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Positive food effects may be observed for low aqueous soluble compounds, these effects could potentially be circumvented using lipid based formulations. However, as all compounds are not chemically stable in lipid based systems, alternative dosage regimes could be investigated to evade the stability issue. The two aims for this present study were therefore; i) to investigate if a nutritional drink, Fresubin Energy®, could induce food effect in humans for the poorly soluble compound cinnarizine; and ii) to investigate if co-administration of a self-nano-emulsifying drug delivery systems (SNEDDS) with a conventional cinnarizine tablet could reduce the observed food-effect. A commercial conventional cinnarizine tablet was dosed to 10 healthy volunteers in a cross-over design in both fasted and fed state, with and without co-administration of a SNEDDS, with a one week wash-out period between dosing. The fed state was induced using a nutritional drink (Fresubin Energy®) and gastric emptying was assessed by administration of paracetamol as a marker. The pharmacokinetic analysis showed that the nutritional drink delayed the uptake and increased the fraction of absorbed cinnarizine, indicative of a food effect on the compound. This was in agreement with a previous dog study and indicates that the nutritional drink can be used for inducing the same level of food effect in humans. Though not statistically significant, the co-administration of SNEDDS exhibited a tendency towards a reduction of the observed food effect and an increased absorption of cinnarizine in the fasted state; based upon the individual ratios, which was not reflected in the mean data. However, the co-administration of SNEEDS in the fasted state, also induce a slower gastric emptying rate, which was observed as a delayed tmax for both cinnarizine and paracetamol.

This study describes various complications related to sample preparation (filtration) during development of a dissolution method intended to discriminate among different fenofibrate immediate-release formulations. Several dissolution apparatus and sample preparation techniques were tested. The flow-through cell apparatus (USP 4) was found unfit for dissolution testing of fenofibrate MeltDose formulations due to clogging of filters and varying flow rates. A mini paddle dissolution setup produced dissolution profiles of the tested formulations that correlated well with clinical data. The work towards the mini paddle dissolution method demonstrates that sample preparation influenced the results. The investigations show that excipients from the formulations directly affected the drug–filter interaction, thereby affecting the dissolution profiles and the ability to predict the in vivo data. With the tested drug–formulation combination, the best in vivo–in vitro correlation was found after filtration of the dissolution samples through 0.45-μm hydrophobic PTFE membrane filters.

This study investigated the oral absorption of drugs in minipigs to predict food effects in man. The protocol was based on a previously described model in dogs and further investigated the food source (i.e., US FDA breakfast or a nutritional drink) and food quantities. Two poorly soluble compounds were investigated [pravastatin (negative food effect) and atazanavir (positive food effect)] in Göttingen minipigs after seven different food regimens. The gastric emptying rate was evaluated by coadministration of acetaminophen. In short, the results demonstrated longer gastric emptying times in minipigs when compared with humans, within a range from 2.3 to 8.4 h dependent on the food regimen. There were no significant differences in drug absorption between fed and fasted state for the two compounds. The study showed that the dog protocol could not be transferred directly to minipigs, but needs further investigation and adjustments in order to get a valid model using Göttingen minipigs for the evaluation of food effects on drug absorption in humans.

Poly(lactic-co-glycolic acid) (PLGA) microspheres containing celecoxib were prepared via electrospraying, and the influence of three processing parameters namely flow rate, solute concentration and drug loading, on the physico-chemical properties of the particles and the drug-release profile was studied. Microspheres with diameters between 2 and 8 μm were produced and a near-monodisperse size distribution was achieved (polydispersivity indices of 6–12%). Further, the inner structure of the particles showed that the internal porosity of the particles increased with increasing solvent concentration. X-ray powder diffraction (XRPD) analysis indicated that the drug was amorphous and remained stable after eight months of storage. Drug release was studied in USP 2 (United States Pharmacopeia Dissolution Apparatus 2) dissolution chambers, and differences in release profiles were observed depending on the parametric values. Changes in release rate were found to be directly related to the influence of the studied parameters on particle size and porosity. The results indicate that electrospraying is an attractive technique for producing drug-loaded microspheres that can be tailored towards an intended drug-delivery application. Compared with the more conventional spray-drying process, it provides better control of particle characteristics and less aggregation during particle formation. In particular, this study demonstrated its suitability for preparing capsules in which the drug is molecularly dispersed and released in a sustained manner to facilitate improved bioavailability.

Microparticles were fabricated for pharmaceutical purposes using electrospraying with the aim to determine the effect of the solvent(s) used. Particles of poly(lactic-co-glycolic acid) (PLGA) and the drug Celecoxib were prepared from acetone, acetonitrile and acetone:methanol with different polymer and drug concentrations. The solvent power, evaporation rate and electrical conductivity of the solvents all had a significant effect on the particle formation process as well as the particle characteristics and drug release profile. Particles were near-spherical and between 2 and 7 μm in diameter with smooth or corrugated surfaces. The drug release rate was mainly dependent on particle size, with larger particles showing slower release. The solvent in which PLGA was poorly soluble resulted in small grainy particles that disintegrated instantaneously with full drug release. It may be concluded that the selection of an appropriate solvent may be a useful way to control particle characteristics and drug release profiles when using electrospraying. © 2012 Elsevier Ltd. All rights reserved.

Micro- and nanoparticle formulations are widely used to improve the bioavailability of low solubility drugs. In this study, electrospraying is introduced as a method for producing drug-loaded microspheres at ambient conditions. PLGA microspheres containing celecoxib, a low solubility drug, were prepared with the objective of producing near-monodisperse microspheres with the drug in a stable amorphous form. We found that it is possible to produce near-monodisperse celecoxib-loaded PLGA microspheres at different polymer:drug ratios. The microspheres produced were in the size range 1-5 μm depending on the polymer:drug ratio and had smooth surfaces. Thermal analysis further indicates that celecoxib is present in an amorphous form inside the microspheres. Drug dissolution studies showed an initial burst release followed by a period of sustained release with the dissolution curve depending on the polymer:drug ratio. Electrospraying is thus a promising method for producing amorphous microspheres of low solubility drugs such as celecoxib. The microsphere properties may be further optimized to achieve an appropriate dissolution profile with the aim of increasing oral bioavailability of low solubility drugs.

Because of increased environmental pressure, there is currently a movement away from more traditional refrigerants such as HCFC's toward refrigerants with lower global warming potential such as carbon dioxide (CO2). However, the use of CO2 as a refrigerant requires a refrigeration cycle with greater extremes of pressure, placing greater demands on the polymer materials used for seals and packing. In this work we have measured the solubility and diffusivity of gaseous CO2 in two polymers used as sealing materials in CO2 refrigeration plants. These are Hydrogenated Nitrile Butadiene Rubber (HNBR) and Ethylene Propylene Diene Monomer (EPDM) which are used in seals such as O-rings. The experiments were performed on a high-pressure microbalance. Solubility results were modelled using an equation of state for polymers (simplified PC-SAFT). The necessary polymer parameters were obtained using a previously published method. The measured results can be successfully correlated using simplified PC-SAFT.

The purpose of this study was to examine the suitability of polystyrene-coated (PS-coated) microcapsules of drug-resin complex for achieving prolonged release of diltiazem-HCl, a highly water-soluble drug, in simulated gastric and intestinal fluid. The drug was bound to Indion 254, a cation-exchange resin, and the resulting resinate was microencapsulated with PS using an oil-in-water emulsion-solvent evaporation method. The effect of various formulation parameters on the characteristics of the microcapsules was studied. Mean diameter and encapsulation efficiency of the microcapsules rose with an increase in the concentration of emulsion stabilizer and the coat/core ratio, while the same characteristics tended to decrease with an increase in the volume of the organic disperse phase. The desorption of drug from the uncoated resinate was quite rapid and independent of the pH of the dissolution media. On the other hand, the drug release from the microcapsules was prolonged for different periods of time depending on the formulation parameters and was also found to be independent of the pH of the dissolution media. Both the encapsulation efficiency and the retardation of drug release were found to be dependent on the uniformity of coating, which in turn was influenced by the formulation parameters. Kinetic studies revealed that the desorption of drug from the resinate obeyed the typical particle diffusion process, whereas the drug release from the microencapsulated resinate followed the diffusion-controlled model in accordance with the Higuchi equation. PS appeared to be a suitable polymer to provide prolonged release of diltiazem independent of the pH of the dissolution media.

Effervescent atomizers belong to the group of internal mixing atomizers. The effervescent approach might be a potential alternative to traditional atomization techniques, e.g., for applications where low atomization air consumption is advantageous In this paper, performance of one proposed design of the effervescent atomizer is investigated and compared to that of a standard pneumatic atomizer. The purpose of the comparison is to evaluate the actual potential of the specific effervescent atomizer in pharmaceutical relevant aqueous coating applications. Aqueous solutions of Hypromellose 5 as well as Povidone K-90F were characterized in terms of rheological properties and surface tension. Solutions were atomized by means of a standard Schlick pneumatic atomizer as well as a customized inside-out type effervescent atomizer. Spray droplet size distributions were recorded by a Spraytec instrument. Increased shear viscosity in the range 24-836 mPa.s had a modest effect on spray mean diameters for pneumatic sprays of the Newtonian solutions of Hypromellose 5. In contrast, mean droplet diameters increased by a factor of 3-5 in pneumatic sprays of Povidone K-90F solutions 11-175 mPa.s in viscosity, where non-Newtonian behavior was observed. Further, sprays of all solutions of Povidone K-90F have considerably larger mean droplet size. The effervescent atomizer atomized low viscosity solutions of Povidone K-90F more efficiently than Hypromellose 5 solutions of corresponding shear viscosity. However, atomization of high viscosity Povidone K-90F results in a coarser spray than that of the corresponding Hypromellose 5 solution. Viscosity, visco-elasticity, and surface tension of solutions all seem to affect atomization efficiency. The pneumatic atomizer was not sensitive to changes in airflow above 8.4 kg/h and liquid flow only had a considerable effect at suboptimal air flows. In its current design the effervescent atomizer improved efficiency throughout the investigated range of air flow of 0.18-0.84 kg/h and consistently produced smaller drops at liquid flow of 10 g/min compared to 35 g/min. In spite of the very low level of air consumption, the effervescent atomizer can produce fine sprays. Within its working range, the standard pneumatic atomizer, however, is capable of producing sprays of even smaller mean droplet size. All together this suggests the described effervescent atomizer as an alternative for applications where advantages of reduced atomization air flow outweigh the disadvantages of a less fine spray, e.g., in coating of attrition-prone substrate.

The giant sarcomeric protein titin contains a protein kinase domain (TK) ideally positioned to sense mechanical load. We identified a signaling complex where TK interacts with the zinc-finger protein nbr1 through a mechanically inducible conformation. Nbr1 targets the ubiquitin-associated p62/SQSTM1 to sarcomeres, and p62 in turn interacts with MuRF2, a muscle-specific RING-B-box E3 ligase and ligand of the transactivation domain of the serum response transcription factor (SRF). Nuclear translocation of MuRF2 was induced by mechanical inactivity and caused reduction of nuclear SRF and repression of transcription. A human mutation in the titin protein kinase domain causes hereditary muscle disease by disrupting this pathway.

Selection of excipients for drug formulations requires both intellectual and experimental considerations as many of the used excipients are affected by physiological factors, e.g., they may be digested by pancreatic enzymes in the gastrointestinal tract. In the present paper we have looked systematically into the differences between Kolliphor ELP, EL, and RH40 and how they affect the bioavailability of fenofibrate, through pharmacokinetic studies in rats and in vitro lipolysis studies. The study design was made as simple as possible to avoid confounding factors, for which reason the tested formulations only comprised an aqueous micellar solution of the model drug (fenofibrate) in varying concentrations (2-25% (w/v)) of the three tested surfactants. Increased concentrations of Kolliphor ELP and EL led to increased fenofibrate AUC0-24h values. For the Kolliphor RH40 formulations, an apparent fenofibrate absorption optimum was seen at 15% (w/v) surfactant, displaying both the highest AUC0-24h and Cmax. The reduced absorption of fenofibrate from the formulation containing the highest level of surfactant (25% w/v) was thought to be caused by some degree of trapping within Kolliphor RH40 micelles. In vitro, Kolliphor ELP and EL were found to be more prone to digestion than Kolliphor RH40, though not affecting the in vivo results. The highest fenofibrate bioavailability was attained from formulations with high Kolliphor ELP/EL levels (25% (w/v)), indicating that these surfactants are the better choice for solubilizing fenofibrate in order to increase the absorption upon oral administration. Due to drug dependent effects of the different types of Kolliphor, more studies are recommended in order to understand which type of Kolliphor is best suited for a given drug.

The aim of the present work was to formulate fast-disintegrating pellets by direct pelletization in a rotary processor. Formulations containing kaolin or bentonite and lactose were agglomerated with or without the addition of crospovidone in an instrumented rotary processor. The effects of the excipients on the amount of wall adhesion, the size and size distribution, the disintegration time, and the shape of the agglomerates, as well as the content of agglomerates > 2800 microns, were investigated. Further, pellets containing a model drug having a low aqueous solubility were prepared, and the drug dissolution profile was compared to that of pellets containing microcrystalline cellulose (MCC). Formulations containing kaolin resulted in fast-disintegrating pellets. Pellets containing bentonite eroded, but did not disintegrate, and the formulations gave rise to large amounts of wall adhesion. The addition of crospovidone increased the water content at the end of liquid addition for all formulations, and resulted in slightly more spherical agglomerates. When comparing formulations containing kaolin and MCC, kaolin gave rise to wider size distributions and a higher amount of agglomerates > 2800 microns, but the drug dissolution rate was much faster. Complete (100%) drug release was seen after 8 min with the kaolin formulation, whereas only 40% was released after 2 hr from the MCC formulation.

Microparticles of Celecoxib, dispersed in a matrix of poly(lactic-co-glycolic acid) (PLGA), were pre- pared by electrospraying using different solvent mixtures to investigate the influence upon particle formation and the resulting particle characteristics. Mixtures consisting of a good solvent, acetone, and an anti-solvent, methanol, for PLGA were studied in different ratios. Properties of the spraying solutions were examined and the resulting mi- croparticles were characterized with regard to size, mor- phology, porosity, solid state form, surface chemistry and drug release. Particle formation was strongly influenced by the polymer molecular conformation during droplet for- mation and by the anti-solvent concentration during droplet drying. A strong correlation was found between particle morphology and the solubility of the polymer in the solvent mixtures. The lack of chain entanglements in droplets containing anti-solvent resulted in compact polymer conformation and grain-like particle morphology. Further, the early precipitation of polymer and low chain interaction with increasing content of anti-solvent resulted in surface enrichment of drug (from 10 and 20 % up to 41 and 57 % respectively), also demonstrated by the increasingly higher drug release rates. The results demonstrate the importance of solvent composition in particle preparation and indicate potential for exploiting this dependence to improve phar- maceutical particle design and performance.

The aim of this study was to elucidate the feasibility of using torque measurement to control the end point of a wet pelletization process in a rotary processor at varying levels of friction plate rotation speed, air gap pressure difference, and batch size. A 1:1 mixture of lactose monohydrate (200 mesh) and microcrystalline cellulose (PH-101) was granulated into pellets in an instrumented laboratory scale rotary processor using water as aqueous binder liquid. A full factorial designed study was performed to investigate the influence of the friction plate rotation speed (600 and 1200 rpm), the air gap pressure difference (1 and 3 kPa), the torque increase (0.4 and 0.8 N.m) and the batch size (500 and 1000 g) on the pellet properties. All pellets produced were round and showed a narrow size distribution. The geometric mean diameter varied from 400 to 1900 microns with a good reproducibility. Increasing the batch size and the rotation speed led to smaller pellets, whereas a higher torque produced larger pellets. This study showed that the process can be controlled by means of the torque increase because it was possible to produce pellets of a reproducible size by stopping the liquid addition at a certain torque level.

Here, we report the synthesis and characterization of an HPMA-based polymer for use as a carrier for the delivery of water soluble drugs. The polymer contains active-sulfhydryl groups for coupling of ligands through a disulfide linkage. The polymer can also be prepared containing pendant amino groups in addition to the active-sulfhydryl moiety. This allows the use of different chemistries to conjugate a variety of ligands to the polymer. We demonstrate that a sulfhydryl-terminated antisense oligonucleotide can be efficiently and rapidly conjugated to the polymer. The polymer-oligonucleotide conjugate is efficiently taken up by cultured cells.

The present study aims at evaluating the ability of a gastro-intestinal in vitro lipolysis model to predict the performance of two lipid formulations and a conventional tablet containing a poorly soluble drug, cinnarizine, in dogs, both in the fasted and fed state. A self-nano-emulsifying drug delivery system (SNEDDS) was either dosed in a hard gelatin capsule (SNEDDS-C) or loaded onto a porous tablet core (SNEDDS-T) and compared to a marketed conventional tablet (Conv) in an in vitro lipolysis model. The model simulates the digestion in the stomach and intestine during either the fasted or the fed state. Whole fat milk (3.5%) was used in the fed state model to mimic the dynamic lipolysis events after ingestion of food. The results were compared to a dog study published in this issue. In the fasted state in vitro lipolysis model, the amount of solubilized cinnarizine decreased in the order SNEDDS-C > SNEDDS-T > Conv, which correlated well with the in vivo bioavailability. In the fed state in vitro lipolysis model, cinnarizine was solubilized to the same degree for all formulations. Compared to the fasted state model, only the performance of the conventional tablet was improved, indicating food effect. This correlated with the in vivo study, where the tablet was the only formulation with a significant food effect. The fasted state model correlated well with the in vivo results and although the fed state model did not accurately predict the fed state in vivo results, it could predict which formulation that would exhibit a food effect.

Purpose To elucidate if a SNEDDS approach can eliminate the food-effect on cinnarizine absorption and to, investigate if a nutritional drink, Fresubin energy, could mimic food effect in dogs for the poorly soluble compound cinnarizine. Method A conventional tablet, a SNEDDS capsule or a SNEDDS tablet, containing cinnarizine, were dosed to beagles dogs in fed or fasted state ( n = 5), with a one week wash-out period between dosing. Dogs were pre-treated with pentagastrin. Fed state was induced by a nutritional drink (Fresubin Energy®). The food-effect was evaluated by comparing T max , C max and Bioavailability ( F ) for the different formulations. Results Food effect was observed on all three parameters for the conventional tablet; T max was delayed 2.5 times and bioavailability increased in fed state (from 20.9 ± 5.7 to 53.8 ± 30.1). Apart from an extended T max (2.5 and 3.3 times longer in fed state compared to fasted state for the SNEDDS tablets and SNEDDS capsules respectively), food effect on absorption for the SNEDDS capsules and SNEDDS tablets was not observed. The SNEDDS capsules had a higher bioavailability in both fed and fasted state compared to SNEDDS tablets ( F fasted = 58.1 ± 16.7, vs. 32.7 ± 11.5), ( F fed = 79.3 ± 14.7 vs. 43.7 ± 6.7) There were no significant differences in bioavailability between the conventional tablet in fed state and the SNEDDS capsules. Conclusion Food effect was observed when dosing cinnarizine with ingestion of the nutritional drink Fresubin Energy. Food effect on cinnarizine could be significantly reduced by dosing either as a SNEEDS capsule or a SNEDDS tablet, however, the SNEDDS tablet resulted in an overall lower absorption than the SNEDDS capsules in both fed and fasted state. The delay in fed state absorption could not be changed by dosing with SNEDDS formulations.

Introduction Exercise-based rehabilitation programmes have formed the cornerstone of the treatment currently delivered at the Defence Medical Rehabilitation Centre (DMRC) based at Headley Court.Increased operational activity in recent years has meant a concomitant increase in the pressure on Defence rehabilitation resources and a greater need for effective rehabilitation strategies. The aim of this research was to assess the effects of exercise-based rehabilitation on energy expenditure and body composition. Methods A group of nine male volunteers (30±2.4 years) serving with the Armed Forces and suffering from a variety of musculoskeletal lower limb injuries underwent 17 days of exercise-based rehabilitation. Total daily energy expenditure (TEE) was assessed using a portable combined heart rate monitor/accelerometer (Actiheart).Changes in body composition were assessed using dual energy x-ray absorptiometry (DEXA). Results MeanTEE over the entire admission period was 2915±53 kcal/day with no significant difference in TEE observed between training week 1 (W1) and 2 (W2). However, a strong trend towards increased TEE in W1 was observed (p=0.06). No significant change was observed in fat mass (FM), lean body mass (LBM) or body-fat percentage despite the exercise-based rehabilitation programme. Conclusions These results suggest that 17 days of exercise-based rehabilitation is insufficient to observe significant changes in body composition, despite high energy expenditure.

Introduction Resistance training is an important component of rehabilitation due to its ability to increase muscular strength and enhance functional ability. The aim of this study was to assess the effects of two different resistance-training programmes currently used in military rehabilitation. Method 27 male rehabilitation patients, serving with the Armed Forces and suffering from a range of lower limb musculoskeletal injuries were divided into two matched groups. Group 1 (n=14) performed the Daily Adjusted Progressive Resistance Exercise (DAPRE), whereas Group 2 (n=13) performed the Functional Strength Training (FST). An 8 repetition maximum (8RM) deadlift and countermovement vertical jump (CMVJ) test were used as Functional Assessment Tests (FATs) and as measures of changes in strength and power, respectively. Both were conducted on admission and at discharge. Results Lower limb strength and power increased significantly in both the DAPRE (p≤0.001/p≤0.001) and the FST (p≤0.001/0.001) groups. There was no significant difference between groups for either strength (p≥0.05) or power (p≥0.05). Conclusions Short-term resistance training during rehabilitation can lead to gains in strength and power despite differences in programme design. However we conclude that three weeks of resistance training is insufficient duration to see significant differences between different training protocols.

Objective: To examine the effects of a goal setting intervention on self-efficacy, treatment efficacy, adherence and treatment outcome in patients undergoing low back pain rehabilitation. Design: A mixed-model 2 (time) × 3 (group) randomized controlled trial. Setting: A residential rehabilitation centre for military personnel. Subjects: UK military personnel volunteers ( N = 48); mean age was 32.9 (SD 7.9) with a diagnosis of non-specific low back pain. Interventions: Subjects were randomly assigned to either a goal setting experimental group (Exp, n = 16), therapist-led exercise therapy group (C1, n = 16) or non-therapist-led exercise therapy group (C2, n = 16). Treatment duration for all groups was three weeks. Main measures: Self-efficacy, treatment efficacy and treatment outcome were recorded before and after the treatment period. Adherence was rated during regularly scheduled treatment sessions using the Sports Injury Rehabilitation Adherence Scale (SIRAS). The Biering-Sørensen test was used as the primary measure of treatment outcome. Results: ANCOVA results showed that adherence scores were significantly higher in the experimental group (13.70 ± 1.58) compared with C2 (11.74 ± 1.35), ( P < 0.025). There was no significant difference for adherence between the experimental group and C1 ( P = 0.13). Self-efficacy was significantly higher in the experimental group compared to both C1 and C2 ( P < 0.05), whereas no significant difference was found for treatment efficacy. Treatment outcome did not differ significantly between the experimental and two control groups. Conclusions: The findings provide partial support for the use of goal setting to enhance adherence in clinical rehabilitation.

Objective To review the effi cacy of resistance training (RT) as a therapeutic modality in various musculoskeletal conditions. Design Systematic review. Subjects Data from 1545 rehabilitation patients who had participated in structured RT programmes were included into the review. The total number of patients was composed of separate musculoskeletal conditions—chronic low back pain (CLBP) (549), tendinopathy (299), knee osteoarthritis (433), anterior cruciate ligament reconstruction (189) and hip replacement surgery (75). Results Evidence suggests that RT can increase muscle strength, reduce pain and improve functional ability in patients suffering from CLBP, knee osteoarthritis, and chronic tendinopathy and those under recovery after hip replacement surgery. Conclusion RT can be used successfully as a therapeutic modality in several musculoskeletal conditions, especially those of a chronic variety. Although the exact application of training intensity and volume for maximal therapeutic effects is still unclear, it appears that RT guidelines, which have proven effective in a healthy population, can also be successfully applied in a rehabilitation context.

Obtaining a stable formulation with high bioavailability of a poorly water-soluble drug often presents a challenge to the formulation scientist. Transformation of the drug into its more soluble high-energy amorphous form is one method used for improving the dissolution rate of such compounds. The present study uses the spray-drying technique for preparation of solid dispersions (SDs) of tolfenamic acid (TA) and polyvinylpyrrolidone K-30 (PVP). The SDs and TA in the form of a spray-dried powder were initially characterized and compared with a physical mixture and starting materials. Stability of the SDs was monitored over 12 weeks at 25 degrees C and 60% RH. XRPD studies revealed changes in solid state during the formation of the SDs and indicated the presence of TA in the amorphous state. FTIR, together with TGA, suggested molecular interactions (hydrogen-bonding) in the SDs. Dissolution studies proved an increase in the dissolution rate of TA from all SDs. The SDs with higher content of PVP retained TA in the amorphous state throughout the stability study. However, SDs with lower content showed recrystallization of TA after 1 week. Thus, this study reveals the possibility of preparing stable SDs of amorphous TA in PVP with improved dissolution rate.

The aim of the present study was to investigate and compare granule and tablet properties of granules prepared by wet granulation in a rotary processor or a conventional fluid bed. For this purpose the working range of selected process variables was determined and a factorial study with 3 factors (equipment type, filler type, and liquid addition rate) and 1 covariate (fluidizing air flow rate) was performed. Two grades of calcium carbonate with different size and shape characteristics were applied, and the liquid addition and fluidizing air flow rates were investigated in the widest possible range. Dry mixtures of microcrystalline cellulose, polyvinyl povidone, calcium carbonate, and riboflavin, in a 10∶5∶84∶1 ratio, were granulated in both types of equipment. The granulation end point was determined manually in the fluid bed and by torque measurements in the rotary processor. The filler type had a more pronounced effect on granular properties in the fluid bed, but the rotary processor showed a higher dependency on the investigated process variables. The rotary processor gave rise to more dense granules with better flow properties, but the fluid bed granules had slightly better compressional properties. Furthermore, the distribution of a low-dose drug was found to be more homogeneous in the rotary processor granules and tablets. Generally, wet granulation in a rotary processor was found to be a good alternative to conventional fluid bed granulation, especially when cohesive powders with poor flow properties or formulations with low drug content are to be granulated by a fluidizing air technique.

The aim of the present study was to investigate the use of different grades of microcrystalline cellulose (MCC) and lactose in a direct pelletization process in a rotary processor. For this purpose, a mixed 2- and 3-level factorial study was performed to determine the influence of the particle size of microcrystalline cellulose (MCC) (approximately 60 and 105 microm) and lactose (approximately 30, 40, and 55 microm), as well as MCC type (Avicel and Emcocel) on the pelletization process and the physical properties of the prepared pellets. A 1:4 mixture of MCC and lactose was applied, and granulation liquid was added until a 0.45 Nm increase in the torque of the friction plate was reached. All combinations of the 3 factors resulted in spherical pellets of a high physical strength. The particle size of MCC was found to have no marked effect on the amount of water required for agglomerate growth or on the size of the resulting pellets. An increasing particle size of lactose gave rise to more spherical pellets of a more narrow size distribution as well as higher yields. The MCC type was found to affect both the release of the model drug from the prepared pellets and the size distribution. Generally, the determined influence of the investigated factors was small, and direct pelletization in a rotary processor was found to be a robust process, insensitive to variations in the particle size and type of MCC and the particle size of lactose.

The purpose of this study was to investigate the effect of the airflow, the binder concentration, the massing time, the friction plate rotation speed, and the surface structure of the friction plate on melt pelletization in a laboratory scale rotary processor. Lactose monohydrate was melt agglomerated with polyethylene glycol (PEG) 3000 as meltable binder. The study was performed as a full factorial design. An increase in agglomerate size was found when the binder concentration, the massing time, or the friction plate rotation speed was increased. The agglomerate size was also increased when increasing the shearing forces by using a friction plate with a different surface structure. The size distribution of the agglomerates was significantly narrowed when the binder concentration or the shearing forces caused by the friction plate were increased. An increase in the adhesion of material to the friction plate was found when the shearing forces of the friction plate were increased either by the rotation speed or by the surface structure. Generally, the rotary processor was found to be a suitable alternative to melt pelletization in a high shear mixer.

In the present study we investigated the effect of changes in the content of microcrystalline cellulose (MCC) on a direct pelletization process in a rotary processor in which the liquid addition was terminated once a certain increase in torque was produced. Nine different mixtures of MCC and lactose with MCC contents varying from 10% to 100% (w/w) were pelletized using 6 different torque increase levels, and the changes in pellet characteristics were investigated. The pellet characteristics investigated were pellet shape, size, and size distribution as well as the water content of the pellets at the end of liquid addition. To produce spherical agglomerates with suitable characteristics in a reproducible way, a content of at least 20% (w/w) MCC was found necessary. Linear correlations were found between the MCC content and the water content and between the torque increase and the water content, showing that the torque increase is suitable to control the process. A higher torque increase or a higher MCC content was found to increase the water content independently of each other.

Novel AspectAll major protein repositories integrated into a central domain for direct analyses and interpretation in a standard proteomics data analysis software. IntroductionModern proteomics must face the challenge of performing bioinformatics analysis and comparison of large datasets. It is a time consuming and at times nearly impossible task to distinguish known proteins from novel proteins in these data sets without proper annotation and comparison with literature sources. Tools are needed that can handle the complexity of these data including: redundancy (same protein but different accession codes), different protein database accession codes or outdated accession codes and protein annotation. To resolve these issues we have developed a consolidated proteomics database providing annotations to Proteome Discoverer via direct integrated web service technology – a repository that enables efficient data mining and categorizing of large data sets. MethodsAll samples were analyzed on an Orbitrap mass Spectrometer coupled to a nano Easy LC.The proteomics repository database is built using the Sun Java technology and the Microsoft mySQL database technology for optimal performance. Proteome Discoverer version 1.3 is used for database searching and is directly integrated with the proteomics repository.Preliminary DataOur proteomics database contains public sequence databases to form a comprehensive and consistent superset of 13 million protein sequences derived from over 100 million protein records from GenBank, Refseq, EMBL, Flybase, UniProt, Wormbase, Swiss-Prot, Trembl, PIR, IPI, PDB, Ensembl etc., including more than 10 million outdated accession numbers. Proteins are richly annotated by consolidation of annotations from public databases together with high-standards annotation from internal computational enrichment of the sequence data. The integrated database is constantly updated depending on its source, enabling tracking of outdated accession keys. Preliminary results from a comparison of protein annotation coverage in UniProt, NCBI and our proteomics repository on frequently used model organisms’ shows that collecting unique annotation information from multiple sources significantly increases the protein annotation coverage in human, mouse, yeast, C. elegans and E. coli. A quantitative stable isotope labeling proteomics study comparing wild type C. elegans and a nuclear hormone receptor 49 mutant is used as a case study to display the importance of using a consolidated Proteomics repository.