An Intravenous Pharmacokinetic Study of Cannabidiol Solutions in Piglets through the Application of a Validated Ultra-High-Pressure Liquid Chromatography Coupled to Tandem Mass Spectrometry Method for the Simultaneous Quantification of CBD and Its Carboxylated Metabolite in Plasma.

Cannabidiol (CBD) has multiple therapeutic benefits that need to be maximized by optimizing its bioavailability. Numerous formulations are therefore being developed and their pharmacokinetics need to be studied, requiring analytical methods and data from intravenous administration. As CBD is susceptible to hepatic metabolism, the requirement of any method is to quantify metabolites such as 7-COOH-CBD. We demonstrated that CBD and 7-COOH-CBD could be simultaneously and correctly quantified in piglet plasma by using an UHPLC-MS/MS technique. The validated method allowed for an accurate bioanalysis of an intravenously injected solution consisting of CBD-HPßCD complexes. The experimental pharmacokinetic profile of CBD showed multi-exponential decay characterized by a fast apparent distribution half-life (0.25 h) and an elimination half-life of two hours. The profile of 7-COOH-CBD was not linked with the first-pass metabolism, since 80% of the maximum metabolite concentration was reached at the first sampling time point, without any decrease during the period of study. A two-compartment model was optimal to describe the experimental CBD profile. This model allowed us to calculate macro-micro constants and volumes of distribution (Vss = 3260.35 ± 2286.66 mL) and clearance (1514.5 ± 261.16 mL·h-1), showing that CBD is rapidly distributed to peripheral tissues once injected and slowly released into the bloodstream.

Preformulation study for the selection of a suitable polymer for the development of ellagic acid-based solid dispersion using hot-melt extrusion.

Ellagic acid is one of the most studied polyphenolic compounds due to its numerous promising therapeutic properties. However, this therapeutic potential remains difficult to exploit owing to its low solubility and low permeability, resulting in low oral bioavailability. In order to allow an effective therapeutic application of EA, it is therefore necessary to develop strategies that sufficiently enhance its solubility, dissolution rate and bioavailability. For this purpose, solid dispersions based on pre-selected polymers such as Eudragit® EPO, Soluplus® and Kollidon® VA 64, with 5% w/w ellagic acid loading were prepared by hot extrusion and characterized by X-ray diffraction, FTIR spectroscopy and in vitro dissolution tests in order to select the most suitable polymer for future investigations. The results showed that Eudragit® EPO was the most promising polymer for ellagic acid solid dispersions development because its extrudates allowed to obtain a solution supersaturated in ellagic acid that was stable for at least 90 min. Moreover, the resulting apparent solubility was 20 times higher than the actual solubility of ellagic acid. The extrudates also showed a high dissolution rate of ellagic acid (96.25% in 15 min), compared to the corresponding physical mixture (6.52% in 15 min) or the pure drug (1.56% in 15 min). Furthermore, increasing the loading rate of ellagic acid up to 12% in extrudates based on this polymer did not negatively influence its release profile through dissolution tests.

Production challenges of tablets containing lipid excipients: Case study using cannabidiol as drug model.

The aims of this study were, firstly, to select an optimal lipid solid dispersion of cannabidiol among different lipid excipients (Gelucire® 50/13, 48/16, 44/14 and Labrasol®) and inorganic carriers (colloidal silica, Syloid® XDP and Neusilin® US2) through a screening plan. The enhancement of aqueous solubility of cannabidiol from a free-flowing powder with adequate drug content was obtained by mixing cannabidiol (20%) with Gelucire® 50/13 (40%; Gattefossé, France), both incorporated inside mesopores of mesoporous silica Syloid® XDP (40%; Grace, Germany). Secondly, we have studied the tableting properties of this selected dispersion through a Design of Experiments (DoE) by manufacturing tablets with other excipients with using a compression simulator (Styl'One® Evo, Medelpharm, France). The design of experiments included the percentage of lipid solid dispersion, of glidant, of lubricant and different compression forces. The dissolution efficiency, the drug content, the tensile strength and the ejection force were analyzed. The DoE showed that % of dispersion as well as compression forces were the main influential variables. An exit of lipid materials outside the mesopores of silica due to compression process has been highlighted, reflected by reduced tensile strength. This study showed the possibility of manufacturing tablets with lipid materials even if limitations have been highlighted. Indeed, the dispersion percentage must not exceed 27% and compression forces up to 13 kN are required to produce lipid tablets with optimal properties.

Fused deposition modeling 3D printing of solid oral dosage forms containing amorphous solid dispersions: How to elucidate drug dissolution mechanisms through surface spectral analysis techniques?

Many active principles belong to the second class of the Biopharmaceutics Classification System due to their low aqueous solubility. Elaboration of new solid oral forms by hot-melt extrusion and fused deposition modeling appears as a promising tool to increase the dissolution rate of these drugs. Indeed, hot-melt extrusion allows the amorphisation of drugs and forms with complex geometries are built by 3D printing. Therefore, the goal of this work is to enhance the dissolution rate of poorly soluble drugs using hot-melt extrusion coupled with fused deposition modeling. Four formulations containing Affinisol® 15LV, Kollidon® VA64 and a challenging amount of itraconazole (25 % (wt.)) were successfully printed into forms of 20, 50 and 80 % infill densities. Differential scanning calorimetry analysis has shown that itraconazole remained amorphous during 52 weeks. The drug release rate was highly improved compared to itraconazole in a crystalline form. The dissolution rate was influenced by the infill density and the polymer composition of printed forms which could modify respectively the surface to volume ratio and the distribution of the components in the printed forms. One formulation printed with 20 % infill density even had a solubility profile similar to that of Sporanox®, the commercialized drug product in Belgium.

Challenges of fused deposition modeling 3D printing in pharmaceutical applications: Where are we now?

In recent years, fused deposition modeling has become one of the most used three-dimensional printing technologies in the pharmaceutical field. The production of personalized dosage forms for individualized therapy and the modification of the drug release profile by the elaboration of complex geometries make fused deposition modeling a promising tool for small-scale production. However, fused deposition modeling has a considerable number of challenges to overcome. They are divided into three categories of parameters. Material-specific parameters encompass the physicochemical properties of the filament, like thermal, mechanical and rheological properties. They determine the feasibility of the printing process. Operation-specific parameters relate to the processing conditions of printing, such as printing temperature and infill density, which have an influence on the final quality and on the dissolution behavior of the objects. The printer equipment is defined by the machine-specific parameters. Some modifications of this equipment also enhance the performance of the printing process. The aim of this review is to highlight the major fused deposition modeling critical process parameters in the pharmaceutical field and possible solutions in order to speed up the development of objects in the pharmaceutical market.

Cannabidiol aqueous solubility enhancement: Comparison of three amorphous formulations strategies using different type of polymers.

Poor aqueous solubility of terpenophenolic compound Cannabidiol (CBD) is a major issue in the widespread use of this promising therapeutic polyphenol. Moreover, choosing the appropriate strategy to overcome this challenge is time-consuming and based on trial-error processes. The amorphous form of CBD provided higher aqueous solubility as well as faster dissolution rate in comparison with crystalline CBD. Nevertheless, amorphous forms of CBD tend to recrystallize. The aim of this study was to use three different strategies based on the stabilization of the amorphous form. Cyclodextrins (CH3αCD, HPßCD and HPγCD.), mesoporous silicas (Silsol® and Syloid® AL-1FP) and water soluble polymers (Kollidon® VA64, Kollidon® 12PF and Soluplus®) were processed by using the following techniques: freeze-drying, spray-drying, subcritical carbon dioxide impregnation or hot-melt extrusion. All the obtained formulations provided complete amorphous CBD, although the drug loading depend highly of the excipients. CBD-cyclodextrin formulations, processed by freeze-drying or spray-drying, and CBD-mesoporous silica formulations, processed by subcritical CO2 or by atmospheric impregnation, provided significant increase of aqueous solubility. While the use of Kollidon® 12PF did not provided significant increased solubility within 90 min, Kollidon® VA64 has been highlighted as the excipient that exhibits the highest increase of aqueous solubility of this study. Finally, all formulations, excepted CBD-ALFP formulations, showed adequate stability within at least two months.

Three-dimensional printing technology as a promising tool in bioavailability enhancement of poorly water-soluble molecules: A review.

Poor aqueous solubility of active pharmaceutical ingredients (API) is nowadays a major issue in the pharmaceutical field. The combinatorial chemistry provides more and more API with a great therapeutic potential, but with a low aqueous solubility. Among the strategies to overcome this drawback, the use of amorphous solid dispersions (ASD), as well as the increase of surface area, is widely used. The three dimensional (3D) printing technologies appear to be innovative tools allowing the construction of any unconventional forms with different composition, structure or infill; especially by using ASD materials. This review aims to deliver notions about the different 3D printing techniques found in the literature to improve aqueous solubility of several API, namely nozzle-based method, inkjet methods and laser- based methods, as well as guide formulator in terms of formulation parameters that have to be optimized to allow the most suitable impression of innovative medicines.