Anti-hyperuricemic property of 6-shogaol via self-micro emulsifying drug delivery system in model rats: formulation design, in vitro and in vivo evaluation.

The prevalence of hyperuricemia is relatively high worldwide, and a great number of patients are suffering from its complications. 6-shogaol, an alkylphenol compound purified from the root of ginger (Zingiber officinale Roscoe), has been proved to possess diverse pharmacological activities. However, its poor aqueous solubility usually leads to low bioavailability, and further clinical applications will be greatly discounted. The current study aimed to formulate a 6-shogaol-loaded-Self Microemulsifying Drug Delivery System (SMEDDS) to amend low aqueous solubility and bioavailability orally, as well as, potentiate the hyperuricemic activity of the 6-shogaol. SMEDDS was developed with central composite design established on a two system components viz., 18.62% W/W ethyl oleate (oil phase) and ratio of tween 80 (surfactant) to PEG 400 (co-surfactant) (1.73:1, W/W). Based on quadratic model, the navigation of the design space could generate spherically-shaped and homogenous droplets with respective mean particle diameter, polydispersity and of 20.00 ± 0.26 nm and 0.18 ± 0.02. The 6-shogaol-SMEDDS showed significant elevation of cumulative release compared with the free 6-shogaol and more importantly a 571.18% increment in the relative oral bioavailability of the drug. The predominant accumulation of 6-shogaol-SMEDDS in the liver suggested hepatic-targeting potentiality of the drug. Oral administration of 6-shogaol-SMEDDS in hyperuricemic rats also significantly decreased uric acid level and xanthine oxidase activity. Histological studies confirmed formulation groups indeed could provide better protection of kidney than free drug groups. Collectively, these findings indicated that the SMEDDS hold much promise in enhancing the oral delivery and therapeutic efficacy of 6-shogaol.

[6]-Shogaol/ß-CDs inclusion complex: preparation, characterisation, in vivo pharmacokinetics, and in situ intestinal perfusion study.

Aims: The aim was to improve the absorption and bioavailability of [6]-shogaol with ß-cyclodextrin (ß-CD) prior to in vitro and in vivo evaluation. Methods: [6]-Shogaol/ß-CDs inclusion complexes (6-S-ß-CDs) were developed using saturated aqueous solution method and characterised with appropriate techniques. The absorption and bioavailability potential of [6]-shogaol was evaluated via in vivo pharmacokinetics and in situ intestinal perfusion. Results: The results of characterisation showed that 6-S-ß-CDs (drug loading, 7.15%) were successfully formulated. In vitro release study indicated significantly improved [6]-shogaol release. Pharmacokinetic parameters such as Cmax, AUC0-36 h, and oral relative bioavailability (about 685.36%) were substantially enhanced. The in situ intestinal perfusion study revealed that [6]-shogaol was markedly absorbed via passive diffusion in the intestinal segments, and duodenum followed by ileum and jejunum. Conclusions: Cyclodextrin inclusion technology could enhance the intestinal absorption and oral bioavailability of hydrophobic drugs like [6]-shogaol.

Self-Micro-Emulsifying Controlled Release of Eugenol Pellets: Preparation, In vitro/In vivo Investigation in Beagle Dogs.

This report aimed to formulate self-micro-emulsifying (SMEDDS) controlled-release pellets delivery system to improve aqueous solubility and in vivo availability of eugenol, a main constituent of clove oil with multiple pharmacological activities. The optimal formulation of eugenol-SMEDDS was eugenol: ethyl oleate: cremophor EL: 1, 2-propylene glycol at the ratio of 5:5:12:8. The SMEDDS were observed under transmission electron microscopy (TEM), and the size distribution was measured with dynamic laser light scatting (DLS). The particle size, index of dispersity (PDI), and zeta potential (Z-potential) were 68.8 ± 0.1 nm, 0.285 ± 0.031, and - 11.62 ± 0.63 mV, respectively. Eugenol-SMEDDS exhibited substantial increased in vitro dissolution compared with the free eugenol. The eugenol-SMEDDS sustained-release pellets (eugenol-SMEDDS-SR pellets) comprising of eugenol-SMEDDS, hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose (MCC), and ethyl cellulose (EC) coats were obtained via extrusion spheronization technique. Consequently, the obtained pellets observed under scanning electron microscopy (SEM) showed spherical shape with smooth surface, desirable drug loading capacity (7.18 ± 0.17%), greater stability, and controlled release. Meanwhile, the oral test showed that bioavailability of eugenol in pellets was highly improved 23.6-fold to the free eugenol. Overall, these results suggested that the improvement of the oral bioavailability of eugenol-SMEDDS-SR could be due to the successful incorporation of the drug into SMEDDS.

Enhancement of Oral Bioavailability and Anti-hyperuricemic Activity of Isoliquiritigenin via Self-Microemulsifying Drug Delivery System.

The aim of this study was to develop a self-microemulsifying drug delivery system (SMEDDS) for enhancement of the oral bioavailability of isoliquiritigenin (ISL) as well as evaluate its in vivo anti-hyperuricemic effect in rats. The ISL-loaded self-microemulsifying drug delivery system (ISL-SMEDDS) was comprised of ethyl oleate (EO, oil phase), Tween 80 (surfactant), and PEG 400 (co-surfactant). The ISL-SMEDDS exhibited an acceptable narrow size distribution (44.78 ± 0.35 nm), negative zeta potential (- 10.67 ± 0.86 mV), and high encapsulation efficiency (98.17 ± 0.24%). The in vitro release study indicated that the release rates of the formulation were obviously higher in different release media (HCl, pH 1.2; PBS, pH 6.8; double-distilled water, pH 7.0) compared with the ISL solution. The oral bioavailability of the ISL-SMEDDS was enhanced by 4.71 times in comparison with the free ISL solution. More importantly, ISL-SMEDDS significantly reduced uric acid level by inhibiting xanthine oxidase (XOD) activity in the model rats. Collectively, the prepared ISL-SMEDDS proved to be potential carriers for enhancing the solubility and oral bioavailability of ISL, as well as ameliorating its anti-hyperuricemic effect.

Formulation, Characterization, and Pharmacokinetic Studies of 6-Gingerol-Loaded Nanostructured Lipid Carriers.

In this study, an optimized nanostructured lipid carriers (NLCs) were developed and investigated for improving the solubility and oral availability of 6-Gingerol (6G), an active and abundant component of ginger with limited applications due to its poor water solubility plus oral biological availability. The NLCs consisted of a solid lipid (glyceryl monostearate), another liquid lipid (decanoyl/octanoyl-glycerides) and mixed surfactants (Tween 80 and Poloxamer 188), and was prepared by high pressure homogenization method. The optimal 6G-NLC formulation was evaluated through physical properties such as appearance, mean particle size, zeta potential, encapsulation efficiency, and in vitro drug release, alongside techniques viz., transmission electron microscopy (TEM), differential scanning calorimetry (DSC), as well as powder X-ray diffraction (XRD). Pharmacokinetics were also evaluated in rats. The 6G-NLCs prepared with optimal formulation exhibited a homogenous spherical shape with mean particle size and zeta potential of 63.59 ± 5.54 nm and - 12.18 ± 1.06 mV. Encapsulation efficiency and drug loading were 76.71 ± 1.11 and 1.17 ± 0.35%, respectively. In vitro release profile of 6G from NLCs was sustained and fitted with Weibull equation. After oral administration of the 6G-NLCs, drug concentrations in serum, MRT, and AUC0-t were significantly higher as compared with the free 6G suspension. All these results indicated that the developed NLC formulation could be effective and promising drug carriers to improve the water solubility of 6G while sustaining the drug release as well as prolonging in vivo acting time of the drug coupled with oral bioavailability enhancement.

Anti-hyperuricemic and anti-gouty arthritis activities of polysaccharide purified from Lonicera japonica in model rats.

In this present study, we investigated the anti-hyperuricemic and anti-gouty arthritis effect of a puried water-soluble polysaccharide (LJP-1) obtained from Lonicera japonica. A series of characterization of the purified polysaccharide were carried out in this paper. Monosaccharide analysis showed that LJP-1 composed of glucuronic acid, glucose, galactose, arabinose, and xylose at the ratio of 2.43:1:2.09:1.95:1.96, respectively. The estimated molecular weight of LJP-1 was 17.5 kDa. LJP-1 belonged to pyranose and possessed α- and ß -glycosidic configurations. Congo red test showed that LJP-1 had a spatial triple helix structure. In pharmacodynamic experiments, the anti-hyperuricemic activity of LJP-1 was studied using hyperuricemic SD rat model induced via potassium oxonate and hypoxanthine. The result showed that LJP-1 could obviously decrease the serum uric acid level and suppress xanthine oxidase (XOD) activity. Moreover, in the gouty arthritis model established by sodium urate crystals, the degree of swelling of the ankle joint, IL-1ß, IL-6, TNF-α and COX-2-related inflammatory factors levels in murine serum all declined. Taken together, these results demonstrated that LJP-1 has anti-gouty arthritis effect. Therefore, LJP-1 could serve as a promising candidate for developing novel natural anti-gouty agent.

Enhanced Oral Bioavailability, Anti-Tumor Activity and Hepatoprotective Effect of 6-Shogaol Loaded in a Type of Novel Micelles of Polyethylene Glycol and Linoleic Acid Conjugate.

：6-shogaol is a promising anti-cancer and anti-inflammatory agent. However, the treatment effectiveness of 6-shogaol is limited by poor water solubility, poor oral absorption and rapid metabolism. Herein, 6-shogaol loaded in micelles (SMs) were designed to improve 6-shogaol's solubility and bioavailability. The micelles of a PEG derivative of linoleic acid (mPEG2k-LA) were prepared by the nanoprecipitation method with a particle size of 76.8 nm, and entrapment of 81.6 %. Intriguingly, SMs showed a slower release in phosphate buffer saline (PBS) (pH = 7.4) compared to free 6-shogaol while its oral bioavailability increased by 3.2⁻fold in vivo. More importantly, the in vitro cytotoxic effect in HepG2 cells of SMs was significantly higher than free 6-shogaol. Furthermore, SMs could significantly improve the tissue distribution of 6-shogaol, especially liver and brain. Finally, SMs showed a better hepatoprotective effect against carbon tetrachloride (CCl4)-induced hepatic injury in vivo than free 6-shogaol. These results suggest that the novel micelles could potentiate the activities of 6-shogaol in cancer treatment and hepatoprotection.

Novel cuminaldehyde self-emulsified nanoemulsion for enhanced antihepatotoxicity in carbon tetrachloride-treated mice.

OBJECTIVES: Cuminaldehyde self-emulsified nanoemulsion (CuA-SEN) was prepared and optimised to improve its oral bioavailability and antihepatotoxicity. METHODS: Cuminaldehyde self-emulsified nanoemulsion was developed through the self-nanoemulsification method using Box-Behnken Design (BBD) tool while appropriate physicochemical indices were evaluated. The optimised CuA-SEN was characterised via droplet size (DS), morphology, polydispersity index (PDI), zeta potential (ZP), entrapment efficiency, in-vitro release, and pharmacokinetic studies while its antihepatotoxicity was evaluated. KEY FINDINGS: Cuminaldehyde self-emulsified nanoemulsion with acceptable characteristics (mean DS-48.83 ± 1.06 nm; PDI-0.232 ± 0.140; ZP-29.92 ± 1.66 mV; EE-91.51 ± 0.44%; and drug-loading capacity (DL)-9.77 ± 0.75%) was formulated. In-vitro drug release of CuA-SEN significantly increased with an oral relative bioavailability of 171.02%. Oral administration of CuA-SEN to CCl4 -induced hepatotoxicity mice markedly increased the levels of superoxide dismutase, glutathione and catalase in serum. Also, CuA-SEN reduced the levels of tumour necrosis factor-alpha and interleukin-6 in both serum and liver tissues while aspartate aminotransferase, alanine aminotransferase and malonaldehyde levels were significantly decreased. CONCLUSIONS: These findings showed that the improved bioavailability of cuminaldehyde via SEN provided an effective approach for enhancing antioxidation, anti-inflammation and antihepatotoxicity of the drug.

Enhanced oral bioavailability and anti-gout activity of [6]-shogaol-loaded solid lipid nanoparticles.

[6]-Shogaol, an alkylphenol compound purified from the root and stem of ginger (Zingiber officinale), has attracted considerable interest due to its potential anticancer, antioxidative and antirheumatic properties. However, the oral bioavailability of [6]-shogaol has been severely limited because of its poor solubility. In this study, a significant quantity of high-purity [6]-shogaol (yield: 3.6%; purity: 98.65%) was extracted and encapsulated in solid lipid nanoparticles (SLNs) via high-pressure homogenization (encapsulation efficiency: 87.67%) to improve its solubility and oral bioavailability. The resulting [6]-shogaol-loaded solid lipid nanoparticles (SSLNs) were stable, homogeneous and well-dispersed. Its mean particle size and zeta potential were 73.56 ±â€¯5.62 nm and -15.2 ±â€¯1.3 mV, respectively. Importantly, the in vitro release profile and in vivo oral bioavailability of SSLNs were significantly improved compared with the free drug. Furthermore, the SSLNs could remarkably lower the uric acid level via inhibiting the activity of xanthine oxidase and reduce the production of interleukin-1ß (IL-1ß) and tumor necrosis factor (TNF-α) in the hyperuricemia/gouty arthritis rat model, when compared to the free [6]-shogaol. Collectively, SLNs could serve as a promising drug delivery system to improve the oral bioavailability of [6]-shogaol for effective treatment of gouty arthritis.

A novel formulation of [6]-gingerol: Proliposomes with enhanced oral bioavailability and antitumor effect.

[6]-Gingerol, one of the components of the rhizome of Ginger, has a variety of biological activities such as anticoagulant, antioxidative, antitumor, anti-inflammatory, antihypertensive, and so forth. However, as one of the homologous phenolic ketones, [6]-gingerol is insoluble in water which limits its applications. Herein, we prepared [6]-gingerol proliposomes through modified thin-film dispersion method, which was spherical or oval, and physicochemically stable with narrow size distribution. Surprisingly, in vitro release of [6]-gingerol loaded proliposome compared with the free [6]-gingerol was significantly higher and its oral bioavailability increased 5-fold in vivo. Intriguingly, its antitumor effect was enhanced in the liposome formulation. Thus, our prepared [6]-gingerol proliposome proved to be a novel formulation for [6]-gingerol, which significantly improved its antitumor effect.