Many synthetic drugs and biotechnological molecules, such as peptides, proteins and genetic materials, represent the most promising tools in the pharmacological therapy of the next future. Unfortunately, most of these medicines experience serious physico-chemical and pharmacokinetic problems (i.e., in vitro and in vivo instability, rapid clearance, low solubility and membrane permeation). Additionally, API (Active Pharmaceutical Ingredients) may show strong side-effects that limit their therapeutic use and/or their passage from laboratory scale to industrial application. Formulation in appropriate carrier systems may overcome these problems. In the last few years microtechnologies have been applied in pharmaceutics in order to modify API physico-chemical characteristics, to control drug release rate and to obtain a site specific delivery. This approach allows to reduce side effects and to increase both the stability and the therapeutic efficacy of known drugs. Polymeric material generally used to manufacture the microcarriers may modify drug release. Among polymers a special attention has been given to dextrans such as alginate and pectin which possess pH-depended solubility, physico-chemical and mucoadhesive properties useful to control drug delivery. Over the last past decade, the research group in Pharmaceutical Technology of the University of Salerno has been envolved in developing hydrated alginate microspheres (gel-beads) by laminar jet break-up technology (prilling) successively dried by conventional methods. In this context, the aim of the present PhD project was to propose innovative Prilling-based Tandem Techniques for the design and the development of NSAIDs controlled delivery systems useful in the treatment of inflammatory-based diseases. The proposed techniques have been based on the combination of: 1) prilling with microwave-assisted drying, 2) prilling with supercritical fluid-assisted drying, 3) prilling with enteric coating processes. Among various drying/curing techniques, microwave (MW) and supercritical fluid (SF) – assisted technologies have been proposed in the last few years for the production of drug delivery systems. Irradiation with microwaves has gained great interest for its peculiar way of heating materials over conventional methods by interaction of the electromagnetic waves with the irradiated matter. The efficiency of MW-assisted drying process is strongly dependent both on the dielectric, thermal and other physical properties as well as on moisture content of the irradiated material. Therefore, gel-beads with high water content are able to readily interact with microwaves for their dielectric constants that is the overriding factor affecting the efficiency of heat transfer and, in turn, drying performance. Supercritical drying processes has also gained wide acceptance as an alternative to conventional drying techniques. Particularly, supercritical antisolvent extraction (SAE) overcomes the problems encountered with traditional drying methods and preserves the nanoporous structure of the wet gel-beads leading to aerogels. Among the many possible SFs, carbon dioxide (CO2) is the most widely used. It has readily accessible critical points and as a process solvent offers the additional benefits of being non-toxic, non-flammable, environmentally acceptable, inexpensive, and can be used at a mild critical temperature suitable for processing thermally labile compounds. In the course of the research project hydrated biocompatible microcarriers have been manufactured by prilling using alginate, pectin or their blends. It is well now that gelling properties of these polymers are mainly due to the carboxyl groups able to engage in coordination bonds with divalent cations forming a so called “egg-box” structure. However, polymer type and its concentration, as well as cross-linking conditions are key parameters strongly affecting gelled microparticles performance. Therefore, influence of feed composition, cross-linking ions and gelation times on beads characteristics were investigated. The first part of the project was aimed to produce beads by prilling in combination with dielectric or supercritical drying and verify the influence of the applied drying/curing technologies on beads micromeritics, textural properties and drug release behaviour in simulated physiological fluids. The second part of the research was focused on the design and development of core-shell microparticles based on zinc-amidated pectinate core as colon-targeted delivery systems. In this case prilling in combination with enteric coating processes was applied. The double layered platforms can lead to the reduction of drug burst release effect in the upper segment of gastrointestinal tract (GIT), generally experienced by oral conventional formulations of NAIDs, therefore realizing colon targeting During the project many process parameters were intensively examined with the aim to find optimal conditions and to produce monodispersed microparticles in a reproducible way. Specific objectives of this Ph.D project were: • design and development of NSAIDs (i.e., model drugs Ketoprofen, Ketoprofen lysinate and Piroxicam) controlled delivery systems using prilling in combination with MW or SAE (Sections A and B); • development of micro-systems for controlled and colon-specific release of piroxicam useful in early morning pathologies (inflammatory bowel diseases, asthma, arthritis, allergic disorders, chronic pain, cardiovascular diseases, arthritis, arthrosis etc.) treatment (Section C); • optimization of formulation parameters to improve drug bioavailability or to decrease side effects, identified as crucial for effectiveness and efficacy of the systems. In the final part of my project, I experienced an additional SF-assisted technique, called Supercritical Assisted Atomization (SAA), for the production of gentamicin/dextrans microparticles useful in the topical treatment of wound bacterial infections (Section D).
PhD Thesis (SSD CHIM09): PRILLING-BASED TANDEM TECHNIQUES: DESIGN AND DEVELOPMENT OF NSAIDs CONTROLLED DELIVERY SYSTEMS
Giulia Auriemma
Membro del Collaboration Group
2013-01-01
Abstract
Many synthetic drugs and biotechnological molecules, such as peptides, proteins and genetic materials, represent the most promising tools in the pharmacological therapy of the next future. Unfortunately, most of these medicines experience serious physico-chemical and pharmacokinetic problems (i.e., in vitro and in vivo instability, rapid clearance, low solubility and membrane permeation). Additionally, API (Active Pharmaceutical Ingredients) may show strong side-effects that limit their therapeutic use and/or their passage from laboratory scale to industrial application. Formulation in appropriate carrier systems may overcome these problems. In the last few years microtechnologies have been applied in pharmaceutics in order to modify API physico-chemical characteristics, to control drug release rate and to obtain a site specific delivery. This approach allows to reduce side effects and to increase both the stability and the therapeutic efficacy of known drugs. Polymeric material generally used to manufacture the microcarriers may modify drug release. Among polymers a special attention has been given to dextrans such as alginate and pectin which possess pH-depended solubility, physico-chemical and mucoadhesive properties useful to control drug delivery. Over the last past decade, the research group in Pharmaceutical Technology of the University of Salerno has been envolved in developing hydrated alginate microspheres (gel-beads) by laminar jet break-up technology (prilling) successively dried by conventional methods. In this context, the aim of the present PhD project was to propose innovative Prilling-based Tandem Techniques for the design and the development of NSAIDs controlled delivery systems useful in the treatment of inflammatory-based diseases. The proposed techniques have been based on the combination of: 1) prilling with microwave-assisted drying, 2) prilling with supercritical fluid-assisted drying, 3) prilling with enteric coating processes. Among various drying/curing techniques, microwave (MW) and supercritical fluid (SF) – assisted technologies have been proposed in the last few years for the production of drug delivery systems. Irradiation with microwaves has gained great interest for its peculiar way of heating materials over conventional methods by interaction of the electromagnetic waves with the irradiated matter. The efficiency of MW-assisted drying process is strongly dependent both on the dielectric, thermal and other physical properties as well as on moisture content of the irradiated material. Therefore, gel-beads with high water content are able to readily interact with microwaves for their dielectric constants that is the overriding factor affecting the efficiency of heat transfer and, in turn, drying performance. Supercritical drying processes has also gained wide acceptance as an alternative to conventional drying techniques. Particularly, supercritical antisolvent extraction (SAE) overcomes the problems encountered with traditional drying methods and preserves the nanoporous structure of the wet gel-beads leading to aerogels. Among the many possible SFs, carbon dioxide (CO2) is the most widely used. It has readily accessible critical points and as a process solvent offers the additional benefits of being non-toxic, non-flammable, environmentally acceptable, inexpensive, and can be used at a mild critical temperature suitable for processing thermally labile compounds. In the course of the research project hydrated biocompatible microcarriers have been manufactured by prilling using alginate, pectin or their blends. It is well now that gelling properties of these polymers are mainly due to the carboxyl groups able to engage in coordination bonds with divalent cations forming a so called “egg-box” structure. However, polymer type and its concentration, as well as cross-linking conditions are key parameters strongly affecting gelled microparticles performance. Therefore, influence of feed composition, cross-linking ions and gelation times on beads characteristics were investigated. The first part of the project was aimed to produce beads by prilling in combination with dielectric or supercritical drying and verify the influence of the applied drying/curing technologies on beads micromeritics, textural properties and drug release behaviour in simulated physiological fluids. The second part of the research was focused on the design and development of core-shell microparticles based on zinc-amidated pectinate core as colon-targeted delivery systems. In this case prilling in combination with enteric coating processes was applied. The double layered platforms can lead to the reduction of drug burst release effect in the upper segment of gastrointestinal tract (GIT), generally experienced by oral conventional formulations of NAIDs, therefore realizing colon targeting During the project many process parameters were intensively examined with the aim to find optimal conditions and to produce monodispersed microparticles in a reproducible way. Specific objectives of this Ph.D project were: • design and development of NSAIDs (i.e., model drugs Ketoprofen, Ketoprofen lysinate and Piroxicam) controlled delivery systems using prilling in combination with MW or SAE (Sections A and B); • development of micro-systems for controlled and colon-specific release of piroxicam useful in early morning pathologies (inflammatory bowel diseases, asthma, arthritis, allergic disorders, chronic pain, cardiovascular diseases, arthritis, arthrosis etc.) treatment (Section C); • optimization of formulation parameters to improve drug bioavailability or to decrease side effects, identified as crucial for effectiveness and efficacy of the systems. In the final part of my project, I experienced an additional SF-assisted technique, called Supercritical Assisted Atomization (SAA), for the production of gentamicin/dextrans microparticles useful in the topical treatment of wound bacterial infections (Section D).I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
