Senjoti, Faria Gias (2020) Development of a Model for Simultaneous Measurement of Rheology and Dissolution for In Situ Gel Forming Drug Delivery Systems. Doctoral thesis, University of Huddersfield.

In situ gel forming drug delivery systems utilize the concept of undergoing sol-gel transitions on exposure to physiological fluids in response to changes in temperature, pH and/or ionic environment. Gelation in response to the changes in pH/ionic contents are particularly difficult to measure in a biorelevant manner as gelation is often too rapid for adequate mixing of physiological fluids with the polysaccharides prior to loading on to a rheometer. Although, several modifications have been applied to conventional rheometers to facilitate changing environmental conditions, modifications that can change the chemical environment of a sample and simultaneously measure release of active ingredients from in situ gelling formulations has yet to be developed. To address this problem a novel method has been demonstrated using a 3D printed rheo-dissolution cell to simultaneously measure the rheological behaviour and dissolution of drug from the in situ gelling systems on exposure to physiological fluids. The technique was validated and then used to understand the behaviour of a range of in situ gelling formulations.

An in situ gel forming ophthalmic formulation of low acyl gellan gum (gellan) (0.4%) and timolol maleate (TM) (6.8 mg/ml) was prepared based on commercial Timoptol LA®. Rheological evaluation and a drug release study were performed separately using the rheo-dissolution device. This study also highlighted the importance of drug-polymer interaction by indicating electrostatic interactions between the positively charged TM and negatively charged gellan. The concept of rheo-dissolution was further explored with the full experimental set up of the rheo-dissolution cell integrated with a rheometer. An in situ gelling ophthalmic (gellan-TM) and an oral formulation (alginate- metronidazole) were prepared to evaluate the novel technique. The ophthalmic formulations of gellan-TM showed rapid onset of gelation on exposure to simulated lacrimal fluid (SLF) (pH 7.5) and release slowed down with increased gellan concentrations (0.6% to 0.8% w/v). Rheo-dissolution experiments performed on the oral formulation of revealed the formation of a strong gel with rapid gelation on exposure to simulated gastric fluid (pH 1.2). Rapid release was observed while the gel was structuring, which then slowed down (~53% in 7h) once gelation was complete. The pH of the media was increased to 8.0, which resulted in a dramatic increase of MNZ release (~96% in 7h) and degradation of the alginate gel. Finally, an in situ gelling ophthalmic formulation of gellan was prepared using flurbiprofen (FBP) (a poorly soluble drug) and 2-hydroxypropyl-β-cyclodextrin (HβCD) inclusion complex. This work highlighted the difficulties of incorporating the sodium salt form FBP in in situ gelling systems prepared using gellan because of the tendency of gellan to cross link with salts. Besides the rheo-dissolution study, ex-vivo permeation study was performed which showed higher percentage of FBP permeation (~55% in 6h) in the inclusion complex formulation compared with FBP sodium in the commercial product Ocufen® (~37% in 6h).

FINAL THESIS - Senjoti.pdf - Accepted Version
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