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.

Electronic and thermal lensing in diode end-pumped Yb:YAG laser rods and discs

The lensing effects in diode end-pumped Yb:YAG laser rods and discs are studied. Two mechanisms of refractive-index changes are taken into account, thermal and electronic (due to the difference between the excited- and ground-state Yb polarisabilities), as well as pump-induced deformation of the laser crystal. Under pulsed pumping, the electronic lensing effect prevails over the thermal one in both rods and discs. In rods pumped by a highly focused cw beam, the dioptric power of the electronic lens exceeds that of the thermal lens, whereas in discs steady-state lensing is predominantly due to the thermal mechanism. © 2009 Kvantovaya Elektronika and Turpion Ltd.

Population lensing vs thermal lensing in Yb:YAG rods and disks

The induced lenses in the Yb:YAG rods and disks end-pumped by a Gaussian beam were analyzed both analytically and numerically. The thermally assisted mechanisms of the lens formation were considered to include: the conventional volume thermal index changes ("dn/dT"), the bulging of end faces, the photoelastic effect, and the bending (for a disk). The heat conduction equations (with an axial heat flux for a disk and a radial heat flux for a rod), and quasi-static thermoelastic equations (in the plane-stress approximation with free boundary conditions) were solved to find the thermal lens power. The population rate equation with saturation (by amplified spontaneous emission or an external wave) was examined to find the electronic lens power in the active elements.

Shell-side transfer in shell-and-tube heat exchangers

Local mass transfer coefficients were determined by using the electrochemical technique. A simple model of a heat exchanger with segmental nickel tube joined to p.v.c. rods replaced the exchanger tubes. Measurements were made for both no-Ieakage, semi-leakage and total leakage configurations. Baffle-spacings of 47.6 mm, 66.6 mm, 97 mm and 149.2 mm wer studied. Also studied were the overall exchanger pressure drops for each configuration. The comparison of the heat transfer data with this work showed good agreement at high flow rates for the no-leakage case, but the agreement became poor for lower flow rates and leakage configurations. This disagreement was explained by non-analogous driving forces existing in the two systems. The no-leakage data showed length-wise variation of transfer coefficients along the exchanger length. The end compartments showing transfer coefficients inferior by up to 26% compared to tbe internal compartments, depending on Reynolds number. With the introduction of leakage streams this variation however became smaller than the experimental accuracy. A model is outlined to show the characteristic behaviour of individual electrode segments within the compartment. This was able to discriminate between cross and window zones for the no- leakage case, but no such distinction could be made for the leakage case. A flow area was found which, when incorporated in the Reynolds number, enabled the correlation of baffle-cut and baffle-spacing parameters for the no-leakage case . This area is the free flow area determined at the baffle edge. Addition of the leakage area to this flow area resulted in correlation of all commercial leakage geometrical parameters. The procedures used to correlate the pressure drop data from a total of eighteen different configurations on a single curve are also outlined.

High speed DSC (hyper-DSC) as a tool to measure the solubility of a drug within a solid or semi-solid matrix

Conventional differential scanning calorimetry (DSC) techniques are commonly used to quantify the solubility of drugs within polymeric-controlled delivery systems. However, the nature of the DSC experiment, and in particular the relatively slow heating rates employed, limit its use to the measurement of drug solubility at the drug's melting temperature. Here, we describe the application of hyper-DSC (HDSC), a variant of DSC involving extremely rapid heating rates, to the calculation of the solubility of a model drug, metronidazole, in silicone elastomer, and demonstrate that the faster heating rates permit the solubility to be calculated under non-equilibrium conditions such that the solubility better approximates that at the temperature of use. At a heating rate of 400°C/min (HDSC), metronidazole solubility was calculated to be 2.16 mg/g compared with 6.16 mg/g at 20°C/min. © 2005 Elsevier B.V. All rights reserved.

Molecular investigations into vaginal immunization with HIV gp41 antigenic construct H4A in a quick release solid dosage form

A robust vaginal immune response is considered essential for an effective prophylactic vaccine that prevents transmission of HIV and other sexually acquired diseases. Considerable attention has recently focused on the potential of vaginally administered vaccines as a means to induce such local immunity. However, the potential for vaccination at this site remains in doubt as the vaginal mucosa is generally considered to have low immune inductive potential. In the current study, we explored for the first time the use of a quick release, freeze-dried, solid dosage system for practical vaginal administration of a protein antigen. These solid dosage forms overcome the common problem associated with leakage and poor retention of vaginally administered antigen solutions. Mice were immunized vaginally with H4A, an HIV gp41 envelope based recombinant protein, using quick release, freeze-dried solid rods, and the immune responses compared to a control group immunized via subcutaneous H4A injection. Vaginally immunized mice failed to elicit robust immune responses. Our detailed investigations, involving cytokine analysis, the stability of H4A in mouse cervicovaginal lavage, and elucidation of the state of H4A protein in the immediate-release dosage form, revealed that antigen instability in vaginal fluid, the state of the antigen in the dosage form, and the cytokine profile induced are all likely to have contributed to the observed lack of immunogenicity. These are important factors affecting vaginal immunization and provide a rational basis for explaining the typically poor and variable elicitation of immunity at this site, despite the presence of immune responsive cells within the vaginal mucosae. In future mucosal vaccine studies, a more explicit focus on antigen stability in the dosage form and the immune potential of available antigen-responsive cells is recommended.

Sustained release of the CCR5 inhibitors CMPD167 and maraviroc from vaginal rings in rhesus macaques

Antiretroviral entry inhibitors are now being considered as vaginally administered microbicide candidates for the prevention of the sexual transmission of human immunodeficiency virus. Previous studies testing the entry inhibitors maraviroc and CMPD167 in aqueous gel formulations showed efficacy in the macaque challenge model, although protection was highly dependent on the time period between initial gel application and subsequent challenge. In this paper, we describe the sustained release of maraviroc and CMPD167 from matrix-type silicone elastomer vaginal rings both in vitro and in vivo. Both inhibitors were released continuously during 28 days from rings in vitro at rates of 100 to 2,500 µg/day. In 28-day pharmacokinetic studies in rhesus macaques, the compounds were measured in the vaginal fluid and vaginal tissue; steady-state fluid concentrations were ~10(6)-fold greater than the 50% inhibitory concentrations (IC(50)s) for simian human immunodeficiency virus 162P3 inhibition in macaque lymphocytes in vitro. Plasma concentrations for both compounds were very low. The pretreatment of macaques with Depo-Provera (DP), which is commonly used in macaque challenge studies, was shown to significantly modify the biodistribution of the inhibitors but not the overall amount released. Vaginal fluid and tissue concentrations were significantly decreased while plasma levels increased with DP pretreatment. These observations have implications for designing macaque challenge experiments and also for ring performance during the human female menstrual cycle.

Novel high water content hydrogels

Hydrogels may be described as cross-linked hydrophilic polymers that swell but do not dissolve in water. The production of high water content hydrogels was the subject of investigation. Based upon copolymer compositions that had already achieved commercial success as biomaterials, new monomers were added or substituted in and the effects observed. The addition of N-isopropyl acrylamide to an acrylamide-based composition that had previously been designed to become a contact lens, produced materials that showed smart effects in that the water content showed dependence on the temperature of the hydrating solution. Such thermo-responsive materials have potential uses in drug delivery, ultrafiltration and cell culture surfaces. Proteoglycans in nature have an important role to play in structural support where a highly hydrophilic structure maintains lubricious surfaces. Certain functional groups that impart this hydrophilicity are present in certain sulphonate monomers, Bis(3-sulphopropyl ester) itaconate, dipotassium salt (SPI), 3-Sulphopropyl ester acrylate, potassium salt (SPA) and Sodium 2-(acrylamido)-2-methyl propane sulphonate (NaAMPS). These monomers were incorporated into a HEMA-based copolymer that had been designed initially as a contact lens and the resulting effects examined. Highly hydrophilic materials resulted that showed reduced protein deposition over the neutral core material. It is postulated that a sulphonate group would have a larger number of hydration shells around it than for example methacrylic acid, leading to more dynamic exchange and so reducing the adsorption of biological solutes. A cationic monomer was added to bring back the net anionic nature of the sulphonate hydrogels and the effects studied. Ionic interactions were found to cause a reduction in the water content of the resulting materials as the mobility of the network decreased, leading to stiffer but less extensible materials. The presence of a net dominant charge, whether negative or positive, appeared to act to reduce protein deposition, but increasing equivalence in the amount of both charges served to present a more 'neutral' surface and deposition subsequently increased. The grafting of hydrophilic hydrogel layers onto silicone elastomer was attempted and the results evaluated using dynamic contact angle measurements. Following plasma oxidation to reduce the surface energy barrier to aqueous grafting chemistry, it was found that the wettability of the modified elastomers could be significantly enhanced by such treatment. The SPA-grafted material in particular hinted at an osmotic drive for rehydration that may be exploited in biomaterials.

The steady performance of a porous and compliant aerostatic thrust bearing

Recent developments in aerostatic thrust bearings have included: (a) the porous aerostatic thrust bearing containing a porous pad and (b) the inherently compensated compliant surface aerostatic thrust bearing containing a thin elastomer layer. Both these developments have been reported to improve the bearing load capacity compared to conventional aerostatic thrust bearings with rigid surfaces. This development is carried one stage further in a porous and compliant aerostatic thrust bearing incorporating both a porous pad and an opposing compliant surface. The thin elastomer layer forming the compliant surface is bonded to a rigid backing and is of a soft rubber like material. Such a bearing is studied experimentally and theoretically under steady state operating conditions. A mathematical model is presented to predict the bearing performance. In this model is a simplified solution to the elasticity equations for deflections of the compliant surface. Account is also taken of deflections in the porous pad due to the pressure difference across its thickness. The lubrication equations for flow in the porous pad and bearing clearance are solved by numerical finite difference methods. An iteration procedure is used to couple deflections of the compliant surface and porous pad with solutions to the lubrication equations. Comparisons between experimental results and theoretically predicted bearing performance are in good agreement. However these results show that the porous and compliant aerostatic thrust bearing performance is lower than that of a porous aerostatic thrust bearing with a rigid surface in place of the compliant surface. This discovery is accounted to the recess formed in the bearing clearance by deflections of the compliant surface and its effect on flow through the porous pad.

Local and systemic delivery of a novel group of inhibitors of transglutaminase enzyme: A potential approach for treating of catheter-related complications and liver fibrosis

The present thesis investigates targeted (locally and systemically) delivery of a novel group of inhibitors of enzyme transglutaminases (TGs). TGs are a widely distributed group of enzymes that catalyse the formation of isopeptide bonds between the y-carboxamide group of protein-bound glutamines and the a-amino group of protein-bound lysines or polyamines. The first group of the novel inhibitors tested were the tluorescently labelled inhibitors of Factor XIIIa (FXIIIa). These small, non-toxic inhibitors have the potential to prevent stabilisation of thrombi by FXIIIa and consequently increase the natural rate of thrombolysis, in addition it reduces staphylococcal colonisation of catheters by inhibiting their FXIIIa¬mediated cross-linking to blood clot proteins on the central venous catheter (CVCs) surface. The aim of this work was to incorporate the FXIIIa inhibitor either within coating of polyurethane (PU) catheters or to integrate it into silicone catheters, so as to reduce the incidence of thrombotic occlusion and associated bacterial infection in CVCs. The initial work focused on the incorporation of FXIIIa inhibitors within polymeric coatings of PU catheters. After defining the key characteristics desired for an effective polymeric-coating, polyvinylpyrrolidone (PVP), poly(lactic-co-glycolic acid) (PLGA) or their combination were studies as polymers of choice for coating of the catheters_ The coating was conducted by dip-coating method in a polymer solution containing the inhibitor. Upon incubation of the inhibitor-and polymer-coated strips in buffer, PVP was dissolved instantly, generating fast and significant drug release, whilst PLGA did not dissolve, yielding a slow and an insufficient amount of drug release. Nevertheless, the drug release profile was enhanced upon employing a blend solution of PVP and PLGA. The second part of the study was to incorporate the FXIIIa inhibitor into a silicone elastomer; results demonstrated that FXIIIa inhibitor can be incorporated and released from silicone by using citric acid (CA) and sodium bicarbonate (SB) as additives and the drug release rate can be controlled by the amount of incorporated additives in the silicone matrix. Furthermore, it was deemed that the inhibitor was still biologically active subsequent to being released from the silicone elastomer strips. Morphological analysis confirmed the formation of channels and cracks inside the specimens upon the addition of CA and SB. Nevertheless, the tensile strength, in addition to Young's modulus of silicone elastomer strips, decreased constantly with an increasing amount of amalgamated CA/ SB in the formulations. According to our results, incorporation of FXIIIa inhibitor into catheters and other medical implant devices could offer new perspectives in preventing bio-material associated infections and thrombosis. The use of tissue transglutaminase (T02) inhibitor for treating of liver fibrosis was also investigated. Liver fibrosis is characterized by increased synthesis and decreased degradation of the extracellular matrix (ECM). Transglutaminase-mediated covalent cross-linking is involved in the stabilization of ECM in human liver fibrosis. Thus, TG2 inhibitors may be used to counteract the decreased degradation of the ECM. The potential of a liposome based drug delivery system for site specific delivery of the fluorescent TG2 inhibitor into the liver was investigated; results indicated that the TG2 inhibitor can be successfully integrated into liposomes and delivered to the liver, therefore demonstrating that liposomes can be employed for site-specific delivery of TG2 inhibitors into the liver and TG2 inhibitor incorporating liposomes could offer a new approach in treating liver fibrosis and its end stage disease cirrhosis.

Wear of abrasion resisting materials

The wear behaviour of a series of chromium containing white irons has been investigated under conditions of high stress grinding abrasion using a specimen on track abrasion testing machine. The measured abrasion resistance of the irons has been explained in terms of microstructure and hardness and with respect to the wear damage observed at and beneath abraded surfaces. During abrasion material removal occurred by cracking and detachment from the matrix of eutectic carbides as well as by penetration and micromachining effects of the abrasive grits being crushed at the wearing surface. Under the particular test conditions used martensitic matrix structures gave higher resistance to abrasion than austenitic or pearlitic. However, no simple relationship was found between general hardness or matrix microhardness at wear surfaces and abrasion resistance, and the test yielded pessimistic results for austenitic irons. The fine structures of the 15% Cr and 30% Cr alloys were studied by thin foil transmission electron microscopy. It was found that both the matrix and carbide constituents could be thinned for examination at 100 Kv using conventional dishing followed by ion beam thinning. Flany of the rodlike eutectic N7C3 carbides were seen to consist of clusters of scalier rods with individual 117C3 crystals quite often containing central cores of matrix constituent. 3oth eutectic and secondary N7C3 carbides were found to contain stacking faults on planes normal to the basal plane. In the eutectic carbides in the 30A Cr iron there was evidence of an in-situ PI7C3 C. transition which had taken place during the hardening heat treatment of this alloy. In the as-cast austenitic matrix iron strain induced martensite was produced at the wear surface contributing to work hardening. The significance of these findings have been discussed in relation to wear performance.

Indwelling catheters and medical implants with FXIIIa inhibitors:a novel approach to the treatment of catheter and medical device-related infections

Central venous catheters (CVCs) are being utilized with increasing frequency in intensive care and general medical wards. In spite of the extensive experience gained in their application, CVCs are related to the long-term risks of catheter sheath formation, infection, and thrombosis (of the catheter or vessel itself) during catheterization. Such CVC-related-complications are associated with increased morbidity, mortality, duration of hospitalization, and medical care cost [1]. The present study incorporates a novel group of Factor XIIIa (FXIIIa, plasma transglutaminase) inhibitors into a lubricious silicone elastomer in order to generate an optimized drug delivery system whereby a secondary sustained drug release profile occurs following an initial burst release for catheters and other medical devices. We propose that the incorporation of FXIIIa inhibitors into catheters, stents, and other medical implant devices would reduce the incidence of catheter sheath formation, thrombotic occlusion, and associated staphylococcal infection. This technique could be used as a local delivery system for extended release with an immediate onset of action for other poorly aqueous soluble compounds. © 2012 Elsevier B.V. All rights reserved.

Pharmacokinetics of a CCR5 inhibitor in rhesus macaques following vaginal, rectal and oral application

Objectives: This study measured and compared the pharmacokinetics of CMPD167, a small molecule antiretroviral CCR5 inhibitor with potential as an HIV microbicide, following vaginal, rectal and oral administration in rhesus macaques. Methods: Avaginal hydroxyethylcellulose (HEC) gel, a rectal HEC gel, a silicone elastomer matrix-type vaginal ring and an oral solution, each containing CMPD167, were prepared and administered to rhesus macaques pretreated with Depo-Provera. CMPD167 concentrations in vaginal fluid, vaginal tissue (ring only), rectal fluid and blood plasma were quantified by HPLC-mass spectrometry. Results: CMPD167 concentrations measured in rectal fluid, vaginal fluid and blood plasma were highly dependent on both the route of administration and the formulation type. Although rectal and vaginal fluid concentrations were highest when CMPD167 was administered locally (via either gel or ring), lower concentrations of the drug were also measured in these compartments following administration at the remote mucosal site or orally. CMPD167 levels in the vaginal and rectal fluid following oral administration were relatively low compared with local administration. Conclusions: The study provides clear evidence for vaginal-rectal and rectal-vaginal drug transfer pathways and suggests that oral pre-exposure prophylaxis with CMPD167 may be less efficacious at preventing sexual transmission of HIV-1 than topically applied products. ©The Author 2013.

Synthesis of CuS and CuS/ZnS core/shell nanocrystals for photocatalytic degradation of dyes under visible light

High quality CuS and CuS/ZnS core/shell nanocrystals (NCs) were synthesized in a large quantity using a facile hydrothermal method at low temperatures of 60 C and evaluated in the photodegradation of Rhodamine B (RhB) under visible light irradiation. Synthesis time plays an important role in controlling the morphology, size and photocatalytic activity of both CuS and CuS/ZnS core/shell NCs which evolve from spherical shaped particles to form rods with increasing reaction time, and after 5 h resemble "flower" shaped morphologies in which each "flower" is composed of many NCs. Photocatalytic activity originates from photo-generated holes in the narrow bandgap CuS, with encapsulation by large bandgap ZnS layers used to form the core/shell structure that improves the resistance of CuS towards photocorrosion. Such CuS/ZnS core/shell structures exhibit much higher photocatalytic activity than CuS or ZnS NCs alone under visible light illumination, and is attributed to higher charge separation rates for the photo-generated carriers in the core/shell structure. © 2013 Elsevier B.V.

Preparation and property testing of compatibilized poly(l-lactide)/thermoplastic polyurethane blends

Poly(l-lactide) (PLL) has been blended with a polycaprolactone-based thermoplastic polyurethane (TPU) elastomer as a toughening agent and a poly(l-lactide-co-caprolactone) (PLLCL) copolymer as a compatibilizer. Both 2-component (PLL/TPU) and 3-component (PLL/TPU/PLLCL) blends were prepared by melt mixing, characterized, hot-pressed into thin sheets and their tensile properties tested. The results showed that, although the TPU could toughen the PLL, the blends were largely immiscible leading to phase separation. However, addition of the PLLCL copolymer improved blend compatibility. The best all-round properties were found for the 3-component blend of composition PLL/TPU/PLLCL = 90/10/10 parts by weight.