Colloidal Formulations Research Articles

Food Effect on Oral Bioavailability: Old and New Questions.

Food Effect on Oral Bioavailability: Old and New Questions.

β-oxalylamino-substituted O-ethyl N-arylcarbamates and N-ethyl-N′-arylureas encapsulated into micelles of vinylimidazole–vinylcaprolactam copolymer

Low-molecular-weight compounds—β-oxalylamino-substituted O-ethyl carbamates and unsymmetrical ureas showing biological activity—have been synthesized and encapsulated into micelles of vinylimidazole–vinylcaprolactam copolymers. Solubilization in micelles has provided a preparation of water-soluble colloidal formulation of these compounds suitable for practical application.

Neuroprotection against apoptosis of SK-N-MC cells using RMP-7- and lactoferrin-grafted liposomes carrying quercetin.

A drug delivery system of quercetin (QU)-encapsulated liposomes (LS) grafted with RMP-7, a bradykinin analog, and lactoferrin (Lf) was developed to permeate the blood–brain barrier (BBB) and rescue degenerated neurons, acting as an Alzheimer’s disease (AD) pharmacotherapy. This colloidal formulation of QU-encapsulated LS grafted with RMP-7 and Lf (RMP-7-Lf-QU-LS) was used to traverse human brain microvascular endothelial cells (HBMECs) regulated by human astrocytes (HAs) and to treat SK-N-MC cells after an insult with cytotoxic β-amyloid (Aβ) fibrils. We found that surface RMP-7 and Lf enhanced the ability of QU to cross the BBB without inducing strong toxicity and damaging the tight junction. In addition, RMP-7-Lf-QU-LS significantly reduced Aβ-induced neurotoxicity and improved the viability of SK-N-MC cells. Compared with free QU, RMP-7-Lf-QU-LS could also significantly inhibit the expression of phosphorylated c-Jun N terminal kinase, phosphorylated p38, and phosphorylated tau protein at serine 202 by SK-N-MC cells, indicating an important role of RMP-7, Lf, and LS in protecting neurons against apoptosis. RMP-7-Lf-QU-LS is a promising carrier targeting the BBB to prevent Aβ-insulted neurodegeneration and may have potential in managing AD in future clinical applications.

A glucose-targeted mixed micellar formulation outperforms Genexol in breast cancer cells

Breast cancer represents the top cancer among women, accounting 521.000 deaths per year. Development of targeted nanomedicines to breast cancer tissues represents a milestone to reduce chemotherapy side effects. Taking advantage of the over-expression of glucose (Glu) membrane transporters in breast cancer cells, we aim to expand the potential of a paclitaxel (PTX)-loaded mixed micellar formulation based on polyvinyl caprolactam-polyvinylacetate-polyethylene glycol graft copolymer (Soluplus®) and D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) by its surface decoration with Glu moieties. The glycopolymer (Soluplus(Glu)) was obtained by microwave-assisted ring opening reaction of δ-gluconolactone initiated by Soluplus®. The glycosylation was confirmed by 1H NMR and by agglutination assays employing Concanavalin A. The hydrodynamic diameter of Soluplus(Glu) micelles was characterized by dynamic light scattering (100.3±3.8nm) as well as the critical micellar concentration value (0.0151% w/v). Then, a mixed micelle formulation employing Soluplus®, Soluplus(Glu) and TPGS (3:1:1wt ratio) loaded with PTX (4mg/mL) was developed as a multifunctional nanocarrier. Its in vitro anticancer performance in MCF-7 (1.6-fold) and MDA-MB-231 (14.1-fold) was significantly enhanced (p<0.05) versus the unique commercially available micellar-based PTX-nanoformulation (Genexol®). Furthermore, the in vitro PTX cellular uptake assays revealed that the drug intracellular/cell content was significantly (p<0.05) higher for the Glu-containing mixed micelles versus Genexol® after 6h of incubation with MCF-7 (30.5-fold) and MDA-MB-231 (5-fold). Overall, results confirmed the potential of our Glu-decorated mixed colloidal formulation as an intelligent nanocarrier for PTX-targeted breast cancer chemotherapy.

Ranibizumab biosimilar/polyethyleneglycol-conjugated gold nanoparticles as a novel drug delivery platform for age-related macular degeneration

Ranibizumab is a first-line therapy against age-related macular degeneration. For further improvement of ranibizumab-based treatment, we developed ranibizumab biosimilar (Mab)/polyethyleneglycol (PEG)-conjugated small gold nanoparticles (core size: approximately 5 nm) as a novel platform of ranibizumab biosimilar (Mab) delivery. Mab/PEG-conjugated gold nanoparticles were successfully prepared, and the particles were characterized by transmission electron microscopy and dynamic light scattering method. The mean diameters of Mab/PEG-conjugated gold nanoparticles and PEG-conjugated gold nanoparticles were varied using different lengths of PEG chain (5 kDa and 10 kDa). The Mab conjugation efficiency was optimized by changing the amount of PEG in preparation, which showed a high conjugation efficiency (>70%). We found that Mab/PEG-conjugated gold nanoparticles effectively inhibited the tube formation of human umbilical vein endothelial cells based on Matrigel in vitro. PEG-conjugated gold nanoparticles without Mab inhibited the tube formation unexpectedly. The Mab/PEG-conjugated gold nanoparticles did not affect cell proliferation in human endothelial cells. These results suggest that Mab/PEG-conjugated gold nanoparticles can be used as a good and novel colloidal formulation against angiogenesis-related diseases in local sites such as age-related macular degeneration.

Colloidal Apatite Nanoparticles: Insights on their Interaction with Cells and Artificial Lipid Membranes

Biomimetic nanocrystalline apatites are analogous to bone mineral. They can be exploited not only for bone regeneration applications, but it is also possible to take advantage of their biomimetic features to explore novel domains of research such as in nanomedicine, if the nanoparticles are stabilized as a colloidal formulation. In this contribution, we concentrate on AEP/HMP-stabilized colloidal apatite nanoparticles (NPs) and on their interaction with different types of cells so as to get experimental evidence on their low cytotoxicity, non-proinflammatory potential, and good compatibility with Red Blood Cells. We then started to explore their interaction with an artificial free-standing phospholipid bilayer, as a simplified model for cell membranes: results indicate, for the first time, that these colloidal apatite NPs can modulate phospholipid bilayer membrane properties, and may even favor the permeation of small molecules (illustrated here with luminescent FITC), which could ultimately be exploited for nanomedicine applications in view of enhancing intracellular drug delivery.

Practical guide to single layer centrifugation of stallion semen

SummaryThe technique of single layer centrifugation through species‐specific colloids has been gaining acceptance over the last few years as a practical method of improving the sperm quality of stallion semen for artificial insemination. This article explains the background to the technique and the different colloid formulations used, suggests some applications of the technique with particular reference to the equine breeding industry, describes the method in detail, and finally provides some guidance for problem solving. It is intended as a practical guide for those considering using the technique to improve sperm quality and pregnancy rates in equine artificial insemination and embryo transfer.

Bioinspired Calcium Phosphate Nanoparticles Featuring as Efficient Carrier and Prompter for Macrophage Intervention in Experimental Leishmaniasis.

To develop a biocompatible and bioresorbable calcium phosphate (CaP) nanoparticles (NPs) bearing Amphotericin B (AmB) with an aim to provide macrophage specific targeting in visceral leishmaniasis (VL). CaP-AmB-NPs were architectured through emulsion precipitation method. The developed formulation was extensively characterized for various parameters including in-vitro and in-vivo antileishmanial activity. Moreover, plasma pharmacokinetics, tissue biodistribution and toxicity profile were also assessed. Optimized CaP-AmB-NPs exhibited higher entrapment (71.1 ± 6.68%) of AmB. No trend related to higher hemolysis was apparent in the developed formulation as evidenced in commercially available colloidal and liposomal formulations. Cellular uptake of the developed CaP-AmB-NPs was quantified through flow cytometry in J774A.1 cell line, and a 23.90 fold rise in uptake was observed. Fluorescent microscopy also confirmed the time dependent rise in uptake. In-vivo multiple dose toxicity study demonstrated no toxicity upto 5mg/kg dose of AmB. Plasma kinetics and tissue distribution studies established significantly higher concentration of AmB in group treated with CaP-AmB-NPs in liver and spleen as compared to CAmB, LAmB and AmB suspension group. In-vivo animal experimental results revealed that the CaP-AmB-NPs showed higher splenic parasite inhibition compared to CAmB and LAmB in leishmania parasite infected hamsters. The investigated CaP-AmB-NPs are effective in provoking macrophage mediated uptake and collectively features lower toxicity and offers a suitable replacement for available AmB-formulations for the obliteration of intra-macrophage VL parasite.

NANO-POLISHING SUBSTRATES FOR OPTICS AND MICROELECTRONICS

As a result of research of polishing single crystal materials it was shown that the polishing flat surfaces of optoelectronic elements of single crystal silicon carbide is advantageously carried out by using a polishing slurry of the powders based on MAX-phase Ti3AlC2 and colloidal nanoparticulate systems, and single crystal sapphire - using suspensions of diamond micron powders of the cubic boron nitride powders and MAX-phase Ti3AlC2. Nano-polishing surfaces of elements of single crystal sapphire should be performed using colloidal nanoparticulate systems or traditional formulations based on colloidal silica. It is also shown that the polishing efficiency of single crystal silicon carbide and sapphire is inversely proportional to the transfer energy, the maximum value of which correspond to a minimum roughness.

Controlled Penetration of a Novel Dimeric Ceramide into and across the Stratum Corneum Using Microemulsions and Various Types of Semisolid Formulations

Ceramides (CERs) are integral parts of the intercellular lipid lamellae of the stratum corneum (SC), which is responsible for the barrier function of the skin. Many skin diseases such as atopic dermatitis and psoriasis are associated with the depletion or disturbance of the level of CERs in the SC. Administration of an exogenous novel dimeric ceramide (dCER) deep into the SC may help to stabilize the SC barrier substantially and to treat some skin disease conditions. Consequently, with the help of the existing technology, it might be possible to formulate various pharmaceutical dosage forms that can facilitate penetration of dCER into the SC. Therefore, the penetration of dCER was studied using a high-performance liquid chromatography/atmospheric-pressure ionization/mass spectrometry method for the detection and quantification of exogenous dCER in the SC as well as other skin layers. Penetration studies were carried out in the Franz diffusion cell using excised human skin ex vivo. Penetration of dCER was studied with 3 model formulations: a colloidal formulation (microemulsion), a cream formulation with ethoxydiglycol as penetration enhancer and a nanoformulation. The highest concentrations of dCER in the different skin layers were found after application of the cream with penetration enhancer. Surprisingly, the lowest concentrations of dCER in the different skin layers were found after application of the microemulsion.

Effect of Single Layer Centrifugation on reactive oxygen species and sperm mitochondrial membrane potential in cooled stallion semen.

Additional means are needed for evaluating the quality of stallion spermatozoa in semen doses for AI. Mitochondrial membrane potential (ΔΨm) has been linked to fertility in some species, but is rarely used in the evaluation of cooled stallion semen; metabolic activity may be associated with reactive oxygen species production (ROS). In the present study, ΔΨm and ROS production were measured in doses of cooled stallion semen. The effect of colloid centrifugation on these parameters was also investigated. In this case, colloid centrifugation involves centrifuging a sperm sample through a silane-coated silica colloid formulation to retrieve the most robust spermatozoa. High and low ΔΨm in cooled stallion semen varied between stallions and between ejaculates, but was not affected by single-layer centrifugation (SLC). The SLC-selected spermatozoa produced significantly less hydrogen peroxide than controls (P < 0.001), which could explain the increased longevity and retention of fertilising capacity seen in previous studies. For SLC samples, ΔΨm was positively associated with viable spermatozoa that were not producing reactive oxygen species (r = 0.49; P < 0.001) and negatively associated with ROS production (for superoxide: r = -0.4, P < 0.01; for hydrogen peroxide: r = -0.39, P < 0.05). There was no clear association between ΔΨm and ROS production in control samples.

Stearic acid crystals stabilization in aqueous polymeric dispersions

In wet granulation processes, coatings or binders generally consist of mixtures of various raw materials that confer or enhance specific properties to the final product. Typically, a coating solution is composed of water, film forming polymer (such as hydroxypropyl-methylcellulose, HPMC) and filler (such as stearic acid, SA).One of the important issues in wet granulation processes is the stability of the aqueous coating (or binder) dispersion. An unstable dispersion results in the agglomeration of the colloidal particles, thereby affecting the film coating properties and eventually the coating process.In this study, we use dissipative particle dynamics (DPD) to elucidate the structure of aqueous colloidal formulations. DPD is a coarse-grained molecular dynamics simulation method where the materials are described as a set of soft beads interacting according to the Flory–Huggins (1942) model. The DPD simulation results are compared to experimental results obtained by Cryogenic-SEM and particle size distribution analysis.It is shown from the DPD simulation results that the HPMC polymer is able to form a layer that covers SA particles and thus produces stable colloids. Microcrystalline cellulose (MCC) also covers SA agglomerate but it is not able to diffuse inside its inner core. The agglomerate structure is characterized via the density distribution and the polymer chain end-to-end distance.Experimental results show similar trends; particle size distribution analysis shows that in the presence of HPMC, the majority of SA particles are below 1μm in diameter, also MCC is able to prevent the formation of big SA agglomerates and may be a better stabilizing agent than HPMC. SEM images reveal that HPMC surrounds SA agglomerates with a hatching textured film and anchors on their surface.

Stable Colloidal Drug Aggregates Catch and Release Active Enzymes.

Small molecule aggregates are considered nuisance compounds in drug discovery, but their unusual properties as colloids could be exploited to form stable vehicles to preserve protein activity. We investigated the coaggregation of seven molecules chosen because they had been previously intensely studied as colloidal aggregators, coformulating them with bis-azo dyes. The coformulation reduced colloid sizes to <100 nm and improved uniformity of the particle size distribution. The new colloid formulations are more stable than previous aggregator particles. Specifically, coaggregation of Congo Red with sorafenib, tetraiodophenolphthalein (TIPT), or vemurafenib produced particles that are stable in solutions of high ionic strength and high protein concentrations. Like traditional, single compound colloidal aggregates, the stabilized colloids adsorbed and inhibited enzymes like β-lactamase, malate dehydrogenase, and trypsin. Unlike traditional aggregates, the coformulated colloid-protein particles could be centrifuged and resuspended multiple times, and from resuspended particles, active trypsin could be released up to 72 h after adsorption. Unexpectedly, the stable colloidal formulations can sequester, stabilize, and isolate enzymes by spin-down, resuspension, and release.

Unusually high thermal stability and peroxidase activity of cytochrome c in ionic liquid colloidal formulation.

Ionic liquid (IL) surfactant choline dioctylsulfosuccinate, [Cho][AOT], formed polydispersed vesicular structures in the IL, ethylmethylimidazolium ethylsulfate, [C2mim][C2OSO3]. Cytochrome c dissolved in such a colloidal medium has shown very high peroxidase activity (∼2 times to that in neat IL and ∼4 times to that in an aqueous buffer). Significantly, the enzyme retained both structural stability and functional activity in IL colloidal solutions up to 180 °C, demonstrating the suitability of the system as a high temperature bio-catalytic reactor.

Structure of aqueous colloidal formulations used in coating and agglomeration processes: Mesoscale model and experiments

In coating and agglomeration processes, the properties of the final product, such as solubility, size distribution, permeability and mechanical resistance, depend on the process parameters and the binder (or coating) solution properties. These properties include the type of solvent used, the binder composition and the affinity between its constituents.In this study, we used mesoscale simulations to investigate the structure of agglomerates formed in aqueous colloidal formulations used in coating and granulation processes. The formulations include water, a film forming polymer (Hydroxypropyl-methylcellulose, HPMC), a hydrophobic filler (Stearic acid, SA) and a plasticizer (Polyethylene glycol, PEG). For the simulations, dissipative particle dynamics (DPD) and a coarse-grained approach were used. In the DPD method, the materials are described as a set of soft beads interacting according to the Flory–Huggins model. The repulsive interactions between the beads were evaluated using the solubility parameter (δ) as input, where δ was calculated by all-atom molecular dynamics. The DPD simulation results were compared to experimental results obtained by cryogenic-SEM and particle size distribution analysis.DPD simulation results showed that the HPMC polymer is able to adsorb in depth into the inner core of SA particle and covers it with a thick layer. We also observed that the structure of HPMC-SA mixture varies under different amounts of SA. For high amounts of SA, HPMC is unable to fully stabilize SA. Affinity between the binder materials was deduced from the DPD simulations and compared with Jarray et al. (2014) theoretical affinity model.Experimental results presented similar trends; particle size distribution analysis showed that for low percentage of SA (below 10% w/w) and in the presence of HPMC, the majority of SA particles are below 1μm in diameter. Cryogenic-SEM images reveal that SA crystals are covered and surrounded by HPMC polymer. SA crystals remain dispersed and small in size for low percentages of SA.

Influence of Nanoscale Surface Roughness on Colloidal Force Measurements.

Forces between colloidal particles determine the performances of many industrial processes and products. Colloidal force measurements conducted between a colloidal particle AFM probe and particles immobilized on a flat substrate are valuable in selecting appropriate surfactants for colloidal stabilization. One of the features of inorganic fillers and extenders is the prevalence of rough surfaces-even the polymer latex particles, often used as model colloidal systems including the current study, have rough surfaces albeit at a much smaller scale. Surface roughness is frequently cited as the reason for disparity between experimental observations and theoretical treatment but seldom verified by direct evidence. This work reports the effect of nanoscale surface roughness on colloidal force measurements carried out in the presence of surfactants. We applied a heating method to reduce the mean surface roughness of commercial latex particles from 30 to 1 nm. We conducted force measurements using the two types of particles at various salt and surfactant concentrations. The surfactants used were pentaethylene glycol monododecyl ether, Pluronic F108, and a styrene/acrylic copolymer, Joncryl 60. In the absence of the surfactant, nanometer surface roughness affects colloidal forces only in high salt conditions when the Debye length becomes smaller than the surface roughness. The adhesion is stronger between colloids with higher surface roughness and requires a higher surfactant concentration to be eliminated. The effect of surface roughness on colloidal forces was also investigated as a function of the adsorbed surfactant layer structure characterized by AFM indentation and dynamic light scattering. We found that when the layer thickness exceeds the surface roughness, the colloidal adhesion is less influenced by surfactant concentration variation. This study demonstrates that surface roughness at the nanoscale can influence colloidal forces significantly and should be taken into account in colloidal dispersion formulations.

Biomimetic Apatite-Based Functional Nanoparticles as Promising Newcomers in Nanomedicine: Overview of 10 Years of Initiatory Research

Biomimetic calcium phosphate apatites, analogous to bone mineral, may now be produced synthetically. Their intrinsic biocompatibility and the nanometer dimensions of their constitutive crystals not only allow one to envision applications in bone tissue regeneration, but also in other medical fields such as nanomedicine, and in particular in view of cell diagnosis. In this mini-review, we look back at 10 years of our dedicated research, and summarize the main advances made in terms of preparation, physical-chemical characterizations and biological evaluations of colloidal formulations of biomimetic apatite-based nanoparticles, which we illustrate here with the angle of cancer diagnosis. The confirmed exceptional biocompatibility of these engineered nanoparticles, associated to the possibility to confer them luminescence properties by way of controlled lanthanide doping, and their capacity to be internalized by cells, including with cancer cell addressing abilities (shown here as a proof of concept), underline that biomimetic apatite-based colloidal nanoparticles are particularly promising for nanomedicine applications, for example related to diseased cells diagnosis. Multidisciplinary research on these functional nanoparticles, initiated as described here, has now generated emulation in the scientific community where the concept of apatite nanoparticles for nanomedicine is being, gratifyingly, appropriated.

Co-delivery of chemosensitizing siRNA and an anticancer agent via multiple monocomplexation-induced hydrophobic association

Synergistic combination of gene targeting and chemotherapy by co-delivering siRNA and anticancer drugs has widely been investigated to develop siRNA-based therapeutics for cancer treatment. Despite clinical potential of this approach, big challenges still remain such as delivery efficiency or stability/biocompatibility of the siRNA delivery system. Here we report a simple and biocompatible co-delivering formulation based on a unique complexation method, i.e., multiple monocomplexation-induced hydrophobic association between Bcl-2 targeting siRNA and a monocationic anticancer agent (benzethonium chloride, BZT). A colloidal formulation of the hydrophobically associated multiple monocomplex (HMplex) composed of siRNA, BZT and Pluronic F-68 was spontaneously constructed by physical mixing of the ternary constituents. In vitro and in vivo studies revealed that the ternary HMplex with a low charge ratio (N/P=4) possesses a tightly complexed stable nanostructure with Pluronic surface and small colloidal size less than 10nm, which allowed for 1) suitable protection of siRNA in serum-rich physiological environment, 2) efficient intracellular transfection into the cytoplasm, and 3) successful peritumoral co-delivery into the tumor tissue with dense interstitial matrix. Compared to non-targeting HMplexes between scrambled siRNA and BZT, Bcl-2 targeting HMplexes enhanced significantly both mRNA down-regulation by siRNA and apoptosis induction by BZT, and thus greatly suppressed the tumor volume when administered to highly aggressive and resistant human breast cancer xenografts (MDA-MB-231) in mice. These results elucidate that the co-complexed siRNA and BZT were liberated by intracellular decomplexation to trigger a synergistically combined therapeutic action. The successful siRNA/chemodrug co-delivery in vivo via peritumoral route and the greatly promoted therapeutic efficacy thereby represent the clinical potential of HMplexes for adjuvant locoregional cancer treatment by gene-targeted combination therapy.

Long Term Stability Evaluation of Prostacyclin Released from Biomedical Device through Turbiscan Lab Expert.

Therapeutic guidelines indicate prostacyclin as the first line of treatment in inflammation and vascular diseases. Prostacyclins prevent formation of the platelet plug involved in primary hemostasis by inhibiting platelet activation and, combined with thromboxane, are effective vasodilators in vascular damage.Trans-Atlantic Inter-Society Consensus Document on Management of Peripheral Arterial Disease II guidelines indicates prostacyclins; in particular, Iloprost, as the first therapeutic option for treating peripheral arterial disease. However, therapeutic efficacy of Iloprost has witnessed several drawbacks that have occurred in patients receiving repeated weekly administration of the drug by intravenous infusions. Adverse reactions arose under perfusion with Iloprost for 6 h and patient compliance was drastically decreased. Biomedical devices could provide a suitable alternative to overcome these drawbacks. In particular, elastomeric pumps, filled with Iloprost isotonic solution, could slowly release the drug, thus decreasing its side effects, representing a valid alternative to hospitalization of patients affected by peripheral arterial disease. However, the home therapy treatment of patients requires long-term stability of Iloprost in solution-loaded elastomeric pumps.The aim of this work was to investigate the long-term stability of Iloprost isotonic solution in biomedical devices using Turbiscan technology. Turbiscan Lab Expert (L’Union, France) predicts the long-term stability of suspensions, emulsions and colloidal formulations by measuring backscattering and transmission of particulates dispersed in solution. The formulations were evaluated by measuring the variation of physical-chemical properties of colloids and suspensions as a function of backscattering and transmission modifications. In addition, the release profile of Iloprost isotonic solution from the biomedical device was evaluated.

Solvent selection causes remarkable shifts of the "Ouzo region" for poly(lactide-co-glycolide) nanoparticles prepared by nanoprecipitation.

Polymer nanoparticles (NPs) offer versatile novel biological features of interest for drug delivery applications. "Ouzo diagrams" allowed for a systematic manufacture of specified colloidal formulations by the widely used nanoprecipitation process. Surprisingly, despite the well-documented relevance of the applied organic solvent for nanoprecipitation, its effect on the actual status of the "Ouzo region" was so far not studied. Herein, investigations were undertaken to account for the potential impact of the solvent type on the "Ouzo diagrams" for poly(lactide-co-glycolide) (PLGA) and tetrahydrofuran (THF), 1,4-dioxane, acetone and dimethyl sulfoxide (DMSO). The "Ouzo region" shifted considerably to higher polymer fractions upon solvent change (rank order: THF < 1,4-dioxane < acetone < DMSO). Assuming a one-to-one transformation of detached PLGA-bearing solvent droplets (droplet diameter for THF: ∼800 nm, 1,4-dioxane: ∼700 nm, acetone: ∼500 nm and DMSO: ∼300 nm) into non-divisible polymer aggregates upon solvent displacement, facilitated to predict the size of NPs found within the "Ouzo region" (size range: 40-200 nm). In conclusion, application of "Ouzo diagrams" is a valuable tool for drug delivery research and will most-likely replace the "trial-and-error"-approach to identify the operating window for the production of stable colloidal formulations by the nanoprecipitation technique.