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Biomedical subjects

Robert Price

Publications and source records attributed to Robert Price.

At least 19 recordsLinked to original sources
PubMed2006

In vitro investigation of drug particulates interactions and aerosol performance of pressurised metered dose inhalers.

PURPOSE: To determine a relationship between adhesive and cohesive inter-particulate forces of interactions and in vitro performance in pressurised metered dose inhalers (pMDIs) suspension formulations. METHODS: Interparticulate forces of salbutamol sulphate (SS), budesonide (BUD) and formoterol fumarate dihydrate (FFD) were investigated by in situ atomic force microscopy (AFM) in a model propellant 2H, 3H perfluoropentane (HPFP). Experimental data were analysed using the recently developed cohesive/adhesive analysis method (CAB) and compared with in vitro deposition performances in pMDIs systems using Andersen cascade impactor (ACI). RESULTS: The in vitro investigation suggested that the micronised drug materials had significantly different aerosolisation profiles when manufactured as single or combination formulations. In general, the greatest significant differences were observed between SS single drug and SS-BUD and SS-FFD combinations. Analysis of the in vitro performance for the SS only formulation suggested that the cohesive nature of SS (as predicted by the CAB and observed with AFM) led to tightly bound flocs that did not fully deaggregate upon aerosolisation. CONCLUSIONS: It is suggested that the relationship between interparticulate interactions and in vitro performance of pMDIs suspension systems, when compared to direct measurement of the adhesion/cohesion forces, indicated good correlation. This approach may be useful in expediting the development of pMDI formulation and predicting performance.

Adhesiveness↗
PubMed2006

Dehydration of trehalose dihydrate at low relative humidity and ambient temperature.

The physico-chemical behaviour of trehalose dihydrate during storage at low relative humidity and ambient temperature was investigated, using a combination of techniques commonly employed in pharmaceutical research. Weight loss, water content determinations, differential scanning calorimetry and X-ray powder diffraction showed that at low relative humidity (0.1% RH) and ambient temperature (25 degrees C) trehalose dihydrate dehydrates forming the alpha-polymorph. Physical examination of trehalose particles by scanning electron microscopy and of the dominant growth faces of trehalose crystals by environmentally controlled atomic force microscopy revealed significant changes in surface morphology upon partial dehydration, in particular the formation of cracks. These changes were not fully reversible upon complete rehydration at 50% RH. These findings should be considered when trehalose dihydrate is used as a pharmaceutical excipient in situations where surface properties are key to behaviour, for example as a carrier in a dry powder inhalation formulations, as morphological changes under common processing or storage conditions may lead to variations in formulation performance.

Calorimetry, Differential Scanning↗
PubMed2006

Commissioning and quality assurance of a commercial stereotactic treatment-planning system for extracranial IMRT.

A 3D treatment-planning system (TPS) for stereotactic intensity-modulated radiotherapy (IMRT) using a micro-multileaf collimator has been made available by Radionics. In this work, we report our comprehensive quality assurance (QA) procedure for commissioning this TPS. First, the accuracy of stereotaxy established with a body frame was checked to ensure accurate determination of a target position within the planning system. Second, the CT-to-electron density conversion curve used in the TPS was fitted to our site-specific measurement data to ensure the accuracy of dose calculation and measurement verification in a QA phantom. Using the QA phantom, the radiological path lengths were verified against known geometrical depths to ensure the accuracy of the ray-tracing algorithm. We also checked inter- and intraleaf leakage/transmission for adequate jaw settings. Measurements for dose verification were performed in various head/neck and prostate IMRT treatment plans using the patient-specific optimized fluence maps. Both ion chamber and film were used for point dose and isodose distribution verifications. To ensure that adjacent organs at risk receive dose within the expectation, we used the Monte Carlo method to calculate dose distributions and dose-volume histograms (DVHs) for these organs at risk. The dosimetric accuracy satisfied the published acceptability criteria. The Monte Carlo calculations confirmed the measured dose distributions for target volumes. For organs located on the beam boundary or outside the beam, some differences in the DVHs were noticed. However, the plans calculated by both methods met our clinical criteria. We conclude that the accuracy of the XKnifetrade mark RT2 treatment-planning system is adequate for the clinical implementation of stereotactic IMRT.

Brain Neoplasms↗
PubMed2006

Predicting the behavior of novel sugar carriers for dry powder inhaler formulations via the use of a cohesive-adhesive force balance approach.

The aim of this work was to utilize the recently developed cohesive-adhesive balance (CAB) technique for analyzing quantitative AFM measurements to compare the relative forces of interaction of micronized salbutamol sulfate particles and a selection of specifically grown sugar substrates (beta cyclodextrin, lactose, raffinose, trehalose and xylitol). The interfacial behavior was subsequently related to the in-vitro delivery performance of these sugars as carrier particles in dry powder inhalation (DPI) formulations. The CAB analysis indicated that the rank order of adhesion between salbutamol sulfate and the sugars was beta cyclodextrin < lactose < trehalose < raffinose < xylitol. The beta cyclodextrin was the only substrate with which salbutamol sulfate demonstrated a greater cohesive behavior. All other sugars exhibited an adhesive dominance. In-vitro deposition performance of the salbutamol sulfate based carrier DPI formulations showed that the rank order of the fine particle fraction (FPF) was beta cyclodextrin > lactose > raffinose > trehalose > xylitol. A linear correlation (R(2) = 0.9572) was observed between the FPF and cohesive-adhesive ratios of the AFM force measurements. The observed link between CAB analysis of the interactive forces and in-vitro performance of carrier based formulations suggested a fundamental understanding of the relative balance of the various forces of interaction within a dry powder formulation may provide a critical insight into the behavior of these formulations.

Adhesiveness↗
PubMed2006

The use of colloid probe microscopy to predict aerosolization performance in dry powder inhalers: AFM and in vitro correlation.

The atomic force microscope (AFM) colloid probe technique was utilized to measure cohesion forces (separation energy) between three drug systems as a function of relative humidity (RH). The subsequent data was correlated with in vitro aerosolization data collected over the same RH range. Three drug-only systems were chosen for study; salbutamol sulphate (SS), triamcinolone acetonide (TAA), and di-sodium cromoglycate (DSCG). Analysis of the AFM and in vitro data suggested good correlations, with the separation energy being related inversely to the aerosolization performance (measured as fine particle fraction, FPF(LD)). In addition, the relationship between, cohesion, RH, and aerosolization performance was drug specific. For example, an increase in RH between 15% and 75% resulted in increased cohesion and decreased FPF(LD) for SS and DSCG. In comparison, for TAA, a decrease in cohesion and increased FPF(LD) was observed when RH was increased (15-75%). Linear regression analysis comparing AFM with in vitro data indicated R(2) values > 0.80, for all data sets, suggesting the AFM could be used to indicate in vitro aerosolization performance.

Administration, Inhalation↗
PubMed2006

The influence of fine excipient particles on the performance of carrier-based dry powder inhalation formulations.

The inclusion of a small amount of fine particle excipient in a carrier-based dry powder inhalation system is a well researched technique to improve formulation performance and is employed in the pharmaceutical industry. The removal of intrinsic fines from a lactose carrier has been found to decrease formulation performance, whereas adding fines of many different materials into formulations increased performance. Changing the particle size of these fines, the amount added and the technique by which they were prepared also affected formulation behaviour. Despite this body of research, there is disagreement as to the mechanism by which fines improved formulation performance, with two main hypotheses presented in the literature. The first hypothesis suggested that fines prevent the drug from adhering to the strongest binding sites on the carrier, whilst the second proposed that fine particles of drug and excipient form mixed agglomerates that are more easily dispersed and deaggregated during aerosolisation. The evidence in support of each hypothesis is limited and it is clear that future research should aim to produce stronger mechanistic evidence. The investigation of interparticulate interactions using techniques such as atomic force microscopy and inverse gas chromatography may prove useful in achieving this aim.

Adhesiveness↗
PubMed2006

Novel temperature controlled surface dissolution of excipient particles for carrier based dry powder inhaler formulations.

The surface of lactose monohydrate was modified by solution phase variable temperature dissolution. Lactose monohydrate crystals were added to a known volume of a saturated solution of lactose monohydrate at 25 degrees C. The temperature of the mixture was then ramped to either 30, 35, 40, or 50 degrees C to produce lactose monohydrate batches with reduced levels of fines and lower surface roughness. A dramatic decrease in surface roughness with increasing dissolution temperature was visually observed using scanning electron microscopy. Particle size analysis suggested that the level of lactose fines was reduced after treatment at the lowest dissolution temperature, 30 degrees C. Evaluation of the samples' drug aerosolization using a twin stage impinger, after blending with salbutamol sulphate, suggested that even though there were dramatic changes in roughness and particle size distribution after surface dissolution at 30 degrees C, there was no significant difference in aerosolization as measured by fine particle fraction. However, after surface dissolution at 35 degrees C, there was an increase in fine particle fraction. Surface dissolution at even higher temperatures did not result in any further increase in fine particle fraction. These observations suggest that surface roughness and fines play an important role in the aerosolization of salbutamol sulphate, but the inter-relationships are not straightforward.

Adrenergic beta-Agonists↗
PubMed2005

Comparative study of erythritol and lactose monohydrate as carriers for inhalation: atomic force microscopy and in vitro correlation.

The adhesion of micronised salbutamol sulphate to two carrier excipients, lactose monohydrate and erythritol, was investigated using the atomic force microscope (AFM) colloid probe technique and correlated with their respective physico-mechanical properties and aerosolisation performance. The particle size, morphology and moisture sorption properties of the carriers were similar thereby allowing direct comparison of functionality. AFM force measurements (n = 1024 force curves) were obtained between salbutamol sulphate drug probes (n = 4) and the excipients, as 63-90 microm sieve fractions and atomically smooth crystals. In general, significant differences in drug adhesion to lactose monohydrate and erythritol were observed (ANOVA, p<0.05), with erythritol exhibiting relatively greater adhesiveness. A linear relationship between drug probe adhesion to lactose monohydrate and drug probe adhesion to erythritol was established with salbutamol sulphate-lactose monohydrate adhesion being 60-70% of that of the erythritol system. In vitro analysis suggested good correlation with the adhesion measurements. The aerosolisation of salbutamol sulphate from erythritol carrier particles was significantly less (ANOVA, p<0.05) than from lactose monohydrate, with a fine particle dose (<6.4 microm) of 41.9 +/- 7.4 microg and 24.9 +/- 3.1 microg for the lactose monohydrate and erythritol carriers, respectively (n = 3).

Administration, Inhalation↗
PubMed2005

Target localization for post-prostatectomy patients using CT and ultrasound image guidance.

We conducted a study comparing B-mode acquisition and targeting (BAT) ultrasound alignments based on CT data in the postoperative setting. CT scans were obtained with a Primatom CT-on-rails on nine patients. Two CT scans were obtained each week, while setup error was minimized by BAT ultrasounds. For the first three patients, a direct comparison was performed. For the next six patients, a template based on the shifts from the week 1 CT during treatment was used for subsequent setup. Comparison of isocenter shifts between the BAT ultrasound and CT was made by the difference, absolute difference, and improvement (using CT alignments as the reference technique). A total of 90 image comparisons were made. The average interfraction motion was 3.2 mm in the lateral, 3.0 mm in the longitudinal, and 5.1 mm in the AP direction. The results suggest that the CTbased ultrasound templates can improve the localization of the prostate bed when the initial displacements are greater than 4 mm. For initial displacements smaller than 4 mm, the technique neither improved nor worsened target localization. However, ultrasound alignments performed without the use of a template deteriorated patient positioning for two out of three patients, demonstrating that the use of a CT template was beneficial even at small initial displacements.

Humans↗
PubMed2005

Growth spiral activity and step velocities on a crystal surface.

The normal growth rates and slopes of the dominant growth spirals on a crystal face were measured using a novel application of interferometry and atomic force microscopy. The dislocations responsible for the spirals were also observed directly. In this way it was shown that the velocities of similar steps on growth spirals of different activity, growing simultaneously on the same crystal face, were the same, and hence independent of the growth spirals to which they belonged. With this information the relative activities of the spirals were quantified and discussed in terms of hollow dislocation cores and the back-stress effect.

Journal Article↗
PubMed2005

Surface energy and interparticle forces correlations in model pMDI formulations.

PURPOSE: To compare experimental measurements of particle cohesion and adhesion forces in a model propellant with theoretical measurements of the interfacial free energy of particulate interactions; with the aim of characterizing suspension stability of pressurized metered dose inhalers (pMDIs). METHODS: Interparticulate forces of salbutamol sulfate, budesonide, and formoterol fumarate dihydrate were investigated by in situ atomic force microscopy (AFM) in a model propellant 2H,3H perfluoropentane. The surface thermodynamic properties were determined by contact angle (CA) and inverse gas chromatography (IGC). Experimental data were compared with theoretical work of adhesion/cohesion using a surface component approach (SCA), taking into account both dispersive and polar contributions of the surface free energy. RESULTS: Results indicated that the measured forces of interaction between particles in model propellant could not be accounted for by theoretical treatment of the dispersive surface free energies via CA and IGC. A correlation between theoretical work of adhesion/cohesion and AFM measurements was observed upon the introduction of the polar interfacial interactions within the SCA model. CONCLUSIONS: It is suggested that the polar contributions of the surface free energy measurements of particles may play a crucial role in particle interaction within propellant-based systems. Together with the application of a SCA model, this approach may be capable of predicting suspension stability of pMDI formulations.

Albuterol↗
PubMed2005

The influence of dose on the performance of dry powder inhalation systems.

The relationship between drug/lactose ratio and aerosolisation performance of conventional carrier based formulations was investigated using the twin stage impinger. A dose range of approximately 10-450 microg of drug in a 50 mg lactose carrier formulation was studied. Statistical differences in both the fine particle dose and fine particle fraction were observed across the dosage range (ANOVA, p<0.05). In general, no statistically significant difference (Fishers Pairwise, p<0.05) in fine particle dose was observed between drug levels of approximately 10 microg and 135 microg, whereas a linear decrease in fine particle fraction was observed across the same drug level range (R2=0.977). Increasing the dose from approximately 135 microg to 450 microg resulted in a statistically significant increase in both fine particle dose and fraction (ANOVA p<0.05). Such observations may be attributed to the occupation of 'active' carrier sites by drug particles at low drug concentration, since the quantity of drug particles liberated from the carrier during aerosolisation remains constant at the lower dosing regimes.

Drug Delivery Systems↗
PubMed2005

On the physical transformations of processed pharmaceutical solids.

Atomic force microscopy Phase Imaging, an adaptation of Tapping Mode AFM was used to visualise physico-mechanical variations on the surface of crystalline materials after being subjected to mechanically induced lattice damage. Large crystals (100-500 microm) of lactose were nucleated on AFM sample stubs, imaged and subjected to a milling process. The milled samples were then imaged at specific humidity using Phase Imaging. Phase and Amplitude images of the re-crystallised lactose suggested an ordered crystalline state with multiple platelets present across the surface. In comparison, the morphology and surface properties after a 1-min mill time suggested milling had a dramatic effect on the surface characteristics of the re-crystallised lactose. Phase and Topographical imaging during exposure to elevated humidities (70% RH) indicated both morphological and physico-mechanical changes that may be linked to surface amorphous re-crystallisation.

Crystallization↗
PubMed2005

Effect of balance training on muscle activity used in recovery of stability in children with cerebral palsy: a pilot study.

This study explored possible neural mechanisms that contribute to improvements in balance control produced by reactive balance training in children with cerebral palsy (CP). Six children with CP (four males, two females; mean age 9y 4mo), two with spastic hemiplegia (Gross Motor Function Classification System [GMFCS] level I) and four with spastic diplegia (GMFCS level II,) were given 5 days of intensive training in reactive balance control (100 perturbations per day on a moveable force platform). Surface electromyography was used to characterize changes in neuromuscular responses pretraining, immediately posttraining, and 1 month posttraining. Training in reactive balance control resulted in improvements in directional specificity of responses (a basic level of response organization) and other spatial/temporal characteristics including: (1) faster activation of muscle contraction after training, allowing children to recover stability faster; (2) emergence of a distal-proximal muscle sequence; and (3) improved ability to modulate the amplitude of muscle activity (increased amplitude of agonist and decreased amplitude of antagonist, reducing coactivation). Each child with spastic hemiplegia or diplegia showed a different combination of factors that contributed to improved performance; the level of change in neural factors depended on the severity of involvement of the child: hemiplegia vs diplegia, and level of involvement within each diagnostic category.

Adolescent↗
PubMed2005

Dynamic vapor sorption properties of sodium starch glycolate disintegrants.

Dynamic vapor sorption (DVS) was used to determine the moisture sorption properties of sodium starch glycolates. The results were compared to similarly obtained data for potato starch, pregelatinized starch, microcrystalline cellulose (MCC), and crystalline lactose. As expected, sodium starch glycolates exhibit a large mass gain at 90% relative humidity (RH), compared to the other anhydroglucose-based excipients. However, the sorption capacities of potato starch and the modified starches between 10%-70% RH were similar. Analysis of the DVS data using the Brunauer-Emmett-Teller (BET) and Guggenheim, Anderson, and deBoer (GAB) theories to obtain the so-called monolayer (Xm), as expected, showed that there was an increasing Xm with apparent mass gain that is probably related to crystallinity, purity, and surface area and represents the number and accessibility of amorphous anhydroglucose units present. The value of x(m) was related to the degree of crystallinity or order as determined by X-ray diffraction, suggesting that x(m) can be used to further describe the amorphous nature of semi-crystalline polymers containing anhydroglucose units, in particular the chemically modified sodium starch glycolate. Additionally, it appears that the sorption capacity between 10%-70% RH is not dramatically affected by the presence or type of cross-linking and sodium carboxymethylation (in sodium starch glycolates) and gelatinization (in pregelatinized starch) and that the superdisintegrant properties of the sodium starch glycolates are a consequence of some water-structure interaction that is well beyond the available number of hydration sites, as represented by x(m). Further evaluation of the structure and sorption properties of excipients may aid the development of disintegrants for solid dosage forms.

Absorption↗
PubMed2005

Dosimetry validation of treatment room shielding design.

Intensity-modulated radiation therapy (IMRT) can lead to an increase in leakage radiation. The total number of monitor units (MUs) for IMRT is typically 2-5 times that for conventional treatments [the ratio of the two is used to derive the effective modulation scaling factor (MSFeff)]. Shielding calculations for IMRT can be done by applying the MSFeff to measured exposures under conservative conditions (standard beam setup 40 cm x 40 cm field, 45 degrees collimator angle) to account for the increased leakage. In this work, we verified this approach for two existing vaults housing a Siemens Primart 6 MV linac and a Varian 21Ex 10 MV linac. We measured the cumulative exposures at various locations around the vaults for typical IMRT cases and for the standard beam setup using the same MUs. For the standard beam setup, the IMRT gantry angles and eight equally spaced angles were used. Estimations of weekly exposures for IMRT were carried out using exposure rates measured under standard beam setup and the MSFeff averaged over 20 treatment cases. The accumulated exposures under realistic IMRT conditions were 30%-50% lower than the estimated values using equally spaced gantry angles except for two locations where the real IMRT leakage was higher than the estimated value by approximately 10%. Measurements using the same gantry angles yielded similar results. Our results indicate that it is adequate to use the MSFeff and previously measured exposures to estimate the leakage increase due to IMRT for an existing vault. Different approaches should be followed when considering primary or secondary barriers since the standard beam setup is overestimating the exposures behind primary barriers compared to IMRT. In such cases, a 10 cm x 10 cm field can be used for more accurate shielding evaluation.

Computer-Aided Design↗
PubMed2004

The potential use of Raman mapping to investigate in vitro deposition of combination pressurized metered-dose inhalers.

Scanning near-infrared Raman microscopy has been used to map aerosol particulate deposits produced from pressurized metered-dose inhalers (pMDI). A commercially available combination asthma therapy pMDI (Ventide, Allen and Hanbury, UK), containing salbutamol and beclometasone dipropionate, was analyzed by conventional in vitro quantitative analysis and scanning Raman microscopy. Raman maps, taken from Andersen cascade impactor plate stages 3 and 5 (over 100 x 100 microm areas) suggested good correlation with chemical analysis of the respective stages. Scanning Raman microscopy allows visual differentiation between formulation components (not possible using conventional imaging techniques), while potentially allowing chemical quantification.

Aerosols↗