Enhanced solubility and oral bioavailability of Midostaurin by development of solid self- nanoemulsified drug delivery system

다국어 초록 (Multilingual Abstract)

Enhanced solubility and oral bioavailability of Midostaurin by development of solid self-nanoemulsified drug delivery system Chul Hyun Park Department of Pharmaceutical Engineering Graduate School of Dankook University Dankook University Advisor: Professor. Hee Sook Hwang This study aimed to develop a solid self-nanoemulsifying drug delivery system (S-SNEDDS) to enhance the solubility and oral bioavailability of Midostaurin (MID). Midostaurin is a drug included in Novartis' Rydapt®, which received FDA approval in 2017 for the treatment of acute myeloid leukemia. Structurally, MID is characterized by multiple fused hydrocarbon rings forming a nonpolar molecule, resulting in very low aqueous solubility but high permeability, classifying it as a BCS Class II drug. Because the drug's absorption is significantly limited at the dissolution stage, pharmaceutical approaches to improve solubility are particularly important. In this study, the effects of various oils and surfactants on MID solubility were examined. Liquid SNEDDS (L- SNEDDS) were formulated using MID, Oleic acid, Kolliphor RH40, and Tween 80. These L- SNEDDS were converted into solid SNEDDS (S-SNEDDS) using spray drying with various hydrophobic and hydrophilic carriers. The solubility, dissolution, physicochemical properties, and pharmacokinetics of these formulations were thoroughly investigated and compared to raw MID. S-SNEDDS utilizing the hydrophilic carrier β-cyclodextrin (β-CD) significantly improved the solubility and dissolution compared with the raw MID. Oral bioavailability ranked as follows: S- SNEDDS B4 > LS > raw MID. Additionally, the S-SNEDDS transformed into an amorphous form, which is beneficial for enhancing solubility and bioavailability. Overall, these promising findings suggest that the developed S-SNEDDS formulation can significantly improve the oral bioavailability of MID, providing potential for better therapeutic outcomes in acute myeloid leukemia treatment.

목차 (Table of Contents)

• I Introduction 1
• II Materials and Methods 5
• 1. Materials 5
• 2. Solubility screening of MID 6
• 3. Development of MID-loaded solid-SNEDDS 6
• 4. Physicochemical characterization 6
• 4.1 Morphology 6
• 4.2 Solid-state characterization 6
• 4.3 Fourier-transform infrared spectroscopy analysis 7
• 5. Drug content 7
• 6. Drug aqueous solubility 7
• 7. Drug release 8
• 8. Pharmacokinetics 8
• 8.1 Animal care and ethical approval 8
• 8.2 In vivo Pharmacokinetics studies 8
• 8.3 Analytical procedure 9
• 8.4 Sample preparation 9
• 9. Statistical analysis 10
• III. Results and Discussion 11
• 3.1. Selection of optimal excipients 11
• 3.2. Comparison of Characterization of Particle Size and PDI 11
• 3.3. Comparison of aqueous solubility and dissolution 12
• 3.4. Comparison of physicochemical characteristics 13
• 3.5. Pharmacokinetics 16
• Ⅳ. Conclusion 18
• References 20
• Korean abstract 47
• Acknowledgment 49