Bioavailability studies with Digoxin-Sandoz® and Lanoxin®

Summary Various brands of digoxin tablets, and even different batches of one brand, may differ greatly in bioavailability. Digoxin-Sandoz^® tablets have been compared with Lanoxin^® manufactured between 1969 and 1972 and after May 1972. Comparisons were also made between and within batches of Digoxin-Sandoz tablets. Three separate cross-over studies were conducted involving a total of 20 volunteers. Digoxin-Sandoz tablets were shown to have a constant bioavailability and to produce plasma concentrations very similar to new Lanoxin. Storage for 2 years of one batch of Digoxin-Sandoz did not alter the bioavailability. Particle size was shown to influence bioavailability. Care should be exercised when plasma data alone are interpreted as an index of bioavailability. Measures of bioavailability based on plasma data obtained up to 6 h after administration differed from those based on cumulative urinary excretion data (in this study by a factor of about 2), which can lead to the belief that a difference in bioavailability is much greater than is actually the case. Data from cumulative urinary excretion, collected over a sufficiently long period of time, are likely to be the most reliable method for determining the bioavailability of a substance such as digoxin.     

Salmon calcitonin-loaded Eudragit® and Eudragit®-PLGA nanoparticles: in vitro and in vivo evaluation

The main objective of this study was to prepare salmon calcitonin (sCT)-loaded Eudragit®RSPO, Eudragit®L100 and Eudragit®-poly(lactic-co-glycolic acid) blend nanoparticles for in vitro and in vivo evaluation as an oral drug delivery system. The prepared nanoparticles ranged in size from 179.7 to 308.9?nm with a polydispersity index between 0.051 and 2.75, and had surface charges ? ?11 to +6?mV. Efficient sCT encapsulation and release was observed with all the nanoparticle formulations. The polymer type was an important factor that influenced the release characteristics and the in vivo hypocalcemic effect. Nanoparticle formulations were also prepared with sodium taurodeoxycholate (NaTDC) and characterized. No statistically significant difference was noted between the hypocalcemic effect of any of the nanoparticle formulations with and without NaTDC (p?>?0.05). The use of Eudragit®RSPO nanoparticles appears to be a potential approach for the oral delivery of sCT.     

Salmon calcitonin-loaded Eudragit® and Eudragit®-PLGA nanoparticles: in vitro and in vivo evaluation

The main objective of this study was to prepare salmon calcitonin (sCT)-loaded Eudragit?RSPO, Eudragit?L100 and Eudragit?-poly(lactic-co-glycolic acid) blend nanoparticles for in vitro and in vivo evaluation as an oral drug delivery system. The prepared nanoparticles ranged in size from 179.7 to 308.9?nm with a polydispersity index between 0.051 and 2.75, and had surface charges ~ -11 to +6?mV. Efficient sCT encapsulation and release was observed with all the nanoparticle formulations. The polymer type was an important factor that influenced the release characteristics and the in vivo hypocalcemic effect. Nanoparticle formulations were also prepared with sodium taurodeoxycholate (NaTDC) and characterized. No statistically significant difference was noted between the hypocalcemic effect of any of the nanoparticle formulations with and without NaTDC (p?>?0.05). The use of Eudragit?RSPO nanoparticles appears to be a potential approach for the oral delivery of sCT.     

Molecular Dynamics Simulations and Experimental Results Provide Insight into Clinical Performance Differences between Sandimmune® and Neoral® Lipid-Based Formulations

Pharmaceutical Research - Molecular dynamics (MD) simulations provide an in silico method to study the structure of lipid-based formulations (LBFs) and the incorporation of poorly water-soluble...     

In vitro testing of controlled release theophylline preparations: Theolair ®, Theograd® and Theolin®

Three dissolution methods,i.e. a paddle type, theusp disintegration and a column method, were used to characterize the release from three controlled release theophylline preparations,i.e. Theolair Retard® 250, Theolin Retard® 300 and Theograd® 350. The release profiles proved to be dependent upon agitation intensity and pH or a combination of both, but the sensitivity towards these variables differed markedly between the products tested.     

Oxytrex®: an oxycodone and ultra-low-dose naltrexone formulation

Oxytrex^® (Pain Therapeutics, Inc.) is an oral opioid that combines a therapeutic amount of oxycodone with an ultra-low dose of the antagonist naltrexone. Animal data indicate that this combination minimizes the development of physical dependence and analgesic tolerance while prolonging analgesia. Oxytrex is in late-stage clinical development by Pain Therapeutics for the treatment of moderate-to-severe chronic pain. To evaluate the safety and efficacy of the oxycodone/naltrexone combination, three clinical studies have been conducted, one in healthy volunteers and the other two in patients with chronic pain. The putative mechanism of ultra-low-dose naltrexone is to prevent an alteration in G-protein coupling by opioid receptors that is associated with opioid tolerance and dependence. Opioid agonists are initially inhibitory but become excitatory through constant opioid receptor activity. The agonist/antagonist combination of Oxytrex may reduce the conversion from an inhibitory to an excitatory receptor, thereby decreasing the development of tolerance and physical dependence.     

Coagulation status in patients with coronary artery disease taking 100 mg aspirin and healthy volunteers using PFA-100® and ROTEM®

Previous investigation revealed that age is a major risk factor for thomboembolic events. Earlier studies with thrombelastography have demonstrated procoagulant activity in elderly patients with coronary artery disease. The aim of the present study was to investigate age-related differences in the coagulation status of patients with documented coronary artery disease, healthy elderly and healthy young volunteers with the rotation thrombelastography (ROTEM?) and PFA-100?. Measured with ROTEM?, mean clot formation time (CFT (EXTEM)) in healthy young volunteers (120.8 ± 73.5 s) was significantly longer than in healthy elderly (78.3 ± 36.7 s, p < 0.05) and in patients with coronary artery disease (74.3 ± 59.1 s, p < 0.05). No difference was found between healthy elderly and patients with coronary artery disease. The lowest value for mean maximum clot formation (MCF (EXTEM)) was seen in healthy young volunteers (57.0 ± 6.1 mm) which was significantly different to healthy elderly (61.9 ± 4.8 mm, p < 0.05) and patients with coronary artery disease (65.3 ± 8.4 mm, p < 0.05). No difference could be found between healthy elderly and patients with coronary artery disease, although a trend to higher mean MCF (EXTEM) and lower mean CFT (EXTEM)in patients with coronary artery disease was found. Measured with the collagen/epinephrine cartridge of the PFA-100?, healthy young volunteers (166.4 ± 59.5 s) had numerical but insignificantly longer mean closure times compared to healthy elderly (138.5 ± 53.3 s). These findings point to agerelated differences in thrombelastographic parameters. The ROTEM? analysis indicates an increased coagulability in patients with coronary artery disease and healthy elderly compared to healthy young volunteers.     

Bleomycin delivery into cancer cells in vitro with ultrasound and SonoVue® or BR14® microbubbles

Abstract

Background: Cell exposure to ultrasound (US) in the presence of contrast agent microbubbles (MBs) can result in cell sonoporation that can be exploited for drug or gene delivery. Anticancer drug bleomycin (BLM), used in sonoporation, can effectively eliminate tumor cells in vitro and in vivo. Nevertheless, sonoporation mechanism is not known, thus different US parameters and MB types are used. Recently, we proposed that efficiency of cell sonoporation can be related to the efficiency of MB sonodestruction.

Purpose: We analyzed human tumor cells viability in response to BLM, US and MB treatment.

Methods: Human glioblastoma astrocytoma (U-87 MG) or colon cancer (HCT-116) cells were exposed to US in the presence of BLM and either SonoVue® or BR14® MBs. MB sonodestruction was evaluated according to US signal attenuation.

Results: Both HCT-116 and U-87 MG cell viability following US exposure decreased up to 30%. Decrease in cell viability followed similar tendency as MB sonodestruction, which suggests direct relationship between MB sonodestruction and BLM intracellular delivery.

Conclusion: Sonoporation is a feasible method to deliver BLM in to several types of human cancer cell lines. Efficiency of cell sonoporation correlated well with MB sonodestruction, providing a possibility to optimize US parameters by measuring MB sonodestruction.     

Comparative Study of the Pharmacokinetics and Bioequivalence of Meldonium and Mildronate® Preparations

Pharmaceutical Chemistry Journal - Acomparative study of the pharmacokinetics, bioequivalence, and safety of two marketed meldonium dosage forms Meldonium Organika (meldonium, 500 mg capsules,...     

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.     

The Effects of Pluronic® Block Copolymers and Cremophor® EL on Intestinal Lipoprotein Processing and the Potential Link with P-Glycoprotein in Caco-2 Cells

Purpose. This investigation was performed to study the effects of Pluronic® block copolymers and Cremophor® EL on intestinal lipoprotein processing and to investigate a potential link between lipoprotein processing and P-glycoprotein. Methods. Caco-2 cells were used to monitor changes in lipoprotein production and secretion following exposure to excipients. Effects on P-glycoprotein were monitored using cyclosporin A as a model substrate. Results. A range of surfactants commonly used as pharmaceutical excipients in lipid-based oral drug delivery systems, including Pluronic® block copolymers L81, P85, and F68 and Cremophor® EL, inhibited intestinal lipoprotein secretion. The effects were concentration dependent and reversible. The mechanism of inhibition appears to be related to the assembly and secretion of lipoproteins rather than to initial intracellular triglyceride synthesis. A strong correlation was found between excipient-mediated inhibition of lipoprotein secretion and inhibition of P-glycoprotein efflux, implying a link between the two biochemical processes. Conclusions. The ability of such bioactive excipients to simultaneously manipulate different cellular processes must be considered in selecting excipients for oral drug delivery systems. Such information is particularly relevant when the drug is lipophilic, a candidate for P-glycoprotein efflux, and where intestinal lymphatic targeting via chylomicron stimulation is desirable.     

DCVax®-Brain and DC vaccines in the treatment of GBM

Background: DCVax^®-Brain (Northwest Biotherapeutics, Inc., Bethesda, MD, USA) is a personalized treatment for brain tumors. Its approach of administering autologous tumor antigen-bearing dendritic cells (DCs) has garnered hope for more effective and less toxic therapy for patients with malignant brain tumors including glioblastoma multiforme (GBM). DCVax-Brain composition and efficacy are not fully disclosed, although sponsors claim it is poised to critically test clinical DC vaccine efficacy in GBM patients. Objective: This review examines the efficacy of DC vaccine therapy in treating GBM patients. Review question: To determine if the approach of DC vaccination followed by DCVax-Brain shows ample clinical promise in GBM patients. Search strategy: All published reports of DC vaccination for GBM and press releases regarding DCVax-Brain findings were evaluated. Critical appraisal of reports and summary of outcomes: Published DC vaccine trials for high-grade glioma patients suggest favorable clinical outcomes not easily ascribed to non-treatment parameters. Evidence of possible selection bias exists in many reports, but efforts to account for this are evident in the most recent publications. Conclusion: DC vaccine trials provide evidence of low toxicity in GBM patients and effective induction of antitumor immunity in the latest publications correlate with clinical improvements. Preliminary reports on DCVax-Brain clinical outcomes seem to follow these trends.     

Polymorphic behaviour of Compritol®888 ATO as bulk lipid and as SLN and NLC

Compritol®888 ATO (glycerol behenate) is widely used as a pharmaceutical excipient in the field of solid dosage forms due to its lubricating properties. It is an amphiphilic material with a high melting point (～70°C) and, therefore, it can also be used to prepare aqueous colloidal dispersions. The aim of this paper is to study the suitability of Compritol®888 ATO for the production of solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) for the entrapment of a lipophilic model drug. This study assesses the crystalline structure of the bulk lipid, as well as the changes that occur in its crystal lattice with the addition of ‘impurities’, such as oil (α-tocopherol) and drug (ketoconazole), using DSC and X-ray diffraction analysis before and after thermal stress. Aqueous SLN and NLC dispersions were produced using an appropriate surfactant/co-surfactant system and their physicochemical stability was assessed by PCS, LD, DSC and by WAXS. It was found that the crystalline lattice of Compritol®888 ATO is composed of very small amounts of the unstable α polymorphic form characteristic of triacylglycerols, which disappears after thermal stress of bulk lipid. Mixing oils and drug molecules which are soluble in this lipid decreased its lattice organization and, thus, was revealed to be suitable for production of lipid nanoparticles containing ketoconazole. However, particle growth could not be avoided during shelf life.     

Cypher® versus Taxus®: the stent war

Cypher^® (sirolimus-eluting stent) and Taxus^® (paclitaxel-eluting stent) have been approved for use in percutaneous coronary intervention. Both of the stents have shown superiority over bare metal stents in reducing major adverse cardiac events, restenosis rates and target vessel revascularisation. Results of clinical trials with head-to-head comparison of Taxus and Cypher stents in patients with obstructive coronary artery diseases have recently been reported. This review compares the performance of Cypher and Taxus stents as noted in observational studies and clinical trials in various types of coronary artery lesions.     

Fabrication and characterization of extruded and spheronized beads containing carbopol® 974P,NF resin

Carbopol® 974P, NF resin is a synthetic, cross-linked, acrylic acid polymer. It becomes tacky when wetted, which introduces handling difficulties with techniques involving water or other fluid. To reduce tack, the water for wetting was replaced by an aqueous solution of a strong electrolyte. The effect of the concentration and type of electrolyte on the adhesive force of the wet mass was measured. A correlation was found between the charge density of the cation and the minimum salt concentration necessary to eliminate problems associated with tack. Beads containing chlorpheniramine maleate, Carbopol®, Avicel PH101, and electrolytes were successfully manufactured by extrusionspheronization. The Carbopol® concentration, as well as the pH and ionic strength of the dissolution medium and the rotation speed of the paddles, can modify drug release.     

HPLC determination and pharmacokinetics of the new original domestic drug dibufelon®

A simple, specific, sensitive, and precise high-performance liquid chromatography (HPLC) assay with UV detection has been developed for quantitative determination of fenozan acid in human blood plasma. Using this method, the pharmacokinetics of the new domestic preparation dibufelon (OOO Consortium-PIK, Russia) were investigated after a single peroral administration of an 800-mg dose in 12 healthy volunteers. It is established that the drug is rapidly absorbed from the GI tract into the systemic blood flow [C _max ,178 ± 29 ng/mL; T _max, 3.9 ± 0.5 h; AUC _0–∞, 1434 ± 269 (ng ∙ h)/mL; C _max/AUC _0–∞, 0.135 ± 0.011 L/h], rather well retained in humans (MRT, 8.6 ± 0.8 h; T ₁/₂, 5.3 ± 0.8 h), and, despite a rapid total clearance (Cl _t ,824 ± 167 L/h), penetrates well into organs and tissues (V _Z , 5590 ± 1204 L).