Self-micellizing solid dispersion of thymoquinone with enhanced biopharmaceutical and nephroprotective effects.

The present study was designed to develop a self-micellizing solid dispersion (SMSD) containing Thymoquinone (TQM), a phytonutrient obtained from Nigella sativa seeds, aiming to improve its biopharmaceutical and nephroprotective functions. The apparent solubility of TQM in polymer solutions was used to choose an appropriate amphiphilic polymer that could be used to make an SMSD system. Based on the apparent solubility, Soluplus® was selected as an appropriate carrier, and mixing with TQM, SMSD-TQM with different loadings of TQM (5-15%) was made by solvent evaporation and freeze-drying techniques, respectively, and the formulations were optimized. The optimized SMSD-TQM was evaluated in terms of particle size distribution, morphology, release characteristics, pharmacokinetic behavior, and nephroprotective effects in a rat model of acute kidney injury. SMSD-TQM significantly improved the dissolution characteristics (97.8%) of TQM in water within 60 min. Oral administration of SMSD-TQM in rats exhibited a 4.9-fold higher systemic exposure than crystalline TQM. In a cisplatin-induced (6 mg/kg, i.p.) acute kidney-damaged rat model, oral SMSD-TQM (10 mg/kg) improved the nephroprotective effects of TQM based on the results of kidney biomarkers and histological abnormalities. These findings suggest that SMSD-TQM might be efficacious in enhancing the nephroprotective effect of TQM by overcoming biopharmaceutical limitations.

Longevity Spinach (Gynura procumbens) Ameliorated Oxidative Stress and Inflammatory Mediators in Cisplatin-Induced Organ Dysfunction in Rats: Comprehensive in†vivo and in silico Studies.

This study focused to assess the efficacy of Gynura procumbens (GP) leaf extract against cisplatin (CP)-induced hepatorenal complications in Wister albino rats. Additionally, it aims to detect polyphenolic compounds using high-performance liquid chromatography with diode-array detection (HPLC-DAD). The rats were treated intraperitoneally with CP (7.5 mg/kg) to mediate hepatorenal damage. They were then treated with GP extract (75 and 150 mg/kg, P.O.) for 7 consecutive days. Although GP extract significantly ameliorated CP-mediated hepatorenal biomarkers like alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine, and blood urea nitrogen (BUN) levels in a dose-dependent manner, GP extract at 150 mg/kg dose normalized hepatorenal biomarkers ALP (45.11 U/L), ALT (34 U/L), AST (29 U/L), creatinine (10.3 mg/dl) and BUN (11.19 mg/dl) while comparing to control and disease group. Similarly, though it significantly reduced CP-induced oxidative stress inducers, including nitric oxide (NO) and advanced oxidative protein products (AOPP), higher dose (150 mg/kg) exhibited better activity in reducing NO (281.54 mmol/gm tissue in liver and 52.73 mmol/gm tissue in the kidney) and AOPP (770.95 mmol/mg protein in liver and 651.90 mmol/mg protein in the kidney). Besides, it showed better enhancement in the antioxidant enzymes superoxide dismutase, and glutathione levels at a higher dose (150 mg/kg). Histopathological studies showed that CP caused collagen accumulation in the liver and kidney tissues. GP extract drained the collagen mass and acted against hepatorenal damage. Ellagic acid, gallic acid, quercetin hydrate, kaempferol, and rutin hydrate were revealed in GP extract. In-silico modelling showed good docking scores of the polyphenolic compounds with molecular targets including CYP4502E1, NF-κB, caspase-3, and TNF-α. GP could be an effective therapeutic option for management of anticancer drugs' complications like CP-induced organ damage, although clinical studies are required to establish herbal formulation.

Strategic application of liposomal system to R-α-lipoic acid for the improvement of nutraceutical properties.

R-α-lipoic acid (RLA) and dihydrolipoic acid (DHLA), a reduced form of RLA, are potent endogenous antioxidants that can reduce oxidative damage. Despite their numerous nutraceutical potentials, clinical applications of RLA are still limited due to its poor solubility and stability problems. This study aimed to develop an RLA-loaded liposome (LIP/RLA) for the improvement of nutraceutical properties. LIP/RLA was developed by a typical solvent injection method. Uniform liposomes of LIP/RLA were observed by transmission electron microscopy, and the mean particle size was calculated to be ∼150 nm from the data of dynamic light scattering. LIP/RLA could prevent the degradation of RLA even under acidic conditions (pH 1.2) possibly due to the encapsulation of RLA into the liposomal structure. In the release test under pH6.8 with lipase, LIP/RLA showed relatively rapid release of RLA, possibly due to the lipolysis of phospholipids by lipase. After the oral administration of LIP/RLA (10 mg-RLA/kg, p.o.) in rats, the systemic exposures of RLA and DHLA increased by 2.8- and 5.8-fold, respectively. In a rat model of acute hepatic injury induced by carbon tetrachloride (CCl4) (0.7 mL-CCl4/kg, p.o.), orally dosed LIP/RLA (3 mg-RLA/kg, p.o.) resulted in 78.7% and 86.4% reductions of plasma alanine aminotransferase, and aspartate aminotransferase, respectively; however, RLA was found to be less effective possibly due to the poor oral absorption. The RLA-loaded liposomal system might be a promising carrier for poorly water-soluble materials with poor stability under acidic conditions, as well as RLA, to improve their oral absorption and nutraceutical properties.

GC-MS-employed phytochemical characterization, synergistic antioxidant, and cytotoxic potential of Triphala methanol extract at non-equivalent ratios of its constituents.

Triphala is a famous triherbal drug, comprising three herb fruits, including Terminalia chebula (Haritaki), Terminalia bellirica (Bibhitaki), and Phyllanthus emblica (Amalaki). It is enriched with vitamin C, polyphenols, flavonoids, sterols, saponins, etc., and is well-documented for its potent antioxidant, anticancer, chemoprotective, antimicrobial, and anti-inflammatory effects. This research was conducted to evaluate the synergistic antioxidative and cytotoxic potential of mixtures of the individual constituents of Triphala at their nonequivalent ratios along with the chemical characterization of individual constituents of Triphala to identify and quantify individual compounds. The antioxidative potential was measured using total antioxidant capacity (TAC), DPPH free radical scavenging assay, and total phenolic content (TPC) tests. The cytotoxic potential was assessed on brain cancer cells (N4X4) using MTT assay, and phytochemical characterization was performed by GS-MS analysis. Nonequivalent ratios of Triphala constituents exhibited significantly higher synergistic antioxidant and cytotoxic potential than the equivalent ratios of them. Moreover, the nonequivalent ratio where the quantity of Amalaki was doubled than the other two constituents showed the highest synergistic antioxidant and cytotoxic effect. GC-MS analysis of individual constituents of Triphala identified and quantified the presence of a wide array of compounds, and fatty acid, fatty acid ester, triterpene, and aminoglycoside remained the predominant class of compounds. Thus, it can be inferred that the observed bioactivities can be attributed to the phytocompounds characterized and extracts at the nonequivalent ratio of Triphala constituents where Amalaki is doubled can be more effective in treating oxidative degenerative diseases and glioblastoma.

Self-emulsifying drug delivery system of (R)-α-lipoic acid to improve its stability and oral absorption.

The present study was designed to develop a self-emulsifying drug delivery system (SEDDS) of (R)-α-lipoic acid (RLA) to improve the physicochemical and nutraceutical properties of RLA. RLA/SEDDS was prepared using medium-chain triglycerides, Tween 80, and polyethylene glycol 400 as oil, surfactant, and co-surfactant, respectively. The preferable composition of SEDDS was selected according to a pseudo-ternary phase diagram for improved emulsification properties, and its physicochemical and pharmacokinetic properties were evaluated. RLA/SEDDS showed the immediate formation of fine micelles with a mean droplet size of approximately 260 nm when introduced into aqueous media. In simulated gastric fluid, this system could significantly improve the dissolution behavior of RLA and prevent the degradation of RLA, possibly due to the encapsulation of RLA into the emulsion structure. Following the oral administration of RLA/SEDDS (10 mg RLA/kg) in rats, systemic exposure to RLA and dihydrolipoic acid (DHLA), a reduced form of RLA, increased by 7- and 3-fold, respectively. The improved dissolution and gastric stability of RLA could contribute to enhancing systemic exposure to RLA and DHLA after oral administration. From these findings, RLA/SEDDS might be an efficacious dosage option for improving the oral bioavailability as well as nutraceutical properties of RLA.

Assessment of knowledge, perception, and awareness about self-medication practices among university students in Nepal.

The objective of the present study was to assess the perceptions, knowledge, and awareness of self-medication practice among the university students in Nepal. This descriptive cross-sectional, questionnaire-based study was conducted on randomly selected 620 students from three different universities in Nepal. The study results revealed that 95.4% of students had reported self-medication, among which analgesics and antipyretic medications were mostly used (66 %); followed by anti-ulcerants (35.3%), antibiotics (33.9%), anti-allergic preparations (20%), and other categories (10.3%) of drugs. Study results also showed that, the major cause of self-medication was minor illness, and the prescriptions which were previously used to treat the similar disease conditions were the main source of motivation to do so. A significant portion of the respondents believed that self-medication might be acceptable to treat minor illness. Furthermore, students demonstrated variable responses regarding the doses, safety, toxicities, and health hazards towards self-medication without having appropriate knowledge of drugs. The findings of this study revealed the necessity of building awareness and strict implementation of the jurisdiction to minimize the practice of self-medication.

Impact of drying on dissolution behavior of carvedilol-loaded sustained release solid dispersion: development and characterization.

PURPOSE: The present study aimed to develop carvedilol (CAR)-loaded (25% w/w) sustained release solid dispersion (SRSD), for enhanced dissolution and to explore the applicability of different industrially accessible drying techniques. METHODS: SRSD-CAR containing different ratios of polymers were prepared and physicochemically characterized. Dissolution study was carried out in both sink and supersaturated conditions to identify the possible enhancement in dissolution behavior. RESULTS: Based on the solubility study, Kolliphor® P188 and Eudragit® RSPO (50:25, % w/w) ratio exhibited the highest solubility among the samples and was chosen as the optimal composition of SRSD-CAR for further characterization. The crystallinity assessments of the optimized formulation indicated amorphization of CAR in the formulation, bring about improved solubility of CAR. The infrared spectroscopic study revealed minor transitions; demonstrating the absence of significant interactions between drug and carrier. Furthermore, the SRSD-CAR exhibited immediate formation of nano particles when dispersed in water. Dissolution study revealed significant improvement in dissolution behavior, with a release of CAR in a gradual manner compared to crystalline CAR. From the dissolution kinetics analysis, the Korsmeyer Peppas model fit the best and diffusion was predominant in release of CAR. The drug release pattern showed insignificant differences between the SRSD-CAR formulations prepared by rotary vacuum drying and freeze drying. CONCLUSION: From these experimental findings, SRSD approach might be a favorable dosage option for CAR, offering improved biopharmaceutical properties.

Improved biopharmaceutical properties of carvedilol employing α-tocopheryl polyethylene glycol 1000 succinate-based self-emulsifying drug delivery system.

The main objective of this study was to develop a self-emulsifying drug delivery system (SEDDS) of carvedilol (CAR) with improved oral absorption and hepatoprotective properties. SEDDS-CAR was prepared based on d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) and physicochemically characterized. Pharmacokinetic behaviors after the oral administration of CAR samples in rats were evaluated to clarify the possible enhancement of the oral absorption of CAR. The hepatoprotective effects of orally dosed CAR samples were assessed in a rat model of acute hepatic injury induced by carbon tetrachloride (CCl4). SEDDS-CAR showed the immediate formation of fine micelles with a mean droplet size of 84 nm when introduced in aqueous media. SEDDS-CAR improved the dissolution behavior of CAR in distilled water as evidenced by at least five-fold higher solubility than the equilibrium solubility of CAR. After the single oral administration of SEDDS-CAR (10 mg-CAR/kg) in rats, enhanced CAR exposure was observed with an increase of AUC0-∞ showing a 2.5-fold increase compared with crystalline CAR. In CCl4-treated rats, orally dosed SEDDS-CAR (10 mg-CAR/kg, p.o.) led to 91.8 and 91.2% reductions of ALT and AST, respectively; however, crystalline CAR was found to be less effective. From these findings, SEDDS-CAR might be an efficacious oral dosage option for enhancing the hepatoprotective potential of CAR.

Amorphous solid dispersions of carvedilol along with pH-modifiers improved pharmacokinetic properties under hypochlorhydoria.

Carvedilol (CAR) belongs to biopharmaceutics classification system class-II drugs, with poor aqueous solubility and pH-dependent solubility. The present study aimed to develop a novel amorphous solid dispersion (ASD) of CAR with acidic counter ions for pH modifications in microenvironment to improve the pharmacokinetic properties under hypochlorhydric conditions. CAR-ASD was prepared by freeze-drying in combination with counter ions and hydroxypropyl cellulose, and their physicochemical properties including dissolution behavior, storage stability, and photostability were characterized. Pharmacokinetic studies were carried out after oral administration of CAR samples in both normal and omeprazole-treated (30 mg/kg, p.o.) rats as a hypochlorhydria model. Among the tested six counter ions, citric acid (CA) was found to be a preferable pH-modifier of CAR with respect to the dissolution profile and photostability (both potency and colorimetric evaluation). In CAR-ASD formulation with 50% loading of CA (CAR-ASD/CA50), amorphization of CAR was observed during the preparation process. After the oral administration of crystalline CAR in rats under hypochlorhydric condition, there was a 34.4% reduction in the systemic exposure of CAR compared with that in normal rats. However, orally-dosed CAR-ASD/CA50 resulted in limited alterations of pharmacokinetic behavior between normal and omeprazole-treated rats. From these findings, addition of CA as pH-modifier in CAR-ASD might provide consistent pharmacokinetic behavior of CAR even under hypochlorhydric conditions.