Development of Oral In Situ Gelling Liquid Formulations of Garcinia Extract for Treating Obesity.

Novel in situ gelling liquid formulations incorporating garcinia extract were developed to achieve prolonged delivery of hydroxycitric acid (HCA), an active compound displaying anti-obesity function, following oral administration. The optimized formulation was composed of sodium alginate (1.5% w/v), hydroxypropyl methylcellulose (HPMC K100) (0.25% w/v), calcium carbonate (1% w/v) and garcinia extract (2% w/v). The formulation displayed rapid gelation in less than a minute on exposure to 0.1 N hydrochloric acid (pH 1.2) and remained afloat for more than 24 h. The formulations were capable of gradually releasing more than 80% of HCA load over 8 h, depending on the composition. The resulting gels exhibited high values of gel strength by texture analysis, suggesting they would offer resistance to breakdown under the action of stomach content movement. The optimized formulation loaded garcinia extract significantly reduced lipid accumulation in 3T3-L1 adipocyte cells and displayed moderate anti-inflammatory activity by inhibiting the production of nitric oxide (NO) in LPS-stimulated RAW 264.7 macrophage cells. These findings demonstrate that oral in situ gelling liquid formulations based on sodium alginate and HPMC K100 offer much potential for sustained delivery of HCA and other anti-obesity compounds.

Comparative Inhibitory Efficacy on the iNOS/NO System of Curcuminand Tetrahydrocurcumin-Self-Microemulsifying Liquid Formulation in Chronic Gastric Ulcer Model.

BACKGROUND: Curcumin was found to accelerate gastric ulcer healing by the main mechanism, i.e., the suppression of iNOS mediated inflammation. Although Tetrahydrocurcumin (THC) is claimed to be an active antioxidant element of curcumin, its antiulcer activity has not been systematically examined. The utility of Self-Microemulsifying Drug Delivery Systems (SMEDDSs) for curcumin and THC formulations in the liquid form was also found to increase the rate and extent of release of curcumin- and THC-SMEDDS. Nevertheless, the beneficial antiulcer effect of these nanoproducts has not yet been evaluated. OBJECTIVE: This study aimed to evaluate and compare the antiulcer efficacy of curcumin- and THCSMEDDS through the inhibition of the iNOS/NO system in the rat model. METHODS: Antiulcer efficacy was compared in terms of the ability to accelerate healing of gastric ulcer including the efficient inhibitory action on inflammatory NO production in activated macrophages and iNOS mRNA expression at the ulcerated area. RESULTS: THC was found to have less ulcer healing capacity than curcumin with a lack of significant inhibitory effect on the iNOS/NO system. The SMEDDS used in the study significantly increased the inhibitory efficacy of THC on iNOS/NO production and iNOS mRNA expression compared to the inhibitory potency of curcumin. An oral administration of curcumin- or THC-SMEDDS once a day was appropriate for exerting a comparable curative efficacy to a twice-daily oral administration of curcumin or THC. CONCLUSION: The SMEDDS used in the study was observed to enhance the inhibitory efficacy of the antiulcer drug on the iNOS/NO system, leading to a reduction of daily dosing and dosing frequency.

Enhanced Oral Bioavailability and Improved Biological Activities of a Quercetin/Resveratrol Combination Using a Liquid Self-Microemulsifying Drug Delivery System.

Both quercetin and resveratrol are promising plant-derived compounds with various well-described biological activities; however, they are categorized as having low aqueous solubility and labile natural compounds. The purpose of the present study was to propose a drug delivery system to enhance the oral bioavailability of combined quercetin and resveratrol. The suitable self-microemulsifying formulation containing quercetin together with resveratrol comprised 100 mg Capryol 90, 700 mg Cremophor EL, 200 mg Labrasol, 20 mg quercetin, and 20 mg resveratrol, which gave a particle size of 16.91 ± 0.08 nm and was stable under both intermediate and accelerated storage conditions for 12 months. The percentages of release for quercetin and resveratrol in the self-microemulsifying formulation were 75.88 ± 1.44 and 86.32 ± 2.32%, respectively, at 30 min. In rats, an in vivo pharmacokinetics study revealed that the area under the curve of the self-microemulsifying formulation containing quercetin and resveratrol increased approximately ninefold for quercetin and threefold for resveratrol compared with the unformulated compounds. Moreover, the self-microemulsifying formulation containing quercetin and resveratrol slightly enhanced the in vitro antioxidant and cytotoxic effects on AGS, Caco-2, and HT-29 cells. These findings demonstrate that the self-microemulsifying formulation containing quercetin and resveratrol could successfully enhance the oral bioavailability of the combination of quercetin and resveratrol without interfering with their biological activities. These results provide valuable information for more in-depth research into the utilization of combined quercetin and resveratrol.

Raft-forming gastro-retentive formulations based on Centella asiatica extract-solid dispersions for gastric ulcer treatment.

Liquid raft-forming formulations comprising solid dispersions of glycoside-rich Centella asiatica extract and Eudragit® EPO (GR-SD) were developed to achieve prolonged delivery of the glycosides, asiaticoside (AS) and madecassoside (MS) in the stomach and thus increase the effectiveness of gastric ulcer treatment. Solid dispersions of GR extract and Eudragit® EPO (GR-SD, weight ratio 1:0.5) resulted in the highest solubility of AS (41.7 mg/mL) and MS (29.3 mg/mL) and completed dissolution of both glycosides occurred in SGF within 10 min. The optimized raft-forming formulation was composed of alginate (2%), HPMC K-100 (0.5%), GR-SD (1.2%), and calcium carbonate (0.5%) as a calcium source and carbon dioxide producer. The formulation provided sufficient raft strength (> 7.0 g), rapid floating behavior in SGF (~30 s), and sustained release of AS (more than 80%) and MS (85%) over 8 h. GR-SD-based formulations administered once daily to rats for two days at a dose of 10 mg AS/kg reduced the severity of gastric ulcer induced by indomethacin with a greater curative efficacy than those of unformulated GR extract and a standard antiulcer agent: lansoprazole (p < 0.05). These findings demonstrate that GR-SD-based raft-forming systems offer significant promise for improving the treatment of gastric ulcers induced by non-steroidal anti-inflammatory drugs.

Strategies for Improving Healing of the Gastric Epithelium Using Oral Solid Dispersions Loaded with Pentacyclic Triterpene-Rich Centella Extract.

The pentacyclic triterpenoid compounds in Centella asiatica extract, mainly consisting of asiaticoside (AS), asiatic acid (AA), madecassoside (MS), and madecassic acid (MA), possess wound healing and anti-ulcer properties, but their low aqueous solubility and dissolution rate are disadvantageous for oral administration. In this study, pentacyclic triterpene-rich centella extract (PRE) was combined with Eudragit® EPO as a hydrophilic polymer using solvent evaporation to produce a solid dispersion (PRE-ESD). The optimum PRE/Eudragit ratio of 1:2 enhanced the solubility and dissolution of glycosides (AS > 3.5 folds, MS > 2 folds) and aglycones (AA > 65 folds and MA > 56 folds) in 0.1 N hydrochloric acid (pH 1.2). DSC, XRD, and FT-IR analysis showed that the four pentacyclic triterpenes in PRE existed in the amorphous state in the solid dispersion. Moreover, almost 100% of the compounds were released from the solid dispersion within 2 h. The effects of PRE-ESD on cell proliferation and wound healing in vitro were investigated in human gastric epithelial cell lines (AGS cells). Exposure to PRE-ESD (equivalent to PRE concentration of 10 µg/mL) promoted cell proliferation and enhanced 'wound closure' in the scratch assay of wound healing by 82% compared with non-treated groups. Unformulated MA and AA aglycones did not exhibit a wound healing effect. Moreover, PRE-ESD was found to accelerate wound closure compared with either AS or MS, indicating that the wound healing properties of PRE-ESD are conferred by the active compounds AS and MS that are presented in PRE.

Polyacetal-Based Combination Therapy for the Treatment of Prostate Cancer.

The high incidence of prostate carcinogenesis has prompted the search for novel effective treatment approaches. We have employed curcumin (Curc) and diethylstilbestrol (DES) to synthesize a series of polyacetal (PA)-based combination conjugates for prostate cancer (PCa) treatment. Given their bihydroxyl functionalities, Curc and DES molecules were incorporated into a PA mainchain using a one-pot reaction between diols and divinyl ethers. The PA-conjugates released both drugs under acidic conditions, such as those found in the tumor microenvironment, endosomes, or lysosomes, while remaining stable at neutral pH 7.4. The drug ratio was optimized to achieve anticancer drug synergism with elevated cytotoxicity against LNCaP-hormone-dependent human PCa cells conferred via the induction of S phase cell cycle arrest by the upregulation of p53 and CDK inhibitors p21Waf/CIP1 and downregulation of cyclin D1. The application of rationally designed PA-Curc-DES combination conjugates represents a potentially exciting new treatment for prostate cancer.

A Self-Microemulsifying Formulation of Oxyresveratrol Prevents Amyloid Beta Protein-Induced Neurodegeneration in Mice.

The polyphenol compound, oxyresveratrol (OXY) possesses potent antioxidant and neuroprotective properties of potential utility in the treatment of Alzheimer's disease. However, the low oral bioavailability limits its neuroprotective effect and clinical application. The neuroprotective effect of orally administered OXY-loaded self-microemulsifying drug delivery system (OXY-SMEDDS) was compared with free OXY in vivo. Mice were orally administered either free OXY or OXY-SMEDDS once daily at a dose of 90, 180, or 360 mg/kg for 14 d. Mice received a single intracerebroventricular injection of the neurotoxic amyloid ß (Aß)25 - 35 peptide at day 8 during oral treatment. The OXY-SMEDDS formulation resulted in four-times reduction of the free OXY dose required for prevention of neurotoxicity effects due to Aß25 - 35 peptide as demonstrated by a significant decline in behavior impairments, lipid oxidation levels, and neuronal cell loss in all hippocampal subfields (p < 0.0001). These results indicate the potential of OXY-SMEDDS by oral delivery to improve the efficacy of this compound in the treatment of Alzheimer's disease.

A Novel Self-Microemulsifying System for the Simultaneous Delivery and Enhanced Oral Absorption of Curcumin and Resveratrol.

The use of curcumin and resveratrol in combination has now become increasingly of interest because of their synergistic effects as therapeutic agents for various diseases, especially cancer. To overcome the poor oral bioavailability of both compounds and improve patient compliance, a novel self-microemulsifying formulation containing curcumin together with resveratrol was developed. Capryol 90, Cremophor EL, and Labrasol were selected as the oil, surfactant, and co-surfactant in the formulation, respectively, based on the solubility study of both compounds. More than 70 % and 80 % of curcumin and resveratrol, respectively, were released in 20 min. The formulation formed a fine oil in water microemulsion with droplet sizes in aqueous media of 15-20 nm. In addition, the formulation containing curcumin and resveratrol showed greater antioxidant activity than that of the formulations with individual compounds, while the cytotoxic activity against HT-29 of the co-formulation (IC50 = 18.25 µM; curcumin and resveratrol in the ratio 1 : 1) was less than the formulation with only curcumin (IC50 = 30.1 µM) and only resveratrol (IC50 = 25.4 µM). After oral administration to rabbits, the self-microemulsifying formulation containing curcumin together with resveratrol increased the total plasma concentrations of curcumin and resveratrol by 10-fold and 6-fold, respectively, compared to the unformulated combination. This study clearly demonstrated the potential use of the self-microemulsifying formulation for co-delivery, and enhanced oral absorption of poorly water-soluble natural compounds. In addition, the combination was found to produce synergistic antioxidant activity and cytotoxicity against HT-29 cells.

Influence of surfactants in self-microemulsifying formulations on enhancing oral bioavailability of oxyresveratrol: Studies in Caco-2 cells and in vivo.

Self-microemulsifying drug delivery systems (SMEDDS) containing two types (Tween80 and Labrasol) and two levels (low; 5% and high; 15%) of co-surfactants were formulated to evaluate the impact of surfactant phase on physical properties and oral absorption of oxyresveratrol (OXY). All formulations showed a very rapid release in the simulated gastric fluid (SGF) pH 1.2. After dilution with different media, the microemulsion droplet sizes of the Tween80-based (∼26 to 36 nm) were smaller than that of the Labrasol-based systems (∼34 to 45 nm). Both systems with high levels of surfactant increased the Caco-2 cells permeability of OXY compared to those with low levels of surfactant (1.4-1.7 folds) and the unformulated OXY (1.9-2.0 folds). It was of interest, that there was a reduction (4.4-5.3 folds) in the efflux transport of OXY from both systems compared to the unformulated OXY. The results were in good agreement with the in vivo absorption studies of such OXY-formulations in rats. Significantly greater values of Cmax and AUC(0-10h) (p<0.05) were obtained from the high levels of Tween80-based (F(r,0-10h) 786.32%) compared to those from the Labrasol-based system (F(r,0-10h) 218.32%). These finding indicate the importance of formulation variables such as type and quantity of surfactant in the SMEDDS to enhance oral drug bioavailability.

Development and evaluation of gastroretentive raft forming systems incorporating curcumin-Eudragit® EPO solid dispersions for gastric ulcer treatment.

Novel raft forming systems incorporating curcumin-Eudragit® EPO solid dispersions were developed to prolong the gastric residence time and provide for a controlled release therapy of curcumin to treat gastric ulcers. The solid dispersions of curcumin with Eudragit® EPO were prepared by the solvent evaporation method at various ratios to improve the solubility and the dissolution of curcumin. The optimum weight ratio of 1:5 for curcumin to Eudragit® EPO was used to incorporate into the raft forming systems. The raft forming formulations were composed of curcumin-Eudragit® EPO solid dispersions, sodium alginate as a gelling polymer and calcium carbonate for generating divalent Ca(2+) ions and carbon dioxide to form a floating raft. All formulations formed a gelled raft in 1min and sustained buoyancy on the 0.1N hydrochloric acid (pH 1.2) surface with a 60-85% release of curcumin within 8h. The curative effect on the acetic acid-induced chronic gastric ulcer in rats was determined. The curcumin raft forming formulations at 40mg/kg once daily showed a superior curative effect on the gastric ulcer in terms of the ulcer index and healing index than the standard antisecretory agent: lansoprazole (1mg/kg, twice daily) and a curcumin suspension (40mg/kg, twice daily). These studies demonstrated that the new raft forming systems containing curcumin solid dispersions are promising carriers for a stomach-specific delivery of poorly soluble lipophilic compounds.

Modification of oral absorption of oxyresveratrol using lipid based nanoparticles.

The aim of this study was to develop and assess nanostructured lipid carriers (NLC) compared to solid lipid nanoparticles (SLN) for improving the oral bioavailability of oxyresveratrol (OXY). The OXY formulated as SLN (OXY-SLN) and NLC (OXY-NLC) were prepared by a high shear homogenization technique. The optimized OXY-NLC (NLC3) produced smaller nanoparticle sizes (96±0.9nm) than that of the OXY-SLN (108±0.3nm) with a homogeneous size distribution and a high zeta potential. The spherical NLC had a significantly higher efficiency for OXY entrapment (89±0.1%) and a better stability than the SLN after storage for 12 months at 4±2°C according to parameters such as smaller particles, greater zeta potential and a higher loading capacity (p<0.05). Differential scanning calorimetry (DSC) showed a less ordered crystalline structure of NLC than SLN. The accumulated drug in an amorphous state in the NLC was also confirmed by powder X-ray diffraction (PXRD). The in vitro release profiles of the OXY-NLC showed a more sustained release compared to the SLN and unformulated OXY. The in vivo pharmacokinetic profiles implied enterohepatic recycling of OXY in the Wistar rat. Meanwhile, the oral absorption pattern of OXY was modified by both types of lipid nanoparticles. The SLN and NLC increased the relative bioavailability of OXY to 125% and 177%, respectively, compared with unformulated OXY. These findings indicated that NLC could be used as a potential carrier to improve the oral bioavailability of OXY.

Liquid and solid self-microemulsifying drug delivery systems for improving the oral bioavailability of andrographolide from a crude extract of Andrographis paniculata.

The purpose of this study was to develop self-microemulsifying formulations of an Andrographis paniculata extract in liquid and pellet forms for an improved oral delivery of andrographolide. The optimized liquid self-microemulsifying drug delivery system (SMEDDS) was composed of A. paniculata extract (11.1%), Capryol 90 (40%), Cremophor RH 40 (40%) and Labrasol (8.9%). This liquid SMEDDS was further adsorbed onto colloidal silicon dioxide and microcrystalline cellulose, and converted to SMEDDS pellets by the extrusion/spheronization technique. The microemulsion droplet sizes of the liquid and pellet formulations after dilution with water were in the range of 23.4 and 30.3 nm. The in vitro release of andrographolide from the liquid SMEDDS and SMEDDS pellets was 97.64% (SD 1.97%) and 97.74% (SD 3.36%) within 15 min, respectively while the release from the initial extract was only 10%. The oral absorption of andrographolide was determined in rabbits. The C(max) value of andrographolide from the A. paniculata extract liquid SMEDDS and SMEDDS pellet formulations (equivalent to 17.5mg/kg of andrographolide) was 6-fold and 5-fold greater than the value from the initial extract in aqueous suspension (equivalent to 35 mg/kg of andrographolide), respectively. In addition, the AUC(0-12h) was increased 15-fold by the liquid SMEDDS and 13-fold by the SMEDDS pellets compared to the extract in aqueous suspension, respectively. The results clearly indicated that the liquid and solid SMEDDS could be effectively used to improve the dissolution and oral bioavailability that would also enable a reduction in the dose of the poorly water soluble A. paniculata extract.

Development and evaluation of granule and emulsifiable concentrate formulations containing Derris elliptica extract for crop pest control.

Derris elliptica Benth. extracts containing rotenone have long been used as natural insecticides, but time-consuming preparation processes and the short shelf life of the extract limit their use in pest control. In this study, stable water-dispersible granules and emulsifiable concentrate liquids containing Derris extract (equivalent to 5% w/w of rotenone) were developed with simple techniques. Accelerated degradation kinetics of rotenone in the Derris extract, and in both formulations, indicated that its degradation followed first-order kinetics. The predicted half-life (t(1/2)) and shelf life (t(90%)) at 30 degrees C of rotenone in Derris extract were 520 and 79 days, respectively. Derris granules and emulsifiable concentrate clearly prolong the stability of rotenone 8-fold (t(90%) = 633 days) and 1.4-fold (t(90%) = 110 days), respectively. The study of rotenone degradation after application onto plants indicated that both formulations would be effective for up to 3 days after spraying. Preliminary efficacy testing indicated that the Derris emulsifiable concentrate was clearly more effective than Derris water-dispersible granules in controlling Spodoptera litura (Fabricius) (Lepidoptera: Noctuidae).

Extraction of rotenone from Derris elliptica and Derris malaccensis by pressurized liquid extraction compared with maceration.

The extraction of active compounds from plants is one of the most critical steps in the commercial development of natural products for medicinal, herbicidal or pesticidal use. The focus of this study was to compare conventional maceration and pressurized liquid extraction (PLE) techniques for the efficient extraction of rotenone from the stem and root of Derris elliptica Benth and Derris malaccensis Prain. The effects of experimental variables, such as solvent, temperature and pressure, on PLE efficiency have been studied. Chloroform was determined to be a good extraction solvent (rotenone content 40.6%, w/w) compared to commonly used solvent, 95% ethanol (rotenone content 15.0%, w/w). The optimal conditions for PLE were 50 degrees C and 2000 psi. PLE showed higher extraction efficiency (rotenone content 46.1%, w/w) as compared with conventional maceration method (rotenone content 40.6%, w/w). The order of rotenone content found in crude extract obtained by optimized method from the highest to the lowest was root (46.1%, w/w) and stem (9.4%, w/w) of D. elliptica and stem of D. malaccensis (5.2%, w/w), respectively. Moreover, the results from this study indicated that PLE was considerably less time and solvent consuming (30 min, 3 ml/g of dried sample) than the conventional maceration techniques (72 h, 10 ml/g of dried sample).