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Barbara Buchan PhD thesis.pdf4.85 MBAdobe PDFView/Open
Title: Formulation studies on cysteamine for the treatment of nephropathic cystinosis.
Authors: Buchan, Barbara Elizabeth
Supervisors: Kay, Graeme
Matthews, Kerr H.
Cairns, Don
Keywords: Cystinosis
Modified release
Issue Date: Aug-2011
Publisher: Robert Gordon University
Abstract: Nephropathic cystinosis is a rare autosomal recessive disease characterised by raised lysosomal levels of cystine in the cells of almost all organs. It is treated by regular oral and topical administration of the aminothiol, cysteamine(Cystagon™), which possesses an offensive taste and smell. The oral form frequently causes emesis,and should be administered every six hours to be maximally effective. The topical eye drop treatment requires hourly application to be most effective.In an attempt to reduce this frequency and improve the treatment, the preparation and evaluation of three alternative cysteamine containing formulations (suppositories, long-acting ophthalmic gels and an inhaler) was undertaken. The physiochemical properties, stability and release profiles of the active (cysteamine or phe conjugate) from the formulations were evaluated. The suppositories released cysteamine over a 20-40 minute period with a T75= 10-13minutes. They were most stable at 4°C. The analysis of the ophthalmic gels demonstrated that a weak gel network was formed at low shear stress, the bioadhesion of the gel was increased with inclusion of a cysteamine derivative (e.g.mean force of 0.067N compared to 0.107N with compound included) and eight-hour, first order release from the gel was observed. There was significant adhesion observed between the ophthalmic gels and bovine corneal tissue. The pulmonary microspheres were spherical and within the optimum size range for deep lung delivery (1-5μm). However, Andersen Cascade Impactor analysis revealed poor deep lung penetration. In conclusion, these results demonstrated that more development work was required to produce a useful pulmonary formulation of cysteamine, however, formulation of an ocular applicable gel or suppository was readily achievable. The suppository preparations may be particularly beneficial for the treatment of infants, whilst the ophthalmic gel preparations could be developed for daily or overnight use. With respect to pulmonary delivery, microspheres in the optimum size range were produced. However, deep lung targeting was prevented by static agglomeration, which requires further investigation.
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