Drug loading to mesoporous silica carriers by solvent evaporation: A comparative study of amorphization capacity and release kinetics.

The sorption of poorly aqueous soluble active pharmaceutical ingredients (API) to mesoporous silica carriers is an increasingly common formulation strategy for dissolution rate enhancement for this challenging group of substances. However, the success of this approach for a particular API depends on an array of factors including the properties of the porous carrier, the loading method, or the attempted mass fraction of the API. At present, there is no established methodology for the rational selection of these parameters. In the present work, we report a systematic comparison of four well-characterised silica carriers and seven APIs loaded by the same solvent evaporation method. In each case, we find the maximum amorphization capacity by x-ray powder diffraction analysis and measure the in vitro drug release kinetics. For a selected case, we also demonstrate the potential for bioavailability enhancement by a permeation essay.

Validity of cycloheximide chylomicron flow blocking method for the evaluation of lymphatic transport of drugs.

BACKGROUND AND PURPOSE: Lymphatic transport of drugs after oral administration is an important mechanism for absorption of highly lipophilic compounds. Direct measurement in lymph duct cannulated animals is the gold standard method, but non-invasive cycloheximide chylomicron flow blocking method has gained popularity recently. However, concerns about its reliability have been raised. The aim of this work was to investigate the validity of cycloheximide chylomicron flow blocking method for the evaluation of lymphatic transport using model compounds with high to very high lipophilicity, that is, abiraterone and cinacalcet. EXPERIMENTAL APPROACH: Series of pharmacokinetic studies were conducted with abiraterone acetate and cinacalcet hydrochloride after enteral/intravenous administration to intact, lymph duct cannulated and/or cycloheximide pre-treated rats. KEY RESULTS: Mean total absolute oral bioavailability of abiraterone and cinacalcet was 7.0% and 28.7%, respectively. There was a large and significant overestimation of the lymphatic transport extent by the cycloheximide method. Mean relative lymphatic bioavailability of abiraterone and cinacalcet in cycloheximide method was 28-fold and 3-fold higher than in cannulation method, respectively. CONCLUSION AND IMPLICATIONS: Cycloheximide chylomicron flow blocking method did not provide reliable results on lymphatic absorption and substantially overestimated lymphatic transport for both molecules, that is, abiraterone and cinacalcet. This non-invasive method should not be used for the assessment of lymphatic transport and previously obtained data should be critically revised.

Bioavailability Enhancement and Food Effect Elimination of Abiraterone Acetate by Encapsulation in Surfactant-Enriched Oil Marbles.

Abiraterone acetate has limited bioavailability in the fasted state and exhibits a strong positive food effect. We present a novel formulation concept based on the so-called oil marbles (OMs) and show by in vitro and in vivo experiments that the food effect can be suppressed. OMs are spherical particles with a core-shell structure, formed by coating oil-based droplets that contain the dissolved drug by a layer of powder that prevents the cores from sticking and coalescence. OMs prepared in this work contained abiraterone acetate in the amorphous form and showed enhanced dissolution properties during in vitro experiments when compared with originally marketed formulation of abiraterone acetate (Zytiga®). Based on in vitro comparison of OMs containing different oil/surfactant combinations, the most promising formulation was chosen for in vivo studies. To ensure relevance, it was verified that the food effect previously reported for Zytiga® in humans was translated into the rat animal model. The bioavailability of abiraterone acetate formulated in OMs in the fasted state was then found to be enhanced by a factor of 2.7 in terms of AUC and by a factor of 4.0 in terms of Cmax. Crucially, the food effect reported in the literature for other abiraterone acetate formulations was successfully eliminated and OMs showed comparable extent of bioavailability in a fed-fasted study. Oil marbles therefore seem to be a promising formulation concept not only for abiraterone acetate but potentially also for other poorly soluble drugs that reveal a positive food effect.

Identification and Pharmaceutical Characterization of a New Itraconazole Terephthalic Acid Cocrystal.

The crystallization of poorly soluble drug molecules with an excipient into new solid phases called cocrystals has gained a considerable popularity in the pharmaceutical field. In this work, the cocrystal approach was explored for a very poorly water soluble antifungal active, itraconazole (ITR), which was, for the first time, successfully converted into this multicomponent solid using an aromatic coformer, terephthalic acid (TER). The new cocrystal was characterized in terms of its solid-state and structural properties, and a panel of pharmaceutical tests including wettability and dissolution were performed. Evidence of the cocrystal formation was obtained from liquid-assisted grinding, but not neat grinding. An efficient method of the ITR-TER cocrystal formation was ball milling. The stoichiometry of the ITR-TER phase was 2:1 and the structure was stabilized by H-bonds. When comparing ITR-TER with other cocrystals, the intrinsic dissolution rates and powder dissolution profiles correlated with the aqueous solubility of the coformers. The rank order of the dissolution rates of the active pharmaceutical ingredient (API) from the cocrystals was ITR-oxalic acid > ITR-succinic acid > ITR-TER. Additionally, the ITR-TER cocrystal was stable in aqueous conditions and did not transform to the parent drug. In summary, this work presents another cocrystal of ITR that might be of use in pharmaceutical formulations.

Preclinical evaluation of new formulation concepts for abiraterone acetate bioavailability enhancement based on the inhibition of pH-induced precipitation.

Abiraterone acetate is a potent drug used for the treatment of metastatic castration resistant prostate cancer. However, currently marketed product containing crystalline abiraterone acetate exhibits strong positive food effect which results in strict dosing regimen. In the present work, a rational approach towards design of novel abiraterone acetate formulations that would allow increased bioavailability on a fasting stomach and thus decreased food effect is presented. Precipitation experiments in biorelevant media were designed to assess pH induced precipitation of the drug and a pool of polymeric excipients was then screened for their potential to inhibit precipitation. The best performing polymeric excipients were subsequently used as carriers for the preparation of amorphous solid dispersions. Two main approaches were followed in order to formulate the drug. The first approach relies on the suppression of precipitation from a supersaturated solution whereas the second one is based on the hypothesis that when the release of the drug is tuned, optimal uptake of the drug can be reached. Optimized formulation prototypes were tested in a rat animal model in an incomplete block, randomized bioequivalence study to assess their relative bioavailability under fasting conditions. We show that both formulation approaches lead to increased bioavailability of abiraterone acetate on a fasting stomach with bioavailability in rats being enhanced up to 250% compared to the original drug product containing crystalline drug.

Virtual Prototyping and Parametric Design of 3D-Printed Tablets Based on the Solution of Inverse Problem.

The problem of designing tablet geometry and its internal structure that results into a specified release profile of the drug during dissolution was considered. A solution method based on parametric programming, inspired by CAD (computer-aided design) approaches currently used in other fields of engineering, was proposed and demonstrated. The solution of the forward problem using a parametric series of structural motifs was first carried out in order to generate a library of drug release profiles associated with each structural motif. The inverse problem was then solved in three steps: first, the combination of basic structural motifs whose superposition provides the closest approximation of the required drug release profile was found by a linear combination of pre-calculated release profiles. In the next step, the final tablet design was constructed and its dissolution curve found computationally. Finally, the proposed design was 3D printed and its dissolution profile was confirmed experimentally. The computational method was based on the numerical solution of drug diffusion in a boundary layer surrounding the tablet, coupled with erosion of the tablet structure encoded by the phase volume function. The tablets were 3D printed by fused deposition modelling (FDM) from filaments produced by hot-melt extrusion. It was found that the drug release profile could be effectively controlled by modifying the tablet porosity. Custom release profiles were obtained by combining multiple porosity regions in the same tablet. The computational method yielded accurate predictions of the drug release rate for both single- and multi-porosity tablets.