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1.
Tommaso Iannitti Julio César Morales-Medina Alessandro Coacci Beniamino Palmieri 《Pharmaceutical research》2016,33(12):2879-2890
Background
In the field of aesthetic medicine there is an increasing demand for safe and effective hyaluronic acid (HA) fillers to counteract the aging process.Methods and Aims
We designed a study to evaluate the safety and histological biocompatibility of Aliaxin® Global Performance, a cross-linked HA filler and Viscoderm® Skinkò E, a product composed of non-cross-linked HA and a complex including vitamins, antioxidants, amino acids and minerals injected into the skin of guinea pigs. Then, we translated our findings into the clinical setting, administering a combination of these compounds to patients seeking a facial rejuvenation procedure targeting moderate-to-severe wrinkles affecting the nasolabial folds.Results
The animal study showed that the two compounds did not induce any significant inflammatory reactions and increased collagen and elastic fibers in the skin. In the clinical setting, injection of Aliaxin® Global Performance, followed by Viscoderm® Skinkò E, resulted in a higher improvement in nasolabial fold hydration, trans-epidermal water loss and wrinkle aesthetic appearance, if compared with a protocol based on Aliaxin® Global Performance alone.Conclusion
In summary, we show evidence on the safety and mechanism underlying two new HA-based compounds of different cross-linkage and composition, proposing that they can be safely used in combination in patients seeking facial rejuvenation procedures with long-lasting efficacy.2.
Aim
To develop age- and gender-specific normative values for the physical function subscales of the WOMAC® and AUSCAN Indices.Methods
A scannable survey questionnaire capable of capturing WOMAC® and AUSCAN Index and demographic information was developed, pre-tested, and distributed to a stratified random sample of 24,000 members of the Australian general public generated by the Australian Electoral Commission (AEC).Results
Age- and gender-specific WOMAC® and AUSCAN normative values were estimated based on approximately 5,500 subjects. Age-related differences were noted at the subscale level. In general, disability increased with age for all items and both Indices.Conclusions
Normative values provide opportunity for benchmarking the health status of individuals against their age- and gender-matched peers in the general population. These normative values provide unique opportunities, for using the WOMAC® and AUSCAN Indices in benchmarking applications, in both clinical practice and research.3.
Liem Andhyk Halim Maripaz Márquez Roel F. Maas-Bakker Gilberto Castañeda-Hernández Wim Jiskoot Huub Schellekens 《Pharmaceutical research》2018,35(11):226
Purpose
Filgrastim, a recombinant human granulocyte-colony stimulating factor, is widely used to treat congenital and acquired neutropenia. Following patent expiration of the innovator filgrastim product, biosimilar filgrastim products have been approved in the EU and shown to be comparable with the innovator with respect to quality, safety and efficacy. In less regulated markets, copy filgrastim products are available but data about their quality are scarce. In the present study, we provide a head-to-head comparative study on the quality of biosimilar and copy filgrastim products.Methods
Innovator filgrastim product, Neupogen®, two EU-licensed biosimilars, Zarzio® and Tevagrastim®, and two copy filgrastim products, Biocilin® and PDgrastim®, were subjected to peptide mapping, circular dichroism spectroscopy, fluorescence spectroscopy, sodium dodecyl sulfate polyacrylamide gel electrophoresis, high performance size-exclusion chromatography, reversed-phase ultra-performance liquid chromatography, endotoxin test, flow imaging microscopy and in vitro potency assay.Results
Zarzio® and Tevagrastim® have comparable quality to Neupogen®, while Biocilin® showed a significantly lower and PDgrastim® a higher specific activity. Moreover, PDgrastim® showed a higher level of impurities and a lower thermo stability than the other products.Conclusions
Except for the deviating specific activities of the two copy filgrastim products, we found no substantial differences in product quality between the filgrastim products studied.4.
Nicholas Mason-Smith Daniel J. Duke Alan L. Kastengren Daniela Traini Paul M. Young Yang Chen David A. Lewis Daniel Edgington-Mitchell Damon Honnery 《Pharmaceutical research》2017,34(4):718-729
Purpose
Sprays from pressurised metered-dose inhalers are produced by a transient discharge of a multiphase mixture. Small length and short time scales have made the investigation of the governing processes difficult. Consequently, a deep understanding of the physical processes that govern atomisation and drug particle formation has been elusive.Methods
X-ray phase contrast imaging and quantitative radiography were used to reveal the internal flow structure and measure the time-variant nozzle exit mass density of 50 µL metered sprays of HFA134a, with and without ethanol cosolvent. Internal flow patterns were imaged at a magnification of 194 pixels/mm and 7759 frames per second with 150 ps temporal resolution. Spray projected mass was measured with temporal resolution of 1 ms and spatial resolution 6 µm?×?5 µm.Results
The flow upstream of the nozzle comprised large volumes of vapour at all times throughout the injection. The inclusion of ethanol prevented bubble coalescence, altering the internal flow structure and discharge. Radiography measurements confirmed that the nozzle exit area is dominantly occupied by vapour, with a peak liquid volume fraction of 13%.Conclusion
Vapour generation in pMDIs occurs upstream of the sump, and the dominant volume component in the nozzle exit orifice is vapour at all times in the injection. The flow in ethanol-containing pMDIs has a bubbly structure resulting in a comparatively stable discharge, whereas the binary structure of propellant-only flows results in unsteady discharge and the production of unrespirable liquid masses.5.
Jesper Østergaard Emil Meng-Lund Susan Weng Larsen Claus Larsen Karsten Petersson James Lenke Henrik Jensen 《Pharmaceutical research》2010,27(12):2614-2623
Purpose
This study was conducted to characterize UV imaging as a platform for performing in vitro release studies using Nicorette® nicotine patches as a model drug delivery system.Methods
The rate of nicotine release from 2 mm diameter patch samples (Nicorette®) into 0.067 M phosphate buffer, pH 7.40, was studied by UV imaging (Actipix SDI300 dissolution imaging system) at 254 nm. The release rates were compared to those obtained using the paddle-over-disk method.Results
Calibration curves were successfully established which allowed temporally and spatially resolved quantification of nicotine. Release profiles obtained from UV imaging were in qualitative agreement with results from the paddle-over-disk release method.Conclusion
Visualization as well as quantification of nicotine concentration gradients was achieved by UV imaging in real time. UV imaging has the potential to become an important technology platform for conducting in vitro drug release studies.6.
Hideyuki?Sato Hiroki?Suzuki Keisuke?Yakushiji Jennifer?Wong Yoshiki?Seto Robert?K.?Prud’homme Hak-Kim?Chan
Purpose
This study was undertaken to evaluate the biopharmaceutical properties of cyclosporine A (CsA)-loaded nano-matrix particles for inhalation.Methods
Nano-matrix particles of CsA with mannitol (nCsAm) were prepared by a flash nano-precipitation technique employing a multi-inlet vortex mixer and evaluated in terms of physicochemical properties, anti-inflammatory effect in the rat model of airway inflammation, pharmacokinetic behavior, and distributions of CsA to side-effect-related organs after intratracheal administration.Results
In nCsAm, spherical nano-particles of CsA were covered with mannitol and the mean particle size was 1.3 μm. The in vitro Next Generation Impactor analysis demonstrated fine inhalation performance with a fine particle fraction value of 65.8%. Intratracheal nCsAm (100 μg-CsA/rat) significantly attenuated the recruitment of inflammatory cells into the airway in the rat model of airway inflammation, followed by suppression of the inflammatory biomarkers. After intratracheal nCsAm at a pharmacologically effective dose (100 μg-CsA/rat), there was a 42–47-fold decrease in the distribution of CsA to side-effect-related organs such as the kidney and liver compared with oral CsA at a toxic dose (10 mg-CsA/kg), potentially leading to avoidance of systemic side-effects of CsA.Conclusion
Upon these findings, nCsAm prepared with the flash nano-precipitation technique could be a novel dosage form of CsA for inhalation therapy of airway inflammation with a better safety margin.7.
J. Lederhofer J. van Lent F. Bhoelan Z. Karneva A. de Haan J.C. Wilschut T. Stegmann 《Pharmaceutical research》2018,35(9):172
Purpose
Characterization of virosomes, in late stage preclinical development as vaccines for Respiratory Syncytial Virus (RSV), with a membrane-incorporated synthetic monophosphoryl lipid A, 3D-PHAD® adjuvant.Methods
Virosomes were initially formed by contacting a lipid film containing 3D-PHAD® with viral membranes solubilized with the short chain phospholipid DCPC, followed by dialysis, later by adding solubilized 3D-PHAD to viral membranes, or to preformed virosomes from DMSO.Results
Virosomes formed from lipid films contained the membrane glycoproteins G and F, at similar F to G ratios but lower concentrations than in virus, and the added lipids, but only a fraction of the 3D-PHAD®. By single particle tracking (SPT), the virosome size distribution resembled that seen by cryo-electron microscopy, but dynamic light scattering showed much larger particles. These differences were caused by small virosome aggregates. Measured by SPT, virosomes were stable for 300 days. 3DPHAD ® incorporation in virosomes could be enhanced by providing the adjuvant from DCPC solubilized stock, but also by adding DMSO dissolved adjuvant to pre-formed virosomes. Virosomes with 0.1 mg/mg of 3D-PHAD®/viral protein from DMSO induced antibody titers similar to those by virosomes containing 0.2 mg/mg of DCPC-solubilized 3D-PHAD®.Conclusions
Stable 3D-PHAD® adjuvanted RSV virosomes can be formulated.8.
Purpose
To investigate the influence of mouthpiece geometry on the amount of throat deposition and device retention produced using a dry powder inhaler (Aerolizer®), along with the subsequent effect on the overall inhaler performance.Materials and Methods
Computational Fluid Dynamics analysis of the flowfield generated in the Aerolizer® with various modified mouthpiece geometries (including cylindrical, conical and oval designs) was used in conjunction with experimental dispersions of mannitol powder using a multi-stage liquid impinger to determine how the overall inhaler performance varied as the mouthpiece geometry was modified.Results
Geometry of the inhaler mouthpiece had no effect on device retention or the inhaler dispersion performance. In contrast, the mouthpiece geometry strongly affected the amount of throat deposition by controlling the axial component of the exit air flow velocity. The radial motion of the emitted aerosol jet was found to have little effect on throat deposition in representative mouth–throat models. Despite the reduced throat deposition, there was no difference in the overall inhaler performance.Conclusions
For cases where low throat deposition is a key design parameter, this study demonstrates that the amount of throat deposition can be reduced by making minor modifications to the inhaler mouthpiece design.9.
Aim
A preliminary evaluation of mobile phone technology for repeated independent remote data capture using the mobile phone-based m-WOMAC® NRS 3.1 Index.Methods
Following orientation to the m-WOMAC® Index, and initial completion in the office, patients took the phones home and independently completed the Index on four subsequent occasions over 12 days, sending their data each time to a server in USA.Results
Three men and nine women with hip (n = 2) and knee (n = 10) OA successfully completed the m-WOMAC® Index on each occasion. Average time to completing the Index at termination was 4.8 min. The majority of patients rated logging on/opening the application, completing the m-WOMAC® Index on the phone, and sending data as very easy (10–11/12), and were very confident (11/12) in continuing to use the phone to report their symptoms.Conclusions
These data support the feasibility of repeated independent remote data capture using the m-WOMAC® NRS3.1 Index.10.
Bouquet W Deleye S Staelens S De Smet L Van Damme N Debergh I Ceelen WP De Vos F Remon JP Vervaet C 《Pharmaceutical research》2011,28(7):1653-1660
Purpose
To evaluate the tumour growth delay of a peritoneal carcinomatosis (PC) of colorectal origin after intraperitoneal chemotherapy with paclitaxel/randomly-methylated-β-cyclodextrin (Pac/RAME-β-CD) versus Taxol® at normo- and hyperthermic conditions in rats.Methods
Hyperthermic intraperitoneal chemotherapy (HIPEC) was performed 7 days post implantation of the tumour with both formulations at a Pac concentration of 0.24 mg/ml. Tumour evaluation was performed via positron emission tomography (PET) and magnetic resonance imaging (MRI) imaging, measuring tumour activity and tumour volume, respectively. Scans were taken at 2 and 7 days post treatment.Results
PET and MRI data showed a significant reduction in tumour activity and tumour volume for rats treated with Pac/RAME-β-CD (at normo- and hyperthermic conditions), compared to the control group. Treatment with Taxol® did not result in a significant reduction of tumour activity and tumour volume. No significant differences between the normo- and hyperthermic conditions were observed for both formulations, indicating that hyperthermia and paclitaxel were not synergistic despite the direct cytotoxic effect of hyperthermia.Conclusion
Monitoring tumour growth via PET and MRI indicated that Pac/RAME-β-CD inclusion complexes had a significantly higher efficacy compared to Taxol® in a rat model for peritoneal carcinomatosis.11.
Michael Hodgman Michael G. Holland Ulrich Englich Susan M. Wojcik William D. Grant Erich Leitner 《Journal of medical toxicology》2016,12(4):391-395
Introduction
Whole bowel irrigation (WBI) is a management option for overdose of medications poorly adsorbed to activated charcoal, with modified release properties, or for body packers. Polyethylene glycol (PEG) is a mixture of ethylene oxide polymers of varying molecular weight. PEG with an average molecular weight of 3350 g/mol is used for WBI. PEG electrolyte lavage solution has been shown in vitro to hasten the dissolution of acetaminophen. The impact of PEG on the pharmacokinetics of extended release pharmaceuticals is unknown. Lower average molecular weight PEG mixtures are used as solvents and excipients. We sought to investigate the impact of PEG on the release of morphine from several extended release morphine formulations.Methods
An in vitro gastric model was developed. To test the validity of our model, we first investigated the previously described interaction of ethanol and Avinza®. Once demonstrated, we then investigated the effect of PEG with several extended release morphine formulations.Results
In the validation portion of our study, we confirmed an ethanol Avinza® interaction. Subsequently, we did not observe accelerated release of morphine from Avinza® or generic extended release morphine in the presence of PEG.Conclusion
The use of PEG for gastric decontamination following ingestion of these extended release morphine formulations is unlikely to accelerate morphine release and aggravate intoxication.12.
Mariya A. Pindrus James L. Cole Japneet Kaur Steven J. Shire Sandeep Yadav Devendra S. Kalonia 《Pharmaceutical research》2017,34(11):2250-2259
Purpose
To systematically analyze shape and size of soluble irreversible aggregates and the effect of aggregate formation on viscosity.Methods
Online light scattering, refractive index and viscosity detectors attached to HPLC (Viscotek®) were used to study aggregation, molecular weight and intrinsic viscosity of bovine serum albumin (BSA). Irreversible aggregates were generated by heat stress. Bulk viscosity was measured by an oscillating piston viscometer.Results
As BSA was heated at a higher concentration or for a longer time, the relative contribution, molecular weight and intrinsic viscosity of aggregate species increased. Molecular shape was evaluated from intrinsic viscosity values, and aggregates were estimated to be more asymmetric than monomer species. The presence of aggregates resulted in an increase in bulk viscosity when relative contribution of very high molecular weight species exceeded 10%.Conclusions
For model system and conditions studied, generation of higher order aggregate species was concluded to be associated with an increase in molecular asymmetry. Elevated viscosity in the presence of aggregated species points to molecular asymmetry being a critical parameter affecting solution viscosity of BSA.13.
Nicholas Mason-Smith Daniel J. Duke Alan L. Kastengren Peter J. Stewart Daniela Traini Paul M. Young Yang Chen David A. Lewis Julio Soria Daniel Edgington-Mitchell Damon Honnery 《Pharmaceutical research》2016,33(5):1249-1258
Purpose
Typical methods to study pMDI sprays employ particle sizing or visible light diagnostics, which suffer in regions of high spray density. X-ray techniques can be applied to pharmaceutical sprays to obtain information unattainable by conventional particle sizing and light-based techniques.Methods
We present a technique for obtaining quantitative measurements of spray density in pMDI sprays. A monochromatic focused X-ray beam was used to perform quantitative radiography measurements in the near-nozzle region and plume of HFA-propelled sprays.Results
Measurements were obtained with a temporal resolution of 0.184 ms and spatial resolution of 5 μm. Steady flow conditions were reached after around 30 ms for the formulations examined with the spray device used. Spray evolution was affected by the inclusion of ethanol in the formulation and unaffected by the inclusion of 0.1% drug by weight. Estimation of the nozzle exit density showed that vapour is likely to dominate the flow leaving the inhaler nozzle during steady flow.Conclusions
Quantitative measurements in pMDI sprays allow the determination of nozzle exit conditions that are difficult to obtain experimentally by other means. Measurements of these nozzle exit conditions can improve understanding of the atomization mechanisms responsible for pMDI spray droplet and particle formation.14.
Sylvie Fernandez Stéphanie Chevrier Nicolas Ritter Bruno Mahler Frédéric Demarne Frédéric Carrière Vincent Jannin 《Pharmaceutical research》2009,26(8):1901-1910
Purpose
Labrasol® and Gelucire® 44/14 are defined admixtures of acylglycerols and PEG esters which are substrates for digestive lipases.Methods
We investigated their in vitro gastrointestinal lipolysis to understand which compounds are, after digestion, responsible for keeping poorly water-soluble drugs in solution. The precipitation of piroxicam and cinnarizine formulated in these excipients during the gastrointestinal lipolysis was also studied.Results
Monoacylglycerols and PEG monoesters are the largest compounds present at the end of gastric phase whereas PEG-monoesters are the largest compounds after the duodenal phase. The precipitation of piroxicam is mainly due to the gastric lipolysis. In the control experiments performed without digestive lipases, cinnarizine formulated in Labrasol® was found to precipitate upon dilution of the gastric medium to form the solution mimicking the duodenal medium. In the presence of gastric lipase, Labrasol® was hydrolyzed and the precipitation of cinnarizine was not observed in this case. When the cinnarizine was formulated with Gelucire® 44/14 the precipitation was only due to the dilution of the gastric medium.Conclusion
Our study highlights the importance of the gastrointestinal lipolysis and the associated phenomena such as the dilution of chyme by biliary and pancreatic secretions in vivo, on the solubilisation of poorly water-soluble drugs formulated with lipid-based excipients.15.
Tinne Monteyne Liza Heeze Severine Therese F. C. Mortier Klaus Oldörp Ruth Cardinaels Ingmar Nopens Chris Vervaet Jean-Paul Remon Thomas De Beer 《Pharmaceutical research》2016,33(10):2481-2494
Purpose
Twin screw hot melt granulation (TS HMG) is a valuable, but still unexplored alternative to continuous granulation of moisture sensitive drugs. However, knowledge of the material behavior during TS HMG is crucial to optimize the formulation, process and resulting granule properties. The aim of this study was to evaluate the agglomeration mechanism during TS HMG using a rheometer in combination with differential scanning calorimetry (DSC).Methods
An immiscible drug-binder formulation (caffeine-Soluplus®) was granulated via TS HMG in combination with thermal and rheological analysis (conventional and Rheoscope), granule characterization and Near Infrared chemical imaging (NIR-CI).Results
A thin binder layer with restricted mobility was formed on the surface of the drug particles during granulation and is covered by a second layer with improved mobility when the Soluplus® concentration exceeded 15% (w/w). The formation of this second layer was facilitated at elevated granulation temperatures and resulted in smaller and more spherical granules.Conclusion
The combination of thermal and rheological analysis and NIR-CI images was advantageous to develop in-depth understanding of the agglomeration mechanism during continuous TS HMG and provided insight in the granule properties as function of process temperature and binder concentration.16.
Purpose
To develop a device for simultaneous measurement of particle aerodynamic diameter and electrostatic charge of inhalation aerosols.Method
An integrated system consisting of an add-on charge measurement device and a liquid impinger was developed to simultaneously determine particle aerodynamic diameter and electrostatic charge. The accuracy in charge measurement and fine particle fraction characterization of the new system was evaluated. The integrated system was then applied to analyze the electrostatic charges of a DPI formulation composed of salbutamol sulphate-Inhalac 230® dispersed using a Rotahaler®.Results
The charge measurement accuracy was comparable with the Faraday cage method, and incorporation of the charge measurement module had no effect on the performance of the liquid impinger. Salbutamol sulphate carried negative charges while the net charge of Inhalac 230® and un-dispersed salbutamol sulphate was found to be positive after being aerosolized from the inhaler. The instantaneous current signal was strong with small noise to signal ratio, and good reproducibility of charge to mass ratio was obtained for the DPI system investigated.Conclusions
A system for simultaneously measuring particle aerodynamic diameter and aerosol electrostatic charges has been developed, and the system provides a non-intrusive and reliable electrostatic charge characterization method for inhalation dosage forms.17.
Priya Batheja Yifan Song Philip Wertz Bozena Michniak-Kohn 《Pharmaceutical research》2009,26(7):1689-1700
Purpose
Development of transdermal and topical formulations requires extensive skin permeation testing and the availability of reproducible test models. We have worked on development of a Human Skin Equivalent (HSE) by culture with a combination of additives, including the PPAR-α agonist clofibrate, in order to simulate the cutaneous barrier of human skin.Methods
HSEs were constructed by culturing human keratinocytes on dermal matrices consisting of human fibroblasts and collagen and cultured in specific growth conditions (combination of clofibrate, ascorbic acid and fatty acids). The resulting HSEs were characterized for their morphology, lipid composition and permeability profile and compared to human skin and EpidermFT®.Results
The unique media growth additives combination normalized the lipid profile and significantly increased the permeability barrier of the HSEs to caffeine and hydrocortisone (p?p?Conclusions
Culture with the growth media additives combination produced a pronounced effect on the permeability barrier of the HSEs. Further validation of permeability with additional agents could comprise the first step toward their use in skin permeability screening.18.
Yumi Yamamoto Pyry A. Välitalo Dirk-Jan van den Berg Robin Hartman Willem van den Brink Yin Cheong Wong Dymphy R. Huntjens Johannes H. Proost An Vermeulen Walter Krauwinkel Suruchi Bakshi Vincent Aranzana-Climent Sandrine Marchand Claire Dahyot-Fizelier William Couet Meindert Danhof Johan G. C. van Hasselt Elizabeth C. M. de Lange 《Pharmaceutical research》2017,34(2):333-351
Purpose
Predicting target site drug concentration in the brain is of key importance for the successful development of drugs acting on the central nervous system. We propose a generic mathematical model to describe the pharmacokinetics in brain compartments, and apply this model to predict human brain disposition.Methods
A mathematical model consisting of several physiological brain compartments in the rat was developed using rich concentration-time profiles from nine structurally diverse drugs in plasma, brain extracellular fluid, and two cerebrospinal fluid compartments. The effect of active drug transporters was also accounted for. Subsequently, the model was translated to predict human concentration-time profiles for acetaminophen and morphine, by scaling or replacing system- and drug-specific parameters in the model.Results
A common model structure was identified that adequately described the rat pharmacokinetic profiles for each of the nine drugs across brain compartments, with good precision of structural model parameters (relative standard error <37.5%). The model predicted the human concentration-time profiles in different brain compartments well (symmetric mean absolute percentage error <90%).Conclusions
A multi-compartmental brain pharmacokinetic model was developed and its structure could adequately describe data across nine different drugs. The model could be successfully translated to predict human brain concentrations.19.
Francesca Buttini Irene Pasquali Gaetano Brambilla Diego Copelli Massimiliano Dagli Alberi Anna Giulia Balducci Ruggero Bettini Viviana Sisti 《Pharmaceutical research》2016,33(3):701-715
Purpose
The aim of this work was to evaluate the effect of two different dry powder inhalers, of the NGI induction port and Alberta throat and of the actual inspiratory profiles of asthmatic patients on in-vitro drug inhalation performances.Methods
The two devices considered were a reservoir multidose and a capsule-based inhaler. The formulation used to test the inhalers was a combination of formoterol fumarate and beclomethasone dipropionate. A breath simulator was used to mimic inhalatory patterns previously determined in vivo. A multivariate approach was adopted to estimate the significance of the effect of the investigated variables in the explored domain.Results
Breath simulator was a useful tool to mimic in vitro the in vivo inspiratory profiles of asthmatic patients. The type of throat coupled with the impactor did not affect the aerodynamic distribution of the investigated formulation. However, the type of inhaler and inspiratory profiles affected the respirable dose of drugs.Conclusions
The multivariate statistical approach demonstrated that the multidose inhaler, released efficiently a high fine particle mass independently from the inspiratory profiles adopted. Differently, the single dose capsule inhaler, showed a significant decrease of fine particle mass of both drugs when the device was activated using the minimum inspiratory volume (592 mL).20.
Jehad M. Nasereddin Nikolaus Wellner Muqdad Alhijjaj Peter Belton Sheng Qi 《Pharmaceutical research》2018,35(8):151