Design and principles of multiple trace element delivery via ionic chelation
- 주제(키워드) Trace element-citrate ionic complex , Trisodium citrate dihydrate , Enhanced pH stability , Controlled bioavailability , Reduced pain scores , Sprague–Dawley rat model
- 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/000000036151
- 본문언어 영어
- 저작권 아주대학교 논문은 저작권에 의해 보호받습니다.
초록/요약
Trace elements such as zinc （Zn）, copper （Cu）, manganese （Mn）, chromium （Cr）, and selenium （Se） are essential cofactors in human metabolism and are commonly supplemented in patients receiving total parenteral nutrition （TPN）. The commercial product Multitrace®-5 （MT5） stability, physicochemical properties and patient-friendly therapeutic performance for parenteral maintains solubility of these trace elements through sulfuric acid pH adjustment under highly acidic pH 2.5 conditions, causing intravenous injection-related irritation, bruising and pain. The aims of this study was to investigate an acid-free ionic chelate of trace elements with good nutrition supplementation. Trisodium citrate dihydrate （TCD） was selected as a multifunctional excipient with chelating and buffering properties. Trace element – citrate ionic chelates （TCIC） were prepared at different stoichiometric ratios and characterized by FT-IR, FE-SEM, and Raman spectroscopy, confirming stable coordinated chelation. The TCIC containing ≥15 mg/mL TCD retained trace metal solubility without precipitation and enhanced stability for 8 weeks’ storage at 60 °C. Osmolality was also tolerable and close to physiological levels. Based on solubility, stability and osmolarity, TCIC （F5） with 15 mg TCD was selected as the optimal 2.1 molar ratio. Preliminary pharmacokinetic studies in rats, TCIC （F5） demonstrated that Zn, Cu, and Se achieved systemic exposures comparable to MT5, while Mn and Cr displayed significantly lower plasma concentration due to the difference of bonding strength via coordination numbers and slow ligand exchange kinetics, promoting redistribution and enhanced renal elimination rather than reduced absorption. Furthermore, the behavioral parameters to pain scores were highly improved, eliciting markedly reduced nociceptive responses and minimal vascular discoloration. These findings indicate that TCD can be utilized to improve the in vitro and in vivo performance via ionic chelation to overcome the intrinsic limitation of current acidic-based MT5, providing enhanced physicochemical stability, physiological osmolality, and tolerability of TCIC. The current TCIC （F5） can be used as a promising and patient-friendly alternative for intravenous trace element supplementation, particularly in light of recent clinical and regulatory shifts of MT5 by eliminating Cr and reducing Mn content in half.
more목차
1. Introduction 1
2. Materials and Methods 5
2.1. Materials. 5
2.2. Preparation of injection formulations 5
2.3. Solubility studies under pH variation 9
2.4. Complex formation studies 9
2.5. Stability testing 10
2.6. Osmolality measurement 11
2.7. Field emission scanning electron microscopy (FE-SEM). 11
2.8. FT-IR spectroscopy 12
2.9. Raman spectroscopy 12
2.10. Quantification of metal ions by ICP-OES. 12
2.11. Pharmacokinetic study in rats 13
2.12. Pain score test 15
2.13. Statistical analysis 17
3. Results and Discussion 18
3.1. Effect of pH on metal ion solubility. 18
3.1.1. Scientific interpretation 26
3.2. Stability of formulations under accelerated storage conditions . 26
3.2.1. Physicochemical stability under accelerated storage conditions 26
3.2.2. Osmolality measurement 33
3.3. Characterization of metal–citrate coordination complexes 36
3.3.1. FT-IR spectral analysis of citrate complexes 37
3.3.2. Surface morphology using FE-SEM 42
3.3.3. Raman spectroscopy analysis 46
3.3.4. Raman spectroscopy analysis 54
3.4. In Vivo Pharmacokinetic Studies 55
3.5. Pain behavior assessment in rats after intravenous injection 62
4. Conclusions 70
5. References 75
