Models and methods to characterise levonorgestrel release from intradermally administered contraceptives

Microneedle (MN)-based technologies have been proposed as a means to facilitate minimally invasive sustained delivery of long-acting hormonal contraceptives into the skin. Intradermal administration is a new route of delivery for these contraceptives and therefore no established laboratory methods or experimental models are available to predict dermal drug release and pharmacokinetics from candidate MN formulations. This study evaluates an in vitro release (IVR) medium and a medium supplemented with ex vivo human skin homogenate (SH) as potential laboratory models to investigate the dermal release characteristics of one such hormonal contraceptive that is being tested for MN delivery, levonorgestrel (LNG), and provides details of an accompanying novel two-step liquid–liquid drug extraction procedure and sensitive reversed-phase HPLC–UV assay. The extraction efficiency of LNG was 91.7 ± 3.06% from IVR medium and 84.6 ± 1.6% from the medium supplemented with SH. The HPLC–UV methodology had a limit of quantification of 0.005 µg/mL and linearity between 0.005 and 25 µg/mL. Extraction and detection methods for LNG were exemplified in both models using the well-characterised, commercially available sustained-release implant (Jadelle®). Sustained LNG release from the implant was detected in both media over 28 days. This study reports for the first time the use of biologically relevant release models and a rapid, reliable and sensitive methodology to determine release characteristics of LNG from intradermally administered long-acting drug delivery systems

Embeddable sustained-release microneedles for intradermal contraceptive delivery

There is still an emerging need for effective, accessible and convenient contraception methods, particularly in low resource countries. About 923 million (> 50%) of reproductive-aged women living in low- and middle-income countries attempted to prevent pregnancy in 2019, however, 218 million among them did not have access to any form of modern contraceptives. Providing women of reproductive age with access to family planning services is a fundamental human right and allows them to decide freely on whether and when they want to have children, and how many children they have. Addressing this unmet need would reduce the incidence of unintended pregnancies and improve maternal and child health. Commercially-available long-acting reversible contraceptives (LARCs), such as subcutaneous implants (up to 5-7 years activity) and intramuscular injectables (3 months activity), maintain controlled daily release of hormones; thus, offer improved user compliance and convenience. They require however painful invasive administration and, in the case of implants, removal, typically by skilled healthcare professionals and generate biohazardous sharps waste. Microneedles are micron-scaled projections designed to puncture the uppermost layer of skin, stratum corneum, to facilitate transdermal or intradermal delivery of therapeutics into the cutaneous compartment, in a painless and blood-free manner. This thesis aims to develop an alternative method of contraception whereby the contraceptive is delivered into skin using microneedles which slowly degrade to provide 6-months contraceptive activity. Two biodegradable microneedle designs were manufactured by academic and industrial project partners. Candidate polymer formulations for the biodegradable microneedles were loaded with a synthetic progestin, levonorgestrel, and characterised for drug release kinetics. These studies were performed in conventional drug release media and a novel media supplemented with human skin homogenate. The use of these media, accompanied by sensitive and selective drug extraction and analytical protocols, enabled the characterisation of levonorgestrel release in a more biologically relevant environment. Sustained release kinetics of levonorgestrel were achieved from different biodegradable formulations in both media over a period of up to 9 months. The skin insertion performance of polymer only and levonorgestrel loaded biodegradable microneedles was assessed using human and porcine skin explants. In these studies, MN deployment was facilitated using several prototype applicator devices. Skin puncture experiments in ex vivo skin demonstrated that microneedles had sufficient tip sharpness and mechanical robustness to penetrate the skin surface. Microneedle performance varied between the polymer only and levonorgestrel loaded microneedles, with the microneedle composition and design, as well as the applicator mechanism, playing a key role in determining their efficiency. In conclusion, this thesis explored two novel designs of biodegradable polymer MNs to address the unmet need for contraception in low resource countries. The MN systems developed in this project hold great promise for sustained intradermal delivery of contraceptives for 6-months activity. This could provide an intermediate option to existing LARCs which have shorter, e.g. 3 months (intramuscular injections), or longer, e.g. 5-7 years (hormonal subcutaneous implants and intrauterine systems) duration of action. This MN-mediated contraceptive approach is also anticipated to improve user acceptability and compliance

Antimicrobial release from a lipid bilayer titanium implant coating is triggered by Staphylococcus aureus alpha-haemolysin

Infections represent a significant challenge in joint replacements, often leading to the need for high-risk revision surgeries. There is an unmet need for novel technologies that are triggered by pathogens to prevent long-term joint replacement infections. The use of supported lipid bilayers (SLBs) with encapsulated antimicrobial agents, which are responsive to bacterial virulence factors, offers an exciting approach to achieving this goal. In this study, Ti was functionalised using octadecylphosphonic acid (ODPA) to form an SLB with an encapsulated antibiotic (novobiocin), effective against methicillin-resistant Staphylococcus aureus. Using the solvent-assisted method, the SLB with encapsulated novobiocin was developed on the surface of ODPA-modified Ti quartz crystal microbalance (QCM) sensors. QCM monitoring and fluorescence microscopy supported the successful formation of a planar SLB with encapsulated novobiocin. Incorporation of novobiocin in the SLB resulted in significantly reduced attachment and viability of S. aureus NCTC 7791, with no significant reduction in human bone marrow stromal cell viability. Additionally, in the presence of varying concentrations of α-haemolysin, a virulence factor from S. aureus, the SLB demonstrated a dose-dependent release pattern. The findings indicate the possibility of creating a biocompatible implant coating that releases an antimicrobial in the presence of a bacterial virulence factor, in a dose-dependent manner

Effect of non-cross-linked calcium on characteristics, swelling behaviour, drug release and mucoadhesiveness of calcium alginate beads

In this study, ibuprofen-loaded calcium alginate beads (CABs) with varying amounts of non-cross-linked calcium (NCL-Ca) were prepared using different washing methods. The influence of NCL-Ca on beads properties was investigated. Increasing the number or duration of washes led to significant decreases in the amount of NCL-Ca whereas the impact of the volume of washes was not significant. Approximately 70% of the initial amount of Ca(2+) was NCL-Ca which was removable by washing while only 30% was cross-linked (CL-Ca). Ca(2+) release from the CABs was bimodal; NCL-Ca was burst-released followed by a slower release of CL-Ca. Washing methods and the amount of NCL-Ca had significant influences on the encapsulation efficiency, beads weight, beads swelling, drug release profile and the mucoadhesiveness of CABs. This study highlighted the importance of washing methods and the amount of NCL-Ca to establish CABs properties and understand their behaviour in the simulated intestinal fluids (SIFs)