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Taste-masked and Controlled-release Formulations of Chloroquine

Ng, Anna; (1992) Taste-masked and Controlled-release Formulations of Chloroquine. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Chloroquine remains the treatment of choice for malaria in many countries despite the appearance of drug resistance. Even with children, chloroquine is normally administered orally, despite its bitter taste which is not masked by sweetening agents. The aim of this work was to formulate a taste-masked, sustained release preparation of chloroquine microcapsules using a multiple emulsion/solvent extraction technique. In the first part of this work, surface rheological measurements were used to establish the film forming properties of different types of acacia, which is the most common polymer used in this process. Of the three types investigated, acacia tears were found to exhibit the highest surface viscoelasticity and were therefore used for all subsequent studies. Direct addition of chloroquine diphosphate to aqueous solutions of anionic poly electrolytes such as carrageenan and Eudragit L100, resulted in precipitation due to an acid-base reaction occuring between the cationic drug and the anionic polymer. It was therefore not possible to incorporate the drug in the inner aqueous phases of multiple emulsions containing these polymers (the original method of preparation). This was overcome by using a modified method which incorporated the drug in the middle oily layer of the multiple emulsion. Diffusion studies demonstrated the partitioning of chloroquine from an oily phase to an aqueous phase, the amount of which was enhanced in the presence of anionic polyelectrolytes in the aqueous phase, which bound to the basic chloroquine molecules and acted as a "sink". Scanning electron microscopy (SEM) and differential scanning calorimetry (DSC) were used to study the physical state of the drug present in the polymer matrix after solvent extraction. This was done by investigating cast chloroquine-ethylcellulose films. Although chloroquine crystals were present in the films as shown by SEM, DSC was unable to detect the presence of such an entity. In order to establish a manufacturing procedure, the following manufacturing parameters were investigated using a model formulation: (1) the phase volume ratios of both the primary and secondary emulsions, (2) concentration of polymers and (3) the different methods used for solvent extraction and drying. The effects of these parameters on the surface morphology and particle size distribution of the microcapsules were determined. The rate of drug release was found to be dependent on the pH of the dissolution medium and was also found to increase with a decrease in the particle size distribution of the microcapsules. The combination consisting of Eudragit L100 as the inner aqueous phase polymer, Ethylcellulose NIO NF as the oily phase polymer and acacia as the outer aqueous phase polymer was chosen for further development. The chloroquine content of these microcapsules increased with the starting amount of chloroquine (theoretical content) and the Eudragit L100 concentration in the inner aqueous phase. Increasing the Eudragit L100 concentration in the inner aqueous phase improved the sustained release characteristic of the formulation. The rate of drug release was decreased by increasing the ethylcellulose concentration in the middle oily phase of the multiple emulsion. Annealing these microcapsules decreased the rate of drug release. Stability studies were then performed on the final formulation selected for the in vivo study. The formulation of chloroquine (30.7%w/w) microcapsules (0.75%w/v Eudragit L100 / 10%w/v Ethylcellulose NIO NF / 8%w/v Acacia) was submitted for clinical study with six healthy volunteers. There were no significant differences in the bioavailabilities of the microcapsule formulation and the chloroquine diphosphate tablets (reference dosage form). The elimination half lives, the maximum plasma concentrations and the time at which they occur, were however significantly different, showing sustained release. The inter-subject variation was notably smaller with the microcapsule formulation compared with the tablets. Stored microcapsules showed similar rate of drug release to the fresh microcapsules but a higher peak concentration was observed probably due to experimental error.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Taste-masked and Controlled-release Formulations of Chloroquine
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
URI: https://discovery.ucl.ac.uk/id/eprint/10123387
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