Oral drug delivery remains the most physiological and therefore the most preferred, simplest and easiest administration route. Nevertheless, a multitude of potentially clinically important drugs will ...not reach the market or achieve their full potential unless their oral bioavailability is improved by formulation. The aim of this review is to present an overview of properties, formulation, excipients and characterization of solid dispersions corresponding to one of the different formulation strategies for design and development of poorly soluble drugs. This work will review and compare in detail the evolution of solid dispersions focused on the different methods of formulation and production of solid dispersions, their stability, their release properties, their pharmacokinetics and methods for their physicochemical characterization.
Cyclosporine (CsA) has a selective property of suppressing various T-lymphocyte functions. This is of utmost importance in preventing allograft rejection by several organ transplantations, as well as ...in the treatment of systemic and local autoimmune disorders. However, the poor water solubility of CsA can be a major hurdle for its absorption into the blood stream, which leads to low bioavailability and thus less efficacy. The aim of this study was to prepare, characterize, and evaluate in vitro as well as in vivo, the potential of the innovative CsA drug delivery system. The latter contains CsA in spherical amorphous solid dispersion (SASD) which is embedded in an original α-cyclodextrin and β-cyclodextrin polymer mixture (Poly-αβ-CD) as a multifunctional amorphous carrier. The new developed SASD formulation showed that CsA was molecularly dispersed in αβ-cyclodextrins in an amorphous form, as was confirmed by physicochemical characterization studies. Interestingly, the peptide secondary structure, and thus, the drug activity was not impacted by the preparation of SASD as was shown by circular dichroism. Furthermore, the in vitro CsA release profile kinetics was almost identical to the commercially available product Neoral
. This study presents the first in vivo proof-of-concept for a novel drug delivery system based on Poly-αβ-CD containing CsA, with SASD allowing for increased bioavailibility. The pharmacokinetic parameters of cyclosporine A from the spherical spray-dried dispersion formulation was demonstrated in a "rat" animal model. For comparison, the commercially available Neoral® was studied. Importantly, the pharmacokinetic parameters were improved by extending
from 2 to 3 h after the oral administration in rats, and eventually preventing the enterohepatic circulation. All these results clearly demonstrate the improved pharmacokinetic parameters and enhanced bioavailability of CsA in the new developed drug delivery system. These data demonstrated the superiority of the newly developed Poly-αβ-CD formulation for oral administration of the poorly soluble CsA in vivo without altering its secondary structure. Poly-αβ-CD can be a very useful tool for the oral administration of poorly water-soluble drugs.
Abstract The in vivo X-ray micro-computed tomography (micro-CT) is a very powerful and non-invasive tool used to establish high-resolution images with isotropic voxels in typical scan times ranging ...from minutes to tenths of minutes. This preclinical imaging technology is primarily adapted to visualize bones. X-ray imaging of soft tissues is made possible by using opaque compounds, providing contrast through tissue vascularization. Thus, using control agents with a long-lasting time in the blood, active or passive targeting of soft tissue is made possible in small animals. In this respect, the use of hydrophilic iodinated X-ray contrast media remains limited due to their rapid blood clearance, albeit at a slightly slower pace in humans as compared with rodents. The development of an iodinated contrast medium with increased vascular residence time is thus necessary. This is precisely the scope of the present paper, which will review and compare in detail the different vectors used as long-circulating iodinated contrast agents for micro-CT, i.e. liposomes, nano-emulsions, micelles, dendrimers and other polymeric particles. The discussion is focused, for each of these nanoparticulate systems, on their method of formulation and production, their stability properties, encapsulation properties, release properties, pharmacokinetics, and toxicology. The different aspects relative to the adaptation of these properties and physico-chemical characteristics for blood pool contrast agents aimed at angiographic micro-CT applications are also discussed. The aim of this review is to propose an overview into the formulation and properties of iodinated micro-CT contrast agents for preclinical applications.
In the present study, new polymer microspheres of amphotericin B (AmB) were prepared by a spray drying technique using cyclodextrin polymers (Poly-CD) to improve the solubility and dissolution of ...AmB, to prevent in vivo toxic AmB aggregations. Formulations were characterized through scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), thermal analysis, Raman spectroscopy, particle size, drug purity test and in vitro release studies. The analysis indicated that the chemical structure of AmB remained unchanged in the amorphous solid dispersion, but the structure was changed from crystalline to amorphous. AmB was completely release from such optimized formulations in dissolution media in 40 min. This work may contribute to a new generation of spherical amorphous solid dispersion using a cyclodextrin polymer, which has implications for the possibility of drug development for oral utilization or as powder aerosols for pulmonary administration.
Abstract Inorganic nanomaterials based on heavy elements represent a new class of contrast agents for X-ray computed tomography (CT). Recent advances have shown that these materials are highly suited ...for CT imaging due to their high density and X-ray absorption capabilities. In this contribution, we demonstrated that tungsten oxide (WO3 ) nanoparticles coated by poly- ε -caprolactone (PCL) can be used as efficient contrast agent for CT imaging. The obtained particles were characterized by electron microscopy (TEM and SEM), and dynamic light scattering (DLS). We also validated their use for enhanced in vivo imaging, since these nanoparticles were observed to display high X-ray attenuation properties and circulation time (up to 3 h), permitting blood pool imaging.
The context of the this research is the development of nanoparticulate systems exhibiting long circulation times in the blood pool, loaded with X-ray contrasting compounds, to be used as blood pool ...contrast agents in computed tomography. This study presents an original, new and simple formulation of radiopaque nano-emulsions composed of iodinated oil, formed by a spontaneous emulsification method. As a result, extremely monodisperse, iodinated nano-droplets were generated, ranging in size from 20 to 190 nm, presenting an iodine concentration of around 85 mg I/mL, and coated with a polyethylene glycol shell which ensured their stealth properties against the immune system in the blood stream. In vivo assays demonstrated a significant contrast effect, along with a long residence in the blood pool. This study highlights novel nano-formulations used as efficient contrast agents for preclinical X-ray imaging applications, along with simple and efficient alternatives for the generation of iodinated nano-emulsions.
Purpose
The coronavirus disease 2019 (COVID-19) pandemic reshaped the usual risk: benefit equilibrium that became a trade-off between the infection exposure risk for the patient (and for staff) and ...the risk associated with delaying or cancelling the nuclear medicine examination. This study aimed at quantifying the impact of the first COVID-19 lockdown in France on nuclear medicine examination volume together with volume of examination cancellation and non-attendance.
Methods
We retrospectively assessed the volume of planned examinations from 1 month before to 1 month after the first lockdown in French high-volume nuclear medicine departments (NMD) sharing the same information management system including both university hospitals, UH (
n
= 7), and cancer centres, CC (
n
= 2).
Results
The study enrolled 31,628 consecutive patients referred for a nuclear medicine examination performed or not (NMEP or NMEnP). The total volume of NMEP significantly dropped by 43.4% between the 4 weeks before and after the starting of the lockdown. The comparison of the percentage of NMEP and NMEnP between UH and CC is significantly different (
p
< 0.001). The percentage of NMEP during the study was 67.9% in UH vs 84.7% in CC. Percentages of NMEnP in UH and CC were due respectively to cancellation by the patient (14.9 vs 7.4%), cancellation by the NMD (9.5 vs 3.4%), cancellation by the referring physician (5.1 vs 4.4%) and non-attender patients (2.7 vs 0.2%).
Conclusion
The study underlines the public health issue caused by COVID-19 above the pandemic itself and should be useful in preparing for potential resource utilisation and staffing requirements.
Abstract Micro-computed tomography (micro-CT) is an emerging imaging modality, due to the low cost of the imagers as well as their efficiency in establishing high-resolution (1–100 μm) ...three-dimensional images of small laboratory animals and facilitating rapid, structural and functional in vivo visualization. However use of a contrast agent is absolutely necessary when imaging soft tissues. The main limitation of micro-CT is the low efficiency and toxicity of the commercially available blood pool contrast agents. This study proposes new, efficient and non-toxic contrast agents for micro-CT imaging. This formulation consists of iodinated vitamin E ( α -tocopheryl 2,3,5-triiodobenzoate) as an oily phase, formulated as liquid nano-emulsion droplets (by low-energy nano-emulsification), surrounded by a hairy PEG layer to confer stealth properties. The originality and strength of these new contrast agents lie not only in their outstanding contrasting properties, biocompatibility and low toxicity, but also in the simplicity of their fabrication: one-step synthesis of highly iodinated oil (iodine constitutes 41.7% of the oil molecule weight) and its spontaneous emulsification. After i.v. administration in mice (8.5% of blood volume), the product shows stealth properties towards the immune system and thus acts as an efficient blood pool contrast agent ( t1/2 = 9.0 h), exhibiting blood clearance following mono-exponential decay. A gradual accumulation predominantly due to hepatocyte uptake is observed and measured in the liver, establishing a strong hepatic contrast, persistent for more than four months. To summarize, in the current range of available or developed contrast agents for preclinical X-ray imaging, this agent appears to be one of the most efficient.
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•Dosimetry for SIRT is becoming of paramount importance to achieve the best outcome.•Computer aided voxel-based dosimetry is different from conventional dosimetry.•Tumor overlap by ...SIRT and tumoral dosimetry are related to the overall survival.•Voxel-based dosimetry should be included in management of SIRT patients.
Selective Internal Radiation Therapy (SIRT) is used for the treatment of hepatic tumors. The aim of this retrospective study was to compare two dosimetric approaches based on 99mTc-MAA SPECT/CT and 90Y PET/CT, using Simplicit90Y™ versus the supplier suggested method of activity calculation.
A total of 19 patients underwent 21 SIRT after baseline angiography and 99mTc-MAA SPECT/CT, followed by 90Y PET/CT. Overlap between 99mTc-MAA and 90Y-microspheres was quantified with different thresholds isocontours. The perfused volume and tumor absorbed dose were estimated using Simplicit90Y™ based on SPECT/CT and PET/CT, then compared with the supplier suggested method. These data were related to overall survival to evaluate their prognostic impact.
The overlap between PET/CT and SPECT/CT was dependent on thresholds, decreasing with an increasing threshold. The overlap between the 99mTc-MAA and 90Y-microspheres biodistributions versus the tumor distribution on morphological imaging was suboptimal, in particular for small tumor volume. The tumor absorbed dose estimated after 90Y PET/CT was not different from tumor absorbed dose estimated after SPECT/CT. The Perfused lobe absorbed dose was significantly lower while the volume of the perfused lobe was significantly higher when estimated by Simplicit90Y™ compared to the supplier suggested conventional approach. A statistical parameter based on overlap between tumor and 90Y-microspheres distribution as well as tumoral dosimetry was significantly related to the overall survival.
Post-treatment imaging remains paramount to estimate the irradiation dosimetry, due to an imperfect overlap. The perfused volume could be estimated from functional imaging, given its impact on dosimetry. Finally, survival seems related to tumoral overlap and dosimetry.
Impact of free surfactant (Cremophor ELP) on the pharmacokinetics of iodinated nano-emulsions produced by emulsification by spontaneous surfactant diffusion. The reduction of free surfactant induced ...a decrease of the nano-emulsions half-life in blood.
This study presents new important aspects in the design of contrast agents for X-ray preclinical imaging. The first one is a new simple formulation of long circulating contrast agents, formulated from a commercial iodinated oil, and resulting in CT contrast agents containing more than twice the iodine concentration commercial contrast agents. The second point is a methodological aspect, utilizing tangential filtration for reducing the residual surfactants in the bulk phase and serving as well for concentrating droplets (and iodine) in the suspension. The last point is a more general aspect regarding the influence of the free surfactant on the pharmacokinetics and biodistribution of the nano-emulsion droplets on mice. We showed that cross-flow filtration is efficient for concentrating the droplets and reducing the concentration of free surfactant from 10wt.% to 1wt.%, without any changes in the nano-emulsion droplet morphologies or surface properties. We also showed that the presence of free surfactant has a significant impact on the elimination way of the nano-emulsion droplets, shared between liver and kidneys. The purified nano-emulsions are preferentially eliminated by the kidneys in contrast to raw nano-emulsions, predominantly eliminated by the liver. In practice, for two similar suspensions, half-life decreases from 4.1±1.10h to 2.5±0.77h before and after purification. Since the design and development of long circulating systems are critical in numerous domains, and not for preclinical CT imaging, this study presents important results in that field, taken under a formulation and technical point of view.
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