Encapsulation of water insoluble drugs in mesoporous silica nanoparticles using supercritical carbon dioxide

Mesoporous silica nanoparticles MCM – 41 were synthesized with two dimensional hexagonal p6mm symmetry, high specific surface area(~ 980m2/g) narrow pore size and an average particle size of 186 nm. The produced nanoparticles were used to encapsulate carbamazepine through a supercritical carbon dioxide process combined with various organic solvents. Supercritical processing was found to provide increased drug encapsulation. The loaded MCM - 41 nanoparticles were analyzed using X–ray diffraction and differential scanning calorimetry (DSC) to investigate the crystalline state of the encapsulated carbamazepine and it was found to be dependent on the nature of the organic solvent. Carbamazepine showed increased dissolution rates under sink conditions. Viability studies of Caco – 2 cells demonstrated negligible cytotoxicity for the MCM–41 nanoparticles

Engineering and manufacturing of pharmaceutical co-crystals : a review on solvent-free manufacturing technologies

Design and synthesis of pharmaceutical cocrystals have received great interest in the recent years. Cocrystallization of drug substances offer a tremendous opportunity for the development of new drug products with superior physical and pharmacological properties such as solubility, stability, hydroscopicity, dissolution rates and bioavailability. It is now possible to engineer and develop cocrystals via ‘green chemistry' and environmental friendly approaches such as solid-state synthesis in the absence of organic solvents. In addition, significant efforts are placed on computational screening, cocrystal manufacturing in a continuous manner and real-time monitoring for quality purposes by using various analytical tools. Pharmaceutical cocrystals are not fully exploited yet and there is a lot of ground to cover before they can be successfully utilized as medical products

Preparation and characterisation of free flowing solid lipid based drug delivery systems using a twin screw extruder

In this study, a continuous manufacturing process was developed for adsorbing liquid self-emulsifying drug delivery system (SEDDS) on mesoporous silica carriers in order to produce solid free flowing SEDDS powders. An optimized liquid SEDDS, consisting of Labrafil M 1944 CS, Labrasol and Capryol 90 (15, 80, 5 %w/w), was developed. The formulation spontaneously formed a homogenous emulsion with a droplet size of less than 200 nm (in water) and possessed pH robustness (pH 1.2, pH 6.8). Two grades of mesoporous silica were investigated as solid carriers, namely Syloid XDP 3050 and 3150. A twin screw extruder, setup in the granulation configuration, was employed to assess the mixing and adsorption of liquid SEDDS onto silica particles in a continuous process. Screw configuration, ratio of solid carrier to liquid SEDDS, powder and liquid feed rates and screw speed were identified as important parameters. These parameters were tested and optimized to achieve free flowing solid SEDDS. The maximum lipid loading of Syloid XDP 3050 and 3150 was 1:2 and 1:2 to less than 1:3 ratios, respectively. Although increasing liquid SEDDS loading increased the cohesive properties of the silica particles, the resulting powders afforded acceptable flow rate indexes as determined by powder rheometry. Similar self-emulsification behaviour was observed for solid and liquid SEDDS. With increasing lipid loading, the droplet size of emulsified solid SEDDS increased and changed from a unimodal to a bimodal size distributions. This effect was more pronounced for Syloid XDP3050. Syloid XDP 3150 was less sensitive to droplet size changes as its z-average diameters at 1:2-1:3 ratio were similar to the optimized liquid SEDDS. Targeting a lipid loading ratio of 2:1, process parameters were varied to maximise material throughput. The investigated continuous process of adsorbing liquid SEDDs onto solid carriers produced solid SEDDS with good flow properties. Syloid XDP 3150 seemed more robust to the process than Syloid XDP 3050

Bioinspired Silica Offers a Novel, Green, and Biocompatible Alternative to Traditional Drug Delivery Systems

Development of drug delivery systems (DDS) is essential in many cases to remedy the limitations of free drug molecules. Silica has been of great interest as a DDS due to being more robust and versatile than other types of DDS (e.g., liposomes). Using ibuprofen as a model drug, we investigated bioinspired silica (BIS) as a new DDS and compared it to mesoporous silica (MS); the latter has received much attention for drug delivery applications. BIS is synthesized under benign conditions without the use of hazardous chemicals, which enables controllable in situ loading of drugs by carefully designing the DDS formulation conditions. Here, we systematically studied these conditions (e.g., chemistry, concentration, and pH) to understand BIS as a DDS and further achieve high loading and release of ibuprofen. Drug loading into BIS could be enhanced (up to 70%) by increasing the concentration of the bioinspired additive. Increasing the silicate concentration increased the release to 50%. Finally, acidic synthesis conditions could raise loading efficiency to 62% while also increasing the total mass of drug released. By identifying ideal formulation conditions for BIS, we produced a DDS that was able to release fivefold more drug per weight of silica when compared with MCM-41. Biocompatibility of BIS was also investigated, and it was found that, although ∼20% of BIS was able to pass through the gut wall into the bloodstream, it was nonhemolytic (∼2% hemolysis at 500 μg mL–1) when compared to MS (10% hemolysis at the same concentration). Overall, for DDS, it is clear that BIS has several advantages over MS (ease of synthesis, controllability, and lack of hazardous chemicals) as well as being less toxic, making BIS a real potentially viable green alternative to DDS

<i>In vitro - in vivo </i>relations for the parenteral liposomal formulation of Amphotericin B:A clinically relevant approach with PBPK modeling

In vitro release testing is a useful tool for the quality control of controlled release parenteral formulations, but in vitro release test conditions that reflect or are able to predict the in vivo performance are advantageous. Therefore, it is important to investigate the factors that could affect drug release from formulations and relate them to in vivo performance. In this study the effect of media composition including albumin presence, type of buffer and hydrodynamics on drug release were evaluated on a liposomal Amphotericin B formulation (Ambisome®). A physiologically based pharmacokinetic (PBPK) model was developed using plasma concentration profiles from healthy subjects, in order to investigate the impact of each variable from the in vitro release tests on the prediction of the in vivo performance. It was found that albumin presence was the most important factor for the release of Amphotericin B from Ambisome®; both hydrodynamics setups, coupled with the PBPK model, had comparable predictive ability for simulating in vivo plasma concentration profiles. The PBPK model was extrapolated to a hypothetical hypoalbuminaemic population and the Amphotericin B plasma concentration and its activity against fungal cells were simulated. Selected in vitro release tests for these controlled release parenteral formulations were able to predict the in vivo AmB exposure, and this PBPK driven approach to release test development could benefit development of such formulations.</p

Incidence of Insomnia in OSA patients and its correlations with parameters of polysomnography

Background/Aims: Prevalence of insomnia in obstructive sleep apnoea (OSA) patients has been estimated in many studies and has been found to be a frequent symptom (38% in a recent review 1).Our study aims to estimate the incidence of insomnia in Greek patients presenting to a public hospital sleep clinic, and correlate it with the severity of OSA and parameters of polysomnography (PSG). Methods: 100 patients who visited the sleep unit of the General Hospital ‘Evangelismos’ completed the Athens Insomnia Scale (AIS) and underwent a polysomnographic study. 56% were men, with mean age 54,7±12,5 years and BMI 31,5±6,2. Results: 70% of patients had insomnia. Insomnia (AIS≥6) and OSA (AHI≥5) were coexistent in 71,4 %. There was no correlation between insomnia and severity of OSA. A strong positive correlation was found/evident between difficulty in initiating sleep and number of hypopneas (r: 0,20 p:0,049), diminished functioning during the day and leg movements (r:0,21 p:0,050) and between daytime sleepiness and wake after sleep onset (WASO) (r:0,2 p:0,038). A negative correlation was found between overnight awakenings and sleep efficiency (r: -0,23 p: 0,021). Also, negative correlation was found between early morning awakening and minimum SpO2 (r=0.27, p=0,021), and between insufficient duration of sleep (r:-0,22 p: 0,021) and minimum SpO2. Conclusions: We found a high incidence of insomnia in patients with OSA, which does not correlate with severity of OSA. Contrary to many other studies, insomnia was not more common in women. More studies are required to clarify the significance of the positive correlation between insomnia and number of hypopneas and minimum SpO2

Microfluidic encapsulation method to produce stable liposomes containing iohexol

Since the discovery of X-rays in the late 1890s, several medical imaging techniques have been developed, such as Computed Tomography (CT), Magnetic Resonance Imaging (MRI) and Ultrasound Imaging, which are used daily to diagnose, monitor, or treat medical conditions. Some of these techniques include the use of contrast agents to enhance the contrast images, therefore, toxic effects must be considered. Among these, Contrast-Induced Nephropathy (CIN) is an acute renal failure resulting from the administration of iodinated contrast media (CM). To date, there is no definitive treatment for CIN and several prevention approaches have been evaluated. Nanoparticles (NPs) represent a promising strategy for treatment and prevention of CIN, due to their ability to deliver CM during diagnosis imaging. In this study, iohexol-containing liposomes were produced using microfluidic technique for first time. Several phosphocholine lipids (e.g. DMPC, DOPC, DPPC and DSPC) with cholesterol (2:1 ratio) were investigated and DLS, FTIR and in vitro release studies at 37 °C were performed, with stability studies conducted on the best formulation. The microfluidic method allowed to obtain a high encapsulation efficiency (over 70%), and release profiles showed an iohexol release around or less than 0.12 mg/ml after 2 h for the majority of the formulations, which is not toxic to the kidney cells