery of Fluconazole
    • Authors: Carmen Anatolia Gafitanu; Daniela Filip; Corina Cernatescu; Daniela Rusu; Cristina Gabriela Tuchilus; Doina Macocinschi; Mirela-Fernanda Zaltariov
      Pages: 2185 - 2196
      Abstract: Purpose Aim of this work was preparation of bioadhesive gel formulations based on Hydroxypropyl methylcellulose (HPMC), Poly(acrylic acid) (PAA) or Sodium alginate (SA) loaded with anise/fluconazole β-cyclodextrin inclusion complexes in 1:2 and 1:3 ratios intended for vaginal applications. Methods Freeze-drying method was effectively utilized and superporous morphology was obtained. The superporous morphology of the lyophilized gels, dynamic water vapor sorption measurements, drug release kinetics studies and their antimicrobial activities are presented. Results HPMC content influences especially the sorption/desorption behaviour of HPMC-based PAA gels and the morphology of the gel formulations with fluconazole/β-cyclodextrin inclusion complexes, due to the interactions among the gel networks absorbing water molecules. It was found that fluconazole release kinetics correspond to quasi-Fickian, Fickian diffusion and non-Fickian mechanisms for the studied hydrogels. The tested vaginal formulations with β-cyclodextrin inclusion complexes exhibited selectivity toward S. aureus ATCC 25923 and all tested Candida strains in comparison with the gel formulation without β-cyclodextrin. Conclusions The fluconazole/β cyclodextrin inclusion complexes ensure a controlled release of fluconazole over a few days, the highest amount of drug release (92%) being observed after 43 h. These bioadhesive gel formulations could be very promising topical alternative for treatment of vaginal fungal infections.
      PubDate: 2017-10-01
      DOI: 10.1007/s11095-017-2226-z
      Issue No: Vol. 34, No. 10 (2017)
  • Rhamnolipids Enhance in Vivo Oral Bioavailability of Poorly Absorbed
    • Authors: El-Sayed Khafagy; Mona F. El-Azab; Mohamed E. H. ElSayed
      Pages: 2197 - 2210
      Abstract: Purpose This report describes the effect of rhamnolipids (RLs) on the tight junctions (TJ) of the intestinal epithelium using the rat in-situ closed loop model. Methods We investigated the transport of 5 (6)-carboxyfluorescein (CF) and fluorescein isothiocyanate-labeled dextrans with average molecular weights of 4.4 and 10 kDa (FD-4 and FD-10) when co-administered with different concentrations of RLs. Lactate dehydrogenase (LDH) leakage assay and histopathological examination of treated intestinal loops were used to assess potential toxicity of RLs. Further, the effect of kaempferol on accelerating the resealing of the tight junctions in vivo was also investigated Results Data shows that administration of different RLs concentrations (1.0–5.0% v/v) increased CF absorption through rat intestine by 2.84- and 15.82-folds with RLs concentrations of 1.0% and 5.0% v/v, respectively. RLs exhibited size-dependent increase on FD-4 and FD-10 absorption. Dosing RLs at 1.0% v/v didn’t cause a significant LDH leakage or histopathological changes to intestinal mucosa compared to higher concentrations, which showed a progressive damaging effect. Using kaempferol, a natural flavonoid that stimulates the assembly of the TJs, proved to enhance the recovery of barrier properties of the intestinal mucosa treated with high concentrations of RLs (2.5% and 5% v/v). Conclusions These results collectively illustrate the ability of RLs to enhance oral bioavailability of different molecules across the intestinal epithelial membrane in a concentration- and time-dependent fashion.
      PubDate: 2017-10-01
      DOI: 10.1007/s11095-017-2227-y
      Issue No: Vol. 34, No. 10 (2017)
  • Injectable Sustained-Release Depots of PLGA Microspheres for Insoluble
           Drugs Prepared by hot-Melt Extrusion
    • Authors: Yuting Guo; Yunning Yang; Luying He; Rong Sun; Chenguang Pu; Bin Xie; Haibing He; Yu Zhang; Tian Yin; Yanjiao Wang; Xing Tang
      Pages: 2211 - 2222
      Abstract: Purpose Progesterone (PRG) was selected as a model drug to develop a long-acting injection system for poorly water-soluble drugs. Methods Microspheres with high density-low porosity were prepared by hot-melt extrusion (HME) combined with wet-milling as the representative formulation, and a microcrystal suspension was also studied as a comparison. The morphology, particle size and distribution, polymorphism, drug distribution, density and porosity were characterized by scanning electron microscopy, laser diffraction particle size analyzer, power X-ray diffraction and DSC respectively. The in vivo performance of the different formulations within 7 days after intramuscular injection was evaluated in male SD rats. Results The drug-loading rate of the microspheres could be as high as 40%. The average initial burst release of the microspheres (PLGA lactide:glycolide = 75:25) was only 6.7% much lower than that of the microsuspension (25.7%) and a sustained release was exhibited for at least 7 days. The release mechanism was speculated to be as follows. The microspheres are a drug depot with drug microcrystals in the PLGA matrix which is a layer by layer honeycomb structure. Conclusions Microspheres prepared by HME combined with wet-milling could achieve a long-term sustained release effect as a novel long-acting formulation strategy.
      PubDate: 2017-10-01
      DOI: 10.1007/s11095-017-2228-x
      Issue No: Vol. 34, No. 10 (2017)
  • Dependence of Friability on Tablet Mechanical Properties and a Predictive
           Approach for Binary Mixtures
    • Authors: Shubhajit Paul; Changquan Calvin Sun
      Abstract: Purpose To systematically assess the dependence of friability on tablet mechanical properties, compaction pressure, and tablet porosity. Methods Several common excipients and their mixtures exhibiting diverse mechanical properties were analyzed. Tablet elastic modulus, hardness, brittleness, porosity, and tensile strength were determined using standard techniques and then were correlated to tablet friability both individually and as a group to derive a universal model. Results Viscoelastic starch exhibits the highest friability followed by brittle excipients (mannitol, DCPA, and LM) and then ductile excipients (HPC and MCC). A reasonably accurate model for predicting pharmaceutically relevant range of friability, up to 3%, of binary mixtures is presented based on friability of individual components. In addition, a multivariate model between friability and different mechanical parameters was developed, based on which the weight loss propensity of tablets may be predicted. Conclusions The experimental findings and predictive model are useful for expedited development and optimization of tablet formulation using a minimum amount of API.
      PubDate: 2017-10-05
      DOI: 10.1007/s11095-017-2273-5
  • A Novel Phenylchromane Derivative Increases the Rate of Glucose Uptake in
           L6 Myotubes and Augments Insulin Secretion from Pancreatic Beta-Cells by
           Activating AMPK
    • Authors: Naomi Rozentul; Yosef Avrahami; Moran Shubely; Laura Levy; Anna Munder; Guy Cohen; Erol Cerasi; Shlomo Sasson; Arie Gruzman
      Abstract: Purpose A series of novel polycyclic aromatic compounds that augment the rate of glucose uptake in L6 myotubes and increase glucose-stimulated insulin secretion from beta-cells were synthesized. Designing these molecules, we have aimed at the two main pathogenic mechanisms of T2D, deficient insulin secretion and diminished glucose clearance. The ultimate purpose of this work was to create a novel antidiabetic drug candidate with bi-functional mode of action. Methods All presented compounds were synthesized, and characterized in house. INS-1E cells and L6 myoblasts were used for the experiments. The rate of glucose uptake, mechanism of action, level of insulin secretion and the druggability of the lead compound were studied. Results The lead compound (6-(1,3-dithiepan-2-yl)-2-phenylchromane), dose- and time-dependently at the low μM range increased the rate of glucose uptake in L6 myotubes and insulin secretion in INS-1E cells. The compound exerted its effects through the activation of the LKB1 (Liver Kinase B1)-AMPK pathway. In vitro metabolic parameters of this lead compound exhibited good druggability. Conclusions We anticipate that bi-functionality (increased rate of glucose uptake and augmented insulin secretion) will allow the lead compound to be a starting point for the development of a novel class of antidiabetic drugs.
      PubDate: 2017-10-05
      DOI: 10.1007/s11095-017-2271-7
  • Model Informed Pediatric Development Applied to Bilastine: Ontogenic PK
           Model Development, Dose Selection for First Time in Children and PK Study
    • Authors: Valvanera Vozmediano; Ander Sologuren; John C. Lukas; Nerea Leal; Mónica Rodriguez
      Abstract: Purpose Bilastine is an H1 antagonist whose pharmacokinetics (PK) and pharmacodynamics (PD) have been resolved in adults with a therapeutic oral dose of 20 mg/day. Bilastine has favorable characteristics for use in pediatrics but the PK/PD and the optimal dose in children had yet to be clinically explored. The purpose is to: (1) Develop an ontogenic predictive model of bilastine PK linked to the PD in adults by integrating current knowledge; (2) Use the model to design a PK study in children; (3) Confirm the selected dose and the study design through the evaluation of model predictability in the first recruited children; (4) Consider for inclusion the group of younger children (< 6 years). Methods A semi-mechanistic approach was applied to predict bilastine PK in children assuming the same PD as described in adults. The model was used to simulate the time evolution of plasma levels and wheal and flare effects after several doses and design an adaptive PK trial in children that was then confirmed using data from the first recruits by comparing observations with model predictions. Results PK/PD simulations supported the selection of 10 mg/day in 2 to <12 year olds. Results from the first interim analysis confirmed the model predictions and design hence trial continuation. Conclusion The model successfully predicted bilastine PK in pediatrics and optimally assisted the selection of the dose and sampling scheme for the trial in children. The selected dose was considered suitable for younger children and the forthcoming safety study in children aged 2 to <12 years.
      PubDate: 2017-10-02
      DOI: 10.1007/s11095-017-2248-6
  • Targeted Metabolomics Identifies Pharmacodynamic Biomarkers for BIO 300
           Mitigation of Radiation-Induced Lung Injury
    • Authors: Jace W. Jones; Isabel L. Jackson; Zeljko Vujaskovic; Michael D. Kaytor; Maureen A. Kane
      Abstract: Purpose Biomarkers serve a number of purposes during drug development including defining the natural history of injury/disease, serving as a secondary endpoint or trigger for intervention, and/or aiding in the selection of an effective dose in humans. BIO 300 is a patent-protected pharmaceutical formulation of nanoparticles of synthetic genistein being developed by Humanetics Corporation. The primary goal of this metabolomic discovery experiment was to identify biomarkers that correlate with radiation-induced lung injury and BIO 300 efficacy for mitigating tissue damage based upon the primary endpoint of survival. Methods High-throughput targeted metabolomics of lung tissue from male C57L/J mice exposed to 12.5 Gy whole thorax lung irradiation, treated daily with 400 mg/kg BIO 300 for either 2 weeks or 6 weeks starting 24 h post radiation exposure, were assayed at 180 d post-radiation to identify potential biomarkers. Results A panel of lung metabolites that are responsive to radiation and able to distinguish an efficacious treatment schedule of BIO 300 from a non-efficacious treatment schedule in terms of 180 d survival were identified. Conclusions These metabolites represent potential biomarkers that could be further validated for use in drug development of BIO 300 and in the translation of dose from animal to human.
      PubDate: 2017-10-02
      DOI: 10.1007/s11095-017-2200-9
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