Metabolism and pharmacokinetics of the anti-hepatitis C virus nucleotide prodrug GS-6620.

The anti-hepatitis C virus nucleotide prodrug GS-6620 employs a double-prodrug approach, with l-alanine-isopropyl ester and phenol moieties attached to the 5'-phosphate that release the nucleoside monophosphate in hepatocytes and a 3'-isobutyryl ester added to improve permeability and oral bioavailability. Consistent with the stability found in intestinal homogenates, following oral administration, intact prodrug levels in blood plasma were the highest in dogs, followed by monkeys, and then were the lowest in hamsters. In contrast, liver levels of the triphosphate metabolite at the equivalent surface area-adjusted doses were highest in hamsters, followed by in dogs and monkeys. Studies in isolated primary hepatocytes suggest that relatively poor oral absorption in hamsters and monkeys was compensated for by relatively efficient hepatocyte activation. As intestinal absorption was found to be critical to the effectiveness of GS-6620 in nonclinical species, stomach pH, formulation, and food effect studies were completed in dogs. Consistent with in vitro absorption studies in Caco-2 cells, the absorption of GS-6620 was found to be complex and highly dependent on concentration. Higher rates of metabolism were observed at lower concentrations that were unable to saturate intestinal efflux transporters. In first-in-human clinical trials, the oral administration of GS-6620 resulted in poor plasma exposure relative to that observed in dogs and in large pharmacokinetic and pharmacodynamic variabilities. While a double-prodrug approach, including a 3'-isobutyryl ester, provided higher intrinsic intestinal permeability, this substitution appeared to be a metabolic liability, resulting in extensive intestinal metabolism and relatively poor oral absorption in humans.

[Care for dying patients in the emergency department]. / Versorgung sterbender PatientInnen in der Notaufnahme.

Patients at the end of life frequently receive care in emergency departments. Emergency physicians are faced with caring for both patients who pass away suddenly following an acute illness or injury despite rescue efforts, as well as those who are dying from a chronic condition or high age. To provide proper care and respect the patients' wishes regarding invasive treatments, emergency physicians should be knowledgeable about advance directives and have effective communication skills when delivering bad news to patients and their family. In addition, a basic understanding of palliative care is necessary for physicians to effectively manage symptoms.

[Recommendations for Education in Sonography in Prehospital Emergency Medicine (pPOCUS): Consensus paper of DGINA, DGAI, BAND, BV-ÄLRD, DGU, DIVI and DGIIN]. / Empfehlungen zur Sonografieausbildung in der prähospitalen Notfallmedizin (pPOCUS): Konsensuspapier von DGINA, DGAI, BAND, BV-ÄLRD, DGU, DIVI und DGIIN.

Point-of-care sonography is a precondition in acute and emergency medicine for the diagnosis and initiation of therapy for critically ill and injured patients. While emergency sonography is a mandatory part of the training for clinical acute and emergency medicine, it is not everywhere required for prehospital emergency medicine. Although some medical societies in Germany have already established their own learning concepts for emergency ultrasound, a uniform national training concept for the use of emergency sonography in the out-of-hospital setting is still lacking. Experts of several professional medical societies have therefore joined forces and developed a structured training concept for emergency sonography in the prehospital setting. The consensus paper serves as quality assurance in prehospital emergency sonography.

[Recommendations for Education in Sonography in Prehospital Emergency Medicine (pPOCUS): Consensus paper of DGINA, DGAI, BAND, BV-ÄLRD, DGU, DIVI and DGIIN]. / Empfehlungen zur Sonografieausbildung in der prähospitalen Notfallmedizin (pPOCUS): Konsensuspapier von DGINA, DGAI, BAND, BV-ÄLRD, DGU, DIVI und DGIIN.

Point-of-care sonography is a precondition in acute and emergency medicine for the diagnosis and initiation of therapy for critically ill and injured patients. While emergency sonography is a mandatory part of the training for clinical acute and emergency medicine, it is not everywhere required for prehospital emergency medicine. Although some medical societies in Germany have already established their own learning concepts for emergency ultrasound, a uniform national training concept for the use of emergency sonography in the out-of-hospital setting is still lacking. Experts of several professional medical societies have therefore joined forces and developed a structured training concept for emergency sonography in the prehospital setting. The consensus paper serves as quality assurance in prehospital emergency sonography.

Influence of additives on melt viscosity, surface tension, and film formation of dry powder coatings.

BACKGROUND: Limited information on thermally cured dry-powder coatings used for solid dosage forms has been available in the literature. AIM: The aim of this study was to characterize the film formation process of Eudragit L 100-55 dry-powder coatings and to investigate the influence of film additives on melt viscosity and surface tension. METHODS: The coating process employed no liquids and the plasticizer was combined with the polymer using hot melt extrusion. Thermoanalytical methods including differential scanning calorimetry and thermogravimetric analysis (TGA) were used to investigate the thermal properties of the dry-coating formulations. The rheological behavior of the coating formulations were characterized with the extrusion torque, and the surface energy parameters were determined from contact angle measurements. The influence of the level of triethyl citrate (TEC) as plasticizer and polyethylene glycol (PEG) 3350 in the polymer film on film formation was investigated using a digital force tester. RESULTS: TGA confirmed thermal stability of all coating excipients at the investigated curing conditions. Increasing TEC levels and the addition of PEG 3350 as a low melting excipient in the coating reduced the viscosity of the polymer. Plasticization of the polymer with TEC increased the surface free energy, whereas the admixture of 10% PEG 3350 did not affect the surface free energy of Eudragit L 100-55. The spreading coefficient of the polymers over two sample tablet formulations was reduced with increasing surface free energy. During the curing process, puncture strength, and elongation of powder-cast films increased. The effect of curing time on the mechanical properties was dependent on the plasticizer content. CONCLUSIONS: The incorporation of TEC and PEG 3350 into the Eudragit L 100-55 powder coating formulation improved film formation. Mechanical testing of powder-cast films showed an increase of both elongation and puncture strength over the curing process as criterion for polymer particle fusion, where film formation progressed faster at high plasticizer levels.

Properties of theophylline tablets dry powder coated with Eudragit((R)) E PO and Eudragit((R)) L 100-55.

The aim of the present study was to investigate the influence of Eudragit((R)) E PO on the drug release mechanism of Eudragit((R)) L 100-55 film coatings applied to theophylline tablets by a dry powder coating technique. The process was entirely liquid-free. Calculation of the Flory-Huggins interaction parameter based on solubility parameters suggested immiscibility of the two copolymers. MDSC thermograms were characterized by two glass transitions for the investigated Eudragit((R)) E PO/Eudragit((R)) L 100-55 ratios and confirmed incomplete miscibility of the copolymers at processing conditions. FT-IR analysis was employed to study binding interactions of the polymers. Due to the higher affinity of the plasticizer, triethyl citrate, for Eudragit((R)) E PO compared to Eudragit((R)) L 100-55, redistribution of the plasticizer was observed during the curing phase of the process. Plasticizer migration also affected the initial phase of drug release from powder-coated theophylline tablets that were stored for four weeks. Drug release from powder-coated tablets was dependent on the polymer blend ratio, coating thickness, and the pH of the dissolution medium. A broad range of pH dependent theophylline release profiles were obtained as a function of the polymer blend ratio. The particle size of the coating powder influenced the microstructure of the film coating.

Properties of theophylline tablets dry powder coated with Eudragit E PO and Eudragit L 100-55.

The aim of the present study was to investigate the influence of Eudragit E PO on the drug release mechanism of Eudragit L 100-55 film coatings applied to theophylline tablets by a dry powder coating technique. The process was entirely liquid-free. Calculation of the Flory-Huggins interaction parameter based on solubility parameters suggested immiscibility of the two copolymers. MDSC thermograms were characterized by two glass transitions for the investigated Eudragit E PO/Eudragit L 100-55 ratios and confirmed incomplete miscibility of the copolymers at processing conditions. FT-IR analysis was employed to study binding interactions of the polymers. Due to the higher affinity of the plasticizer, triethyl citrate, for Eudragit E PO compared to Eudragit L 100-55, redistribution of the plasticizer was observed during the curing phase of the process. Plasticizer migration also affected the initial phase of drug release from powder-coated theophylline tablets that were stored for four weeks. Drug release from powder-coated tablets was dependent on the polymer blend ratio, coating thickness, and the pH of the dissolution medium. A broad range of pH dependent theophylline release profiles were obtained as a function of the polymer blend ratio. The particle size of the coating powder influenced the microstructure of the film coating.

Influence of processing parameters and formulation factors on the drug release from tablets powder-coated with Eudragit L 100-55.

The aim of this study was to develop a dry powder coating process for chlorpheniramine maleate (CPM) tablets using Eudragit L 100-55 as the delayed release polymer. Powder coating, a water and organic solvent-free process, was investigated as a method to prevent the migration of an ionizable, highly water soluble model drug into the polymeric film during the coating process. Eudragit L 100-55 was pre-plasticized with triethyl citrate (TEC) using hot-melt extrusion at levels of 20%, 30%, and 40%, based on the polymer weight. The extrudate was subsequently cut into pellets and cryogenically ground into a fine powder. Talc was incorporated into the coating powder as an anti-tack agent. PEG 3350 was used as a primer for the powder coating of tablets with pre-plasticized Eudragit L 100-55. The addition of polyethylene glycol 3350 (PEG 3350) to the pre-plasticized Eudragit L 100-55 was necessary to enhance the adhesion of the coating powder to the tablet cores. PEG 3350 also improved film formation and coalescence of the polymeric particles due to its plasticization effects on the acrylic polymer. For comparison, theophylline tablets were also coated with pre-plasticized Eudragit L 100-55. Theophylline was selected as a less water soluble model drug. The powder coating process was performed in a modified laboratory scale spheronizer. The drug release rate was dependent both on TEC content and the coating level. The stability of the powder-coated CPM tablets was confirmed at 25 degrees C/60% RH over a storage time of 12 weeks.

Evaluation of the USP dissolution test method A for enteric-coated articles by planar laser-induced fluorescence.

The USP drug release standard for delayed-release articles method A was evaluated using planar laser-induced fluorescence (PLIF). Prior authors have suggested that high pH "hot spots" could develop during the buffer medium addition of the method A enteric test. Additionally, previous studies have shown heterogeneous flow patterns and low-shear regions in the USP Apparatus II dissolution vessel, which may result in poor mixing of the buffer and acid media during the pH neutralization step of the method A enteric test. In this study, PLIF was used to evaluate the mixing patterns and evolution of pH neutralization during the buffer medium addition with rhodamine-B dye and the pH-sensitive dye fluorescein, respectively. Additionally, a comparison of the methods A and B enteric tests was performed with enteric-coated tablets containing rhodamine-B in the film so as to image the dissolution rate of the coating polymer with PLIF in order to determine if rapid buffer addition for the method A procedure accelerates the rate of film coat dissolution. Rapid addition of the 250 mL of buffer medium over 5 s to the 750 mL of acidic medium shows efficient mixing and pH neutralization due to the generation of large-scale stirring and enhanced turbulence resulting from the descending buffer medium. Slow addition near the paddle shaft over 5 min showed segregation in the recirculating region around the paddle shaft. In contrast, slow addition near the vessel wall introduces the medium into fluid outside of the recirculation region and enables transport over the entire vessel. Enteric-coated tablets tested according to method A with rapid medium addition and method B enteric tests performed identically, indicating no difference in polymer dissolution rate between the two tests. From the results of the PLIF imaging studies with rhodamine-B, fluorescein, and enteric-coated tablets, it was seen that "hot spots" affecting the dissolution performance of enteric dosage forms are not generated during the neutralization step of the method A enteric test namely when the media is added rapidly or outside of the recirculating region that surrounds the paddle shaft.

Influence of hydroxyethylcellulose on the drug release properties of theophylline pellets coated with Eudragit RS 30 D.

The objective of this study was to investigate the influence of a hydrophilic polymer, hydroxyethylcellulose (HEC), on the release properties of theophylline from pellets coated with Eudragit RS 30 D, and the physicochemical properties of Eudragit RS 30 D cast films. The release rate of theophylline from Eudragit RS 30 D coated pellets decreased during storage at 25 degrees C/60% RH due to the further coalescence of colloidal acrylic particles. In addition, water-vapor permeability and tensile strength of Eudragit RS 30 D cast film decreased after 1-month storage at 25 degrees C/60% RH. The presence of 10% hydroxyethylcellulose in the coating formulation was shown to stabilize the drug release rate from coated pellets, the water-vapor permeability and the tensile strength of free films. Atomic force microscopy and scanning electronic microscopy were used to demonstrate that the HEC was immiscible with Eudragit RS 30 D in the cast films. The stabilization effect of HEC was investigated and determined to be due to the formation of an incompatible phase between the latex particles which impaired further coalescence of the colloidal acrylic particles.

Discovery of the first C-nucleoside HCV polymerase inhibitor (GS-6620) with demonstrated antiviral response in HCV infected patients.

Hepatitis C virus (HCV) infection presents an unmet medical need requiring more effective treatment options. Nucleoside inhibitors (NI) of HCV polymerase (NS5B) have demonstrated pan-genotypic activity and durable antiviral response in the clinic, and they are likely to become a key component of future treatment regimens. NI candidates that have entered clinical development thus far have all been N-nucleoside derivatives. Herein, we report the discovery of a C-nucleoside class of NS5B inhibitors. Exploration of adenosine analogs in this class identified 1'-cyano-2'-C-methyl 4-aza-7,9-dideaza adenosine as a potent and selective inhibitor of NS5B. A monophosphate prodrug approach afforded a series of compounds showing submicromolar activity in HCV replicon assays. Further pharmacokinetic optimization for sufficient oral absorption and liver triphosphate loading led to identification of a clinical development candidate GS-6620. In a phase I clinical study, the potential for potent activity was demonstrated but with high intra- and interpatient pharmacokinetic and pharmacodynamic variability.

Dry powder coating of pharmaceuticals: a review.

Over the last half century, film coating technology has evolved significantly in terms of compositions and manufacturing processes, allowing for greater functionality, flexibility and efficiency. Driven by a combination of cost considerations and functionality, a range of dry powder coating technologies have been developed in both academic and industrial settings. These technologies can be generally classified into three major types based on the layer formation process: liquid assisted, thermal adhesion and electrostatic. In addition to specific manufacturing processes that must be implemented to achieve the desired product attributes, many of these techniques also require the use of novel excipients and specific formulations to provide acceptable manufacturability. This review summarizes the current dry powder coating technologies and highlights their industrial applicability with publicly disclosed case studies. Commentary on the future directions of dry powder coating is also provided.

Influence of polymeric subcoats on the drug release properties of tablets powder-coated with pre-plasticized Eudragit L 100-55.

The aim of the study was to investigate the properties of sodium valproate tablets that were dry powder-coated with pre-plasticized Eudragit L 100-55. Polyethylene glycol 3350 (PEG 3350) was used as primer to facilitate initial coating powder adhesion. Solubility parameters were employed to determine the wetting properties of the PEG 3350 primer. Additional PEG 3350 within the powder coating formulation was required to enable powder adhesion to the tablet cores. The application of a subcoat of either Eudragit E PO or Eudragit RL PO facilitated adhesion of the enteric polymer to the tablet cores and reduced the amount PEG 3350 required in the coating formulation. Since reduction of the PEG 3350 content produced less water-vapor permeable films, the enteric coating level necessary to control the drug release was decreased. PEG 3350 and Methocel K4M were incorporated in both Eudragit E PO and Eudragit RL PO subcoating formulations as pore forming agents. The influence of the pore forming excipients on physicochemical properties of free powder-cast films was investigated. The miscibility of the PEG 3350 and Methocel K4M in the film coating was correlated with their ability to function as pore forming agent.