In vitro and in vivo assessment of curcumin-quercetin loaded multi-layered 3D-nanofibroporous matrix prepared by solution blow-spinning for full-thickness burn wound healing.

Burn wounds (BWs) cause impairment of native skin tissue and may cause significant microbial infections that demand immediate care. Curcumin (Cur) and quercetin (Que) exhibit antimicrobial, hemocompatibility, ROS-scavenging, and anti-inflammatory properties. However, its instability, water insolubility, and low biological fluid absorption render it challenging to sustain local Cur and Que doses at the wound site. Therefore, to combat these limitations, we employed blow-spinning and freeze-drying to develop a multi-layered, Cur/Que-loaded gelatin/chitosan/PCL (GCP-Q/C) nanofibroporous (NFP) matrix. Morphological analysis of the NFP-matrix using SEM revealed a well-formed multi-layered structure. The FTIR and XRD plots demonstrated dual-bioactive incorporation and scaffold polymer interaction. Additionally, the GCP-Q/C matrix displayed high porosity (82.7 ± 2.07 %), adequate pore size (∼121 µm), enhanced water-uptake ability (∼675 % within 24 h), and satisfactory biodegradation. The scaffolds with bioactives had a long-term release, increased antioxidant activity, and were more effective against gram-positive (S. aureus) and gram-negative (E. coli) bacteria than the unloaded scaffolds. The in vitro findings of GCP-Q/C scaffolds showed promoted L929 cell growth and hemocompatibility. Additionally, an in vivo full-thickness BW investigation found that an implanted GCP-Q/C matrix stimulates rapid recuperation and tissue regeneration. In accordance with the findings, the Gel/Ch/PCL-Que/Cur NFP-matrix could represent an effective wound-healing dressing for BWs.

Sustainable, economical and rapid treatment of multiple lung diseases using therapeutic potential of curcumin nanoparticles.

The study was designed to prepare pure curcumin nanoparticles in rapid and simple way for target specific drug delivery to kill bacteria lying deep down within the alveoli of lungs via inhaler. Three different methods including evaporation precipitation of nanosuspension (ENP), solid dispersion (SD) and anti-solvent precipitation (ASP) were selected to prepare nanocurcumin in pure form in very simple way. This was done to compare their efficiency in terms of particle size obtained and water solubility and bacterial toxicity of as prepared curcumin nanoparticles. In this comparative study, curcumin NPs obtained from three different methods having particles size 65.3 nm, 98.7 nm and 47.4 nm respectively. The NPs were characterized using various techniques like SEM, XRD, UV-Visible and FTIR for their particle size determination and solubility evaluation. These particles were screened off against five bacterial strains causing lung diseases. AB3 prepared by ASP method, being smallest sized nanostructures, showed maximum solubility in water. These nanoparticles can be used as drug directly via inhaler to the target area without using any support or nano-carrier. In this way minimum dose formulation is required to target bacteria.

Assessment of Various Food Proteins as Structural Materials for Delivery of Hydrophobic Polyphenols Using a Novel Co-Precipitation Method.

In this study, sodium caseinate (NaCas), soy protein isolate (SPI), and whey protein isolate (WPI) were used as structural materials for the delivery of rutin, naringenin, curcumin, hesperidin, and catechin. For each polyphenol, the protein solution was brought to alkaline pH, and then the polyphenol and trehalose (as a cryo-protectant) were added. The mixtures were later acidified, and the co-precipitated products were lyophilized. Regardless of the type of protein used, the co-precipitation method exhibited relatively high entrapment efficiency and loading capacity for all five polyphenols. Several structural changes were seen in the scanning electron micrographs of all polyphenol-protein co-precipitates. This included a significant decrease in the crystallinity of the polyphenols, which was confirmed by X-ray diffraction analysis, where amorphous structures of rutin, naringenin, curcumin, hesperidin, and catechin were revealed after the treatment. Both the dispersibility and solubility of the lyophilized powders in water were improved dramatically (in some cases, >10-fold) after the treatment, with further improvements observed in these properties for the powders containing trehalose. Depending on the chemical structure and hydrophobicity of the tested polyphenols, there were differences observed in the degree and extent of the effect of the protein on different properties of the polyphenols. Overall, the findings of this study demonstrated that NaCas, WPI, and SPI can be used for the development of an efficient delivery system for hydrophobic polyphenols, which in turn can be incorporated into various functional foods or used as supplements in the nutraceutical industry.

Assessment of synthesized chitosan/halloysite nanocarrier modified by carbon nanotube for pH-sensitive delivery of curcumin to cancerous media.

Constructing a system to carry medicine for more effective remedy of cancer has been a leading challenge, as the number of cancer cases continues to increase. In this present research, a curcumin-loaded chitosan/halloysite/carbon nanotube nanomixture was fabricated by means of water/oil/water emulsification method. The drug loading efficiency (DL) and entrapment efficiency (EE), as a result, reached 42 % and 88 %, respectively and FTIR and XRD analysis confirmed the bonding between the drug and nanocarrier. Morphological observation through FE-SEM and characterization through DLS analysis demonstrated that the average size of nanoparticles is 267.37 nm. Assessment of release within 96 h in pH 7.4 and 5.4 showed sustained release. For more investigation, release data was analyzed by diverse kinetic models to understand the mechanism in the release procedure. An MTT assay was also carried out, and the results illustrated apoptosis induction on MCF-7 cells and exhibited ameliorated cytotoxicity of the drug-loaded nanocomposite compared to the free curcumin. These findings suggest that the unique pH-responsive chitosan/halloysite/carbon nanotube nanocomposite might make a good option for drug delivery systems, particularly for the cancer treatment.

Curcumin encapsulated polylactic acid nanoparticles embedded in alginate/gelatin bioinks for in situ immunoregulation: Characterization and biological assessment.

Curcumin is a known naturally occurring anti-inflammatory agent derived from turmeric, and it is commonly used as a herbal food supplement. Here, in order to overcome the inherent hydrophobicity of curcumin (Cur), polylactic acid (PLA) nanoparticles (NPs) were synthesised using a solvent evaporation, and an oil-in-water emulsion method used to encapsulate curcumin. Polymeric NPs also offer the ability to control rate of drug release. The newly synthesised NPs were analysed using a scanning electron microscope (SEM), where results show the NPs range from 50 to 250 nm. NPs containing graded amounts of curcumin (0 %, 0.5 %, and 2 %) were added to cultures of NIH3T3 fibroblast cells for cytotoxicity evaluation using the Alamar Blue assay. Then, the curcumin NPs were incorporated into an alginate/gelatin solution, prior to crosslinking using a calcium chloride solution (200 nM). These hydrogels were then characterised with respect to their chemical, mechanical and rheological properties. Following hydrogel optimization, hydrogels loaded with NP containing 2 % curcumin were selected as a candidate as a bioink for three-dimensional (3D) printing. The biological assessment for these bioinks/hydrogels were conducted using THP-1 cells, a human monocytic cell line. Cell viability and immunomodulation were evaluated using lactate dehydrogenase (LHD) and a tumour necrosis factor alpha (TNF-α) enzyme-linked immunosorbent (ELISA) assay, respectively. Results show that the hydrogels were cytocompatible and supressed the production of TNF-α. These bioactive hydrogels are printable, supress immune cell activation and inflammation showing immense potential for the fabrication of tissue engineering constructs.

Curcumin-loaded carrageenan nanoparticles: Fabrication, characterization, and assessment of the effects on osteoblasts mineralization.

The use of Curcumin (CR) as a bioactive molecule to prevent and treat inflammation- related diseases is widespread. However, the high hydrophobicity hinders the in vivo bioavailability of CR, reducing its therapeutic index. In the present study, we described the use of nanoparticles (NPs) made of kappa-carrageenan (κ-Carr), a sulphated polysaccharide, as cost-effective, biodegradable and biocompatible CR carriers. CR-loaded κ-Carr nanoparticles (CR@Carr NPs) were prepared by mixing a κ-Carr aqueous solution with a CR ethanolic solution. The final suspension was centrifuged and re-suspended in phosphate buffer solution. The NPs' size was tuned by changing the concentration of the polysaccharide. CR@CarrNPs displayed high CR incorporation efficiency (~80 wt%) and a double-exponential curve of CR release at physiological conditions (37 °C and pH 7.4) with a cumulative drug release of 32 wt% after 24 h for the smaller NP. Our results also showed that CR@CarrNPs were not cytotoxic to osteoblasts at concentrations up to 1 µM. Confocal microscopy images revealed the internalization of CR by the cells guided by the NPs. Cells treated with CR@CarrNPs exhibited higher activity of alkaline phosphatase and higher expression of the main osteogenic genes (Sp7, Col1 and Runx2), and mineralized the extracellular matrix in a higher extent compared to the cells cultivated in absence of the NPs. We posited that these effects were related to the NP-driven internalization of CR by osteoblasts. Our study sheds light on the possible use of CR@CarrNPs as efficient and safe therapeutic tools for the treatment of bone-related diseases.

Improved Synthesis of Asymmetric Curcuminoids and Their Assessment as Antioxidants.

In this paper, the syntheses of twelve asymmetric curcumin analogs using Pabon's method are reported. Generally, the previously reported yields of asymmetric curcuminoids, such as 9a (53%), 9c (38%), and 9k (38%), have been moderate or low. Herein, we propose that the low yields were due to the presence of water and n-BuNH2 in the reaction media. To prove this formulated hypothesis, we have demonstrated that the yields can be improved by adding molecular sieves (MS) (4 Å) to the reaction mixture, thus reducing the interference of water. Therefore, improved yields (41-76%) were obtained, except for 9b (36.7%), 9g (34%), and 9l (39.5%). Furthermore, compounds 9b, 9d, 9e, 9f, 9g, 9h, 9i, 9j, and 9l are reported herein for the first time. The structures of these synthetic compounds were determined by spectroscopic and mass spectrometry analyses. The free radical scavenging ability of these synthetic asymmetric curcuminoids was evaluated and compared to that of the positive control butylated hydroxytoluene (BHT). Among the synthesized asymmetric curcuminoids, compounds 9a (IC50 = 37.57 ± 0.89 µM) and 9e (IC50 = 37.17 ± 1.76 µM) possessed effective 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging abilities, and compounds 9h (IC50 = 11.36 ± 0.65 µM) and 9i (IC50 = 10.91 ± 0.77 µM) displayed potent 2,2'-azinobis-(3-ethylbenzthiazoline-6-sulphonate) (ABTS) radical scavenging abilities comparable to that of curcumin (IC50 = 10.14 ± 1.04 µM). Furthermore, all the synthetic asymmetric curcuminoids were more active than BHT.

The protective effect of natural phenolic compound on the functional and structural responses of inhibited catalase by a common azo food dye.

In this research retrieval effects of natural yellow (NY) on the performance of carmoisine (CAR) inhibited bovine liver catalase (BLC) was studied using multispectral and theoretical methods. Kinetic studies showed that CAR inhibited BLC through competitive inhibition (IC50 value of 2.24 × 10-6 M) while the addition of NY recover the activity of CAR-BLC up to 82% in comparison with the control enzyme. Circular dichroism data revealed that NY can repair the structural changes of BLC, affected by CAR. Furthermore, an equilibrium dialysis study indicated that NY could reduce the stability of the CAR-catalase complex. The surface plasmon resonance (SPR) data analysis indicated a high affinity of NY to BLC compared to CAR and the binding of NY led to a decrease in the affinity of the enzyme to the inhibitor. On the other hand, fluorescence and molecular docking studies showed that the quenching mechanism of BLC by CAR occurs through a static quenching process, and van der Waals forces and hydrogen bonding play a crucial role in the binding of CAR to BLC. MLSD data demonstrated that NY could increase the binding energy of CAR-BLC complex from -7.72 kJ mol-1 to -5.9 kJ mol-1, leading to complex instability and catalase activity salvage.

In vivo assessment of the antischistosomal activity of curcumin loaded nanoparticles versus praziquantel in the treatment of Schistosoma mansoni.

Schistosomiasis is a serious parasitic infection affecting millions worldwide. This study aimed to explore the anti-schistosomal activity of curcumin and curcumin loaded gold-nanoparticles (Cur-GNPs) with or without praziquantel (PZQ). We used six groups of the C57BL/6 mice in which five groups were infected with Schistosoma Mansoni (S. mansoni) cercariae and exhibited, separately, to different treatment regimens of curcumin, curcumin loaded nanoparticle, and PZQ, in addition to one untreated group which acts as a control. Mice were sacrificed at the 8th week where both worms and eggs were counted in the hepatic and porto-mesenteric vessels in the liver and intestine, respectively, in addition to a histopathological examination of the liver granuloma. Curcumin caused a significant reduction in the worms and egg count (45.45%) at the 3rd week. A significant schistosomicidal effect of PZQ was found in all groups. Cur-GNPs combined with PZQ 97.4% reduction of worm burden in the 3rd week and the highest reduction in the intestinal and hepatic egg content, as well, besides 70.1% reduction of the granuloma size. The results suggested the curcumin in combination with PZQ as a strong schistosomicidal regimen against S. mansoni as it alters the hematological, biochemical, and immunological changes induced.

Combining in vitro digestion model with cell culture model: Assessment of encapsulation and delivery of curcumin in milled starch particle stabilized Pickering emulsions.

To investigate the encapsulation and oral delivery efficiency of milled starch particles stabilized Pickering emulsions for lipophilic bioactive compounds, in vitro digestion model coupled with Caco-2 cells models were used. Physicochemical and biological properties of curcumin encapsulated Pickering emulsions were analyzed regarding to emulsion structure, curcumin retention, in vitro digestion, in vitro anti-proliferate ability and cellular uptake. Milled starch particles stabilized Pickering emulsion system was able to protect curcumin against harsh gastric conditions. Around 80% of the encapsulated curcumin was retained after 2 h of simulated gastric digestion. By being encapsulated in Pickering emulsion, the bioaccessibility of curcumin was increased from 11% for curcumin in bulk oil phase to 28% under simulated intestinal digestion process. The resulting curcumin-loaded micelle phase from digested emulsion exhibited significant anti-cancer ability and enhanced cellular uptake. This research provides an exploratory study on the possible future application of milled starch particles stabilized Pickering emulsions as nutraceutical delivery vehicles in the creation of novel functional foods.

Inhibition and assessment of the biophysical gating properties of GluA2 and GluA2/A3 AMPA receptors using curcumin derivatives.

The development of efficacious and safe drugs for the treatment of neurological diseases related to glutamate toxicity has been a focus in neuropharmacological research. Specifically, discovering antagonists to modulate the activity and kinetics of AMPA receptors, which are the fastest ligand-gated ion channels involved in excitatory neurotransmission in response to glutamate. Thus, the current study investigated novel curcumin derivatives on the biophysical properties of AMPA receptors, specifically on the homomeric GluA2 and the heteromeric GluA2/A3 subunits and assessed for inhibitory actions. The biophysical parameter (i.e., desensitization, deactivation, and peak currents) were measured by using whole-cell patch clamp electrophysiology with and without the administration of the derivatives onto HEK293 cells. CR-NN, CR-NNPh, CR-MeNH, and CR-NO of the tested derivatives showed inhibition on all AMPA receptors up to 6 folds. Moreover, the inhibitory derivatives also increased desensitization and deactivation, which further intensifies the compounds' neuroprotective effects. However, CR-PhCl, CR-PhF, and CR-PhBr did not show any significant changes on the peak current, deactivation or desensitization rates. By comparison to other discovered and widely used antagonist, the prepared curcumin derivatives are not selective to a specific AMPA subunit, instead implement its effect in the same way between all types of AMPA receptors. Additionally, the obtained results provide derivatives that not only noncompetitively inhibit AMPARs but also decrease its biophysical kinetics, specifically desensitization and deactivation rates. Hence, to potentially serve as a new AMPAR inhibitor with therapeutic potential, the current study provides compounds that are non-selective and non-competitive antagonist, which also effect the desensitization and deactivation rates of the receptor.

Assessment of dynamic bioaccessibility of curcumin encapsulated in milled starch particle stabilized Pickering emulsions using TNO's gastrointestinal model.

Pickering emulsions stabilized by milled starch particles have been developed as a novel food-grade formulation to enhance the bioaccessibility of poorly soluble bioactive compounds (i.e., curcumin) by controlling the digestion of lipids in the human gastrointestinal (GI) tract. The dynamic bioaccessibilities of curcumin with and without encapsulation in the Pickering emulsion were evaluated using the dynamic TNO's gastrointestinal (TIM-1) model. For comparison, their digestion profiles were also studied using the in vitro pH-stat lipolysis model. With the combination of two in vitro models, the effect of the milled starch particle stabilized Pickering emulsions on the bioaccessibility of curcumin was fully revealed. There are large differences between the bioaccessibility values of curcumin samples obtained by these two models. Simulated small intestinal lipolysis in the pH-stat model revealed that the bioaccessibility of curcumin encapsulated in the Pickering emulsion was 27.6%, which was larger than 22.1% for free curcumin suspended in the bulk oil phase. The bioaccessibility of curcumin was 50.7% in the emulsion system and 7.8% in the bulk oil when using the TIM-1 model, which simulated the digestion conditions of the entire human GI tract. The digestion mechanism of the milled starch particle stabilized Pickering emulsions in the upper GI tract was well elucidated by the TIM-1 model. The gradual release and improved dissolution profile of the milled starch particle stabilized Pickering emulsions highlighted their potential as delivery systems for lipophilic bioactive compounds.

Curcumin-loaded self-nanomicellizing solid dispersion system: part II: in vivo safety and efficacy assessment against behavior deficit in Alzheimer disease.

Curcumin (CUR), a natural polyphenolic compound, is considered as one of the most potential candidates against Alzheimer disease (AD) by targeting multiple pathologies such as amyloid-beta, tau phosphorylation, and oxidative stress. Poor physicochemical profile and oral bioavailability (BA) are the major contributors to its failure in clinical trials. Lack of success in numerous drug clinical trials for the treatment of AD urges the need of repositioning of CUR. To overcome its limitation and enhance oral BA, Novel CUR Formulation (NCF) was developed using self-nanomicellizing solid dispersion strategy which displayed 117-fold enhancement in oral BA of CUR. NCF was tested using SH-SY5Y695 APP human neuroblastoma cell line against the cytotoxicity induced by copper metal ion, H2O2, and Aß42 oligomer and compared with CUR control. The safety and efficacy of NCF on mice AD-like behavioral deficits (open field, novel objective recognition, Y-maze, and Morris water maze tests) were assessed in transgenic AD (APPSwe/PS1deE9) mice model. In SH-SY5Y695 APP human neuroblastoma cell line, NCF showed better safety and efficacy against the cytotoxicity due to the significantly enhancement of cellular uptake. It not only prevents the deterioration of cognitive functions of the aged APPSwe/PS1deE9 mice during aging but also reverses the cognitive functions to their much younger age which is also better than the currently available approved options. Moreover, NCF was proved as well tolerated with no appearance of any significant toxicity via oral administration. The results of the study demonstrated the potential of NCF to improve the efficacy of CUR without compromising its safety profile, and pave the way for clinical development for AD.

Assessment of Novel Curcumin Derivatives as Potent Inhibitors of Inflammation and Amyloid-ß Aggregation in Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative disorder affecting the elderly population worldwide. Brain inflammation plays a key role in the progression of AD. Deposition of senile plaques in the brain stimulates an inflammatory response with the overexpression of pro-inflammatory mediators, such as the neuroinflammatory cytokine. interleukin-6. Curcumin has been revealed to be a potential agent for treating AD following different neuroprotective mechanisms, such as inhibition of aggregation and decrease in brain inflammation. We synthesized new curcumin derivatives with the aim of providing good anti-aggregation capacity but also improved anti-inflammatory activity. Nine curcumin derivatives were synthesized by etherification and esterification of the aromatic region. From these derivatives, compound 8 exhibited an anti-inflammatory effect similar to curcumin, while compounds 3, 4, and 10 were more potent. Moreover, when the anti-aggregation activity is considered, compounds 3, 4, 5, 6, and 10 showed biological activity in vitro. Compound 4 exhibited a strong anti-aggregation effect higher than curcumin. Monofunctionalized curcumin derivatives showed better bioactivity than difunctionalized compounds. Moreover, the presence of bulky groups in the chemical structure of curcumin derivatives decreased bioactivity.

A cost-effective method to prepare curcumin nanosuspensions with enhanced oral bioavailability.

BACKGROUND: Nanosuspension is one of the most promising strategies to improve the oral bioavailability of insoluble drugs. The existing techniques applied to produce nanosuspensions are classified as "bottom-up" or "top-down" methods, or a combination of both. Curcumin (CUR), a Biopharmaceutics Classification System (BCS) class IV substance, is a promising drug candidate in view of its good bioactivity, but its use is limited due to its poor solubility and permeability. In the present study, CUR nanosuspensions were developed to enhance CUR oral bioavailability using a cost-effective method different from conventional techniques. RESULTS: The physicochemical properties of CUR nanosuspensions were characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The crystalline state of CUR in different nanosuspensions analyzed using differential scanning calorimeter (DSC) and X-ray diffraction analysis (PXRD) confirmed its amorphous state. In vitro dissolution degree of the prepared CUR nanosuspensions using TPGS or Brij78 as stabilizer was greatly increased. Pharmacokinetic studies demonstrated that the oral bioavailability of CUR was increased 3.18 and 3.7 times after administration of CUR/TPGS nanosuspensions or CUR/Brij78 nanosuspensions, when compared with the administration of CUR suspension. CONCLUSIONS: CUR nanosuspensions produced by our cost-effective method could improve its oral bioavailability. In addition, the low-cost and time-saving method reported here is highly suitable for a fast and inexpensive preparation.

Computational approach for the assessment of inhibitory potency against beta-amyloid aggregation.

Beta-amyloid (Aß) plaques are one of the hallmarks of Alzheimer's disease. Their presence in the brain leads to neurodegeneration and memory decline. Therefore, search for new drugs able to decrease formation of such deposits is of great interest. Our previously developed multifunctional compounds inhibited transformation of monomers into fibrils. Herein, we describe the computational approach for the assessment of inhibitory activity against Aß aggregation. The influence of novel inhibitors on amyloid Aß17-42 was studied by employing of molecular docking and all-atom molecular dynamics simulations. We found that the number of intermolecular backbone hydrogen bonds at the end of 100ns MD simulation was correlated with the level of anti-aggregation potency of studied compounds. Such data may be successfully applied to in silico design of novel inhibitors of Aß aggregation.

Synthesis and biological assessment of novel N-(hydroxy/methoxy)alkyl ß-enaminone curcuminoids.

Curcumin, a natural compound extracted from the rhizomes of Curcuma Longa, is known to display pronounced anticancer activity but lacks good pharmacokinetic properties. In that respect, augmenting the water solubility by structural modification of the curcumin scaffold may result in improved bioavailability and pharmacokinetics. A possible scaffold modification, especially important for this study, concerns the imination of the labile ß-diketone moiety in curcumin. Previous work revealed that novel N-alkyl ß-enaminones showed a similar water solubility as compared to curcumin, accompanied by a stronger anti-proliferative activity. To extend this ß-enaminone compound library, new analogues were prepared in this work using more polar amines (hydroxyalkylamines and methoxyalkylamines instead of alkylamines) with the main purpose to improve the water solubility without compromising the biological activity of the resulting curcuminoids. Compared to their respective parent compounds, i.e. curcumin and bisdemethoxycurcumin, the bisdemethoxycurcumin N-(hydroxy/methoxy)alkyl enaminone analogues showed better water solubility, antioxidant and anti-proliferative activities. In addition, the curcumin enaminones displayed activities comparable to or better than curcumin, and the water solubility was improved significantly. The constructed new analogues may thus be of interest for further exploration concerning their impact on oxidative stress related diseases such as cancer.

Cost-effective alternative to nano-encapsulation: Amorphous curcumin-chitosan nanoparticle complex exhibiting high payload and supersaturation generation.

While the wide-ranging therapeutic activities of curcumin have been well established, its successful delivery to realize its true therapeutic potentials faces a major challenge due to its low oral bioavailability. Even though nano-encapsulation has been widely demonstrated to be effective in enhancing the bioavailability of curcumin, it is not without drawbacks (i.e. low payload and costly preparation). Herein we present a cost-effective bioavailability enhancement strategy of curcumin in the form of amorphous curcumin-chitosan nanoparticle complex (or curcumin nanoplex in short) exhibiting a high payload (>80%). The curcumin nanoplex was prepared by a simple yet highly efficient drug-polysaccharide complexation method that required only mixing of the curcumin and chitosan solutions under ambient condition. The effects of (1) pH and (2) charge ratio of chitosan to curcumin on the (i) physical characteristics of the nanoplex (i.e. size, colloidal stability and payload), (ii) complexation efficiency, and (iii) production yield were investigated from which the optimal preparation condition was determined. The nanoplex formation was found to favor low acidic pH and charge ratio below unity. At the optimal condition (i.e. pH 4.4. and charge ratio=0.8), stable curcumin nanoplex (≈260nm) was prepared at >90% complexation efficiency and ≈50% production yield. The amorphous state stability, colloidal stability, and in vitro non-cytotoxicity of the nanoplex were successfully established. The curcumin nanoplex produced prolonged supersaturation (3h) in the presence of hydroxypropyl methylcellulose (HPMC) at five times of the saturation solubility of curcumin. In addition, curcumin released from the nanoplex exhibited improved chemical stability owed to the presence of chitosan. Both results (i.e. high supersaturation and improved chemical stability) bode well for the ability of the curcumin nanoplex to enhance the bioavailability of curcumin clinically.

Assessment of the relative performance of a confined impinging jets mixer and a multi-inlet vortex mixer for curcumin nanoparticle production.

The relative performance of two specially designed mixers for nanoparticle production, namely, two-stream confined impinging jets with dilution mixer (CIJ-D-M) and four-stream multi-inlet vortex mixer (MIVM), was evaluated using the model compound, curcumin (CUR), under defined conditions of varying mixing rate and organic solvent. In the absence of turbulent fluctuations, higher mixing rate tended to generate finer particles. Among the three water-miscible organic solvents tested, acetone afforded the smallest particle size and the narrowest particle size distribution. Both mixers were capable of reproducibly fabricating CUR nanoparticles with particle size below 100 nm and high encapsulation efficiency (>99.9%). Specifically, CIJ-D-M yielded nanoparticles with smaller size and polydispersity index while the particles obtained by the MIVM displayed better short-term stability. In addition, CIJ-D-M tended to produce a mixture of irregular nanoaggregates and primary nanoparticles while roughly spherical nanoparticles were generated with the MIVM. The observed particle size and morphological differences could be attributed to the differences in the configuration of the mixing chamber and the related mixing order.

Optimization of curcumin nanoemulsion for intranasal delivery using design of experiment and its toxicity assessment.

The objective of the study was to optimize curcumin nanoemulsion for intranasal delivery using design of experiment. Box-Behnken design was constructed using oil, surfactant and co-surfactant concentration as independent variables and their affect on response y1 (globule size) and y2 (zeta potential) were studied. The ANOVA test identified the significant factors that affected the responses. For globule size, percentage of oil, surfactant and co-surfactant were identified as significant model terms whereas for zeta potential, oil and co-surfactant were found to be significant. Critical factors affecting the responses were identified using perturbation and contour plots. The derived polynomial equation and contour graph aid in predicting the values of selected independent variables for preparation of optimum nanoemulsion with desired properties. Further, 2(4) factorial design was used to study influence of chitosan on particle size and zeta potential. The formulations were subjected to in vitro cytotoxicity using SK-N-SH cell line and nasal ciliotoxicity studies. The developed formulations did not show any toxicity and were safe for intranasal delivery for brain targeting. In vitro diffusion studies revealed that nanoemulsions had a significantly higher release compared to drug solution. Ex vivo diffusion studies were carried out using sheep nasal mucosa fixed onto Franz diffusion cells. Mucoadhesive nanoemulsion showed higher flux and permeation across sheep nasal mucosa.