Characterization of the Rheological, Mucoadhesive, and Drug Release Properties of Highly Structured Gel Platforms for Intravaginal Drug Delivery

This investigation describes the formulation and characterization of theologically structured vehicles (RSVs) designed for improved drug delivery to the vagina. Interactive, multicomponent, polymeric platforms were manufactured containing hydroxyethylcellulose (HEC, 5% w/w) polyvinylpyrrolidone (PVP, 4% w/w), Pluronic (PL, 0 or 10% w/w), and either polycarbophil (PC, 3% w/w) or poly(methylvinylether-co-maleic anhydride) (Gantrez S97, 3% w/w) as a mucoadhesive agent. The rheological (torsional and dynamic), mechanical (compressional), and mucoadhesive properties were characterized and shown to be dependent upon the mucoadhesive agent used and the inclusion/exclusion of PL. The dynamic theological properties of the gel platforms were also assessed following dilution with simulated vaginal fluid (to mimic in vivo dilution). RSVs containing PC were more rheologically structured than comparator formulations containing GAN. This trend was also reflected in formulation hardness, compressibility, consistency, and syringeability. Moreover, formulations containing PL (10% w/w) were more theologically structured than formulations devoid of PL. Dilution with simulated vaginal fluids significantly decreased rheological structure, although RSVs still retained a highly elastic stnicture (G' > G '' and tan delta <1). Furthermore, RSVs exhibited sustained drug release properties that were shown to be dependent upon their rheological structure. It is considered that these semisolid drug delivery systems may be useful as site-retentive platforms for the sustained delivery of therapeutic agents to the vagina.

‘Risk, Politics and the ‘Scientification’ of Political Judgement: Prisoner Release and Conflict Transformation in Northern Ireland’

Drawing on research in Northern Ireland into the process of release under the Belfast/Good Friday Agreement, this article explores the identification and classification of risk in relation to prisoners released early under the Sentences (NI) Act. The main argument is that conflict, post-conflict and transitional conditions expose more starkly the political underpinnings of risk-management strategy and the article demonstrates the particular variant of Politicized Risk Assessment (PRA) recently used in the release of prisoners in Northern Ireland

Granular fertilizer drying and agglomeration in storage

In the manufacture of granular NPK fertilizer the product is cooled before packaging and storage in moisture-proof bags. It has been shown that the temperature of the fertilizer prior to packing is significant in that at high temperatures, drying of the granules takes place in the bag which causes an increase in the humidity of the air surrounding the granules and thus an increase in moisture content at the granule - granule interface. This surface moisture was shown to increase the likelihood of agglomeration in the fertilizer by a capillary adhesion/unconfined yield stress model. An iterative model was set up to establish conditions that would prevent drying occurring, which takes into account fertilizer drying rate, fertilizer cooling rate cooling rate and the effect of coating oils on the drying mechanism.

Mast cell mediator release in nonasthmatic subjects after endobronchial adenosine challenge

Background: Adenosine 5′-monophosphate (AMP) has been shown to cause bronchoconstriction in atopic subjects but to have no effect on nonatopic nonasthmatic subjects. Endobronchial AMP challenge has previously been shown to cause mast cell mediator release in asthmatic subjects, but it is unknown whether a similar response occurs in atopic nonasthmatic and nonatopic nonasthmatic control subjects who have no response to inhalation AMP challenge.

Objective: This study examined the change in mast cell–derived products after endobronchial saline challenge and AMP challenge in subjects with and without a positive inhalation response to AMP.

Methods: Inhalation challenge with AMP challenge was performed in normal, atopic nonasthmatic, and atopic asthmatic subjects. Levels of mast cell mediators were measured after endobronchial adenosine challenge and after placebo endobronchial saline challenge.

Results: There were significant increases in histamine, tryptase, protein, and prostaglandin D2 levels (P = .02, P = .02, P = .01, and P = .01, respectively) after AMP challenge compared with after saline challenge in nonatopic nonasthmatic subjects. There was no significant increase in any mediator in either of the other 2 groups.

Conclusion: This study suggests dissociation between mediator release and bronchoconstriction in response to AMP.

A two compartment in vitro release model for the testing of HIV microbicide formulations

BACKGROUND: In vitro release testing of vaginal formulations is usually performed in a one-compartment model (OCM) where the release medium, usually comprising pH-adjusted water, an aqueous surfactant solution or a solvent-water solution, provides sink conditions throughout the release experiment. Although this model is useful in evaluating the effect of formulation parameters upon release, it rarely reflects in vivo conditions. Here we report use of a two-compartment diffusion cell model (TCM, comprising a small volume donor, a large volume receptor, and separated by a model epithelial membrane) to more closely mimic in vivo vaginal release and tissue absorption following administration of a UC781 vaginal ring.

METHODS: Macaque-sized matrix silicone elastomer vaginal rings containing 100mg UC781 were prepared by injection molding, and in vitro release testing performed using both OCM (20mL simulated vaginal fluid, SVF) and TCM (5mL SVF in donor cell and variable quantities of Tween 80; silicone elastomer membrane; 100mL 3:2 ethanol/water in receptor cell). In the TCM, drug levels were measured by HPLC in both donor and receptor cells, representing fluid and tissue levels respectively. Rings containing 100mg UC781 and 10% w/w Tween 80 were also manufactured and tested.

RESULTS: The amount of UC781 released from rings was significantly influenced by the choice of release model. Greatest release (56mg/14 days) was measured in the ethanol/water OCM, compared with no measurable release into SVF only. Increasing the concentration of Tween 80 in the SVF medium (1, 3 and 5% w/w) led to increased UC781 release (11, 16 and 18mg, respectively), demonstrating that vaginal fluid solubility of UC781 may be rate-determining in vivo. In the TCM, UC781 accumulates in the receptor cell medium over time, despite not being measured in the donor medium containing the ring device. Incorporation of Tween 80 directly into the ring provided enhanced release in both donor and receptor cells.

CONCLUSIONS: Release of UC781 was influenced by the choice of release medium and the inclusion of Tween 80 in the ring. Although use of SVF-only in the OCM indicated no measurable UC781 release from rings, data from the TCM confirms that UC781 is not only released but is also capable of penetrating across the model epithelial membrane. The TCM may therefore provide a more representative in vitro release model for mimicking in vivo absorption.