Polymeric Materials for Controlled Ophthalmic Drug Delivery

Proliferative vitreoretinopathy, a potentially blinding condition, involves excessive proliferation of retinal pigment epithelium (RPE) cells and is the main complication following retinal detachment (RD). Complicated cases of RD are treated with silicone oil (SiO) tamponades which can potentially be used as drug reservoirs. The aim of this study was to investigate different methodologies to develop a sustained and controlled drug release of anti-proliferative and anti inflammatory drugs from SiO tamponades using all-trans retinoic acid (atRA) and ibuprofen (Ibu). In detailed studies of atRA and Ibu, including atRA degradation behaviour, the drugs were found to be non-toxic to an adult RPE cell line (ARPE 19) below 10-5 M. The solubility of both drugs in SiO was assessed using radioisotope techniques. Prodrugs of atRA and Ibu were synthesised via conjugation to polyethylene oxide (PEO), and cleavage of the resulting ester bond, toxicity towards RPE cells, solubility in SiO and release into media were assessed. Prodrug cleavage was successful in vitro for Ibu but not achieved in the case of atRA due to its highly conjugated nature. Cytotoxicity assays showed PEO attachment had no effect on cytotoxicity and PEO prodrug solubility in SiO followed the expected trend of decreasing solubility with increased PEO chain length. Overall the saturation concentration of drug in SiO achieved through the use of PEO-prodrugs was too low for an effective therapy. Lipophilic prodrugs with a poly(dimethylsiloxane) (PDMS) pro-moiety were synthesised and investigated. Their cleavage was problematic due to PDMS being highly hydrophobic and cleavage could only be achieved in vitro when a small hydrophilic spacer was added between PDMS and the drug. The effects of PDMS prodrugs as additives in SiO were investigated and the presence of PDMS-atRA in SiO was shown to have a positive effect on both atRA solubility and longevity of release. The clinically-relevant release period (6-8 weeks) was independent of atRA starting concentration but dependant on the PDMS-atRA concentration within the blend. This has potential for further development into tamponade drug reservoirs for future patient benefits. A series of linear and branched amphiphilic copolymer architectures were also evaluated as additives for SiO. Monomer selection included oligoethylene oxide methacrylate (OEGMA), 2-hydroxyethyl methacrylate, PDMS-methacrylate (PDMSMA) and the brancher PDMS-dimethacrylate (PDMSDMA). SiO solubility of p(OEGMA-co-PDMSDMA) was investigated and copolymers which contained the smallest hydrophilic and largest lipophilic components only achieved small solubility (0.1 % v/v). To overcome these solubility issues, hydrophobic PDMSMA monomer was utilised. Both linear p(PDMSMA-co-OEGMA) and branched p(PDMSMA-co-OEGMA-co-PDMSDMA) were successfully synthesised and displayed high solubility within SiO, up to 40-50 % v/v. The potential for SiO tamponades as long-acting drug reservoirs has been demonstrated after inclusion of a novel end-modified PDMS additive leading to long term release of atRA. The formation of novel polymer architectures that show considerable miscibility with SiO also shows the scope of the opportunity for further additive development to tailor release profiles

Adherence to anti-retroviral therapy among HIV patients in Bangalore, India

<p>Abstract</p> <p>Introduction</p> <p><it>Human Immunodeficiency Virus </it>(HIV) has an estimated prevalence of 0.9% in India (5.2 million). Anti-retroviral drugs (ARV) are the treatments of choice and non-adherence is an important factor in treatment failure and development of resistance, as well as being a powerful predictor of survival. This study assesses adherence to ARV in HIV positive patients in Bangalore, India, a country where only 10% of those who need therapy are receiving it.</p> <p>Methods</p> <p>A cross-sectional anonymous questionnaire survey of 60 HIV antibody positive patients was carried out with patients attending HIV outpatient services at two centres: The Chest and Maternity Centre, Rajajinagar, and Wockhardt Hospital and Heart Institute, Bangalore. Consent was obtained. Translation was done by a translator and doctors where required. Data was analysed using SPSS statistical analysis.</p> <p>Results</p> <p>A response rate of 88% (53/60) was achieved. The mean patient age was 39.98 years, with 50% aged 30–40, and 73.6% of participants being male. Mean family size was 4.8 (1–13). 21% lived less than 50 kms and 21% greater than 400 kms from clinic.</p> <p>60% reported they were fully adherent. Adherence was statistically significantly linked to regular follow-up attendance (70.5%, p = 0.002). No other results were statistically significant but trends were found. "100% adherence" trends were seen in older patients, male gender, those from larger families, those who had a previous AIDS defining illness, those taking fewer tablets, and without food restrictions. Commonest side-effects causing non-adherence were metabolic reasons (66%) and GI symptoms (50%). No trends were seen for education level, family income, distance travelled to clinic, time since diagnosis, or time on ART.</p> <p>Conclusion</p> <p>Regular attendance for follow up was statistically significant for 100% lifetime adherence. Positive trends were seen in those in larger families, older, those who had AIDS defining illness, simple regimes, and without side-effects. Education, income, distance travelled and length of time diagnosed or treated had no effect on adherence.</p

Mucus-responsive functionalized emulsions: design, synthesis and study of novel branched polymers as functional emulsifiers

Mucus lines the moist cavities throughout the body, acting as barrier by protecting the underlying cells against the external environment, but it also hinders the permeation of drugs and drug delivery systems. As the rate of diffusion is low, the development of a system which could increase retention time at the mucosal surface would prove beneficial. Here, we have designed a range of branched copolymers to act as functional mucus-responsive oil-in-water emulsifiers comprising the hydrophilic monomer oligo(ethylene glycol) methacrylate and a hydrophobic dodecyl initiator. The study aimed to investigate the importance of chain end functionality on successful emulsion formation, by systematically replacing a fraction of the hydrophobic chain ends with a secondary poly(ethylene glycol) based hydrophilic initiator in a mixed-initiation strategy; a decrease of up to 75 mole percent of hydrophobic chain ends within the branched polymer emulsifiers was shown to maintain comparative emulsion stability. These redundant chain ends allowed for functionality to be incorporated into the polymers via a xanthate based initiator containing a masked thiol group; thiol groups are known to have mucoadhesive character, due to their ability to form disulfide bonds with the cysteine rich areas of mucus. The mucoadhesive nature of emulsions stabilised by thiol-containing branched copolymers was compared to non-functional emulsions in the presence of a biosimilar mucosal substrate and enhanced adherence to the mucosal surface was observed. Importantly, droplet rupture and mucus triggered release of dye-containing oil was seen from previously highly-stable thiol-functional emulsions; this observation was not mirrored by non-functional emulsions where droplet integrity was maintained even in the presence of mucus

Sustained-release drug delivery systems

AbstractThe design and development of a sustained-release drug delivery system targeting the administration of active pharmaceutical ingredients (APIs) to the eye could overcome the limitations of topically administered eye drops. Understanding how to modify or design new materials with specific functional properties that promote the attachment and release of specific drugs over longer time periods, alongside understanding clinical needs, can lead to new strategic opportunities to improve treatment options. In this paper we discuss two approaches to the design or modification of materials to produce a sustained therapeutic effect. Firstly, we discuss how the synthesis of a peptide hydrogel from a naturally-derived antimicrobial material led to the design of a bandage contact lens which may be able to be used prophylactically to reduce post-surgery infection. Secondly, we discuss how silicone oil tamponade agents used to treat retinal detachments can have adjunctive behaviour to enhance the solubility of the anti-proliferative drug retinoic acid and produce a sustained release over several weeks. These studies are the result of close partnerships between clinical ophthalmologists, materials scientists, and chemists, and illustrate how these partnerships can lead to comprehensive understandings that have the potential to change patient outcomes.</jats:p

Ex vivo transdermal delivery of 3H-labelled atovaquone solid drug nanoparticles: a comparison of topical, intradermal injection and microneedle assisted administration

Ex vivo transdermal permeation and deposition of atovaquone solid drug nanoparticles. Topical administration exhibited limited penetration, intradermal injection delivered a burst release and the microneedle assisted route offered sustained delivery.</jats:p