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

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.

2.1. Materials

Piroxicam (PX) was kindly gifted from Medical Union Pharmaceutical (MUP) Co., Egypt. Polyethylene sorbitan monooleate (Tween^® 80), Freund’s complete adjuvant (CFA), Sorbitan monooleate (Span^® 80), Cholesterol Brij 52^®, and cellulose membrane dialysis bags were obtained from Sigma-Aldrich Chemie GmbH, Steinheim, Germany. Captex^® GTO was kindly donated by Abitec Corporation, Janesville, WI, USA. Dimethyl sulfoxide (DMSO) and triacetin were purchased from Merck KGaA, Darmstadt, Germany. Sodium di-hydrogen orthophosphate-1-hydrate (Minimum Assay 98%), di-sodium hydrogen orthophosphate anhydrous (Minimum Assay Acidimetric 98%), and sodium chloride were acquired from ADWIC, Egypt. Eudragit^® Rl 100 was bought from Evonik Operations GmbH, Germany. PURASORB^® PDLG 7502 was a kind gift From Corbion Co., Amsterdam, The Netherlands.

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El Hoffy, N.M.; Yacoub, A.S.; Ghoneim, A.M.; Ibrahim, M.; Ammar, H.O.; Eissa, N. Computational Amendment of Parenteral In Situ Forming Particulates’ Characteristics: Design of Experiment and PBPK Physiological Modeling. Pharmaceutics 2023, 15, 2513.
https://doi.org/10.3390/pharmaceutics15102513

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