Selecting the particle size distribution for drugs with low water solubility – mathematical model

Arav, Yehuda; Bercovier, Michel; Parnas, H.

doi:10.3109/03639045.2011.634808

Cited by 5 publications

(23 citation statements)

References 44 publications

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“…The transit term describes the concomitant propulsion of dissolved levodopa by the SI walls toward its end and the mixing. As was mentioned above, the SI is described as a continuous tube similar to 12,14,24 , but contrary to the compartmental approach 15,58 . The propulsion of the dissolved levodopa toward the distal SI is described by a convection term of the mean velocity, while the mixing along the SI is described as a dispersion term (that is, an effective diffusion term).…”

Section: Methodsmentioning

confidence: 99%

“…The levodopa that was released is rapidly dissolved 23,24 , and emptied continuously to the SI. That is, the time scale of the dissolution process is much shorter than the is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) time scale of the other processes in the stomach (see Methods for details).…”

Section: Modeling the Oral Absorption Of Controlled Release Levodopamentioning

confidence: 99%

Section: Mathematical Modelmentioning

confidence: 99%

“…The levodopa that was released is rapidly dissolved 23,24 , and emptied continuously to the SI. That is, the time scale of the dissolution process is much shorter than the time scale of the other processes in the stomach (see Methods for details).…”

Section: Introductionmentioning

confidence: 99%

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Model-based optimization of controlled release formulation of levodopa for Parkinson’s disease

Arav

Zohar²

2023

Preprint

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Levodopa is the current standard of care for Parkinson's disease, but chronic therapy has been associated with motor complications. Maintaining sustained and constant blood concentrations may reduce these complications, but designing a controlled release formulation (CRF) that delivers such a profile is challenging. To facilitate the development of such formulation, we developed and validated a physiologically based mathematical model. Analysis of experimental results using the model shows that levodopa is well absorbed along the entire small intestine and that levodopa in the stomach causes fluctuations during the first 3 hours after administration. Based on these insights, we used the model to develop guidelines for an optimal CRF for different stages of PD. Such formulation is expected to produce steady concentrations and prolong therapeutic duration by 50% over a common CRF with a lower dose, thereby increasing the patient's compliance with the dosage regime.

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Section: Methodsmentioning

confidence: 99%

Section: Modeling the Oral Absorption Of Controlled Release Levodopamentioning

confidence: 99%

Section: Mathematical Modelmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Model-based optimization of controlled release formulation of levodopa for Parkinson’s disease

Arav

Zohar²

2023

Preprint

Self Cite

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“…The levodopa that was released is rapidly dissolved 26 , 39 , and emptied continuously to the SI. That is, the time scale of the dissolution process is much shorter than the time scale of the other processes in the stomach.…”

Section: Methodsmentioning

confidence: 99%

Model-based optimization of controlled release formulation of levodopa for Parkinson’s disease

Arav,

Zohar

2023

Sci Rep

Self Cite

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Levodopa is currently the standard of care treatment for Parkinson’s disease, but chronic therapy has been linked to motor complications. Designing a controlled release formulation (CRF) that maintains sustained and constant blood concentrations may reduce these complications. Still, it is challenging due to levodopa’s pharmacokinetic properties and the notion that it is absorbed only in the upper small intestine (i.e., exhibits an “absorption window”). We created and validated a physiologically based mathematical model to aid the development of such a formulation. Analysis of experimental results using the model revealed that levodopa is well absorbed throughout the entire small intestine (i.e., no “absorption window”) and that levodopa in the stomach causes fluctuations during the first 3 h after administration. Based on these insights, we developed guidelines for an improved CRF for various stages of Parkinson’s disease. Such a formulation is expected to produce steady concentrations and prolong therapeutic duration compared to a common CRF with a smaller dose per day and a lower overall dose of levodopa, thereby improving patient compliance with the dosage regime.

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Advances in Modeling Approaches for Oral Drug Delivery: Artificial Intelligence, Physiologically Based Pharmacokinetic, and First-Principal Models

Arav

2024

Preprint

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Oral drug absorption is the primary route for drug administration. However, this process hinges on multiple factors, including the drug’s physicochemical properties, formulation characteristics, and gastrointestinal physiology. Given its intricacy and the exorbitant costs associated with experimentation, the trial-and-error method proves prohibitively expensive. Theoretical models have emerged as a cost-effective alternative by assimilating data from diverse experiments and theoretical considerations. These models fall into three categories: data-driven models, encompassing classical pharmacokinetics, quantitative-structure models (QSAR), and machine/deep learning. Mechanism-based models include quasi-equilibrium, steady-state, and physiologically based pharmacokinetics, alongside first principles such as molecular dynamics and continuum models. This review provides an overview of recent modeling endeavors across these categories, evaluating their respective advantages and limitations. Additionally, a primer on partial differential equations and their numerical solutions is included in the supplementary materials, recognizing their utility in modeling physiological systems despite their mathematical complexity limiting their widespread application in this field.

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Selecting the particle size distribution for drugs with low water solubility – mathematical model

Abstract: The results of this work provide the formulator with guidelines to select both r(m) and gSTD that guarantee optimal absorption.

Cited by 5 publications

References 44 publications

Model-based optimization of controlled release formulation of levodopa for Parkinson’s disease

Model-based optimization of controlled release formulation of levodopa for Parkinson’s disease

Model-based optimization of controlled release formulation of levodopa for Parkinson’s disease

Advances in Modeling Approaches for Oral Drug Delivery: Artificial Intelligence, Physiologically Based Pharmacokinetic, and First-Principal Models

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