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1.  Bioequivalence of Sandoz methylphenidate osmotic-controlled release tablet with Concerta® (Janssen-Cilag) 
The aim was to assess the bioequivalence of Sandoz methylphenidate osmotic-controlled release (OCR) tablets (Sandoz [Methylphenidate[ MPH OCR) with Concerta®, a methylphenidate formulation indicated for the treatment of attention deficit/hyperactivity disorder (ADHD). Four open-label, randomized, single-dose, two-way crossover bioequivalence studies were conducted in healthy subjects: three fasting studies with 54-, 36- and 18-mg doses of methylphenidate, and one fed study with the 54-mg dose. The d- and l-threo-methylphenidate plasma levels were quantified using liquid chromatographic methods with tandem mass spectrometry (LC MS/MS). Bioequivalence of the formulations was accepted if the 90% geometric confidence intervals of the ratio of least-squares means of Sandoz MPH OCR to Concerta® of ln-transformed area under the curve (AUC0–t) and Cmax were within the acceptance range of 80–125%. All studies met the bioequivalence criteria, and 90% geometric confidence intervals for AUC0–t and Cmax were within the predefined range. All plasma concentration time curves for Sandoz MPH OCR under fasting conditions showed a biphasic profile comparable with Concerta®, confirmed by bioequivalence of the partial metrics AUC0–2h, AUC2-24 h, Cmax(0–2 h) and Cmax(2–24 h). Both products were well tolerated and no relevant differences in the safety profiles were observed. It was concluded that Sandoz MPH OCR is bioequivalent to Concerta® in terms of rate and extent of absorption when administered as a single dose of one extended-release tablet of 54, 36, or 18 mg under fasting conditions and at a dose of 54 mg under fed conditions.
doi:10.1002/prp2.72
PMCID: PMC4317218
ADHD; bioequivalence; Concerta®; extended release; methylphenidate; osmotic-controlled release; Sandoz
2.  Release Characteristics of Quetiapine Fumarate Extended Release Tablets Under Biorelevant Stress Test Conditions 
AAPS PharmSciTech  2013;15(1):230-236.
The aim of the present work was the investigation of robustness and reliability of drug release from 50 to 400 mg quetiapine extended release HPMC matrix tablets towards mechanical stresses of biorelevant intensity. The tests were performed under standard conditions (USP apparatus II) as well as under simulated gastrointestinal stress conditions. Mechanical stresses including pressure and agitation were applied by using the biorelevant dissolution stress test apparatus as it has been introduced recently. Test algorithms already established in previous studies were applied to simulate fasting gastrointestinal conditions. The dissolution experiments demonstrated striking differences in the product performance among standard and stress test conditions as well as dose strengths. In USP apparatus II, dissolution profiles were affected mainly by media pH. The dissolution experiments performed in biorelevant dissolution stress test device demonstrated that stress events of biorelevant intensity provoked accelerated drug release from the tablets.
Electronic supplementary material
The online version of this article (doi:10.1208/s12249-013-0050-2) contains supplementary material, which is available to authorized users.
doi:10.1208/s12249-013-0050-2
PMCID: PMC3909154  PMID: 24297600
biorelevant dissolution testing; burst release quetiapine; dissolution stress test; dose dumping
3.  Development of Hydrophobized Alginate Hydrogels for the Vessel-Simulating Flow-Through Cell and Their Usage for Biorelevant Drug-Eluting Stent Testing 
AAPS PharmSciTech  2013;14(3):1209-1218.
The vessel-simulating flow-through cell (vFTC) has been used to examine release and distribution from drug-eluting stents in an in vitro model adapted to the stent placement in vivo. The aim of this study was to examine the effect of the admixture of different hydrophobic additives to the vessel wall simulating hydrogel compartment on release and distribution from model substance-coated stents. Four alginate-based gel formulations containing reversed-phase column microparticles LiChroprep® RP-18 or medium-chain triglycerides in form of preprocessed oil-in-water emulsions Lipofundin® MCT in different concentrations were successfully developed. Alginate and modified gels were characterized regarding the distribution coefficient for the fluorescent model substances, fluorescein and triamterene, and release as well as distribution of model substances from coated stents were investigated in the vFTC. Distribution coefficients for the hydrophobic model substance triamterene and the hydrophobized gel formulations were up to four times higher than for the reference gel. However, comparison of the obtained release profiles yielded no major differences in dissolution and distribution behavior for both fluorescent model substances (fluorescein, triamterene). Comparison of the test results with mathematically modeled data acquired using finite element methods demonstrated a good agreement between modeled data and experimental results indicating that gel hydrophobicity will only influence release in cases of fast releasing stent coatings.
doi:10.1208/s12249-013-0011-9
PMCID: PMC3755162  PMID: 23918507
biorelevant dissolution testing; drug-eluting stent; hydrophobized hydrogel; release; vessel-simulating flow-through cell
4.  An Automated System for Monitoring and Regulating the pH of Bicarbonate Buffers 
AAPS PharmSciTech  2013;14(2):517-522.
The bicarbonate buffer is considered as the most biorelevant buffer system for the simulation of intestinal conditions. However, its use in dissolution testing of solid oral dosage forms is very limited. The reason for this is the thermodynamic instability of the solution containing hydrogen carbonate ions and carbonic acid. The spontaneous loss of carbon dioxide (CO2) from the solution results in an uncontrolled increase of the pH. In order to maintain the pH on the desired level, either a CO2 loss must be completely avoided or the escaped CO2 has to be replaced by quantitative substitution, i.e. feeding the solution with the respective amount of gas, which re-acidifies the buffer after dissociation. The present work aimed at the development of a device enabling an automatic pH monitoring and regulation of hydrogen carbonate buffers during dissolution tests.
doi:10.1208/s12249-013-9933-5
PMCID: PMC3666009  PMID: 23468339
bicarbonate media; hydrogen carbonate buffer; modified release; physiological buffers; biorelevant dissolution
5.  In Vitro Determination of Drug Transfer from Drug-Coated Balloons 
PLoS ONE  2013;8(12):e83992.
Drug-coated balloons are medical devices designed to locally deliver drug to diseased segments of the vessel wall. For these dosage forms, drug transfer to the vessel wall needs to be examined in detail, since drug released into the blood is cleared from the site. In order to examine drug transfer, a new in vitro setup was developed combining the estimation of drug loss during advancement to the site of application in a model coronary artery pathway with a hydrogel compartment representing, as a very simplified model, the vessel wall. The transfer of fluorescent model substances as well as the drug paclitaxel from coated balloons to the simulated vessel wall was evaluated using this method. The model was suitable to quantify the fractions transferred to the hydrogel and also to qualitatively assess distribution patterns in the hydrogel film. In the case of fluorescein sodium, rhodamin b and paclitaxel, vast amounts of the coated substance were lost during the simulated passage and only very small fractions of about 1% of the total load were transferred to the gel. This must be attributed to good water solubility of the fluorescent substances and the mechanical instability of the paclitaxel coating. Transfer of the hydrophobic model substance triamterene was however nearly unaffected by the preliminary tracking procedure with transferred fractions ranging from 8% to 14%. Analysis of model substance distribution yielded inhomogeneous distributions indicating that the coating was not evenly distributed on the balloon surface and that a great fraction of the coating liquid did not penetrate the folds of the balloon. This finding is contradictory to the generally accepted assumption of a drug depot inside the folds and emphasizes the necessity to thoroughly characterize in vitro performance of drug-coated balloons to support the very promising clinical data.
doi:10.1371/journal.pone.0083992
PMCID: PMC3877149  PMID: 24391863
6.  An Oral-Controlled Release Drug Delivery System for Liquid and Semisolid Drug Formulations 
AAPS PharmSciTech  2011;12(4):1183-1185.
A novel oral drug delivery system for the controlled release of liquid drugs, drug solutions, and semisolid drug preparations is presented that is utilizing the constant vapor pressure of liquefied gas. The system is equipped with a capillary as an element determining the drug delivery rate and contains a liquefied propellant with a suitable boiling point below human body temperature. In the dissolution studies, polyacrylate gels of different viscosities containing paracetamol as model drug were used. Zero-order release kinetics was obtained. The release rates were dependent on the gel viscosity. Besides, by gel viscosity, the drug release rates could also be modified by changing the propellant type and the capillary parameters such as length or diameter. Accordingly, the new system enables a wide range of drug delivery kinetics which can be modified in a case-by-case basis in order to match the desired drug delivery characteristics.
doi:10.1208/s12249-011-9689-8
PMCID: PMC3225522  PMID: 21918919
controlled delivery of liquids; controlled release; extended release; oral drug delivery system
7.  Magneto-Optical Relaxation Measurements of Functionalized Nanoparticles as a Novel Biosensor 
Sensors (Basel, Switzerland)  2009;9(6):4022-4033.
Measurements of magneto-optical relaxation signals of magnetic nanoparticles functionalized with biomolecules are a novel biosensing tool. Upon transmission of a laser beam through a nanoparticle suspension in a pulsed magnetic field, the properties of the laser beam change. This can be detected by optical methods. Biomolecular binding events leading to aggregation of nanoparticles are ascertainable by calculating the relaxation time and from this, the hydrodynamic diameters of the involved particles from the optical signal. Interaction between insulin-like growth factor 1 (IGF-1) and its antibody was utilized for demonstration of the measurement setup applicability as an immunoassay. Furthermore, a formerly developed kinetic model was utilized in order to determine kinetic parameters of the interaction. Beside utilization of the method as an immunoassay it can be applied for the characterization of diverse magnetic nanoparticles regarding their size and size distribution.
doi:10.3390/s90604022
PMCID: PMC3291896  PMID: 22408511
magnetic nanoparticles; magneto-optical relaxation; immunoassay; IGF-1 assay

Results 1-7 (7)