Investigation of second-meal intake time and bioequivalence of tadalafil-loaded orodispersible films
- 주제(키워드) Tadalafil , ODF , IVIVC , Pharmacokinetic , Bioavailability
- 주제(DDC) 615.1
- 발행기관 아주대학교 일반대학원
- 지도교수 Beom-Jin Lee
- 발행년도 2024
- 학위수여년월 2024. 8
- 학위명 박사
- 학과 및 전공 일반대학원 약학과
- 실제URI http://www.dcollection.net/handler/ajou/000000034223
- 본문언어 영어
- 저작권 아주대학교 논문은 저작권에 의해 보호받습니다.
초록/요약
Tadalafil (TD) has poor water solubility but is well absorbed without affecting food intake when administered orally. Owing to patient adherence and therapeutic characteristics, a TD-loaded orodispersible film (TDF) is preferable. However, the mechanistic role of dietary status on the clinical pharmacokinetic analysis of TDF in healthy human volunteers should be investigated because the gastrointestinal environment varies periodically according to meal intervals, alt-hough commercial 20 mg TD-loaded tablets (TD-TAB, Cialis® tablet) may be taken with or with-out food. TDF was prepared by dispersing TD in an aqueous solution and polyethylene glycol 400 to ensure good dispersibility of the TD particles. In the fasting state, each T/R of Cmax and AUC between TD-TAB and TDF showed bioequivalence with 0.936–1.105 and 1.012–1.153, respec-tively, and dissolution rates in 1000 mL water containing 0.5% SLS were equivalent. In contrast, TDF was not bioequivalent to TD-TAB under the fed conditions by the Cmax T/R of 0.610–0.798. The increased dissolution rate of TDF via the micronization of drug particles and the reduced viscosity of the second meal content did not significantly affect the bioequivalence. Interestingly, an increase in second meal intake time from 4 h to 6 h resulted in the bioequivalence by the Cmax T/R of 0.851–0.998 of TD-TAB and TDF. The predictive diffusion direction model for physi-cal digestion of TD-TAB and TDF in the stomach after the first and second meal intake was suc-cessfully simulated using computational fluid dynamics modeling, accounting for the delayed drug diffusion of TDF caused by prolonged digestion of stomach contents under postprandial conditions.
more목차
1. Introduction 1
2. Materials and Methods 6
2.1. Materials 6
2.2. Preliminary screening of dispersion agents 7
2.3. TDF formulation preparation 8
2.4. Physicochemical characterization of TDF formulations 9
2.4.1. Scanning electron microscopy (SEM) 9
2.4.2. Particle size distribution (PSD) 9
2.4.3. Dissolution study 10
2.4.4. Disintegration test 10
2.5. Analysis of TD uniformity in TDF 10
2.6. The simulation of meal viscosity 11
2.7. The simulation of drug diffusion rate in the postprandial stomach conditions 14
2.7.1. The diffusion rate under simulated-meal conditions 14
2.7.2. The diffusion rate under simulated-viscosity conditions 16
2.8. Pharmacokinetics and bioequivalence test in healthy human volunteer 17
2.8.1. Fasting-state study 19
2.8.2. Fed-state study 20
2.8.3. Analysis of drug concentration in blood 21
2.8.4. Pharmacokinetic parameter calculation and analysis 22
3. Results and Discussion 23
3.1. Screening of dispersion agents and formulation design 23
3.2. The dissolution rate of TD-loaded formulations 30
3.3. The simulated postprandial diffusion rate 37
3.3.1. The viscosity of simulated-meal 37
3.3.2. The diffusion rate under simulated-meal conditions 39
3.3.3. The diffusion rate under simulated-viscosity conditions 41
3.4. Comparative bioequivalence studies 44
3.5. Mechanistic understanding on the importance of second meal intake time 58
4. Conclusions 68
5. Graphical abstract 69
Reference 71
