A Mechanistic Model for Acidic Drug Release Using Microspheres Made of PLGA 50:50

Sevim, Kevser; Pan, Jia-Yu

doi:10.1021/acs.molpharmaceut.6b00313

Cited by 14 publications

(20 citation statements)

References 22 publications

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“…This can be attributed to the acidic nature of ibuprofen, which can dissociate in the water-filled pores locally decreasing the μpH also during the early degradation stage. This effect was reproduced by the model of Sevim and Pan 19 and confirmed by the result of the here developed model, which are depicted in Figure 3.…”

Section: ■ Results and Discussionsupporting

confidence: 85%

“…Sevim and Pan 19 proposed a model for the degradation of PLGA microspheres where acid catalysis is explicitly taken into account tracking the concentration of H + ions; the authors also considered the impact on μpH provided by the loading and dissociation of an acidic drug. The model showed that drug dissociation enhanced the degradation rate by virtue of the resulting low μpH value, consistently with experimental data.…”

Section: ■ Introductionmentioning

confidence: 99%

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Modeling the Microenvironment-Dependent Degradation of Drug-Loaded Polylactic-co-glycolic Microparticles

Casalini

Cingolani

Scibona

2021

Ind. Eng. Chem. Res.

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Aliphatic polyesters gained an important role in the biomedical field, finding applications as drug delivery devices, fixation screws, and suture threads, to name a few. Indeed, they merge several properties of interest, such as biocompatibility, tunable properties, and in situ hydrolytic degradation. Crucial parameters for device performances, like drug release rate and mechanical properties, are strongly influenced by polymer degradation. The main phenomena governing hydrolysis are now wellassessed and rationalized in literature; a relevant role is played by the microenvironmental pH (μpH), since hydrolysis is catalyzed in both acid and alkaline environments. A reliable μpH estimation is challenging because the microenvironment is the result of several factors: generation of acidic polymer fragments (kinetics), their partition in the water-filled pores and their dissociation (thermodynamics) and their accumulation in the device core (transport phenomena). This scenario is further complicated by the presence of an acid/basic active compound. In this work, we propose a detailed model for the microenvironmental-dependent degradation of microparticles made of polylactic-co-glycolic acid as a reference system for their relevance; in particular, μpH is explicitly calculated taking into account the dissociation, the partition and the diffusion of monomer and the drug in the water-filled pores. Comparison with experimental data showed that the model provides a quantitative estimation of molecular weight decay over time; intraparticle μpH is in good agreement in average terms, although results suggested that the dissociation of heavier water-soluble polymer fragments must be also accounted for. Model outcomes also showed that the presence of an active compound can promote acid or basic catalysis and enhance degradation rate, as observed experimentally. A quantitative agreement (in terms of molecular weight decay and cumulative release over time) could be obtained with further refinement of input parameters; overall, results suggested that a reliable description of particle morphology and a more accurate thermodynamic model (to properly account for dissociation and partition as a function of composition and μpH in the water-filled pores) are envisaged to obtain a more robust evaluation of microenvironmental effects.

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Section: ■ Results and Discussionsupporting

confidence: 85%

Section: ■ Introductionmentioning

confidence: 99%

Modeling the Microenvironment-Dependent Degradation of Drug-Loaded Polylactic-co-glycolic Microparticles

Casalini

Cingolani

Scibona

2021

Ind. Eng. Chem. Res.

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“…Because the typical size of drug particles is much smaller than the characteristic diffusion distance in a drug-loaded polymer, the actual morphology of the drug particles are ignored and the drug-loaded polymer is treated as a continuum solid. Assuming Fick's law for diffusion, the oligomer and drug concentrations, , and are governed by [23]…”

Section: Rate Equation For Oligomer and Drug Diffusionmentioning

confidence: 99%

A model for hydrolytic degradation and erosion of biodegradable polymers

Sevim

Pan

2018

Acta Biomaterialia

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In order to design bioresorbable implants, it is important to have a mathematical model to predict polymer degradation and corresponding drug release. However, very different behaviours of polymer degradation have been observed and there is no single model that can capture all these behaviours. For the first time, the model presented in this paper is capable of capture all these observed behaviours by switching on and off different underlying mechanisms. Unlike the existing reaction-diffusion models, the model presented here can follow the degradation and drug release all the way to the full disappearance of an implant.

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“…A significant amount of work has been done on the mathematical modeling of drug release profiles from polymeric microspheres, to predict drug release rates and provide insight into the fundamental processes that govern release. ,− However, the physical and chemical processes involved in drug release from biodegradable polymeric matrixes are complex, and factors such as drug solubility and its diffusion coefficient in the polymer matrix may change in time in response to polymer chain scission and influx of water. Although mechanistic models for drug-eluting depots such as the Higuchi model or the Korsmeyer–Peppas model have been used to describe drug release profiles from microspheres, − most release profiles are best described by nonmechanistic sigmoidal curve fitting models .…”

Section: Introductionmentioning

confidence: 99%

Effect of Particle Size on Drug Loading and Release Kinetics of Gefitinib-Loaded PLGA Microspheres

et al. 2016

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Polymeric microspheres have gained widespread application as drug eluting depots. Typically, drug-loaded polymeric microspheres are prepared by oil-in-water emulsification which yields a product with a broad size distribution. The aim of the present study was to investigate the properties of different size-fractions of drug-loaded microspheres, in order to delineate whether particle size governs drug loading efficiency and release profile. Gefitinib-loaded PLGA-based microspheres were prepared using an oil-in-water solvent evaporation method and wet-sieved to obtain well-defined size fractions of 5 ± 1, 32 ± 4, 70 ± 3, and 130 ± 7 μm, respectively. The average drug loading of unfractionated microspheres was 6.3 ± 0.4% w/w, while drug loading of sieved fractions ranged from 2.4 ± 0.3 to 7.6 ± 0.9% w/w for smallest to largest microparticles. X-ray diffraction (XRD) and differential scanning calorimetry (DSC) analysis demonstrated that gefitinib was amorphously dispersed in the PLGA matrix, with no apparent shift in the T of PLGA indicating the absence of direct molecular interactions of the drug and polymer due to the formation of small drug particles embedded in PLGA. In vitro drug release was studied with microspheres embedded in dextran hydrogels to avoid their aggregation during the incubation conditions. Microspheres smaller than 50 μm showed rapid diffusion-based release reaching completion within 2 days when particles have not degraded yet. Larger microspheres, however, showed a sigmoidal release pattern that continued for three months in which diffusion (early stage) as well as particle erosion (later stage) governed drug release. Scanning electron microscopy (SEM) and polymer degradation data showed that larger microspheres degraded faster than smaller ones, which is in line with autocatalytic PLGA degradation upon acidification within the core of microparticles. In conclusion, we showed that different size-fractions of drug-loaded microspheres showed quite distinct drug loading and release kinetics. Control of microparticle size by fractionation is therefore an important determinant for obtaining well-defined and reproducible sustained release depots.

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A Mechanistic Model for Acidic Drug Release Using Microspheres Made of PLGA 50:50

Cited by 14 publications

References 22 publications

Modeling the Microenvironment-Dependent Degradation of Drug-Loaded Polylactic-co-glycolic Microparticles

Modeling the Microenvironment-Dependent Degradation of Drug-Loaded Polylactic-co-glycolic Microparticles

A model for hydrolytic degradation and erosion of biodegradable polymers

Effect of Particle Size on Drug Loading and Release Kinetics of Gefitinib-Loaded PLGA Microspheres

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