Thermosensitive hydrogels of poly(methyl vinyl ether-co-maleic anhydride) - Pluronic (R) F127 copolymers for controlled protein release

Thermosensitive hydrogels are of a great interest due to their many biomedical and pharmaceutical applications. In this study, we synthesized a new series of random poly (methyl vinyl ether-co-maleic anhydride) (Gantrez (R) AN, GZ) and Pluronic (R) F127 (PF127) copolymers (GZ-PF127), that formed thermosensitive hydrogels whose gelation temperature and mechanical properties could be controlled by the molar ratio of GZ and PF127 polymers and the copolymer concentration in water. Gelation temperatures tended to decrease when the GZm/PF127 ratio increased. Thus, at a fixed GZm/PF127 value, sol-gel temperatures decreased at higher copolymer concentrations. Moreover, these hydrogels controlled the release of proteins such as bovine serum albumin (BSA) and recombinant recombinant kinetoplastid membrane protein of Leishmania (rKMP-11) more than the PF127 system. Toxicity studies carried out in J774.2 macrophages showed that cell viability was higher than 80%. Finally, histopathological analysis revealed that subcutaneous administration of low volumes of these hydrogels elicited a tolerable inflammatory response that could be useful to induce immune responses against the protein cargo in the development of vaccine adjuvants.

Lack of in vitro-in vivo correlation for a UC781-releasing vaginal ring in macaques

This study describes the preclinical development of a matrix-type silicone elastomer vaginal ring device designed to provide controlled release of UC781, a non-nucleoside re- verse transcriptase inhibitor. Testing of both human- and macaque-sized rings in a sink condition in vitro release model demonstrated continuous UC781 release in quantities consid- ered sufficient to maintain vaginal fluid concentrations at levels 82–860-fold higher than the in vitro IC50 (2.0 to 10.4 nM) and therefore potentially protect against mucosal trans- mission of HIV. The 100-mg UC781 rings were well tolerated in pig-tailed macaques, did not induce local inflammation as determined by cytokine analysis and maintained median con- centrations in vaginal fluids of UC781 in the range of 0.27 to 5.18 mM during the course of the 28-day study. Analysis of residual UC781 content in rings after completion of both the in vitro release and macaque pharmacokinetic studies revealed that 57 and 5 mg of UC781 was released, respectively. The pharmacokinetic analysis of a 100-mg UC781 vaginal ring in pig-tailed macaques showed poor in vivo–in vitro correlation, attributed to the very poor solubility of UC781 in vaginal fluid and resulting in a dissolution-controlled drug release mecha- nism rather than the expected diffusion-controlled mechanism.

Disulfiram-loaded immediate and extended release vaginal tablets for the localised treatment of cervical cancer

Objectives: To develop and manufacture both immediate and sustained release vaginal tablets containing the anticancer drug disulfiram, which has the potential to be used as a non-invasive treatment for cervical cancer. 
Methods: Disulfiram-loaded vaginal tablets were manufactured at pilot scale using the direct compression method. These tablets were tested in accordance with the European Pharmacopeia testing of solid dosage form guidelines. They were also tested using a biorelevant dissolution method as well as a dual-chambered release model designed to better mimic the dynamic nature of the vaginal vault.
Key findings: We have developed both immediate and sustained release vaginal tablets, which when manufactured at pilot scale are within the limits set by the European Pharmacopeia for the testing of solid dosage forms. Furthermore, these tablets are capable of releasing disulfiram in vitro using the dual-chambered release model at levels 25 000 times and 35 000 times greater than its IC50 concentration for the HeLa cervical cancer cell line. 
Conclusions: The successful pilot manufacture and testing of both the immediate and sustained release disulfiram-loaded vaginal tablets warrant further investigation, using an in-vivo model, to assess their potential for use as a non-invasive treatment option for cervical cancer.

Diagenetic Alterations and Reservoir Quality Evolution of Lower Cretaceous Fluvial Sandstones: Nubian Formation, Sirt Basin, North-Central Libya

Lower Cretaceous meandering and braided fluvial sandstones of the Nubian Formation form some of the most important subsurface reservoir rocks in the Sirt Basin, north-central Libya. Mineralogical, petrographical and geochemical analyses of sandstone samples from well BB6-59, Sarir oilfield, indicate that the meandering fluvial sandstones are fine- to very fine-grained subarkosic arenites (av. Q91F5L4), and that braided fluvial sandstones are medium- to very coarse-grained quartz arenites (av. Q96F3L1). The reservoir qualities of these sandstones were modified during both eodiagenesis (ca. <70oC; <2 km) and mesodiagenesis (ca. >70oC; >2km). Reservoir quality evolution was controlled primarily by the dissolution and kaolinitization of feldspars, micas and mud intraclasts during eodiagenesis, and by the amount and thicknessof grain-coating clays, chemical compaction and quartz overgrowths during mesodiagenesis. However, dissolution and kaolinitization of feldspars, micas and mud intraclasts resulted in the creation of intercrystalline micro- and mouldic macro-porosity and permeability during eodiagenesis, which were more widespread in braided fluvial than in meandering fluvial sandstones. This was because of the greater depositional porosity and permeability in the braided fluvial sandstones which enhanced percolation of meteoric waters. The development of only limited quartz overgrowths in the braided fluvial sandstones, in which quartz grains are coated by thick illite layers, retained high porosity and permeability (12-23 % and 30- 600 mD). By contrast, meandering fluvial sandstones underwent porosity loss as a result of quartz overgrowth development on quartz grains which lack or have thin and incomplete grain-coating illite (2-15 % and 0-0.1mD). Further loss of porosity in the meandering fluvial sandstones occurred as a result of chemical compaction (pressuredissolution) induced by the occurrence of micas along grains contacts. Otherdiagenetic alterations, such as the growth of pyrite, siderite, dolomite/ankerite and albitization, had little impact on reservoir quality. The albitization of feldspars may have had minor positive influence on reservoir quality throughthe creation of intercrystalline micro-porosity between albite crystals.The results of this study show that diagenetic modifications of the braided and meandering fluvial sandstones in the Nubian Formation, and resulting changes in reservoir quality, are closely linked to depositional porosity and permeability. They are also linked to the thickness of grain-coating infiltrated clays, and to variations in detrital composition, particularly the amounts of mud intraclasts, feldspars and mica grains as well as climatic conditions.

Static and dynamic degradation of sintered calcium phosphate ceramics

The chemical compositions of calcium phosphate materials are similar to that of bone making them very attractive for use in the repair of critical size bone defects. The bioresorption of calcium phosphate occurs principally by dissolution. To determine the impact of composition and flow conditions on dissolution rates, calcium phosphate tablets were prepared by slip casting of ceramic slips with different ratios of hydroxyapatite (HA) and ß-tricalcium phosphate (ß-TCP). Dissolution was evaluated at pH4 using both a static and dynamic flow regime. Both the composition of the HA:ß-TCP tablet and flow regime noticeably influenced the rate of dissolution; the 50:50 HA:ß-TCP composition demonstrating the greatest level of dissolution, and, exposure of the ceramic specimens to dynamic conditions producing the highest rate of dissolution. Understanding the impact of phase composition and flow condition with respect to the dissolution of calcium phosphate will aid in the development and improvement of materials for bone substitution.

Grazing under experimental hypercapnia and elevated temperature does not affect the radula of a chiton (Mollusca, Polyplacophora, Lepidopleurida)

Chitons (class Polyplacophora) are benthic grazing molluscs with an eight-part aragonitic shell armature. The radula, a serial tooth ribbon that extends internally more than half the length of the body, is mineralised on the active feeding teeth with iron magnetite apparently as an adaptation to constant grazing on rocky substrates. As the anterior feeding teeth are eroded they are shed and replaced with a new row. The efficient mineralisation and function of the radula could hypothetically be affected by changing oceans in two ways: changes in seawater chemistry (pH and pCO(2)) may impact the biomineralisation pathway, potentially leading to a weaker or altered density of the feeding teeth; rising temperatures could increase activity levels in these ectothermic animals, and higher feeding rates could increase wear on the feeding teeth beyond the animals' ability to synthesise, mineralise, and replace radular rows. We therefore examined the effects of pH and temperature on growth and integrity in the radula of the chiton Leptochiton asellus. Our experiment implemented three temperature (similar to 10, 15, 20 degrees C) and two pCO(2) treatments (similar to 400 mu atm, pH 8.0; similar to 2000 mu atm, pH 7.5) for six treatment groups. Animals (n = 50) were acclimated to the treatment conditions for a period of 4 weeks. This is sufficient time for growth of ca. 7-9 new tooth rows or 20% turnover of the mineralised portion. There was no significant difference in the number of new (non-mineralised) teeth or total tooth row count in any treatment. Examination of the radulae via SEM revealed no differences in microwear or breakage on the feeding cusps correlating to treatment groups. The shell valves also showed no signs of dissolution. As a lineage, chitons have survived repeated shifts in Earth's climate through geological time, and at least their radulae may be robust to future perturbations.

Identification of MnCr2O4 nano-octahedron in catalysing pitting corrosion of austenitic stainless steels

Pitting corrosion of stainless steels, one of the classical problems in materials science and electrochemistry, is generally believed to originate from the local dissolution in MnS inclusions, which are more or less ubiquitous in stainless steels. However, the initial location where MnS dissolution preferentially occurs is known to be unpredictable, which makes pitting corrosion a major concern. In this work we show, at an atomic scale, the initial site where MnS starts to dissolve in the presence of salt water. Using in situ ex-environment transmission electron microscopy (TEM), we found a number of nano-sized octahedral MnCr2O4 crystals (with a spinel structure and a space group of Fd (3) over barm) embedded in the MnS medium, generating local MnCr2O4/MnS nano-galvanic cells. The TEM experiments combined with first-principles calculations clarified that the nano-octahedron, enclosed by eight {1 1 1} facets with metal terminations, is "malignant", and this acts as the reactive site and catalyses the dissolution of MnS. This work not only uncovers the origin of MnS dissolution in stainless steels, but also presents an atomic-scale evolution in a material's failure which may occur in a wide range of engineering alloys and biomedical instruments serving in wet environments. (C) 2010 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Design of a Dissolving Microneedle Platform for Transdermal Delivery of a Fixed-Dose Combination of Cardiovascular Drugs

Microneedles (MNs) are a minimally invasive drug delivery platform, designed to enhance transdermal drug delivery by breaching the stratum corneum. For the first time, this study describes the simultaneous delivery of a combination of three drugs using a dissolving polymeric MN system. In the present study, aspirin, lisinopril dihydrate, and atorvastatin calcium trihydrate were used as exemplar cardiovascular drugs and formulated into MN arrays using two biocompatible polymers, poly(vinylpyrrollidone) and poly(methylvinylether/maleic acid). Following fabrication, dissolution, mechanical testing, and determination of drug recovery from the MN arrays, in vitro drug delivery studies were undertaken, followed by HPLC analysis. All three drugs were successfully delivered in vitro across neonatal porcine skin, with similar permeation profiles achieved from both polymer formulations. An average of 126.3 ± 18.1 μg of atorvastatin calcium trihydrate was delivered, notably lower than the 687.9 ± 101.3 μg of lisinopril and 3924 ± 1011 μg of aspirin, because of the hydrophobic nature of the atorvastatin molecule and hence poor dissolution from the array. Polymer deposition into the skin may be an issue with repeat application of such a MN array, hence future work will consider more appropriate MN systems for continuous use, alongside tailoring delivery to less hydrophilic compounds.

Interlaboratory studies on in vitro test methods for estimating in vivo resorption of calcium phosphate ceramics

A potential standard method for measuring the relative dissolution rate to estimate the resorbability of calcium-phosphate-based ceramics is proposed. Tricalcium phosphate (TCP), magnesium-substituted TCP (MgTCP) and zinc-substituted TCP (ZnTCP) were dissolved in a buffer solution free of calcium and phosphate ions at pH 4.0, 5.5 or 7.3 at nine research centers. Relative values of the initial dissolution rate (relative dissolution rates) were in good agreement among the centers. The relative dissolution rate coincided with the relative volume of resorption pits of ZnTCP in vitro. The relative dissolution rate coincided with the relative resorbed volume in vivo in the case of comparison between microporous MgTCPs with different Mg contents and similar porosity. However, the relative dissolution rate was in poor agreement with the relative resorbed volume in vivo in the case of comparison between microporous TCP and MgTCP due to the superimposition of the Mg-mediated decrease in TCP solubility on the Mg-mediated increase in the amount of resorption. An unambiguous conclusion could not be made as to whether the relative dissolution rate is predictive of the relative resorbed volume in vivo in the case of comparison between TCPs with different porosity. The relative dissolution rate may be useful for predicting the relative amount of resorption for calcium-phosphate-based ceramics having different solubility under the condition that the differences in the materials compared have little impact on the resorption process such as the number and activity of resorbing cells.

Olefin / Paraffin separation using Task-Specific Materials based on Ionic Liquids: Advances in Gas Processing

In this work, 1-hexene was extracted from its mixtures with n-hexane in varying ratios using a task specific ionic liquid. Herein, the ionic liquid (IL) 1-butyl-3-methylimidazolium nitrate, [BMIM][NO3], was used and examined with and without the addition of a metal salt. The impact of water on both selectivity and distribution coefficient was also tested. Four potential metal salts were investigated, the results of which demonstrate that the dissolution of transition-metal salts in the IL improves the separation of 1-hexene from n-hexane through metal-olefin complexation. Additionally, the presence of water in IL solutions containing metal salt enhances this selectivity. Finally, UNIFAC was used to correlate the experimental LLE data with good accuracy.

Novel Supercritical Carbon Dioxide Impregnation Technique for the Production of Amorphous Solid Drug Dispersions: A Comparison to Hot Melt Extrusion

The formulation of BCS Class II drugs as amorphous solid dispersions has been shown to provide advantages with respect to improving the aqueous solubility of these compounds. While hot melt extrusion (HME) and spray drying (SD) are among the most common methods for the production of amorphous solid dispersions (ASDs), the high temperatures often required for HME can restrict the processing of thermally labile drugs, while the use of toxic organic solvents during SD can impact on end-product toxicity. In this study, we investigated the potential of supercritical fluid impregnation (SFI) using carbon dioxide as an alternative process for ASD production of a model poorly water-soluble drug, indomethacin (INM). In doing so, we produced ASDs without the use of organic solvents and at temperatures considerably lower than those required for HME. Previous studies have concentrated on the characterization of ASDs produced using HME or SFI but have not considered both processes together. Dispersions were manufactured using two different polymers, Soluplus and polyvinylpyrrolidone K15 using both SFI and HME and characterized for drug morphology, homogeneity, presence of drug-polymer interactions, glass transition temperature, amorphous stability of the drug within the formulation, and nonsink drug release to measure the ability of each formulation to create a supersaturated drug solution. Fully amorphous dispersions were successfully produced at 50% w/w drug loading using HME and 30% w/w drug loading using SFI. For both polymers, formulations containing 50% w/w INM, manufactured via SFI, contained the drug in the γ-crystalline form. Interestingly, there were lower levels of crystallinity in PVP dispersions relative to SOL. FTIR was used to probe for the presence of drug-polymer interactions within both polymer systems. For PVP systems, the nature of these interactions depended upon processing method; however, for Soluplus formulations this was not the case. The area under the dissolution curve (AUC) was used as a measure of the time during which a supersaturated concentration could be maintained, and for all systems, SFI formulations performed better than similar HME formulations.

A design strategy of large grain lithium-rich layered oxides for lithium-ion batteries cathode

Li-rich materials are considered the most promising for Li-ion battery cathodes, as high capacity can be achieved. However, poor cycling stability is a critical drawback that leads to poor capacity retention. Here a strategy is used to synthesize a large-grain lithium-rich layered oxides to overcome this difficulty without sacrificing rate capability. This material is designed with micron scale grain with a width of about 300 nm and length of 1-3 μm. This unique structure has a better ability to overcome stress-induced structural collapse caused by Li-ion insertion/extraction and reduce the dissolution of Mn ions, which enable a reversible and stable capacity. As a result, this cathode material delivered a highest discharge capacity of around 308 mAh g^-1 at a current density of 30 mA g^-1 with retention of 88.3% (according to the highest discharge capacity) after 100 cycles, 190 mAh g^-1 at a current density of 300 mA g^-1 and almost no capacity fading after 100 cycles. Therefore, Lithium-rich material of large-grain structure is a promising cathode candidate in Lithium-ion batteries with high capacity and high cycle stability for application. This strategy of large grain may furthermore open the door to synthesize the other complex architectures for various applications.

Biogeochemical relationships of arsenic in the Haor Basin of Bangladesh

Biogeochemical relationships and the level of arsenic (As) contamination of groundwater and surface sediments in the Haor Basin of Bangladesh were assessed to see if surface sediments gave any indication of underlying As cycling. The Haor areas under study have been found to be affected with high As (up to 331 μg/L) in groundwater, with contamination of both shallow and deep aquifers. Highly significant relationships of As with Dissolved Organic Carbon (DOC) in groundwater and Total Carbon (TC) and Organic Carbon (OC) in sediments are indicative of reductive dissolution of iron (Fe) and/or manganese (Mn) oxides/oxyhydroxides coupled with biodegradation of organic matter as the dominant processes to release As in groundwater. This study also reveals that As geochemistry in the surface sediments has limited influence on As geochemistry in the groundwater of the Haor Basins. © 2012 Taylor & Francis Group.

Probing The effects of Experimental Conditions on the Character of Drug-Polymer Phase Diagrams Constructed Using Flory-Huggins Theory

Purpose: Amorphous drug-polymer solid dispersions have been found to result in improved drug dissolution rates when compared to their crystalline counterparts. However, when the drug exists in the amorphous form it will possess a higher Gibb’s free energy than its associated crystalline state and can recrystallize. Drug-polymer phase diagrams constructed through the application of the Flory Huggins (F-H) theory contain a wealth of information regarding thermodynamic and kinetic stability of the amorphous drug-polymer system. This study was aimed to evaluate the effects of various experimental conditions on the solubility and miscibility detections of drug-polymer binary system. Methods: Felodipine (FD)-Polyvinylpyrrolidone (PVP) K15 (PVPK15) and FD-Polyvinylpyrrolidone/vinyl acetate (PVP/VA64) were the selected systems for this research. Physical mixtures with different drug loadings were mixed and ball milled. These samples were then processed using Differential Scanning Calorimetry (DSC) and measurements of melting point (Tend) and glass transition (Tg) were detected using heating rates of 0.5, 1.0 and 5.0°C/min. Results: The melting point depression data was then used to calculate the F-H interaction parameter (χ) and extrapolated to lower temperatures to complete the liquid–solid transition curves. The theoretical binodal and spinodal curves were also constructed which were used to identify regions within the phase diagram. The effects of polymer selection, DSC heating rate, time above parent polymer Tg and polymer molecular weight were investigated by identifying amorphous drug miscibility limits at pharmaceutically relevant temperatures. Conclusion: The potential implications of these findings when applied to a non-ambient processing method such as Hot Melt Extrusion (HME) are also discussed.

Using Flory-Huggins phase diagrams as a pre-formulation tool for the production of amorphous solid dispersions; a comparison between hot-melt extrusion and spray drying

Objectives: Amorphous drug forms provide a useful method of enhancing the dissolution performance of poorly water-soluble drugs; however, they are inherently unstable. In this article, we have used Flory–Huggins theory to predict drug solubility and miscibility in polymer candidates, and used this information to compare spray drying and melt extrusion as processes to manufacture solid dispersions.
Method:  Solid dispersions were characterised using a combination of thermal (thermogravimetric analysis and differential scanning calorimetry) and spectroscopic (Fourier transform infrared spectroscopy (FTIR) and X-ray diffraction methods. 
Key Findings: Spray drying permitted generation of amorphous solid dispersions to be produced across a wider drug concentration than melt extrusion. Melt extrusion provided sufficient energy for more intimate mixing to be achieved between drug and polymer, which may improve physical stability. It was also confirmed that stronger drug–polymer interactions might be generated through melt extrusion. Remixing and dissolution of recrystallised felodipine into the polymeric matrices did occur during the modulated differential scanning calorimetry analysis, but the complementary information provided from FTIR confirms that all freshly prepared spray-dried samples were amorphous with the existence of amorphous drug domains within high drug-loaded samples. 
Conclusion: Using temperature–composition phase diagrams to probe the relevance of temperature and drug composition in specific polymer candidates facilitates polymer screening for the purpose of formulating solid dispersions.