Nanocarriers of amphiphilic polymeric materials represent versatile delivery systems for poorly w... more Nanocarriers of amphiphilic polymeric materials represent versatile delivery systems for poorly water soluble drugs. In this work the technique of solvent evaporation from multiple emulsions was applied to produce nanovectors based on new amphiphilic copolymer, the α,β-poly(N-2-hydroxyethyl)-dl-aspartamide-polylactic acid (PHEA-PLA), purposely synthesized to be used in the controlled release of active molecules poorly soluble in water. To this aim an amphiphilic derivative of PHEA, a hydrophilic polymer, was synthesized by derivatization of the polymeric backbone with hydrophobic grafts of polylactic acid (PLA). The achieved copolymer was thus used to produce nanoparticles loaded with α tocopherol (vitamin E) adopted as lipophilic model molecule. Applying a protocol based on solvent evaporation from multiple emulsions assisted by ultrasonic energy and optimizing the emulsification process (solvent selection/separation stages), PHEA-PLA nanostructured particles with total α tocopherol entrapment efficiency (100%), were obtained. The drug release is expected to take place in lower times with respect to PLA due to the presence of the hydrophilic PHEA, therefore the produced nanoparticles can be used for semi-long term release drug delivery systems.
In this paper, the philosophy of a research in pharmacology field, driven by an engineering appro... more In this paper, the philosophy of a research in pharmacology field, driven by an engineering approach, was described along with some case histories and examples. The improvement in the testing methods for pharmaceutical systems (in-vitro techniques), as well as the proposal and the testing of mathematical models to describe the pharmacokinetics (in-silico techniques) are reported with the aim of pointing out methodologies and tools able to reduce the need of expensive and ethical problematic in-vivo measurements.
Alginate solutions in the presence of bivalent ions can form ionic cross-linked gels. In particul... more Alginate solutions in the presence of bivalent ions can form ionic cross-linked gels. In particular gelation conditions the gel structure can be characterized by great anisotropy with the presence of straight capillaries along a preferential direction. These materials can find applications mainly in high-tech sectors, like tissue engineering, where the gel characteristics play a crucial role. Despite the need of mastering the capillary formation and properties, the process remains a poorly known problem, and its development is left to trial and error procedures. In this work a quantitative approach to the description of the capillary formation process has been developed. The theory proposed by Treml et al. (2003) has been implemented and extended to an alginate different from the one used in that study and two different ions (calcium and copper). Some of the model parameters have been derived through simple measurements; others have been scaled using proper scaling equations. Experiments have been performed in different gelation conditions, varying alginate and ionic solution concentrations, to highlight the effects of these parameters on the anisotropic structure and to validate the model. In all the analyses done, the model has performed nicely showing a good reliability in the prediction of gel characteristics like capillary formation, capillary length and process time.
Crystallization of polymer melts, taking place during processing, can have a great impact on the ... more Crystallization of polymer melts, taking place during processing, can have a great impact on the processing, mainly because it can cause a large increase in the viscosity. Therefore, knowledge of the crystallization kinetics as a function of the thermo-mechanical history experienced by the polymer and the relation of the rheological behavior to the crystalline state is of importance for the modeling of the process. In this work we carried out isothermal crystallization experiments, using DSC and stress controlled rotational rheometry. The time evolution of the relative crystallinity and the normalized complex viscosity evolutions are correlated by a novel technique which allows the simultaneous analysis of several experiments, even if they are not carried out at same temperatures, which is the main requirement of traditional techniques. This new approach is adopted to obtain an experimental relationship between the crystallinity and the dynamic viscosity. An empirical model, able to...
Experimental procedures are pointed out to analyze the mass transfer during the dissolution of Di... more Experimental procedures are pointed out to analyze the mass transfer during the dissolution of Diclofenac containing tablets (a NSAID, non-steroidal anti-inflammatory drug) in neutral aqueous bulk. Polymer matrix erosion and drug release phenomena are studied in a batch system where tables were immersed for different residence time. INTRODUCTION Controlled drug delivery is a key topic in pharmacology and a lot of researchers over all the world are currently involved in related studies 1-2. The most frequent route of drug administration is the oral one, i.e. the assumption of drug through the mouth, even if a lot of different routes are currently investigated. The analysis of drug effectiveness requires going into details of: (i) the drug characterization, i.e. the deep knowledge of the properties of the substances with which one is dealing with; (ii) the knowledge of the ways the human body takes up and eliminates drugs (pharmacokinetics) and of the effect of the drugs on the human ...
Introduction This work is focused on the preparation and characterization of biomedical devices. ... more Introduction This work is focused on the preparation and characterization of biomedical devices. Those biodegradable and biocompatible systems were realized using matrix of PLA in which Hydrotalcite (the carrier), loaded with diclofenac sodium (the active molecule chosen as model drug), have been dispersed The system of inorganic (Hydrotalcite) and drug (Diclofenac) was noted by the acronym HDik. The final goal of this research is to compare the drug release from the two kinds of membranes with the aim of clarify the transport phenomena which take place. Experimental Samples preparation The samples were realized using different operative conditions and with two different techniques: a) solvent casting to obtain compact membranes; b) electrospinning, to obtain porous membranes. Solvent casting technique The compact membranes were obtained by mixing the polymer and the HDik with acetone (the solvent), then by allowing the film casting by solvent evaporation, at room temperature for on...
Pharmaceuticals were often produced as small powders, and a common way to get fine particles is t... more Pharmaceuticals were often produced as small powders, and a common way to get fine particles is the spray drying process, where the most important step is the atomization. In the conventional atomization techniques the break-up of a liquid jet in droplets was caused by the transformation or by the transfer of large amounts of energy. In the single fluid atomizers, the pressure energy was changed in kinetic energy by passing in small orifices (nozzle atomizers), or the kinetic energy was supplied by rotary parts (rotary wheel atomizers). In the two fluids atomizers, the force drag (due to the difference in kinetic energy) at the interface between the two fluids causes the liquid to produce a thin film which is then reduced in threads and finally gives up to the droplets. A process which requires much less energy, and which produces droplets with a low momentum (since it works involving low velocities), is the ultrasonic atomization. In this process, the droplets were produced by spre...
La maggior parte delle trasformazioni industriali (stampaggio, filatura, filmatura) dei materiali... more La maggior parte delle trasformazioni industriali (stampaggio, filatura, filmatura) dei materiali polimerici prevedono la formatura del manufatto a partire dal materiale fuso, seguito dalla solidificazione per raffreddamento. Per i materiali semicristallini la solidificazione comporta anche la formazione di strutture ordinate (i cosiddetti cristalliti), se le condizioni di processo lo consentono (ad esempio se la velocità di raffreddamento non è troppo elevata). Durante la solidificazione ovviamente la risposta reologica del materiale cambia, passando dal comportamento del fluido (solitamente si tratta di fluidi non-newtoniani) al comportamento del solido. La conoscenza della reologia del materiale durante il processo è di enorme rilievo industriale, sia per la gestione dei processi che per la loro modellazione [1]. Oggetto del presente lavoro è l'analisi del comportamento reologico di un polipropilene isotattico a diverse temperature, e la messa a punto e la taratura di un mode...
International journal of pharmaceutics, Jan 28, 2015
Controlled release by oral administration is mainly achieved by pharmaceuticals based on hydrogel... more Controlled release by oral administration is mainly achieved by pharmaceuticals based on hydrogels. Once swallowed, a matrix made of hydrogels experiences water up-take, swelling, drug dissolution and diffusion, polymer erosion. The detailed understanding and quantification of such a complex behavior is a mandatory prerequisite to the design of novel pharmaceuticals for controlled oral delivery. In this work, the behavior of hydrogel-based matrices has been investigated by means of several experimental techniques previously pointed out (gravimetric, and based on texture analysis); and then all the observed features were mathematically described using a physical model, defined and recently improved by our research group (based on balance equations, rate equations and swelling predictions). The agreement between the huge set of experimental data and the detailed calculations by the model is good, confirming the validity of both the experimental and the theoretical approaches.
Nucleic Acid Based Drugs (NABDs) constitute a class of promising and powerful therapeutic new age... more Nucleic Acid Based Drugs (NABDs) constitute a class of promising and powerful therapeutic new agents with limited side effects, potentially useable against a wide range of diseases, including cancer. Among them, the short interfering RNAs (siRNAs), represent very effective molecules. Despite their in vitro efficacy, the major drawback that limits siRNAs usage consists in a difficult delivery due to their very low stability in physiological fluids, and to their limited membrane-permeability through physiological barriers. On the other hand, the liposomes (lipid bilayers closed in vesicles of various sizes) represent interesting drug delivery systems (DDSs) which can be tailored in order to get the best performance in terms of load, vesicle size and transfection yield. In this work, the current state of study in these two fields, and the connections between them, are briefly summarized.
In this work an engineering approach, consisting in an experimental procedure and a model to deri... more In this work an engineering approach, consisting in an experimental procedure and a model to derive the data, was presented and applied to improve the testing methods of pharmaceuticals. The permeability of several active molecules have been evaluated across a synthetic membrane. The permeability of these drugs measured through the artificial membrane were successfully correlated to their in-vivo permeability. The relationship with in-vivo permeability was derived, and then a rule to design systems to simulate the intestinal absorption was proposed to reduce the need for expensive and ethical problematic in-vivo measurements.
Remifentanil is a new opioid derivative drug characterized by a fast onset and by a short time of... more Remifentanil is a new opioid derivative drug characterized by a fast onset and by a short time of action, since it is rapidly degraded by esterases in blood and other tissues. Its pharmacokinetic and pharmacodynamics properties make remifentanil a very interesting molecule in the field of 0anesthesia. However a complete and versatile pharmacokinetic description of remifentanil still lacks. In this work a three-compartmental model has been developed to describe the pharmacokinetics of remifentanil both in the case in which it is administered by intravenous constant-rate infusion and by bolus injection. The model curves have been compared with experimental data published in scientific papers and the model parameters have been optimized to describe both ways of administration. The ad hoc model is adaptable and potentially useful for predictive purposes.
Development and optimization of novel production techniques for drug delivery systems are fundame... more Development and optimization of novel production techniques for drug delivery systems are fundamental steps in the "from the bench to the bedside" process which is the base of translational medicine. In particular, in the current scenery where the need for reducing energy consumption, emissions, wastes and risks drives the development of sustainable processes, new pharmaceutical manufacturing does not constitute an exception. In this paper, concepts of process intensification are presented and their transposition in drug delivery systems production is discussed. Moreover, some examples on intensified techniques, for drug microencapsulation and granules drying, are reported.
Nanocarriers of amphiphilic polymeric materials represent versatile delivery systems for poorly w... more Nanocarriers of amphiphilic polymeric materials represent versatile delivery systems for poorly water soluble drugs. In this work the technique of solvent evaporation from multiple emulsions was applied to produce nanovectors based on new amphiphilic copolymer, the α,β-poly(N-2-hydroxyethyl)-dl-aspartamide-polylactic acid (PHEA-PLA), purposely synthesized to be used in the controlled release of active molecules poorly soluble in water. To this aim an amphiphilic derivative of PHEA, a hydrophilic polymer, was synthesized by derivatization of the polymeric backbone with hydrophobic grafts of polylactic acid (PLA). The achieved copolymer was thus used to produce nanoparticles loaded with α tocopherol (vitamin E) adopted as lipophilic model molecule. Applying a protocol based on solvent evaporation from multiple emulsions assisted by ultrasonic energy and optimizing the emulsification process (solvent selection/separation stages), PHEA-PLA nanostructured particles with total α tocopherol entrapment efficiency (100%), were obtained. The drug release is expected to take place in lower times with respect to PLA due to the presence of the hydrophilic PHEA, therefore the produced nanoparticles can be used for semi-long term release drug delivery systems.
In this paper, the philosophy of a research in pharmacology field, driven by an engineering appro... more In this paper, the philosophy of a research in pharmacology field, driven by an engineering approach, was described along with some case histories and examples. The improvement in the testing methods for pharmaceutical systems (in-vitro techniques), as well as the proposal and the testing of mathematical models to describe the pharmacokinetics (in-silico techniques) are reported with the aim of pointing out methodologies and tools able to reduce the need of expensive and ethical problematic in-vivo measurements.
Alginate solutions in the presence of bivalent ions can form ionic cross-linked gels. In particul... more Alginate solutions in the presence of bivalent ions can form ionic cross-linked gels. In particular gelation conditions the gel structure can be characterized by great anisotropy with the presence of straight capillaries along a preferential direction. These materials can find applications mainly in high-tech sectors, like tissue engineering, where the gel characteristics play a crucial role. Despite the need of mastering the capillary formation and properties, the process remains a poorly known problem, and its development is left to trial and error procedures. In this work a quantitative approach to the description of the capillary formation process has been developed. The theory proposed by Treml et al. (2003) has been implemented and extended to an alginate different from the one used in that study and two different ions (calcium and copper). Some of the model parameters have been derived through simple measurements; others have been scaled using proper scaling equations. Experiments have been performed in different gelation conditions, varying alginate and ionic solution concentrations, to highlight the effects of these parameters on the anisotropic structure and to validate the model. In all the analyses done, the model has performed nicely showing a good reliability in the prediction of gel characteristics like capillary formation, capillary length and process time.
Crystallization of polymer melts, taking place during processing, can have a great impact on the ... more Crystallization of polymer melts, taking place during processing, can have a great impact on the processing, mainly because it can cause a large increase in the viscosity. Therefore, knowledge of the crystallization kinetics as a function of the thermo-mechanical history experienced by the polymer and the relation of the rheological behavior to the crystalline state is of importance for the modeling of the process. In this work we carried out isothermal crystallization experiments, using DSC and stress controlled rotational rheometry. The time evolution of the relative crystallinity and the normalized complex viscosity evolutions are correlated by a novel technique which allows the simultaneous analysis of several experiments, even if they are not carried out at same temperatures, which is the main requirement of traditional techniques. This new approach is adopted to obtain an experimental relationship between the crystallinity and the dynamic viscosity. An empirical model, able to...
Experimental procedures are pointed out to analyze the mass transfer during the dissolution of Di... more Experimental procedures are pointed out to analyze the mass transfer during the dissolution of Diclofenac containing tablets (a NSAID, non-steroidal anti-inflammatory drug) in neutral aqueous bulk. Polymer matrix erosion and drug release phenomena are studied in a batch system where tables were immersed for different residence time. INTRODUCTION Controlled drug delivery is a key topic in pharmacology and a lot of researchers over all the world are currently involved in related studies 1-2. The most frequent route of drug administration is the oral one, i.e. the assumption of drug through the mouth, even if a lot of different routes are currently investigated. The analysis of drug effectiveness requires going into details of: (i) the drug characterization, i.e. the deep knowledge of the properties of the substances with which one is dealing with; (ii) the knowledge of the ways the human body takes up and eliminates drugs (pharmacokinetics) and of the effect of the drugs on the human ...
Introduction This work is focused on the preparation and characterization of biomedical devices. ... more Introduction This work is focused on the preparation and characterization of biomedical devices. Those biodegradable and biocompatible systems were realized using matrix of PLA in which Hydrotalcite (the carrier), loaded with diclofenac sodium (the active molecule chosen as model drug), have been dispersed The system of inorganic (Hydrotalcite) and drug (Diclofenac) was noted by the acronym HDik. The final goal of this research is to compare the drug release from the two kinds of membranes with the aim of clarify the transport phenomena which take place. Experimental Samples preparation The samples were realized using different operative conditions and with two different techniques: a) solvent casting to obtain compact membranes; b) electrospinning, to obtain porous membranes. Solvent casting technique The compact membranes were obtained by mixing the polymer and the HDik with acetone (the solvent), then by allowing the film casting by solvent evaporation, at room temperature for on...
Pharmaceuticals were often produced as small powders, and a common way to get fine particles is t... more Pharmaceuticals were often produced as small powders, and a common way to get fine particles is the spray drying process, where the most important step is the atomization. In the conventional atomization techniques the break-up of a liquid jet in droplets was caused by the transformation or by the transfer of large amounts of energy. In the single fluid atomizers, the pressure energy was changed in kinetic energy by passing in small orifices (nozzle atomizers), or the kinetic energy was supplied by rotary parts (rotary wheel atomizers). In the two fluids atomizers, the force drag (due to the difference in kinetic energy) at the interface between the two fluids causes the liquid to produce a thin film which is then reduced in threads and finally gives up to the droplets. A process which requires much less energy, and which produces droplets with a low momentum (since it works involving low velocities), is the ultrasonic atomization. In this process, the droplets were produced by spre...
La maggior parte delle trasformazioni industriali (stampaggio, filatura, filmatura) dei materiali... more La maggior parte delle trasformazioni industriali (stampaggio, filatura, filmatura) dei materiali polimerici prevedono la formatura del manufatto a partire dal materiale fuso, seguito dalla solidificazione per raffreddamento. Per i materiali semicristallini la solidificazione comporta anche la formazione di strutture ordinate (i cosiddetti cristalliti), se le condizioni di processo lo consentono (ad esempio se la velocità di raffreddamento non è troppo elevata). Durante la solidificazione ovviamente la risposta reologica del materiale cambia, passando dal comportamento del fluido (solitamente si tratta di fluidi non-newtoniani) al comportamento del solido. La conoscenza della reologia del materiale durante il processo è di enorme rilievo industriale, sia per la gestione dei processi che per la loro modellazione [1]. Oggetto del presente lavoro è l'analisi del comportamento reologico di un polipropilene isotattico a diverse temperature, e la messa a punto e la taratura di un mode...
International journal of pharmaceutics, Jan 28, 2015
Controlled release by oral administration is mainly achieved by pharmaceuticals based on hydrogel... more Controlled release by oral administration is mainly achieved by pharmaceuticals based on hydrogels. Once swallowed, a matrix made of hydrogels experiences water up-take, swelling, drug dissolution and diffusion, polymer erosion. The detailed understanding and quantification of such a complex behavior is a mandatory prerequisite to the design of novel pharmaceuticals for controlled oral delivery. In this work, the behavior of hydrogel-based matrices has been investigated by means of several experimental techniques previously pointed out (gravimetric, and based on texture analysis); and then all the observed features were mathematically described using a physical model, defined and recently improved by our research group (based on balance equations, rate equations and swelling predictions). The agreement between the huge set of experimental data and the detailed calculations by the model is good, confirming the validity of both the experimental and the theoretical approaches.
Nucleic Acid Based Drugs (NABDs) constitute a class of promising and powerful therapeutic new age... more Nucleic Acid Based Drugs (NABDs) constitute a class of promising and powerful therapeutic new agents with limited side effects, potentially useable against a wide range of diseases, including cancer. Among them, the short interfering RNAs (siRNAs), represent very effective molecules. Despite their in vitro efficacy, the major drawback that limits siRNAs usage consists in a difficult delivery due to their very low stability in physiological fluids, and to their limited membrane-permeability through physiological barriers. On the other hand, the liposomes (lipid bilayers closed in vesicles of various sizes) represent interesting drug delivery systems (DDSs) which can be tailored in order to get the best performance in terms of load, vesicle size and transfection yield. In this work, the current state of study in these two fields, and the connections between them, are briefly summarized.
In this work an engineering approach, consisting in an experimental procedure and a model to deri... more In this work an engineering approach, consisting in an experimental procedure and a model to derive the data, was presented and applied to improve the testing methods of pharmaceuticals. The permeability of several active molecules have been evaluated across a synthetic membrane. The permeability of these drugs measured through the artificial membrane were successfully correlated to their in-vivo permeability. The relationship with in-vivo permeability was derived, and then a rule to design systems to simulate the intestinal absorption was proposed to reduce the need for expensive and ethical problematic in-vivo measurements.
Remifentanil is a new opioid derivative drug characterized by a fast onset and by a short time of... more Remifentanil is a new opioid derivative drug characterized by a fast onset and by a short time of action, since it is rapidly degraded by esterases in blood and other tissues. Its pharmacokinetic and pharmacodynamics properties make remifentanil a very interesting molecule in the field of 0anesthesia. However a complete and versatile pharmacokinetic description of remifentanil still lacks. In this work a three-compartmental model has been developed to describe the pharmacokinetics of remifentanil both in the case in which it is administered by intravenous constant-rate infusion and by bolus injection. The model curves have been compared with experimental data published in scientific papers and the model parameters have been optimized to describe both ways of administration. The ad hoc model is adaptable and potentially useful for predictive purposes.
Development and optimization of novel production techniques for drug delivery systems are fundame... more Development and optimization of novel production techniques for drug delivery systems are fundamental steps in the "from the bench to the bedside" process which is the base of translational medicine. In particular, in the current scenery where the need for reducing energy consumption, emissions, wastes and risks drives the development of sustainable processes, new pharmaceutical manufacturing does not constitute an exception. In this paper, concepts of process intensification are presented and their transposition in drug delivery systems production is discussed. Moreover, some examples on intensified techniques, for drug microencapsulation and granules drying, are reported.
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