Sandimmun Neoral即将批准上市

山道士公司为它的环抱素口服新制剂（sandimmunneoral，SN）在欧洲的几个国家里提出上市申请，预计首批制剂将在明年上半年进入市场。公司认为，它将直接取代山地明（sandimmun）的位置，覆盖其已有的和新增加的适应证。SN是由环抱素的微乳液和一定量的酸、脂和盐所组成，其形态类似于软明胶胶囊包裹的液体制剂。目前，市场上的山地明在个体间和个体内的血药浓度上具有较大的变异性及在吸收上依赖胆汁，因此需开发SN。该公司认为，由于此制剂的组成合理，从而保证了它具有可预测的吸收度，而在此之前，山地明在吸收上的较大变异性需要经…     

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.     

Metabolism of the thiocarbamate herbicide SUTAN® in rats

1. The metabolism of the thiocarbamate herbicide SUTAN° (butylate) was studied after administration of single oral doses of [isobutyl-1-¹⁴C]SUTAN to male and female rats.

2. The radiolabelled dose was rapidly absorbed and excreted, with 79% of the dose excreted in the urine in 72?h. The small percentages of radioactivity excreted in the faeces and as ¹⁴CO₂ were significantly higher (P≤0.05) in males than in females.

3. SUTAN was extensively metabolized, and no unmetabolized SUTAN was found in the urine. A total of 18 of the 29 urinary metabolites were identified, and identified metabolites represented 83–88% of the urinary radioactivity.

4. Diisobutylamine was the major urinary metabolite in both males and females, averaging 51% of the urinary radioactivity.

5. Other significant urinary metabolites included primary hydroxylated and tertiary hydroxylated diisobutylamines and a series of mercapturic acid pathway metabolites, including an S-glucuronide and several hydroxylated and unhydroxylated mercapturates.

6. Oxidations at the three alkyl groups produced a variety of minor urinary metabolites, and hydroxylation of the primary or tertiary carbon on the isobutyl groups, followed by an intramolecular reaction, generated a series of minor cyclized metabolites.     

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.     

Effect of Device Design on the Aerosolization of a Carrier-Based Dry Powder Inhaler—a Case Study on Aerolizer® Foradile®

The objective of this study is to investigate the effect of device design of the Aerolizer^® on the aerosolization of a carrier-based dry powder inhaler formulation (Foradile^®). The Aerolizer was modified by reducing the air inlet size and mouthpiece length to 1/3 of the original dimensions, or by increasing the grid voidage. Aerosolization of the powder formulation was assessed on a multi-stage liquid impinger at air flow rates of 30, 60, and 100 L/min. Coupled CFD-DEM simulations were performed to investigate the air flow pattern and particle impaction. There was no significant difference in the aerosolization behavior between the original and 1/3 mouthpiece length devices. Significant increases in FPF total and FPF emitted were demonstrated when the inlet size was reduced, and the results were explained by the increases in air velocity and turbulence from the CFD analysis. No significant differences were shown in FPF total and FPF emitted when the grid voidage was increased, but more drugs were found to deposit in induction port and to a lesser extent, the mouthpiece. This was supported by the CFD-DEM analysis which showed the particle–device collisions mainly occurred in the inhaler chamber, and the cross-grid design increased the particle–device collisions on both mouthpiece and induction port. The air inlet size and grid structure of the Aerolizer^® were found to impact significantly on the aerosolization of the carrier-based powder.     

Effects of Subchronic Dermal Application of Break-Free CLP® in CD-1 Mice

For some years, those involved with the safety assessment of chemicals have in one way or another considered the degree to which data on either skin sensitization potential or on carcinogenicity may inform them on the other endpoint for a particular substance. In this work, we have taken a pragmatic perspective on the question and assessed mutagens, rather than carcinogens, and sensitizers as this better reflects the potential for biological macromolecule interaction. A dataset of 100 substances, the majority of which have come under scrutiny for one reason or another during our own toxicology investigations, was interrogated. We focused on the extent to which results from the primary screen for skin sensitization correlated with the results from the two in vitro tests used as a screen for mutagenicity, namely the bacterial mutation assay and the in vitro chromosome aberration assay. Although there was some concordance between the two endpoints, as standalone methods, neither predicted the other particularly accurately, with 32% showing disagreement. It is probable that there are several critical elements missing from this top level assessment, not least an appreciation of which substances are positive in mutagenicity tests via non‐genotoxic mechanisms which could seriously impair such a correlation between results from the two different endpoints.     

Mechanistic Investigation of Pluronic® Based Nano-crystalline Drug-polymer Solid Dispersions

Purpose

To understand the mechanism of nano-crystalline drug formation in Pluronic® (i.e., poly(ethylene oxide-block-propylene oxide) triblock copolymers) based drug-polymer solid dispersions.

Materials and Methods

Four polymers, Pluronic® F127, F108, F68 and PEG 8000, which have different poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO) ratio and chain length, were co-spray dried with BMS-347070, a COX-2 inhibitor, to form 50/50 (w/w) drug-polymer solid dispersions. The solid dispersions were analyzed by powder X-ray diffraction (PXRD), modulated differential scanning calorimetry (mDSC), and hot-stage microscopy. Average size of drug crystallites in different polymers was calculated by the Scherrer equation based on peak-broadening effect in PXRD. Two other drug compounds, BMS-A and BMS-B, were also spray dried with Pluronic® F127, and the solid dispersions were analyzed by PXRD and mDSC.

Results

The average size of BMS-347070 crystallites in PEG 8000, F127, F108 and F68 polymers was 69, 80, 98 and 136 nm, respectively, and the degree of BMS-347070 crystallinity is the lowest in PEG 8000. Hot-stage microscopy showed that 50/50 drug-polymer dispersions crystallized in a two-step process: a portion of the polymer crystallizes first (Step 1), followed by crystallization of drug and remaining polymer (Step 2). The T _g value of the BMS-347070/Pluronic® dispersions after Step 1 (i.e., T _g1) was measured and/or calculated to be 15–26°C, and that of BMS-347070/PEG 8000 was 60°C. Solid dispersions of BMS-A and BMS-B in Pluronic® F127 have T _g1 of 72 and 3°C, respectively; and PXRD showed BMS-A remained amorphous after ～3 weeks under ambient condition, while BMS-B crystallized in F127 with an average crystallite size of 143 nm.

Conclusions

The size of drug crystallites in the drug-polymer solid dispersions is independent of polymer topology, but is caused kinetically by a combined effect of nucleation rate and crystal growth rate. When drug-Pluronic® solid dispersions crystallize at room temperature, that is close to the T _g1 of the systems, a fast nucleation rate and a relatively slow crystal growth rate of the drug synergistically produced small crystallite size. While the much higher T _g1 value of drug-PEG 8000 led to a slower nucleation rate and an even slower crystal growth rate at room temperature, therefore, small crystallite size and low drug crystallinity were observed. Results from BMS-A/Pluronic® and BMS-B/Pluronic® systems confirmed this kinetic theory.

     

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,...     

A case of accidental ingestion of a salbutamol sulfate inhalant, Venetlin®

Pediatricians examine increasing numbers of children with bronchial asthma every year. In Japan, medical institutions can provide standardized therapies according to the Japanese Pediatric Guideline for the Treatment and Management of Asthma 2005. Inhalation therapy is highly beneficial, and a substantial proportion of patients choose to purchase inhalators and practice inhalation therapy at home. Recently, we experienced a case of accidental ingestion of a salbutamol sulfate inhalant by a non-asthmatic child, which reminded us anew of the importance of managing the medicines for asthma. We also recognized the need to educate patients and their families on the knowledge of these medicines. In this report, we analyze the case and discuss measures that pediatricians can implement to avoid accidental inhalant ingestion by children.     

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.     

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.     

Reformulation of Stmerin® D CFC formulation using HFA propellants

Stmerin^® D was reformulated using hydrofluoroalkanes (HFA-134a and HFA-227) as alternative propellants instead of chlorofluorocarbons (CFCs), where the active ingredients were suspended in mixed CFCs (CFC-11/CFC-12/CFC-114). Here, we report the suspension stability and spray performance of the original CFC formulation and a reformulation using HFAs.

We prepared metered dose inhalers (MDI) using HFAs with different surfactants and co-solvents, and investigated the effect on suspension stability by visual testing. We found that the drug suspension stability was poor in both HFAs, but was improved, particularly for HFA-227, by adding a middle chain fatty acid triglycerides (MCT) to the formulation. However, the vapor pressure of HFA-227 is higher than a CFC mixture and this increased the fine particle dose (FPD). Spray performance was adjusted by altering the actuator configuration, and the performance of different actuators was tested by cascade impaction. We found the spray performance could be controlled by the configuration of the actuator. A spray performance comparable to the original formulation was obtained with a 0.8 mm orifice diameter and a 90° cone angle. These results demonstrate that the reformulation of Stmerin^® D using HFA-227 is feasible, by using MCT as a suspending agent and modifying the actuator configuration.     

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.     

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.     

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.     

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.     

Antimicrobial activity of Ankaferd Blood Stopper® against nosocomial bacterial pathogens

The aim of this study is to investigate the in vitro antimicrobial activity of Ankaferd Blood Stopper® against methicillin-resistant Staphylococcus aureus (MRSA), Enterococcus species, Escherichia coli, Pseudomonas species, Acinetobacter species and Klebsiella species of nosocomial origin. Ankaferd inhibited growth in 72.4% to 100% of the bacteria tested, depending on the type of the isolate. As a result, it can be stated that Ankaferd inhibits the in vitro growth of nosocomial bacteria. This is a novel, important finding since severe hospital infections coexist with many hemostatic disorders, and the use of Ankaferd may increase hemostatic potential in such clinical conditions.