Publications by authors named "Nikoletta Fotaki"

54 Publications

Investigating the Impact of Crohn's Disease on the Bioaccessibility of a Lipid-Based Formulation with an In Vitro Dynamic Gastrointestinal Model.

Mol Pharm 2021 04 3;18(4):1530-1543. Epub 2021 Mar 3.

Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, U.K.

The aim of the study was to investigate the impact of Crohn's disease (CD) on the performance of a lipid-based formulation of ciprofloxacin in a complex gastrointestinal simulator (TIM-1, TNO) and to compare the luminal environment in terms of bile salt and lipid composition in CD and healthy conditions. CD conditions were simulated in the TIM-1 system with a reduced concentration of porcine pancreatin and porcine bile. The bioaccessibility of ciprofloxacin was similar in simulated CD and healthy conditions considering its extent as well as its time course in the jejunum and ileum filtrate. Differences were observed in terms of the luminal concentration of triglycerides, monoglycerides, and fatty acids in the different TIM-1 compartments, indicating a reduction and delay in the lipolysis of formulation excipients in CD. The quantitative analysis of bile salts revealed higher concentrations for healthy conditions (standard TIM-1 fasted-state protocol) in the duodenum and jejunum TIM-1 compartments compared to published data in human intestinal fluids of healthy subjects. The reduced concentrations of bile salts in simulated CD conditions correspond to the levels observed in human intestinal fluids of healthy subjects in the fasted state.A lipidomics approach with ultra performance liquid chromatography (UPLC)/mass spectrometry (MS) has proven to be a time-efficient method to semiquantitatively analyze differences in fatty acid and bile salt levels between healthy and CD conditions. The dynamic luminal environment in CD and healthy conditions after administration of a lipid-based formulation can be simulated using the TIM-1 system. For ciprofloxacin, an altered luminal lipid composition had no impact on its performance indicating a low risk of altered performance in CD patients.
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http://dx.doi.org/10.1021/acs.molpharmaceut.0c00807DOI Listing
April 2021

Current challenges and future perspectives in oral absorption research: An opinion of the UNGAP network.

Adv Drug Deliv Rev 2021 04 18;171:289-331. Epub 2021 Feb 18.

College of Pharmaceutical Sciences, Ritsumeikan University, Shiga, Japan.

Although oral drug delivery is the preferred administration route and has been used for centuries, modern drug discovery and development pipelines challenge conventional formulation approaches and highlight the insufficient mechanistic understanding of processes critical to oral drug absorption. This review presents the opinion of UNGAP scientists on four key themes across the oral absorption landscape: (1) specific patient populations, (2) regional differences in the gastrointestinal tract, (3) advanced formulations and (4) food-drug interactions. The differences of oral absorption in pediatric and geriatric populations, the specific issues in colonic absorption, the formulation approaches for poorly water-soluble (small molecules) and poorly permeable (peptides, RNA etc.) drugs, as well as the vast realm of food effects, are some of the topics discussed in detail. The identified controversies and gaps in the current understanding of gastrointestinal absorption-related processes are used to create a roadmap for the future of oral drug absorption research.
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http://dx.doi.org/10.1016/j.addr.2021.02.001DOI Listing
April 2021

Factors Affecting Successful Extrapolation of Ibuprofen Exposure from Adults to Pediatric Populations After Oral Administration of a Pediatric Aqueous Suspension.

AAPS J 2020 11 12;22(6):146. Epub 2020 Nov 12.

Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis, 157 84, Zografou, Athens, Greece.

The importance of physiologically based pharmacokinetic (PBPK) model refinement with data acquired in adults using a pediatric formulation under age-relevant dosing conditions in order to extrapolate drug exposure to infants was recently demonstrated for paracetamol. In the present investigation, the aim was to evaluate the importance of similar PBPK model refinement for a low-solubility weak acid, ibuprofen, to simulate exposure across pediatric populations, i.e., infants, young children, and schoolchildren. After developing and evaluating adult disposition and oral absorption models for the aqueous suspension of ibuprofen, ibuprofen performance was extrapolated to pediatrics simulating exposure as a function of different prandial and dosing conditions: fasted conditions, reference-meal fed conditions (solid-liquid meal), and infant-formula fed conditions (homogeneous liquid). Successful predictions were achieved when employing the refined model for fasted state conditions or for fed state conditions relevant to specific age groups, i.e., infant formula for infants and reference meal for children. The present study suggested that ibuprofen performance was primarily guided by gastric emptying and showed sensitivity towards formulation characteristics and pH changes in the small intestine. Better understanding of luminal conditions in pediatrics and age-dependent ibuprofen post-absorptive processes could improve modeling confidence for ibuprofen, as well as other drugs with similar characteristics.
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http://dx.doi.org/10.1208/s12248-020-00522-4DOI Listing
November 2020

Predicting budesonide performance in healthy subjects and patients with Crohn's disease using biorelevant in vitro dissolution testing and PBPK modeling.

Eur J Pharm Sci 2021 Feb 24;157:105617. Epub 2020 Oct 24.

Department of Pharmacy and Pharmacology, University of Bath, Bath, UK. Electronic address:

Objectives: Drug product performance might be affected in Crohn's disease (CD) patients compared to healthy subjects due to pathophysiological changes. Since a low number of clinical studies is performed in this patient population, physiologically-based pharmacokinetic (PBPK) models with integrated results from biorelevant in vitro dissolution studies could be used to assess differences in the bioavailability of drugs. Using this approach, budesonide was used as model drug and its performance in healthy subjects and CD patients was predicted and compared against observed pharmacokinetic data. The in vitro release tests, under healthy versus CD conditions, revealed a similar extent of drug release from a controlled-release budesonide formulation in the fasted state, whereas in the fed state a lower extent was observed with CD. Differences in the physiology of CD patients were identified in literature and their impact on budesonide performance was investigated with a PBPK model, revealing the highest impact on the simulated bioavailability for the reduced hepatic CYP3A4 enzyme abundance and lower human serum albumin concentration. For CD patients, a higher budesonide exposure compared to healthy subjects was predicted with a PBPK population adapted to CD physiology and in agreement with observed pharmacokinetic data. Budesonide performance in the fasted and fed state was successfully predicted in healthy subjects and CD patients using PBPK modeling and in vitro release testing. Following this approach, predictions of the direction and magnitude of changes in bioavailability due to CD could be made for other drugs and guide prescribers to adjust dosage regimens for CD patients accordingly.
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http://dx.doi.org/10.1016/j.ejps.2020.105617DOI Listing
February 2021

Affinity of Lipophilic Drugs to Mixed Lipid Aggregates in Simulated Gastrointestinal Fluids.

J Pharm Sci 2021 01 14;110(1):186-197. Epub 2020 Oct 14.

Department of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, UK. Electronic address:

Mixed lipid aggregates, comprising of bile salts and phospholipids, present in the small intestine assist in drug solubilization and subsequent drug dissolution and absorption through the intestinal epithelium. The increased variability in their levels, observed physiologically, may create challenges not only for in vivo bioavailability and bioequivalence studies, but also for in vitro bio-predictive studies as correlations between in vitro and in vivo data are not always successful. The current study investigated the impact of biorelevant dissolution media, with physiologically relevant sodium taurocholate and lecithin levels, on the apparent solubility and affinity of lipophilic compounds with a wide range of physicochemical properties (drug ionization, drug lipophilicity, molecular weight) to mixed lipid aggregates. Apparent solubility data in biorelevant dissolution media for the studied neutral drugs, weak bases and weak acids were compared against a phosphate buffer pH 6.5 in the absence of these lipidic components. Presence of mixed lipid aggregates enhanced the apparent solubility of the majority of compounds and the use of multivariate data analysis identified the significant parameters affecting drug affinity to mixed lipid aggregates based on the chemical class of the drug. For neutral drugs, increasing bile salt concentrations and/or drug lipophilicity resulted in greater enhancement in apparent solubility at 24-hr. For weak bases and weak acids, the effect of increasing bile salt levels on apparent solubility depended mostly on an interplay between drug lipophilicity and drug ionization.
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http://dx.doi.org/10.1016/j.xphs.2020.09.053DOI Listing
January 2021

Impact of Food and Drink Administration Vehicles on Paediatric Formulation Performance Part 2: Dissolution of Montelukast Sodium and Mesalazine Formulations.

AAPS PharmSciTech 2020 Oct 15;21(7):287. Epub 2020 Oct 15.

Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, UK.

Paediatric medicines are not always age-appropriate, causing problems with dosing, acceptability and adherence. The use of food and drinks as vehicles for medicine co-administration is common practice, yet the impact on drug bioavailability, safety and efficacy remains unaddressed. The aim of this study was to use in vitro dissolution testing, under infant simulating conditions, to evaluate the effect of co-administration with vehicles on the dissolution performance of two poorly soluble paediatric drugs. Dissolution studies of mesalazine and montelukast formulations were conducted with mini-paddle apparatus on a two-stage approach: simulated gastric fluid followed by addition of simulated intestinal fluid. The testing scenarios were designed to reflect daily administration practices: direct administration of formulation; formulation co-administered with food and drinks, both immediately after mixing and 4 h after mixing. Drug dissolution was significantly affected by medicine co-administration with vehicles, compared to the direct administration of formulation. Furthermore, differences were observed on drug dissolution when the formulations were mixed with different vehicles of the same subtype. The time between preparation and testing of the drug-vehicle mixture also impacted dissolution behaviour. Drug dissolution was shown to be significantly affected by the physicochemical properties and composition of the vehicles, drug solubility in each vehicle and drug/formulation characteristics. Ultimately, in this study, we show the potential of age-appropriate in vitro dissolution testing as a useful biopharmaceutical tool for estimating drug dissolution in conditions relevant to the paediatric population. The setup developed has potential to evaluate the impact of medicine co-administration with vehicles on paediatric formulation performance.
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http://dx.doi.org/10.1208/s12249-020-01815-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7561592PMC
October 2020

Successful Extrapolation of Paracetamol Exposure from Adults to Infants After Oral Administration of a Pediatric Aqueous Suspension Is Highly Dependent on the Study Dosing Conditions.

AAPS J 2020 09 30;22(6):126. Epub 2020 Sep 30.

Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis, 157 84 Zografou, Athens, Greece.

Extending licensed drug use to the pediatric population has become an essential part of the drug development process. Nonetheless, ethical concerns limit clinical testing in pediatric populations and data collected from oral bioavailability and food effect studies in adults are often extrapolated to the target pediatric (sub)populations. However, based on published information, food effects on drug absorption in infants may not be adequately evaluated by data collected in adults. In the present study, a physiologically based pharmacokinetic (PBPK) approach for modeling paracetamol suspension data collected in adults was proposed with the ultimate aim to investigate whether extrapolation to infants is substantially affected by the dosing conditions applied to adults. The development of the PBPK model for adults was performed using GastroPlus™ V9.7, and after scaling to infants considering physiological, anatomical, and drug clearance changes, extrapolation of the different dosing conditions was performed by applying dosing conditions dependent on changes on the paracetamol gastric emptying process. Successful simulations of previously observed plasma concentration levels in infants were achieved when extrapolating from fasted and infant formula-fed conditions data. Data collected following the reference meal appeared less useful for simulating paracetamol suspension performance in infants. The proposed methodology deserves further evaluation using high-quality clinical data both in adults and in infants.
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http://dx.doi.org/10.1208/s12248-020-00504-6DOI Listing
September 2020

The use of PBPK/PD to establish clinically relevant dissolution specifications for zolpidem immediate release tablets.

Eur J Pharm Sci 2020 Dec 29;155:105534. Epub 2020 Aug 29.

Institute of Pharmaceutical Technology, Goethe University, Germany; Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Division of Translational Medicine and Pharmacology, Max von Lauer St. 9, Frankfurt am Main, 60438, Germany. Electronic address:

Background: Zolpidem is a non-benzodiazepine hypnotic agent which has been shown to be effective in inducing and maintaining sleep in adults and is one of the most frequently prescribed hypnotics in the world. For drugs that are used to treat sleeping disorders, the time to reach the maximum concentration (T) of the drug in plasma is important to achieving a fast onset of action and this must be maintained when switching from one product to another.

Objectives: The main objective of the present work was to create a PBPK/PD model for zolpidem and establish a clinically relevant "safe space" for dissolution of zolpidem from the commercial immediate release (IR) formulation. A second objective was to analyze literature pharmacokinetic data to verify the negative food effect ascribed to zolpidem and consider its ramifications in terms of the "safe space" for dissolution.

Methods: Using dissolution, pharmacokinetic and pharmacodynamic data, an integrated PBPK/PD model for immediate release zolpidem tablets was constructed in Simcyp®. This model was used to identify the clinically relevant dissolution specifications necessary to ensure efficacy.

Results: According to the simulations, as long as 85% of the drug is released in 45 minutes or less, the impact on the PK and PD profiles of zolpidem would be minimal. According to the FDA, the drug has to dissolve from the test and reference products at a similar rate and to an extent of 85% in not more than 30 minutes to pass bioequivalence via the BCS-biowaiver test. Thus, the BCS-biowaiver specifications are somewhat more stringent than the "safe space" based on the PBPK/PD model. Published data from fasted and fed state pharmacokinetic studies suggest but do not prove a negative food effect of zolpidem.

Conclusions: A PBPK/PD model indicates that current BCS-biowaiver criteria are more restrictive for immediate release zolpidem tablets than they need to be. In view of the close relationship between PK and PD, it remains advisable to avoid taking zolpidem tablets with or immediately after a meal, as indicated by the Stilnox® labeling.
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http://dx.doi.org/10.1016/j.ejps.2020.105534DOI Listing
December 2020

Gastrointestinal diseases and their impact on drug solubility: Crohn's disease.

Eur J Pharm Sci 2020 Sep 7;152:105459. Epub 2020 Jul 7.

Department of Pharmacy and Pharmacology, University of Bath, Bath, UK. Electronic address:

In order to investigate differences in drug solubilisation and dissolution in luminal fluids of Crohn's disease (CD) patients and healthy subjects, biorelevant media representative of CD patients were developed using information from literature and a Design of Experiment (DoE) approach. The CD media were characterised in terms of surface tension, osmolality, dynamic viscosity and buffer capacity and compared to healthy biorelevant media. To identify which drug characteristics are likely to present a high risk of altered drug solubility in CD, the solubility of six drugs was assessed in CD media and solubility differences were related to drug properties. Identified differences in CD patients compared to healthy subjects were a reduced concentration of bile salts, a higher gastric pH and a higher colonic osmolality. Differences in the properties of CD compared to healthy biorelevant media were mainly observed for surface tension and osmolality. Drug solubility of ionisable compounds was altered in gastric CD media compared to healthy biorelevant media. For drugs with moderate to high lipophilicity, a high risk of altered drug solubilisation in CD is expected, since a significant negative effect of log P and a positive effect of bile salts on drug solubility in colonic and fasted state intestinal CD media was observed. Simulating the conditions in CD patients in vitro offers the possibility to identify relevant differences in drug solubilisation without conducting expensive clinical trials.
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http://dx.doi.org/10.1016/j.ejps.2020.105459DOI Listing
September 2020

Gastrointestinal diseases and their impact on drug solubility: Celiac disease.

Eur J Pharm Sci 2020 Sep 6;152:105460. Epub 2020 Jul 6.

Department of Pharmacy and Pharmacology, University of Bath, Bath, UK. Electronic address:

The aim of this study was to develop an in vitro tool for predicting drug solubility and dissolution in intestinal fluids of patients with Celiac disease (CED). Biorelevant media for patients with CED were developed based on published information and a Design of Experiment (DoE) approach. The CED biorelevant media were characterised according to their surface tension, osmolality, dynamic viscosity and buffer capacity. By performing solubility studies of six drugs with different physicochemical properties in CED media, we aimed to identify drugs at high risk of altered luminal solubility in CED patients. Identified differences in CED patients compared to healthy subjects were related to a higher concentration of bile salts, lecithin and cholesterol and included as factors in the DoE resulting in 8 CED biorelevant media. Differences in media properties were observed for the surface tension between biorelevant media based on CED patients and healthy subjects. In terms of solubility, only a minimal effect of CED on the solubility of the hydrophilic neutral compound azathioprine was observed. For neutral moderately lipophilic compounds (budesonide, celecoxib), a higher surfactant concentration resulted in most cases in a higher drug solubility, while it was specific to each drug whether this was mainly driven by bile salts or lecithin. In comparison, drug solubilisation of ionisable compounds with moderate to high lipophilicity was less impacted by CED differences. The developed biorelevant CED media serve as in vitro tool to identify the main media factors impacting on drug solubility.
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http://dx.doi.org/10.1016/j.ejps.2020.105460DOI Listing
September 2020

Gastrointestinal diseases and their impact on drug solubility: Ulcerative Colitis.

Eur J Pharm Sci 2020 Sep 6;152:105458. Epub 2020 Jul 6.

Department of Pharmacy and Pharmacology, University of Bath, Bath, UK. Electronic address:

For poorly soluble compounds, drug product performance in patients with Ulcerative Colitis (UC) compared to healthy subjects can be affected due to differences in drug solubility in GI fluids. A risk assessment tool was developed to identify compounds with a high risk of altered solubility in the GI fluids of UC patients. Pathophysiological changes impacting on the composition of GI fluids in UC patients were considered and UC biorelevant media representative of the stomach, intestine and colon were developed based on biorelevant media based on healthy subjects and literature data using a Design of Experiment approach. The UC media were characterised and revealed differences in surface tension, osmolality and buffer capacity compared to media based on healthy subjects. The solubility of six drugs was investigated in UC biorelevant media and results were related to media- and drug-dependent factors. A lower drug solubility in UC intestinal media was observed for compounds with a high lipophilicity. In UC simulated colonic fluids, drug solubility was altered for ionisable compounds. Additionally, a higher solubility of neutral lipophilic drugs was observed in UC fasted state colonic media with increased concentrations of soluble proteins. The developed UC biorelevant media offer the possibility to identify the risk of altered drug solubilisation in UC patients without conducting expensive clinical trials. A high risk was related to drug ionization properties and lipophilicity in the current study with all investigated drugs showing differences in solubility in biorelevant media based on UC patients compared to healthy subjects.
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http://dx.doi.org/10.1016/j.ejps.2020.105458DOI Listing
September 2020

Interpolymer Complexes of Eudragit Copolymers as Novel Carriers for Colon-Specific Drug Delivery.

Polymers (Basel) 2020 Jun 30;12(7). Epub 2020 Jun 30.

Institute of Pharmacy, Kazan State Medical University, 16 Fatykh Amirkhan Street, 420012 Kazan, Russian Federation.

Interpolymer complexes (IPC) based on Eudragit EPO and Eudragit S100 were investigated as potential carriers for oral controlled drug delivery to the colon. IPC samples were prepared by mixing copolymer solutions in organic solvents (ethanol, isopropanol:acetone mixture (60:40, ) and tetrahydrofuran). According to the data of elemental analysis, FTIR-spectroscopy, X-ray photoelectron spectroscopy and thermal analysis these IPCs have excess of anionic copolymer (Eudragit S100) in their structure; they are stabilized by hydrogen and ionic intermacromolecular bonds and do not include free copolymer domains. IPC have pH-independent swelling properties in the media mimicking gastrointestinal tract (GIT) conditions and provide colon-specific delivery of indomethacin in buffer solutions (pH 1.2; 5.8; 6.8; 7.4) and in biorelevant media (fasted state simulated gastric fluid, fasted state simulated intestinal fluid-version 2 and fasted stated simulated colonic fluid).
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http://dx.doi.org/10.3390/polym12071459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407155PMC
June 2020

Impact of Magnesium Stearate Presence and Variability on Drug Apparent Solubility Based on Drug Physicochemical Properties.

AAPS J 2020 05 21;22(4):75. Epub 2020 May 21.

Department of Pharmacy and Pharmacology, University of Bath, Bath, BA2 7AY, UK.

Excipients are major components of oral solid dosage forms, and changes in their critical material attributes (excipient variability) and/or amount (excipient variation) in pharmaceutical formulations may present a challenge for product performance. Understanding the biopharmaceutical factors affecting excipient performance is recommended for the successful implementation of excipient variability on Quality by Design (QbD) approaches. The current study investigated the impact of magnesium stearate (MgSt) variability on the apparent solubility of drugs with a wide range of physicochemical properties (drug ionization, drug lipophilicity, drug aqueous solubility). Compendial and biorelevant media were used to assess the role of gastrointestinal (GI) conditions on the excipient effects on drug apparent solubility. The lipophilic nature of MgSt decreased the apparent solubility of most compounds. The reduction in drug apparent solubility was more pronounced for highly soluble and/or highly ionized drugs and in presence of more highly crystalline or smaller particle size MgSt. The use of multivariate data analysis revealed the critical physicochemical and biopharmaceutical factors and the complex nature of excipient variability on the reduction in drug apparent solubility. The construction of a roadmap combining drug, excipient and medium characteristics allowed the identification of the cases where the presence of excipient or excipient variability may present risks for oral drug performance.
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http://dx.doi.org/10.1208/s12248-020-00449-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242257PMC
May 2020

A new medium-throughput screening design approach for the development of hydroxymethylnitrofurazone (NFOH) nanostructured lipid carrier for treating leishmaniasis.

Colloids Surf B Biointerfaces 2020 Sep 1;193:111097. Epub 2020 May 1.

University of São Paulo, Faculty of Pharmaceutical Sciences, São Paulo, SP, Brazil. Electronic address:

Hydroxymethilnitrofurazone (NFOH) is a nitrofurazone derivative and has potential use in treating leishmaniasis. However, due to low water solubility and bioavailability, NFOH has failed in in vivo tests. Nanostructured lipid carrier (NLC) is an alternative to overcome these limitations by improving pharmacokinetics and modifying drug delivery. This work is focused on developing a novel NFOH-loaded NLC (NLC-NFOH) using a D-optimal mixture statistical design and high-pressure homogenization, for oral administration to treat leishmaniasis. The optimized NLC-NFOH consisted of Mygliol® 840, Gelucire® 50/13, and Precirol® ATO 5 as lipids. These lipids were selected using a rapid methodology Technobis Crystal 16 T M, microscopy, and DSC. Different tools for selecting lipids provided relevant scientific knowledge for the development of the NLC. NLC-NFOH presented a z-average of 198.6 ± 5.4 nm, PDI of 0.11 ± 0.01, and zeta potential of -13.7 ± 0.7 mV. A preliminary in vivo assay was performed by oral administration of NLC-NFOH (2.8 mg/kg) in one healthy male Wistar rat (341 g) by gavage. Blood from the carotid vein was collected, and the sample was analyzed by HPLC. The plasma concentration of NFOH after 5 h of oral administration was 0.22 μg/mL. This same concentration was previously found using free NFOH in the DMSO solution (200 mg/kg), which is an almost 100-fold higher dose. This study allowed a design space development approach of the first NLC-NFOH with the potential to treat leishmaniasis orally.
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http://dx.doi.org/10.1016/j.colsurfb.2020.111097DOI Listing
September 2020

Co-administration of Paediatric Medicines with Food and Drinks in the Context of Their Physicochemical Properties-a Global Perspective on Practices and Recommendations.

AAPS J 2020 03 4;22(2):54. Epub 2020 Mar 4.

Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, UK.

Medicine co-administration with food or drink vehicles is a common administration practice in paediatrics. The aims of this review were (i) to describe the current recommended strategies for co-administration of paediatric medicines with food and drinks (vehicles); (ii) to compare current administration recommendations from different countries; and (iii) to obtain a global perspective on the rationale behind the choice of recommended vehicle, in the context of the physicochemical properties of the drug and formulation. This study used a defined search strategy on the practices of paediatric medicine co-administration with vehicles, recommended in a commonly used paediatric and neonatal handbook, in addition to the information previously gathered from UK formularies. Logistic regression analysis was performed to further understand the biopharmaceutical basis of the choice of recommended vehicle for medicine co-administration. Differences were identified in the type of vehicles globally recommended for medicine co-administration. Ultimately, a statistical model was developed which provided an understanding on which vehicle is recommended for use with drugs/formulations, with basis on their biopharmaceutical properties. Overall, this review highlights the areas where further information is needed to support standardised procedures and guide the recommendation of age-appropriate and acceptable vehicles for use in the co-administration of paediatric medicines. Unified requirements are needed for harmonisation of the practice of medicine co-administration with vehicles. In vitro and/or in silico tools should be developed to evaluate the potential clinical outcomes of this practice during paediatric drug development.
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http://dx.doi.org/10.1208/s12248-020-0432-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056676PMC
March 2020

Investigation of drug partition kinetics to fat in simulated fed state gastric conditions based on drug properties.

Eur J Pharm Sci 2020 Apr 20;146:105263. Epub 2020 Feb 20.

Department of Pharmacy and Pharmacology, University of Bath, Bath, UK. Electronic address:

The presence of fat in the gastric environment can affect the pharmacokinetic behaviour of drugs with mechanisms which have not been yet fully understood. The objective of the current study was to assess the drug partition to the lipid part of the fed gastric content under different emulsification conditions, using in vitro discriminating setups. The model drugs used in the study were selected on the basis of different physicochemical properties (lipophilicity, ionization, molecular weight and aqueous solubility) and different food effect observed in in vivo human studies. Fed State Simulated Gastric Fluid prepared with skimmed milk (FeSSGF) and anhydrous milk fat were used as surrogates for the aqueous and fat portions of the fed gastric environment respectively. An optimized biphasic model was developed so as to predict the differences in partition rate constants to fat, for model drugs of a wide range of the properties mentioned above. The experimental data and the use of statistical analysis revealed that molecular weight, molecular weight and log D interaction and negative food effect act as negative factors to the rate constants of fat partition, while absence of food effect and logD interaction with aqueous solubility affect the rate constants of partition to fat favourably.
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http://dx.doi.org/10.1016/j.ejps.2020.105263DOI Listing
April 2020

Development of an Aerosol Dose Collection Apparatus for In Vitro Dissolution Measurements of Orally Inhaled Drug Products.

AAPS J 2020 02 13;22(2):47. Epub 2020 Feb 13.

Office of Testing and Research, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA.

The aim of the study was to develop a robust and standardized in vitro dissolution methodology for orally inhaled drug products (OIDPs). An aerosol dose collection (ADC) system was designed to uniformly deposit the whole impactor stage mass (ISM) over a large filter area for dissolution testing. All dissolution tests were performed under sink conditions in a sodium phosphate buffered saline solution containing 0.2%w/w sodium dodecyl sulphate. An adapted USP Apparatus V, Paddle over Disk (POD), was used throughout the study. The dissolution characteristics of the ISM dose of a commercial metered-dose inhaler (MDI) and a range of dry powder inhaler (DPI) formulations containing inhaled corticosteroids were tested. The uniform distribution of the validated ISM dose considerably reduced drug loading effects on the dissolution profiles for both MDI and DPI formulations. The improvement in the robustness and discriminatory capability of the technique enabled characterization of dissolution rate differences between inhaler platforms and between different DPI product strengths containing fluticasone propionate. A good correlation between in vivo mean absorption time and in vitro dissolution half-life was found for a range of the inhaled corticosteroids. The ADC system and the reproducible in vitro POD dissolution measurements provided a quantitative-based approach for measuring the relationship between the influence of device and the dispersion characteristics on the aerosol dissolution of low solubility compounds. The in vitro dissolution method could potentially be applied as a dissolution methodology for compendial, quality control release testing, and during development of both branded orally inhaled drug products and their generic counterparts.
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http://dx.doi.org/10.1208/s12248-020-0422-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7021740PMC
February 2020

Biopharmaceutical Understanding of Excipient Variability on Drug Apparent Solubility Based on Drug Physicochemical Properties. Case Study: Superdisintegrants.

AAPS J 2020 02 11;22(2):46. Epub 2020 Feb 11.

Department of Pharmacy and Pharmacology, University of Bath, Bath, BA2 7AY, UK.

The presence of different excipient types/brands in solid oral dosage forms may affect product performance and drug bioavailability. Understanding the biopharmaceutical implications of superdisintegrant variability (changes in material properties), variation (changes in excipient amount) and interchangeability (use of different excipient types with the same intended functionality) in oral drug performance would be beneficial for the development of robust final dosage forms. The current study investigated the impact of superdisintegrants (sodium starch glycolate, croscarmellose sodium, crospovidone) on the apparent solubility of drugs with different physicochemical properties (drug ionisation, drug lipophilicity, drug aqueous solubility). Compendial and biorelevant media were used to assess the impact of gastrointestinal conditions on the effects of excipient on drug apparent solubility. For the majority of compounds, changes in drug apparent solubility were not observed in superdisintegrant presence, apart from the cases of highly ionised compounds (significant decrease in drug solubility) and/or compounds that aggregate/precipitate in solution (significant increase in drug solubility). Excipient variability did not greatly affect the impact of excipients on drug apparent solubility. The use of multivariate data analysis identified the biopharmaceutical factors affecting excipient performance. The construction of roadmaps revealed that superdisintegrants may be of low risk for the impact of excipients on oral drug performance based on drug solubility alone; superdisintegrants activity could still be a risk for oral bioavailability due to their effects on tablet disintegration.
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http://dx.doi.org/10.1208/s12248-019-0406-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012964PMC
February 2020

In vitro conditions for performance evaluation of products for intravascular administration: Developing appropriate test media using Amphotericin B as a model drug.

Eur J Pharm Sci 2020 Feb 3;143:105174. Epub 2019 Dec 3.

Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, United Kingdom. Electronic address:

Currently, there are no compendial in vitro release tests specifically indicated for parenteral formulations. Consideration of biorelevant and clinically relevant test media represents a valuable approach for the development of in vitro tests that ideally can provide information on the formulation performance in vivo. The aim of this study was to investigate the effect of different media components on the solubility of Amphotericin B (a poorly soluble highly protein-bound drug) in order to develop biorelevant and clinically relevant media for future in vitro release testing from its liposomal formulation. Three categories of media were considered in the development approach: Category 1 media: effect of albumin concentration; category 2 media: effect of biorelevant concentrations of plasma components (bile salts, phospholipids, cholesterol, albumin); category 3 media: attaining clinically relevant solubility with biorelevant and synthetic surfactants with and without albumin and setting the basis for the development of a simulated hypoalbuminaemic plasma medium. All the surfactants tested increased Amphotericin B solubility while the simultaneous presence of albumin had a negative effect on solubility. Clinically relevant media with the use of biorelevant or synthetic surfactants and albumin were developed. One medium in which the solubility of Amphotericin B was reduced was identified as potential candidate medium to simulate hypoalbuminaemic plasma. The development of biorelevant and clinically relevant media and understanding the effect of media components and their interactions, supports future development of meaningful in vivo predictive release tests for parenteral formulations.
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http://dx.doi.org/10.1016/j.ejps.2019.105174DOI Listing
February 2020

On the Design of Food Effect Studies in Adults for Extrapolating Oral Drug Absorption Data to Infants: an Exploratory Study Highlighting the Importance of Infant Food.

AAPS J 2019 12 2;22(1). Epub 2019 Dec 2.

Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis, 157 84, Zografou, Greece.

In the present investigation, it was explored whether food effect on drug absorption in adults is similar with the food effect after administration of an infant meal with the drug product to adults. After confirming lack of pharmaceutical and pharmacokinetic interaction, a paracetamol suspension and an ibuprofen suspension were co-administered to eight healthy adults on a crossover basis in three different occasions, i.e. in the fasted state (as defined by regulatory agencies, fasted conditions), in the fed state (as defined by regulatory agencies, fed conditions) and under conditions simulating the fed state in infants (infant fed conditions). Unlike under fed conditions, under infant fed conditions early exposure was significantly lower than under fasted conditions for both paracetamol and ibuprofen. Also, for ibuprofen, C values under infant fed conditions were significantly higher than under fed conditions. These data suggest that, even for drugs with non-problematic absorption administered in simple dosage forms, food effects in infants may not be adequately evaluated if the protocol suggested by regulatory agencies is applied. The usefulness of the methodology employed in the present investigation for simulating the fed state in infants deserves further evaluation. Until then, food effects in infants should be considered cautiously or be evaluated in infants.
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http://dx.doi.org/10.1208/s12248-019-0380-4DOI Listing
December 2019

Establishing virtual bioequivalence and clinically relevant specifications using in vitro biorelevant dissolution testing and physiologically-based population pharmacokinetic modeling. case example: Naproxen.

Eur J Pharm Sci 2020 Feb 27;143:105170. Epub 2019 Nov 27.

Institute of Pharmaceutical Technology, Goethe University, Frankfurt am Main, Germany; Fraunhofer IME - Translational Pharmacology and Medicine, Carl-von-Noorden Platz 9, Frankfurt am Main, Germany. Electronic address:

Background: Physiologically-based population pharmacokinetic modeling (popPBPK) coupled with in vitro biopharmaceutics tools such as biorelevant dissolution testing can serve as a powerful tool to establish virtual bioequivalence and set clinically relevant specifications. One of several applications of popPBPK modeling is in the emerging field of virtual bioequivalence (VBE), where it can be used to streamline drug development by implementing model-informed formulation design and to inform regulatory decision-making e.g., with respect to evaluating the possibility of extending BCS-based biowaivers beyond BCS Class I and III compounds in certain cases.

Methods: In this study, Naproxen, a BCS class II weak acid was chosen as the model compound. In vitro biorelevant solubility and dissolution experiments were performed and the resulting data were used as an input to the PBPK model, following a stepwise workflow for the confirmation of the biopharmaceutical parameters. The naproxen PBPK model was developed by implementing a middle-out approach and verified against clinical data obtained from the literature. Once confidence in the performance of the model was achieved, several in vivo dissolution scenarios, based on model-based analysis of the in vitro data, were used to simulate clinical trials in healthy adults. Inter-occasion variability (IOV) was also added to critical physiological parameters and mechanistically propagated through the simulations. The various trials were simulated on a "worst/best case" dissolution scenario and average bioequivalence was assessed according to C, AUC and T.

Results: VBE results demonstrated that naproxen products with in vitro dissolution reaching 85% dissolved within 90 min would lie comfortably within the bioequivalence limits for C and AUC. Based on the establishment of VBE, a dissolution "safe space" was designed and a clinically relevant specification for naproxen products was proposed. The interplay between formulation-related and drug-specific PK parameters (e.g., t1/2) to predict the in vivo performance was also investigated.

Conclusion: Over a wide range of values, the in vitro dissolution rate is not critical for the clinical performance of naproxen products and therefore naproxen could be eligible for BCS-based biowaivers based on in vitro dissolution under intestinal conditions. This approach may also be applicable to other poorly soluble acidic compounds with long half-lives, providing an opportunity to streamline drug development and regulatory decision-making without putting the patient at a risk.
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http://dx.doi.org/10.1016/j.ejps.2019.105170DOI Listing
February 2020

In Vitro-In Vivo Correlations Based on In Vitro Dissolution of Parent Drug Diltiazem and Pharmacokinetics of its Metabolite.

Pharmaceutics 2019 Jul 16;11(7). Epub 2019 Jul 16.

Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, UK.

In this study a novel type of in vitro-in vivo correlation (IVIVC) is proposed: The correlation of the in vitro parent drug dissolution data with the in vivo pharmacokinetic data of drug's metabolite after the oral administration of the parent drug. The pharmacokinetic data for the parent drug diltiazem (DTZ) and its desacetyl diltiazem metabolite (DTZM) were obtained from an in vivo study performed in 19 healthy volunteers. The pharmacokinetics of the parent drug and its metabolite followed a pseudomono-compartmental model and deconvolution of the DTZ or DTZM plasma concentration profiles was performed with a Wagner-Nelson-type equation. The calculated in vivo absorption fractions were correlated with the in vitro DTZ dissolution data obtained with USP 2 apparatus. A linear IVIVC was obtained for both DTZ and DTZM, with a better correlation observed for the case of the metabolite. This type of correlation of the in vitro data of the parent compound with the in vivo data of the metabolite could be useful for the development of drugs with active metabolites and prodrugs.
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http://dx.doi.org/10.3390/pharmaceutics11070344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6680613PMC
July 2019

Co-delivery of buparvaquone and polymyxin B in a nanostructured lipid carrier for leishmaniasis treatment.

J Glob Antimicrob Resist 2019 09 13;18:279-283. Epub 2019 Jun 13.

Department of Pharmacy, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil. Electronic address:

Objectives: This study aimed to describe the preparation and in vitro evaluation of a surface-modified nanostructured lipid carrier (NLC) using chitosan and dextran for co-delivery of buparvaquone (BPQ) and polymyxin B (PB) against leishmaniasis.

Methods: The NLC was prepared using high-pressure homogenisation. Polymyxin B binding and surface modification with biopolymers were achieved by electrostatic interaction. In vitro cytotoxicity was assessed in mouse peritoneal macrophages, and leishmanicidal activity in amastigotes of Leishmania infantum.

Results: The performance attributes of BPQ-NLC, BPQ-NLC-PB[A] (anionic) and BPQ-NLC-PB[C] (cationic) were respectively: Z-average 173.9 ± 1.6, 183.8 ± 4.5 and 208.8 ± 2.6 nm; zeta potential -19.6 ± 1.5, -20.1 ± 1.1 and 31.1 ± 0.8 mV; CC 583.4 ± 0.10, 203.1 ± 0.04 and 5.7 ± 0.06 μM; IC 229.0 ± 0.04, 145.7 ± 0.04 and 150.5 ± 0.02 nM. The NLC in vitro leishmanicidal activity showed up to 3.1-fold increase when compared with free BPQ (P <  0.05, α = 0.05).

Conclusions: The developed NLC proved to be a promising formulation with which to overcome the drawbacks of current leishmaniasis treatment by the co-delivery of two alternative drugs and a macrophage targeting modified surface.
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http://dx.doi.org/10.1016/j.jgar.2019.06.006DOI Listing
September 2019

Potential prediction of formulation performance in paediatric patients using biopharmaceutical tools and simulation of clinically relevant administration scenarios of nifedipine and lorazepam.

Br J Clin Pharmacol 2019 08 18;85(8):1728-1739. Epub 2019 Jun 18.

Department of Pharmacy and Pharmacology, University of Bath, Bath, UK.

Aims: This study explores the impact of paediatric patient related factors and choice of formulation on the dissolution characteristics of nifedipine and lorazepam, 2 drug substances regularly applied in very young patients and in compounded formulations.

Methods: Dissolution experiments were designed to reflect clinical practice in a paediatric hospital, with respect to dosage forms, feeding regimens and methods of administration. Solubility studies addressed the influence of age and prandial state. Drug solubility and dissolution experiments were conducted in biorelevant media and adapted age-specific (neonate and infant) media. Dissolution studies were performed with the mini-paddle apparatus and the flow-through cell apparatus.

Results: Dissolution of nifedipine formulations was not affected by age-related changes of the fasted state simulated gastrointestinal fluids, and by disintegration of the formulation before administration. However, a significant difference in nifedipine's dissolution rate from commercial tablets and compounded capsules was observed. The dissolution of lorazepam tablets was affected by fasted- vs fed-state media, but it was deemed less likely to be clinically relevant. The significant effect of fed-state media on nifedipine's solubility was considered to have possible clinical relevance since very young patients are almost continuously in a fed state.

Conclusion: The in vitro results obtained from these studies reveal the potential of biorelevant solubility and dissolution studies reflecting clinical practice to predict drug performance in paediatric patients.
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http://dx.doi.org/10.1111/bcp.13956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624402PMC
August 2019

Biorelevant release testing of biodegradable microspheres intended for intra-articular administration.

Eur J Pharm Biopharm 2019 Jun 21;139:115-122. Epub 2019 Mar 21.

Department of Pharmacy and Pharmacology, University of Bath, Bath, UK. Electronic address:

Characterization of controlled release formulations used for intra-articular (IA) drug administration is challenging. Bio-relevant synovial fluids (BSF), containing physiologically relevant amounts of hyaluronic acid, phospholipids and proteins, were recently proposed to simulate healthy and osteoarthritic conditions. This work aims to evaluate the performance of different controlled release formulations of methylprednisolone (MP) for IA administration, under healthy and disease states simulated conditions. Microspheres differed in grade of poly(lactide-co-glycolide) and in the theoretical drug content (i.e. 23 or 30% w/w). Their performance was compared with the commercially available suspension of MP acetate (MPA). Under osteoarthritic state simulated condition, proteins increased the MPA release and reduced the MPA hydrolysis rate, over 48 h. Regarding microspheres, the release patterns over 40 days were significantly influenced by the composition of BSF. The pattern of the release mechanism and the amount released was affected by the presence of proteins. Protein concentration affected the release and the concentration used is critical, particularly given the relevance of the concentrations to target patient populations, i.e. patients with osteoarthritis.
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http://dx.doi.org/10.1016/j.ejpb.2019.03.019DOI Listing
June 2019

Application of the relationship between pharmacokinetics and pharmacodynamics in drug development and therapeutic equivalence: a PEARRL review.

J Pharm Pharmacol 2019 Apr 22;71(4):699-723. Epub 2019 Feb 22.

Institute of Pharmaceutical Technology, Goethe University, Frankfurt am Main, Germany.

Objectives: The objective of this review was to provide an overview of pharmacokinetic/pharmacodynamic (PK/PD) models, focusing on drug-specific PK/PD models and highlighting their value added in drug development and regulatory decision-making.

Key Findings: Many PK/PD models, with varying degrees of complexity and physiological understanding have been developed to evaluate the safety and efficacy of drug products. In special populations (e.g. paediatrics), in cases where there is genetic polymorphism and in other instances where therapeutic outcomes are not well described solely by PK metrics, the implementation of PK/PD models is crucial to assure the desired clinical outcome. Since dissociation between the pharmacokinetic and pharmacodynamic profiles is often observed, it is proposed that physiologically based pharmacokinetic and PK/PD models be given more weight by regulatory authorities when assessing the therapeutic equivalence of drug products.

Summary: Modelling and simulation approaches already play an important role in drug development. While slowly moving away from 'one-size fits all' PK methodologies to assess therapeutic outcomes, further work is required to increase confidence in PK/PD models in translatability and prediction of various clinical scenarios to encourage more widespread implementation in regulatory decision-making.
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http://dx.doi.org/10.1111/jphp.13070DOI Listing
April 2019

Surface Dissolution UV Imaging for Investigation of Dissolution of Poorly Soluble Drugs and Their Amorphous Formulation.

AAPS PharmSciTech 2019 Feb 13;20(3):113. Epub 2019 Feb 13.

Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, UK.

The aim of this study is to investigate the dissolution properties of poorly soluble drugs from their pure form and their amorphous formulation under physiological relevant conditions for oral administration based on surface dissolution ultraviolet (UV) imaging. Dissolution of two poorly soluble drugs (cefuroxime axetil and itraconazole) and their amorphous formulations (Zinnat and Sporanox) was studied with the Sirius Surface Dissolution Imager (SDI). Media simulating the fasted state conditions (compendial and biorelevant) with sequential media/flow rate change were used. The dissolution mechanism of cefuroxime axetil in simulated gastric fluid (SGF), fasted state simulated gastric fluid (FaSSGF) and simulated intestinal fluid (SIF) is predominantly swelling as opposed to the convective flow in fasted state simulated intestinal fluid (FaSSIF-V1), attributed to the effect of mixed micelles. For the itraconazole compact in biorelevant media, a clear upward diffusion of the dissolved itraconazole into the bulk buffer solution is observed. Dissolution of itraconazole from the Sporanox compact is affected by the polyethylene glycol (PEG) gelling layer and hydroxypropyl methylcellulose (HPMC) matrix, and a steady diffusional dissolution pattern is revealed. A visual representation and a quantitative assessment of dissolution properties of poorly soluble compounds and their amorphous formulation can be obtained with the use of surface dissolution imaging under in vivo relevant conditions.
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http://dx.doi.org/10.1208/s12249-019-1317-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6394625PMC
February 2019

Highly Water-Soluble Orotic Acid Nanocrystals Produced by High-Energy Milling.

J Pharm Sci 2019 05 30;108(5):1848-1856. Epub 2018 Dec 30.

Department of Pharmacy, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.

Orotic acid (OA), a heterocyclic compound also known as vitamin B13, has shown potent antimalarial and cardiac protection activities; however, its limited water solubility has posed a barrier to its use in therapeutic approaches. Aiming to overcome this drawback, OA freeze-dried nanocrystal formulations (FA, FB, and FC) were developed by using the high-energy milling method. Polysorbate 80 (FA) and povacoat (FC) were used alone and combined (FB) as stabilizers. Nanocrystals were fully characterized by dynamic light scattering, laser diffraction, transmission electron microscopy, thermal analysis (thermogravimetry and derivative thermogravimetry, and differential scanning calorimetry), and X-ray powder diffraction revealing an acceptable polydispersity index, changes in the crystalline state with hydrate formation and z-average of 100-200 nm, a remarkable 200-time reduction compared to the OA raw material (44.3 μm). Furthermore, saturation solubility study showed an improvement of 13 times higher than the micronized powder. In addition, cytotoxicity assay revealed mild toxicity for the FB and FC formulations prepared with povacoat. OA nanocrystal platform can deliver innovative products allowing untapped the versatile potential of this drug substance candidate.
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http://dx.doi.org/10.1016/j.xphs.2018.12.015DOI Listing
May 2019

Preliminary pharmacokinetic study of the anticancer 6BIO in mice using an UHPLC-MS/MS approach.

J Pharm Biomed Anal 2019 Feb 25;164:317-325. Epub 2018 Oct 25.

Division of Pharmacognosy and Natural Products Chemistry, School of Pharmacy, National and Kapodistrian University of Athens, Panepistimioupoli Zografou, 15771, Athens, Greece. Electronic address:

Indirubins represent a group of natural and synthetic products with bio-activities against numerous human cancer cell lines acting by inhibiting protein kinases. The natural sources of indirubins are plants of Isatis sp., Indigofera sp., and Polygonum sp., recombinant bacteria, mammalian urine and some marine mollusks. Specifically, the halogenated derivative 6-bromo indirubin-3'-oxime (6BIO) possesses increased selectivity against GSK-3. However, to our knowledge, no analytical method to determine 6BIO in biological fluids has been developed till now. Therefore, a rapid, sensitive and high throughput UHPLC-MS/MS methods were developed and validated to evaluate the concentrations of 6BIO in mice plasma. Plasma samples were pre-treated by protein precipation using cold mixture of methanol: acetonitrile (9:1, v/v) and separations were carried out on a Hypersil Gold C18 column (50 × 2.1 mm i.d.; 1.9 μm p.s.) using 0.1% acetic acid and methanol as mobile phase at a flow rate of 500 mL/min in a gradient mode. For quantitation, a hybrid LTQ-Orbitrap MS equipped with an electro-spray ionization source was used applying a selected reaction monitoring (SRM) option. The monitored transitions were m/z 354.0 → 324.0 for 6BIO and 297.1 → 282.1 for afromorsin (used as the internal standard) in the negative mode. Following the EMA, ICH and FDA guidelines for validation of analytical procedures, the assay method was fully validated in terms of selectivity, linearity, recovery, matrix effect, accuracy, precision, stability, and robustness. The validated methods were successfully applied to the pharmacokinetic studies of 6BIO following an oral administration to mice at the dose of 50 mg/kg. The results indicated that 6BIO possesses a T of 30 min, a half-life of 1 h, and low plasma bioavailability.
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http://dx.doi.org/10.1016/j.jpba.2018.10.039DOI Listing
February 2019
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