Over the last few years, interest in development of controlled drug delivery systems grew. DDS are able to improve the efficiency of a pharmaceutical therapy by controlling drug release site and times, and to decrease side effects. In case of capsular devices, this is made possible by the proper selection of the polymeric material which constitutes wall and of appropriate excipients, referred to as release enhancer or release modifiers. This thesis investigated the production of elongated particles and fibres made of Pullulan, a biopolymer already in use in pharmaceutical field, in order to incorporate it with hydroxyl propyl methyl cellulose acetate succinate, HPMCAS, matrix of capsular device for drug release in gastrointestinal tract. The function of these particles is form a percolation path within the matrix so as to increase its dissolution rate. The process selected for the production of fibrils was spray drying. Aqueous and hydro alcoholic solutions containing different amount of Pullulan were first characterized for what concern shear viscosity, extensional viscosity and solvent evaporation and then used in spray drying. The rheological characterization highlighted a significant lot to lot variability in Pullulan average molecular weight, and evidenced the essential role of solution viscoelasticity in fibres formation by spray drying. As matter of facts, an optimal range of viscosity was found, in which allowed to get the maximum fibre productivity irrespective of Pullulan molecular weight. During the process an adverse effect of time after the preparation of the hydroalcoholic solution was observed, maybe related to the dimension of Pullulan random coils in semidiluted regime. The phenomenon will be object of further investigation. From the process development activity of the thesis allowed to define a set of conditions for the production of a mixture of fibrillary and spherical particles on a scale large enough to allow their mixing with HPMCAS matrix. The modified matrix was then injection moulded and its release performances tested. Surprisingly, the release of the fibre filled matrix is not different, or even worse, than that of particle filled one. This results may be attributed to the higher level of packing pressure used in the production of the former. Further work is however needed to confirm this hypothesis.
Negli ultimi anni è cresciuto l'interesse per lo sviluppo di Drug Delivery Systems, sistemi di rilascio di farmaci. I DDS sono in grado di migliorare l'efficienza di una terapia controllando il luogo e il tempo di rilascio del farmaco e di ridurre gli effetti collaterali. Nel caso di dispositivi capsulari, ciò è reso possibile dalla corretta selezione del materiale polimerico che costituisce le pareti e di appropriati eccipienti per modificare e migliorare il rilascio. In questo lavoro è stata studiata la produzione di particelle e fibre di Pullulano, un biopolimero già in uso in campo farmaceutico. Esse sono state incorporate nella matrice di idrossipropil metilcellulosa acetato succinato, HPMCAS, di un dispositivo capsulare per il rilascio di farmaci nel tratto gastrointestinale. La funzione delle fibre è quello di formare un percorso percolativo all'interno della matrice in modo da aumentare il suo tasso di dissoluzione. Il processo utilizzato per la produzione di fibre è lo spray drying. Le soluzioni acquose e idroalcoliche contenenti diverse quantità di Pullulano sono state inizialmente caratterizzate per quanto riguarda la viscosità a taglio, la viscosità estensionale e l'evaporazione del solvente; successivamente sono state processate tramite spray drying. La caratterizzazione reologica ha evidenziato dapprima una notevole variabilità dei lotti di Pullulano per quanto riguarda il peso molecolare e in secondo luogo il ruolo essenziale della viscoelasticità della soluzione nella formazione delle fibre mediante spray drying. Inoltre, è stato trovato il range ottimale di viscosità, in cui è possibile ottenere la massima produttività di fibre indipendentemente dal peso molecolare del Pullulano. Durante il processo è stato osservato un effetto negativo del tempo sulla soluzione idroalcolica, forse correlata alla dimensione dei random coils di Pullulano in regime semidiluito. Il fenomeno deve essere oggetto di ulteriori indagini. Durante lo sviluppo della tesi è stato possibile definire un insieme di condizioni per la produzione di fibre e particelle su una scala abbastanza grande da permetterne la miscelazione con la matrice di HPMCAS. I dischi sono stati prodotti per stampaggio ad iniezione e le loro prestazioni di rilascio sono state testate. Il rilascio dei dischi contenenti fibre, tuttavia, è risultato essere uguale, se non meno efficiente, rispetto ai dischi contenenti solo particelle. Questi risultati possono essere dovuti alle pressioni troppo alte utilizzate in fase di stampaggio. Saranno comunque necessari ulteriori studi per confermare questa ipotesi.
Pullulan as a release modifier for drug delivery systems : effect of rheological behaviour of its solutions on the processability by spray drying
AMBROSETTI, RICCARDO
2017/2018
Abstract
Over the last few years, interest in development of controlled drug delivery systems grew. DDS are able to improve the efficiency of a pharmaceutical therapy by controlling drug release site and times, and to decrease side effects. In case of capsular devices, this is made possible by the proper selection of the polymeric material which constitutes wall and of appropriate excipients, referred to as release enhancer or release modifiers. This thesis investigated the production of elongated particles and fibres made of Pullulan, a biopolymer already in use in pharmaceutical field, in order to incorporate it with hydroxyl propyl methyl cellulose acetate succinate, HPMCAS, matrix of capsular device for drug release in gastrointestinal tract. The function of these particles is form a percolation path within the matrix so as to increase its dissolution rate. The process selected for the production of fibrils was spray drying. Aqueous and hydro alcoholic solutions containing different amount of Pullulan were first characterized for what concern shear viscosity, extensional viscosity and solvent evaporation and then used in spray drying. The rheological characterization highlighted a significant lot to lot variability in Pullulan average molecular weight, and evidenced the essential role of solution viscoelasticity in fibres formation by spray drying. As matter of facts, an optimal range of viscosity was found, in which allowed to get the maximum fibre productivity irrespective of Pullulan molecular weight. During the process an adverse effect of time after the preparation of the hydroalcoholic solution was observed, maybe related to the dimension of Pullulan random coils in semidiluted regime. The phenomenon will be object of further investigation. From the process development activity of the thesis allowed to define a set of conditions for the production of a mixture of fibrillary and spherical particles on a scale large enough to allow their mixing with HPMCAS matrix. The modified matrix was then injection moulded and its release performances tested. Surprisingly, the release of the fibre filled matrix is not different, or even worse, than that of particle filled one. This results may be attributed to the higher level of packing pressure used in the production of the former. Further work is however needed to confirm this hypothesis.File | Dimensione | Formato | |
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https://hdl.handle.net/10589/147287