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,...     

Preparation and characterization of metformin hydrochloride loaded-Eudragit®RSPO and Eudragit®RSPO/PLGA nanoparticles

The aim of the present study was to develop and characterize metformin HCl-loaded nanoparticle formulations. Nanoparticles were prepared by the nanoprecipitation method using both a single polymer (Eudragit^®RSPO) and a polymer mixture (Eudragit/PLGA). The mean particle size ranged from 268.8 to 288?nm and the nanoparticle surface was positively charged (9.72 to 10.1 mV). The highest encapsulation efficiency was observed when Eudragit®RSPO was used. All formulations showed highly reproducible drug release profiles and the in vitro drug release in phosphate buffer (pH?=?6.8) ranged from 92 to 100% in 12?h. These results suggest that Eudragit^®RSPO or Eudragit/PLGA nanoparticles might represent a promising sustained-release oral formulation for metformin HCl, reducing the necessity of repeated administrations of high doses to maintain effective plasma concentrations, and thus, increasing patient compliance and reducing the incidence of side-effects.     

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.     

Influence of Type and Level of Water-Soluble Additives on Drug Release and Surface and Mechanical Properties of Surelease® Films

Ethylcellulose in combination with water-soluble additives has been used in the development of microporous membrane-coated dosage forms. In the present study, application of three types of water-soluble additives, namely polyethylene glycols (PEG 400, 3350, and 8000), maltodextrins (Maltrin M150, M100, and M040 in the order of lower to higher average polymer size and molecular weight; dextrose equivalence 16.9, 11.1, and 4.8, respectively), and xylitol, as porosity modifiers in the films of a commercially available aqueous ethylcellulose dispersion (Surelease/E-7-7060 plasticized with glyceryl tricaprylate/caprate) was investigated. The effect of type and level of these additives on drug release characteristics and surface and mechanical properties of the polymeric films was studied. Each additive was incorporated at 20 and 30% levels in the polymeric dispersion based on its solids content. Ibuprofen tablets were coated using the polymeric dispersion with and without additive at 3% w/w coat level in a fluid-bed equipment. The coated tablets were evaluated for their drug release rate, coat reflectivity (gloss), Brinell hardness, and elastic modulus. Differential scanning calorimetric analysis of the films was performed to determine the physico-chemical changes in the applied film-coats. The rate of drug release, hence film porosity, was observed to be dependent on the type and level of the additive added. The molecular weight of the additive and its concentration in the polymeric dispersion had significant influence on the rate of drug release, hardness, and elasticity of the film-coats.     

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.     

Influence of ethanol on swelling and release behaviors of Carbopol®-based tablets

The aim of this work was to investigate the effect of ethanol on the in vitro swelling and release behaviors of Carbopol^®-based tablets. The swelling behavior of drug-free compacts and the release of model drugs (metformin HCl, caffeine and theophylline) from matrix tablets were evaluated in acidic and buffered media with 0, 20 and 40% (v/v) ethanol. Release data were analyzed by fitting to Higuchi and Peppas models and calculation of similarity factor (f₂). ANOVA tests were performed to determine significant factors on swelling and release. It was found that ethanol affects swelling and erosion of drug-free Carbopol^® compacts, and the effect was highly dependent on medium pH. For matrix tablets, no dose dumping due to ethanol was manifested. The release rate and mechanism, however, were significantly affected by ethanol concentration as indicated by ANOVA applied to the constant, K_H, from Higuchi model and the exponent, n, from Peppas model, respectively. The effect of ethanol on release was further confirmed by similarity factor results, which indicated that ethanol led to different release profiles (f₂ < 50) in seven of eight cases for matrices containing metformin HCl and in three of eight cases for matrices containing caffeine and theophylline.     

Fabrication and evaluation of Eudragit® polymeric films for transdermal delivery of piroxicam

The aims of this work were to develop and characterize the prolonged release piroxicam transdermal patch as a prototype to substitute oral formulations, to reduce side effects and improve patient compliance. The patches were composed of film formers (Eudragit^®) as a matrix backbone, with PVC as a backing membrane and PEG200 used as a plasticizer. Results from X-ray diffraction patterns and Fourier transform-infrared spectroscopy indicated that loading piroxicam into films changed the drug crystallinity from needle to an amorphous or dissolved form. Piroxicam films were prepared using Eudragit^® RL100 and Eudragit^® RS100 as film formers at various ratios from 1:0 to 1:3. Films prepared solely by Eudragit^® RL100 showed the toughest and softest film, while other formulations containing Eudragit^® RS100 were hard and brittle. Drug release kinetic data from the films fitted with the Higuchi model, and the piroxicam release mechanism was diffusion controlled. Among all formulation tested, Eudragit^® RL100 films showed the highest drug release rate and the highest drug permeation flux across human epidermal membrane. Increasing drug loading led to an increase in drug release rate. Eudragit^® can be used as a film former for the fabrication of piroxicam films.     

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.     

Comparison of electrospun and extruded Soluplus®-based solid dosage forms of improved dissolution

Electrospinning (ES) and extrusion of a poorly water-soluble active pharmaceutical ingredient were used to improve its dissolution, which is a major challenge in the field of pharmaceutical technology. Spironolactone was applied as model drug and recently developed polyvinyl caprolactame-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus?) was used as carrier matrix and solubilizer. ES of the polymer matrix from ethanol solution was optimized at first without spironolactone and then the cosolution of the drug and the carrier was used for forming electrospun fibers. It resulted in real solid solution due to its very efficient amorphization effect. On the contrary, a low amount of crystalline spironolactone appeared in the extrudates according to Raman microscopy, X-ray diffraction (XRD), scanning electron microscopy (SEM) and energy-dispersive spectrometry (EDS). Raman microspectrometry had the lowest detection limit of spironolactone crystals compared with XRD and differential scanning calorimetry. Both ES and extrusion techniques resulted in significantly improved dissolution. Electrospun ultrafine fibers increased the dissolution more effectively, owing to the formed solid solution and huge surface. The developed continuous technologies demonstrate great potential to tackle the challenge of inadequate dissolution of poorly water-soluble drugs in several cases.     

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.     

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).     

Detection of counterfeit Viagra® by Raman microspectroscopy imaging and multivariate analysis

During the past years, pharmaceutical counterfeiting was mainly a problem of developing countries with weak enforcement and inspection programs. However, Europe and North America are more and more confronted with the counterfeiting problem. During this study, 26 counterfeits and imitations of Viagra^® tablets and 8 genuine tablets of Viagra^® were analysed by Raman microspectroscopy imaging.After unfolding the data, three maps are combined per sample and a first PCA is realised on these data. Then, the first principal components of each sample are assembled. The exploratory and classification analysis are performed on that matrix.PCA was applied as exploratory analysis tool on different spectral ranges to detect counterfeit medicines based on the full spectra (200-1800 cm⁻¹), the presence of lactose (830-880 cm⁻¹) and the spatial distribution of sildenafil (1200-1290 cm⁻¹) inside the tablet. After the exploratory analysis, three different classification algorithms were applied on the full spectra dataset: linear discriminant analysis, k-nearest neighbour and soft independent modelling of class analogy.PCA analysis of the 830-880 cm⁻¹ spectral region discriminated genuine samples while the multivariate analysis of the spectral region between 1200 cm⁻¹ and 1290 cm⁻¹ returns no satisfactory results.A good discrimination of genuine samples was obtained with multivariate analysis of the full spectra region (200-1800 cm⁻¹). Application of the k-NN and SIMCA algorithm returned 100% correct classification during both internal and external validation.     

Bioavailability of Sandimmun® versus Sandimmun Neoral®: a meta-analysis of published studies

For the past 25 years, cyclosporine A (CyA) has played a pivotal role in transplant immunosuppressant therapy. From the availability of the 2 primary marketed formulations (Sandimmun? and Sandimmun Neoral?, Novartis), confusion has existed with regard to whether these two formulations are bioequivalent. Due to the underlying clinical relevance of this information, we therefore conducted a meta-analysis of all available comparative pharmacokinetic studies to assess whether the two different CyA formulations, Sandimmun? and Sandimmun Neoral?, can be considered bioequivalent. All clinical studies that compared the bioavailability of the 2 formulations in organ transplant recipients were considered for analysis. We searched computerised databases (Embase/Excerpta Medica and Medline/PubMed) from their inception to May 2010. Only studies with AUC values determined at 12 hours were considered for analysis. Relative bioavailability was calculated with 90 percent confidence intervals (CI) for Sandimmun? (test substance) versus Sandimmun Neoral? (reference substance) according to Schuirmann?s Two One-Sided Tests Procedure and the Classical Shortest CI. Homogeneity of data was tested using the Χ(2) test. Fifteen studies were considered for meta-analysis and none of these studies reported AUC values in the 80-125 percent range required for the bioequivalence of two formulations. The overall bioavailability for Sandimmun? versus the microemulsion formulation Sandimmun Neoral? was 76 percent, with upper CI limits lower than 80 percent in some cases. Mean AUC values for Sandimmun? were significantly lower than those for Sandimmun Neoral? (p<0.01). This study demonstrates that the 2 main cyclosporine formulations, Sandimmun? and Sandimmun Neoral?, cannot be considered bioequivalent.     

Influence of Plasticizer Type and Coat Level on Surelease® Film Properties

Two commercially available formulations of aqueous ethylcellulose dispersion differing in their plasticizer, i.e., Surelease/E-7-7050 containing dibutyl sebacate (DBS) and Surelease/E-7-7060 containing glyceryl tricaprylate/caprate (GTC), were evaluated and compared for their film properties as a function of polymeric coat level. Ibuprofen tablets were coated at 1, 2, 3, and 5% w/w levels using each Surelease formulation, and the coated tablets were evaluated for their drug release characteristics, coat reflectivity (gloss), surface texture, Brinell hardness, and elastic modulus. The drug release was dependent on the coat level and followed Hixson–Crowell cube-root model at 1% coat level. However, at ≥2% coat levels, the release from tablets coated with GTC plasticized formulation appeared to be best described by non-Fickian release mechanism and that from tablets coated with DBS plasticized formulation appeared to follow apparent zero-order release mechanism. At equal coat levels, tablets coated with GTC plasticized Surelease yielded lower drug release rates, higher reflectivity (gloss), lower surface roughness, higher Brinell hardness, and lower elastic modulus than those coated with DBS plasticized formulation. A good correlation was observed between the drug release rates and the reflectivity and surface texture of the coated tablets. The film-coats of GTC plasticized formulation were harder and more elastic than those of DBS plasticized formulation indicating better mechanical integrity.     

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.     

Preparation and Analgesic Activity of Eudragit RS100® Microparticles Containing Diflunisal

Two different techniques, the quasi-emulsion solvent diffusion method and spray drying that provide polar and nonpolar preparation environments, were used to prepare microspheres from Eudragit RS100® (RS) (acrylic/methacrylic copolymer) incorporating the nonsteroidal anti-inflammatory drug diflunisal. The effects of pH on the preparation medium and drug/polymer ratio on production yield and drug incorporation, as well as on the in vitro drug release at pH 1.2 and 6.8 from tabletted microparticles, were evaluated. The drug-polymer interactions and the effect of diflunisal incorporation in the polymer matrix on drug crystallinity have been evaluated by using differential scanning calorimetry, IR and ultraviolet spectroscopy, x-ray diffraction, and microscopy analysis. A preliminary biological assay confirmed that diflunisal maintains its analgesic activity after intraperitoneal administration to rats.     

Pharmacological properties of Myrtacine® and its potential value in acne treatment

This study aimed at evaluating the antiproliferative, antibacterial, and anti-inflammatory properties of an ethanolic myrtle extract (Myrtacine?) in vitro, characterising its potential active compounds (myrtucommulones A and B') by structural analysis, and evaluating their biological activity. Antiproliferative activity was assessed by the BrdU incorporation assay in HaCat keratinocytes and inhibitory and bactericidal activities against P. ACNES strains by measuring the minimal inhibitory concentration (MIC) and D value. Anti-inflammatory effect was evaluated by measuring 6-keto-prostaglandin F1 α and [3H]-arachidonic acid metabolite production in keratinocytes stimulated for inflammation. Myrtacine? inhibited keratinocyte proliferation by 27?% and 76?% at 1 and 3?μg/mL, respectively (p?相似文献