As the oral route has always been the simplest and most appreciated way to administer drugs, the increasing number of new active drugs with very low solubility in water become a serious issue for the effectiveness of new medicinal specialties. Thus far, the best solution to this issue seems to be nanonization, i.e. the production of drugs as nanocrystals, which, by dramatically increasing crystal surface-volume ratio, reduces drug melting temperature with a relevant increase of drug solubility. Owing to experimental difficulties – presence of impurities, polymorphic forms, and Ostwald ripening phenomenon, i.e. the growth of the larger crystals at the expense of the smaller ones during dissolution – the determination of drugs solubility as a function of their dimension may be achieved only by a theoretical and numerical route. For these motives, the nanocrystals melting process was modeled from a thermodynamic point of view for the spheric, cylindrical, and parallelepiped-shaped geometry, by subsequently implementing the obtained mathematical model in Fortran programming language and numerically solving the written equations. The results obtained from the conducted studies are comparable to those deriving from molecular dynamics simulations. Being thermodynamically unstable, however, nanocrystals recrystallize unless they are trapped inside stabilizing carriers such as, for instance, polymeric matrices. Thus, controlled release pharmaceutical systems, constituted by an active principle and a physically or chemically reticulated polymer, were considered. The influence of viscoelastic properties of polymeric networks on drug release was, hence, evaluated by developing an ad hoc mathematical model. The numerical solution with Gauss-Seidel’s method of the model partial differential equations system was seeked with an implicit scheme based on the control volumes strategy, by implementing that in Fortran programming language. One of the most interesting aspects of the developed model consists in the possibility of measuring its various parameters by means of different experimental techniques such as, for instance, rheology, low-field NMR, and release tests. After deepening the importance of crystals shape selected to model organic drugs solubility and evaluating the influence of viscoelastic properties on the drug release from polymeric networks, the creation of a physiologically-oriented mathematical model, able to study the in vivo drug release, drug absorption, distribution, metabolism, and elimination (ADME) with particular attention to the evaluation of drug bioavailability increase related to the use of drug nanocrystals loaded into polymeric networks, was pursued. The mathematical model, constituted by a system of ordinary and partial differential equations, was implemented in Fortran programming language. This model allows comparing different formulations of the same drug or the same formulation for different drugs, evaluating effect of different doses, mean sizes and distribution of particles, and of drug solid states, i.e. amorphous, nanocrystalline, and macrocrystalline. One of the most important results of this study is the quantitative evaluation of the interaction between release kinetics and the subsequent ADME processes. Indeed, the proposed model demonstrates that the in vivo release kinetics may result different from the in vitro one owing to the effect of living tissues. In conclusion, the present model may be take into consideration and further developed as a useful tool for designing different oral release systems.

Drug nanocrystals in drug delivery and pharmacokinetics

CHIARAPPA, GIANLUCA
2018-02-23

Abstract

As the oral route has always been the simplest and most appreciated way to administer drugs, the increasing number of new active drugs with very low solubility in water become a serious issue for the effectiveness of new medicinal specialties. Thus far, the best solution to this issue seems to be nanonization, i.e. the production of drugs as nanocrystals, which, by dramatically increasing crystal surface-volume ratio, reduces drug melting temperature with a relevant increase of drug solubility. Owing to experimental difficulties – presence of impurities, polymorphic forms, and Ostwald ripening phenomenon, i.e. the growth of the larger crystals at the expense of the smaller ones during dissolution – the determination of drugs solubility as a function of their dimension may be achieved only by a theoretical and numerical route. For these motives, the nanocrystals melting process was modeled from a thermodynamic point of view for the spheric, cylindrical, and parallelepiped-shaped geometry, by subsequently implementing the obtained mathematical model in Fortran programming language and numerically solving the written equations. The results obtained from the conducted studies are comparable to those deriving from molecular dynamics simulations. Being thermodynamically unstable, however, nanocrystals recrystallize unless they are trapped inside stabilizing carriers such as, for instance, polymeric matrices. Thus, controlled release pharmaceutical systems, constituted by an active principle and a physically or chemically reticulated polymer, were considered. The influence of viscoelastic properties of polymeric networks on drug release was, hence, evaluated by developing an ad hoc mathematical model. The numerical solution with Gauss-Seidel’s method of the model partial differential equations system was seeked with an implicit scheme based on the control volumes strategy, by implementing that in Fortran programming language. One of the most interesting aspects of the developed model consists in the possibility of measuring its various parameters by means of different experimental techniques such as, for instance, rheology, low-field NMR, and release tests. After deepening the importance of crystals shape selected to model organic drugs solubility and evaluating the influence of viscoelastic properties on the drug release from polymeric networks, the creation of a physiologically-oriented mathematical model, able to study the in vivo drug release, drug absorption, distribution, metabolism, and elimination (ADME) with particular attention to the evaluation of drug bioavailability increase related to the use of drug nanocrystals loaded into polymeric networks, was pursued. The mathematical model, constituted by a system of ordinary and partial differential equations, was implemented in Fortran programming language. This model allows comparing different formulations of the same drug or the same formulation for different drugs, evaluating effect of different doses, mean sizes and distribution of particles, and of drug solid states, i.e. amorphous, nanocrystalline, and macrocrystalline. One of the most important results of this study is the quantitative evaluation of the interaction between release kinetics and the subsequent ADME processes. Indeed, the proposed model demonstrates that the in vivo release kinetics may result different from the in vitro one owing to the effect of living tissues. In conclusion, the present model may be take into consideration and further developed as a useful tool for designing different oral release systems.
GRASSI, Mario
PRICL, SABRINA
30
2016/2017
Settore ING-IND/24 - Principi di Ingegneria Chimica
Università degli Studi di Trieste
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11368/2917681
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