Oral delivery strategies for the controlled release of cimetidine

It is advantageous to develop controlled release dosage forms utilising site-specific delivery or gastric retention for those drugs with frequent or high dosing regimes. Cimetidine is a potent and selective H2 -reception antagonist used in the treatment of various gastrointestinal disorders and localisation in the upper gastrointestinal tract could significantly improve the drug absorption. Three strategies were undertaken to prepare controlled release systems for the delivery of cimetidine to the GI tract. Firstly, increasing the contact time of the dosage form with the mucus layer which coats the gastrointestinal tract, may lead to increased gastric residence times. Mucoadhesive microspheres, by forming a gel-like structure in contact with the mucus, should prolong the contact between the delivery system and the mucus layer, and should have the potential for releasing the drug in sustained and controlled manner. Gelatin microspheres were prepared, optimised and characterised for their physicochemical properties. Crosslinking concentration, particle size and cimetidine loading influenced drug release profiles. Particle size was influenced by surfactant concentration and stirring speed. Mucoadheisve polymers such as alginates, chitosans, carbopols and polycarbophil were incorporated into the microspheres using different strategies. The mucoadhesion of the microspheres was determined using in vitro surface adsorption and ex vivo rat intestine models. The surface-modification strategy resulted in highest levels of microsphere adhesion, with chitosan, carbopols and polycarbophil as the most successful candidates for improvement of adhesion, with over 70% of the microspheres retained ex vivo. Specific targeting agent UEA I lectin was conjugated to the surface of gelatin microspheres, which enhanced the adhesion of the microspheres. Alginate raft systems containing antacids have been used extensively in the treatment of gastro-oesophageal disease and protection of the oesophageal mucosa from acid reflux by forming a viscous raft layer on the surface of the stomach content, and could be an effective delivery system for controlled release of cimetidine.

The controlled release of macromolecules from macroporous hydrophyllic polymer matrices

This work has used novel polymer design and fabrication technology to generate bead form polymer based systems, with variable, yet controlled release properties, specifically for the delivery of macromolecules, essentially peptides of therapeutic interest. The work involved investigation of the potential interaction between matrix ultrastructural morphology, in vitro release kinetics, bioactivity and immunoreactivity of selected macromolecules with limited hydrolytic stability, delivered from controlled release vehicles. The underlying principle involved photo-polymerisation of the monomer, hydroxyethyl methacrylate, around frozen ice crystals, leading to the production of a macroporous hydrophilic matrix. Bead form matrices were fabricated in controllable size ranges in the region of 100µm - 3mm in diameter. The initial stages of the project involved the study of how variables, delivery speed of the monomer and stirring speed of the non solvent, affectedthe formation of macroporous bead form matrices. From this an optimal bench system for bead production was developed. Careful selection of monomer, solvents, crosslinking agent and polymerisation conditions led to a variable but controllable distribution of pore sizes (0.5 - 4µm). Release of surrogate macromolecules, bovine serum albumin and FITC-linked dextrans, enabled factors relating to the size and solubility of the macromolecule on the rate of release to be studied. Incorporation of bioactive macromolecules allowed retained bioactivity to be determined (glucose oxidase and interleukin-2), whilst the release of insulin enabled determination of both bioactivity (using rat epididymal fat pad) and immunoreactivity (RIA). The work carried out has led to the generation of macroporous bead form matrices, fabricated from a tissue biocompatible hydrogel, capable of the sustained, controlled release of biologically active peptides, with potential use in the pharmaceutical and agrochemical industries.

The release of nitric oxide from S-nitrosothiols promotes angiogenesis

Free nitric oxide (NO) reacts with sulphydryl residues to form S-nitrosothiols, which act as NO reservoirs. We sought to determine whether thiol-preserving agents and antioxidants, such as dithiothreitol (DTT) and vitamin C, induce NO release from S-nitrosylated proteins in endothelial cell cultures to promote angiogenesis. NO release was measured directly in cell supernatants using a Sievers NO Analyser, and in vitro angiogenesis was assessed by quantifying capillary-like tube network formation of porcine aortic endothelial cells (PAEC) on growth factor-reduced Matrigel. Incubation of PAEC with DTT or vitamin C significantly increased NO release in a concentration-dependent manner. However, the nitric oxide synthase (NOS) inhibitors, L-NNA and L-NIO, had no effect on DTT- or vitamin C-induced NO release, and there was no concomitant increase in the phosphorylation of endothelial NOS at serine-1177 following DTT or vitamin C treatment. DTT and vitamin C increased capillary-like tube network formation by nine- and two-fold, respectively, and the addition of copper ions doubled the effect of vitamin C. Surprisingly, DTT maintained endothelial tube networks for up to one month under serum-free conditions, and selective inhibitors of guanylyl cyclase (ODQ) and PKG (KT-5823) blocked this, demonstrating the requirement of cyclic GMP and PKG in this process. Both DTT and vitamin C are capable of releasing sufficient NO from S-nitrosothiols to induce capillary morphogenesis. This study provides the first evidence that increased denitrosylation leads to increased bioavailability of NO, independent of NOS activity, to promote sustained angiogenesis.

Microporous polycaprolactone matrices for drug delivery and tissue engineering:the release behaviour of bioactives having extremes of aqueous solubility

Microporous polycaprolactone (PCL) matrices loaded with hydrophobic steroidal drugs or a hydrophilic drug - pilocarpine hydrochloride - were produced by precipitation casting using solutions of PCL in acetone. The efficiency of steroid incorporation in the final matrix (progesterone (56 %) testosterone (46 %) dexamethasone (80 %)) depended on the nature of the drug initially co-dissolved in the PCL solution. Approximately 90 % w/w of the initial load of progesterone, 85 % testosterone and 50 % dexamethasone was released from the matrices in PBS at 37°C over 8 days. Pilocarpine hydrochloride (PH)-loaded PCL matrices, prepared by dispersion of powder in PCL solution, released 70-90 % of the PH content over 12 days in PBS. Application of the Higuchi model revealed that the kinetics of steroid and PH release were consistent with a Fickian diffusion mechanism with corresponding diffusion coefficients of 5.8 × 10-9 (progesterone), 3.9 × 10 -9 (testosterone), 7.1 × 10-10 (dexamethasone) and 22 × 10-8 cm2/s (pilocarpine hydrochloride). The formulation techniques described are expected to be useful for production of implantable, insertable and topical devices for sustained delivery of a range of bioactive molecules of interest in drug delivery and tissue engineering.

Scaffolds for controlled release of cartilage growth factors

International audience

Comparison of ultrafine particle release from hardcopy devices in emission test chambers and office rooms

The release of ultrafine particles (UFP) from laser printers and office equipment was analyzed using a particle counter (FMPS; Fast Mobility Particle Sizer) with a high time resolution, as well as the appropriate mathematical models. Measurements were carried out in a 1 m³ chamber, a 24 m³ chamber and an office. The time-dependent emission rates were calculated for these environments using a deconvolution model, after which the total amount of emitted particles was calculated. The total amounts of released particles were found to be independent of the environmental parameters and therefore, in principle, they were appropriate for the comparison of different printers. On the basis of the time-dependent emission rates, “initial burst” emitters and constant emitters could also be distinguished. In the case of an “initial burst” emitter, the comparison to other devices is generally affected by strong variations between individual measurements. When conducting exposure assessments for UFP in an office, the spatial distribution of the particles also had to be considered. In this work, the spatial distribution was predicted on a case by case basis, using CFD simulation.

Test of the enemy release hypothesis: the native magpie moth prefers a native fireweed (Senecio pinnatifolius) to its introduced congener (S.Madagascariensis)

Abstract The enemy release hypothesis predicts that native herbivores will either prefer or cause more damage to native than introduced plant species. We tested this using preference and performance experiments in the laboratory and surveys of leaf damage caused by the magpie moth Nyctemera amica on a co-occuring native and introduced species of fireweed (Senecio) in eastern Australia. In the laboratory, ovipositing females and feeding larvae preferred the native S. pinnatifolius over the introduced S. madagascariensis. Larvae performed equally well on foliage of S. pinnatifolius and S. madagascariensis: pupal weights did not differ between insects reared on the two species, but growth rates were significantly faster on S. pinnatifolius. In the field, foliage damage was significantly greater on native S. pinnatifolius than introduced S. madagascariensis. These results support the enemy release hypothesis, and suggest that the failure of native consumers to switch to introduced species contributes to their invasive success. Both plant species experienced reduced, rather than increased, levels of herbivory when growing in mixed populations, as opposed to pure stands in the field; thus, there was no evidence that apparent competition occurred.

Transforming Queensland VET : Challenges and Opportunities (Volume 1)

The volume is a collection of papers that address issues associated with change in the delivery of VET programs in Queensland, foreshadowed by the release of The Queensland Skill Plan in 2006. Issues that relate to the implementation of the Actions identified in the Queensland Skills Plan are the focus of the collection. In particular, the incorporation of Information Communication Technologies (ICTs) and e-learning approaches in the delivery of training packages is a key topic, how such change can be managed in the delivery of training programs, as well as broader professional development issues for VET practitioners. Change at an organisational level is the focus of two papers. Lyn Ambrose uses ideas from Diffusion of Innovations Theory to consider how the adoption eLearning in a TAFE community can be addressed. The paper by Susan Todhunter also discusses the organisational challenges in change initiatives in TAFE Institutes. Specific issues related to in the professional development of VET teachers are the focus of the papers by Mary Campbell, Sharon Altena, and Judy Gronold. Mary Campbell discusses the importance of building staff capabilities within the TAFE system and how this might be managed. Sharon Altena considers how professional development programs are currently delivered and how new approaches to professional development for TAFE teachers are needed to ensure changes can be sustained in teaching practice. The paper by Judy Gronold takes up a specific challenge for VET practitioners in the Queensland Skills Plan. She addresses issues related to embedding employability skills into training delivery in order to address industries’ need for flexible, multi-skilled productive workers. Mark Driver discusses the issues resulting from increased number of mature-aged learners in VET programs and how this change in the demographic profile of students presents challenges to the VET system. In the paper by David McKee, implications in the incorporation of ICTs into trade training are discussed and the need for effective change management strategies to ensure a smooth transition to new ways of delivering trade training. Finally, in the paper by David Roberts, the potential of Problem-Based Learning (PBL) approaches in VET training and the role of ICTs within such approaches are discussed. David uses horticulture training as an example to discuss the issues in implementing PBL effectively in VET programs. These papers were completed by the authors as a part of their postgraduate studies at QUT. The views reported are those of the authors and should not be attributed to the Queensland Department of Education, Training and the Arts.

Can students with low vision maintain sustained reading rates?

Purpose: Students with low vision may be disadvantaged when compared with their normally sighted peers, as they frequently work at very short working distances and need to use low vision devices. The aim of this study was to examine the sustained reading rates of students with low vision and compare them with their peers with normal vision. The effects of visual acuity, acuity reserve and age on reading rate were also examined. Method: Fifty-six students (10 to 16 years of age), 26 with low vision and 30 with normal vision were required to read text continuously for 30 minutes. Their position in the text was recorded at two-minute intervals. Distance and near visual acuity, working distance, cause of low vision, reading rates and reading habits were recorded. Results: A total of 80.7 per cent of the students with low vision maintained a constant reading rate during the 30 minutes of reading, although they read at approximately half the rate (104 wpm) compared with their normally sighted peers (195 wpm). Only four of the low vision subjects could not complete the reading task. Reading rates increased significantly with acuity reserve and distance and near visual acuity but there was no significant relationship between age and sustained reading rate. Conclusions: The majority of students with low vision were able to maintain appropriate reading rates to cope in integrated educational settings. Surprisingly only relatively few subjects (16 per cent) used their prescribed low vision devices even though the average accommodative demand was 9 D and generally, they revealed a greater dislike of reading compared to students with normal vision.

Sex on premises venue (SOPV) health promotion project in response to sustained increases in HIV notifications

Background: Due to increases in HIV notifications in Queensland, a health promotion outreach project was developed with sex on premises venues (SOPV) in Brisbane. Methods: A health promotion officer (HPO) promoted safer sex behaviours among SOPV patrons over 14 months, including providing information, counselling and skills to enhance safer sexual behaviours and providing referrals. Surveys were introduced to facilitate discussions regarding HIV/sexually transmissible infections, testing and safer sex practices. Results: The project demonstrated feasibility within this highly sexualised environment, and was enhanced by careful monitoring and revising the procedure to improve patron/staff responses to the project. The introduction of a survey instrument was a significant contributor to the project’s effectiveness, providing opportunities for patrons to discuss a variety of key sexual health issues. Conclusions: This initiative reflected effective partnering between the Health Department, a community HIV/lesbian, gay, bisexual and transgender organisation and private industry. Despite initial difficulties, the presence of a health worker within an SOPV was acceptable to patrons and allowed for brief interventions to be conducted. This project was deemed effective for a limited time period and within certain constraints.