Aqueous-based Formulations Research Articles

A Curcumin-BODIPY Dyad and Its Silica Hybrid as NIR Bioimaging Probes.

In this paper we describe the synthesis of a novel bichromophoric system in which an efficient photoinduced intercomponent energy transfer process is active. The dyad consists of one subunit of curcumin and one of BODIPY and is able to emit in the far-red region, offering a large Stokes shift, capable of limiting light scattering processes for applications in microscopy. The system has been encapsulated in MCM-41 nanoparticles with dimensions between 50 and 80 nm. Both the molecular dyad and individual subunits were tested with different cell lines to study their effective applicability in bioimaging. MCM-41 nanoparticles showed no reduction in cell viability, indicating their biocompatibility and bio-inertness and making them capable of delivering organic molecules even in aqueous-based formulations, avoiding the toxicity of organic solvents. Encapsulation in the porous silica structure directed the location of the bichromophoric system within cytoplasm, while the dyad alone stains the nucleus of the hFOB cell line.

Performance of Oleic Acid and Soybean Oil in the Preparation of Oil-in-Water Microemulsions for Encapsulating a Highly Hydrophobic Molecule

This work analyzes the dispersion of a highly hydrophobic molecule, (9Z)-N-(1,3-dihydroxyoctadecan-2-yl)octadec-9-enamide (ceramide-like molecule), with cosmetic and pharmaceutical interest, by exploiting oil-in-water microemulsions. Two different oils, oleic acid and soybean oil, were tested as an oil phase while mixtures of laureth-5-carboxylic acid (Akypo) and 2-propanol were used for the stabilization of the dispersions. This allowed us to obtain stable aqueous-based formulations with a relatively reduced content of oily phase (around 3% w/w), that may enhance the bioavailability of this molecule by its solubilization in nanometric oil droplets (with a size range of 30–80 nm), that allow the incorporation of a ceramide-like molecule of up to 3% w/w, to remain stable for more than a year. The nanometric size of the droplet containing the active ingredient and the stability of the formulations provide the basis for evaluating the efficiency of microemulsions in preparing formulations to enhance the distribution and availability of ceramide-like molecules, helping to reach targets in cosmetic and pharmaceutical formulations.

Nose-to-brain delivery of phenytoin and its hydrophilic prodrug fosphenytoin combined in a microemulsion - formulation development and in vivo pharmacokinetics.

Phenytoin is a low aqueous solubility antiepileptic drug, but its phosphate ester prodrug fosphenytoin is soluble, although less permeable. In a previous study, the intranasal administration of aqueous-based formulations of fosphenytoin led to high but delayed phenytoin bioavailability compared to the intravenous route. In this work, we hypothesized that formulating an association of the prodrug fosphenytoin and the drug phenytoin (the active and diffusible form), could result in a faster and/or more effective brain targeting. Hence, nano or microemulsions containing both active drug and prodrug were developed and characterized regarding viscosity, osmolality, pH, mean size and in vitro drug release. Then, in vivo pharmacokinetics of a selected microemulsion containing fosphenytoin and phenytoin was evaluated in mice following intranasal administration and compared with a similar microemulsion containing fosphenytoin only. Both microemulsions led to higher brain drug levels at short time points than previously developed simpler aqueous based fosphenytoin formulations, likely due to the microemulsion's permeation enhancing effect. In addition, having a small amount of phenytoin in the formulation led to an equivalent maximum brain drug concentration and an overall higher absolute bioavailability, with a prolonged drug exposure. Hence, it can be concluded that if there is a need for a fast and prolonged therapeutic effect, a drug/phosphate ester prodrug combination in a microemulsion is ideal, but if a fast effect is all that is needed, having the prodrug alone could be enough, while considering a formulation with permeation enhancing components.

Rheology and Pinching Dynamics of Associative Polysaccharide Solutions

Associative polysaccharides, decorated by multiple but short, side-chain hydrophobic stickers (typically 6–20 carbon long) that associate in solution, are used as thickeners for an extensive range of aqueous-based formulations. Characterizing and elucidating the influence of stickers on the response to extensional flows that spontaneously arise in pinching necks formed during spraying, jetting, or coating fluids have remained longstanding experimental and analytical challenges due to relatively low viscosity and elasticity of industrially relevant systems. In this contribution, we contrast the shear rheology as well as extensional rheology and pinching dynamics of hydrophobically modified hydroxyethyl cellulose (hmHEC, Mw = 300 kg/mol) as a sticky polymer with the bare chain of a higher molecular weight (hydroxyethyl cellulose (HEC), Mw = 720 kg/mol) using the recently developed dripping-onto-substrate (DoS) rheometry protocols. We show that sticker associations enhance zero shear viscosity and relaxation time (elasticity), and both quantities display stronger concentration-dependent variation for sticky polymers. Striking differences are observed in neck shapes, radius evolution profiles, and extensional viscosity plotted as a function of strain as well as strain rate. We present a comprehensive analysis of changes in pinching dynamics, concentration-dependent variation in steady, terminal viscosity as well as filament lifespan as a function of the sticky polymer concentration and describe the influence of multiple stickers on the macromolecular strain, relaxation, and dynamics of associative polysaccharides.

Nanoemulsions for the Encapsulation of Hydrophobic Actives

This work analyzes the dispersion of two highly hydrophobic actives, (9Z)-N-(1,3-dihydroxyoctadecan-2-yl)octadec-9-enamide (ceramidelike molecule) and 2,6-diamino-4-(piperidin-1-yl)pyrimidine 1-oxide (minoxidil), using oil-in-water nanoemulsions with the aim of preparing stable and safe aqueous-based formulations that can be exploited for enhancing the penetration of active compounds through cosmetic substrates. Stable nanoemulsions with a droplet size in the nanometric range (around 200 nm) and a negative surface charge were prepared. It was possible to prepare formulations containing up to 2 w/w% of ceramide-like molecules and more than 10 w/w% of minoxidil incorporated within the oil droplets. This emulsions evidenced a good long-term stability, without any apparent modification for several weeks. Despite the fact that this work is limited to optimize the incorporation of the actives within the nanoemulsion-like formulations, it demonstrated that nanoemulsions should be considered as a very promising tool for enhancing the distribution and availability of hydrophobic molecules with technological interest.

Deposition characteristics of a novel intranasal formulation of azelastine hydrochloride plus fluticasone propionate in an anatomic model of the human nasal cavity.

Background: Intranasal antihistamines and steroids should be delivered in a volume and with a technique that allow for optimal drug retention within the entire nasal cavity, maximize local absorption by the nasal mucosa, and, subsequently, increase the potential for the most desirable local availability and therapeutic effect. Objective: This in vitro evaluation simulated nasal medication deposition and evaluated the extent of runoff. MP-AzeFlu, a novel intranasal formulation of azelastine hydrochloride (AZE) plus fluticasone propionate (FP), was compared with sequential sprays of available commercial products with the individual medication components. Methods: A model of a normal adult human nasal cavity was used to visualize deposition of nasal spray products. A single spray of MP-AzeFlu (0.137 mL [137 μg of AZE/50 μg of FP]) or single sequential sprays of AZE nasal spray (0.137 mL [137 μg]) followed by brand name or generic FP nasal spray (0.100 mL [50 μg]) were manually actuated into the model. The interior was coated with a water-sensitive dye that changes to magenta when exposed to aqueous-based formulations. A slight vacuum was applied during spray delivery to simulate sniffing. The results were photographed by using anterior and lateral views. Results: Three replicates of MP-AzeFlu showed no dripping from the front of the nostril or backflow from the nasal cavity. However, three replicates of AZE nasal spray, followed by a brand name or generic FP nasal spray, showed significant dripping from the front of the nostril and backflow from the nasal cavity. Conclusion: A single spray of MP-AzeFlu resulted in no runoff compared with sequential dosing of the two other therapeutic products. Product runoff is likely due to the volume exceeding the capacity of the nasal cavity model. Furthermore, the common clinical dosing regimen of two sprays per nostril of each of the individual components would promote even greater increased undesirable flooding and leakage.

A Sacrificial Route for Soft Porous Polymers Synthesized via Frontal Photo-Polymerization.

Within the very large range of porous polymers and a related immense scope of applications, we investigate here a specific route to design soft porous polymers with controlled porosity: we use aqueous-based formulations of oligomers with mineral particles which are solidified into a hydrogel upon photo-polymerization; the embedded particles are then chemically etched and the hydrogel is dried to end up with a soft porous polymeric scaffold with micron-scale porosity. Morphological and physical features of the porous polymers are measured and we demonstrate that the porosity of the final material is primarily determined by the amount of initially dispersed sacrificial particles. In addition, the liquid formulations we use to start with are convenient for a variety of material forming techniques such as microfluidics, embossing, etc., which lead to many different morphologies (monoliths, spherical particles, patterned substrates) based on the same initial material.

Thermally triggerable, anchoring block copolymers for use in aqueous inkjet printing

Towards the goal of shifting from toxic organic solvents to aqueous-based formulations in commercial inkjet printing, a series of well-defined amphiphilic block copolymers have been synthesized via RAFT polymerization.

A Live Bio-Therapeutic for Mastitis, Containing Lactococcus lactis DPC3147 With Comparable Efficacy to Antibiotic Treatment.

Bovine mastitis is an ongoing significant concern in the dairy and agricultural industry resulting in substantial losses in milk production and revenue. Among the predominant etiological agents of bovine mastitis are Staphylococcus aureus, Streptococcus uberis, Streptococcus dysgalactiae, and Escherichia coli. Currently, the treatment of choice for bovine mastitis involves the use of commercial therapeutic antibiotic formulations such as TerrexineTM, containing both kanamycin and cephalexin. Such antibiotics are regularly administered in more than one dose resulting in the withholding of milk for processing for a number of days. Here, we describe the optimization of a formulation of Lactococcus lactis DPC3147, that produces the two-component bacteriocin lacticin 3147, in a liquid paraffin-based emulsion (formulation hereafter designated ‘live bio-therapeutic’) for the first time and compare it to the commercial antibiotic formulation TerrexineTM, with a view to treating cows with clinical/sub-clinical mastitis. Critically, in a field trial described here, this ‘ready-to-use’ emulsion containing live L. lactis DPC3147 cells exhibited comparable efficacy to TerrexineTM when used to treat mastitic cows. Furthermore, we found that the L. lactis cells within this novel emulsion-based formulation remained viable for up to 5 weeks, when stored at 4, 22, or 37°C. The relative ease and cost-effective nature of producing this ‘live bio-therapeutic’ formulation, in addition to its enhanced shelf life compared to previous aqueous-based formulations, indicate that this product could be a viable alternative therapeutic option for bovine mastitis. Moreover, the single-dose administration of this ‘live bio-therapeutic’ formulation is a further advantage, as it can expedite the return of the milk to the milk pool, in comparison to some commercial antibiotics. Overall, in this field trial, we show that the live bio-therapeutic formulation displayed a 47% cure rate compared to a 50% cure rate for a commercial antibiotic control, with respect to curing cows with clinical/sub-clinical mastitis. The study suggests that a larger field trial to further demonstrate efficacy is warranted.

Effect of oil cakes and garlic aqueousbased formulations of trichoderma viride on management of meloidogyne incognita in chilli

Abstract Root-knot nematode, Meloidogyne incognita (Kofoid and White) is a major threat to chilli (Capsicum annum) cultivation, by forming root galls and subsequent wilting. These nematodes live in soil, roots debris and reported surviving in other Solanaceae crops. Chemical application of nematicides cause impact on environment, therefore biocontrol using antagonistic fungi is desired to tackle this problem. This research is aimed to evaluate the effect of Trichoderma viride and its formulations on management of M. incognita. Oil cakes such as neem (Azadiracta indica), gingelly (Sesamum indicum), Mahua (Madhuca longifolia) and garlic (Allium sativum) extracts were used to evaluate the growth and sporulation of T. viride. Chilli variety MI-2 was used. Among the four preparations, neem oil cake recorded high spore yield of 1.75 ×107 spores/ml. Similarly gingelly oil cake and garlic produced the spore yields of 1.57 ×107 spores/ml and 1.368 ×107 spores/ml, respectively. Comparatively Mahua oil cake obtained low spore yield of 7.87×106 spores/ml. Plant growth was significant (P<0.05) in the application of neem oil cake formulation (30.42 cm). Extent of galling was significantly low with garlic (9.00) and neem (9.25). These results confirmed that the formulations of neem, gingelly oil cake extracts and garlic aqueous extract stimulated the chilli plant growth, productivity and reduced the nematode infestation. Above all, neem oil cake and garlic are the best formulations that can be used to manage M. incognita

Formulation optimization of lecithin-enhanced pickering emulsions stabilized by chitosan nanoparticles for hesperidin encapsulation

Hesperidin is a flavonoid that exhibits reduced solubility in aqueous-based formulations. In the present study, hesperidin was encapsulated in food-grade oil-in-water (O/W) lecithin-enhanced Pickering emulsions that were stabilized by chitosan nanoparticles via a rotor-stator homogenizer. The objective of the experiment was to investigate the effects of formulation factors, i.e., chitosan nanoparticles (ChiNP), lecithin concentration, and the oil-to-water (O/W) ratio, on the physical stability of hesperidin-loaded emulsions. The mean droplet size (d3,2) and emulsion stability index (ESI) were predicted using the response surface methodology. The optimal formulation conditions were achieved when using concentrations of 1.1% (w/w) of ChiNP, 4.4% (w/w) of lecithin, and an O/W ratio of 0.24 (v/v), with a high ESI of 0.78 ± 0.06, a d3,2 of 2.5 ± 0.87 μm, and a polydispersity index (PDI) of 0.33. Therefore, the models explained 98% of the response variability. The emulsion characterizations, using confocal laser scanning microscopy (CLSM) micrographs, showed direct evidence that the ChiNP were adsorbed at the interface between the oil and water phases. Detailed microstructures of the emulsion droplets were visualized by Scanning Electron Microscopy (SEM), corroborating the potential of ChiNP as wall material for the development of Pickering emulsions. The shelf-life estimation of the hesperidin emulsions was characterized using an automated analytical centrifuge. The results inferred a long shelf-life for the emulsions since the obtained creaming velocity was lower. In conclusion, this versatile and straightforward approach can be potentially applied in the encapsulation of several oil-soluble active compounds for food applications.

Benchtop MRI for pharmacokinetic evaluation of two aqueous-based nano-scaled formulations of oleic acid stabilized magnetite nanocrystals

Background: The interplay between numerous factors, including the size, shape, coating, surface charge and composition of particles is known to affect the pharmacokinetics and biodistribution of superparamagnetic iron oxides (SPIOs). This makes understanding the role of each factor independently quite challenging.Methods: In the present study, the in vivo magnetic resonance imaging (MRI), biodistribution and hepatic clearance evaluations of two SPIOs Formulations A and B developed from ∼13.5 nm hydrophobic oleic acid stabilized monodisperse magnetite nanocrystals core and lipid-based amphiphilic stabilizers were performed using a prototype benchtop MR imager (22 MHz) and pulsed nuclear magnetic resonance (NMR) system (20 MHz), respectively. Formulation A was composed of mPEG-2000-DSPE and Formulation B was composed of Phospholipon-100H, sucrose ester M-1695 and Cremophor RH-40.Results: The in vivo MRI investigations showed that both formulations were safe and effective as potential liver MR contrast agents with sustained liver contrast for at least seven days. In addition, ex vivo relaxometric investigations revealed that the formulations predominantly distribute to the liver and spleen following I.V. injection. The hepatic clearance kinetics determined based on the relaxometric quantification method indicated that both formulations exhibited a biphasic clearance process with a slow terminal clearance half-life of 11.5 and 12.7 days, respectively, for Formulations A and B.Conclusions: The results of this study showed the potential biomedical applications of the investigated magnetopharmaceutical formulations as MRI contrast agents.

Optimization of Freeze-Drying Cycle for Tert-Butanol–Based Formulations of Ibuprofen

We carried out the formulation set-up and thermodynamics as well as morphological characterization of two systems: an aqueous-based formulation and an organic-solvent-based formulation with tert-butanol (TBA) at eutectic composition (20% TBA + water 80% by mass) containing ibuprofen as the model pharmaceutical active component. The goal was to carry out the optimization of a soft freeze-drying cycle for heat-sensitive drugs. The organic-based ibuprofen formulation had a glass transition temperature significantly higher compared to that of the aqueous-based ibuprofen formulation, which allowed much higher sublimation temperatures for these systems in comparison with the pure water-based ibuprofen formulations. The morphological study of the frozen organic-based formulation showed unexpected behavior in comparison with previous literature data reported for water-based formulations. For the same freezing rates, the mean diameters of the solvent crystals of organic-based formulations were much larger than that of ice crystals of aqueous-based formulation, which led to a freeze-dried matrix of higher permeability. In contrast to what was observed with the aqueous-based formulations, the freezing rates, in the range of classical industrial values investigated, had no significant effect on the supercooling of the liquid ibuprofen formulations tested as well as on the nucleation temperatures and on the morphology of the organic solvent crystals. All these singular characteristics, with lower sublimation enthalpies and higher equilibrium vapor pressure values previously measured with the same formulations in our laboratory, explain the large reduction of sublimation times observed during the soft freeze-drying processes for heat-sensitive drugs with organic (TBA)-based formulations.

A Cationic Peptide, TAT-Cd0, Inhibits Herpes Simplex Virus Type 1 Ocular Infection In Vivo

To test the in vivo activity of a peptide derived from the protein transducing domain of the human immunodeficiency virus (HIV) Tat protein, TAT-Cd°, in a murine herpes simplex type 1 (HSV-1) keratitis model. the efficacy of TAT-CD° was assessed in a postinfection treatment model with different concentrations (1 mg/mL, 0.1 mg/mL, 0.01 mg/mL) of the peptide in one of four delivery vehicles: artificial tears, PBS, methylcellulose, and aquaphor cream. Treatment began within 4 or 24 hours postinfection. Viral titers in the tear film were determined by plaque assay. TAT-Cd° reduced the severity of keratitis in all of the delivery vehicles tested when treatment started, 4 hours postinfection. Peptide in the tears or PBS delivery vehicle had the most significant reduction in disease severity and delayed the onset of vascularization and stromal keratitis. The percentage of mice presenting with disease was also significantly reduced and viral titers were reduced by 1 log at 24 hours postinfection in mice treated with 1 mg/mL TAT-Cd°, suggesting that inhibiting replication early is sufficient to achieve clinical effects. Lower concentrations were not effective and delaying treatment by 24 hours was also not effective. This study shows that TAT-Cd° is an effective antiviral against HSV-1 strain KOS when applied shortly postinfection and that aqueous-based formulations are more suitable.

A simplified and rapid high-performance liquid chromatographic assay for ketoprofen in isopropyl myristate.

A high-performance liquid chromatographic (HPLC) procedure for quantitating ketoprofen in isopropyl myristate (IPM), a compound widely used as a receptor medium in drug diffusion studies of topical aqueous-based formulations, is developed. Previously reported HPLC assays for ketoprofen in IPM have employed relatively complex and tedious methods for purifying the IPM prior to injection onto the HPLC column. The present assay method utilizes a direct injection of the IPM-based sample onto a new reversed-phase ODS column and employs ultraviolet detection at 265 nm. Propyl paraben is employed as the internal standard. The mobile phase consists of acetonitrile-methanol-water (36:54:10, v/v/v) at a flow rate of 1.2 mL/min. The calibration curves are linear (correlation coefficient r > or = 0.988) over concentration ranges of 0.625-10 micrograms/mL and 6.25-100 micrograms/mL. The within-day and between-day precision exhibit coefficients of variation of 1.3-3.3%, and the accuracy (reported as relative error of the mean) varies from -1.9% to 0.6%. The retention times for ketoprofen and propyl paraben are approximately 2.3 and 3.3 min, respectively. The total run time per sample is approximately 7 min. The minimum quantitatable concentration is approximately 0.625 microgram/mL. The assay is stability-indicating, rapid, reproducible, sensitive, and readily adaptable for assaying other non-steroidal anti-inflammatory drugs.

Hydrophobically Associating Polymers As Rheology Modifiers

Hydrophobically associating water-soluble polymers are essentially hydrophilic polymer chains containing a small number of strongly hydrophobic groups, distributed or located at some priviledged sites on the chains. In aqueous media, hydrophobic units tend to associate in order to minimize their exposure to water, leading to reversible intra- and intermolecular hydrophobic junction networks, at even very low polymer concentrations. Such temporary networks influence strongly the linear and nonlinear rheological properties of the solutions and make such polymers candidates as rheology modifiers in aqueous-based formulations such as drilling fluids. In this paper, we present the main rheological characteristics of hydrophobically associating water-soluble polymers, the influence of the presence of a surfactant on their rheological properties and the rheology of solutions containing a mixture of associating and non-associating water-soluble polymers.

Improved delivery through biological membranes. XLV. Synthesis, physical-chemical evaluation, and brain uptake studies of 2-chloroethyl nitrosourea delivery systems.

The dihydropyridine in equilibrium with pyridinium redox chemical delivery system (CDS) was supplied to two 2-chloroethylnitrosoureas, i.e., HECNU and CCNUOH, and the physicochemical properties of the delivery systems were studied to assess their potential as improved delivery forms to the CNS. Detailed physicochemical evaluation and brain uptake studies were performed on one of the delivery systems (CCNUOH-CDS) derived from trans-4-hydroxy-CCNU, an active metabolite of CCNU. Two aqueous-based formulations derived from hydroxypropyl-beta-cyclodextrin (HP beta CD) and Tween 80:ethanol:water system were developed for CCNUOH-CDS to overcome the poor aqueous solubility conferred upon it by its high lipophilicity. The formulations enabled a 200- to 400-fold improvement in the water solubility of CCNUOH-CDS. Dose- and vehicle-dependent comparative tissue distribution studies in rats indicated improved brain-to-organ ratios of the delivery system at lower doses.