Entity

Time filter

Source Type

Nottingham, United Kingdom

Sousa T.,University College London | Yadav V.,University College London | Zann V.,Quotient Clinical | Borde A.,Astrazeneca | And 2 more authors.
Journal of Pharmaceutical Sciences | Year: 2014

Azo- bonded prodrugs of 5-aminosalicylic acid (mesalazine)-sulfasalazine, balsalazide, and olsalazine, which are used in the treatment of ulcerative colitis, rely on colonic bacteria to cleave the azo bond and liberate the active drug in the large intestine. The aim of this study was to use an in vitro colonic simulator to determine the rates of metabolism of these three prodrugs in the presence of colonic bacteria, and to link the data to results obtained previously in humans. In individual fecal slurries prepared from five different donors, sulfasalazine degradation was rapid and virtually complete within 4 h, confirming the ubiquitous nature of azo-reduction between individuals. In pooled fecal slurry, the rate of degradation of sulfasalazine was faster (t1/2 , 32.8 min) than balsalazide (t1/2 , 80.9 min) and olsalazine (t1/2 , 145.1 min). These results are in agreement with data in humans, where it was found that sulfasalazine was more extensively metabolized on passage through the human colon than the other two drugs. These findings indicate that other than the azo bond itself, the broader chemical structure of the molecules play a role in the degradation of this class of compound, and highlight the utility of this in vitro model to evaluate the metabolism of drugs in the presence of colonic microbiota. ©2014 Wiley Periodicals Inc. and the American Pharmacists Association. Source


Nicholson S.J.,Bristol Myers Squibb | Timmins P.,Bristol Myers Squibb | Dockens R.C.,Bristol Myers Squibb | Connor A.,Quotient Clinical | And 5 more authors.
Biopharmaceutics and Drug Disposition | Year: 2012

Reducing the maximum plasma concentration whilst maintaining the exposure was shown to ameliorate adverse events following the oral administration of 6-hydroxybuspirone. This observation, along with a desire to provide for once daily dosing of this compound, provided the basis for the development of an extended release formulation. Hydrophilic matrix tablets based on hydroxypropyl methylcellulose and containing citric acid to provide for an acid microenvironment were prepared and evaluated by in vitro drug release studies and in vivo pharmacokinetic and scintigraphic studies using samarium oxide (153Sm) labelled dosage forms. The dosage forms were found to release the contained drug by a predominantly diffusion mechanism and the release rate was relatively independent of environmental pH. Following administration of the extended release formulations to volunteers, comparative pharmacokinetic data indicated that the extended release formulations provided for a reduction in the maximum plasma concentration of 64-70% relative to that provided by the same dose given as an oral solution, whilst maintaining exposure relative to the oral solution. By examination of absorption curves derived by Wagner-Nelson analysis of pharmacokinetic data it was noted that drug release in vivo correlated well with drug release observed in vitro and no marked change in rate of absorption was noted when dosage forms were located in and releasing drug in the colon. The robust control of drug release seen in vitro translated to a good in vivo performance. Copyright © 2012 John Wiley & Sons, Ltd. Source


Parasrampuria D.A.,Daiichi Sankyo | Kanamaru T.,Daiichi Sankyo | Connor A.,Quotient Clinical | Wilding I.,Quotient Clinical | And 3 more authors.
Journal of Clinical Pharmacology | Year: 2015

Two studies in healthy subjects assessed the absorption of edoxaban when delivered to specific locations within the gastrointestinal tract using Enterion capsules. In study 1 (single-dose, 4-way crossover), 8 participants received edoxaban 60 mg as immediate-release (IR) tablets (treatment A), as powder formulation delivered to the distal small bowel (treatment B) or ascending colon (treatment C), or as an aqueous suspension delivered to the ascending colon (treatment D). In study 2 (single-dose, 2-way crossover), 10 participants received edoxaban 30 mg as IR tablets (treatment E) or in granulate formulation with fumaric acid 50 mg, added to acidify the local gastrointestinal tract and enhance solubility, delivered to the ascending colon (treatment F). Peak and total exposure following targeted drug delivery to the distal gastrointestinal tract were significantly lower than with IR tablet delivery. In study 1, total exposure ratios of treatments B, C, and D compared with A were 14.9%, 7.9%, and 6.1%, respectively. In study 2, relative total exposure was 12.6% for treatment F despite the fumaric acid. Time to peak concentration was longer with higher variability for edoxaban delivered to the distal gastrointestinal tract compared with the IR tablet. These data indicate that edoxaban absorption occurs predominantly in the proximal small intestine. © 2015, The Authors. The Journal of Clinical Pharmacology Published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology. Source


Connor A.,Quotient Clinical | Evans P.,Quotient Clinical
Biopharmaceutics and Drug Disposition | Year: 2011

Danoprevir, a potent, selective inhibitor of HCV NS3/4A protease, has a short half-life in humans. Therefore, the feasibility of a controlled release (CR) formulation to allow less frequent dosing was investigated using experimental approaches and physiological modeling to examine whether danoprevir is absorbed in the colon. Danoprevir absorption was studied in portal-vein-cannulated monkeys and in monkeys surgically modified to make intraduodenal, intrajejunal, intracolonic and oral administration possible. In portal-vein-cannulated monkeys, absorption was apparent up to 24 h after administration. The observed relative bioavailability from intracolonic delivery in the monkey was approximately 30% relative to oral administration, consistent with the model prediction of 40%. Human relative bioavailability for a tablet delivered to the colon compared with an immediate release (IR) formulation was predicted to be 4-28%. Preclinical data and modeling suggested that CR development would be challenging for this Biopharmaceutics Classification System Class IV compound. Therefore, a confirmative study in healthy volunteers was conducted to investigate the relative bioavailability of danoprevir in various regions of the gastrointestinal tract. In a randomized, open-label, crossover study, subjects received 100 mg danoprevir IR soft gel capsule, 100 mg danoprevir solution delivered to the distal small bowel and colon via an Enterion™ capsule (a remotely activated capsule for regional drug delivery) and 100 mg danoprevir powder to the colon via an Enterion™ capsule. The relative bioavailability of danoprevir (compared with IR) delivered to the colon was 6.5% for a solution and 0.6% for a powder formulation, indicating that a CR formulation is not feasible. Copyright © 2011 John Wiley & Sons, Ltd. Copyright © 2011 John Wiley & Sons, Ltd. Source


News Article | April 13, 2016
Site: http://www.biosciencetechnology.com/rss-feeds/all/rss.xml/all

Quotient Clinical, the Translational Pharmaceutics company, has expanded its clinical spray drying capability through the acquisition of a Niro Mobile Minor Spray Dryer. Quotient has a proven track record of developing spray-dried dispersions to overcome drug compound solubility issues, and the addition of a larger scale spray dryer will allow the production of a range of batch sizes, from milligrams up to two kilograms. Sited at Quotient’s new GMP facility at MediCity in Nottingham, UK – scheduled to open later in 2016 – this expansion is a direct response to customer requests for ongoing product development support, including toxicology and later stage clinical studies. Nikki Whitfield, VP of Pharmaceutical Sciences, commented: “Poor solubility is increasingly prevalent in drug pipelines across the industry. We have established a broad suite of formulation approaches within our Translational Pharmaceutics platform to address these complex solubility and bioavailability challenges, and this latest investment will allow us to efficiently scale up the production of optimized formulations to support our clients’ downstream clinical development programs.”

Discover hidden collaborations