The present work explores the possibility to exploit the hydrolytic activity of the enzyme cellulase to improve the release performance of oral modified release dosage forms having as functional polymer hydroxypropyl methylcellulose (HPMC), a hydrophilic cellulose derivative which is substrate of the enzyme itself. Previous examples of the use of enzymes in drug delivery were investigated through a literature survey, which highlighted their high potential as formulation aids. The possible benefits coming from the inclusion of a cellulolytic product commercially available as a powder (Sternzym® C13030) into drug delivery systems (DDSs) were initially assessed on HPMC-based hydrophilic matrices (HMs) for oral prolonged release. The study was carried out on tableted matrices containing increasing amount of enzymatic product, so that its effect, also in terms of concentration dependence, could be evaluated with respect to enzyme-free systems by means of mass loss studies, release tests and measurements of fronts positions over time. Moreover, viscosity and permeability tests were carried out on HPMC solutions to which different amount of Sternzym® C13030 were added. The shorter polymer chains generated by the ongoing hydrolytic action of cellulase led to a progressively weaker gel, i.e. more permeable and less viscous over time, with increasing enzyme amounts. Mathematical modeling of release profiles and fronts position over time confirmed that the enzyme is able to bring about a progressive reduction of the gel layer resistance. Accordingly, higher release rates were observed in cellulase-containing matrices as well as a greater extent of the erosion phenomenon, ultimately resulting into a shift towards zero-order kinetics of drug release associated with a tendency to synchronization of the movement of the erosion and swelling fronts, both in terms of direction and rate. Stability concerns were also taken into account. The enzymatic product, although showing a pH dependent activity, was never inactivated in the tested pH values, chosen to be representative of the main districts of the gastrointestinal tract. Temperature and humidity conditions very likely to occur during pharmaceutical processesing did not impact on the final release performance of the compacts. Moreover, matrices were found able to maintain their release performance after 2 years storage in a refrigerator. The same commercially available product, Sternzym® C13030, was also included into the spray coated high viscosity HMPC-based retarding layer of a time-based DDSs having a reservoir configuration. Since the rapid hydrolytic action of cellulase on HPMC ruled out the possibility to spray a co-solution, tablet cores were coated up to different coating thicknesses alternating layers of Methocel® K4M with thin films of Sternzym® C13030. Cellulase-containing systems presented a profile characterized by a prompt and quantitative drug release, without the slow diffusional release after units break-up, which, on the other hand, was highlighted in reference systems having retarding layers of the same thickness but made of polymer alone. Although the enzyme tended to reduce lag phase extent, its reproducibility resulted clearly improved and the differences with reference systems in terms of its duration were statistically significant only for the highest coating level investigated.
EVALUATION OF HYDROLYTIC ENZYMES IN THE DESIGN OF ORAL DRUG DELIVERY SYSTEMS / I. Filippin ; tutor: A. Foppoli ; coordinatore: G. Vistoli. - Dipartimento Scienze Farmaceutiche (DiSFarm), Via Mangiagalli 25, Milano.. Dipartimento di Scienze Farmaceutiche, 2024 Feb 13. 36. ciclo, Anno Accademico 2022/2023.
EVALUATION OF HYDROLYTIC ENZYMES IN THE DESIGN OF ORAL DRUG DELIVERY SYSTEMS
I. Filippin
2024
Abstract
The present work explores the possibility to exploit the hydrolytic activity of the enzyme cellulase to improve the release performance of oral modified release dosage forms having as functional polymer hydroxypropyl methylcellulose (HPMC), a hydrophilic cellulose derivative which is substrate of the enzyme itself. Previous examples of the use of enzymes in drug delivery were investigated through a literature survey, which highlighted their high potential as formulation aids. The possible benefits coming from the inclusion of a cellulolytic product commercially available as a powder (Sternzym® C13030) into drug delivery systems (DDSs) were initially assessed on HPMC-based hydrophilic matrices (HMs) for oral prolonged release. The study was carried out on tableted matrices containing increasing amount of enzymatic product, so that its effect, also in terms of concentration dependence, could be evaluated with respect to enzyme-free systems by means of mass loss studies, release tests and measurements of fronts positions over time. Moreover, viscosity and permeability tests were carried out on HPMC solutions to which different amount of Sternzym® C13030 were added. The shorter polymer chains generated by the ongoing hydrolytic action of cellulase led to a progressively weaker gel, i.e. more permeable and less viscous over time, with increasing enzyme amounts. Mathematical modeling of release profiles and fronts position over time confirmed that the enzyme is able to bring about a progressive reduction of the gel layer resistance. Accordingly, higher release rates were observed in cellulase-containing matrices as well as a greater extent of the erosion phenomenon, ultimately resulting into a shift towards zero-order kinetics of drug release associated with a tendency to synchronization of the movement of the erosion and swelling fronts, both in terms of direction and rate. Stability concerns were also taken into account. The enzymatic product, although showing a pH dependent activity, was never inactivated in the tested pH values, chosen to be representative of the main districts of the gastrointestinal tract. Temperature and humidity conditions very likely to occur during pharmaceutical processesing did not impact on the final release performance of the compacts. Moreover, matrices were found able to maintain their release performance after 2 years storage in a refrigerator. The same commercially available product, Sternzym® C13030, was also included into the spray coated high viscosity HMPC-based retarding layer of a time-based DDSs having a reservoir configuration. Since the rapid hydrolytic action of cellulase on HPMC ruled out the possibility to spray a co-solution, tablet cores were coated up to different coating thicknesses alternating layers of Methocel® K4M with thin films of Sternzym® C13030. Cellulase-containing systems presented a profile characterized by a prompt and quantitative drug release, without the slow diffusional release after units break-up, which, on the other hand, was highlighted in reference systems having retarding layers of the same thickness but made of polymer alone. Although the enzyme tended to reduce lag phase extent, its reproducibility resulted clearly improved and the differences with reference systems in terms of its duration were statistically significant only for the highest coating level investigated.File | Dimensione | Formato | |
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