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. 2023 Oct 23;15(10):2513.
doi: 10.3390/pharmaceutics15102513.

Computational Amendment of Parenteral In Situ Forming Particulates' Characteristics: Design of Experiment and PBPK Physiological Modeling

Nada M El Hoffy  1 , Ahmed S Yacoub  1   2 , Amira M Ghoneim  1 , Magdy Ibrahim  3 , Hussein O Ammar  1 , Nermin Eissa  4
Affiliations

Computational Amendment of Parenteral In Situ Forming Particulates' Characteristics: Design of Experiment and PBPK Physiological Modeling

Nada M El Hoffy et al. Pharmaceutics. .

Abstract

Lipid and/or polymer-based drug conjugates can potentially minimize side effects by increasing drug accumulation at target sites and thus augment patient compliance. Formulation factors can present a potent influence on the characteristics of the obtained systems. The selection of an appropriate solvent with satisfactory rheological properties, miscibility, and biocompatibility is essential to optimize drug release. This work presents a computational study of the effect of the basic formulation factors on the characteristics of the obtained in situ-forming particulates (IFPs) encapsulating a model drug using a 21.31 full factorial experimental design. The emulsion method was employed for the preparation of lipid and/or polymer-based IFPs. The IFP release profiles and parameters were computed. Additionally, a desirability study was carried out to choose the optimum formulation for further morphological examination, rheological study, and PBPK physiological modeling. Results revealed that the type of particulate forming agent (lipid/polymer) and the incorporation of structure additives like Brij 52 and Eudragit RL can effectively augment the release profile as well as the burst of the drug. The optimized formulation exhibited a pseudoplastic rheological behavior and yielded uniformly spherical-shaped dense particulates with a PS of 573.92 ± 23.5 nm upon injection. Physiological modeling simulation revealed the pioneer pharmacokinetic properties of the optimized formulation compared to the observed data. These results assure the importance of controlling the formulation factors during drug development, the potentiality of the optimized IFPs for the intramuscular delivery of piroxicam, and the reliability of PBPK physiological modeling in predicting the biological performance of new formulations with effective cost management.

Keywords: PBPK; PDLG; cholesterol; design of experiment; in situ forming nanoparticles; lipid; parenteral; polymer; targeted drug delivery.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Example of 3D-response surface plots for the effect of formulation factors on (A) PS, (B) Box–Cox transformation for PS, (C) PDI, (D) Q0.5, (E) MDT, and (F) Box–Cox transformation for MDT.
Figure 2
Figure 2
(A) Release profile of the prepared IFPs and (B) the desirability study marked with the chosen formulation.
Figure 3
Figure 3
Release profiles of the chosen formulation IFP3 against modified formulations with (A) structural additives and (B) different solvents.
Figure 4
Figure 4
(A) Transmission electron micrograph (TEM) of the optimized formulations (IFP3-EBD). (B) PBPK simulated PX plasma concentration–time curves following IM application of IFP3-EBD.
See this image and copyright information in PMC

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