The characterization of the pectin/alginate nanoparticle for encapsulation of hydroxypropyl-ß-cyclodextrin-complexed naringin and its effects on cellular uptake and oxidative stress in Caco-2 cells.

Naringin (NR) and hydroxypropyl-ß-cyclodextrin (HPCD) can form a water-soluble complex, but it is unstable. This study aimed to investigate the characterization of the pectin/alginate hydrogel nanoparticles (HNPs) loading HPCD-complexed naringin. The encapsulation efficiency and loading capacity of the HNPs for NR were found to be 79.23 % ± 1.31 % and 23.79 % ± 0.67 %, respectively. HNPs had an average diameter of 409.5 ± 8.5 nm, a PDI of 0.237 ± 0.014, and a zeta-potential of -33.5 ± 0.2. FTIR, XRD, and DSC analysis confirmed that the NR-HPCD complex was embedded into the HNPs. In simulated gastrointestinal digestion, the HNPs exhibited a lower cumulative release rate compared to free NR. In Caco-2 cells, the HNPs were more efficiently transported into the cells. Consequently, the HNPs resulted in a greater decrease in ROS levels, more recovery of mitochondrial membrane potential and higher content of glutathione. This study provided a carrier for encapsulating NR, making it possible for use in food or functional food.

Investigating the prilling/vibration technique to produce gastric-directed drug delivery systems for misoprostol.

Prilling/vibration technique to produce oral microcapsules was explored to achieve local delivery of misoprostol (MIS), a prostaglandin E1 analogue indicated for the treatment of gastric-duodenal ulcers, at the gastric mucosa. To improve MIS chemical stability and reduce its associated systemic side effects, drug delivery systems were designed and developed as microcapsules consisting of a core of sunflower oil and MIS (Fs6 and Fs14) or a MIS complex with hydroxypropyl-beta-cyclodextrin (HP-ß-CD) (Fs18), confirmed by specific studies, and a polymeric shell. The produced microcapsules showed high encapsulation efficiencies for those with MIS solubilized in sunflower oil (>59.86 %) and for the microcapsules with MIS/HP-ß-CD (97.61 %). To demonstrate the ability of these systems to deliver MIS into the stomach, swelling and drug release experiments were also conducted in simulated gastric fluid. Among the three formulations, FS18 showed gastric release within 30 min and was the most advantageous formulation because the presence of the MIS/HP-ß-CD inclusion complex ensured a greater ability to stabilise MIS in the simulated gastric environment. In addition, these new systems have a small size (<540 µm), and good flow properties and the dose of the drug could be easily adapted using different amounts of microcapsules (flexibility), making them a passepartout for different age population groups.

Effects of oral HPΒCD-angiotensin-(1-7) supplementation on recreational mountain bike athletes: a crossover study.

BACKGROUND: Supplementation with Angiotensin-(1-7) [(Ang-1-7)] has received considerable attention due to its possible ergogenic effects on physical performance. The effects of a single dose of Ang-(1-7) on the performance of mountain bike (MTB) athletes during progressive load tests performed until the onset of voluntary fatigue have previously been demonstrated. This study tested the effects of Ang-(1-7) in two different exercise protocols with different metabolic demands: aerobic (time trial) and anaerobic (repeated sprint). METHODS: Twenty one male recreational athletes were given capsules containing an oral formulation of HPßCD-Ang-(1-7) (0.8 mg) and HPßCD-placebo (only HPßCD) over a 7-day interval; a double-blind randomized crossover design was used. Physical performance was examined using two protocols: a 20-km cycling time trial or 4 × 30-s repeated all-out sprints on a leg cycle ergometer. Data were collected before and after physical tests to assess fatigue parameters, and included lactate levels, and muscle activation during the sprint protocol as evaluated by electromyography (EMG); cardiovascular parameters: diastolic and systolic blood pressure and heart rate; and performance parameters, time to complete (time trial), maximum power and mean power (repeated sprint). RESULTS: Supplementation with an oral formulation of HPßCD-Ang-(1-7) reduced basal plasma lactate levels and promoted the maintenance of plasma glucose levels after repeated sprints. Supplementation with HPßCD-Ang-(1-7) also increased baseline plasma nitrite levels and reduced resting diastolic blood pressure in a time trial protocol. HPßCD-Ang-(1-7) had no effect on the time trial or repeat sprint performance, or on the EMG recordings of the vastus lateralis and vastus medialis. CONCLUSIONS: Supplementation with HPßCD-Ang-(1-7) did not improve physical performance in time trial or in repeated sprints; however, it promoted the maintenance of plasma glucose and lactate levels after the sprint protocol and at rest, respectively. In addition, HPßCD-Ang-(1-7) also increased resting plasma nitrite levels and reduced diastolic blood pressure in the time trial protocol. TRIAL REGISTRATION: RBR-2nbmpbc, registered January 6th, 2023. The study was prospectively registered.

Effect of Receptor Solution in Studies of In Vitro Permeation Test (IVPT).

In Vitro Permeation Test (IVPT) is commonly used to evaluate skin penetration of chemicals and performance of dermatological products. For a permeant with low aqueous solubility, an additive that is expected not to alter the skin barrier can be used in the receptor solution to improve permeant solubility. The objective of this study was to (a) evaluate the effects of these additives in IVPT receptor solution on skin permeability of model permeants and skin electrical resistance and (b) determine the solubility of the permeants in these receptor solutions. Bovine serum albumin (BSA), 2-hydroxypropyl-beta-cyclodextrin (HPCD), ethanol, nonionic surfactant Brij-98, and propylene glycol were the additives, and phosphate buffered saline (PBS) was the control. Steady-state skin permeability coefficients and resistances were determined. The receptor solutions examined in this study did not cause a significant increase in skin permeability or decrease in resistance (less than 40 % changes) except 25 % ethanol. The receptor solution containing 25 % ethanol induced an approximately twofold average increase in skin permeability and reduced skin electrical resistance by approximately threefold. The receptor solution of 2.5 % HPCD provided the highest levels of solubility for the model lipophilic permeants, while 0.2 % Brij-98 and 5 % ethanol showed the lowest solubility enhancement from those in PBS.

Design, optimization and pharmacokinetic evaluation of PLGA phosphatidylcholine hybrid nanoparticles of triamcinolone acetonide loaded in situ gel for topical ocular delivery.

Posterior uveitis (PU), which often has an autoimmune origin, can be treated effectively with synthetic glucocorticoid triamcinolone acetonide (TAA). Due to the limitations of topical TAA administration reaching the posterior segment of the eye, the drug is injected directly into the eye through an intravitreal injection. In this study, we prepared TAA loaded poly(lactic-co-glycolic acid) phosphatidylcholine hybrid nanoparticles (TAA-PLHNPs) using the principles of design of experiments (DoE) for topical ocular administration. The mean particle size (nm) and drug loading efficiency (LE%) for the optimized formulations were 163 ± 2.8 nm and 39 ± 1.9%, respectively. The TAA-PLHNPs were then loaded into the dual responsive in situ gel that we reported in our previous work. In vitro assessments were done to show that the formulations are safe for ocular administration. Finally, in vivo ocular pharmacokinetic studies were performed to compare pharmacokinetic parameters of TAA-PLHNPs and TAA-PLHNPs loaded in situ gel with each other and with the previously reported conventional formulation of TAA (aqueous suspension of TAA with 20% hydroxypropyl ß-cyclodextrin (TAA-HP-ß-CD-Susp)). TAA-PLHNPs loaded dual responsive in situ gel (TAA-PLHNP-ISG) achieved higher concentrations of TAA in the vitreous humor (Cmax of 946.53 ng/mL) and sustained (MRT0-∞ of 16.26 h) the drug concentrations for longer period of time compared to aqueous suspension of TAA-PLHNPs (TAA-PLHNP-Susp) and TAA-HP-ß-CD-Susp.

The Protective Effects of Moisturizer Containing Potentilla anserina Extract in the Topical Treatment of Skin Damage Caused by Masks.

The use of face masks during the COVID-19 pandemic resulted in significant societal changes, particularly for individuals with sensitive skin. To address this issue, the researchers explored traditional medicine and identified Potentilla anserina extract as a potential solution due to its anti-inflammatory and moisturizing effects. This research investigated how this extract influences skin hydration, barrier function, and itching. The findings revealed that the extract had a hydrating effect by elevating Aquaporin-3 (AQP3) expression. Additionally, the study demonstrated that the extract improved skin barrier function, with Filaggrin (FLG) expression being approximately three times higher (p < 0.001) in the Potentilla-anserina-extract-treated group compared to the control group and the genes associated with itching being reduced. In this process, we researched and developed HPßCD (hydroxypropyl-ß-cyclodextrin)-Liposome containing Potentilla anserina extract, gradually and sustainably releasing the active components of the Potentilla anserina extract. During four weeks of clinical trials involving individuals wearing masks for over 6 h a day, a moisturizer containing Potentilla anserina extract demonstrated a notable reduction in skin redness. Hemoglobin values (A.U.), which serve as indicators of skin redness, showed decreases of 5.06% and 6.74% in the test area inside the mask after 2 and 4 weeks, respectively, compared to the baseline measurements. Additionally, the moisturizer containing Potentilla anserina extract notably decreased Trans Epidermal Water Loss (TEWL), with reductions of 5.23% and 9.13% observed in the test area inside the mask after 2 and 4 weeks, respectively. The moisturizer, especially in the test area treated with the extract-containing moisturizer, significantly enhanced skin hydration compared to the control group. The Corneometer values (A.U) exhibited notable increases of 11.51% and 15.14% in the test area inside the mask after 2 and 4 weeks, respectively. These discoveries emphasize the potential of Potentilla anserina extract and its utility in tackling skin issues caused by mask wearing, including enhancing moisture, fortifying the skin's barrier, and alleviating itching. These results indicate that moisturizers incorporating specific ingredients provide greater benefits compared to conventional moisturizers.

Ex Vivo Drug Screening Assay with Artificial Membranes: Characterizing Cholesterol Desorbing Competencies of Beta-Cyclodextrins.

Despite advancements in contemporary therapies, cardiovascular disease from atherosclerosis remains a leading cause of mortality worldwide. Supported lipid bilayers (SLBs) are membrane interfaces that can be constructed with varying lipid compositions. Herein, we use a solvent-assisted lipid bilayer (SALB) construction method to build SLB membranes with varying cholesterol compositions to create a lipid-sterol interface atop a piezoelectric sensor. These cholesterol-laden SLBs were utilized to investigate the mechanisms of various cholesterol-lowering drug molecules. Within a flow-cell, membranes with varying cholesterol content were exposed to cyclodextrins 2-hydroxypropyl-beta-cyclodextrin (HPßCD) and methyl-beta-cyclodextrin (MßCD). Quartz-crystal microgravimetry with dissipation monitoring (QCM-D) enabled the collection of in vitro, real-time changes in relative areal mass and dissipation. We define the cholesterol desorbing competency of a cyclodextrin species via measures of the rate of cholesterol removal, the rate of the transfer of membrane-bound cholesterol to drug-complexed cholesterol, and the binding strength of the drug to the cholesterol-ladened membrane. Desorption data revealed distinct cholesterol removal kinetics for each cyclodextrin while also supporting a model for the lipid-cholesterol-drug interface. We report that MßCD removes a quantity of cholesterol 1.61 times greater, with a speed 2.12 times greater, binding affinity to DOPC lipid interfaces 1.97 times greater, and rate of internal cholesterol transfer 3.41 times greater than HPßCD.

Optimization of ß-Cyclodextrin-Assisted Extraction of Apigenin and Luteolin from Chrysanthemum indicum L. Using Response Surface Methodology Combined with Different Optimization Algorithms and Evaluation of Its Antioxidant Capacity.

Cyclodextrins and their derivatives have shown successful applications in extracting active compounds from medicinal plants. However, the use of ß-cyclodextrin derivatives for extracting apigenin and luteolin from Chrysanthemum indicum L. remains unexplored. Additionally, the application of nature-inspired optimization algorithms in optimizing extraction conditions has been limited. Therefore, this study was performed with the aims of optimizing the extraction of apigenin and luteolin from C. indicum with the assistance of 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD) using response surface methodology combined with various optimization algorithms, including desirability function approach, genetic algorithm, particle swarm optimization, and firefly algorithm. The results showed that the optimal conditions obtained by the four algorithms were consistent, with an extraction time of 60 min, HP-ß-CD concentration of 30 mg/mL, and a solvent-to-solid ratio of 24 mg/mL. At these conditions, the apigenin and luteolin contents were 1.362±0.008 and 8.724±0.117 mg/g, respectively. The results also showed that HP-ß-CD-assisted extraction exhibited significantly higher apigenin and luteolin contents compared to conventional solvent. Comparable results were also yielded from the antioxidant assay. Our study suggested that the nature-inspired optimization algorithms might be potential options in enhancing the effectiveness of the traditional response surface methodology for the optimization of extraction of natural products.

Improving Solubility and Permeability of Hesperidin through Electrospun Orange-Peel-Extract-Loaded Nanofibers.

Orange peel, which is a rich source of polyphenolic compounds, including hesperidin, is produced as waste in production. Therefore, optimization of the extraction of hesperidin was performed to obtain its highest content. The influence of process parameters such as the kind of extraction mixture, its temperature and the number of repetitions of the cycles on hesperidin content, the total content of phenolic compounds and antioxidant (DPPH scavenging assay) as well as anti-inflammation activities (inhibition of hyaluronidase activity) was checked. Methanol and temperature were key parameters determining the efficiency of extraction in terms of the possibility of extracting compounds with the highest biological activity. The optimal parameters of the orange peel extraction process were 70% of methanol in the extraction mixture, a temperature of 70 °C and 4 cycles per 20 min. The second part of the work focuses on developing electrospinning technology to synthesize nanofibers of polyvinylpyrrolidone (PVP) and hydroxypropyl-ß-cyclodextrin (HPßCD) loaded with hesperidin-rich orange peel extract. This is a response to the circumvention of restrictions in the use of hesperidin due to its poor bioavailability resulting from low solubility and permeability. Dissolution studies showed improved hesperidin solubility (over eight-fold), while the PAMPA-GIT assay confirmed significantly better transmucosal penetration (over nine-fold). A DPPH scavenging assay of antioxidant activity as well as inhibition of hyaluronidase to express anti-inflammation activity was established for hesperidin in prepared electrospun nanofibers, especially those based on HPßCD and PVP. Thus, hesperidin-rich orange peel nanofibers may have potential buccal applications to induce improved systemic effects with pro-health biological activity.

Effect of hydroxypropyl-ß-cyclodextrin and lecithin co-stabilized nanoemulsions on the konjac glucomannan/pullulan film.

In this study, the various ratio of hydroxypropyl-ß-cyclodextrin (HPCD) to lecithin (LEC) was 0:1, 0.5:1, 1:1, 1.5:1 and 2:1 (w/w) co-stabilized cinnamon essential oil (CEO) nanoemulsions were prepared. These nanoemulsions were successfully incorporated in the konjac glucomannan/pullulan polysaccharides-based film matrix. The composition of nanoemulsions and the effect of various nanoemulsions on rheological, mechanical, Water vapor permeability, optical, color, morphology properties, and CEO retention rate of the composite films were characterized. The results demonstrated that HPCD and LEC nanoemulsions had small particle size under 120 nm and high stability during 21 days storage, the incorporation of nanoemulsions reduced the viscosity of film-solution, transmittance, Water vapor permeability and mechanical properties of films, but an appropriate HPCD content 1:1 w/w of nanoemulsions could restored the mechanical properties of the films. Otherwise, 1:1 w/w of nanoemulsion film also exhibited a more compact and uniform structure, Furthermore, 2:1 w/w of nanoemulsion films with high retention rate of CEO, and the antioxidant and better antibacterial activities against E. coli and S. aureus. The nanoemulsion films utilized in this study also prolonged the shelf life of Agaricus bisporus mushrooms and cherries while maintaining their commercial value.

Evaluation of deodorization techniques using cyclodextrins on the headspace volatiles and antioxidant properties of onion.

Sulphur-containing volatiles in onion produce unpleasant odors and this limit their usage in foods. To expand its application, several additives including α-cyclodextrin (α-CD), ß-cyclodextrin (ß-CD), 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD), and chitosan were added to onion solution and evaluated for their effect on sulphur-containing volatiles. Also, antioxidant property using 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay and oxidative stabilities in an oil-in-water (O/W) emulsion were carried out. The total volatile contents were decreased in the order of α-CD (50.1%), ß-CD (49.3%), HP-ß-CD (46.2%), and chitosan (7%). Meanwhile, HP-ß-CD showed the highest DPPH radical scavenging ability followed by ß-CD, α-CD, and chitosan with decreasing order. The ß-CD significantly enhanced the oxidative stability of the O/W emulsion, whereas α-CD and ß-HP-CD showed prooxidative behavior. Overall, ß-CD might be used as a sulphur-containing volatile decreasing agent, which could keep the antioxidant properties of onion in the O/W emulsion.

Natural deep eutectic solvents combined with cyclodextrins: A novel strategy for chokeberry anthocyanins extraction.

Innovative eco-friendly methods based on natural deep eutectic solvents (NaDES) coupled with ultrasound-assisted extraction were employed for chokeberry anthocyanins extractions. Nine different NaDES composed of choline chloride as a hydrogen bond acceptor and organic acids (lactic, citric, malic), sugars (glucose, fructose), polyols (glycerol, 1,2-propanediol, sorbitol), and an amide (urea) as hydrogen bond donors were screened. Malic acid-containing NaDES was selected for optimization extraction conditions (time, temperature, water in NaDES) by response surface methodology. Optimal conditions for simultaneously maximizing the anthocyanins extraction (cyanidin-3-O-glucoside, cyanidin-3-O-galactoside, cyanidin-3-O-arabinoside, total anthocyanins) were 42.7 °C, 90 min, and 40 % (w/w) water in NaDES. In the next stage of this study, the possibility to improve anthocyanins extraction at elevated temperatures by incorporating different concentrations of hydroxypropyl-ß-cyclodextrin into selected NaDES was investigated. The extraction was improved at hydroxypropyl-ß-cyclodextrin concentrations up to 3 % (w/w). To clarify the interaction of NaDES components and anthocyanins, a molecular dynamic simulation was conducted.

Design and Optimization of Rivaroxaban-Cyclodextrin-Polymer Triple Complex Formulation with Improved Solubility.

Purpose: This study aimed to ensure the convenience of administration and reproducibility of efficacy, regardless of the meal, by improving the solubility of rivaroxaban (RIV). Methods: RIV is a non-vitamin K antagonist oral anticoagulants that exhibits a coagulation effect by directly inhibiting coagulation factor Xa. However, RIV has a very low solubility; therefore, it must be administered with a meal at high doses. We used a drug- hydroxypropyl-beta-cyclodextrin (CD)-water-soluble polymer triple complex (R-C-P complex) to solubilize RIV. Using Minitab, we evaluated the effect of each factor on RIV solubility and developed an optimal R-C-P complex formulation. The amount of CD, amount of polymer, and polymer type were set as the independent variables X1, X2, and X3, respectively. RIV solubility (Y1) and dissolution rate for 45 min in pH 4.5 medium (Y2) and pH 1.2 medium (Y3) were set as response variables. Results: The most efficient RIV solubilization effect was obtained from the composition using CD and HPMC 2208, and physicochemical properties and dissolution parameters were analyzed. RIV in the R-C-P complex was present in an amorphous form and showed high solubility. Unlike commercial products, it showed a 100% dissolution rate. The R-C-P complex formulation secured high RIV solubility and 100% release regardless of pH. Conclusion: The results imply that high-dose RIV can be administered regardless of the meal, reducing the risk of changing the drug effect due to the patient's administration mistake.

Ultrasound-Assisted Water Extraction of Gentiopicroside, Isogentisin, and Polyphenols from Willow Gentian "Dust" Supported by Hydroxypropyl-ß-Cyclodextrin as Cage Molecules.

The residue after sieving ("dust") from the willow gentian underground parts is an unexploited herbal tea by-product, although it contains valuable bioactive compounds. Cyclodextrins as efficient green co-solvents, cage molecules, and multifunctional excipients could improve the extraction and contribute to the added value of the resulting extracts. The objective of this study was to determine the optimal conditions for the extraction of gentiopicroside, isogentisin, and total phenolics (TPC) from willow gentian "dust" using ultrasound-assisted water extraction coupled with hydroxypropyl-ß-cyclodextrin (HPßCD). The influence of extraction temperature (X1: 20-80 °C), time (X2: 20-50 min), and HPßCD concentration (X3: 2-4% w/v) was analyzed employing the response surface methodology (RSM). The optimal extraction conditions for simultaneously maximizing the extraction yield of all monitored responses were X1: 74.89 °C, X2: 32.57 min, and X3: 3.01% w/v. The experimentally obtained response values under these conditions (46.96 mg/g DW for gentiopicroside, 0.51 mg/g DW for isogentisin, and 12.99 mg GAE/g DW for TPC) were in close agreement with those predicted, thus confirming the suitability and good predictive accuracy of the developed RSM models. Overall, the developed extraction system could be an applicable alternative strategy to improve the extraction of bioactive compounds from the underutilized "dust" of willow gentian underground parts.

Curcumin-loaded hydroxypropyl-ß-cyclodextrin inclusion complex with enhanced dissolution and oral bioavailability for epilepsy treatment.

Curcumin, the main bioactive component of turmeric, has a wild range of beneficial effects on central nervous diseases, including anti-Alzheimer's disease, antioxidant stress, and anti-inflammation. Currently, it has been demonstrated the anti-epileptic potential. However, curcumin has poor water solubility, high sensitivity to light and heat, and low absorption, which results in low bioavailability and greatly limits the clinical application of curcumin, as well as the elusive effects in anti-epileptic treatment.This study aimed to develop a curcumin hydroxypropyl-ß-cyclodextrin inclusion complex (CUR-HP-ß-CD) to improve its bioavailability and facilitate its potential development as an anti-epileptic drug. The CUR-HP-ß-CD was generated by the solvent evaporation method, which has efficient entrapment, high solubility, and facilitated bioavailability and brain distribution.The solubility of the CUR-HP-ß-CD was 63.5, 60.1, and 52.9 times that of the unformulated curcumin in H2O, HCl (pH 1.2), and PBS (pH 6.8), respectively. The bioavailability of CUR-HP-ß-CD is improved 2.8 times and 38.7 folds higher brain concentrations. Moreover, the therapeutic anti-epileptic effects of CUR-HP-ß-CD were much more effective in pentylenetetrazol (PTZ)-induced zebrafish and mouse models.This study showed a simple and reproducible strategy to effectively improve the bioavailability and therapeutic effects of curcumin, which could be potentially used in epilepsy treatment.

Improved oral nutraceutical-based intervention for the management of obesity: pterostilbene-loaded chitosan nanoparticles.

Aim: To formulate and assess the oral anti-obesity effect of polymeric-based pterostilbene (PS)-loaded nanoparticles. Methods: Pterostilbene-hydroxypropyl ß-cyclodextrin inclusion complex loaded in chitosan nanoparticles (PS/HPßCD-NPs) were prepared and characterized in vitro. Cytotoxicity, pharmacokinetics and anti-obesity effects were assessed on Caco-2 cell line and high-fat-diet-induced obesity rat model, respectively. In vivo assessment included histological examination, protein and gene expression of obesity biomarkers in adipose tissues. Results: Safe PS/HPßCD-NPs were successfully prepared with improved bioavailability compared with free PS. PS/HPßCD-NPs showed an improved anti-obesity effect, as supported by histological examination, lipid profile, UCP1 gene expression and protein expression of SIRT1, COX2, IL-6 and leptin. Conclusion: Orally administered PS nanoparticles represent a new and promising anti-obesity strategy owing to the sustainable weight loss and minimal side effects; this may be of great socio-economic impact.

Weight gain or obesity represents a major health risk and leads to diseases including cancer and heart disease. Most anti-obesity medications have significant side effects, and there are notable challenges concerning their availability in the body to produce an effect. Pterostilbene is a herbal drug with beneficial anti-obesity effects. However, it has problems such as poor solubility which restrict its use. The aim of the study was to formulate pterostilbene in a nano-based delivery system and fully characterize its anti-obesity effect when given orally. We evaluated the safety and anti-obesity effects of pterostilbene nanoparticles in cells and in obese rats fed on a high-fat diet. We also looked at how the body absorbs, distributes and gets rid of these nanoparticles. The prepared nanoparticles were nontoxic, with an improved anti-obesity effect; they decreased cholesterol levels and helped in changing white fat (which stores fat) to brown fat (which burns calories). We conclude that the developed pterostilbene nanoparticles, given orally, are a new and promising anti-obesity strategy given their long-lasting effect on weight loss and the minimal side effects. This may be of great economic and societal impact.

A novel gedunin-2-hydroxypropyl-ß-cyclodextrin inclusion complex improves anti-nociceptive and anti-inflammatory activities of gedunin in rodents.

Gedunin is a bioactive compound, obtained from Entandrophragma angolense (EA), which has limited therapeutic usefulness due to poor aqueous solubility and first-pass effects. Cyclodextrins are cyclic oligosaccharides that form complexes with poorly soluble compounds, thus enhancing their pharmacological activity. In this article, we evaluated the pharmacological activities of gedunin-2-hydroxypropyl-ß-cyclodextrin complex (GCD) in rodents. The antinociceptive activity of GCD (50, 100, 200 mg/kg) and Gedunin (50mg/kg) was tested in acetic acid-induced writhing and formalin-induced paw licking in mice. The anti-inflammatory activity was investigated in carrageenan-induced paw oedema and air pouch inflammation models in rats. Leucocytes counts, Tumour Necrosis Factor-alpha (TNF-α) level, nitric oxide, malondialdehyde, reduced glutathione, and myeloperoxidase enzyme activities were assessed in the air pouch exudate. The GCD (200mg/kg) significantly decreased writhing response, reduced licking duration and decreased oedema compared with gedunin and control. Exudate volume and leucocyte count were significantly reduced by GCD (200 mg/kg), it decreased myeloperoxidase activity and inhibited TNF-α release. The carrageenan-induced GSH depletion, increased malondialdehyde and nitrite levels were significantly reversed by GCD (200 mg/kg) relative to gedunin and control.  The GCD complex demonstrated significant antinociceptive and anti-inflammatory activities relative to gedunin alone via mechanisms associated with inhibition of oxidative stress and inflammation in rodents.

Improvement in Solubility-Permeability Interplay of Psoralens from Brosimum gaudichaudii Plant Extract upon Complexation with Hydroxypropyl-ß-cyclodextrin.

Psoralen (PSO) and 5-methoxypsoralen (5-MOP) are widely used drugs in oral photochemotherapy against vitiligo and major bioactive components of root bark extract of Brosimum gaudichaudii Trécul (EBGT), previously standardized by LC-MS. However, the exceptionally low water solubility of these psoralens can cause incomplete and variable bioavailability limiting their applications and patient adherence to treatment. Therefore, the purpose of this work was to investigate the effects of 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD) inclusion complex on the solubility and jejunal permeability of PSO and 5-MOP from EBGT. Characterization of inclusion complexes were evaluated by current methods in nuclear magnetic resonance studies on aqueous solution, Fourier transform infrared spectroscopy, thermal analysis, and scanning electron microscopy in solid state. Ex vivo rat jejunal permeability was also investigated and compared for both pure psoralens and plant extract formulation over a wide HP-ß-CD concentration range (2.5 to 70 mM). Phase solubility studies of the PSO- and 5-MOP-HP-ß-CD inclusion complex showed 1:1 inclusion complex formation with small stability constants (Kc < 500 M−1). PSO and 5-MOP permeability rate decreased after adding HP-ß-CD by 6- and 4-fold for pure standards and EBGT markers, respectively. Nevertheless, the complexation with HP-ß-CD significantly improved solubility of PSO (until 10-fold) and 5-MOP (until 31-fold). As a result, the permeability drop could be overcome by solubility augmentation, implying that the HP-ß-CD inclusion complexes with PSO, 5-MOP, or EBGT can be a valuable tool for designing and developing novel oral drug product formulation containing these psoralens for the treatment of vitiligo.

The challenge of flavonoid/cyclodextrin complexation in a complex matrix of the quercetin, luteolin, and 3-O-methylquercetin.

The complexation of herbal constituents with cyclodextrin has been a useful tool to improve their aqueous solubility. However, the simultaneous complexation of these compounds still lacks detailed studies. The present study investigated the multicomplexation of quercetin (QCT), luteolin (LUT), and 3-O-methylquercetin (3OMQ) with (2-hydroxypropyl)-ß-cyclodextrin (HPßCD), when they are simultaneously contained in a flavonoid-enriched fraction (FEF) of Achyrocline satureioides. The phase-solubility diagram revealed a linear correlation between the flavonoids solubility and the HPßCD concentration, demonstrating the formation of complexes with a 1:1 stoichiometric ratio, which was confirmed by ESI-MS. Negative ΔG0 values indicated that complexation was spontaneous. Flavonoids/HPßCD interactions were evidenced by FT-IR, DSC, SEM, and 1D and 2D NMR. The last one showed the formation of inclusion complexes by insertion of the B-ring of the flavonoids into the cavity of HPßCD. Unexpectedly, the FEF/HPßCD complex showed a radical scavenger potential lower than the FEF. The HPLC analysis revealed that the complex contained different flavonoid ratio than the fraction. Thus, the antioxidant capacity of the samples was demonstrated to be related to the ratio among the flavonoids, rather than to the total flavonoids. These new findings are very useful for developing herbal cyclodextrin-based products from A. satureioides or other herbal products.

Limonene, a citrus monoterpene, non-complexed and complexed with hydroxypropyl-ß-cyclodextrin attenuates acute and chronic orofacial nociception in rodents: Evidence for involvement of the PKA and PKC pathway.

BACKGROUND: Chronic orofacial pain is a serious public health problem with a prevalence of 7-11% in the population. This disorder has different etiologies and characteristics that make pharmacological treatment difficult. Natural products have been shown to be a promising source of treatments for the management of chronic pain, as an example the terpenes. PURPOSE: The aim of this study was to evaluate the anti-nociceptive and anti-inflammatory effects of one of these terpenes, d-limonene (LIM - a common monoterpene found in citrus fruits) alone and complexed with hydroxypropyl-ß-cyclodextrin (LIM/HPßCD) in preclinical animal models. METHODS: Orofacial pain was induced by the administration of hypertonic saline on the corneal surface, the injection of formalin into the temporomandibular joint (TMJ), or chronic constriction injury of the infraorbital nerve (CCI-IoN). The study used male Wistar rats and Swiss mice treated with LIM (50 mg/kg), LIM/HPßCD (50 mg/kg), vehicle (control), gabapentin or morphine, and eyes wiping (induced by hypertonic saline), face rubbing (formalin-induced in TMJ) or mechanical hyperalgesia (provoked by CCI-IoN) were assessed. Additionally, ELISA was used to measure TNF-α, and western blot analysis to assess levels of PKAcα, NFκB, p38MAPK and phosphorylated PKC substrates. Serum levels of aspartate aminotransferase (AST) and alanine transferase (ALT) were also evaluated. RESULTS: LIM and LIM/HPßCD significantly reduced (p < 0.001) corneal nociception and formalin-induced TMJ nociception. In addition, both substances attenuated (p < 0.001) mechanical hyperalgesia in the CCI-IoN model. The antinociceptive effect induced by LIM and HPßCD/LIM was associated with decreased TNF-α levels, downregulation of the NFκB and p38MAPK signalling pathways and reduced PKC substrate phosphorylation and PKA immunocontent. Moreover, the results demonstrated that complexation with HPßCD was able to decrease the therapeutic dose of LIM. CONCLUSION: LIM was found to be a promising molecule for the treatment of orofacial pain due to its capacity to modulate some important mediators essential to the establishment of pain, and HPßCD can be a key tool to improve the profile of LIM.