Third-Generation Solid Dispersion Through Lyophilization Enhanced Oral Bioavailability of Resveratrol.

Resveratrol (RES) is a biopharmaceutical classification system (BCS) class II compound with low solubility and high permeability. Several strategies have been explored to overcome the low bioavailability of RES, making the formation of solid dispersions (SDs) one of the most promising. This study aimed at the development of a RES third-generation SD prepared by lyophilization as a strategy to improve RES solubility, dissolution, and oral bioavailability. Eudragit E PO was selected as the hydrophilic carrier in a 1:2 (RES:carrier) ratio, and Gelucire 44/14 as the surfactant, at 16% (w/w) of RES. Differential scanning calorimetry (DSC), scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FTIR), polarized light microscopy (PLM), X-ray powder diffraction (XRPD), and particle size distribution (Morphologi 4 Malvern) were used for solid-state characterization and to confirm the conversion of RES to the amorphous state in the SD. Third-generation SD presented an 8-, 12-, and 8-fold increase of RES solubilized compared to pure RES at pH 1.2, 4.5, and 6.8, respectively, and a 10-fold increase compared to the physical mixture (PM), at pH 6.8, after 24 h. In the gastric environment, the dissolution rate of third-generation SD and PM was similar, and 2-fold higher than pure RES after 30 min, while at pH 6.8, third-generation SD presented approximately a 5-fold increase in comparison to pure RES and PM. Third-generation SD presented higher in vitro intestinal permeability compared to its PM and second-generation SD (without Gelucire 44/14). A 2.4 and 1.7-fold increase of RES permeated, respectively in Caco-2 and Caco-2/HT2-MTX models, was obtained with third-generation SD compared to PM, after 3 h. Third-generation SD allowed a 3-fold increase of RES bioavailability compared to second-generation SD, after oral administration of 200 mg/kg of RES to Wistar rats. Enhanced RES oral bioavailability was obtained not only by solubility and dissolution improvement, but also by the interference of Gelucire 44/14, with RES metabolism, and inhibition of P-gp-mediated efflux. The presence of excipients like Gelucire 44/14 in the SD allows for greater bioavailability of orally administered RES, making it easier to obtain some of the physiological benefits demonstrated by this molecule.

Third-generation solid dispersion combining Soluplus and poloxamer 407 enhances the oral bioavailability of resveratrol.

Resveratrol is a very promising anti-oxidant drug candidate with low oral bioavailability due to its intrinsic poor water solubility, intestinal efflux and metabolization mechanisms. Resveratrol solubility high-throughput screening with different carriers was performed showing an enhancement above 2000-fold with Soluplus® and Tween® 80. The former was selected as a carrier at the ratio of resveratrol: Soluplus® (1:2). Then, third-generation solid dispersions were developed with Gelucire® and poloxamer 407 at 5 and 15% to resveratrol: Soluplus® (1:2). All formulations enhanced solubility around 2-fold when compared to resveratrol: Soluplus® (1:2) solid dispersion. Caco-2 cells permeability studies showed that both surfactants increased drug permeability and the fraction recovered (2-fold) suggesting that these could reduce efflux mechanism and metabolism. Formulation with 15% poloxamer 407 demonstrated most promising results and was selected for further studies. In in vivo studies, resveratrol:Soluplus®: poloxamer 407 (1:2-15%) third generation solid dispersion presented an AUCo-t of 279 ± 54 ng.h/mL and a Cmax of 134 ± 78 ng/mL, 2.5 fold higher than solid dispersion without poloxamer 407. This work reports the development of third-generation solid dispersion that significantly improved resveratrol bioavailability. This was accomplished by an increased solubility and most probably by reducing intestinal efflux and metabolism mechanisms.

Oral nanoparticles based on gellan gum/pectin for colon-targeted delivery of resveratrol.

Nanoparticles based on gellan gum/pectin blends were designed for colon-targeted release of resveratrol (RES). Their impact on drug release rates and permeability were evaluated using Caco-2 cell model and mucus secreting triple co-culture model. Polymeric nanoparticles (PNP) were successfully prepared by nebulization/ionotropic gelation, achieving high drug loading (>80%). PNP were spherical with a low positive charge density (+5mV) and exhibited diameters of around 330 nm. Developed PNP were able to promote effective modulation of drug release rates, so that only 3% of RES was released in acidic media over 2 h, and, in pH 6.8, the drug was released in a sustained manner, reaching 85% in 30 h. The permeability of RES-loaded PNP in the Caco-2 model was 0.15%, while in the triple co-culture model, in the presence of mucus, it reached 5.5%. The everted gut sac experiment corroborated the low permeability of RES-loaded PNP in the presence or absence of mucus and highlighted their high ability to interact with the intestinal tissue. Results indicate that the novel PNP developed in this work are safe and promising carriers for controlled delivery of RES at the colon.

Multicomponent self nano emulsifying delivery systems of resveratrol with enhanced pharmacokinetics profile.

Resveratrol is a drug with high potential for clinical application based on experimental models. Though, resveratrol translation to clinical use has not been successful yet due to its poor pharmacokinetics, related to poor solubility and fast metabolism. The use of drug delivery systems, namely self-emulsifying drug delivery systems (SEDDS), may be a viable strategy to overcome the poor in vivo performance of resveratrol. In this work, a rational development of two different ternary SEDDS was conducted. Experimental data showed that quantitative variations on SEDDS composition impacted dispersion and robustness to dilution of SEDDS, as well as loading capacity and droplet size. Formulations composed of Lauroglycol® 90/Labrasol®/Capryol® PGMC (12.5/75.0/12.5) (Lau/Lab/Cap) and Tween® 80/Transcutol®/Imwitor® 742 (33.3/33.3/33.3) (T80/Trans/Imw) featured improved performance and were selected for further studies. T80/Trans/Imw formulation yield faster emulsification and originated smaller droplet size, with lower cumulative percentile of 90% of particles (D90) (below 200 nm), as compared to the than Lau/Lab/Cap formulation. Higher resveratrol permeation rate was observed in Caco-2 cell monolayer permeability studies for both formulations as compared to the free drug. Reduction of the metabolization and/or efflux of resveratrol was also noticed in the case of SEDDs, as suggested by the increased recovery of total drug. Plasmatic drug concentrations in rats observed after oral gavage indicate that both formulations provided faster resveratrol absorption than free drug, resulting in shorter Tmax values (30 min vs. 2 h). No statistically significant differences were observed for AUC0-t values of both formulations and the free drug. Still, Cmax for the Lau/Lab/Cap SEDDs formulation was 2-fold higher than for the free drug. These findings suggest that SEDDS can increase resveratrol solubility and reduce its metabolization, resulting in an overall improvement of its oral pharmacokinetics profile.

Gellan Gum/Pectin Beads Are Safe and Efficient for the Targeted Colonic Delivery of Resveratrol.

This work addresses the establishment and characterization of gellan gum:pectin (GG:P) biodegradable mucoadhesive beads intended for the colon-targeted delivery of resveratrol (RES). The impact of the polymer carrier system on the cytotoxicity and permeability of RES was evaluated. Beads of circular shape (circularity index of 0.81) with an average diameter of 914 µm, Span index of 0.29, and RES entrapment efficiency of 76% were developed. In vitro drug release demonstrated that beads were able to reduce release rates in gastric media and control release for up to 48 h at an intestinal pH of 6.8. Weibull's model correlated better with release data and b parameter (0.79) indicated that the release process was driven by a combination of Fickian diffusion and Case II transport, indicating that both diffusion and swelling/polymer chains relaxation are processes that contribute equally to control drug release rates. Beads and isolated polymers were observed to be safe for Caco-2 and HT29-MTX intestinal cell lines. RES encapsulation into the beads allowed for an expressive reduction of drug permeation in an in vitro triple intestinal model. This feature, associated with low RES release rates in acidic media, can favor targeted drug delivery from the beads in the colon, a promising behavior to improve the local activity of RES.

Measuring the emulsification dynamics and stability of self-emulsifying drug delivery systems.

Self-emulsifying drug delivery systems (SEDDS) are one of the most promising technologies in the drug delivery field, particularly for addressing solubility and bioavailability issues of drugs. The development of these drug carriers excessively relies in visual observations and indirect determinations. The present manuscript intended to describe a method able to measure the emulsification of SEDDS, both micro and nano-emulsions, able to measure the droplet size and to evaluate the physical stability of these formulations. Additionally, a new process to evaluate the physical stability of SEDDS after emulsification was also proposed, based on a cycle of mechanical stress followed by a resting period. The use of a multiparameter continuous evaluation during the emulsification process and stability was of upmost value to understand SEDDS emulsification process. Based on this method, SEDDS were classified as fast and slow emulsifiers. Moreover, emulsification process and stabilization of emulsion was subject of several considerations regarding the composition of SEDDS as major factor that affects stability to physical stress and the use of multicomponent with different properties to develop a stable and robust SEDDS formulation. Drug loading level is herein suggested to impact droplets size of SEDDS after dispersion and SEDDS stability to stress conditions. The proposed protocol allows an online measurement of SEDDS droplet size during emulsification and a rationale selection of excipients based on its emulsification and stabilization performance.

The biopharmaceutical classification system of excipients.

The increasing number of new chemical entities is bringing new challenges to the field of drug delivery. These drugs present bioavailability issues that are frequently associated with intestinal metabolism or efflux mechanisms. Some excipients, particularly surfactants, have demonstrated a capacity to interfere with these mechanisms, improving drug bioavailability. Consequently, these excipients can no longer be considered as inert and should be subject to special considerations from a regulatory perspective. In the present manuscript, the state-of-the-art research related to these abilities of excipients to interfere with intestinal metabolism and efflux mechanisms are presented and discussed. Here, a biopharmaceutical classification system of excipients is proposed for the first time as a tool in the development of new products and for regulatory purposes.

Amorphous solid dispersions: Rational selection of a manufacturing process.

Amorphous products and particularly amorphous solid dispersions are currently one of the most exciting areas in the pharmaceutical field. This approach presents huge potential and advantageous features concerning the overall improvement of drug bioavailability. Currently, different manufacturing processes are being developed to produce amorphous solid dispersions with suitable robustness and reproducibility, ranging from solvent evaporation to melting processes. In the present paper, laboratorial and industrial scale processes were reviewed, and guidelines for a rationale selection of manufacturing processes were proposed. This would ensure an adequate development (laboratorial scale) and production according to the good manufacturing practices (GMP) (industrial scale) of amorphous solid dispersions, with further implications on the process validations and drug development pipeline.

Dosage form proportionality and food effect of the final tablet formulation of eslicarbazepine acetate: randomized, open-label, crossover, single-centre study in healthy volunteers.

OBJECTIVE: To investigate the dosage form proportionality and food effect of the final tablet formulation of eslicarbazepine acetate (ESL) in healthy volunteers. METHODS: This was a randomized, three-way crossover, single-centre study in 18 healthy volunteers. Subjects received a single dose of oral ESL 800 mg following a standard meal in one period, and following 10 hours of fasting in two separate periods (in the form of one 800 mg tablet [reference] or two 400 mg tablets [test]). The statistical method was based upon the 90% confidence interval (CI) of maximum observed plasma drug concentration (C(max)), area under the plasma concentration time curve (AUC) from time zero to the last sampling time at which concentrations were at or above the lower limit of quantification (AUC(t)) and AUC from time zero to infinity (AUC(infinity)) geometric means ratios (GMRs) of BIA 2-005, the enantiomeric mixture of the ESL active metabolite eslicarbazepine and its enantiomer R-licarbazepine. Bioequivalence was assumed when the 90% CI of the test/reference GMR fell within the bioequivalence acceptance interval (80.00, 125.00). RESULTS: Following a single dose of ESL 800 mg in the forms of two 400 mg tablets and one 800 mg tablet, the test/reference GMR (%) and 90% CI for C(max), AUC(t) and AUC(infinity) were 100.78% (93.91, 108.16), 100.37% (97.82, 102.99) and 100.48% (97.91, 103.13), respectively. Following administration of one 800 mg tablet in fed (test) and fasting (reference) conditions, the test/reference GMR and 90% CI for C(max), AUC(t) and AUC(infinity) were 100.96% (94.08, 108.35), 96.79% (94.34, 99.32) and 96.75% (94.27, 99.29), respectively. Treatments were well tolerated. CONCLUSIONS: The bioequivalence criteria between the ESL 400 mg and 800 mg tablets were met and dosage form proportionality was demonstrated. The presence of food had no influence on ESL pharmacokinetics, indicating that ESL can be administered without regard to meals with no significant effects on drug disposition or extent of systemic exposure.

Solid dispersions as strategy to improve oral bioavailability of poor water soluble drugs.

Solid dispersions are one of the most promising strategies to improve the oral bioavailability of poorly water soluble drugs. By reducing drug particle size to the absolute minimum, and hence improving drug wettability, bioavailability may be significantly improved. They are usually presented as amorphous products, mainly obtained by two major different methods, for example, melting and solvent evaporation. Recently, surfactants have been included to stabilize the formulations, thus avoiding drug recrystallization and potentiating their solubility. New manufacturing processes to obtain solid dispersions have also been developed to reduce the drawbacks of the initial process. In this review, it is intended to discuss the recent advances related on the area of solid dispersions.