Poly(lactide-co-glycolide) [PLGA] is the most exploited biodegradable and biocompatible material in the pharmaceutical field for the preparation of long- acting parenteral formulations, despite there are limitations related to the PLGA itself or to the final product to face with. These mainly include the limited ability in encapsulating hydrophilic compounds, the physical and chemical instabilities in aqueous media, the detrimental effect of the sterilization methods and the drop off in the micro-environmental pH upon degradation. Hence, there is the need to find new strategies for their overcoming. This doctoral thesis aimed to exploit the functionalization of PLGA backbone with anti-oxidants (g-AA-PLGA) and a novel biodegradable material, containing polyesters segments in a multi-block poly(urethane) organization, to address the main limitations related to PLGA, with emphasis on nano-particulate drug delivery systems. PLGA grafted to caffeic acid (g-CA-PLGA) nanoparticles (NP) showed an improved uptake in endothelial cells (EC) and smooth muscle cells (SMC), the representative cell populations in the artery wall. Thus, they were worth of interest for the loading of fluvastatin in restenosis prevention. The proliferation inhibition of human SMC was not significantly affected after the encapsulation of fluvastatin within g-CA-PLGA NP, with the effective concentration being 4 mcM compared to the 1 mcM of free fluvastatin, suggesting a control of the polymer on the drug release. A higher dose was necessary in the case of EC, indicating the possibility to inhibit SMC proliferation while the healing of the endothelium is on-going. All these aspects highlight the suitability of this system in the prevention of restenosis, after the local delivery with the angioplasty balloon (Chapter 1). However, during the development of the formulation, the selection and optimization of the drying process is required, also with the aim to coat the angioplasty balloon with eluting-NP. In this context, a preliminary study was performed and the obtained results revealed that maltodextrins (MDX), an excipient widely used in the pharmaceutical industry, can be also advantageously used as drying auxiliary agent. Indeed, they permit an easily reconstitution of NP dispersion in aqueous media, independently of the selected drying technique, namely spray-drying or freeze-drying. The performances of such excipient were demonstrated in the case of both PLGA and g-CA-PLGA NP (Chapter 2). The multi-block poly(ester-urethane) DegraPol® displays biocompatibility and biodegradability and consequently it is already used for the preparation of medical devices by electrospinning. Conversely, the possibility to design long-acting parenteral formulations is unknown as well as the possibility to conferee a spherical shape with the desired particle size and a narrow distribution. The performed work demonstrated that the emulsion/solvent evaporation method was the optimal process, with the possibility to cover size range from nano- to micro-meters. Nevertheless, the dispersant medium should be carefully studied, given the tendency of the particles to form aggregates due to the almost neutral Z-potential of the material (Chapter 3). All together the collected results, along with the known stability to sterilization process (ionizing radiations for g-AA-PLGA and ethylene oxide for DegraPol®), demonstrated that both PLGA grafted to anti-oxidant and DegraPol® are suitable materials for preparing particulate drug delivery systems that can overcome some of the limitations associated to PLGA. As a general consideration, it should be underlined that formulation development cannot be disconnected from the regulatory framework. Particularly for long-acting parenteral formulations, the elaboration of an appropriate in vitro test to study the release of the drug is critical, given the complexity in the set-up of methods able to efficiently discriminate products that can have different in vivo behaviour (Chapter 4). In the case of PLGA microspheres intended to sustain the release of a drug after the intra-articular administration, a bio-relevant approach was followed in the attempt to evaluate their performance under healthy and disease states simulated conditions. Formulation parameters such as PLGA lactide/glycolide ratio and the amount of drug encapsulated should be carefully considered to properly optimize the formulation. Furthermore, proteins contained in the release medium simulating the disease condition affected the release behaviour of microspheres. This suggests that simple buffers (i.e., PBS at physiological pH) cannot correctly figure out the conditions occurring in vivo after the administration, much less the pathological situation (Chapter 5).

DEVELOPMENT OF NOVEL BIODEGRADABLE MATERIALS STABLE TO STERILIZATION FOR THE PREPARATION OF DRUG DELIVERY SYSTEMS / G. Magri ; tutor: F. Cilurzo ; supervisore: P. Minghetti ; supervisore: F. Selmin ; supervisore: N. Fotaki. - : . DIPARTIMENTO DI SCIENZE FARMACEUTICHE, 2019 Jan 29. ((31. ciclo, Anno Accademico 2018. [10.13130/magri-giulia_phd2019-01-29].

DEVELOPMENT OF NOVEL BIODEGRADABLE MATERIALS STABLE TO STERILIZATION FOR THE PREPARATION OF DRUG DELIVERY SYSTEMS

MAGRI, GIULIA
2019-01-29

Abstract

Poly(lactide-co-glycolide) [PLGA] is the most exploited biodegradable and biocompatible material in the pharmaceutical field for the preparation of long- acting parenteral formulations, despite there are limitations related to the PLGA itself or to the final product to face with. These mainly include the limited ability in encapsulating hydrophilic compounds, the physical and chemical instabilities in aqueous media, the detrimental effect of the sterilization methods and the drop off in the micro-environmental pH upon degradation. Hence, there is the need to find new strategies for their overcoming. This doctoral thesis aimed to exploit the functionalization of PLGA backbone with anti-oxidants (g-AA-PLGA) and a novel biodegradable material, containing polyesters segments in a multi-block poly(urethane) organization, to address the main limitations related to PLGA, with emphasis on nano-particulate drug delivery systems. PLGA grafted to caffeic acid (g-CA-PLGA) nanoparticles (NP) showed an improved uptake in endothelial cells (EC) and smooth muscle cells (SMC), the representative cell populations in the artery wall. Thus, they were worth of interest for the loading of fluvastatin in restenosis prevention. The proliferation inhibition of human SMC was not significantly affected after the encapsulation of fluvastatin within g-CA-PLGA NP, with the effective concentration being 4 mcM compared to the 1 mcM of free fluvastatin, suggesting a control of the polymer on the drug release. A higher dose was necessary in the case of EC, indicating the possibility to inhibit SMC proliferation while the healing of the endothelium is on-going. All these aspects highlight the suitability of this system in the prevention of restenosis, after the local delivery with the angioplasty balloon (Chapter 1). However, during the development of the formulation, the selection and optimization of the drying process is required, also with the aim to coat the angioplasty balloon with eluting-NP. In this context, a preliminary study was performed and the obtained results revealed that maltodextrins (MDX), an excipient widely used in the pharmaceutical industry, can be also advantageously used as drying auxiliary agent. Indeed, they permit an easily reconstitution of NP dispersion in aqueous media, independently of the selected drying technique, namely spray-drying or freeze-drying. The performances of such excipient were demonstrated in the case of both PLGA and g-CA-PLGA NP (Chapter 2). The multi-block poly(ester-urethane) DegraPol® displays biocompatibility and biodegradability and consequently it is already used for the preparation of medical devices by electrospinning. Conversely, the possibility to design long-acting parenteral formulations is unknown as well as the possibility to conferee a spherical shape with the desired particle size and a narrow distribution. The performed work demonstrated that the emulsion/solvent evaporation method was the optimal process, with the possibility to cover size range from nano- to micro-meters. Nevertheless, the dispersant medium should be carefully studied, given the tendency of the particles to form aggregates due to the almost neutral Z-potential of the material (Chapter 3). All together the collected results, along with the known stability to sterilization process (ionizing radiations for g-AA-PLGA and ethylene oxide for DegraPol®), demonstrated that both PLGA grafted to anti-oxidant and DegraPol® are suitable materials for preparing particulate drug delivery systems that can overcome some of the limitations associated to PLGA. As a general consideration, it should be underlined that formulation development cannot be disconnected from the regulatory framework. Particularly for long-acting parenteral formulations, the elaboration of an appropriate in vitro test to study the release of the drug is critical, given the complexity in the set-up of methods able to efficiently discriminate products that can have different in vivo behaviour (Chapter 4). In the case of PLGA microspheres intended to sustain the release of a drug after the intra-articular administration, a bio-relevant approach was followed in the attempt to evaluate their performance under healthy and disease states simulated conditions. Formulation parameters such as PLGA lactide/glycolide ratio and the amount of drug encapsulated should be carefully considered to properly optimize the formulation. Furthermore, proteins contained in the release medium simulating the disease condition affected the release behaviour of microspheres. This suggests that simple buffers (i.e., PBS at physiological pH) cannot correctly figure out the conditions occurring in vivo after the administration, much less the pathological situation (Chapter 5).
CILURZO, FRANCESCO
ALDINI, GIANCARLO
PLGA; DegraPol; nanoparticles; microparticles; parenteral drug delivery; long-acting injectables
Settore CHIM/09 - Farmaceutico Tecnologico Applicativo
DEVELOPMENT OF NOVEL BIODEGRADABLE MATERIALS STABLE TO STERILIZATION FOR THE PREPARATION OF DRUG DELIVERY SYSTEMS / G. Magri ; tutor: F. Cilurzo ; supervisore: P. Minghetti ; supervisore: F. Selmin ; supervisore: N. Fotaki. - : . DIPARTIMENTO DI SCIENZE FARMACEUTICHE, 2019 Jan 29. ((31. ciclo, Anno Accademico 2018. [10.13130/magri-giulia_phd2019-01-29].
Doctoral Thesis
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