Abstract:
:The stability of a freeze-dried model protein, ribonuclease A (RNase), was investigated under accelerated storage conditions at 45 degrees C for time periods up to 60 days. Because RNase is a fairly stable molecule around pH 7, lyophilization was performed in phosphate buffers at pH 4.0 or 10.0 to accelerate degradation kinetics. Degradation was studied by measuring enzymatic activity, the concentrations of soluble monomeric RNase, soluble aggregated (polymerized) RNase, and insoluble aggregated RNase following reconstitution of the lyophilized material at different times. The presence of air in the vial headspace accelerated degradation in the solid state in all cases. When argon or nitrogen was employed in the headspace, degradation kinetics were reduced, implying that molecular oxygen was involved in the degradation process. This interpretation was supported by the observation that 0.05% (w/v) EDTA in the formulation prior to freeze-drying retarded RNase degradation dramatically. EDTA was believed to chelate cations which may have been introduced with the buffer salts in trace quantities sufficient to catalyze autoxidation reactions. Incorporation of antioxidants ascorbic acid (at pH 4.0) and POBN (a spin trap which could have functioned as an antioxidant at pH 10.0) accelerated the degradation of RNase and appeared, in both cases, to be involved in interactions with the protein molecules. Additionally, in the presence of the antioxidants RNase degradation appeared to be accelerated by light. Although there is strong support for the oxidative hypothesis, the possibility of other competing reactions cannot be discounted. These investigations demonstrate the importance of challenging the extrapolation of some of our well-established ideas concerning small molecule solution kinetics to macromolecules in the solid state.
journal_name
Pharm Resjournal_title
Pharmaceutical researchauthors
Townsend MW,Byron PR,DeLuca PPdoi
10.1023/a:1015959604616subject
Has Abstractpub_date
1990-10-01 00:00:00pages
1086-91issue
10eissn
0724-8741issn
1573-904Xjournal_volume
7pub_type
杂志文章abstract:PURPOSE:Drug particle physical properties are critical for the efficiency of a drug delivered to the lung. The purpose of this study was to produce ultrafine sumatriptan succinate particles for inhalation. METHODS:Sumatriptan succinate particles were produced via reactive precipitation without any surfactants. Several...
journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1007/s11095-008-9586-3
更新日期:2008-09-01 00:00:00
abstract:PURPOSE:Recombinant human platelet glycoprotein Ibalpha-immunoglobulin G1 chimeric proteins (GPIbalpha-Ig) have varying levels of anti-thrombotic activities based on their ability to compete for platelet mediated adhesion to von Willebrand Factor (vWF). Valine substituted GPIbalpha-Ig chimeras, at certain position, inc...
journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1007/s11095-006-9018-1
更新日期:2006-08-01 00:00:00
abstract:PURPOSE:There is evidence that cholesterol affects the ATPase and transport functions of P-glycoprotein (P-gp). To study the influence of cholesterol on P-gp in a well defined lipid environment, we reconstituted P-gp in egg phosphatidylcholine (PhC) and PhC/cholesterol proteoliposomes with negligible residual amounts o...
journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1007/s11095-007-9326-0
更新日期:2007-11-01 00:00:00
abstract::Semitelechelic poly[N-(2-hydroxypropyl)methacrylamide]s (ST-PHPMA) containing one amino end-group and differing in molecular weight were synthesized by radical polymerization in the presence of 2-aminoethanethiol (AET) as chain transfer agent. These polymers were covalently attached via amide bonds to the surface of n...
journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1023/a:1016247206531
更新日期:1995-05-01 00:00:00
abstract::The binding of diflunisal to hydroxypropyl-beta-cyclodextrin (HP beta CD), bovine serum albumin (BSA), human serum albumin (HSA), normal human plasma, and mixed solutions of HP beta CD/protein was studied at 25 degrees C, pH 7.4, by potentiometry using an electrode selective to diflunisal. The experimental data for di...
journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1023/a:1018901912619
更新日期:1994-01-01 00:00:00
abstract:PURPOSE:To characterize the distribution of water among various components in a powder blend using solid-state NMR spectroscopy. METHODS:Water sorption behavior of theophylline anhydrate and excipients was determined by dynamic vapor sorption (DVS) and Karl Fischer Titration (KFT) after storing them in humidity chambe...
journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1007/s11095-016-1972-7
更新日期:2016-10-01 00:00:00
abstract:PURPOSE:Overexpression of the serine protease urokinase (uPA) is recognised as an important biomarker of metastatic disease and a druggable anticancer target. Plasminogen activator inhibitor type-2 (PAI-2/SerpinB2) is a specific uPA inhibitor with proven potential for use in targeted therapy. However, PAI-2 is rapidly ...
journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1007/s11095-014-1517-x
更新日期:2015-03-01 00:00:00
abstract:PURPOSE:To evaluate the reaction of a large series of pharmacologically significant 1,4-dihydropyridine (1,4-DHP) compounds with superoxide (O2.-) in dimethylsulfoxide using differential pulse voltammetry and controlled potential electrolysis. METHODS:Differential pulse voltammetry was used to track the consumption of...
journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1023/a:1022291624933
更新日期:2003-02-01 00:00:00
abstract::Many drugs and desirable phytochemicals are bitter, and bitter tastes are aversive. Food and pharmaceutical manufacturers share a common need for bitterness-masking strategies that allow them to deliver useful quantities of the active compounds in an acceptable form and in this review we compare and contrast the chall...
journal_title:Pharmaceutical research
pub_type: 杂志文章,评审
doi:10.1007/s11095-014-1480-6
更新日期:2014-11-01 00:00:00
abstract::Although much effort has been devoted to opioid research since the identification of enkephalins, understanding of the physiological importance and mechanisms of action of endogenous opioids lags behind understanding of opiate alkaloids such as morphine. In recent years, several novel approaches have been refined with...
journal_title:Pharmaceutical research
pub_type: 杂志文章,评审
doi:10.1023/a:1015809702296
更新日期:1991-01-01 00:00:00
abstract::The transport of thyrotropin releasing hormone (TRH) in rabbit buccal mucosa in vitro has been investigated with respect to (a) rate and type of metabolism of TRH on mucosal and serosal sides of buccal mucosa, (b) mechanism of TRH transport including charge effect on its permeability, and (c) pathway and rate-limiting...
journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1023/a:1015883217858
更新日期:1992-09-01 00:00:00
abstract:PURPOSE:The present investigation describes a formulative study for the development of innovative drug delivery systems for bromocriptine. METHODS:Solid lipid nanoparticles (SLN) based on different lipidic components have been produced and characterized. Morphology and dimensional distribution have been investigated b...
journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1007/s11095-007-9514-y
更新日期:2008-07-01 00:00:00
abstract:PURPOSE:The major objectives of this study were to 1) develop a new mathematical model describing all phases of drug release from bioerodible microparticles; 2) evaluate the validity of the theory with experimental data; and 3) use the model to elucidate the release mechanisms in poly(lactide-co-glycolide acid)-based m...
journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1023/a:1021457911533
更新日期:2002-12-01 00:00:00
abstract:PURPOSE:To quantitatively compare in vitro dissolution data in biorelevant and compendial media, to investigate whether in vitro differences are reflected in the simulated plasma profile and to specify under which circumstances prediction of the plasma profile of orally administered lipophilic drugs can be achieved. M...
journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1023/a:1011071401306
更新日期:2001-03-01 00:00:00
abstract:PURPOSE:Critical steps in the subcellular processing of poly(ethylene imine)/nucleic acid complexes, especially endosomal/lysosomal escape, were visualized by using living cell confocal laser scanning microscopy (CSLM) to obtain an insight into their mechanism. METHODS:Living cell confocal microscopy was used to exami...
journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1023/a:1014212630566
更新日期:2002-02-01 00:00:00
abstract::Nucleoside transporters play a critical role in the absorption, disposition, and targeting of therapeutically used nucleosides and nucleoside analogs. This review is focused on the Na(+)-dependent, concentrative nucleoside transporters which are found in a variety of cells including renal, intestinal and hepatic epith...
journal_title:Pharmaceutical research
pub_type: 杂志文章,评审
doi:10.1023/a:1012113931332
更新日期:1997-11-01 00:00:00
abstract:PURPOSE:The purpose of the study is to characterize glycine crystallization during freezing of aqueous solutions as a function of the glycine salt form (i.e., neutral glycine, glycine hydrochloride, and sodium glycinate), pH, and ionic strength. METHODS:Crystallization was studied by thermal analysis, microscopy, x-ra...
journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1023/a:1016223101872
更新日期:1995-10-01 00:00:00
abstract:PURPOSE:We investigated the characteristics of transport of an organic anion, p-aminohippurate (PAH), at the apical membrane in a kidney epithelial cell line OK. METHODS:Efflux and uptake of [14C]PAH across the apical membrane were measured using OK cell monolayers grown on microporous membrane filters. RESULTS:PAH e...
journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1023/a:1021437306990
更新日期:2002-12-01 00:00:00
abstract::Animal models are used commonly in various stages of drug discovery and development to aid in the prospective assessment of drug-drug interaction (DDI) potential and the understanding of the underlying mechanism for DDI of a drug candidate. In vivo assessments in an appropriate animal model can be very valuable, when ...
journal_title:Pharmaceutical research
pub_type: 杂志文章,评审
doi:10.1007/s11095-010-0157-z
更新日期:2010-09-01 00:00:00
abstract::A method is described for the assay of phenobarbital N-glucosylation using UDP-D-[6-3H]glucose. The radioactive phenobarbital N-glucoside conjugates [(5R)-PBG, (5S)-PBG] formed during the incubations were resolved from each other and from uncharacterized radioactive products by semipreparative HPLC. The product ratio ...
journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1023/a:1015889707922
更新日期:1992-05-01 00:00:00
abstract::The conditions under which the absorption enhancer palmitoyl L-carnitine chloride (PCC) improved the bioavailability of the poorly absorbed antibiotic cefoxitin throughout the rat intestine has been studied. Cefoxitin alone was appreciably absorbed only in the duodenum (31% vs less than 7% elsewhere). PCC solutions (3...
journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1023/a:1018977021183
更新日期:1992-02-01 00:00:00
abstract::Liver fibrosis is a pathological condition originating from liver damage that leads to excess accumulation of extracellular matrix (ECM) proteins in the liver. Viral infection, chronic injury, local inflammatory responses and oxidative stress are the major factors contributing to the onset and progression of liver fib...
journal_title:Pharmaceutical research
pub_type: 杂志文章,评审
doi:10.1007/s11095-014-1497-x
更新日期:2015-02-01 00:00:00
abstract:PURPOSE:The aim of the study is to investigate the effect of polymer blending on entrapment and release of ganciclovir (GCV) from poly(D,L-lactide-co-glycolide) (PLGA) microspheres using a set of empirical equations. METHODS:Two grades of PLGA, PLGA 7525 [D,L-lactide:glycolide(75:25), MW 90,000-126,000 Da] and Resomer...
journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1007/s11095-005-9042-6
更新日期:2006-01-01 00:00:00
abstract::Apigenin, a naturally occurring plant flavone, abundantly present in common fruits and vegetables, is recognized as a bioactive flavonoid shown to possess anti-inflammatory, antioxidant and anticancer properties. Epidemiologic studies suggest that a diet rich in flavones is related to a decreased risk of certain cance...
journal_title:Pharmaceutical research
pub_type: 杂志文章,评审
doi:10.1007/s11095-010-0089-7
更新日期:2010-06-01 00:00:00
abstract::The effects of tertiary amine-containing basic drugs on the enzymes located in the mitochondria and the effect of monoamine oxidase inhibitors (MAOIs) on drug accumulation in lung mitochondria have been studied. Various basic drugs inhibited MAO activity but not other mitochondrial marker enzymes. The potency of MAO i...
journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1023/a:1015964623098
更新日期:1989-10-01 00:00:00
abstract::Using brine shrimp lethality to direct fractionation, extracts of the bark of Annona bullata Rich. (Annonaceae) have yielded 16 alpha-hydroxy-(-)-kauranoic acid as a bioactive plant constituent. This previously known diterpene showed significant (ED50 8.25 x 10(-2) micrograms/ml) and selective cytotoxicity against A-5...
journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1023/a:1015819422479
更新日期:1990-04-01 00:00:00
abstract:PURPOSE:To analyze the mechanics of some pharmaceutical agglomerates during uniaxial confined compression by using compression parameters derived from the Heckel, Kawakita and Adams equations, and to study the influence of these compression parameters on the tablet-forming ability of agglomerates. METHODS:Force and di...
journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1023/a:1007575120817
更新日期:2000-08-01 00:00:00
abstract::Knowledge of comparative solubility profiles of a base and its hydrochloride salt is important in selecting one form over the other for dosage form design. The studies with two model bases, namely, tiaramide and papaverine, showed that, except during phase transition from a base to a salt or vice versa, the pH-solubil...
journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1023/A:1016382426347
更新日期:1985-03-01 00:00:00
abstract:PURPOSE:The aim of this work is to design new chitosan conjugates able to self-organize in aqueous solution in the form of micrometer-size platelets. When mixed with amphotericin B deoxycholate (AmB-DOC), micro-platelets act as a drug booster allowing further improvement in AmB-DOC anti-Candida albicans activity. METH...
journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1007/s11095-017-2117-3
更新日期:2017-05-01 00:00:00
abstract:PURPOSE:Orally absorbable anticancer medications have great advantages for conventional cancer therapies to patients. Here we evaluated the potent anticancer effect of orally absorbable LHD, a chemical conjugate of low-molecular-weight heparin and deoxycholic acid, on tumor graft growth models. METHODS:We characterize...
journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1007/s11095-009-9989-9
更新日期:2009-12-01 00:00:00