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Pharmaceutical Research

Jose A Suárez Del Pino, Rohit Kolhatkar
PURPOSE: HSP90 (Heat shock protein 90kD) has been validated as a therapeutic target in Castrate Resistant Prostate Cancer. Unfortunately, HSP90 inhibitors suffer from dose-limiting toxicities that hinder their clinical applications. Previously developed polymeric delivery systems for HSP90 inhibitors had either low drug content or low biological activity suggesting the need for better delivery system for HSP90 inhibitors. METHODS: We developed a simplified synthetic strategy to prepare polyethylene glycol based water-soluble polymeric system for model HSP90 inhibitor geldanamycin (GDM)...
September 14, 2017: Pharmaceutical Research
Pavan Kumar Prathipati, Subhra Mandal, Gregory Pon, Renuga Vivekanandan, Christopher J Destache
PURPOSE: Non-adherence to the antiretroviral (ARV) regimen is a critical factor in determining efficacy of ARV drugs for pre-exposure prophylaxis (PrEP). A long-acting parenteral formulation may be an effective alternative to daily oral dosing. A pharmacokinetic and tissue distribution study of drug-loaded nanoparticle (NP) was performed in female humanized CD34(+)-NSG mice. METHODS: Mice received 200 mg/kg each of tenofovir alafenamide (TAF) and elvitegravir (EVG) as free drugs (TAF + EVG solution) or as drug loaded NP (TAF + EVG NP) formulation by subcutaneous (SubQ) administration...
September 13, 2017: Pharmaceutical Research
Baochun Yang, Mei Shen, Jianqiang Liu, Fei Ren
PURPOSE: Metal-organic frameworks (MOFs) have shown great potentials as drug delivery carriers, but the conventional methods for MOFs synthesis limited their use in biomedicine. The aim of this study was engineered tumor-targeted zinc nanoscale MOFs encapsulating chemotherapy drug. METHODS: We employed post-synthetic modification to construct tumor cell-targeted nanoscale zinc MOFs (nanoMOFs) functionalized with folate as the targeting ligand that binds specifically to folate receptors on tumor cells...
September 8, 2017: Pharmaceutical Research
Hanah Mesallati, Lidia Tajber
PURPOSE: To improve the pharmaceutical properties of amorphous ciprofloxacin (CIP) succinate salts via formulation as polymer/amorphous salt solid dispersions (ASSDs). METHODS: ASSDs consisting of an amorphous CIP/succinic acid 1:1 or 2:1 salt dispersed in PVP or Soluplus were produced by spray drying and ball milling. The solid state characteristics, miscibility, stability, solubility and passive transmembrane permeability of the ASSDs were then examined. RESULTS: The ASSDs had higher glass transition and crystallization temperatures than the corresponding amorphous succinate salts, and were also more stable during long-term stability studies...
September 5, 2017: Pharmaceutical Research
Nusrat Chowdhury, Imran Vhora, Ketan Patel, Ravi Doddapaneni, Arindam Mondal, Mandip Singh
PURPOSE: Non-small cell lung cancer is the leading cause of cancer related deaths globally. Considering the side effects and diminishing chemosensitivity to chemotherapy, novel treatment approaches are sought. Hence, we aim to develop a liposomal co-delivery system of pDNA expressing shRNA against PFKFB3 (pshPFKFB3) and docetaxel (DTX). METHODS: Cationic DTX liposomes complexed with pshPFKFB3 (PSH-DL) were developed. In vitro cell line studies were performed to evaluate transfection, PFKFB3 mRNA silencing, cytotoxicity, pGP inhibition, and protein markers expression...
September 5, 2017: Pharmaceutical Research
Tze Ning Hiew, Rongying Huang, Ivan Popov, Yuri Feldman, Paul Wan Sia Heng
PURPOSE: This study explored the potential of combining the use of moisture sorption isotherms and dielectric relaxation profiles of starch and sodium starch glycolate (SSG) to probe the location of moisture in dried and hydrated samples. METHODS: Starch and SSG samples, dried and hydrated, were prepared. For hydrated samples, their moisture contents were determined. The samples were probed by dielectric spectroscopy using a frequency band of 0.1 Hz to 1 MHz to investigate their moisture-related relaxation profiles...
September 5, 2017: Pharmaceutical Research
Derek Reichel, Louis T Curtis, Elizabeth Ehlman, B Mark Evers, Piotr Rychahou, Hermann B Frieboes, Younsoo Bae
PURPOSE: To develop polymer nanoassemblies (PNAs) modified with halofluorochromic dyes to allow for the detection of liver metastatic colorectal cancer (CRC) to improve therapeutic outcomes. METHODS: We combine experimental and computational approaches to evaluate macroscopic and microscopic PNA distributions in patient-derived xenograft primary and orthotropic liver metastatic CRC tumors. Halofluorochromic and non-halofluorochromic PNAs (hfPNAs and n-hfPNAs) were prepared from poly(ethylene glycol), fluorescent dyes (Nile blue, Alexa546, and IR820), and hydrophobic groups (palmitate), all of which were covalently tethered to a cationic polymer scaffold [poly(ethylene imine) or poly(lysine)] forming particles with an average diameter < 30 nm...
August 24, 2017: Pharmaceutical Research
Hovhannes J Gukasyan, Tomomi Uchiyama, Kwang-Jin Kim, Carsten Ehrhardt, Sharon K Wu, Zea Borok, Edward D Crandall, Vincent H L Lee
PURPOSE: Studies were conducted in primary cultured rat alveolar epithelial cell monolayers to characterize peptide transporter expression and function. METHODS: Freshly isolated rat lung alveolar epithelial cells were purified and cultured on permeable support with and without keratinocyte growth factor (KGF). Messenger RNA and protein expression of Pept1 and Pept2 in alveolar epithelial type I- and type II-like cell monolayers (±KGF, resp.) were examined by RT-PCR and Western blotting...
August 22, 2017: Pharmaceutical Research
Syunsuke Yamamoto, Masatoshi Karashima, Noriyasu Sano, Chiharu Fukushi, Kimio Tohyama, Yuta Arai, Hideki Hirabayashi, Nobuyuki Amano
PURPOSE: Although Göttingen minipigs have been widely used for the evaluation of skin absorption, the correlation of minipig skin permeability with human skin absorption remains unclear. This study was designed to investigate the prediction of human plasma concentrations after dermal application of drug products using skin permeability data obtained from minipigs. METHODS: First, in vitro skin permeabilities of seven marketed transdermal drug products were evaluated in minipigs, and compared with in vitro human skin permeability data...
August 21, 2017: Pharmaceutical Research
Johan Nicolaï, Louise Thevelin, Qi Bing, Bruno Stieger, Hugues Chanteux, Patrick Augustijns, Pieter Annaert
PURPOSE: Vincristine is known to interfere with OATP-mediated uptake of other compounds, hinting that vincristine itself could be a substrate of OATP transporters. The present study therefore aimed to investigate the role of OATP transporters in the hepatocellular disposition of vincristine. METHODS: Vincristine uptake was studied in suspended rat and human hepatocytes as well as OATP-transfected Chinese hamster ovary (CHO) cells in the absence and presence of OATP transporter inhibitors...
August 21, 2017: Pharmaceutical Research
Jialin Mao, Peter Fan, Susan Wong, Jianshuang Wang, Moulay Hicham Alaoui Ismaili, Brian Dean, Cornelis E C A Hop, Matthew Wright, Yuan Chen
PURPOSE: The exposure of G2917 decreased by four-fold at oral doses of 100 mg/kg twice daily for seven days in cynomolgus monkeys. Additional investigative work was conducted to understand: (1) the causes for the significant reduction in G2917 exposure in monkeys; (2) the extrapolation of in vitro induction data to in vivo findings in monkeys, and (3) the relevance of this pre-clinical finding to humans at the projected human efficacious dose. METHODS: Pharmacokinetic and induction potency (in vitro and in vivo) of G2917 in monkeys, and the in vitro human induction potency were studied...
August 16, 2017: Pharmaceutical Research
Jeroen Van Renterghem, Chris Vervaet, Thomas De Beer
PURPOSE: The aim of this study was to investigate (i) the influence of drug solid-state (crystalline or dissolved in the polymer matrix) on the melt viscosity and (ii) the influence of the drug concentration, temperature and shear rate on polymer crystallization using rheological tests. METHODS: Poly (ethylene oxide) (PEO) (100.000 g/mol) and physical mixtures (PM) containing 10-20-30-40% (w/w) ketoprofen or 10% (w/w) theophylline in PEO were rheologically characterized...
August 15, 2017: Pharmaceutical Research
Bowen Jiang, Hua Yu, Yongrong Zhang, Hanping Feng, Stephen W Hoag
PURPOSE: There are many important diseases whose treatment could be improved by delivering a therapeutic protein to the colon, for example, Clostridium difficile infection, ulcerative colitis and Crohn's Disease. The goal of this project was to investigate the feasibility of colonic delivery of proteins using multiparticulate beads. METHODS: In this work, bovine serum albumin (BSA) was adopted as a model protein. BSA was spray layered onto beads, followed by coating of an enteric polymer EUDRAGIT® FS 30 D to develop a colonic delivery system...
August 14, 2017: Pharmaceutical Research
Naresh Mittapelly, Maharshi Thalla, Gitu Pandey, Venkatesh Teja Banala, Shweta Sharma, Abhishek Arya, Sandeep Mishra, Kalyan Mitra, Shubha Shukla, Prabhat Ranjan Mishra
PURPOSE: The aim of the present study was to prepare a patient friendly long acting donepezil (D) nanocrystals (NCs) formulation, with a high payload for i.m administration. As the native D hydrochloride salt has high aqueous solubility it is necessary to increase its hydrophobicity prior to the NCs formation. METHODS: D was ionically paired with embonic acid (E) in aqueous media and was successfully characterized using techniques like DSC, PXRD, FT-IR, NMR etc...
August 14, 2017: Pharmaceutical Research
Sharvari Bhagwat, Uta Schilling, Mong-Jen Chen, Xiangyin Wei, Renishkumar Delvadia, Mohammad Absar, Bhawana Saluja, Günther Hochhaus
PURPOSE: The ability of two semi-mechanistic simulation approaches to predict the systemic pharmacokinetics (PK) of inhaled corticosteroids (ICSs) delivered via dry powder inhalers (DPIs) was assessed for mometasone furoate, budesonide and fluticasone propionate. METHODS: Both approaches derived the total lung doses and the central to peripheral lung deposition ratios from clinically relevant cascade impactor studies, but differed in the way the pulmonary absorption rate was derived...
August 10, 2017: Pharmaceutical Research
Varun Kushwah, Ashish Kumar Agrawal, Chander Parkash Dora, David Mallinson, Dimitrios A Lamprou, Ramesh C Gupta, Sanyog Jain
PURPOSE: The present study reports a novel conjugate of gemcitabine (GEM) with bovine serum albumin (BSA) and thereof nanoparticles (GEM-BSA NPs) to potentiate the therapeutic efficacy by altering physicochemical properties, improving cellular uptake and stability of GEM. METHODS: The synthesized GEM-BSA conjugate was extensively characterized by NMR, FTIR, MALDI-TOF and elemental analysis. Conjugation mediated changes in structural conformation and physicochemical properties were analysed by fluorescence, Raman and CD spectroscopy, DSC and contact angle analysis...
August 9, 2017: Pharmaceutical Research
Carolyn Schutt, Stuart Ibsen, Eran Zahavy, Santosh Aryal, Stacey Kuo, Selin Esener, Michael Berns, Sadik Esener
PURPOSE: A major challenge facing nanoparticle-based delivery of chemotherapy agents is the natural and unavoidable accumulation of these particles in healthy tissue resulting in local toxicity and dose-limiting side effects. To address this issue, we have designed and characterized a new prodrug nanoparticle with controllable toxicity allowing a locally-delivered light trigger to convert the payload of the particle from a low to a high toxicity state. METHODS: The nanoparticles are created entirely from light-activatable prodrug molecules using a nanoprecipitation process...
August 8, 2017: Pharmaceutical Research
Kohta Mohri, Kengo Nagata, Shozo Ohtsuki, Shiori Toyama, Mao Nonomura, Yuki Takahashi, Yoshinobu Takakura, Makiya Nishikawa, Shinji Sakuma
PURPOSE: We previously demonstrated that the immunostimulatory activity of CpG DNA is increased by the formation of polypod-like structures. The present study was designed to elucidate the mechanism underlying this increase. METHODS: Tripodna (three pods) and hexapodna (six pods) were prepared. The cellular uptake of Alexa Fluor 488-labeled DNA samples was examined in several cell lines by measuring the MFI of cells. TNF-α release from RAW264.7 cells was measured after addition of polypodna containing CpG motifs...
August 8, 2017: Pharmaceutical Research
Matthew J Herpin, Hugh D C Smyth
PURPOSE: Despite being the most prominent dosage form for topical ocular delivery, eye-drops have several well-recognized drawbacks. Addressing these limitations, in this work we introduce a novel method to accurately deliver ophthalmic medications to the surface of the eye at relatively low volume and low velocity. By aerosolizing a medicament and dispensing it in the form of a toroidal vortex, commonly known as a "smoke ring", several major drawbacks associated with topical drug delivery can be avoided...
August 7, 2017: Pharmaceutical Research
Jonathan T Su, Ryan S Teller, Priya Srinivasan, Jining Zhang, Amy Martin, Samuel Sung, James M Smith, Patrick F Kiser
PURPOSE: Design of intravaginal rings (IVRs) for delivery of antiretrovirals is often guided by in vitro release under sink conditions, based on the assumption that in vivo release will follow a similar release profile. METHODS: We conducted a dose-ranging study in the female reproductive tract of pigtail macaques using matrix IVRs containing IQP-0528, a poorly soluble but highly potent antiretroviral drug with an IC90 of 146 ng/mL. These IVRs consisted of drug-loaded segments, 15...
August 2, 2017: Pharmaceutical Research
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