Lipid Nanoparticles: An Effective Tool to Improve the Bioavailability of Nutraceuticals.

Nano-range bioactive colloidal carrier systems are envisaged to overcome the challenges associated with treatments of numerous diseases. Lipid nanoparticles (LNPs), one of the extensively investigated drug delivery systems, not only improve pharmacokinetic parameters, transportation, and chemical stability of encapsulated compounds but also provide efficient targeting and reduce the risk of toxicity. Over the last decades, nature-derived polyphenols, vitamins, antioxidants, dietary supplements, and herbs have received more attention due to their remarkable biological and pharmacological health and medical benefits. However, their poor aqueous solubility, compromised stability, insufficient absorption, and accelerated elimination impede research in the nutraceutical sector. Owing to the possibilities offered by various LNPs, their ability to accommodate both hydrophilic and hydrophobic molecules and the availability of various preparation methods suitable for sensitive molecules, loading natural fragile molecules into LNPs offers a promising solution. The primary objective of this work is to explore the synergy between nature and nanotechnology, encompassing a wide range of research aimed at encapsulating natural therapeutic molecules within LNPs.

Anti-inflammatory mechanisms of eucalyptol rich Eucalyptus globulus essential oil alone and in combination with flurbiprofen.

Inflammation is the core contributor in the pathogenesis of various acute and chronic illness including appendicitis, bronchitis, arthritis, cancer and neurological diseases. NSAIDs, commonly used medications for inflammatory diseases, on prolonged use cause GI bleeding, ulcers and many more issues. Plant-based therapeutic agents including essential oils in combination with low-dose synthetic drugs have been shown to produce synergistic effects and reduce complications of synthetic drugs. This study was designed to evaluate the anti-inflammatory, analgesic and anti-pyretic properties of Eucalyptus globulus essential oil alone and in combination with flurbiprofen. GC-MS analysis was performed to screen chemical composition of oil. In vitro anti-inflammatory assay (membrane stabilization assay) and in vivo inflammatory acute (carrageenan and histamine-induced paw oedema) and chronic (cotton pellet-induced granuloma and Complete Freund's adjuvant-induced arthritis) models were performed to check anti-inflammatory properties. Acetic acid-induced algesia and yeast-induced pyrexia models were performed to check analgesic and anti-pyretic properties. qRT-PCR was performed to study the effect of treatments on the expression of inflammatory biomarkers. GC-MS analysis of E. globulus essential oil showed the presence of eucalyptol along with other active biomolecules. 500 + 10 mg/kg of oil-drug combination showed significantly (p < 0.05) better in vitro membrane stabilization effects as compared with groups treated with 500 mg/kg of E. globulus oil and 10 mg/kg of Flurbiprofen alone. 500 + 10 mg/kg of oil-drug combination showed significantly (p < 0.05) better anti-inflammatory, analgesic and antipyretic effects as compared to 500 mg/kg of E. globulus oil alone in all in vivo models. When comparison was done between 500 + 10 mg/kg of oil-drug combination-treated and 10 mg/kg Flurbiprofen-treated group, the former group showed significantly (p < 0.05) better anti-inflammatory and anti-pyretic effects, but there were non-significant differences in the analgesic model. Animal group treated with 10 mg/kg of Flurbiprofen showed significantly (p < 0.05) better anti-inflammatory and analgesic effects than group treated with 500 mg/kg of oil alone while, there were non-significant differences in anti-pyretic effects. qRT-PCR analysis showed significant (p < 0.05) down-regulation in the expression of IL-4 and TNF-α in serum samples of animals treated with 500 + 10 mg/kg of oil-drug combination as compared to the diseased control (arthritic) group. Overall, the current research demonstrates that Eucalyptus globulus essential oil in combination with flurbiprofen showed better anti-inflammatory, analgesic and anti-pyretic effects than oil and flurbiprofen alone which is attributed to the down-regulation of pro-inflammatory biomarkers (IL-4 and TNF-α). Further studies are required to formulate a stable dosage form and to check the anti-inflammatory efficacy in different inflammatory disorders.

Physicochemical, rheological and antifungal evaluation of miconazole nitrate organogels for topical delivery.

Topical preparations have a problem of being wiped off after a short time, which results in low activity of the active moiety. In this research, topical organogels (OGs) were prepared with different oils for the controlled action of miconazole nitrate. Various oils were checked for their gel-forming ability. Controlled release OGs were prepared with a 15% concentration of glyceryl monostearate. Differential scanning calorimetry was performed to study the thermal behavior of gels. X-ray diffraction revealed that the drug was changed into an amorphous form from the crystalline form. The absence of any interaction between the active ingredient and excipients was concluded by Fourier Transform Infrared spectroscopy. Permeability studies were carried out with cellulose acetate membrane by using Franz diffusion cell containing phosphate buffer saline pH 7.4. The release of drug followed the Weibull model. A frequency sweep test was performed to study the rheological behavior of optimized formulations. Rheology revealed the true nature of formulations whether they are gels or just viscous fluids. Images of scanning electron microscopy showed a network formed by the gelator molecules. The antifungal activity was checked against C. albicans and A. niger and it was best by the formulation made by TT. It was concluded that all the OGs gave controlled topical antifungal action.

Preparation and evaluation of oral self-microemulsifying drug delivery system of Chlorophyll.

OBJECTIVE: This study was aimed at improving the water solubility and oral bioavailability of Chl by self-microemulsifying drug delivery system (Chl-SMEDDS). METHODS: Compatibility experiments, pseudo-ternary phase diagram and central composite design were used to optimize the formulation. The selected systems were further evaluated for physical characteristics, including particle size, zeta potential, and appearance. The stability, in vitro dispersion test, and in vivo intestinal perfusion experiments were used to evaluate the SMEDDS. RESULTS: The optimal composition of Chl-SMEDDS included: Labrafil M 1944 CS (35%), kolliphor RH 40 (46%), Transcutol HP (19%) and 60 mg/g Chl. The appearance of water emulsified Chl-SMEDDS was green and transparent. The particle size, ζ-potential, and transmission electron microscopy studies showed that spherical globules of Chl-SMEDDS with a size of about 22.82 ± 1.29 nm and a negative surface charge of -24.21 ± 3.45 mV were obtained. Chl-SMEDDS could remain stable at 25 °C and 4 °C for at least 6 months. The dispersion test showed that Chl-SMEDDS dispersed spontaneously to form microemulsion after disintegration of capsule shell and 90% drug dispersed in just 30 min in pH 1.2 HCl without any drug precipitation during the test period. In vivo intestinal perfusion experiment revealed that the main absorption site for Chl-SMEDDS was duodenum. CONCLUSIONS: This study indicates that SMEDDS formulation could be an effective strategy for the oral administration of Chl.

Fabrication and characterization of itraconazole loaded anisotropic solid lipid-mannitol microstructures for enhanced antifungal activity.

Anisotropic microparticles containing flower like morphologies have recently attracted significant attention due to their potentially varied application range. Aim of the present work was to build an anisotropic drug delivery system (ASLMMSs) for the encapsulation and enhancement of antifungal activity of a hydrophobic antifungal drug i.e. itraconazole (IRL) with the combination of lipophilic (lipids) as well as hydrophilic (mannitol) materials. Encapsulation efficiency (EE) due to glyceryl monosteatrate (G.ASLMMSs) was 89.02%, whereas Precirol ATO5 formulation (P.ASLMMSs) showed 96.98% EE. FTIR analysis discovered the hydrogen bonding and Vander Waal's forces between lipids and mannitol, while evaluation of XRD data revealed the detailed structural and microstructural characterization indicating the crystallinity of final formulations. Observation under SEM revealed that the final formulations grew in the form of flower like morphologies. These flower-like structures were more obvious for P.ASLMMSs. The increment in dissolution rate (>80% in 6h) could be attributed to the mannitol. Dilutions of Itraconazole loaded anisotropic solid lipid mannitol microstructures (ASLMMSs) in water at concentration range of (500µg/mL, 250µg/mL, 125µg/mL and 75µg/mL) exhibited increased antifungal activity, while free IRL dilution in water showed no zone of inhibition. Both formulations, specifically P.ASLMMSs could signify a promising drug delivery system for lipophilic antifungal drugs.

Development and evaluation of oral fast disintegrating film of ranitidine HCl by solvent casting method.

Here, we developed oral fast disintegrating film (ODF) of ranitidine hydrochloride (RHCl) by solvent casting method and assessed the impact of various formulation ingredients i.e. polymer concentration, type of plasticizers and superdisintegrants. Optimized film was developed with hydroxypropyl methyl cellulose (HPMC E5, 3% w/v) as film matrix, propylene glycol (PG) (10% w/w of polymer) as plasticizer and Pearlitol flash® (PF) (10% w/w of polymer) as release modifier. This film was chosen based on appearance, transparency, thickness, folding endurance and in vitro disintegration time (DT). Later on, optimized film was loaded with drug (50% w/w of polymer) (A12), which disintegrated within 15 seconds and released 81% of RHCl within two minutes. Furthermore, FTIR studies confirmed the absence of drug film ingredients interaction. SEM showed even distribution of RHCl and all excipients. Thus, A12 will be palatable for geriatric patients and helpful to avoid premature intestinal degradation.

Methanolic extract of Ephedra ciliata promotes wound healing and arrests inflammatory cascade in vivo through downregulation of TNF-α.

Chronic wounds may lead to the development of various pathological conditions such as diabetic foot ulcers and pressure sores. The current study evaluated wound healing and anti-inflammatory potentials of methanolic extract of Ephedra ciliata using series of in vivo models. Methanolic extract of Ephedra ciliata was prepared by maceration (Ec.Me). Qualitative and quantitative (HPLC) phytochemical and metal analyses were conducted to explore the chemical and metal profiles of Ec.Me. Safety profile (behavioural) and, antimicrobial, antioxidant, wound healing, anti-inflammatory and anti-angiogenic potentials of Ec.Me were evaluated using well-established in vitro and in vivo models. ELISA assay was performed to estimate the effects of Ec.Me treatment on serum levels of TNF-α. HPLC analysis identified quercetin as one of the major compounds in Ec.Me. Safety study data showed that Ec.Me was safe up to the dose of 2000 mg/kg. Antimicrobial assay data showed that Ec.Me was active against bacterial (Staphylococcus aureus) as well as fungal (Candida albicans and Aspergillus niger) strains. Ec.Me showed modertate antioxidant potential in in vitro and in vivo models. Data of excision and burn wound healing models showed that Ec.Me, promoted wound closure in a dose and time-dependent manner. Treatment with 20% Ec.Me cream and heparin showed almost the same effects with no statistical differences (p > 0.05). Ec.Me also showed time-dependent anti-inflammatory activities in both acute and chronic models. In carrageenan model, treatment with 200 mg/kg of Ec.Me showed comparable anti-inflammatory effects (p > 0.05) with quercetin and indomethacin throughout the study. In cotton pellet granuloma model treatment with 200 mg/kg of Ec.Me and indomethacin inhibited granuloma formation significantly better (p < 0.05) as compared with the rest of the treatment groups. Histopathological examination of skin samples showed marked improvement in architecture with minimal infiltration of inflammatory cells. Data of in vivo angiogenesis assay showed marked improvement in vessels length, density, branching points, total segments and total nets after treatment with Ec.Me, indicating no toxic effects towards vasculature development. Significant (p < 0.05) downregulation of TNF-α was observed in serum samples of animals treated with Ec.Me. Based on data of the current study, it is concluded that quercetin-rich extract of Ephedra ciliata has wound healing and anti-inflammatory potentials via downregulation of TNF-α. Moreover, it is suggested that the antimicrobial activity of Ec.Me prevented microbial invasion, thus promoted natural wound healing mechanisms as well.

Equilibrium, kinetics, thermodynamics and docking studies of Cu2+ ion adsorption over ion-exchange resin and kappa carrageenan blends in blood samples.

Cupric ions are hazardous to human beings and their removal from the body is very necessary. The blends of IRP69H (AMBERLITE IRP-69 [H+] RESIN), DC20H (DOWEX™ 20 [H+] Resin), DMSCH (DOWEX™ MARATHON™ MSC [H+] Resin) and Kappa Carrageenan (κ-) were utilized for the removal of ions of Cu2+ from the blood. They were subjected to docking studies which showed that there is no significant interaction with the blood albumin. IER dose of 0.5 mg/10mL of IRP69H/κ-, DMSCH/κ-, and DC20H/κ- was essential for the 2+ ion removal. At pH 5.4, optimal 2+ ions adsorption efficiency was attained. The adsorption capacities of 2+ were in the order of IRP69H/κ->DC20H/κ->DMSCH/κ-. While the data fitted well to Freundlich, Langmuir and Dubinin-Radushkevich. Pseudo-second order was followed for 2+ adsorption for DMSCH/κ- and DC20H/κ- while the pseudo-first order was demonstrated well for IRP69H/κ-.

Binary inclusion complexes of diflunisal with ß-cyclodextrin and hydroxypropyl-ß-cyclodextrin: Preparation and characterization.

Low aqueous solubility and bioavailability is the limiting factor to achieve desired therapeutic efficacy for variety of new and existing drug moieties. The goal of the present study was to explore the effects of ß-cyclodextrin (ßCD) and hydroxypropyl-ß-cyclodextrin (HPßCD) on the solubility and dissolution profile of diflunisal (DIF) prepared by using two different methods (physical mixing and solvent evaporation) at DIF-cyclodextrins weight ratios of 1:1, 1:2 and 1:4. The phase solubility studies demonstrated that DIF solubility increased proportionally with an increase in ßCD and HPßCD concentration. The inclusion complexes were subjected to characterization of scanning electron microscopy (SEM), fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and X-ray diffractometry (XRD). Solvent evaporation yielded higher DIF solubility than physical mixing method. HPßCD-DIF inclusion complexes yielded higher dissolution profile than ßCD complexes when prepared under same experimental design. FTIR, DSC and XRD confirmed the successful inclusion of DIF into cyclodextrin (ßCD/HPßCD) by both preparation methods with enhanced water solubility and drug release in comparison with pure drug.

Stability indicating RP-HPLC method of dexibuprofen in nanocream formulation: Identification and quantification.

A stability indicating reverse phase-HPLC method was designed for determination of dexibuprofen in drug solution and in nanocream formulation. Chromatographic conditions were optimized simply by adjusting the content and different compositions of reverse phase associated with mobile phases. Different parameters like specificity, limit of quantification (LOQ), limit of detection, linearity, range, system suitability, precision and accuracy were determined. Stability studies of dexibuprofen in nanocream were taken under the stressed situations of alkali, acid, oxidation process, UV and heat degradation. Tailing factor and % RSD were found >2000 and <2% respectively. The method was identified linear over the range of 0.2-1.6mg/ml having co-efficient of correlation 0.9995. Intra-day and inter- day precision and accuracy values for dexibuprofen were < 0.6% and <1.1032 and < 0.3% and 1.10% respectively. Stability studies showed that dexibuprofen was stable in nanocream against alkali, acid, oxidation, UV light and heat. The developed validated method was precise and accurate for the evaluation of dexibuprofen in solution as well as in nanocream formulation.

Hepatoprotective and Renoprotective Properties of Lovastatin-Loaded Ginger and Garlic Oil Nanoemulsomes: Insights into Serum Biological Parameters.

Background and Objectives: Dyslipidemia is gaining much attention among healthcare professionals because of its high association with the malfunctioning of a number of normal physiological and metabolic processes in the body. Obesity is directly interconnected with dyslipidemia and is said to be a denouement of hyperlipidemia and, if left untreated, may lead to intense damage to organs that are directly involved in fat metabolism. The objective of this study was to investigate the synergistic antiobesity and anti-hyperlipidemic activities along with hepato- and renoprotective potential of nanoemulsomes (NES) of lovastatin (LTN)-loaded ginger (GR) and garlic (GL) oils. Materials and Methods: LTN nanoemulsomes co-encapsulated with GR oil and GL oil were prepared by a thin hydration technique. Eight-week-old male Wistar rats weighing 200-250 g were induced with hyperlipidemia via a high-fat diet (HFD) comprising 40% beef tallow. Body weight, serum biochemical lipid parameters, and those for liver and kidney functions, serum TC, LDL-C, vLDL-C, HDL-C, TG, atherogenic index (AI), ALT, AFT, ALP, γ-GT, total protein (TP), serum albumin and globulin ratio (A/G), serum creatinine, blood urea nitrogen (BUN) and blood urea, and histopathology of hematoxylin and eosin (H&E) stained liver and kidney sections of all aforementioned groups were examined in the treated animals. Results: Nanoemulsomes of LTN-loaded GR and GL oils provided synergistic effects with LTN, exerted better ameliorative actions in reducing serum TC, LDL-C, vLDL-C, triglycerides, and AI, and improved serum HDL-C levels. Serum ALT, AST, ALP, and γ-GT levels were in the normal range for nanoemulsome groups. H&E stained liver and kidney sections of these animals confirmed better hepatoprotective and renoprotective effects than LTN alone. Serum biochemical parameters for renal functions also claimed to be in the moderate range for nanoemulsome-treated groups. Conclusion: This study demonstrated that nanoemulsomes of LTN-loaded GR and GL oils synergistically provided better antihyperlipidemic, hepatoprotective, and renoprotective effects as compared to LTN alone.

An assessment of bioavailability of acrylate based pH-sensitive complexes of lovastatin.

Lovastatin (LSN), a potent anti-hyperlipidemic drug, possesses poor bioavailability due to its very low aqueous solubility. The objective of this study was to establish a relationship between increased drug solubility before reaching site of absorption or increasing drug solubility at target absorption site for accentuated bioavailability of LSN. Composites of LSN with oppositely natured pH-sensitive acrylate polymers, cationic Eudragit EPO (EPO) and anionic Eudragit L100 (L100), were fabricated with physical trituration and kneading methods. Formulations were characterized for solubility, FTIR, PXRD, DSC, SEM, dissolution and bioavailability studies in rats. Interestingly, we observed that physical mixtures of EPO outmatched its kneaded formulations, whereas the physical mixtures and kneaded dispersions of L100 were virtually similar in characteristics. EPO was superior in boosting LSN solubility in the respective medium than the L100. Moreover, EPO produced immediate release profile in gastric environment whereas L100 offered sustained release of LSN in intestinal milieu. Bioavailability studies in rats further supported the EPO formulation in terms of shorter Tmax, higher Cmax and heightened AUC.

Development and validation of a stability-Indicating RP-HPLC method for simultaneous estimation of sofosbuvir and velpatasvir in fixed dose combination tablets and plasma.

A simple, specific, sensitive, robust, accurate and precise reverse-phase high performance liquid chromatographic (RP-HPLC) method was developed and validated for simultaneous determination of sofosbuvir (SOF) and velpatasvir (VLP) in fixed dose combination tablets and plasma. Validation parameters, such as system suitability, accuracy, inter-day and intra-day variances, specificity, linearity, limit of detection (LOD), limit of quantification (LOQ), robustness and stability were assessed following the standards set by the International Conference on Harmonization (ICH). The isocratic elution of SOF and VLP was carried out under ambient conditions using ammonium acetate buffer (pH = 7.0), acetonitrile and methanol (20:40:40, v/v/v) as mobile phase flowing through a Promosil C18 column at a flow rate of 1.0 mL/min. The average retention time of SOF and VLP was 3.72 min and 7.09 min, respectively. The LOD and LOQ of SOF were 0.23µg/mL and 2.48µg/mL, respectively; while those of VLP were 0.70µg/mL and 7.52µg/mL, respectively. The regression coefficient (r2) was 0.998. The relative standard deviation (RSD) was less than 2% for precision. The recovery of both the analytes remained within 100±1%. All other validation parameters complied with ICH guidelines. The analytes remained stable throughout the analytical procedure. Moreover, this method was successfully applied to assess the in vitro dissolution of SOF and VLP loaded fixed dose combination tablets. Same method with same mobile phase was applied on rat plasma and there was no interference.

Facile synthesis of mesoporous silica nanoparticles using modified sol-gel method: Optimization and in vitro cytotoxicity studies.

The present study describes the synthesis of mesoporous silica nanoparticles using a modified sol-gel method. Various proportions of acetonitrile-water mixtures were utilized so as to optimize the reaction mixture for facile synthesis of mesoporous silica nanoparticles with controlled particle size for the very first time. After carefully adjusting the water and acetonitrile contents i.e. to 1:1 v/v ratio, a more uniform and small sized nanoparticles were achieved. The resultant particles were 140 nm in size having pore size of approximately 5.9 nm and were safe to be used in the cellular system, as confirmed by the in vitro cytotoxicity studies.

Clove oil based co-surfactant free microemulsion of flurbiprofen: Improved solubility with ameliorated drug-induced gastritis.

Flurbiprofen, an NSAID, is a water insoluble drug that is also notorious for gastric irritation and inflammation. This study was aimed at using a natural gastrprotective oil as the internal phase to develop flurbiprofen micro emulsion (ME) to improve it solubility and ameliorate its gastric side effects. Upon screening of ME components for drug solubility, clove oil, tween 80 and transcutol were identified as the oil, surfactant and co surfactant, respectively, with higher flurbiprofen solubility. Pseudo-ternary phase diagrams revealed that the ME made with surfactant only and without co-surfactant displayed the similar ME region as made with the mixture of surfactant and co-surfactant. Furthermore, drug loaded oil was also used to draw pseudo-ternary phase diagram and a very little decrease in the ME region was observed. Therefore, co-surfactant free flurbiprofen loaded ME was developed to avoid side effects associated with the use of excessive surfactant quantities. ME were found to possess size in the range of 11-41 nm with PDI <0.5 and a slightly negative charge. Conductivity, pH and refractive indices of the selected MEs were well in the range. Drug release studies indicated maximum drug release from MEs within 5 min. Analysis of the gastric mucosa of rats after oral administration of drug solution and drug loaded ME confirmed that clove oil based ME provided significant protection against the NSAIDs induced gastric damage.

Enhanced oral bioavailability of 10-hydroxycamptothecin through the use of poly (n-butyl cyanoacrylate) nanospheres.

The article describes the preparation, physicochemical characterization, drug release, and in vivo behavior of 10-hydroxycamptothecin-loaded poly (n-butyl cyanoacrylate) (PBCA) nanospheres (HCPT-PBCA-NSs). HCPT-PBCA-NSs were successfully prepared via emulsion polymerization of n-butyl cyanoacrylate (BCA) monomer in acidic medium with the aid of two colloidal stabilizers (Poloxamer 188 and Dextran 70). The influence of pH, the time of polymerization, and the dosage of the drug on particle size and encapsulation efficiency (EE) were studied. HCPT-PBCA-NSs were of spherical shape and uniformly dispersed with a particle size of 135.7 nm, and zeta potential of -18.18 mV. EE, drug loading (DL), and yield of HCPT-PBCA-NSs were 51.52, 0.63, and 88.25%, respectively. FTIR, 1H NMR, and DSC showed complete polymerization of BCA monomer and HCPT existed in the form of molecular or amorphous in NSs. In vitro release of the drug from HCPT-PBCA-NSs exhibited sustained-release behavior with an initial burst release and about 60% of HCPT was released from the formulation within 24 h of dialysis. The pharmacokinetic study in healthy rats after oral administration showed that encapsulation of HCPT into PBCA-NSs increased the Cmax about 3.84 times and increased AUC0-t about 5.40 times compared with that of HCPT suspension. It was concluded that PBCA-NSs could be a promising drug carrier to load HCPT for oral drug delivery if efforts are made in the future to improve its poor DL capacity.

Amorphous solid dispersion with increased gastric solubility in tandem with oral disintegrating tablets: a successful approach to improve the bioavailability of atorvastatin.

CONTEXT: Serious efforts have been made to overcome the bioavailability problems of ever increasing number of poorly soluble drugs, including atorvastatin (ATO); however, enhancing its gastric solubility has not received much attention. OBJECTIVES: To improve the bioavailability of ATO by increasing its gastric solubility in a stable oral disintegration tablet (ODT) formulation. MATERIALS AND METHODS: Amorphous solid dispersion (ASD) of ATO with Eudragit® EPO was used as API in ODT formulation. Characterization using Differential scanning calorimetry, Powder X-ray diffraction, Fourier transform infrared drug-polymer interaction simulated by molecular modeling, solubility, dissolution and stability studies together with in vivo evaluation. RESULTS AND DISCUSSION: In ASD there was uniform distribution of drug in the polymer and it retained the amorphous nature without any chemical interactions except the possibility of hydrogen bond formation, with substantially higher gastric solubility. The dissolution profile of the ODT containing ASD was significantly improved >90% within 15 min compared with 25% of plain ATO formulation. In vivo results showed an overall enhancement in the apparent bioavailability (83% and 434% more than Lipitor® and plain amorphous ATO tablets, respectively). Combining the ASD with ODT presents a reliable solution to overcome the low solubility and bioavailability problems of ATO in a simple, robust and cost effective formulation.

Aqueous solubility and degradation kinetics of the phytochemical anticancer thymoquinone; probing the effects of solvents, pH and light.

Thymoquinone (TQ) is a potent anticancer phytochemical with confirmed in vitro efficacy. Its clinical use has not yet established, and very few reports have documented its formulation. There also are no reports about the aqueous solubility and stability of this valuable drug, despite their direct correlation with the in vivo efficacy. In the current research, we have established and validated a stability-indicating HPLC method for the detection of TQ and its degradation products under different conditions. We then investigated the solubility and stability profiles of TQ in aqueous solutions. The stability study was aimed to determine the effect of pH, solvent type and light on the degradation process of TQ, along with the investigation of the kinetics of this degradation. The solubility of TQ varied in different aqueous solvents, and might be compromised due to stability issues. However, these findings confirm that the aqueous solubility is not the major obstacle for the drug formulations mainly due to the considerable water solubility (>500 µg/mL) that may be enough to exert pharmacologic effects if administered via parenteral route. Stability study results showed a very low stability profile of TQ in all the aqueous solutions with rapid degradation that varied with solvent type. The study of the degradation kinetics showed a significant effect of pH on the degradation process. The process followed first order kinetics at more acidic and alkaline pH values, and second order kinetics at pH 5-7.4, regardless of the solvent type. The results also expressed that light has a greater impact on the stability of TQ as a shorter period of exposure led to severe degradation, independent of the solution pH and solvent type. Our results also addressed some discrepancies in previously published researches regarding the formulation and quantification of TQ with suggested solutions. Overall, the current study concludes that TQ is unstable in aqueous solutions, particularly at an alkaline pH, in addition to presenting severe light sensitivity. This data indicates the inappropriateness of aqueous solutions as pharmaceutical vehicles for TQ preparations. To the best of our knowledge, this is the first study describing TQ aqueous solubility and stability that may lead to the development of a stable and effective TQ formulation.

Curcumin Encapsulation in Geranium Oil Microemulsion Elevates Its Antibacterial, Antioxidant, Anti-Inflammatory, and Anticancer Activities.

One of the major challenges with curcumin is its poor solubility in water, which limits its absorption and bioavailability in the body. This study aimed to develop and characterize stable microemulsions (MEs) as MEs increase the dispersibility of curcumin in water and aid its absorption in the body. Curcumin-loaded MEs were developed with the goal of enhancing topical delivery and its pharmacological activity (antioxidant, antibacterial, anticancer activity, and anti-inflammatory). The pseudoternary phase diagram was constructed to find out the desired microemulsion region. The prepared MEs (ME1-ME5) were evaluated for pH, viscosity, size of the particle, electrical conductivity, zeta potential, and ex vivo permeation of the drug. The optimized ME formulation was selected based on particle size and was further evaluated for biological activity (in vitro/vivo). In vitro cytotoxic effects of formulations were checked on the human liver cancer cell line, HEPG2 (a cell line exhibiting epithelial-like morphology that was isolated from a hepatocellular carcinoma). Geranium oil, Tween 80 (as a surfactant), and propylene glycol (as a cosurfactant) were screened out based on solubility to formulate MEs. The optimized ME formulation (ME5), with a composition of 20:50:30 (geranium oil:Tween 80:propylene glycol), exhibited pH 4.36 ± 0.057, conductivity of 40.06 ± 0.05 µS/cm, viscosity of 165 ± 0.37 mPa·s, and droplet diameter of 199.39 ± 0.017 nm. The ex vivo permeation study demonstrated a significant cumulative amount of curcumin permeated in 24 h and had a flux of 130.91 ± 0.02 µg/cm2/h. Antioxidant activity demonstrated that curcumin-loaded microemulsion (ME5) exhibited higher scavenging activity (99.27 ± 0.021%) than blank microemulsion (94.67 ± 0.001%). Optimized curcumin-loaded microemulsion (ME5) exhibited zones of inhibition of 25.18 and 28.37 mm against Escherichia coli and Staphylococcus aureus, respectively. Among the cell lines tested, a higher concentration of ME5 showed the greatest cytotoxicity with a % viability of 8.22 ± 1.09%. Evidently, it also revealed significant in vivo anti-inflammatory effects with 93.29 ± 0.030% inhibition by the carrageenan-induced paw edema model (6 h study) and 88.39 ± 0.002% inhibition by the formalin-induced paw edema model (14 day study). In conclusion, microemulsion was safe and effective for effective delivery of curcumin with the potential for antioxidant, antibacterial, cytotoxic, and in vivo anti-inflammatory activities.

Bile acid/fatty acid integrated nanoemulsomes for nonalcoholic fatty liver targeted lovastatin delivery: stability, in-vitro, ex-vivo, and in-vivo analyses.

BACKGROUND: Controlled and targeted drug delivery to treat nonalcoholic fatty liver disease (NAFLD) can benefit from additive attributes of natural formulation ingredients incorporated into the drug delivery vehicles. METHODS: Lovastatin (LVN) loaded, bile acid (BA) and fatty acid (FA) integrated nanoemulsomes (NES) were formulated by thin layer hydration technique for synergistic and targeted delivery of LVN to treat NAFLD. Organic phase NES was comprised of stearic acid with garlic (GL) and ginger (GR) oils, separately. Ursodeoxycholic acid and linoleic acid were individually incorporated as targeting moieties. RESULTS: Stability studies over 90 days showed average NES particle size, surface charge, polydispersity index, and entrapment efficiency values of 270 ± 27.4 nm, -23.8 ± 3.5 mV, 0.2 ± 0.04 and 81.36 ± 3.4%, respectively. Spherical NES were observed under a transmission electron microscope. In-vitro LVN release depicted non-fickian release mechanisms from GL and GR oils-based NES. Ex-vivo permeation of BA/FA integrated NES through isolated rat intestines showed greater flux than non-integrated ones. CONCLUSION: Liver histopathology of experimental rats together with in-vivo lipid profiles and liver function tests illustrated that these NES possess the clinical potential to be promising drug carriers for NAFLD.