Optimal protection of stabilised dry live bacteria from bile toxicity in oral dosage forms by bile acid adsorbent resins

We previously found that dried live bacteria of a vaccine strain can be temporarily sensitive to bile acids and suggested that Bile Adsorbing Resins (BAR) can be used in oral vaccine tablets to protect dried bacteria from intestinal bile. Here, we report a quantitative analysis of the ability of BAR to exclude the dye bromophenol blue from penetrating into matrix tablets and also sections of hard capsule shells. Based on this quantitative analysis, we made a fully optimised formulation, comprising 25% w/w of cholestyramine in Vcaps™ HPMC capsules. This gave effectively 100% protection of viability from 4% bile, with 4200-fold more live bacteria recovered from this formulation compared to unprotected dry bacteria. From the image analysis, we found that the filler material or compaction force used had no measurable effect on dye exclusion but did affect the rate of tablet hydration. Increasing the mass fraction of BAR gave more exclusion of dye up to 25% w/w, after which a plateau was reached and no further dye exclusion was seen. More effective dye exclusion was seen with smaller particle sizes (i.e. cholestyramine) and when the BAR was thoroughly dried and disaggregated. Similar results were found when imaging dye penetration into capsule sections or tablets. The predictions of the dye penetration study were tested using capsules filled with dried attenuated Salmonella vaccine plus different BAR types, and the expected protection from bile was found, validating the imaging study. Surprisingly, depending on the capsule shell material, some protection was given by the capsule alone without adding BAR, with Vcaps™ HPMC capsules providing up to 174-fold protection against 1% bile; faster releasing Vcaps Plus™ HPMC capsules and Coni Snap™ gelatin capsules gave less protection

Hydroxypropyl Methylcellulose as a Novel Tool for Isothermal Solution Crystallization of Micronized Paracetamol

This document is the Accepted Manuscript version of a Published Work that appeared in final form in Crystal Growth and Design, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see: http://pubs.acs.org/doi/abs/10.1021/cg4009637Pulmonary inhalation is increasingly being selected as a preferred route for the delivery of both small and large drug macromolecules for the treatment of a range of pathologies. The direct crystallization of micronized powders, in particular, paracetamol, remains difficult, as it requires the ability to work in high solution supersaturations where agglomeration, wall crusting, and heterogeneous nucleation hinder the control of crystal size and crystal size distribution. Polymer additives are recognized to help drive the production of a given polymorph or controlling crystal shape by means of adsorption on the crystal surface. With the aim of exploiting the polymer-control nucleation and growth of crystals for enhanced direct crystallization of micronized powders, batch cooling crystallization of paracetamol in water was carried out in the presence of 0.1-0.8% w/w hydroxypropyl methylcellulose (HPMC). In the presence of polymer, the onset of nucleation was delayed and extended beyond the cooling time of the solution, resulting in an isothermal cooling crystallization and the production of micronized paracetamol with a mean crystal size D50, in the range of 15-20 μm and an improved crystal size distribution. Equally, the rate generation of solution cloudiness was reduced by over 3-fold for the highest HPMC concentration tested, with no detectable impact on final product yield. The mechanisms for nucleation delay and growth inhibition by HPMC is unknown; however, a modification of crystals shape observed upon the addition of HPMC to the solution suggested it might be related to mass transfer limitations and intermolecular hydrogen bonding between the large HPMC and the small drug molecules. This technique can potentially be used for direct crystallization of other micronized drugs. © 2014 American Chemical Society

Hydroxypropyl Methylcellulose as a Novel Tool for Isothermal Solution Crystallization of Micronized Paracetamol

Pulmonary inhalation is increasingly being selected as a preferred route for the delivery of both small and large drug macromolecules for the treatment of a range of pathologies. The direct crystallization of micronized powders, in particular, paracetamol, remains difficult, as it requires the ability to work in high solution supersaturations where agglomeration, wall crusting, and heterogeneous nucleation hinder the control of crystal size and crystal size distribution. Polymer additives are recognized to help drive the production of a given polymorph or controlling crystal shape by means of adsorption on the crystal surface. With the aim of exploiting the polymer-control nucleation and growth of crystals for enhanced direct crystallization of micronized powders, batch cooling crystallization of paracetamol in water was carried out in the presence of 0.1–0.8% w/w hydroxypropyl methylcellulose (HPMC). In the presence of polymer, the onset of nucleation was delayed and extended beyond the cooling time of the solution, resulting in an isothermal cooling crystallization and the production of micronized paracetamol with a mean crystal size <i>D</i>₅₀, in the range of 15–20 μm and an improved crystal size distribution. Equally, the rate generation of solution cloudiness was reduced by over 3-fold for the highest HPMC concentration tested, with no detectable impact on final product yield. The mechanisms for nucleation delay and growth inhibition by HPMC is unknown; however, a modification of crystal’s shape observed upon the addition of HPMC to the solution suggested it might be related to mass transfer limitations and intermolecular hydrogen bonding between the large HPMC and the small drug molecules. This technique can potentially be used for direct crystallization of other micronized drugs

Thermal annealed silk fibroin membranes for periodontal guided tissue regeneration

Guided tissue regeneration (GTR) is a surgical procedure applied in the reconstruction of periodontal defects, where an occlusive membrane is used to prevent the fast-growing connective tissue from migrating into the defect. In this work, silk fibroin (SF) membranes were developed for periodontal guided tissue regeneration. Solutions of SF with glycerol (GLY) or polyvinyl alcohol (PVA) where prepared at several weight ratios up to 30%, followed by solvent casting and thermal annealing at 85 °C for periods of 6 and 12 h to produce high flexible and stable membranes. These were characterized in terms of their morphology, physical integrity, chemical structure, mechanical and thermal properties, swelling capability and in vitro degradation behavior. The developed blended membranes exhibited high ductility, which is particular relevant considering the need for physical handling and adaptability to the defect. Moreover, the membranes were cultured with human periodontal ligament fibroblast cells (hPDLs) up to 7 days. Also, the higher hydrophilicity and consequent in vitro proteolytic degradability of these blends was superior to pure silk fibroin membranes. In particular SF/GLY blends demonstrated to support high cell adhesion and viability with an adequate hPDLs’ morphology, make them excellent candidates for applications in periodontal regeneration.info:eu-repo/semantics/publishedVersio

Characterisation of microbial attack on archaeological bone

As part of an EU funded project to investigate the factors influencing bone preservation in the archaeological record, more than 250 bones from 41 archaeological sites in five countries spanning four climatic regions were studied for diagenetic alteration. Sites were selected to cover a range of environmental conditions and archaeological contexts. Microscopic and physical (mercury intrusion porosimetry) analyses of these bones revealed that the majority (68%) had suffered microbial attack. Furthermore, significant differences were found between animal and human bone in both the state of preservation and the type of microbial attack present. These differences in preservation might result from differences in early taphonomy of the bones. © 2003 Elsevier Science Ltd. All rights reserved