Evaluation of the efficacy, safety, and pharmacokinetics of nanodispersible cannabidiol oral solution (150 mg/mL) versus placebo in mild to moderate anxiety subjects: A double blind multicenter randomized clinical trial.

BACKGROUND: Anxiety disorders, an increasingly prevalent global mental health illness, affected approximately 301 million individuals worldwide in 2019. There is an unmet need for the treatment of anxiety disorders, as current therapies are associated with limited response rates, residual symptoms, and adverse effects. OBJECTIVES: To evaluate the efficacy, safety, and pharmacokinetics of nanodispersible cannabidiol (CBD) oral solution versus placebo for the treatment of mild to moderate anxiety disorders. METHODS: This phase 3 prospective, randomized, double blind, parallel group, placebo-controlled, 15-week cohort study took place at multiple sites across India. Eligible participants were randomly assigned to one of the two treatment arms (CBD or placebo) in a 1:1 ratio. RESULTS: 178 participants were randomized to receive CBD (n=89) or placebo (n=89). The study met both primary (GAD-7 and HAM-A scores) and secondary outcomes (CGI-I, CGI-S, PHQ-9 and PSQI scores). The GAD-7 score difference between the end of treatment and baseline for the CBD versus the placebo was -7.02 (S.E: 0.25, 95% CI -7.52; -6.52), p<0.0001. Similarly, the HAM-A score difference at the end of treatment compared to baseline for the CBD versus the placebo was -11.9 (S.E: 0.33, 95% CI -12.6; -11.3), p<0.0001. CONCLUSIONS: Nanodispersible CBD was therapeutically safe with no serious adverse events, well tolerated, and effective for the treatment of mild to moderate anxiety disorders, as well as associated depression and sleep quality disturbances. These results pave way for probable prospective use of nanodispersible CBD formulation for various psychiatry disorders alone or in conjunction with other drugs.

Pharmacokinetic and pharmacodynamic studies of iloperidone-loaded lipid nanoemulsions via oral route of administration.

Iloperidone (IL) is practically insoluble in water and has significant first-pass metabolism, resulting in low oral bioavailability in humans (36%). IL lipid nanoemulsions (IL-LNEs) were prepared to improve oral bioavailability. IL-LNEs were formulated by hot homogenization and ultrasonication method. Soybean oil and egg lecithin in various concentrations as emulsifier were used in the preparation of LNEs. Dynamic light scattering technique was used for globule size analysis. All LNE formulations showed narrow size distribution and the average globule size and Poly Dispersity Index (PDI) were found to be in between 182.2 ± 2.8 to 222.3 ± 1.9 nm and 0.200 ± 0.004 to 0.274 ± 0.005 respectively. Zeta potential values varied from -20.0 ± 0.15 to -28.9 ± 0.30 mV which indicated stability of prepared LNEs. All formulations showed good entrapment efficiency ranging from 99.07 ± 0.01 to 99.28 ± 0.01% when separated using centrisart tubes and the drug content varied from 96.99 ± 0.94 to 99.06 ± 0.36%. Physical stability testing indicated the stability of all LNEs and optimized LNE-IL4 was found stable for 3 months at both refrigerated (4 °C) and room temperature (25 °C). During in vivo studies in wistar rats, the optimized LNE showed 2.47-fold improvement in the oral bioavailability and superior (1.22-fold) pharmacodynamic activity when compared to marketed tablet suspension (Ilosure-4®) in suppressing the hyperlocomotor activity, being induced by MK-801 (Dizocilpine).

Development, characterization, comparative pharmacokinetic and pharmacodynamic studies of iloperidone solid SMEDDS and liquisolid compact.

Iloperidone (ILO) is an anti-psychotic, used in schizophrenia. It has low bioavailability (36%) due to low solubility and first pass effect. Oral solid self microemulsifying drug delivery system (SMEDDS) and liquisolid compact (LSC) of ILO were developed. The hypothesis is to test in vivo performance (PK and PD effects) of these delivery systems, as both systems improve dissolution. Based on solubility Capmul MCM, Labrafac WL 1349 were selected as oils, Lauroglycol 90 and PEG 600 were selected as surfactant and cosurfactant. Syloid XDP was optimized for adsorption of liquid SMEDDS. Syloid XDP and Aerosil 200 were optimized as carrier and coating material in the ratio of 15:1 w/w for liquisolid formulation. SEM and PXRD studies indicated no specific crystallinity due to bulkiness in both formulations, which showed similar flow and release behavior. Pharmacokinetic studies were performed for ILO Coarse suspension (CS), Tablet suspension (TS), optimized solid SMEDDS (A1X) and liquisolid compact (S3) in wistar rats. About 3.80 and 2.19-fold improvements in relative bioavailabilty were found for A1X and S3, respectively, when compared to CS. In comparison to TS, 2.61 and 1.51 fold improvements in bioavailability were found for A1X and S3, respectively. Further, Pharmacodynamic activity was studied by reversal of MK-801 induced hyperlocomotion in rats. A1X and S3 formulations showed maximum reversal after 15 min when compared to CS and found to have similar performance. Thus, in comparison to S3, A1X showed significant difference in pharmacokinetic effects but similar pharmacodynamic effects.

Lipid Nanoemulsions of Rebamipide: Formulation, Characterization, and In Vivo Evaluation of Pharmacokinetic and Pharmacodynamic Effects.

Rebamipide has low oral bioavailability (10%) due to its low solubility and permeability. Lipid nanoemulsions (LNEs) were prepared in order to improve its oral bioavailability. Rebamipide-loaded lipid nanoemulsions were formulated by hot homogenization and ultrasonication method. Olive oil and egg lecithin in various concentrations as emulsifier were used in the preparation of LNEs. The lipid nanoemulsions were evaluated for various parameters. The globule size, polydispersity index (PDI), and zeta potential (ZP) of the formulations ranged from 230.3 ± 3.88 to 279.8 ± 5.76 nm, 0.204 ± 0.008 to 0.246 ± 0.029, and - 27.7 ± 2.05 to - 31.0 ± 1.87 mV, respectively. Entrapment efficiency and assay values ranged from 99.90 ± 0.006 to 99.92 ± 0.002% and 99.3 ± 0.808 to 99.6 ± 0.360, respectively. Physical stability test results revealed that the optimized LNEs were stable for 2 months at both room (25°C) and refrigerated temperature (4°C). The optimized LNE showed 4.32-fold improvement in the oral bioavailability in comparison to a marketed tablet suspension. In vivo anti ulcer activity of rebamipide LNE was studied by testing the prophylactic effect in preventing the mucosal damage in stomach region. The mucosa of stomach in animals was damaged by per oral administration of 80% alcohol. Maximum prophylactic antiulcer activity was observed by per oral delivery of rebamipide as LNE. Our results indicated that LNEs were a promising approach for the oral delivery of rebamipide for systemic effects along with local effects in protecting gastric region, which gets damaged during peptic ulcers.

Development of zolmitriptan transfersomes by Box-Behnken design for nasal delivery: in vitro and in vivo evaluation.

The aim was to prepare an optimized zolmitriptan (ZT)-loaded transfersome formulation using Box-Behnken design for improving the bioavailability by nasal route for quick relief of migraine and further to compare with a marketed nasal spray. Here, three factors were evaluated at three levels. Independent variables include: amount of soya lecithin (X1), amount of drug (X2) and amount of tween 80 (X3). The dependent responses were vesicle size (Y1), flexibility index (Y2) and regression coefficient of drug release kinetics (Y3). Prepared formulations were evaluated for physical characters and an optimal system was identified. Further, in vivo pharmacokinetic study was performed in male wistar rats to compare the amount of drug in systemic circulation after intranasal administration. Optimized ZT-transfersome formulation containing 82.74 mg of lecithin (X1), 98.37 mg of zolmitriptan (X2) and 32.2 mg of Tween 80 (X3) and had vesicle size of 93.3 nm, flexibility index of 20.25 and drug release regression coefficient of 0.992. SEM picture analysis revealed that the vesicles were spherical in morphology and had a size more than 1 µm. The formulations were found to be physically stable upon storage at room temperature up to 2 months period, as there were no significant changes noticed in size and ZP. The nasal bioavailability of optimized transfersome formulation was found to be increased by 1.72 times than that of marketed nasal spray (Zolmist®). The design and development of zolmitriptan as transfersome provided improved nasal delivery over a conventional nasal spray for a better therapeutic effect.

Preparation, Characterization and Evaluation of Quetiapine Fumarate Solid Lipid Nanoparticles to Improve the Oral Bioavailability.

Quetiapine fumarate is an antipsychotic drug with poor oral bioavailability (9%) due to first-pass metabolism. Present work is an attempt to improve oral bioavailability of quetiapine fumarate by incorporating in solid lipid nanoparticles (SLN). Six quetiapine fumarate SLN formulations were developed using three different lipids by hot homogenisation followed by ultrasonication. The drug excipient compatibility was studied by differential scanning calorimetry (DSC). Stable quetiapine fumarate SLNs having a mean particle size of 200-250 nm with entrapment efficiency varying in between 80% and 92% were developed. The physical stability of optimized formulation F3 was checked at room temperature for 2 months. Comparative bioavailability studies were conducted in male Wistar rats after oral administration of quetiapine fumarate suspension and SLN formulation. The relative bioavailability of quetiapine fumarate from optimized SLN preparation was increased by 3.71 times when compared with the reference quetiapine fumarate suspension. The obtained results are indicative of SLNs as potential lipid carriers for improving the bioavailability of quetiapine fumarate by minimizing first-pass metabolism.