Micellar Dispersions Research Articles

Electrochemical characterization of poly(3,4-ethylenedioxythiophene)/κ-carrageenan as a biocompatible conductive coat for biologic applications

Abstract

Deoxycholate-TPGS mixed nanomicelles for encapsulation of methotrexate with enhanced in vitro cytotoxicity on breast cancer cell lines

Biocompatible mixed nanomicelles consisting of sodium deoxycholate and d-α-tocopheryl polyethylene glycol 1000 succinate have been prepared in different molar ratios (100:0, 75:25, 50:50, 25:75 and 0:100) in order to improve the aqueous solubility and in vitro anti-tumor activity of methotrexate. The nanomicelles loaded with methotrexate were prepared without using any organic solvents and characterized in terms of critical micellar concentration, particle size and drug solubilization capacity of the micellar dispersion. The optimized formulation (ratio 25:75) exhibited a spherical shape and a particle size of about 8 nm. The results of the in vitro release assay showed that the micellar system presented a sustained release behaviour compared to the solution of methotrexate. Cell viability studies in MCF-7 and MDA-MB-231 cells revealed that mixed micelles achieved lower IC50 values, in comparison to methotrexate and pralatrexate solutions. The formulated system showed a significant increase in the methotrexate cellular uptake, when compared to the free drug in both cell lines. Furthermore, hemolytic assay confirmed that methotrexate-loaded mixed micelles are compatible with red blood cells. Therefore, the mixed micelles developed in this study might be a potential nano-drug delivery system capable of overcoming in vitro resistance to methotrexate in breast cancer cells.

Amphotericin B loaded solid lipid nanoparticles (SLNs) and nanostructured lipid carrier (NLCs): physicochemical and solid-solution state characterizations

Amphotericin B (AmB) is one of the most effective systemic antifungal agents, but its use is circumscribed by the dose-limiting toxicity of the conventional micellar dispersion formulation, Fungizone®. Significantly lesser toxicity is obtained when AmB incorporated into the aqueous dispersion of lipid nanoparticles. The aim of this study was to develop and characterize AmB loaded solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs). NLC differed from SLN by the presence of liquid lipid, glyceryl tri(caprylate/caprate) in the lipid matrix. Various surfactants i.e. tween 20, cremophor RH40, poloxamer 407 (P407) and Myrj 52 were used to stabilize SLN and NLC. The effect of phospholipid incorporated in those lipid dispersions was also determined. Among surfactants tested, only P407 could stabilize AmB lipid dispersions. There was no chemical reaction occurred between AmB and other components that confirmed by Fourier transform infrared spectroscopy (FT-IR) spectra. The differential scanning calorimetry (DSC), hot-stage microscopy (HSM), powder X-ray diffractometry (PXRD) data showed that AmB was molecularly dispersed or in amorphous form in the lipid matrix. The proton nuclear magnetic resonance (1H-NMR) results showed that in the presence of phospholipid oil clusters within the lipid matrix are formed. These results indicate that SLN and NLC stabilized by P407 and/or phospholipid as the colloidal carrier for AmB were successfully developed.

The encapsulation and release properties of poly(ethylen oxide)/poly(acrylic acid) micelles with respect to α-tocopheryl acetate

ABSTRACTPH-responsive micelles that were formed by asymmetric MOPEO-b-PAAc diblock copolymers with chemically complementary methoxypoly(ethylene oxide)/poly(acrylic acid) blocks were used as nanocarriers to study the encapsulation/release processes of the poorly soluble homologue of α-tocopheryl acetate, known as the analogue of Vitamin E. These nanocarriers showed the high encapsulation degree of α-TOCA (near 100%) which did not depend on the encapsulation pathway (in situ or ex situ). The effect of various factors such as the time, the solution pH and the addition of NaCl on the state and behavior of α-TOCA solutions, micellar dispersions of the diblock copolymer and their micellar compositions were studied and discussed. A methodology for correctly determining the degree of α-TOCA encapsulation and release by the copolymer micelles was described. A gradual release of α-TOCA from micellar nanocarriers in the dialysis of micellar compositions against deionized water and a significant decrease in α-TOCA release in “physiological solution” and, especially, in water with pH =9 was established.

Optimization of β-cyclodextrin consolidated micellar dispersion for promoting the transcorneal permeation of a practically insoluble drug

Development of efficient ocular drug delivery system for antifungal drugs becomes a must nowadays to face and eradicate the widely spread ophthalmic fungal infections. Itraconazole, a triazole antifungal, is struggling to penetrate the cornea and subsequently, its efficacy is limited. The aim of this study was to enhance itraconazole corneal penetration through utilizing the minimum surfactant amount in presence of β-cyclodextrin which acted as a dissolution and permeation enhancer. β-Cyclodextrin consolidated micellar dispersions (CCMD) were prepared after an initial screening to select the composition of surfactant(s). The preparation was done according to a modified melt dispersion technique. The prepared CCMD were characterized through the analysis of their particle size, zeta potential and solubilization efficiency. The optimum formula was chosen based on a factorial response surface analysis and it was composed of 17:1 w/w surfactant/drug, 30:1 w/w cyclodextrin/drug ratios and 0.02% polyethylene oxide. This formula was subjected to in vitro characterization including release, imaging by transmission electron microscope, mucoadhesion, stability, in addition to the determination of the minimum inhibitory concentration. Moreover, the ex vivo/in vivo permeation, safety and efficacy profiles were determined. The optimized CCMD formula was found to be significantly safe, stable, mucoadhesive and efficient to permeate the drug through rabbits’ corneas. Consequently, the optimized CCMD formulation can be a promising, safe and efficient platform for the transcorneal delivery of lipophilic drugs including most antifungals.

Formation and structural properties of acid-induced casein–agar double networks: Role of gelation sequence

Abstract Agar is widely used in yogurt manufacture to improve the stability of milk gels. However, the formation and structural properties of acid-induced casein–agar gel have not been elucidated. In this study, different acidification temperatures were used to evaluate the evolution of acid-induced casein–agar double networks and their microstructure and penetration properties. Agar (0.25%, w/w) was mixed with a micellar casein dispersion (3%, w/w), acidified with glucono-δ-lactone at 30, 37, 42, or 45 °C, respectively, and then cooled to 10 °C. Compared with casein gel alone, the casein–agar gel had a higher firmness and water holding capacity (WHC). Moreover, these acid-induced casein–agar double networks formed different structures depending on the acidification temperature. When acidified below the agar transition temperature (at 30 or 37 °C), the agar formed a weak gel prior to casein network formation that hindered the movement of casein micelles. Therefore, the casein–agar mixtures formed double networks during the acidification stage with relatively low elasticity indexes (EIs). In contrast, casein–agar mixtures acidified above the agar transition temperature (at 42 or 45 °C) formed double networks during the cooling stage that exhibited higher EIs. Cryo-scanning electron microscopy showed denser networks in casein–agar gels acidified above the agar transition temperature. Furthermore, casein–agar gels acidified above the agar transition temperature showed a significantly higher firmness and WHC than those acidified below. Overall, acidification temperature significantly affected the gelation sequence and, thereby, the formation and structural properties of the acid-induced casein–agar double network.

The Use of Trisodium Citrate to Improve the Textural Properties of Acid-Induced, Transglutaminase-Treated Micellar Casein Gels.

In this study, the effect of trisodium citrate on the textural properties and microstructure of acid-induced, transglutaminase-treated micellar casein gels was investigated. Various concentrations of trisodium citrate (0 mmol/L, 10 mmol/L, 20 mmol/L, and 30 mmol/L) were added to micellar casein dispersions. After being treated with microbial transglutaminase (mTGase), all dispersions were acidified with 1.3% (w/v) gluconodelta-lactone (GDL) to pH 4.4–4.6. As the concentration of trisodium citrate increased from 0 mmol/L to 30 mmol/L, the firmness and water-holding capacity increased significantly. The final storage modulus (G′) of casein gels was positively related to the concentration of trisodium citrate prior to mTGase treatment of micellar casein dispersions. Cryo-scanning electron microscopy images indicated that more interconnected networks and smaller pores were present in the gels with higher concentrations of trisodium citrate. Overall, when micellar casein dispersions are treated with trisodium citrate prior to mTGase crosslinking, the resulted acid-induced gels are firmer and the syneresis is reduced.

Fluorescence quenching of α-tocopherol by graphene dispersed in aqueous surfactant solutions

The fluorescence of α-tocopherol in different solutions of zwitterionic (lauryl sulfobetaine, LSB), non-ionic (polyoxyethylene-23-lauryl ether, Brij L23) and cationic (hexadecyltrimethylammonium bromide, CTAB) surfactants, as well as in graphene (G) dispersions in these surfactants at different weight ratios has been comparatively investigated. A quenching phenomenon of the vitamin fluorescence in the micellar dispersions of G has been found, the effect being more pronounced for dispersions in Brij L23. This surfactant causes the highest degree of G exfoliation and is the most effective in stabilizing G dispersions. The fluorescence intensity ratio, calculated in the absence and in the presence of G, increases linearly with G concentration up to 30mgL−1 for dispersions in 5mM Brij L23 and in 5mM CTAB with and without NaCl. A more prominent fluorescence quenching effect is found at low surfactant concentrations, ascribed to a stronger interaction between α-tocopherol and G when the nanomaterial is less covered by the surfactant. Time-resolved fluorescence measurements indicate a static quenching mechanism between α-tocopherol and G. The fluorescence intensity and α-tocopherol concentration in 5mM Brij L23 aqueous solutions and in G (2.0wt%) dispersions in this surfactant follow a linear relationship, as well as the differences of the intensities measured in each case.

Structural Evolution of Wormlike Micellar Fluids Formed by Erucyl Amidopropyl Betaine with Oil, Salts, and Surfactants.

Solutions of extended, flexible cylindrical micelles, often known as wormlike micelles, have great potential as the base for viscoelastic complex fluids in oil recovery, drilling, and lubrication. Here, we study the morphology and nanostructural characteristics of a model wormlike micellar fluid formed from erucyl amidopropyl betaine (EAPB) in water as a function of a diverse range of additives relevant to complex fluid formulation. The wormlike micellar dispersions are extremely oleo-responsive, with even as little as 0.1% hydrocarbon oil causing a significant disruption of the network and a decrease in zero-shear viscosity of around 100-fold. Simple salts have little effect on the local structure of the wormlike micelles but result in the formation of fractal networks at larger length scales, whereas even tiny amounts of small organic species such as phenol can cause unexpected phase transitions. When forming mixtures with other surfactants, a vast array of self-assembled structures are formed, from spheres to ellipsoids, lamellae, and vesicles, offering the ultimate sensitivity in designing formulations with specific nanostructural characteristics.

Membrane protein crystallization in micelles conjugated by nucleoside base-pairing: A different concept.

The dearth of high quality, three dimensional crystals of membrane proteins, suitable for X-ray diffraction analysis, constitutes a serious barrier to progress in structural biology. To address this challenge, we have developed a new crystallization medium that relies on the conjugation of surfactant micelles via base-pairing of complementary hydrophobic nucleosides. Base-pairs formed at the interface between micelles bring them into proximity with each other; and when the conjugated micelles contain a membrane protein, crystal nucleation centers can be stabilized, thereby promoting crystal growth. Accordingly, two hydrophobic nucleoside derivatives - deoxyguanosine (G) and deoxycytidine (C), each covalently bonded to a 10 carbon chain were synthesized and added to an aqueous solution containing octyl β-d-thioglucopyranoside micelles. These hydrophobic nucleosides induced the formation of oil-rich globules after 2days incubation at 19°C or after a few hours in the presence of ammonium sulfate; however, phase separation was inhibited by 100mM GMP. The presence of the membrane protein bacteriorhodopsin in the conjugated - micellar dispersion resulted in the growth within the colorless globules of a variety of purple crystals, the color indicating a functional protein. On this basis, we suggest that conjugation of micelles via base-pair complementarity may provide significant assistance to the structural determination of integral membrane proteins.

Cholesterol-conjugated supramolecular assemblies of low generations polyamidoamine dendrimers for enhanced EGFP plasmid DNA transfection

Aimed to prepare an enhanced gene delivery system with low cytotoxicity and high transfection efficiency, various cholesterol-conjugated derivates of low generation polyamidoamine (PAMAM) dendrimers were prepared. The conjugates were characterized by TNBS assay, FTIR, and 1H-NMR spectroscopy. Self-assembly of the dendrimer conjugates (G1-Chol, G2-Chol, and G3-Chol) was investigated by pyrene assay. Following formation of the complexes between enhanced green fluorescence protein plasmid and the dendrimer conjugates at various N (primary amine)/P (phosphate) mole ratios, plasmid condensation, biologic stability, cytotoxicity, and protein expression were investigated. The conjugates self-assembled into micellar dispersions with the critical micelle concentration values (<50 µg/ml) depending on the dendrimer generation and cholesterol/amine mole ratio. Cholesterol conjugation resulted in higher resistance of the condensed plasmid DNA in a competition assay with heparin sulfate. Also, the transfection efficiency was determined higher for the cholesterol conjugates than unmodified dendrimers in HepG2 cells, showing the highest for G2-Chol at 40 % degree of cholesterol modification (G2-Chol40 %) among various dendrimer generations. Interestingly, such conjugate showed a complete protection of plasmid against serum nucleases. Our results confirmed that the cholesterol conjugation to PAMAM dendrimers of low generations bearing little cytotoxicity improves their several physicochemical and biological characteristics required for an enhanced delivery of plasmid DNA into cells.

Hydrogel formation by the ‘topological conversion’ of cyclic PLA–PEO block copolymers

An amphiphilic cyclic block copolymer consisting of poly(L- or D-lactide) and poly(ethylene oxide), that is, PLLA–PEO or PDLA–PEO, was synthesized from its corresponding linear triblock precursor, PLLA–PEO–PLLA or PDLA–PEO–PDLA, respectively, with alkenyl end groups. A mixture of the micellar dispersions of linear PLLA–PEO–PLLA and linear PDLA–PEO–PDLA formed a gel upon heating, whereas a mixture of the cyclic counterparts did not undergo this phase transition. These results suggest that the gelation behavior is directed by the topology of the polymer components. Furthermore, cyclic PLLA–PEO and cyclic PDLA–PEO block copolymers incorporating photocleavable o-nitrobenzyl units were synthesized. A mixture of the micellar dispersions of these block copolymers formed a gel upon ultraviolet irradiation via the ‘topological conversion’. A mixture of the micellar dispersions of linear PLLA–PEO–PLLA and linear PDLA–PEO–PDLA block copolymers formed a gel upon heating, whereas a mixture of the cyclic counterparts did not undergo this phase transition. These results suggest that the gelation behavior is directed by the topology of the polymer components. Furthermore, cyclic PLLA–PEO and cyclic PDLA–PEO block copolymers incorporating photocleavable o-nitrobenzyl units were synthesized. A mixture of the micellar dispersions of these block copolymers formed a gel upon ultraviolet (UV) irradiation via the ‘topological conversion’.

Au/Ce0.72Zr0.18Pr0.1O2 nanodisperse catalyst for oxidation of carbon monoxide

The nanodisperse Au/Cе0.72Zr0.18Pr0.1O2 catalysts for low-temperature oxidation of carbon monoxide were synthesized. The compounds were identified by XRD, XPS, TEM, ISP-MS, and gas chromatography. The samples containing gold nanoparticles obtained by radiation chemical reduction in reverse micellar dispersion exhibited higher activity than the catalysts obtained by deposition-precipitation (DP) despite the higher content of the active component.

Characterization and biological properties of NanoCUR formulation and its effect on major human cytochrome P450 enzymes

Curcumin (CUR) has been formulated into a host of nano-sized formulations in a bid to improve its in vivo solubility, stability and bioavailability. The aim of this study was to investigate whether the encapsulation of CUR in nanocarriers would impede its biological interactivity, specifically its potential anti-cancer adjuvant activity via the modulation of CYP enzymes in vitro. NanoCUR, a micellar dispersion prepared via a thin film method using only Pluronic F127 as excipient, was amenable to lyophilization, and retained its nano-sized spherical dimensions (17–33nm) upon reconstitution with water followed by dilution to 5μM with HBSS or EMEM. NanoCUR was a weaker cytotoxic agent compared to CUR in solution (sCUR), affecting HepG2 cell viability only when the incubation time was prolonged from 4h to 48h. Correlation with 2h uptake data suggests this was due to a lower cellular uptake rate of CUR from NanoCUR than from sCUR. The poorer CUR accessibility might also account for NanoCUR being a weaker inhibitor of CYP2C9 and CYP2D6 than sCUR. NanoCUR was, however, 1.76-fold more potent against the CYP3A4 (IC50 5.13±0.91μM) metabolic function. The higher activity against CYP3A4 might be attributed to the synergistic action of Pluronic F127, since the blank micellar dispersion also inhibited CYP3A4 activity. Both sCUR and NanoCUR had no effect on the CYP3A4 mRNA levels in the HepG2 cells. NanoCUR therefore, maintained most of the biological activities of CUR in vitro, albeit at a lower potency and response rate.

Gelified reverse micellar dispersions as percutaneous formulations

This study describes the use of lecithin organogels (LO) as versatile vehicles for percutaneous administration of methyl nicotinate (MN), fenretinide (4HPR) and curcumin (CUR). LO are able to increase the solubility of poor water-soluble molecules probably due to the formation of a short-range hexagonal organization of the lecithin cylindrical reverse micelles. After six months from production, no phase separation and an almost absence of aggregates was observed. LO exhibited similar viscosities and rheological behaviour both in the absence and in the presence of drug. The in vitro drug diffusion from LO studied by Franz cell showed that higher viscous vehicles result in lower diffusion coefficient. The microscopic investigation of human skin displayed no significant alterations after treatment with LO and with PBS. In vivo topical activity on erythema after cutaneous application of LO showed that LO-MN induce a strong erythema, while LO-CUR inhibit skin erythema due to CUR anti-inflammatory activity. Tape-stripping experiments performed on skin after topical administration of LO showed a decrease in the amount of CUR in the stratum corneum after 1 h from the occlusion. Shelf life stability studies demonstrated the higher stability of LO-HPR as compared to the others drugs.

Effect of Sophorolipid Biosurfactant on Oil Biodegradation by the Natural Oil-Degrading Bacteria on the Weathered Biodiesel, Diesel and Light Crude Oil

This study investigated the role of natural oil-degrading bacteria in the weathered biodiesel (BD), diesel (D) and light crude oil (L) in oil biodegradation in seawater with and without sophorolipid biosurfactant. Mixtures of artificial seawater and weathered oil with and without sophorolipid dispersant were incubated at 22 ± 1°C and 100 rpm for 28 days. Analysis of the remaining of total petroleum hydrocarbons showed degradation of 43 ± 0.7%, 45 ± 5.7% and 39 ± 4.6% of biodiesel, diesel and light crude oil, respectively, during the natural biodegradation and 44 ± 5%, 47.5 ± 3.9% and 44 ± 1% of biodiesel, diesel and light crude oil, respectively, with sophorolipid by the existing bacteria after 28 days. Characterization of bacteria isolated from the BD, D and L oil by 16S rRNA pyrosequencing showed that the Firmicutes was the dominant phylum in biodiesel (100%) and diesel (53%). The Actinobacteria was dominant in the diesel (47%) and the Proteobacteria (97%) and Actinobacteria (3%) were the two dominant phyla in the light crude oil. The hydrophobicity results showed that the bacteria consumed the hydrocarbons mainly by changing their cell surface structures in the natural biodegradation treatment and increase in the micellar dispersion of hydrocarbons in the biodegradation treatment with the sophorolipid. This study confirmed the significant contribution of natural bacteria in the weathered diesel, biodiesel and light crude oil in the biodegradation and the positive effect of sophorolipid on the biodegradation.

Effect of high pressure - low temperature processing on composition and colloidal stability of casein micelles and whey proteins

The aim of this study was to identify the impact of high pressure treatments at sub-zero temperatures (high pressure - low temperature; HPLT) on milk proteins. Whey protein solutions, micellar casein dispersions and two mixtures (micellar caseins:whey proteins, 80:20 and 20:80, w/w) were pressure treated (100–600 MPa) at pH 7.0 or 5.8 at −15 °C, −35 °C and ambient temperature. Solubility data showed that whey proteins could only be affected by HPLT treatments at pH 7.0 if caseins were present, while effects could be induced at pH 5.8 without the presence of caseins. The caseins formed on the one hand large aggregates (flocs) and on the other hand the solubility was increased by the creation of smaller micelles. The formation of flocs could only be observed for HPLT treated samples, which indicates the formation of different protein interactions in milk protein based samples compared with common HP treatments.

Changes in functionality of whey protein and micellar casein after high pressure – low temperature treatments

Changes in functional properties of micellar caseins (MC) and whey proteins (WPI) due to high pressure – low temperature (HPLT) treatments were investigated and compared to changes induced via high pressure treatments at room temperature (HP). Single whey protein solutions, micellar casein dispersions and two mixtures (micellar caseins:whey proteins weight mixing ratios 80:20 and 20:80) were treated at a concentration of 2% (w/w) and at two different pH values (7.0 and 5.8). Oscillating pendant drop and shear experiments were performed to identify changes in the rheological behavior at the air/water interface and in bulk, respectively. Foaming and emulsification experiments were conducted to investigate further impacts on the functional behavior. Both, HPLT and HP treatments led to a decreased emulsion stability for emulsions from WPI solutions independent from the treatment pH, while the foam stability was increased for these samples. In comparison, the changes for MC dispersions exhibited the same tendency but less pronounced. HPLT treatments of MC rich samples always led to the formation of a few very large flocs which had a major influence on the functional behavior. The rheological behavior of these samples changed from a Newtonian to a shear-thickening behavior. The elastic part of the surface dilatational modulus was increased for a pure WPI solution after HPLT and HP treatments while the viscous part remained unaffected. However, changes in functional properties highly depended on the sample composition and results for mixtures differ from those for pure dispersions.

Physical Characterisation and Long-Term Stability Studies on Quaternary Ammonium Palmitoyl Glycol Chitosan (GCPQ)—A New Drug Delivery Polymer

N-palmitoyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycolchitosan (GCPQ) is a self-assembling polymer, which enables the oral bioavailability of peptide and hydrophobic drugs. In preparation for clinical testing, here we examine GCPQ's synthesis reproducibility, pKa, thermal, and rheological properties. GCPQ was synthesised by acid degradation of glycol chitosan (GC), reaction with palmitic acid N-hydroxysuccinimide (PNS) and methylation. A GC monomer, PNS molar feed ratio of 0.92 together with a gravimetric feed ratio for N-palmitoyl-6-O-glycolchitosan, methyl iodide of 3.3, reproducibly produces GCPQ48 (Mw = 19.9 ± 9.9 kDa, Mn = 13.1 ± 2.4 kDa, mol % palmitoylation = 23 ± 2.7, mol % quaternisation = 10 ± 0.23, n = 56). GCPQ48 decomposes at 218 ± 4.3 °C, is glassy at room temperature (Tg = 164.4 ± 8.5 °C), is a weak base (pKa = 5.99 ± 0.15), and produces micellar dispersions at neutral pH. Below a concentration of 0.07 g mL(-1) , GCPQ48 dispersions showed Newtonian rheological behaviour but at higher concentrations, the polymer undergoes shear thinning because of the chain disentanglement at high shear rates. GCPQ48 forms a network of micelles and concentrated (0.09 g mL(-1) ) dispersions are viscoelastic, with the storage modulus exceeding the loss modulus at high frequencies. Solid GCPQ48 was stable when stored at room temperature for 18 months.

Controlled drug delivery attributes of co-polymer micelles and xanthan-O-carboxymethyl hydrogel particles

Herein, C16 alkyl chain-grafted-xanthan copolymer was synthesized and characterized. The copolymer self-assembled into nanometer-size spherical micellar structures in water and incorporated ∼100% glibenclamide into its deeper lipophilic confines. The micellar dispersion exhibited negative zeta potential value (−27.6mV). The copolymer micelles controlled the drug release rate in phosphate buffer solution (pH 6.8) for an extended period. Further incorporation of drug-loaded copolymer micelles into O-carboxymethyl xanthan hydrogel particles slowed the drug release rate in HCl solution (pH 1.2) as well as in phosphate-buffered solution (pH 6.8) (releasing only ∼8% drug in 2h). The drug release data correlated well with the degree of swelling of the hydrogel particles in different drug release media. Scanning electron microscopy revealed spherical shape of the hydrogel particles (600μm). X-ray diffraction and Fourier transform infrared (FTIR) spectroscopy analyses suggested amorphous encapsulation of the drug and its chemical compatibility with the polymers, respectively. Pharmacodynamic evaluation suggested that the formulations had an immense potential in controlling blood glucose level in animal model over a longer duration. In summary, it was pointed out that the copolymer micelles of glibenclamide, a poor water-soluble anti-diabetic, and their subsequent entrapment into hydrogel particles could be a promising approach in the controlled and effective management of diabetes.