Formulation design and enhanced bioavailability of apixaban
- 주제(키워드) Apixaban , Pharmaceutical excipients , Solubility , P-glycoprotein inhibition , Controlled-release , Polyethylene oxide , TPGS , Enhanced bioavailability
- 주제(DDC) 615.1
- 발행기관 아주대학교 일반대학원
- 지도교수 Beom-Jin Lee
- 발행년도 2026
- 학위수여년월 2026. 8
- 학위명 박사
- 학과 및 전공 일반대학원 약학과
- 실제URI http://www.dcollection.net/handler/ajou/000000036264
- 본문언어 영어
- 저작권 아주대학교 논문은 저작권에 의해 보호받습니다.
초록/요약
The bioavailability of apixaban （APX） is very limited due to the poor water solubility and the P-glycoprotein （P-gp） dependent efflux system. Bases on the screening of pharmaceutical excipients with enhanced solubility and P-gp inhibitory properties of APX, controlled release （CR） formulations containing polyethylene oxide （PEO 1,000,000; 300,000） and D-α-Tocopheryl polyethylene glycol succinate （TPGS） was designed to simultaneously modulate the solubility, release rate and P-glycoprotein inhibition for enhanced bioavailability of APX. In a preliminary pharmacokinetic experiment in rats, a presence of polymers （PEO and HPMC） and TPGS in the minitablet should be crucial for enhanced APX bioavailability via concurrent P-gp inhibition and CR of solubilized APX. Furthermore, PEO and TPGS-based CR matrix tablet （REX-PT） demonstrated enhanced bioavailability in beagle dogs as compared with hydroxypropyl methylcellulose （HPMC K100; 4,000）-based CR matrix tablet （REX-H） and immediate release （IR） commercial reference tablet （Eliquis®） without adding TPGS. Interestingly, REX-PT showed therapeutic bioequivalence to be substituted with twice-a-day Eliquis®, enabling once-daily dosing by achieving comparable systemic exposures. Consequently, the formulation design by utilizing functional pharmaceutical excipients could provide a strategic approach for enhanced bioavailability of low bioavailable and frequent dosing commercial products like APX.
more목차
1. Introduction 1
2. Materials and Methods 4
2.1. Materials 4
2.2. Effect of pharmaceutical excipients on APX solubility 5
2.3. Preparation of APX-loaded minitablet 6
2.4. Preparation of APX-loaded CR matrix tablets 9
2.5. In vitro release studies of APX-loaded minitablet and matrix tablet 11
2.6. Hydrodynamic behaviors of APX-loaded matrix tablets 11
2.7. Field emission scanning electron microscopy (FE-SEM). 12
2.8. Fourier transform infrared (FT-IR) spectroscopy analysis 12
2.9. Preliminary pharmacokinetics of APX-loaded minitablet in rats 13
2.9.1. Animals and study design 13
2.9.2. Administration and blood collection in rats 13
2.9.3. Rat plasma analysis by LC-MS/MS 14
2.10. Comparative bioequivalence of APX-loaded matrix tablet in beagle dogs 15
2.10.1. Study design and animal protocol 15
2.10.2. Administration and blood sampling in beagle dogs 15
2.10.3. LC-MS/MS analysis of plasma APX concentrations 16
2.11. Analysis of pharmacokinetic parameters 18
2.12. Statistical analysis. 19
3. Results and Discussion 20
3.1. Effect of pharmaceutical excipients on APX solubility 20
3.2. Release studies of preliminary APX-loaded minitablets 22
3.3. In vivo pharmacokinetic studies of preliminary APX minitablets 24
3.4. Evaluation of physicochemical properties of APX-loaded matrix tablets 29
3.4.1. Release characteristics 29
3.4.2. Hydrodynamic behaviors 31
3.4.3. FE-SEM morphology 34
3.4.4. FT-IR spectroscopy analysis 36
3.5. In vivo pharmacokinetic performance of matrix tablet in beagle dogs 39
4. Conclusions 45
5. References 46
