Date of Award

1998

Degree Type

Dissertation

Degree Name

Doctor of Philosophy in Pharmaceutical Sciences

Specialization

Pharmaceutics

Department

Pharmaceutics

First Advisor

Serpil M. Kislalioglu

Abstract

Mechanisms governing the release of drugs from controlled delivery systems are mainly diffusion, osmosis and erosion. For poorly soluble drugs, the existing mechanisms are limited to osmosis and/or matrix erosion. These mechanisms are commonly employed to control drug release from single unit and multi-unit dosage forms. More recently, multiunit dosage forms have gained considerable popularity for controlled release technology due to their advantages over single unit dosage forms. However, the mechanism of polymer controlled surface erosion from a multi-unit dosage form has never been reported in the literature. This study describes the development, characterization and evaluation of a matrix pellet system which releases an insoluble drug via polymer controlled surface erosion mechanism. Extrusion/Spheronization method was used to formulate matrix pellets. The effect of various formulation and process parameters affecting the drug release were characterized by analytical techniques such as Differential Scanning Calorimetry, X-Ray Diffractometry, and Mercury Intrusion Porosimetry. Different insoluble drugs were used as model drugs to demonstrate universal applicability of this novel system. The effect of drug solubility was also investigated on the mechanism of drug release from this system. Solid dispersions of the model insoluble drug was formulated to increase its solubility. It was observed that when the drug properties were changed towards increasing solubility in water, the release mechanism and rate also changed from pure surface erosion to erosion/diffusion. Drug release of nifedipine pellets in vivo occurred for more than 24 hours following zero order kinetics in fasted dogs. Thus it was proved that the approach of controlling drug release by polymer controlled surface erosion mechanism from a multi-unit pellet system is possible and such a system may be beneficial than the current marketed dosage forms of insoluble drugs such as nifedipine.

Comments

Mechanisms governing the release of drugs from controlled delivery systems are mainly diffusion, osmosis and erosion. For poorly soluble drugs, the existing mechanisms are limited to osmosis and/or matrix erosion. These mechanisms are commonly employed to control drug release from single unit and multi-unit dosage forms. More recently, multiunit dosage forms have gained considerable popularity for controlled release technology due to their advantages over single unit dosage forms. However, the mechanism of polymer controlled surface erosion from a multi-unit dosage form has never been reported in the literature. This study describes the development, characterization and evaluation of a matrix pellet system which releases an insoluble drug via polymer controlled surface erosion mechanism. Extrusion/Spheronization method was used to formulate matrix pellets. The effect of various formulation and process parameters affecting the drug release were characterized by analytical techniques such as Differential Scanning Calorimetry, X-Ray Diffractometry, and Mercury Intrusion Porosimetry. Different insoluble drugs were used as model drugs to demonstrate universal applicability of this novel system. The effect of drug solubility was also investigated on the mechanism of drug release from this system. Solid dispersions of the model insoluble drug was formulated to increase its solubility. It was observed that when the drug properties were changed towards increasing solubility in water, the release mechanism and rate also changed from pure surface erosion to erosion/diffusion. Drug release of nifedipine pellets in vivo occurred for more than 24 hours following zero order kinetics in fasted dogs. Thus it was proved that the approach of controlling drug release by polymer controlled surface erosion mechanism from a multi-unit pellet system is possible and such a system may be beneficial than the current marketed dosage forms of insoluble drugs such as nifedipine.

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