Finerenone loaded Self-Nanoemulsifying Drug Delivery System with pH modification for enhanced solubility and dissolution = 용해도 및 용출 향상을 위한 pH 조절이 적용된 피네레논 함유 SNEDDS 개발

국문 초록 (Abstract)

pH 조절을 통합한 자가 나노유화 약물 전달 시스템 (SNEDDS)은 친유성과 pH 의존적 용해도를 갖는 비스테로이드성 미네랄코르티코이드 수용체 길항제인 피네레논 (FIN)의 낮은 용출률과 제한된 생체이용률 문제를 해결하기 위해 개발되었다. 계면활성제와 오일은 FIN의 용해도와 장기 안정성 평가를 기반으로 선정되었다. 계면활성제 상에서 유기산을 스크리닝한 결과, 구연산 (CA)은 pH 조절제 중 가장 높은 용해도를 보였으며, SNEDDS 내부 미세환경의 pH를 산성으로 유지함으로써 FIN의 이온화를 증가시키고 과포화 상태를 안정화하여 재결정화를 억제하는 데 기여하였다. SNEDDS의 구성비는 수성 분산액에 분산된 입자 크기를 통해 결정되었다. 최적화된 제형에 대해 장기 보관 안정성, 네 가지 pH 완충액에서의 용출률, 그리고 CA 캡슐화 효율을 평가했다. SNEDDS는 6.87%의 FIN 함량을 나타냈고, 이는 CA를 첨가하지 않은 제형보다 5.58배 높았으며, 20 nm 미만의 입자 크기, 모든 pH 범위에서 일관되고 완전한 용출률 (30분에서 90% 이상)을 나타냈고, 실온에서 8주 후에도 97% 이상의 안정성을 나타냈다. 따라서 본 연구는 pH 조절 기반 SNEDDS가 FIN의 제제화에 있어 용해도 및 용출 향상에 기여할 수 있는 유망한 약물 전달 시스템임을 시사한다.

다국어 초록 (Multilingual Abstract)

Self-nanoemulsifying drug delivery systems (SNEDDS) incorporating pH modification were developed to address the poor dissolution and limited bioavailability of finerenone (FIN), a nonsteroidal mineralocorticoid receptor antagonist with lipophilic properties and pH-dependent solubility. Surfactants and oil phases were selected based on evaluations of FIN solubility and long-term stability. As a result of screening organic acids in surfactant, citric acid (CA) showed the highest solubility among pH modifiers, and contributed to suppressing recrystallization by increasing the ionization of FIN and stabilizing the supersaturation by maintaining the pH of the microenvironment of SNEDDS as acidic. The composition ratio of SNEDDS was determined through particle size dispersed in aqueous dispersion. The optimized formulation was evaluated for long-term storage stability, dissolution rate in four pH buffers, and CA encapsulation efficiency. The SNEDDS had a FIN loading of 6.87%, which was 5.58-fold higher than that of the formulation without CA, and it exhibited a particle size of <20 nm, consistent and complete dissolution rates (>90% at 30 min) in four pH media, and minimal degradation of <3% after 8 weeks at room temperature. These results demonstrate that SNEDDS with pH modifier increases FIN loading and enhances dissolution.

목차 (Table of Contents)

• 국문초록
• ABSTRACT
• List of Tables
• List of Figures
• Abbreviation
• I. Introduction 1
• II. Purpose 7
• III. Materials and Methods 8
• 1. Materials 8
• 2. HPLC Condition 9
• 3. pH Solubility of FIN at 37 °C 9
• 4. Solubility of FIN in surfactant and oil 10
• 5. Dispersion particle size of vehicles 10
• 6. Solubility of organic acid in surfactant 11
• 7. Solubility of FIN in surfactant solution containing CA 12
• 8. Preparation of SNEDDS formulation 12
• 9. Stability of FIN in surfactants and oils, and SNEDDS formulations(F1-F5) 14
• 10. Encapsulation efficiency% of CA 14
• 11. Dissolution study 15
• 12. Differential Scanning Calorimetry (DSC) study 16
• IV. Result and Discussion 17
• 1. pH solubility studies of FIN at 37 °C 17
• 2. Solubility of FIN in surfactants and oils 19
• 3. Stability of FIN in surfactants and oils 21
• 4. Solubility of organic acids in surfactant 23
• 5. Solubility of FIN in surfactants containing CA 25
• 6. Screening of vehicles 27
• 7. FIN loading% of SNEDDS formulations 29
• 8. Stability of FIN in SNEDDS formulations 31
• 9. Encapsulation efficiency% of CA 35
• 10. Dissolution study 38
• 11. DSC study 44
• V. Conclusion 46
• VI. Reference 47
• VII. 감사의 글 52