Non-aqueous silicone elastomer gels as a vaginal microbicide delivery system for the HIV-1 entry inhibitor maraviroc

Aqueous semi-solid polymeric gels, such as those based on hydroxyethylcellulose (HEC) and polyacrylic acid (e.g. Carbopol®), have a long history of use in vaginal drug delivery. However, despite their ubiquity, they often provide sub-optimal clinical performance, due to poor mucosal retention and limited solubility for poorly water-soluble actives. These issues are particularly pertinent for vaginal HIV microbicides, since many lead candidates are poorly water-soluble and where a major goal is the development of a coitally independent, once daily gel product. In this study, we report the use of a non-aqueous silicone elastomer gel for vaginal delivery of the HIV-1 entry inhibitor maraviroc. In vitro rheological, syringeability and retention studies demonstrated enhanced performance for silicone gels compared with a conventional aqueous HEC gel, while testing of the gels in the slug model confirmed a lack of mucosal irritancy. Pharmacokinetic studies following single dose vaginal administration of a maraviroc silicone gel in rhesus macaques showed higher and sustained MVC levels in vaginal fluid, vaginal tissue and plasma compared with a HEC gel containing the same maraviroc loading. The results demonstrate that non-aqueous silicone gels have potential as a formulation platform for coitally independent vaginal HIV microbicides.

Highly thermally responsive hybrid in-fiber sSlab waveguide grating structure with a plastic core and a silica cladding

A 1.2(height)×125(depth)×500(length) micro-slot was engraved along a fiber Bragg grating by chemically assisted femtosecond laser processing. By filling epoxy and UV-curing, waveguide with plastic-core and silica-cladding was created, presenting high thermal responding coefficient of 211pm/°C.

Effect of the Hofmeister anions upon the swelling of a self-assembled pH-responsive hydrogel

We report the effect of a range of monovalent sodium salts on the molecular equilibrium swelling of a simple synthetic microphase separated poly(methyl methacrylate)-block-poly(2-(diethylamino)ethyl methacrylate)-block-poly(methyl methacrylate) (PMMA88-b-PDEA223-b-PMMA88) pH-responsive hydrogel. Sodium acetate, sodium chloride, sodium bromide, sodium iodide, sodium nitrate and sodium thiocyanate were selected for study at controlled ionic strength and pH; all salts are taken from the Hofmeister series (HS). The influence of the anions on the expansion of the hydrogel was found to follow the reverse order of the classical HS. The expansion ratio of the gel measured in solutions containing the simple sodium halide salts (NaCl, NaBr, and NaI) was found to be strongly related to parameters which describe the interaction of the ion with water; surface charge density, viscosity coefficient, and entropy of hydration. A global study which also included nonspherical ions (NaAce, NaNO3 and NaSCN) showed the strongest correlation with the viscosity coefficient. Our results are interpreted in terms of the Collins model,(1) where larger ions have more mobile water in the first hydration cage immediately surrounding the gel, therefore making them more adhesive to the surface of the stationary phase of the gel and ultimately reducing the level of expansion.

Microencapsulation strategies for islet transplantation

A variety of islet microencapsulation techniques have been investigated to establish which method provides the least occlusive barrier to net insulin release in vitro, and optimum biocompatibility for islet implantation in vivo. NMRI mouse islets have been microencapsulated with Na+ -alginate-poly-L-lysine (PLL)/poly-L-ornithine (PLO)-alginate, Ba2+ -alginate and agarose gels. Both free and microencapsulated islets responded to glucose challenge in static incubation and perifusion by significantly increasing their rate of insulin release and theophylline significantly potentiated the insulin response to glucose. While little insulin was released from microencapsulated islets after short term (2 hours) static incubation, significantly greater amounts were released in response to glucose challenge after extended (8-24 hours) incubation. However, insulin release from all types of microencapsulated islets was significantly reduced compared with free islets. Na+ -alginate-PLO-alginate microencapsulated islets were significantly more responsive to elevated glucose than Na+ -alginate-PLL-alginate microencapsulated islets, due to the enhanced porosity of PLO membranes. The outer alginate layer created a significant barrier to glucose/insulin exchange and reduced the insulin responsiveness of microencapsulated islets to glucose. Ba2+ -alginate membrane coated islets, generated by the density gradient method, were the most responsive to glucose challenge. Low concentrations of NG-monomethyl L-arginine (L-NMMA) had no significant effect on glucose stimulated insulin release from either free or microencapsulated islets. However, 1.0 mmol/1 L-NMMA significantly inhibited the insulin response of both free and microencapsulated islets to glucose challenge. In vivo work designed to evaluate the extent of pericapsular fibrosis after 28 days ip. and sc. implantation of microencapsulated islets into STZ-diabetic recipients, revealed that the inclusion of islets within microcapsules increased their immunogenicity and markedly increased the extent of pericapsular fibrosis. When the outer alginate layer was omitted from microcapsules, little or no pericapsular mononuclear cell deposition was observed. The subcutaneous site was not suitable for microencapsulated islet transplantation in NMRI recipient mice. Systemic immunosuppression using cyclosporin A was effective in preventing pericapsular mononuclear cell deposition, while L-NMMA loading into microcapsules had no significant effect on pericapsular fibrosis, although it did maintain the integrity of microencapsulated islets.

An iterative agent bidding mechanism for responsive manufacturing

In today's market, the global competition has put manufacturing businesses in great pressures to respond rapidly to dynamic variations in demand patterns across products and changing product mixes. To achieve substantial responsiveness, the manufacturing activities associated with production planning and control must be integrated dynamically, efficiently and cost-effectively. This paper presents an iterative agent bidding mechanism, which performs dynamic integration of process planning and production scheduling to generate optimised process plans and schedules in response to dynamic changes in the market and production environment. The iterative bidding procedure is carried out based on currency-like metrics in which all operations (e.g. machining processes) to be performed are assigned with virtual currency values, and resource agents bid for the operations if the costs incurred for performing them are lower than the currency values. The currency values are adjusted iteratively and resource agents re-bid for the operations based on the new set of currency values until the total production cost is minimised. A simulated annealing optimisation technique is employed to optimise the currency values iteratively. The feasibility of the proposed methodology has been validated using a test case and results obtained have proven the method outperforming non-agent-based methods.

Robust spatially resolved pressure measurements using MRI with novel buoyant advection-free preparations of stable microbubbles in polysaccharide gels

MRI of fluids containing lipid coated microbubbles has been shown to be an effective toot for measuring the local fluid pressure. However, the intrinsically buoyant nature of these microbubbles precludes lengthy measurements due to their vertical migration under gravity and pressure-induced coalescence. A novel preparation is presented which is shown to minimize both these effects for at least 25 min. By using a 2% polysaccharide gel base with a small concentration of glycerol and 1,2-distearoyl-sn-glycero-3-phosphocholine coated gas microbubbles, MR measurements are made for pressures between 0.95 and 1.44 bar. The signal drifts due to migration and amalgamation are shown to be minimized for such an experiment whilst yielding very high NMR sensitivities up to 38% signal change per bar.

Responsive core−shell latex particles as colloidosome microcapsule membranes

Responsive core-shell latex particles are used to prepare colloidosome microcapsules using thermal annealing and internal cross-linking of the shell, allowing production of the microcapsules at high concentrations. The core-shell particles are composed of a polystyrene core and a shell of poly[2-(dimethylamino)ethyl methacrylate]-b-poly[methyl methacrylate] (PDMA-b-PMMA) chains adsorbed onto the core surface, providing steric stabilisation. The PDMA component of adsorbed polymer shell confers the latex particle thermal and pH responsive characteristics, it also provides glass transitions at lower temperatures than that of the core and reactive amine groups. These features facilitate the formation of stable Pickering emulsion droplets and the immobilisation of the latex particle monolayer on these droplets to form colloidosome microcapsules. The immobilisation is achieved through thermal annealing or cross-linking of the shell at mild conditions feasible for large scale economic production. We demonstrate here that it is possible to anneal the particle monolayer on the emulsion drop surface at 75-86 ºC by using the lower glass transition temperature of the shell compared to that of the polystyrene cores (~108 ºC). The colloidosome microcapsules formed have a rigid membrane basically composed of a monolayer of particles. Chemical cross-linking has also been successfully achieved by confining a cross-linker within the disperse droplet. This approach leads to the formation of single-layered stimulus-responsive soft colloidosome membranes and provides the advantage of working at very high emulsion concentrations since inter-droplet cross-linking is thus avoided. The porosity and mechanical strength of microcapsules are also discussed here in terms of the observed structure of the latex particle monolayers forming the capsule membrane.

Novel pH‐and temperature‐responsive methacrylamide microgels

A novel transition temperature in MeAM copolymer microgels is reported. Despite the fact that MeAM homopolymers do not show thermosensitive properties, a specific synthetic strategy leads to a thermo-responsive swelling behavior that could be potentially useful in medical and/or industrial applications. The pH and temperature-dependent swelling response of microgels of MeAM copolymerized with 2-aminomethylpyridine and ethylenediamine is reported. The changes in particle sizes, which depend on the nature of the surrounding environment, are recorded by QELS. The relation between copolymer structure and its novel behavior is analyzed by several techniques (1H NMR, TGA).

Specific pH‐responsive folate‐conjugate microgels designed for antitumor therapy

Colloidal nanosized folate-conjugated hydrogels for targeted chemotherapy were prepared via a versatile and efficient postsynthetic modification pathway starting from P(NPA-co-NIPAM). The modifications included the introduction of 4-methylpyridine as pH-sensitive pendant groups and the conjugation of folic acid to the microgel network. The microgels showed a specific swelling at pH?gels shows a clear influence on the pH volume transition shifting. The potential of the microgels for anticancer drug release at pH?=?5.0 was confirmed. Therefore, they are a promising targeting carrier for improved anticancer chemotherapy.

Highly thermally responsive hybrid in-fiber slab waveguide grating structure with a plastic core and a silica cladding

A 1.2(height)×125(depth)×500(length) micro-slot was engraved along a fiber Bragg grating by chemically assisted femtosecond laser processing. By filling epoxy and UV-curing, waveguide with plastic-core and silica-cladding was created, presenting high thermal responding coefficient of 211pm/°C.

Highly thermally responsive hybrid in-fiber sSlab waveguide grating structure with a plastic core and a silica cladding

A 1.2(height)×125(depth)×500(length) micro-slot was engraved along a fiber Bragg grating by chemically assisted femtosecond laser processing. By filling epoxy and UV-curing, waveguide with plastic-core and silica-cladding was created, presenting high thermal responding coefficient of 211pm/°C.

Electrospinning pH-responsive block copolymer nanofibers

Electrospinng of a fibrous triblock copolymer consisting of poly(methyl methacrylate-block-poly[2-(diethylamino) ethyl methacrylate]-block-poly(methyl methacrylate) (PMMA-b-PDEA-b-PMMA) has been discussed. A mixed co-solvent system of tetrahydrofuran (THF) and dimethylformamide (DMF) was used to electrospin fibrous PMMA-b-PDEA-b-PMMA and its influence on surface morphology and diameter of the electrospun fiber was also investigated in an attempt to control the fiber diameter. The concentration range between 20 and 40 wt % was found suitable for electrospinning of PMMA-b-PDEA-b-PMMA in a THF/DMF system. It was also observed that the average fiber diameter decreased as the content of DMF was increased. A significant decrease in fiber diameter was observed when moving from a THF solution to a THF/DMF system at a ratio of 70:30.

Chemical specificity in REDOX-responsive materials:the diverse effects of different Reactive Oxygen Species (ROS) on polysulfide nanoparticles

REDOX responsive (nano)materials typically exhibit chemical changes in response to the presence and concentration of oxidants/reductants. Due to the complexity of biological environments, it is critical to ascertain whether the chemical response may depend on the chemical details of the stimulus, in addition to its REDOX potential, and whether chemically different responses can determine a different overall performance of the material. Here, we have used oxidation-sensitive materials, although these considerations can be extended also to reducible ones. In particular, we have used poly(propylene sulfide) (PPS) nanoparticles coated with a PEGylated emulsifier (Pluronic F127); inter alia, we here present also an improved preparative method. The nanoparticles were exposed to two Reactive Oxygen Species (ROS) typically encountered in inflammatory reactions, hydrogen peroxide (H2O2) and hypochlorite (ClO−); their response was evaluated with a variety of techniques, including diffusion NMR spectroscopy that allowed to separately characterize the chemically different colloidal species produced. The two oxidants triggered a different chemical response: H2O2 converted sulfides to sulfoxides, while ClO− partially oxidized them further to sulfones. The different chemistry correlated to a different material response: H2O2 increased the polarity of the nanoparticles, causing them to swell in water and to release the surface PEGylated emulsifier; the uncoated oxidized particles still exhibited very low toxicity. On the contrary, ClO− rapidly converted the nanoparticles into water-soluble, depolymerized fragments with a significantly higher toxicity. The take-home message is that it is more correct to discuss ‘smart’ materials in terms of an environmentally specific response to (REDOX) stimuli. Far from being a problem, this could open the way to more sophisticated and precisely targeted applications.

Responsive hydrophobically associating polymers:a review of structure and properties

Responsive hydrophobically associating polymers can in many ways be considered to be analogous to proteins in their ability to form compact molecules with a defined secondary structure, and hence, functionality. These molecules are characterized by the presence of alternating charged and hydrophobic groups. The balance between charge repulsion and hydrophobic interactions is sensitive to environmental pH and therefore changes in pH produce controllable conformational changes. The change from a charged extended chain to a collapsed uncharged coil structure is sometimes referred to as hypercoiling behaviour and enables the polymer to act as a simple switch between an 'on' and 'off' state. The purpose of this review is to illustrate the structure and behaviour of polymers that exhibit hypercoiling behaviour and to highlight their potential pharmaceutical applications, which in terms of drug delivery is likely to be related to their surface behaviour and solubilizing activity. © 2001 Elsevier Science B.V. All rights reserved.