Abstract. The purpose of this work was to characterize theophylline (THF) cocrystals prepared by spray drying in terms of the physicochemical properties and inhalation performance when aerosolized from a dry powder inhaler. Cocrystals of theophylline with urea (THF-URE), saccharin (THF-SAC) and nicotinamide (THF-NIC) were prepared by spray drying. Milled THF and THF-SAC cocrystals were also used for comparison. The physical purity, particle size, particle morphology and surface energy of the materials were determined. The in vitro aerosol performance of the spray-dried cocrystals, drug-alone and a drugcarrier aerosol, was assessed. The spray-dried particles had different size distributions, morphologies and surface energies. The milled samples had higher surface energy than those prepared by spray drying. Good agreement was observed between multi-stage liquid impinger and next-generation impactor in terms of assessing spray-dried THF particles. The fine particle fractions of both formulations were similar for THF, but drug-alone formulations outperformed drug-carrier formulations for the THF cocrystals. The aerosolization performance of different THF cocrystals was within the following rank order as obtained from both drug-alone and drug-carrier formulations: THF-NIC>THF-URE>THF-SAC. It was proposed that micromeritic properties dominate over particle surface energy in terms of determining the aerosol performance of THF cocrystals. Spray drying could be a potential technique for preparing cocrystals with modified physical properties.
Multilamellar and oligolamellar liposomes were produced from ethanol-based soya phosphatidylcholine proliposome formulations by addition of isotonic sodium chloride or sucrose solutions. The resultant liposomes entrapped up to 62% of available salbutamol sulfate compared with only 1.23% entrapped by conventionally prepared liposomes. Formulations were aerosolized using an air-jet nebulizer (Pari LC Plus) or a vibrating-mesh nebulizer (Aeroneb Pro small mesh, Aeroneb Pro large mesh, or Omron NE U22). All vibrating-mesh nebulizers produced aerosol droplets having larger volume median diameter (VMD) and narrower size distribution than the air-jet nebulizer. The choice of liposome dispersion medium had little effect on the performance of the Pari nebulizer. However, for the Aeroneb Pro small mesh and Omron NE U22, the use of sucrose solution tended to increase droplet VMD, and reduce aerosol mass and phospholipid outputs from the nebulizers. For the Aeroneb Pro large mesh, sucrose solution increased the VMD of nebulized droplets, increased phospholipid output and produced no effect on aerosol mass output. The Omron NE U22 nebulizer produced the highest mass output (approx. 100%) regardless of formulation, and the delivery rates were much higher for the NaCl-dispersed liposomes compared with sucrose-dispersed formulation. Nebulization produced considerable loss of entrapped drug from liposomes and this was accompanied by vesicle size reduction. Drug loss tended to be less for the vibrating-mesh nebulizers than the jet nebulizer. The large aperture size mesh (8 m) Aeroneb Pro nebulizer increased the proportion of entrapped drug delivered to the lower stage of a twin impinger. This study has demonstrated that liposomes generated from proliposome formulations can be aerosolized in small droplets using air-jet or vibrating-mesh nebulizers. In contrast to the jet nebulizer, the performance of the vibrating-mesh nebulizers was greatly dependent on formulation. The high phospholipid output produced by the nebulizers employed suggests that both airjet and vibrating-mesh nebulization may provide the potential of delivering liposome-entrapped or solubilized hydrophobic drugs to the airways.
Abbreviations: (ICU) intensive care unit, (PE) polyethylene, (TGC) tight glycemic controlKeywords: blood glucose, critically ill, insulin, tight glycemic control We aimed to explore the impact of insulin adsorption onto infusion sets in the laboratory and to assess retrospectively if higher insulin doses are required after syringe changes in practice in the ICU. �dsorption is reported to occur �dsorption is reported to occur predominantly during the first hour of infusion, after which binding sites are saturated. 5 There is greater insulin recovery with faster flow rates and higher insulin concentration. 6 The clinical significance of such adsorption in the ICU setting is uncertain. 5In our study-approved by the local ethics committee-adsorption of insulin onto the giving sets used in our adult of insulin onto the giving sets used in our adult ICU was analyzed. The infusion set used was a 5�� ml polypropylene syringe (BD PlastipakThe infusion set used was a 5�� ml polypropylene syringe (BD Plastipak ® ) and 1.6 ml/2���� cm polyethylene (PE) tubing (Cardinal Health, extension set). In the laboratory, the concentration investigated was 1 U/ml (PE) tubing (Cardinal Health, extension set). In the laboratory, the concentration investigated was 1 U/ml In the laboratory, the concentration investigated was 1 U/ml of neutral insulin in sodium chloride ��.9%. The concentrations were determined using a high�performance liquidThe concentrations were determined using a high�performance liquid high�performance liquid chromatography method with a Jupitor 3����, 5 method with a Jupitor 3����, 5 with a Jupitor 3����, 5 μm C18, 25�� mm x 4.6 mm column (Phenomenex), a mobile phase of ), a mobile phase of , a mobile phase of 30% acetonitrile and 0.1% TFA in water, and ultraviolet detection at �10 nm. �ignificant insulin adsorption of 10% ultraviolet detection at �10 nm. �ignificant insulin adsorption of 10% �ignificant insulin adsorption of 10% �ignificant insulin adsorption of 10% occurred during the first hour of an infusion when the infusion rate was 1 ml�h ( of an infusion when the infusion rate was 1 ml/h ( of an infusion when the infusion rate was 1 ml/h (Figure 1). Our experience suggests that this is a common infusion rate used in intensive insulin therapy. �o significant adsorption occurred when the infusion �o significant adsorption occurred when the infusion rate was 4 ml/h, although a trend could be seen with solution leaving the PE tubing at the beginning of the time period having a lower insulin concentration, which increased with time.The infusion rates used before and after an infusion set change were investigated for 1�� ICU patients known to were investigated for 1�� ICU patients known to have been managed with a TGC protocol, aiming for glycemia of 4.4-6.1 mmol/liter, to examine any relationship between the duration of usage of the infusion set and the variation in insulin dosing required. These patients were . These patients were not prescribed drugs known to affect glucose control, such as inotropes and corti...
Nucleotides and nucleosides are not only involved in cellular metabolism but also act extracellularly via P1 and P2 receptors, to elicit a wide variety of physiological and pathophysiological responses through paracrine and autocrine signalling pathways. For the first time, we have used an ion-pair reversed-phase high-performance liquid chromatography ultraviolet (UV)-coupled method to rapidly and simultaneously quantify 12 different nucleotides and nucleosides (adenosine triphosphate, adenosine diphosphate, adenosine monophosphate, adenosine, uridine triphosphate, uridine diphosphate, uridine monophosphate, uridine, guanosine triphosphate, guanosine diphosphate, guanosine monophosphate, guanosine): (1) released from a mouse renal cell line (M1 cortical collecting duct) and (2) in human biological samples (i.e., urine). To facilitate analysis of urine samples, a solid-phase extraction step was incorporated (overall recovery rate ≥ 98 %). All samples were analyzed following injection (100 μl) into a Synergi Polar-RP 80 Å (250 × 4.6 mm) reversed-phase column with a particle size of 10 μm, protected with a guard column. A gradient elution profile was run with a mobile phase (phosphate buffer plus ion-pairing agent tetrabutylammonium hydrogen sulfate; pH 6) in 2–30 % acetonitrile ( v/v ) for 35 min (including equilibration time) at 1 ml min −1 flow rate. Eluted compounds were detected by UV absorbance at 254 nm and quantified using standard curves for nucleotide and nucleoside mixtures of known concentration. Following validation (specificity, linearity, limits of detection and quantitation, system precision, accuracy, and intermediate precision parameters), this protocol was successfully and reproducibly used to quantify picomolar to nanomolar concentrations of nucleosides and nucleotides in isotonic and hypotonic cell buffers that transiently bathed M1 cells, and urine samples from normal subjects and overactive bladder patients. Electronic supplementary material The online version of this article (doi:10.1007/s11302-012-9321-8) contains supplementary material, which is available to authorized users.
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