Characterization of Dose Delivery and Spray Pattern of a Metered-Dose Flunisolide Nasal Spray

Flunisolide is a synthetic fluorinated corticosteroid with significant ant -inflammatory and anti-allergic activities. Flunisolide nasal solution (Nasalide®) is delivered by a unique pump-activated, non-propellant, metered-dose device. A previous paper (1) reported droplet size characterization of the nasal spray by a cascade impactor. This report describes the remaining physical characterizations, namely dose delivery and spray pattern, of this metered-dose delivery system as well as the suitability of the system for a therapeutic corticosteroid nasal solution.

Actuation of flunisolide nasal spray units by 10 subjects over time demonstrated good constancy of dose delivery for up to 24 days of use. The average dose delivery was 0.737 ± 0.040 gm/day (grand mean ± s.d.).

Actuation of similar units by 17 subjects over time showed good constancy of spray pattern, which was defined as the long and short diameters of the impaction pattern of the spray on a TLC plate, for the entire lifetime of the unit.     

In-Vitrodn-Vivo Correlation of Drug Liberation with an Extended Release Peroral Dosage form for Iloprost in Man

Abstract

Iloprost is a chemically stable prostacyclin analogue for which therapeutic efficacy was demonstrated after i.v. infusion treatment in several vascular diseases. In order to facilitate drug therapy and to enlarge therapeutic usability an peroral dosage form for non-hospitalized patients was developed on the basis of an extended release (ER) pellet formulation mimicking therapeutic plasma levels as obtained after i.v. infusion in man. Modified drug liberation was pH-independent and showed an in-vitro release of 75 to 95 5% of dose over 3 h at pH 7.4 using the basket method. In 12 PAOD-patients the pharmacokinetic profile of the ER-formulation in capsules (SH K 529 I/M) was characterized after repeated administration of 150 μg iloprost as compared to a standard i.v. infusion treatment with iloprost (Ilomedin®). Peroral treatment resulted in highly reproducible plasma level profiles in the therapeutic range (> 50 pg/ml) for approx. 6 h, i.e. a similar time period as obtained after i.v. infusion. Half-value duration was approx. 4 h. AUC accounted for 0.8 ± 0.2 ng·h/ml as compared to 1.0 ± 0.2 ng·h/ml (i.v.), bioavailability was 19 ± 5%. A level A correlation (1:1 correlation) of in-vitro liberation and in-vivo absorption could be set up based upon individual plasma level data by means of the Wagner-Nelson method. Linear correlations with a slope of approx. I were obtained when plotting dose fraction released in-vitro vs. dose fraction absorbed in-vivo. Half-lives of liberation in-vitro and in-vivo were similar. A lag-time for the onset of in-vivo absorption was observed caused by disintegration of the dosage form and liquid mediated formation of ER diffusion membrane on the pellets.

The present ER-dosage form of iloprost provides long-lasting plasma levels of iloprost in the therapeutic range and thus might be a clinically effective equivalent of i.v. infusion, which can easily be used by ambulant patients. The intraindividual reproducibility and the correlation of in-vitro and in-vivo performance of the modified release preparation are prerequisites for efficacy, safety and patient compliance.     

Radiation transport calculations for 50 MV photon therapy beam using the Monte Carlo code GEANT4

A new thin transmission target technique for fast dose delivery using narrow scanned photon beams has been developed. High-energy, 50-100 MeV, electron beams of low emittance incident on thin low-Z targets produce narrow and intense high-energy bremsstrahlung beams. However, electrons transmitted through the target are bent from the therapeutic beam by a purging magnet and have to be effectively absorbed in a dedicated electron collector. The electron-photon transport through a treatment head has been studied using the Monte Carlo simulation toolkit Geant4. The Geant4 electromagnetic physics processes have been compared with experimental data of radial dose profiles. The differences between calculated and measured radial dose distributions are approximately 2-10%. Preliminary investigations of the collector design have been carried out in order to minimise secondary electron and photon contamination of the therapeutic beam. The toolkit presented here is promising for further development of narrow photon beam therapy.     

Calculation of the Radiation Dose Absorbed by Human Biological Tissue When Using Imaging Equipment in Radiotherapy

Measurement Techniques - The issues of x-ray dose control during diagnostic and therapeutic procedures using imaging tools are considered. The dose of x-ray radiation absorbed by the biological...     

Neutron dose rate evaluation for medical linear accelerators

During X-ray therapeutic irradiation with energies above the threshold of (X,n) reactions in the structural materials of medical accelerators, a photoneutron fluence is generated. In Brazil, no measurements of neutron doses in radiotherapy rooms are being done yet, when licensing these equipment. Consequently, it is very important to obtain accurate analytical formulae and/or simulation of these dose rates, in order to estimate the increase in dose received by the patient and staff, as well as to correctly project the additional shielding for the treatment room. In this work, we present MCNP simulation of dosimetric quantities at the isocentre of some models of high-energy linear accelerators, and compare it with the values given by the manufacturers, finding good agreement between both.     

Characterization of Dose Delivery and Spray Pattern of a Metered-Dose Flunisolide Nasal Spray

Abstract

Flunisolide is a synthetic fluorinated corticosteroid with significant ant -inflammatory and anti-allergic activities. Flunisolide nasal solution (Nasalide®) is delivered by a unique pump-activated, non-propellant, metered-dose device. A previous paper (1) reported droplet size characterization of the nasal spray by a cascade impactor. This report describes the remaining physical characterizations, namely dose delivery and spray pattern, of this metered-dose delivery system as well as the suitability of the system for a therapeutic corticosteroid nasal solution.

Actuation of flunisolide nasal spray units by 10 subjects over time demonstrated good constancy of dose delivery for up to 24 days of use. The average dose delivery was 0.737 ± 0.040 gm/day (grand mean ± s.d.).

Actuation of similar units by 17 subjects over time showed good constancy of spray pattern, which was defined as the long and short diameters of the impaction pattern of the spray on a TLC plate, for the entire lifetime of the unit.     

A large-scale multicentre study in Belgium of dose area product values and effective doses in interventional cardiology using contemporary X-ray equipment

In this paper, a large-scale multicentre patient dose study performed in eight Belgian interventional cardiology departments is presented. Effective dose (E) was calculated based on a detailed dose-area product (DAP)-registration during each procedure and by using conversion coefficients generated by the Monte Carlo-based computer program PCXMC. Conversion coefficients were found to be 0.177 mSv Gycm(-2) for systems that do not use any additional copper filtration in cineradiography and 0.207 mSv Gycm(-2) for systems that use additional copper filtration in cineradiography. Mean E values of 9.6 and 15.3 mSv for diagnostic and therapeutic procedures, respectively, were obtained. DAP distributions were investigated in order to derive dose reference levels: 71 and 106 Gycm2 for diagnostic and therapeutic procedures, respectively, are proposed. Significant differences were observed in DAP distributions taking into account whether additional copper filtration was used in the cineradiography mode. Apart from the skin, the organs most at risk are lungs and heart. The probability of fatal cancer for the studied population amounted to 1.1x10(-4) and 2.1x10(-4) for diagnostic and therapeutic procedures, respectively, for the age distribution of the patients considered in this multicentre study.     

A New Ibuprofen Pulsed Release Oral Dosage Form

Abstract

Drug constant release is not always the desired solution for controlled drug administration; some therapeutic situations require consecutive pulses of active principle

A biphasic oral delivery system able to release an immediate dose of therapeutic agent as well as a further pulse of drug after some hours could be interesting

In order to obtain such desired releasing performances, a new system (three layer tablet) has been designed with the following characteristics

- an energy source, able to deliver the two divided doses of drug

- a control element, between the drug layers, able to delay the release of the second dose of drug. This control element acts as a barrier and is made with a mixture of water swellable polymers

- an outer film, which is made of water impermeable polymer, that covers the second dose of drug and the barrier

The new system works through subsequent interactions with aqueous fluids of the three different layers of material in the following order

1 - rapid interaction of the uncoated part of the system, and immediate disintegration of the first dose;

2 - slow interaction of the barrier and its gelation;

3 - interaction of the second drug layer and development of a force able to break the barrier thus promoting the release of the second dose of drug. Preliminary in vivo experiments carried out on this biphasic pulsed release device containing Ibuprofen as a model drug, show two distinct peaks in plasma profiles thus indicating that the in vitro results are in good agreement with the in vivo blood levels     

Pitfalls in the Use of Anticoagulants

Anticoagulants are in widespread use for the management of a variety of conditions, ranging from thrombus prevention to the treatment of arterial and venous occlusion. As with any effective therapy, recognition of adverse effects is critically important for the safe use of these drugs. Pitfalls in the use of heparins include dosing in close proximity to invasive procedures; not closely monitoring patients in whom dose adjustments may be required, such as the very obese, the elderly, and patients with renal or hepatic failure; failing to make dose adjustments during pregnancy; and not recognizing when patients are developing heparin‐induced thrombocytopenia or osteoporosis. Pitfalls in the use of unfractionated heparin include delays in achieving a therapeutic activated partial thromboplastin time (aPTT) and failure to consider the effects of protein binding in acutely ill patients. A pitfall in the use of low molecular weight heparin is giving prophylactic doses when therapeutic doses are indicated. Pitfalls in the use of warfarin are stopping heparin before the warfarin is fully effective; failing to maintain the International Normalized Ratio within the therapeutic range; failing to adjust the dose of warfarin because of changes in diet, renal or hepatic failure, and exposure to new drugs; failing to stop warfarin at an appropriate interval before an invasive procedure; and giving warfarin during pregnancy. Pitfalls in the use of thrombin inhibitors include using them with thrombolytic agents; giving them in proximity to invasive procedures; not adjusting the dose for renal or hepatic failure; and failing to consider the effect of these agents on the prothrombin time when initiating warfarin therapy.     

Developments in the internal dosimetry of radiopharmaceuticals

Various radionuclides are used in nuclear medicine in different diagnostic and therapeutic procedures. Recently, interest has grown in therapeutic agents for some interesting applications in nuclear medicine. Internal dose models and methods in use for many years are well established, and can give radiation doses to stylised models representing reference individuals. Kinetic analyses need to be carefully planned, and dose conversion factors that are most similar to the subject in question should be chosen, which can then be tailored somewhat to be more patient-specific. Internal dose calculations, however, are currently not relevant in patient management in internal emitter therapy, as they are not sufficiently accurate or detailed to guide clinical decision-making, and as calculated doses have historically not been well correlated with observed effects on tissues. Great strides are being made at many centres regarding the use of patient image data to construct individualised voxel-based models for more detailed and patient-specific dose calculations, and new findings are encouraging regarding improvement of internal dose models to provide better correlations of dose and effect. These recent advances make it likely that the relevance will soon change to be more similar to that of external beam treatment planning.     

Is hair loss a reality in neuro-interventional radiology?

Reports in the literature of radiation-induced hair loss are becoming increasingly common. This work describes a retrospective dose study of patients (n = 958) undergoing diagnostic (primarily cerebral angiograms) and therapeutic (primarily cerebral embolisation) procedures in a neuro-interventional suite. A comparison of patient doses as dose area product (DAP) readings from a single-plane image intensifier system (mean DAP value of 8772 cGy cm2) were compared with patient doses from a flat panel biplane system (mean DAP value of 7855 cGy cm2). Over 80 % of patients requiring neuro-interventional procedures were found to undergo two procedures or more. An estimated 7 % of therapeutic procedures were found to reach the International Commission on Radiological Protection threshold for temporary epilation.     

Boosting Interleukin‐12 Antitumor Activity and Synergism with Immunotherapy by Targeted Delivery with isoDGR‐Tagged Nanogold

The clinical use of interleukin‐12 (IL12), a cytokine endowed with potent immunotherapeutic anticancer activity, is limited by systemic toxicity. The hypothesis is addressed that gold nanoparticles tagged with a tumor‐homing peptide containing isoDGR, an αvβ3‐integrin binding motif, can be exploited for delivering IL12 to tumors and improving its therapeutic index. To this aim, gold nanospheres are functionalized with the head‐to‐tail cyclized‐peptide CGisoDGRG (Iso1) and murine IL12. The resulting nanodrug (Iso1/Au/IL12) is monodispersed, stable, and bifunctional in terms of αvβ3 and IL12‐receptor recognition. Low‐dose Iso1/Au/IL12, equivalent to 18–75 pg of IL12, induces antitumor effects in murine models of fibrosarcomas and mammary adenocarcinomas, with no evidence of toxicity. Equivalent doses of Au/IL12 (a nanodrug lacking Iso1) fail to delay tumor growth, whereas 15 000 pg of free IL12 is necessary to achieve similar effects. Iso1/Au/IL12 significantly increases tumor infiltration by innate immune cells, such as NK and iNKT cells, monocytes, and neutrophils. NK cell depletion completely inhibits its antitumor effects. Low‐dose Iso1/Au/IL12 can also increase the therapeutic efficacy of adoptive T‐cell therapy in mice with autochthonous prostate cancer. These findings indicate that coupling IL12 to isoDGR‐tagged nanogold is a valid strategy for enhancing its therapeutic index and sustaining adoptive T‐cell therapy.     

Janus Magnetic‐Plasmonic Nanoparticles for Magnetically Guided and Thermally Activated Cancer Therapy

Progress of thermal tumor therapies and their translation into clinical practice are limited by insufficient nanoparticle concentration to release therapeutic heating at the tumor site after systemic administration. Herein, the use of Janus magneto‐plasmonic nanoparticles, made of gold nanostars and iron oxide nanospheres, as efficient therapeutic nanoheaters whose on‐site delivery can be improved by magnetic targeting, is proposed. Single and combined magneto‐ and photo‐thermal heating properties of Janus nanoparticles render them as compelling heating elements, depending on the nanoparticle dose, magnetic lobe size, and milieu conditions. In cancer cells, a much more effective effect is observed for photothermia compared to magnetic hyperthermia, while combination of the two modalities into a magneto‐photothermal treatment results in a synergistic cytotoxic effect in vitro. The high potential of the Janus nanoparticles for magnetic guiding confirms them to be excellent nanostructures for in vivo magnetically enhanced photothermal therapy, leading to efficient tumor growth inhibition.     

Pharmacological activity of ibuprofen released from mesoporous silica

Novel drug delivery systems (DDS) to improve the pharmacokinetic profile of hydrophobic drugs following oral administration are an area of keen interest in drug research. An ideal DDS should not adversely affect drug activity, be capable of delivering a therapeutic dose of drug, and allow homogenous drug loading and drug release. Mesoporous silica has been proposed for this application, with ibuprofen employed as the model drug. It was hypothesised that mesoporous silica MCM-41 is capable of delivering a pharmacologically therapeutic dose of ibuprofen. Ibuprofen-loaded MCM-41 can be prepared reproducibly at a drug to carrier ratio of 30% (wt/wt). The release profile was seen to be 90% within 2 h. Initial assessment of COX-1 inhibitory activity suggests the absence of adverse effects attributable to drug-carrier interaction. The results of this study provide further evidence in support of the proposed use of mesoporous silica in drug delivery.     

External Temperature Effects on Interstitial Instrumentation Therapeutic Heating

Use of interstitial instrumentation for therapeutic heating is often compromised by uncontrollable thermal washout caused by stochastically distributed heat sinks. The heat sinks effects may be mitigated by, among others, control of the external temperature during the heating. For these procedures temporal characterization becomes crucial. We propose transient finite-element analysis (FEA) simulations as a reliable method of modeling the temporal behavior at different external temperatures. Heating curves obtained in measurements of ultrasonic heating in a brain phantom are modeled using the simulations. On achieving good agreement between the simulation and experimental results, we proceeded with the simulation of heating in a complex head model. Heating efficacy is described in terms of extent and volume of thermal dose. The extent and the volume increased by 40% to 100% for the temperatures of 18 to 47 degC. We found that there is monotonic but nonlinear dependence between the extent and the volume of the thermal dose on external temperature     

Challenges and progress in predicting biological responses to incorporated radioactivity

Prediction of risks and therapeutic outcome in nuclear medicine largely rely on calculation of the absorbed dose. Absorbed dose specification is complex due to the wide variety of radiations emitted, non-uniform activity distribution, biokinetics, etc. Conventional organ absorbed dose estimates assumed that radioactivity is distributed uniformly throughout the organ. However, there have been dramatic improvements in dosimetry models that reflect the substructure of organs as well as tissue elements within them. These models rely on improved nuclear medicine imaging capabilities that facilitate determination of activity within voxels that represent tissue elements of approximately 0.2-1 cm(3). However, even these improved approaches assume that all cells within the tissue element receive the same dose. The tissue element may be comprised of a variety of cells having different radiosensitivities and different incorporated radioactivity. Furthermore, the extent to which non-uniform distributions of radioactivity within a small tissue element impact the absorbed dose distribution is strongly dependent on the number, type, and energy of the radiations emitted by the radionuclide. It is also necessary to know whether the dose to a given cell arises from radioactive decays within itself (self-dose) or decays in surrounding cells (cross-dose). Cellular response to self-dose can be considerably different than its response to cross-dose from the same radiopharmaceutical. Bystander effects can also play a role in the response. Evidence shows that even under conditions of 'uniform' distribution of radioactivity, a combination of organ dosimetry, voxel dosimetry and dosimetry at the cellular and multicellular levels can be required to predict response.     

Occupational exposure to staff during endoscopic retrograde cholangiopancreatography in Sudan

Endoscopic retrograde cholangiopancreatography (ERCP) procedure is an invasive technique that requires fluoroscopic and radiographic exposure. The purpose of this study was to determine the occupational dose of ionising radiation at three gastroenterology departments (Fedial, Soba and Ibn seena hospitals) in Khartoum, Sudan. The radiation dose was measured during 55 therapeutic ERCP procedures. Thermoluminescence dosemeters were used. The mean radiation dose for the first operator was 0.27 mGy for the eye lens, 0.21 for the thyroid, 0.32 for the chest, 0.17 for the hand and 0.22 for the leg. The mean radiation dose for the second operator was 0.21 mGy for the hand and 0.20 mGy for the chest, while the mean radiation dose for the nurse was 0.44 mGy for the hand and 0.19 for the chest. The radiation dose received by the staff in these hospitals was found to be higher than most of the values in the literature. The radiation absorbed dose received by the different organs is relatively low. Additional studies need to be conducted for radiation dose optimisation.     

Neutron dose calculation at the maze entrance of medical linear accelerator rooms

Currently, teletherapy machines of cobalt and caesium are being replaced by linear accelerators. The maximum photon energy in these machines can vary from 4 to 25 MeV, and one of the great advantages of these equipments is that they do not have a radioactive source incorporated. High-energy (E > 10 MV) medical linear accelerators offer several physical advantages over lower energy ones: the skin dose is lower, the beam is more penetrating, and the scattered dose to tissues outside the target volume is smaller. Nevertheless, the contamination of undesirable neutrons in the therapeutic beam, generated by the high-energy photons, has become an additional problem as long as patient protection and occupational doses are concerned. The treatment room walls are shielded to attenuate the primary and secondary X-ray fluence, and this shielding is generally adequate to attenuate the neutrons. However, these neutrons are scattered through the treatment room maze and may result in a radiological problem at the door entrance, a high occupancy area in a radiotherapy facility. In this article, we used MCNP Monte Carlo simulation to calculate neutron doses in the maze of radiotherapy rooms and we suggest an alternative method to the Kersey semi-empirical model of neutron dose calculation at the entrance of mazes. It was found that this new method fits better measured values found in literature, as well as our Monte Carlo simulated ones.     

Measurement of neutron dose equivalent to proton therapy patients outside of the proton radiation field

Measurements of neutron dose equivalent values and neutron spectral fluences close to but outside of the therapeutic proton radiation field are presented. The neutron spectral fluences were determined at five locations with Bonner sphere measurements and established by unfolding techniques. More than 50 additional neutron dose equivalent values were measured with LiI and BF₃ thermal neutron detectors surrounded by a 25 cm polyethylene moderating sphere. For a large-field treatment, typical values of neutron dose equivalent per therapeutic proton absorbed dose, H/D, at 50 cm distance from isocenter, range from 1 mSv/Gy (at 0° with respect to the proton beam axis) to 5 mSv/Gy (at 90°). Experiments reveal that H/D varies significantly with the treatment technique, e.g., patient orientation, proton beam energy, and range-modulation. The relative uncertainty in H/D values is approximately 40% (one standard deviation).     

Review of novel materials as photosensitizers towards the bottleneck of photodynamic therapy

Journal of Materials Science - Photodynamic therapy (PDT) is a safe and effective therapeutic option for the management of cancer and other diseases. However, the issues of light (dose and...