Personalising Dosage Forms By 3D Printing and Computer Simulation

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F60461373%3A22340%2F19%3A43919301" target="_blank" >RIV/60461373:22340/19:43919301 - isvavai.cz</a>

Výsledek na webu

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DOI - Digital Object Identifier

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Jazyk výsledku

angličtina

Název v původním jazyce

Personalising Dosage Forms By 3D Printing and Computer Simulation

Popis výsledku v původním jazyce

The emphasis on personalized (precision) medicine in recent years together with new discoveries in diagnostics and pharmacogenomics have led to increased research and development of novel formulation methods and optimized dosage forms. Amongst the most promising newly employed techniques is 3D printing of tablets or films, most notably Fused Deposition Modelling 3D printing (FDM), since it offers the possibility to produce dosage forms with complex structures and defined drug contents, adjusted to the specific needs of each individual patient (potentially also containing multiple drugs with varying release profiles). The tablet geometry and internal structure (which affects the drug release kinetics) is determined by 3D drawings, produced by computer-aided design. In the presented work, mathematical simulation was employed to adjust these tablet structures to achieve desired dissolution profiles of the produced tablets. The composition of biocompatible drug‑loaded filaments, which were produced by hot-melt extrusion and then used as the feed material for the FDM 3D printer, was optimized to achieve reproducible printing with good resolution. Relevant properties of the filaments, such as mechanical stability, dynamic viscosity and composition homogeneity were analyzed and the observed trends were used to determine the ideal composition of the excipients for the filaments. Furthermore, drug structure was analyzed using XRPD and DSC. In the first step, a parametric series of structural motifs (tablets with varying internal infill) was printed and dissolved in controlled conditions, while the concentration of the released drug in time was analyzed using HPLC. This allowed to generate a library of drug release profiles, corresponding to each structural motif. Simultaneously, the release profiles were also produced computationally, which allowed for evaluation of the effectivity of the mathematical model and for its subsequent optimization. Next, the combination of these motifs whose superposition provides the closest approximation of a required drug release profile was found by a linear combination of pre-calculated release profiles. To prove the feasibility of this concept, the combined motifs (tablets, containing two different regions with different infill ratios) were printed and the computational method was able to predict their dissolution behavior with a good accuracy. The employed computational method is based on the 3D numerical solution of drug diffusion in a boundary layer surrounding the tablet, coupled with erosion of the tablet structure encoded by the phase volume function. While the method proved to be able to predict dissolution of complex tablet structures, slight tablet swelling during the dissolution was also observed and is believed to have an impact on the process, therefore new simulation modifications are being tested to take into account this phenomenon and make the methodology universally applicable for a wider range of drugs. In the next stage of the work, the methodology was applied for more complex systems - tablets containing two different materials (each with a different active substance) were printed, the layout of the materials and their infill ratio was again varied to achieve different dissolution profiles and the computational method was further adjusted to be able to predict release profiles of both of the active substances. Lastly, the method was employed to determine, how such a tablet should be designed in order to achieve a desired drug release profile.

Název v anglickém jazyce

Personalising Dosage Forms By 3D Printing and Computer Simulation

Popis výsledku anglicky

The emphasis on personalized (precision) medicine in recent years together with new discoveries in diagnostics and pharmacogenomics have led to increased research and development of novel formulation methods and optimized dosage forms. Amongst the most promising newly employed techniques is 3D printing of tablets or films, most notably Fused Deposition Modelling 3D printing (FDM), since it offers the possibility to produce dosage forms with complex structures and defined drug contents, adjusted to the specific needs of each individual patient (potentially also containing multiple drugs with varying release profiles). The tablet geometry and internal structure (which affects the drug release kinetics) is determined by 3D drawings, produced by computer-aided design. In the presented work, mathematical simulation was employed to adjust these tablet structures to achieve desired dissolution profiles of the produced tablets. The composition of biocompatible drug‑loaded filaments, which were produced by hot-melt extrusion and then used as the feed material for the FDM 3D printer, was optimized to achieve reproducible printing with good resolution. Relevant properties of the filaments, such as mechanical stability, dynamic viscosity and composition homogeneity were analyzed and the observed trends were used to determine the ideal composition of the excipients for the filaments. Furthermore, drug structure was analyzed using XRPD and DSC. In the first step, a parametric series of structural motifs (tablets with varying internal infill) was printed and dissolved in controlled conditions, while the concentration of the released drug in time was analyzed using HPLC. This allowed to generate a library of drug release profiles, corresponding to each structural motif. Simultaneously, the release profiles were also produced computationally, which allowed for evaluation of the effectivity of the mathematical model and for its subsequent optimization. Next, the combination of these motifs whose superposition provides the closest approximation of a required drug release profile was found by a linear combination of pre-calculated release profiles. To prove the feasibility of this concept, the combined motifs (tablets, containing two different regions with different infill ratios) were printed and the computational method was able to predict their dissolution behavior with a good accuracy. The employed computational method is based on the 3D numerical solution of drug diffusion in a boundary layer surrounding the tablet, coupled with erosion of the tablet structure encoded by the phase volume function. While the method proved to be able to predict dissolution of complex tablet structures, slight tablet swelling during the dissolution was also observed and is believed to have an impact on the process, therefore new simulation modifications are being tested to take into account this phenomenon and make the methodology universally applicable for a wider range of drugs. In the next stage of the work, the methodology was applied for more complex systems - tablets containing two different materials (each with a different active substance) were printed, the layout of the materials and their infill ratio was again varied to achieve different dissolution profiles and the computational method was further adjusted to be able to predict release profiles of both of the active substances. Lastly, the method was employed to determine, how such a tablet should be designed in order to achieve a desired drug release profile.

Druh

O - Ostatní výsledky

CEP obor

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OECD FORD obor

20401 - Chemical engineering (plants, products)

Projekt

<a href="/cs/project/TJ02000383" target="_blank" >TJ02000383: Metoda výroby lékové formy, personalizované pro potřeby konkrétního pacienta za pomoci matematické simulace a 3D tisku</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2019

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů