Abstract:
:Dabrafenib is a small-molecule inhibitor of BRAF kinase activity that is currently being developed for the treatment of BRAF V600 mutation-positive melanoma. This clinical, open-label, two-cohort (n = 14 per cohort), randomized study was designed to evaluate the effect of drug substance particle size, and food on the plasma pharmacokinetics of a single oral dose of dabrafenib in patients with BRAF V600 mutation-positive solid tumors. In addition, an exploratory cross-cohort comparison of the relative bioavailability of single-dose dabrafenib administered in gelatin and hydroxypropyl methylcellulose (HPMC) capsules was performed. Higher bioavailability was noted with nonmicronized drug substance (larger particle size), under fasting conditions, and with HPMC capsules. Initial dissolution results at pH 1.2 showed higher dissolution of gelatin relative to HPMC capsules inconsistent with clinical data. Subsequent in vitro dissolution studies were conducted in fasted-state simulated gastric fluid over a 24-h period and showed that HPMC capsules reached a higher percentage of dabrafenib dissolved than gelatin capsules. The presence of HPMC is believed to inhibit precipitation of dabrafenib as the freebase, thereby maintaining a supersaturated solution over an extended period of time. Dabrafenib has been administered in pivotal clinical studies on an empty stomach using micronized drug substance in HPMC capsules.
journal_name
J Pharm Scijournal_title
Journal of pharmaceutical sciencesauthors
Ouellet D,Grossmann KF,Limentani G,Nebot N,Lan K,Knowles L,Gordon MS,Sharma S,Infante JR,Lorusso PM,Pande G,Krachey EC,Blackman SC,Carson SWdoi
10.1002/jps.23519subject
Has Abstractpub_date
2013-09-01 00:00:00pages
3100-9issue
9eissn
0022-3549issn
1520-6017pii
S0022-3549(15)30921-7journal_volume
102pub_type
杂志文章,随机对照试验abstract::Quercetin had been shown to be effective in the management of arthritis. However, bioavailability of quercetin is a concern for such treatment. This work aims at the development of intra-articular drug delivery system by controlled release of quercetin (loaded in microspheres) for the management of rheumatoid arthriti...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.22266
更新日期:2011-01-01 00:00:00
abstract::15-Lipoxygenase (15-LOX) is one of the key enzymes responsible for the formation of oxidized low-density lipoprotein, a major causal factor for atherosclerosis. Δ(9)-Tetrahydrocannabinol (Δ(9)-THC), a major component of marijuana, has suggested to suppress atherosclerosis. Although Δ(9)-THC seems to be attractive for ...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.22354
更新日期:2011-03-01 00:00:00
abstract::A sensitive, specific and reproducible high-performance liquid chromatographic procedure, using the normal phase and radial compression system, is described for the simultaneous determination of corticosterone, hydrocortisone, and dexamethasone in plasma, with prednisolone as the internal standard. Samples were extrac...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600710724
更新日期:1982-07-01 00:00:00
abstract::Chlorpromazine-induced depression of rectal temperatures in rabbits kept at 20 degrees was used to determine relative biophasic drug levels corresponding to observed hypothermic response intensities, which then served to establish a triexponential linear mathematical model describing drug transference and drug action ...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600651110
更新日期:1976-11-01 00:00:00
abstract::The kinetics and pathways for degradation of (+/-)-4'-ethyl-2-methyl-3-(1-pyrrolidinyl)propiophenone hydrochloride (HY-770; 1), a newly developed muscle-relaxing agent, and its analogues were studied in aqueous solution at 50 degrees C, ionic strength 0.5 M, and pH 8.0-12.0. Compound 1 and its four analogues followed ...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600780115
更新日期:1989-01-01 00:00:00
abstract::Papers and patents that deal with polymorphism (crystal systems for which a substance can exist in structures characterized by different unit cells, but where each of the forms has exactly the same elemental composition) and solvatomorphism (systems where the crystal structures of the substance are defined by differen...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章,评审
doi:10.1002/jps.21518
更新日期:2009-05-01 00:00:00
abstract::Previously available GLC methods for ethambutol may only be used to measure quantities of drugs much greater than those found in biological fluids such as plasma and dialysate. A previously published GLC method for plasma samples is extended to measure ethambutol in dialysate. A second GLC method, involving derivatiza...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600670407
更新日期:1978-04-01 00:00:00
abstract::A randomized, two-way, crossover study was performed on 18 normal volunteers to assess the influence of food on the bioavailability of lisinopril, (1-[N2-[(S)-1-carboxy-3-phenylpropyl]-L-lysyl]-L-proline), a long-acting nonsulfhydryl angiotensin converting enzyme inhibitor. A single, 20-mg oral dose of lisinopril was ...
journal_title:Journal of pharmaceutical sciences
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1002/jps.2600750416
更新日期:1986-04-01 00:00:00
abstract::In the present study, the interaction between phenobarbital and activated carbons which is driven by hydrophobic bonding was evaluated. The Two-Mechanism Langmuir-Like Equation was proposed to describe the isotherms for phenobarbital adsorbing to activated carbons. The parameters in the Two-Mechanism Langmuir-Like Equ...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1016/j.xphs.2018.06.018
更新日期:2019-01-01 00:00:00
abstract::The mechanism of drug loading in cross-linked polymers was studied by X-ray photoelectron spectroscopy (XPS). This gave the atomic composition of the surface layers of the loaded polymeric particles so that the exact location of the drug molecules could be identified. Three different lots of popcorn crospovidone and a...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600740911
更新日期:1985-09-01 00:00:00
abstract::The utility of inhaled protein therapeutics to treat lung-resident diseases is limited by protein degradation in the lungs and rapid clearance. This study therefore aimed to evaluate the impact of PEGylation on the lung and systemic exposure of interferon (IFN) α2 after intratracheal administration to rats. An inverse...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.24353
更新日期:2015-04-01 00:00:00
abstract::This study describes the adaptation of conventional titrimetric and spectrophotometric techniques to a microscale for the determination of drug ionization constants (pKa) and partition coefficients (log P). The apparatus for determining pKa and compound purity (or equivalent weight) consists of a three-port conical gl...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1021/js970057s
更新日期:1998-02-01 00:00:00
abstract::A new parameter, the kinetic ratio, is suggested for estimating product potency during storage under ambient warehouse temperatures. Actual warehouse temperature data were integrated using Arrhenius kinetics, and the resulting potency errors, due both to the integration method and to temperature averaging, were evalua...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600690318
更新日期:1980-03-01 00:00:00
abstract::A series of 2-(alpha-hydroxyacetyl)pyridine thiosemicarbazones was synthesized as potential antimalarial and antibacterial agents. Their synthesis was achieved by the condensation of N4-mono- or N4,N4-disubstituted thiosemicarbazides with 2-(alpha-hydroxyacetyl)pyridine. The latter was prepared by selective bromine ox...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600731226
更新日期:1984-12-01 00:00:00
abstract::Single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), and solid-state NMR (SSNMR) techniques are used to analyze the structures of two nonsolvated polymorphs of {4-(4-chloro-3-fluorophenyl)-2-[4-(methyloxy)phenyl]-1,3-thiazol-5-yl} acetic acid. These polymorphs are enantiotropically-related with a...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.21336
更新日期:2008-11-01 00:00:00
abstract::Targeted echogenic liposome dispersions for ultrasonic enhancement of vasoactive and pathological components of endothelium and atherosclerosis have recently been developed. The component lipids required for acoustic and targeting properties include phosphatidylcholine, phosphatidylethanolamine phosphatidylglycerol (P...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.1142
更新日期:2001-12-01 00:00:00
abstract::Alkyl esters (C1--C4) of the four halofumaric acids were tested for antifungal activity against Candida albicans, Aspergillus niger, Mucor mucedo, and Trichophyton mentagrophytes at pH 5.6 and 7.0 in the absence and presence of 10% beef serum in Sabouraud dextrose agar. The most toxic compound to each organism was: C....
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600670443
更新日期:1978-04-01 00:00:00
abstract::The pharmacokinetics of tamsulosin (TAM) was investigated using male Sprague-Dawley rats in which plasma alpha(1)-acid glycoprotein (alpha(1)-AGP) levels were elevated by the subcutaneous injection of 0.2 mL/kg of turpentine oil. alpha(1)-AGP levels increased about eight times after turpentine oil treatment, causing a...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/(SICI)1520-6017(200004)89:4<490::AID-JPS6>
更新日期:2000-04-01 00:00:00
abstract::The human immunodeficiency virus has infected millions of people and the epidemic continues to grow rapidly in some parts of the world. Antiretroviral (ARV) therapy has provided improved treatment and prolonged the life expectancy of patients. Moreover, there is growing interest in using ARVs to protect against new in...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章,评审
doi:10.1016/j.xphs.2016.09.015
更新日期:2016-12-01 00:00:00
abstract::Supercritical fluid extraction (SFE) was shown to be an accurate and precise alternative to liquid extraction for sample preparation of sustained-release felodipine tablets (5 mg potency) while realizing an 80% reduction in solvent consumption. Extractions of felodipine spiked on an inert support were used to evaluate...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600831104
更新日期:1994-11-01 00:00:00
abstract::Two natural products isolated from the plant Daphne genkwa have been shown to possess antileukemic activity in mice. Genkwadaphnin and yuanhuacine were observed to inhibit DNA and protein synthesis in P-388 leukemic cells. A detailed study of the effects of these two diterpene esters on protein synthesis of leukemic c...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600711208
更新日期:1982-12-01 00:00:00
abstract::Various multiparticulate dissolution models that assume a log-normal particle-size distribution are fitted by nonlinear least-squares regression to data from the dissolution of micronized glyburide. Estimates of parameters describing the effective initial particle-size distribution are obtained, together with estimate...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600660603
更新日期:1977-06-01 00:00:00
abstract::Aqueous solutions of several ionizable substances were stored in plastic infusion bags and the sorption of the substances monitored with time. The substances used were p-nitrophenol, p-toluidine, warfarin sodium [3-(alpha-acetonylbenzyl)-4-hydroxycoumarin sodium salt] and trifluoperazine hydrochloride (10-[3-(4-methyl...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600750608
更新日期:1986-06-01 00:00:00
abstract::Nasal administration as a means of delivering therapeutic agents preferentially to the brain has gained significant recent interest. While some substrates appear to be delivered directly to the brain via this route, the mechanisms governing overall brain uptake and exposure remain unclear. Some substrates utilize the ...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章,评审
doi:10.1002/jps.20318
更新日期:2005-06-01 00:00:00
abstract::Drugs possessing the ability to bind to melanin-rich tissue, such as the eye, are linked with higher ocular exposure, and therefore have the potential to affect the efficacy and safety profiles of therapeutics. A high-throughput melanin chromatographic affinity assay has been developed and validated, which has allowed...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.24680
更新日期:2015-12-01 00:00:00
abstract::An electron-capture GLC method to measure nofedone in human serum was developed. A homolog of nofedone was added to the serum as an internal standard before the sample was alkalinized with pH 9.5 phosphate buffer and extracted with ethylene dichloride containing 0.5% isopentyl alcohol. This organic phase was extracted...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600690307
更新日期:1980-05-01 00:00:00
abstract::The recently introduced four-parameter extended Hansen approach was used to study the solubility of p-hydroxybenzoic acid and methyl p-hydroxybenzoate in 32 and 35 individual solvents, respectively. The results are compared with those for benzoic acid in 40 solvents. Seventeen of the thirty-two or 53% of the calculate...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600730211
更新日期:1984-02-01 00:00:00
abstract::Adsorption of proteins to solid-fluid interfaces is often empirically found to promote formation of soluble aggregates and larger, subvisible, and visible particles, but key stages in this process are often difficult to probe directly. Aggregation mediated by adsorption to water-silicon oxide (SiOx) interfaces, akin t...
journal_title:Journal of pharmaceutical sciences
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doi:10.1002/jps.24429
更新日期:2015-06-01 00:00:00
abstract::The advisability of a progressive curtailment of organic solvent film coating offers an incentive to develop latex systems. Here, the use of aqueous colloidal dispersions of cellulose acetate, plasticized with water-soluble additives, is proposed as an alternative way to obtain cellulose acetate membranes either by ca...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600760609
更新日期:1987-06-01 00:00:00
abstract::Flightless I (Flii) is an actin remodeling protein important for cytoskeletal regulation and cellular processes including migration, proliferation, and adhesion. Previous studies have clearly identified Flii as a novel therapeutical target for improved wound repair and have demonstrated Flii regulation using Flii neut...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1016/j.xphs.2017.03.012
更新日期:2017-07-01 00:00:00