Abstract:
:Benzyl alcohol (BA) is the most widely used antimicrobial preservative in multidose protein formulations, and has been shown to cause protein aggregation. Our previous work on a model protein cytochrome c demonstrated that this phenomenon occurs via partial unfolding. Here, we examine the validity of these results by investigating the effect of BA on a pharmaceutically relevant protein, interferon α-2a (IFNA2). IFNA2 therapeutic formulations available on the pharmaceutical market contain BA as a preservative. Isothermal aggregation kinetics and temperature scanning demonstrated that BA induced IFNA2 aggregation in a concentration-dependent manner. With increasing concentration of BA, the apparent aggregation temperature of IFNA2 linearly decreased. Denaturant melts measured using protein intrinsic fluorescence and that of the 1-anilinonaphthalene-8-sulfonic acid dye indicated that IFNA2 stability decreased with increasing BA concentration, populating a partially unfolded intermediate. Changes in nuclear magnetic resonance chemical shifts and hydrogen exchange rates identified the structural nature of this intermediate, which correlated with an aggregation "hot-spot" predicted by computational methods. These results indicate that BA induces IFNA2 aggregation by partial unfolding rather than global unfolding of the entire protein, and is consistent with our earlier conclusions from model protein studies.
journal_name
J Pharm Scijournal_title
Journal of pharmaceutical sciencesauthors
Bis RL,Singh SM,Cabello-Villegas J,Mallela KMdoi
10.1002/jps.24105subject
Has Abstractpub_date
2015-02-01 00:00:00pages
407-15issue
2eissn
0022-3549issn
1520-6017pii
S0022-3549(15)30190-8journal_volume
104pub_type
杂志文章abstract::The nanosizing of poorly soluble drugs as a formulation strategy can eventually enhance their dissolution rate and bioavailability. Standard comminution techniques such as high-pressure homogenization (HPH) or wet bead milling have limitations in reaching the desired mean particle size. Combinative methods have been d...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.23475
更新日期:2013-05-01 00:00:00
abstract::The objective of this study was to investigate product performance of freeze dried l-arginine/sucrose-based formulations under variation of excipient weight ratios, l-arginine counter ions and formulation pH as a matrix to stabilize a therapeutic monoclonal antibody (MAb) during freeze drying and shelf life. Protein a...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.24501
更新日期:2015-07-01 00:00:00
abstract::The intrinsic dissolution rate and solubility of carbamazepine was measured in aqueous solutions of sodium lauryl sulfate (SLS) prepared with two different grades of purity, 95 and 99%, and 95% SLS in 0.15 M NaCl to determine the effect of surface-active impurities and electrolytes. Four significant observations resul...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1021/js960105t
更新日期:1997-03-01 00:00:00
abstract::The geometry and structural features of the inclusion complexes of beta-cyclodextrin (beta-CD) with the chiral antiamnesic drugs (+/-)-1-benzyl-4-hydroxymethylpyrrolidin-2-one (WEB-1868). (+/-)-1-benzenesulfonyl-5-ethoxypyrrolidin-2-one (RU-35929), and (+/-)-1-(3-pyridinlysulfonyl)-5-ethoxypyrrolidin-2-one (RU-47010) ...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600811205
更新日期:1992-12-01 00:00:00
abstract::A series of gem-cichlorocyclopropyl and cyclopropyl analogs of stilbene congeners was synthesized and examined for estrogenic and antiestrogenic activity using the uterotropic assay in the immature mouse. The relative receptor affinity in vitro was determined by measuring [3H]estradiol displacement from the rat uterin...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600711012
更新日期:1982-10-01 00:00:00
abstract::An automated two-phase method for the simultaneous fluorometric determination of the spironolactone metabolites canrenone (II) and canrenoic acid (III) in serum is described. The determination is performed by two dichloroethane extractions of the same serum sample at different pH values. The fluorescence developed in ...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600660820
更新日期:1977-08-01 00:00:00
abstract::Three aspirin derivatives, aspirin phenylalanine ethyl ester, aspirin phenylalanine amide, and aspirin phenyllactic ethyl ester, were investigated with respect to their hydrolysis by alpha-chymotrypsin. Of the three compounds, aspirin phenylalanine ethyl ester was the best substrate, with kcat = 25 sec-1 and Km = 1.3 ...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600701203
更新日期:1981-12-01 00:00:00
abstract::The area under the plasma concentration-time curve (AUC) was measured after an intravenous injection of sodium salicylate and after intragastric administration of aspirin, using either an intermittent sampling and the trapezoid rule (AUC-trapezoid) or the recently introduced constant blood withdrawal method (AUC-integ...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600670644
更新日期:1978-06-01 00:00:00
abstract::Respirable crystals of cromoglycic acid (CA) were prepared by precipitation of CA with hydrochloric acid from aqueous solutions of cromolyn sodium and subsequent recrystallization from hot water or mixtures of dimethyl sulphoxide and water. The properties of the materials were established by melting point measurements...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600780221
更新日期:1989-02-01 00:00:00
abstract::The mechanism of how poly(vinyl alcohol-co-acrylic acid-co-methyl methacrylate) (PVA copolymer) stabilizes an amorphous drug was investigated. Solid dispersions of PVA copolymer, poly(vinyl pyrrolidone) (PVP), and poly(vinyl pyrrolidone-co-vinyl acetate) (PVPVA) with indomethacin (IMC) were prepared. The glass transit...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.24023
更新日期:2014-09-01 00:00:00
abstract::We report a semiquantitative method for determining trace amounts (<1%) of thermodynamically stable forms in polymorphic mixtures, focusing on sample preparation effects on solid phase transitions. Tegafur [5-fluoro-1-(oxolan-2-yl)-1,2,3,4-tetrahydropyrimidine-2,4-dione] was used as a model material in this study. The...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.23323
更新日期:2012-12-01 00:00:00
abstract::The in vitro binding of warfarin by human serum albumin was studied at various temperatures and at pH 7.4 by a frontal gel filtration technique. The results can be best described in terms of a two class-of-binding site model, in which the numbers of primary and secondary sites are constrained to the average values for...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600651127
更新日期:1976-11-01 00:00:00
abstract::Spectrophotometric assay for cycloserine based on the interaction of the drug with 9-methoxyacridine as a chromogenic agent is described. The highly colored substituted acridine product was identified as 9-(d-4-imino-3-isoxazolidinone)acridine. Color development was affected by time and temperature of heating and by t...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600770519
更新日期:1988-05-01 00:00:00
abstract::The dissolution behavior and absorption of mefenamic acid following oral and rectal administration from drug:egg albumin solid dispersions have been studied in comparison with those of the drug alone. The interaction of drug with egg albumin in aqueous solution and solid state were examined by solubility analysis, dia...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600800517
更新日期:1991-05-01 00:00:00
abstract::The purpose of this study was to investigate the feasibility of delivering sinomenine hydrochloride (SH) transdermally using composite dissolving microneedles (DM) which integrated with liquid crystals (H2). The fabricated SH-loaded composite DM was evaluated for their appearance, mechanical strength, irritation, and ...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1016/j.xphs.2017.07.027
更新日期:2017-12-01 00:00:00
abstract::Taxanes such as paclitaxel (Taxol) and docetaxel (Taxotere) are promising agents for use against ovarian cancer and other malignancies. Recently, SB-T-1011, a semisynthetic taxane, has been prepared from 14-hydroxy-10-deacetylbaccatin III. SB-T-1011 shows similar or greater in vitro cytostatic activity than paclitaxel...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600841204
更新日期:1995-12-01 00:00:00
abstract::Cellulose derivatives are commonly used as gelling agents in topical and ophthalmic drug formulations. During the course of manufacturing, cellulose derivatives are believed to generate free radicals. These free radicals may degrade the gelling agent, leading to lower viscosity. Free radicals also may react with the a...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.21632
更新日期:2009-07-01 00:00:00
abstract::Many pathophysiological circumstances vary during 24 h periods. Many physiologic processes undergo biological rhythms, including the sleep-wake rhythm and metabolism. Disruptive effect in the 24 h variations can manifest as the emergence or exacerbation of pathological conditions. So, chronotherapeutics is gaining inc...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章,评审
doi:10.1002/jps.22656
更新日期:2011-09-01 00:00:00
abstract::Statistical assessment of bioavailability and bioequivalence of drug products is generally carried out with a univariate analysis by independently comparing each relevant parameter [such as, area under the drug concentration curve (AUC) and peak drug concentration (Cmax)] of the test and reference products. The assump...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600840620
更新日期:1995-06-01 00:00:00
abstract::A high-performance liquid chromatographic method using a linear elution gradient has been developed for the analysis of sulindac, sulindac sulfone, and sulindac sulfide in plasma, urine, bile, and gastric fluid. The methodology uses reverse-phase, radial compression chromatography with gradient elution, and UV detecti...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600730921
更新日期:1984-09-01 00:00:00
abstract::The objective of the current study was to evaluate the performance of Raman and near-infrared (NIR) techniques combined with chemometrics in characterizing the critical quality attributes of brompheniramine (BP)-tannate complexes. Seven complexes were prepared and evaluated for chemical interactions, solubilities, dis...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.23030
更新日期:2012-04-01 00:00:00
abstract::Three dimensional terahertz pulsed imaging (TPI) was evaluated as a novel tool for the nondestructive characterization of different solid oral dosage forms. The time-domain reflection signal of coherent pulsed light in the far infrared was used to investigate film-coated tablets, sugar-coated tablets, multilayered con...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.20789
更新日期:2007-02-01 00:00:00
abstract::17-(allylamino)-17-demethoxygeldanamycin (17AAG) is a benzoquinone ansamycin Hsp90 inhibitor which has promising anticancer activity in vitro, in animal models and in clinical trials. 17AAG has poor water-solubility which is a potential problem for clinical formulation. The hydroquinone derivative of 17AAG, 17AAG hydr...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.21394
更新日期:2008-12-01 00:00:00
abstract::Application of low-frequency ultrasound has been shown to enhance transdermal transport of drugs (low-frequency sonophoresis). In this paper, we show that the efficacy of low-frequency ultrasound in enhancing transdermal transport can be further increased by its combination with sodium lauryl sulfate (SLS), a well-kno...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/1520-6017(200007)89:7<892::AID-JPS6>3.0.CO
更新日期:2000-07-01 00:00:00
abstract::Aerosolized medicine is one of the fastest growing areas in the pharmaceutical industry. Dry powder aerosols of pharmaceutical compounds are particularly attractive for the prevention and treatment of respiratory diseases but are also emerging as a treatment option for systemic diseases. Engineering particles in dry p...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.23168
更新日期:2012-09-01 00:00:00
abstract::Wounds, particularly burns, are prone to colonization of potentially life-threatening bacteria. Local delivery of antimicrobial agents in sufficient quantities and over longer period of time can reduce risk of burn infections. Mupirocin-in-liposomes-in-hydrogels were proposed as advanced delivery system for improved b...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.23260
更新日期:2012-10-01 00:00:00
abstract::Corneal penetration studies were conducted in unanesthetized albino rabbits using various organic compounds representing both polar and nonpolar species. Very low molecular weight compounds demonstrate rapid uptake into the aqueous humor despite the lipid-like barrier imposed by the corneal epithelium. Evidence that t...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600770103
更新日期:1988-01-01 00:00:00
abstract::Meglumine labeled with carbon-14 was administered orally as 14C-meglumine salicylate to rats and dogs to study its distribution and excretion. The compound was incompletely absorbed; that which was absorbed was rapidly excreted in the urine. Peak blood levels were about 5-10 mug/ml in rats and 2-8 mug/ml in dogs. Tiss...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600660124
更新日期:1977-01-01 00:00:00
abstract::Both nonequilibrium and equilibrium models were proposed to explain the optimal biological response to a set of congeners with respect to the oil-water partition coefficient (P). A detailed analysis of the kinetic model proposed by Hansch demonstrates the bilinear form of the model, with the initial slope of the logar...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600700110
更新日期:1981-01-01 00:00:00
abstract::An automated potentiometric procedure was used for studying in vitro dissolution kinetics of acidic drugs. Theoretical considerations indicated that the pH-stat method could be used to establish approximate sink conditions or, possibly, a perfect sink. Data obtained from dissolution studies using the pH-stat method we...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600670837
更新日期:1978-08-01 00:00:00