Biopharmaceutical studies of slow release, subcutaneous polymeric drug delivery systems

Subcutaneously injected polymeric dosage forms have been used successfully to achieve sustained release of various drugs and peptides. A complex interplay of factors affect drug release rates from such dosage forms, such as nature of dosage form, drug and polymer properties, formulation variables etc. making the prediction of release characteristics challenging. In this thesis, the effect of drug lipophilicity on absorption rates from PLGA microspheres and in situ-forming depots was investigated. The beta-blockers were chosen as model drug compounds, being a homologous group of drugs having similar molecular weights and pKa values, yet widely differing lipophilicities. Alprenolol, metoprolol and atenolol were selected to represent the series based on their experimentally determined octanol-buffer partition coefficients. The first part of the study focused on formulation and characterisation of beta-blocker loaded microspheres with suitable in vitro release profiles. Microspheres were prepared by spray drying, and characterised in terms of particle size, surface morphology, drug loading and release. The beta-blockers represented a considerable challenge owing to their surface-active nature and tendency to suffer a large burst release from microspheres. Efforts were therefore directed towards modifying the formulation to improve the drug release profiles, including emulsion spray drying, addition of competing surfactants and hydrophobic ion pairing. The latter was successful in reducing burst and prolonging release, and microspheres were deemed suitable for in vivo investigation. In situ-forming depot preparations were also formulated with the aim of comparing release profiles and tissue compatibility with the preformed microspheres. Following initial experiments to ascertain intravenous clearance kinetics, the polymeric dosage forms were injected subcutaneously in rats. Drug plasma concentrations were analysed and absorption profiles were determined by deconvolution. It was found that the nature of the dosage form had a significantly greater impact on the rate and extent of absorption than the lipophilicity of the encapsulated drugs

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Biopharmaceutical studies of slow release, subcutaneous polymeric drug delivery systems

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

The DNA sequence of the human X chromosome

The human X chromosome has a unique biology that was shaped by its evolution as the sex chromosome shared by males and females. We have determined 99.3% of the euchromatic sequence of the X chromosome. Our analysis illustrates the autosomal origin of the mammalian sex chromosomes, the stepwise process that led to the progressive loss of recombination between X and Y, and the extent of subsequent degradation of the Y chromosome. LINE1 repeat elements cover one-third of the X chromosome, with a distribution that is consistent with their proposed role as way stations in the process of X-chromosome inactivation. We found 1,098 genes in the sequence, of which 99 encode proteins expressed in testis and in various tumour types. A disproportionately high number of mendelian diseases are documented for the X chromosome. Of this number, 168 have been explained by mutations in 113 X-linked genes, which in many cases were characterized with the aid of the DNA sequence