SocraTec RandD GmbH

Oberursel, Germany

SocraTec RandD GmbH

Oberursel, Germany
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Blume H.,SocraTec CSC GmbH | Blume H.,SocraTec RandD GmbH | Brendel E.,Bayer AG | Brudny-Kloppel M.,Bayer AG | And 4 more authors.
European Journal of Pharmaceutical Sciences | Year: 2011

This is a summary report of the workshop on the EMA Draft Guideline on Validation of Bioanalytical Methods held April 15-16th 2010 in Brussels (Belgium) and jointly organised by the European Bioanalysis Forum (EBF) and the European Federation for Pharmaceutical Sciences (EUFEPS). Aim of the workshop was to discuss the current scientific knowledge in the area of bioanalysis, the regulatory requirements with special focus on the new Draft Guideline and their subsequent implementation to the work in bioanalytical laboratories. Comments on the Draft Guideline were presented and discussed with representatives from regulatory authorities in Europe. The workshop started with discussions on the scope of the Guideline and the need for implementation of GLP. A special focus was set on method validation of chromatographic procedures and subsequent study sample analysis. In addition, requirements for ligand-binding assays were briefly addressed. Intention of this Conference Report is to summarise important aspects of the discussions in order to draw certain conclusions, and to identify points which remain open and may require clarification at a later stage. © 2011 Elsevier B.V.

Anschutz M.,SocraTec R and D GmbH | Wonnemann M.,SocraMetrics | Schug B.,SocraTec R and D GmbH | Toal C.,Bayer Inc. | And 5 more authors.
International Journal of Clinical Pharmacology and Therapeutics | Year: 2010

Objectives: This study was designed to evaluate and compare the bioavailability of two osmotically active formulations of 60 mg nifedipine, Gen-Nifedipine extended release Test tablets (Genpharm ULC, Etobicoke, ON, Canada) and Adalat XL Reference tablets (Bayer Healthcare AG, Leverkusen, Germany) after single dose fasted and fed administration. Materials and methods: The study was performed following a 4-period crossover design with both investigational products obtained from marketed batches. The complete pharmacokinetic evaluation was carried out in 26 healthy male subjects with a median age of 29.5 years (range 18 - 44 years), mean weight of 79.7 kg (range 66.0 - 97.5 kg), and a mean body mass index (BMI) of 24.1 kg/m2 (range 22.1 - 26.9 kg/m2). Tablets were administered with tap water either under fasting conditions or immediately following a high-fat, high-calorie breakfast. Blood samples were taken predose and at pre-defined time points until 48 h post dosing. Samples were protected from light during handling and frozen until analysis. A validated LC-MS/MS method was used for the quantification of nifedipine in plasma samples. All kinetic parameters were determined model-independently for each treatment directly from measured concentrations. Monitoring of subject safety was accomplished by routine monitoring of blood pressure, heart rate and probing for adverse events. Results: In-vitro dissolution curves show later onset and considerably lower quantity of nifedipine release from Test compared to Reference tablets. Under fasting conditions total and maximum exposure, represented by geometric mean AUC0-tlast- and Cmax-values, respectively were 466.7 h·ng/ml (AUC0-tlast) and 21.9 ng/ml (Cmax) for Test and 507.8 h·ng/ml(AUC0-tlast) and 22.0 ng/ml (C max) for Reference tablets. However, the Test product exhibited a notably longer lag-time and less rapid onset of absorption than the Reference tablets. Moreover, the plateau phase is maintained for about 14 hours on Test but for almost 20 hours on Reference. Point estimates (PE) and associated 90% confidence intervals (CI) were determined as 91.8% and 79.9 - 105.5% for AUC0-tlast, as well as 99.8% and 88.6 - 112.4% for Cmax. Larger differences were found for AUC0-9h (PE: 54.8%; CI: 45.8 - 65.5%) determined as parameter for early exposure. Under fed conditions, although the mean plasma concentration time curves look similar in shape, concentrations of Test compared to Reference tablets are considerably lower at all time points until 36 hours after dosing. Again the lag time in onset of drug absorption is notably longer for the Test product. Both, total and maximum exposure, represented by geometric mean values for AUC0-tlast and Cmax, were considerably lower (differences also statistically significant) after administration of Test with 481.8 h·ng/ml for AUC 0-tlast and 25.3 ng/ml for Cmax in comparison to Reference tablets with 595.9 h·ng/ml for AUC0-tlast and 31.9 ng/ml for Cmax. Test/Reference point estimates (PE) and associated 90% confidence intervals (CI) were determined as 80.7% and 73.7 - 88.5% for AUC 0-tlast, as well as 79.6% and 70.3 - 90.0% for Cmax. Differences were also even more expressed for AUC0-9h (PE: 54.9%; CI: 47.4 - 63.5%) determined as parameter for early exposure. Conclusion: The results indicate that although both products are osmotic release systems they are not bioequivalent according to the accepted standards. This difference between both osmotic delivery systems might be substantiated by the fact that the core of the Test product is designed as a monolayer system (containing both, the active ingredient and the osmotic component) while Reference tablets consist of two separate layers. The observed pharmacokinetic differences may have an impact on blood pressure control in patients and thus, should be kept in mind when switching during treatment. ©2010 Dustri-Verlag Dr. K. Feistle.

Jain A.K.,University of Greifswald | Soderlind E.,Astrazeneca | Viriden A.,Astrazeneca | Schug B.,SocraTec RandD GmbH | And 10 more authors.
Journal of Controlled Release | Year: 2014

Four different hydrophilic matrix formulations based on hydroxypropyl methylcellulose (HPMC) were investigated for erosion properties in vivo. Three formulations contained a fixed amount of HPMC (40%) with varying proportions of two HPMC grades with different molecular weights (Methocel K100LV and K4M), and a fourth formulation contained a lower amount of the HPMC of lower molecular weight (20%). The effect of food on the in vivo erosion behavior was investigated on two formulations containing different contents of the same HPMC grade. The in vivo erosion behavior and gastrointestinal transit were investigated using magnetic marker monitoring (MMM). The in vitro and in vivo erosion-time profiles show that the erosion was strongly dependent on the composition of the formulation. The formulations containing a larger proportion of high molecular weight HPMC or higher content of HPMC exhibit relatively slower erosion rate and vice versa. In vivo erosion rates were significantly higher under postprandial administration as compared to fasted state administration. No rapid disintegration of any of the formulations (i.e. formulation failure that can potentially cause dose dumping) was observed. © 2014 Elsevier B.V.

Kambayashi A.,Goethe University Frankfurt | Kambayashi A.,Astellas Pharma Inc. | Blume H.,SocraTec RandD GmbH | Dressman J.B.,Goethe University Frankfurt
European Journal of Pharmaceutics and Biopharmaceutics | Year: 2014

The objective of this research was to characterize the dissolution profile of a poorly soluble drug, diclofenac, from a commercially available multiple-unit enteric coated dosage form, Diclo-Puren® capsules, and to develop a predictive model for its oral pharmacokinetic profile. The paddle method was used to obtain the dissolution profiles of this dosage form in biorelevant media, with the exposure to simulated gastric conditions being varied in order to simulate the gastric emptying behavior of pellets. A modified Noyes-Whitney theory was subsequently fitted to the dissolution data. A physiologically-based pharmacokinetic (PBPK) model for multiple-unit dosage forms was designed using STELLA® software and coupled with the biorelevant dissolution profiles in order to simulate the plasma concentration profiles of diclofenac from Diclo-Puren® capsule in both the fasted and fed state in humans. Gastric emptying kinetics relevant to multiple-units pellets were incorporated into the PBPK model by setting up a virtual patient population to account for physiological variations in emptying kinetics. Using in vitro biorelevant dissolution coupled with in silico PBPK modeling and simulation it was possible to predict the plasma profile of this multiple-unit formulation of diclofenac after oral administration in both the fasted and fed state. This approach might be useful to predict variability in the plasma profiles for other drugs housed in multiple-unit dosage forms. © 2014 Elsevier B.V. All rights reserved.

Stauss-Grabo M.,Engelhard Arzneimittel GmbH and Co. KG | Atiye S.,Engelhard Arzneimittel GmbH and Co. KG | Warnke A.,SocraTec RandD GmbH | Wedemeyer R.S.,SocraTec RandD GmbH | And 2 more authors.
Phytomedicine | Year: 2011

The only saponin drug currently prescribed in any significant amount in monotherapy medicines is ivy. This post-marketing surveillance study (PMSS) aimed at investigating the tolerability and safety of film-coated tablets containing ivy leaves dry extract (extracting medium: ethanol 30%, DER 5-7.5:1 [Prospan® Cough Tablets]) under practice conditions. Adults and children aged 11-85 years of both genders were included. A total of 330 patients suffering from colds accompanied by coughing or from chronic, inflammatory bronchial diseases were scheduled to undergo treatment for a period of at least seven days. The tolerability of the tablets was rated by means of questionnaires. The results of this PMSS reflect the good to very good tolerability of the tablets in the global assessment by both, the practitioner (98.5%) and by the patient (96.4%). This is one of the reasons for the high acceptance and compliance (rated as 'good' in 98.8% of all cases). The safety not only regarding the administration form but also regarding the active substance is thus underlined once again. © 2010 Elsevier GmbH. All rights reserved.

Donath F.,SocraTec R. and D. GmbH | Braeter M.,APOGEPHA | Feustel C.,APOGEPHA
International Journal of Clinical Pharmacology and Therapeutics | Year: 2011

Objective: Two comprehensively designed mono-centric ECG studies were performed to investigate the influence of propiverine hydrochloride and its main metabolite propiverine-N-oxide on cardiac function with regard to QTc prolongation, QTc dispersion and T-wave shape. Methods: The first study was conducted on 24 healthy females, followed by a second study on 24 male patients with coronary heart disease (CHD) and a pathological Pardee-Q-wave in the ECG. Both studies were placebo-controlled and compared the effects of single (30 mg s.i.d.) and multiple dosing (15 mg t.i.d.) of propiverine hydrochloride in a crossover design over 6 and 13 days, respectively. In CHD patients, the ECG was recorded under standardized exercise stress conditions. Results: An effect of propiverine on cardiac safety in healthy women and male patients with CHD could not be determined by the evaluation of QTc intervals derived from ECG under the following conditions: (1) single dosage; (2) steady-state and elevated dosage; (3) healthy female volunteers and male CHD patients; (4) resting and stress conditions in CHD patients. Moreover, other ECG parameters like QT dispersion, T-wave shape, and U-wave occurrence were not affected by propiverine compared to placebo after single or repeated dosing to reach steady-state conditions. Conclusion: These results reflect and confirm preclinical data as well as clinical observations on hundreds of volunteers and numberless patients suffering from overactive bladder syndrome and neurogenic detrusor overactivity who were treated with propiverine hydrochloride over nearly three decades in Europe and Japan. ©2011 Dustri-Verlag Dr. K. Feistle.

Kambayashi A.,Goethe University Frankfurt | Kambayashi A.,Astellas Pharma Inc. | Blume H.,SocraTec RandD GmbH | Dressman J.,Goethe University Frankfurt
European Journal of Pharmaceutics and Biopharmaceutics | Year: 2013

Individual pharmacokinetics after administration of enteric coated tablets are often highly variable and this has been ascribed to the interaction of the dosage form with the physiology of the gastrointestinal tract. This research aimed to explore the influence of interactions between enteric coated tablets and physiological factors such as gastric and intestinal pH as well as gastric emptying on the release of drug from the dosage form and the subsequent plasma profile, using diclofenac as a case example. A physiologically based pharmacokinetic (PBPK) model for monolithic enteric coated dosage forms was designed and coupled with biorelevant dissolution results to predict PK profiles of diclofenac from Voltaren® tablets in both fasted and fed humans. The paddle method was used to obtain the dissolution profiles of diclofenac in biorelevant media. The Noyes-Whitney model was employed to describe the dissolution kinetics. The PBPK model was set up using STELLA® software. A single unit enteric coated tablet was assumed to be emptied from stomach only with the house-keeping wave. Timing of the emptying was simulated using a random number generator to statistically estimate gastric emptying times after ingestion. The lag times and the dissolution rate used as input parameters in the STELLA® model were adjusted according to the pre-exposure period. The oral PK profiles were predicted for each virtual subject individually, and then the mean profiles and standard deviations were calculated. The dissolution profiles were highly affected by the period of pre-exposure in FaSSGF. A long period of pre-exposure of the tablet prolonged the lag time and decreased the dissolution rate. The results of the pharmacokinetic simulations showed that not only the mean profiles in the fasted state but also the variability could be predicted successfully using data generated for the individual virtual subjects. The results emphasize the importance of accounting for the range of pH profiles and gastrointestinal transit in the target population when predicting plasma profiles of enteric coated dosage forms and point to problems in demonstrating bioequivalence for dosage forms of this type. © 2013 Elsevier B.V. All rights reserved.

Blume H.H.,SocraTec R and D GmbH | Wedemeyer R.-S.,SocraTec R and D GmbH | Donath F.,SocraTec R and D GmbH | Roscher K.,Sanofi S.A. | And 7 more authors.
International Journal of Clinical Pharmacology and Therapeutics | Year: 2015

Objectives: To establish the relative bioavailability (rBA) between two p.o. 5-mg levomethadone hydrochloride formulations, i.e., L-Polamidon® 5 mg tablets (test) vs. L-Polamidon® solution for substitution (reference). To assess the safety and tolerability of both formulations. Subject and methods: A total of 33 healthy male subjects, aged 29 ± 6 years (BMI: 23.9 ± 2.5 kg/m2) completed this single center, open-label, randomized, 2-period cross-over study with single dose administrations under fasting conditions and coadministration with naltrexone for safety reasons. Administrations of both investigational products were separated by a washout period of at least 2 weeks, i.e., 13 treatment-free days. The total dose for each subject was 2 × 5 mg resulting in 10 mg levomethadone hydrochloride. For pharmacokinetic evaluation, blood samples were withdrawn until 72 hours postdose. A validated non-stereose-lective liquid chromatography-tandem mass spectroscopy method (LC-MS/MS) was applied for the determination of levomethadone in plasma. The lower limit of quantitation was 0.100 ng/mL. Adverse events were descriptively analyzed in the study population. Results: The geometric means of the parameters related with the extent of total exposure of levomethadone, i.e., AUC0-tlast and AUC0-∞, were 244.422 ng×h/mL and 332.999 ng×h/mL for test and 246.837 ng×h/mL and 329.467 ng×h/mL for reference, respectively. The geometric means of the peak exposure for levomethadone, i.e., Cmax, were 8.923 ng/mL for test and 8.635 ng/mL for reference. The point estimates (PEs) of the Test/Reference (T/R) adjusted geometric mean ratios of AUC0-tlast, AUC0-∞, and Cmax were 99.20%, 101.42%, and 104.11%, respectively, and all of them showed 90%-confidence intervals (CIs) within the range of 80.00 - 125.00% as suggested by regulatory requirements for bioequivalence assessment. In total, 21 subjects experienced 55 AEs during the study, the most frequently reported AE, i.e., headache, accounted for 13 out of the total 55 AEs (23.6%) and no AEs of severe intensity were reported. Conclusions: Bioequivalence could be demonstrated in terms of rate and extent of absorption after administration of test and reference products under naltrexone protection. Concerning the safety evaluation, no negative implications on the possible use of the test formulation could be determined. © 2015 Dustri-Verlag Dr. K. Feistle.

Grape S.,Royal Perth Hospital | Schug S.A.,Royal Perth Hospital | Schug S.A.,University of Western Australia | Schug S.A.,University of Munster | And 2 more authors.
Drugs | Year: 2010

Fentanyl is an opioid initially developed for parenteral administration. While oral administration is not an option due to a high first-pass metabolism, its high potency and lipophilicity have made a number of new routes of administration feasible. The transdermal therapeutic system offers an excellent option for long-term treatment of cancer and chronic pain, achieving stable plasma concentrations over the treatment period. The recent change from reservoir to matrix systems has made these systems more convenient to wear and safer to use, while being bioequivalent. In contrast, the patient-controlled iontophoretic transdermal system has been developed to enable on-demand delivery of transdermal bolus doses of fentanyl to treat postoperative pain. It offers a needle-free system to provide patient-controlled analgesia otherwise offered by intravenous pumps. However, due to technical difficulties the system is currently not clinically available. Oral transmucosal fentanyl utilizes the rapid uptake through the buccal mucosa to achieve high plasma concentrations rapidly and is indicated to treat breakthrough pain in patients who are not opioid-naive. The recently introduced fentanyl buccal tablets offer slightly better pharmacokinetics for the same indication. The intranasal route is another option to achieve rapid uptake of fentanyl, and is currently being investigated to provide acute and breakthrough pain relief. Transpulmonary administration of fentanyl remains experimental and this route of administration is not yet in clinical use. Overall, the specific pharmacological and physicochemical properties of fentanyl have made this compound highly suitable for novel routes of administration in a range of clinical indications. © 2010 Adis Data Information BV. All rights reserved.

Kuhn U.D.,Friedrich - Schiller University of Jena | Anschutz M.,SocraTec R and D GmbH | Schmucker K.,SocraTec R and D GmbH | Schug B.S.,SocraTec R and D GmbH | And 2 more authors.
International Journal of Clinical Pharmacology and Therapeutics | Year: 2010

Objective: N-acetyltransferase 2 (NAT2) genotype-phenotype relation with sulfasalazine as probe drug by means of detailed genotype analysis and kinetic data evaluation. Background: Though phenotype analysis of sulfasalazine metabolism has been described before, genotype investigations in this regard are scarce. The influence of different single point mutations on the metabolism of the sulfasalazine metabolite sulfapyridine (SP) should give more insight into the functionality of different alleles especially with those still under discussion. Methods: In two bioavailability studies performed under comparable conditions with 24 healthy subjects of both genders equally distributed, plasma levels of SP and acetylsulfapyridine (Ac-SP) were determined after oral intake of enteric coated formulations of sulfasalazine (500 mg and 1,000 mg, respectively). The resulting metabolic ratios were calculated. NAT2 genotype was analyzed in parallel for all subjects deducing haplotype set as well as putative functional phenotype as (homozygous or heterozygous) rapid acetylator (RA) or slow acetylator (SA) and correlated with the PK results. Results and discussion: RA genotype in the overall study population was seen with 45.5% (including 6.8% homozygous wildtype *4/*4) and SA genotype with 54.5%. Compared to RA genotype, apparent terminal elimination half-life of SP as well as of Ac-SP was prolonged in the SA genotype population, Cmax and AUC values of SP were higher whereas average Cmax value of Ac-SP was lower (with AUC only some tendency to lower values). In general, phenotype-genotype correlation was good with only few exceptions. Strongest functional effect on enzyme activity was noticed in slow acetylators carrying the 341T > C mutation, followed by 590G > A mutation whereas the influence of 857G > A was considerably less pronounced. Homozygous 803A > G mutation (lysine > arginine shift) did not reveal enzyme activity reduction. © 2010 Dustri-Verlag Dr. K. Feistle.

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