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Biomedical subjects

Robert Price

Publications and source records attributed to Robert Price.

At least 37 records · Page 2Linked to original sources

The surface roughness of lactose particles can be modulated by wet-smoothing using a high-shear mixer.

The surface morphology of a-lactose monohydrate particles was modified by a new wet-smoothing process performed in a high-shear mixer using solvents. Successive steps of wetting and drying of lactose powders during rolling in the mixer's cylindrical bowl were performed. Smoothed particles were tested for size distribution, flow, and packing. The wet-smoothing process flattened the surface and rounded the edges of lactose particles. In comparison with original lactose, an improvement of powder packing and flow properties was evidenced. When the process was performed in the presence of a ternary agent such as magnesium stearate, the smoothing was improved. The evolution of rugosity during the smoothing process was assessed through a fractal descriptor of SEM picture. Atomic force microscopy and surface area measurements quantified the surface rugosity. A very significant reduction of the rugosity, more remarkable in the presence of magnesium stearate, was measured. This new process of powder wet-smoothing allows the preparation of lactose particles with different degrees of smoothed surface for the control of flow and packing properties and particle-particle interactions.

Lactose↗

Visualization of the crystallization of lactose from the amorphous state.

The physical stability and solid-state recrystallization of spray-dried 'amorphous' lactose particles were visualized using environmentally controlled atomic force microscopy (EC-AFM) and conventional optical microscopy. The morphology and crystalline state were investigated as a function of relative humidity (RH) and were correlated with bulk gravimetric vapor sorption measurements that were run in parallel. The metastable nature of amorphous spray-dried lactose particles was apparent at low RHs (<30% RH). Visualization of the recrystallization transformation of amorphous lactose during moisture uptake at 58 and 75% RH suggested only a proportion of the collapsed particles undergoes nucleation and crystal growth. The irregular surface morphology of the recrystallized particles suggested a secondary nucleation and growth process. Primary nucleation of alpha-lactose monohydrate within the non-recrystallized particles required exposure to elevated RH (94% RH). In relation to bulk measurements of moisture-induced amorphous recrystallization of spray-dried lactose, the results suggest that recrystallization of amorphous lactose, above a critical RH, may be induced by the presence of very low levels of a seed material, which may dramatically reduce the activation energy barrier for nucleation and crystal growth.

Crystallization↗

The influence of relative humidity on the cohesion properties of micronized drugs used in inhalation therapy.

The influence of relative humidity (RH) on the cohesion properties of three drugs: salbutamol sulphate (SS), triamcinolone acetonide (TAA), and disodium cromoglycate (DSCG) was investigated using the atomic force microscope (AFM) colloidal probe technique. Micronized drug particles were mounted in heat-sensitive epoxy resin for immobilization. Multiple AFM force-distance curves were conducted between each drug probe and the immobilized drug particulates at 15, 45, and 75% RH using Force-Volume imaging. Clear variations in the cohesion profile with respect to RH were observed for all three micronized drugs. The calculated force and energy of cohesion to separate either micronized SS or DSCG increased as humidity was raised from 15 to 75% RH, suggesting capillary forces become a dominating factor at elevated RH. In comparison, the separation force and energy for micronized TAA particles decreased with increased RH. This behavior may be attributed to long-range attractive electrostatic interactions, which were observed in the approach cycle of the AFM force-distance curves. These observations correlated well with previous aerosolization studies of the three micronized drugs.

Bronchodilator Agents↗

Influence of particle size and shape on flowability and compactibility of binary mixtures of paracetamol and microcrystalline cellulose.

The influence of the size and shape of paracetamol particles on the flow and compression behavior of blends (1:1) of microcrystalline cellulose (MCC) was investigated. The effect of paracetamol particle shape was investigated by using two differently prepared samples, micronized and novel engineered Solution Atomization and Xstallization by Sonication (SAXS) particles, which exhibited similar particle size ranges (2-6 microm). The results were compared to data obtained for an untreated paracetamol sample. The blends containing SAXS particles exhibited increased bulk and tapped density and improved flow, compared to the blend containing micronized particles. This may reflect differences in shape since the SAXS particles exhibited spherical morphology. The compressibility of the blend containing untreated paracetamol was greater than blends containing the SAXS and micronized materials, which may reflect the different drug particle sizes and shapes. However, blends containing the needle-shaped particles of pure untreated sample, exhibited poor compactibility after storage at 10% RH. It was found that increasing the moisture content in the blends by storage at 44% RH resulted in an increase in the compactibility of the samples containing untreated and SAXS paracetamol with the blends containing micronized paracetamol being relatively unaffected. In general, tablets prepared from blends containing smaller particles of paracetamol exhibited significantly greater compactibility compared to tablets prepared containing the larger particle sized untreated paracetamol. The use of small, spherical drug particles may result in improvements in the bulk density, densification and compactibility of blends of paracetamol and microcrystalline cellulose.

Acetaminophen↗

The influence of humidity on the aerosolisation of micronised and SEDS produced salbutamol sulphate.

The influence of storage humidity on the aerosolisation efficiency of micronised and supercritical fluid salbutamol sulphate formulations (containing a lactose carrier) were investigated using the twin stage impinger (TSI). Storage humidity had a significant effect on the aerosolisation efficiency of both micronised and solution enhanced dispersion by supercritical fluids (SEDS) salbutamol sulphate (ANOVA P <0.05), suggesting capillary interactions to be an important factor when considering formulation performance. Furthermore, significant differences between the aerosolisation performance of micronised and SEDS salbutamol sulphate were observed at elevated humidities (>63% RH) (Fishers pairwise P <0.05). It is suggested that such variations may be due to differences in physical stability of the micronised and SEDS produced material. Dynamic vapor sorption, and atomic force microscopy (AFM) phase imaging suggested the micronised material to contain amorphous content that was most likely present on the micronised particulate surfaces. Thus, at high humidity, surface amorphous regions may have the ability to re-crystallize and effectively 'fuse' to the lactose carrier surface. This would potentially reduce the ability for the micronised material to be aerosolized and thus result in a greater decrease in FPF when compared to SEDS produced material at equivalent RH.

Aerosols↗

Muscle responses to seated perturbations for typically developing infants and those at risk for motor delays.

This study examined spatial and temporal organization of muscle activity in response to seated forward platform perturbations in typically developing (TD) infants and in infants at risk for ongoing neuromotor delays. Twelve high-risk (HR) infants (six males, six females) and 12 TD infants (nine males, three females) aged 8 to 10 months (corrected for prematurity), who were all independent sitters, participated in this study. Surface electromyograms recorded muscle responses to forward perturbation in the neck, trunk, and leg (6cm amplitude, 12cm/s). Center of pressure measures were also recorded. The TD infants demonstrated significantly more phasic responses than the HR infants, who had more trials with tonic activity and more trials with no burst of muscle activity (Mann-Whitney U test, two-tailed, p=0.006). The TD infants demonstrated caudalcephalo, directionally appropriate recruitment patterns more often than the HR infants. There were some similarities between the two groups, with no significant difference between any of the center of pressure measures or onset latencies. Results suggest that postural development in HR infants with motor delays is complex. Some elements of seated postural control appear to be developmentally appropriate, e.g. presence of phasic activity in directionally appropriate muscles sequenced in a caudalcephalo pattern. However, frequency of these age appropriate responses was significantly lower in HR infants, who demonstrated many normal, albeit immature, responses, such as cephalocaudally sequenced muscle activity.

Child Development↗

Processing of spherical crystalline particles via a novel solution atomization and crystallization by sonication (SAXS) technique.

PURPOSE: The objective was to develop a single-step pharmaceutical particle engineering technique able to produce particles within a well-defined particle size range while controlling macroscopic spherical morphology and mesoscopic surface topography. METHODS: Paracetamol (acetaminophen) aerosol droplets were generated by spraying a solution via either an electrohydrodynamic atomizer (EHDA) or an air pressure atomizer. The highly supersaturated droplets were collected in a suitable nonsolvent of the drug and crystallized by ultrasonication. Suspended particles were filtered, and their physicochemical properties characterized. RESULTS: The SAXS processed particles showed a relatively homogeneous particle size distribution between 1 and 5 microm. Particles were nominally crystalline in structure. The chemical structure of the active ingredient did not apparently alter during processing. Controlling the solute concentration of the air pressure atomized solution provided a means of controlling the degree of sphericity and particle-size characteristics. In comparison to micronized paracetamol particles, SAXS-produced particulates were generally more uniform in shape with increased nanometer surface roughness. CONCLUSIONS: The SAXS process provides a novel means of producing crystalline particles in a well-defined particle size range. Furthermore, the method offers a range of opportunities in controlling physical properties including surface topography and particle shape.

Acetaminophen↗

The cohesive-adhesive balances in dry powder inhaler formulations I: Direct quantification by atomic force microscopy.

PURPOSE: To obtain a quantitative assessment of the cohesive and adhesive force balance within dry powder inhaler formulations. METHODS: The atomic force microscope (AFM) colloid probe technique was used to measure the adhesive and cohesive force characteristics of dry powder systems containing an active component (budesonide, salbutamol sulphate) and alpha-lactose monohydrate. To minimize the variations in contact area between colloid probe and substrates, nanometer smooth crystal surfaces of the drugs and the excipient were prepared. RESULTS: The uniformity in contact area allowed accurate and reproducible force measurements. Cohesive-adhesive balance (CAB) graphs were developed to allow direct comparison of the interaction forces occurring in model carrier-based formulations. A salbutamol sulphate-lactose system revealed a significant tendency for the two materials to adhere, suggesting a propensity for the powder to form a homogenous blend. In contrast, the budesonide-lactose system exhibited strong cohesive properties suggesting that the formulation may exhibit poor blend homogeneity and potential for segregation upon processing and handling. CONCLUSIONS: The novel approach provides a fundamental insight into the cohesive-adhesive balances in dry powder formulations and further understanding of powder behavior.

Adhesiveness↗

The cohesive-adhesive balances in dry powder inhaler formulations II: influence on fine particle delivery characteristics.

PURPOSE: To investigate the influence of the cohesive-adhesive balances on dry powder formulation aerosolization and delivery characteristics. METHODS: De-agglomeration properties of pharmaceutical powders were investigated using an Aerosizer at various shear forces. Aerosol drug deposition properties of drug-only formulations and carrier-based formulations were investigated using a low-resistance device (Rotahaler) and a high-resistance device (Turbuhaler) via a twin-stage impinger. RESULTS: A paradoxical relationship between particle cohesive strength and de-agglomeration efficiencies of drug-only formulations was observed, where an increase in cohesive strength led to a higher fine particle fraction. A possible explanation for the variation in the fluidization and aerosolization properties between low and high cohesive particles was modeled on the relationship between cohesion, metastable agglomerate size, and the resulting aerodynamic drag force acting on the fluidized agglomerates. The addition of a fine particle lactose carrier influenced the drug deposition patterns in different ways depending on the relative cohesive and adhesive force balances within the formulation. CONCLUSIONS: The use of the colloid Atomic Force Microscrope (AFM) technique in combination with the cohesive-adhesive balance (CAB) system provides a novel preformulation tool for investigating the likely behavior of a dry powder formulation and a possible means of interpreting the possible de-aggregation and dispersion mechanisms of carrier-based formulations.

Adhesiveness↗

The development of a novel high-dose pressurized aerosol dry-powder device (PADD) for the delivery of pumactant for inhalation therapy.

The performance of a novel dry powder inhaler designed to deliver exceptionally high doses was investigated using pumactant as a model powder. Pumactant (a synthetic lung surfactant consisting of a phospholipid mixture), with a 90th percentile particle size of 2.92 microm is highly cohesive, has a high moisture affinity (6.2% w/w at 45% RH), and is predominantly amorphous. The device (pressurized aerosol dry-powder delivery [PADD]) utilizes pressurized gas to aerosolize a powder bed from a reservoir and delivers it through a conventional mouthpiece. The influence of loaded dose on dry powder delivery and can pressure on aerosolization efficiency was investigated. Analysis of the delivered dose studies suggested a linear relationship between loaded dose and delivered dose (R(2) = 0.96, for loaded doses of 0-250 mg), with a delivery efficiency of 70%. Analysis of the aerosolization efficiency using a Marple Miller type impactor suggested fine particle fractions (particles with an aerodynamic diameter of <5 microm) of approximately 30% using canister pressures of 8-14 bars. These results indicate that the PADD device may be a useful tool in delivering high-dose medicaments, as a carrier-free formulation, to the deep lung.

Administration, Inhalation↗

Under pressure: predicting pressurized metered dose inhaler interactions using the atomic force microscope.

Drug particulate interactions in pressurized metered dose inhalers (pMDI) may lead to a decrease in aerosolization efficiency and subsequent efficacy in patient treatment. The interactions between salbutamol sulfate (commonly used in Ventolin pMDIs) and a series of pMDI canister materials were investigated using the atomic force microscope (AFM) colloid probe technique. Approximately 4000 individual force-distance curves were determined for a drug probe and three surfaces (10 x 10 mum areas) in situ, in a model propellant. The area under each force-distance curve was integrated to obtain separation energy values. Median separation energy values followed the rank order borosilicate glass > aluminum > PTFE, suggesting PTFE to be the most suitable canister coating.

Administration, Inhalation↗

Investigation into the effect of humidity on drug-drug interactions using the atomic force microscope.

The atomic force microscope (AFM) has been used to characterize the cohesive nature of a micronized pharmaceutical powder used for inhalation therapy. Salbutamol sulfate (also referred to as albuterol sulfate), a therapeutic drug commonly delivered from dry powder inhalers (DPI), was chosen as a model system because the cohesion and subsequent de-agglomeration during inhalation are critical aspects to the efficacy of such a delivery system. Salbutamol sulfate drug particulates were mounted on V-shaped AFM cantilevers using a novel micromanipulation technique. Force-distance curves obtained from the measurements between cantilever drug probes and model compacts of salbutamol sulfate were integrated to determine separation energies. The effect of humidity (15-75% RH) on the energy required to separate a drug particle from model drug surface was determined using a custom-built perfusion apparatus attached to the AFM. Separation energy measurements over 10 x 10-microm areas of the compact surface (n = 4096) exhibited log normal distributions (apparent linear regression, R(2) >or= 0.97). Significant increases in the median separation energies (p < 0.05) between the salbutamol sulfate drug probes and salbutamol sulfate model surfaces were observed as humidity was increased. This result is most likely attributed to capillary interactions becoming more dominant at higher humidities. This investigation has shown the AFM to be a powerful technique for quantification of the separation energies between micronized drug particulates, highlighting the potential of the AFM as a rapid preformulation tool.

Albuterol↗

The effect of mechanical processing on surface stability of pharmaceutical powders: visualization by atomic force microscopy.

Atomic force microscopy was used to investigate the influence of mechanical processing (milling) on the surface stability of salbutamol sulfate. Phase imaging, a development of tapping mode atomic force microscopy, was used to elucidate variations in the physico-mechanical properties on the surface of salbutamol sulfate crystals by measuring the phase lag of an oscillating tip in contact with the surface. Simultaneous measurements of topographical and phase images indicated an increase in disorder on the surface as milling time was increased. Specific regions on the milled samples, independent of topography, showed large variations in phase shift (> 30 degrees). These regions (not observed on the crystalline salbutamol sulfate) suggested large differences in the physical properties on the surface. It is therefore reasonable to conclude that these regions were likely attributed to mechanically induced amorphous domains.

Drug Stability↗

Airborne particles produced during enamel cleanup after removal of orthodontic appliances.

Airborne particles can be produced during enamel cleanup after the removal of fixed orthodontic appliances. Particles with an aerodynamic diameter of less than 2.5 microm, known as PM2.5, can reach the alveoli of the lungs. The aim of this experiment was to qualitatively determine whether such particles are produced during enamel cleanup at the end of orthodontic treatment. Particles were collected and examined under a scanning electron microscope. Aerodynamic diameters of the particles ranged from approximately 2 to 30 microm. X-ray analysis confirmed not only the presence of components of the adhesives being removed, but also tungsten from the bur and tooth enamel. In conclusion, inhalable particles can be produced during enamel cleanup at the completion of orthodontic treatment. Further investigation is required to determine the clinical significance of such particles, how their production can be minimized, and whether even smaller, fine or ultrafine, particles are produced.

Aerosols↗

Effect of balance training on recovery of stability in children with cerebral palsy.

This study examined the effect of massed practice in balance recovery of stability in six children (four males, two females; mean age 9 years 2 months, SD 2 years, range 7 years 5 months to 12 years 11 months) with cerebral palsy (CP). Four children were diagnosed with spastic diplegia (Gross Motor Function Classification System [GMFCS] level II) and two with spastic hemiplegia (GMFCS level I). A single-subject, multiple-baseline experimental design involving three pairs of children matched for diagnosis was used. A moveable forceplate system was used to test and train reactive balance control. Area per second (i.e. area covered by the center of pressure over a one second period) and time to stabilization from center of pressure measures were calculated following perturbations. The intervention phase consisted of massed practice on the moving platform (100 perturbations/day for 5 days). Analysis included hierarchical linear modeling and a repeated measures ANOVA. All children demonstrated a significant improvement in their ability to recover stability as demonstrated by reduced center of pressure area and time to stabilization following training. These improvements were still present 30 days following completion of training. Results suggest that postural control mechanisms in school-age children (7 to 13 years) with CP are modifiable.

Adolescent↗

Age and features of movement influence motor overflow.

OBJECTIVES: To measure the magnitude and prevalence of motor overflow to the arm at rest during attempted unilateral arm movements. DESIGN: Cross-sectional assessment. SETTING: Motor physiology laboratory. PARTICIPANTS: Healthy young (n=20) and elderly (n=20) adult subjects. MEASUREMENTS: Surface electromyography (EMG) was obtained from bilateral forearm muscles during performance of 12 different unilateral finger-tapping tasks. RESULTS: For all subjects, faster movement rate (F=2.56-3.30, P<.05), cognitive distraction (F=4.09, P<.05), and fatigue (F=15.15, P<.001) were each associated with a significant increase in the magnitude of EMG in the arm intended to be at rest. In elderly subjects, tapping at maximum rate and fatigue were each associated with a further increase in motor overflow across the midline. In addition, better left hand dexterity correlated with greater motor overflow to the right hand during rapid left hand tapping (r=0.63, P<.005). Prevalence of motor overflow was also higher in older subjects for some tasks, for example during 1 Hz tapping by the right index finger (motor overflow present in 45%, vs 15% young subjects, P<.05). CONCLUSION: Several behavioral variables increase motor overflow across the midline in young and elderly adults. Motor overflow was even greater in elderly subjects with the most demanding tasks and was greater in those with better motor status, suggesting that this form of motor system change is a compensatory event of normal aging rather than age-related dysfunction. The results support the hypotheses that healthy aging is associated with an increase in the degree to which brain function is bilaterally organized.

Adult↗

Effect of humidity on aerosolization of micronized drugs.

The variation of aerosolization with humidity for three micronized drugs used in the treatment of asthma was evaluated by using in vitro methods. Micronized samples of disodium cromoglycate (DSCG), salbutamol sulphate, and triamcinolone acetonide (TAA) were stored for 12hr at 15, 30, 45, 60, and 75% relative humidity (RH). A suitable "reservoir" dry powder inhaler was loaded and tested by using a twin-stage impinger at each specific humidity. The aerosolization efficiency of all three micronized drugs was affected by variations in humidity. The percentage of the delivered dose and the fine particle fraction of the loaded dose (FPFLD) for both DSCG and salbutamol sulphate decreased with increasing humidity; with the largest decrease in FPFLD occurring between 45% and 60% RH for DSCG and 60% to 75% RH for salbutamol sulphate. These observations suggest that the adhesion properties for both DSCG and salbutamol sulphate, which govern the aerosolization efficiency, are predominately influenced by capillary interactions. In contrast, the FPFLD for TAA significantly increased as the humidity increased over the range 15% to 75% RH, suggesting that triboelectric forces predominate particle-particle interactions. These variations in drug particulate behavior highlight the importance of an individual formulation approach when developing dry powder inhalation systems.

Administration, Inhalation↗

Motor cortex activation is preserved in patients with chronic hemiplegic stroke.

Many central nervous system conditions that cause weakness, including many strokes, injure corticospinal tract but leave motor cortex intact. Little is known about the functional properties of surviving cortical regions in this setting, in part because many studies have used probes reliant on the corticospinal tract. We hypothesized that many features of motor cortex function would be preserved when assessed independent of the stroke-affected corticospinal tract. Functional MRI was used to study 11 patients with chronic hemiplegia after unilateral stroke that spared regions of motor cortex. Activation in stroke-affected hemisphere was evaluated using 3 probes independent of affected corticospinal tract: passive finger movement, a hand-related visuomotor stimulus, and tapping by the nonstroke index finger. The site and magnitude of cortical activation were similar when comparing the stroke hemisphere to findings in 19 control subjects. Patients activated each of 8 cortical regions with similar frequency as compared to controls, generally with a smaller activation volume. In some cases, clinical measures correlated with the size or the site of stroke hemisphere activation. The results suggest that, despite stroke producing contralateral hemiplegia, surviving regions of motor cortex actively participate in the same proprioceptive, visuomotor, and bilateral movement control processes seen in control subjects.

Aged↗