Magister Pharmaceuticae - MPharm / Fast dispersible tablets (FDTs) are solid single-unit dosage forms that are placed in the mouth and allowed to disperse or dissolve in the saliva without the need of water. The basic approach to formulating FDTs consists of adding a superdisintegrant to a tablet formulation. These tablets offer both the advantages of conventional tablets and liquid dosage forms along with distinctive properties which include accurate dosing, ease of administration, quick onset of action, enhanced bioavailability, and increased patient adherence. FDTs have been found to be effective in remedying therapeutic in-adherence caused by dysphagia (swallowing difficulties) particularly in paediatric and geriatric subjects. There is a strong correlation between therapeutic success and patient adherence especially with HIV/AIDS treatment regimens, consequently the dosage form should be patient friendly and devoid of unappealing characteristics. This study aimed at developing a cost effective fast dispersible tablet of lamivudine using alternative excipients and conventional techniques. Only conventional tablets and oral liquid dosage forms of lamivudine are available on the South African market. Two natural polymers reported to have superdisintegrating properties were selected to serve as multipurpose excipients in this study. The polymers were identified, characterised and compared using thermal, spectroscopic and micromeritic analytical tools. The polymer that displayed the best characteristics in terms of micromeritic, tableting and disintegrating properties was retained and used for the optimum formulation. The optimum formulation was composed of 150 mg of lamivudine, 23% w/w unripe banana powder and 2% w/w magnesium stearate. FDTs of lamivudine were obtained using the compression technique with and without wet granulation. The tablets were assessed as per the United States Pharmacopoeia (USP) guidelines and other evaluation procedures pertaining to FDTs. The wet granulated tablets were found to be less friable and thus more resilient than the directly compressed tablets. In-vitro disintegration of the wet granulated tablets occurred within 50±3 sec in deionised water (pH 7) and 35±2 sec in a phosphate buffer solution (pH 6.8). Consequently, the innovative tablets fulfilled the core requirement of FDTs i.e. rapid disintegration. Drug release studies were carried out by analysing dissolution aliquots of the innovative tablets using a validated High Performance Liquid Chromatography (HPLC) method, and comparing them to Aspen Lamivudine®, a conventional tablet of lamivudine presently on the South African market. Complete dissolution in deionised water (pH 7) was attained within 10 minutes and 30 minutes for the innovative tablets and Aspen Lamivudine® respectively.

Nasal administration has potential for the treatment of indications requiring a fast onset of effect or for drugs with low oral bioavailability. Liquid nasal sprays are relatively common, but can be associated with suboptimal absorption from the nasal cavity; this thesis shows that nasal absorption can be significantly enhanced with a dry powder formulation. It was shown that interactive mixtures, consisting of fine drug particles adhered to the surface of mucoadhesive carrier particles, could be created in a particle size suitable for nasal administration. Sodium starch glycolate (SSG), a common tablet excipient, was used as carrier material. In vitro evaluation of the formulation indicated that the mucoadhesion of the carrier was unlikely to be affected by the addition of a drug. The powder formulation did not improve the in vitro transfer of dihydroergotamine across porcine nasal mucosa compared with a liquid formulation; however, the results were associated with methodological shortcomings. The binding of model substances to SSG and three other excipients was evaluated. Ion exchange interactions were for example detected between SSG and cationic drugs, but these interactions were most extensive at low salt concentrations and should unlikely affect in vivo bioavailability at physiological salt concentrations. Absorption of the peptide drug desmopressin from the SSG nasal formulation, from a novel sublingual tablet formulation and from a commercial nasal liquid spray was evaluated in a clinical trial. While no improvement over the liquid spray was seen with the sublingual tablet, plasma concentrations after the nasal powder formulation were three times higher than those after the liquid spray. All formulations were well accepted by the volunteers. The use of currently available mucoadhesive carrier particles in interactive mixtures offers potential for a new method of producing nasal powder formulations that should also be applicable to large scale production.

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L’objectif de ce projet était de développer une formulation liquisolide (LS) de clozapine ayant des propriétés de dissolution améliorées et évaluer sa stabilité et ainsi que sa robustesse à la modification d’excipients. Le propylène glycol (PG), la cellulose microcrystalline (MCC) et le glycolate d’amidon sodique (SSG) ont été utilisés respectivement en tant que véhicule liquide non volatile, agent de masse et agent désintégrant pour la préparation de comprimés LS. Le dioxyde de silicium colloïdal (CSD), le silicate de calcium (CS) et l'aluminométasilicate de magnésium (MAMS) ont été choisis comme agents d’enrobage sec. La caractérisation complète des mélanges et des comprimés a été effectuée. Le taux de libération des comprimés LS était statistiquement supérieur à celui des comprimés réguliers. La surface spécifique des matériaux d’enrobage avait un effet sur les propriétés d’écoulement des mélanges et la taille des particules des matériaux d’enrobage a eu un effet sur la vitesse de dissolution. Le ratio support/enrobage du mélange de poudres (valeur de R) était un paramètre important pour les systèmes LS et devait être plus grand que 20 afin d’obtenir une meilleure libération du médicament. La formulation choisie a démontré une stabilité pour une période d’au moins 12 mois. La technique LS s’est avéré une approche efficace pour le développement de comprimés de clozapine ayant des propriétés de dissolution améliorées. Les comprimés oro-dispersibles (ODT) sont une formulation innovante qui permettent de surmonter les problèmes de déglutition et de fournir un début d'action plus rapide. Dans l’optique d’améliorer les propriétés de dissolution, un essai a été effectué pour étudier la technique LS dans la formulation des ODT de clozapine. Le PG, la MCC, le CSD et la crospovidone (CP) ont été utilisés respectivement en tant que véhicule liquide non volatile, agent de masse, agent d’enrobage sec et agent superdésintégrant pour la préparation de comprimés oro-dispersibles liquisolides (OD-LST). Le mannitol a été choisi comme agent de masse et agent édulcorant. La saccharine de sodium a été utilisée comme agent édulcorant. La caractérisation complète des comprimés a été effectuée. Le taux de libération des OD-LSTs était statisquement supérieur comparativement aux comprimés ODTs. La formulation choisie a démontré une stabilité pour une période d’au moins 6 mois. Il a été conclu que des ODT de clozapine peuvent être préparés avec succès en utilisant la technologie LS dans le but d’améliorer la désintégration et le taux de dissolution de la clozapine dans la cavité orale. / The objective of this research was to develop a liquisolid (LS) formulation of clozapine with improved dissolution properties and evaluate its robustness to excipient modifications as well as its stability. Propylene glycol (PG), microcrystalline cellulose (MCC) and sodium starch glycolate (SSG) were employed as non-volatile liquid vehicle, carrier material and disintegrant respectively for preparing LS compacts. Colloidal silicon dioxide (CSD), calcium silicate (CS) and magnesium aluminometasilicate (MAMS) were selected as coating materials. Complete characterisation of the blends and tablets was performed. The drug release rates of LS compacts were distinctly higher as compared to regular tablets. The specific surface areas of coating materials had an effect on the flow properties of the blends and the particle sizes of coating materials affected the dissolution rate. The carrier : coating ratio of the powder system (R value) was an important parameter for LS systems and had to be larger than 20 to obtain enhanced drug release. The selected formulation demonstrated stability for a period of at least 12 months. The LS technique was an effective approach to prepare clozapine tablets with enhanced dissolution properties. Orally disintegrating tablets (ODT) constitute an innovative dosage form that overcomes the problems of swallowing and provides a quick onset of action. In view of enhancing dissolution properties an attempt has been made to study LS technique in formulation of ODT of clozapine. PG, MCC, CSD and crospovidone (CP) were employed as non-volatile liquid vehicle, carrier material, coating material and superdisintegrant respectively for preparing orally disintegrating liquisolid tablets (OD-LST). Mannitol was selected as a carrier material and sweetening agent. Sodium saccharin (SS) was employed as a sweetening agent. Complete characterisation of the tablets was performed. The drug release rates of OD-LSTs were distinctly higher as compared to regular ODTs. The selected formulation demonstrated stability for a period of at least 6 months. It was concluded that the ODT of clozapine can be successfully prepared using LS technology in order to improve disintegration and dissolution rate of clozapine in oral cavity.