Design, development and optimisation of veterinary intravaginal controlled release drug delivery systems

摘要

This Thesis begins by discussing the application of controlled drug delivery to the intravaginal delivery of hormones to control the oestrous cycle of farmed animals, with particular emphasis on the delivery of progestagens to cattle and sheep. The introduction highlights the recent advances made by animal physiologists in their knowledge of the oestrous cycle in cattle and sheep and how these advances have impacted upon the manner in which currently available intravaginal controlled release products are used. In addition it discusses the advances pharmaceutical scientists have made in response to the new knowledge.The CIDR®1900 Cattle insert is a commercially available silicone based intravaginal delivery system containing the natural steroid progesterone for fertility regulation in cattle. It was designed in 1987 to be inserted for 12 days. Advances made in oestrous cycle understanding by animal scientists have resulted in this product being inserted for much shorter treatment periods of 7 days. Rathbone et al. recently optimised the CIDR®1900 Cattle insert for seven day insertion periods. The outcome of these scientists work was a manufactured prototype which, when compared to the CIDR®1900 Cattle insert, contained a reduced initial drug load and a much lower residual drug load after use. For commercial production the prototype insert needed to be scaled up. This process required detailed pharmaceutical characterisation, invitro release assessment, invivo bioequivalency and chemical and physical stability studies to be performed on the scaled up product (CIDR®1380 Cattle insert) to ensure the success of the scale up process. This characterisation process forms Chapters Two and Three of this Thesis.Knowledge of the mechanism of release of a drug from a pharmaceutical product provides the formulation scientist with the necessary insight to optimise, further develop or recognise the potential and limitations of a product. Chapter Four explores the mechanism of release of progesterone from the silicone based CIDR® Cattle insert both invitro and invivo. Cumulative release data from both invitro and invivo studies were fitted against conventional mathematical models to determine the mechanism of release of progesterone from the CIDR® Cattle insert. In addition, an experimental method was developed to assess the validity of the models. The method involved taking thin consecutive horizontal slices from the surface of CIDR® Cattle inserts after various periods of release. Cumulative release of progesterone, both invitro and invivo, was linear when plotted against the square root of time, suggesting that release from the CIDR® Cattle insert occurred in accordance with the square root of time mechanism. However, experimental evidence from the horizontal slicing technique only supported the curve fitting evidence for invitro release. When the insert was investigated invivo, the slicing method indicated that a novel release mechanism was in operation which was better described by a zero order process.Chapters Five and Six of this Thesis direct their focus to oestrus control in sheep. Chapter Five utilises information gained from both Rathbone et al. and the work performed in this Thesis on the CIDR® Cattle insert to characterise and optimise the commercially available sheep equivalent of the CIDR ® 1900 Cattle insert (known as the CIDR® Sheep and Goat insert). The Chapter successfully characterises the CIDR® Sheep and Goat insert, defines the parameters of, and tests, an optimised version of this sheep product.The final Chapter of this Thesis investigates the use of poly-(ε-caprolactone) as a platform for the intravaginal delivery of progesterone to control oestrus in sheep. Silicone has certain limitations as a drug delivery platform, and with animal physiologists recent advances in knowledge, pharmaceutical scientists will need more versatile delivery platforms to develop intravaginal drug delivery systems which fulfil the future demands of the animal scientists.