Formulation and In Vivo Evaluation of a Solid Self-Emulsifying Drug Delivery System Using Oily Liquid Tocotrienols as Model Active Substance
Abstract
:1. Introduction
2. Materials and Methods
2.1. Materials
2.2. Preparation and Assessment of s-SEDDS
2.2.1. Solid Carrier Selection
2.2.2. Preparation of s-SEDDS Tocotrienol Powder
2.2.3. Assessment of Self-Emulsification Properties
2.3. Characterisation of the Optimised s-SEDDS
2.3.1. Evaluation of Powder Flow Properties
2.3.2. Release Studies of Mixed Tocotrienols from s-SEDDS
2.3.3. HPLC Analysis
2.3.4. Stability Evaluation of Emulsion Product
2.3.5. Droplet Size Analysis of the Emulsion Products
2.4. In Vivo Oral Bioavailability Studies
2.4.1. Animals
2.4.2. Preparation of Various Mixed Tocotrienol Preparations
2.4.3. Experimental Protocol
2.4.4. Analysis of Plasma Delta-, Gamma- and Alpha-Tocotrienol
2.4.5. Data and Pharmacokinetic Analysis
2.4.6. Statistical Analysis
3. Results
3.1. Solid Carrier Selection
3.2. Assessment of Self-Emulsification Properties
3.3. Characterisation of the Optimised s-SEDDS
3.3.1. Evaluation of Powder Flow Properties
3.3.2. Release Studies of Mixed Tocotrienols from s-SEDDS
3.3.3. Stability Evaluation of Emulsion Product
3.3.4. Droplet Size Analysis of the Emulsion Products
3.4. In Vivo Oral Bioavailability Studies
3.4.1. In Vivo Evaluation of Different s-SEDDS Mixed Tocotrienol Formulations
3.4.2. In Vivo Evaluation of s-SEDDS Versus Liquid SEDDS and Non-Self-Emulsifying Preparations of Tocotrienols
4. Discussion
4.1. Solid Carrier Selection
4.2. Assessment of Self-Emulsification Properties
4.3. Characterisation of the Optimised s-SEDDS
4.4. In Vivo Oral Bioavailability Studies
4.4.1. In Vivo Evaluation of Different s-SEDDS Mixed Tocotrienol Formulations
4.4.2. In Vivo Evaluation of s-SEDDS Versus Liquid SEDDS and Non-Self-Emulsifying Preparations of Tocotrienols
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Study | Group | Sequence of Administration | ||
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Week 1 | Week 2 | Week 3 | ||
I | 1 | B2 | B3 | B1 |
2 | B1 | B2 | B3 | |
3 | B3 | B1 | B2 | |
II | 1 | TRF | B2 | Tocovid Suprabio™ |
2 | Tocovid Suprabio™ | TRF | B2 | |
3 | B2 | Tocovid Suprabio™ | TRF |
Composition of Liquid Mixture (%) | Type of Formulation Tested, Visual Grading Results * and Emulsification Time (Seconds) | ||||
---|---|---|---|---|---|
Code | TRF | Pol | Lab | (1) Liquid Mixture | (2) Solid Formulation |
A1 | 60 | 0 | 40 | A, 4.5 (0.4) | A, 5.9 (0.2) |
A2 | 60 | 20 | 20 | A, 14.4 (0.9) | A, 6.3 (0.7) |
A3 | 60 | 40 | 0 | C | A, 7.0 (0.9) |
B1 | 70 | 0 | 30 | C | A, 5.0 (0.6) |
B2 | 70 | 15 | 15 | A, 11.5 (0.9) | A, 5.2 (0.4) |
B3 | 70 | 30 | 0 | D | A, 6.8 (0.7) |
C1 | 80 | 0 | 20 | D | C |
C2 | 80 | 10 | 10 | D | C |
C3 | 80 | 20 | 0 | D | A, 13.3 (0.8) |
Formulation | Density (g/mL) | CI (%) | HR | Angle of Repose (°) | ||||
---|---|---|---|---|---|---|---|---|
Code | Bulk | Tapped | Value | Class | Value | Class | Value | Class |
B1 | 0.4765 | 0.5179 | 7.94 | Excellent | 1.09 | Excellent | 31.71 | Good |
(0.0002) | (0.0153) | (2.75) | (0.03) | (1.51) | ||||
B2 | 0.4415 | 0.4658 | 5.17 | Excellent | 1.05 | Excellent | 27.52 | Excellent |
(0.0114) | (0.0192) | (1.43) | (0.02) | (0.94) | ||||
B3 | 0.4169 | 0.4415 | 5.56 | Excellent | 1.06 | Excellent | 25.86 | Excellent |
(0.0001) | (0.0056) | (1.20) | (0.01) | (0.97) |
Formulation | Physical Stability | Z-Average | PDI |
---|---|---|---|
Code | (nm) | ||
B1 | No separation | 276.9 (10.7) | 0.528 (0.065) |
B2 | No separation | 226.1 (2.4) | 0.441 (0.035) |
B3 | Slight creaming | 210.8 (7.2) | 0.373 (0.009) |
Delta-Tocotrienol | Gamma-Tocotrienol | Alpha-Tocotrienol | |||||||
---|---|---|---|---|---|---|---|---|---|
Formulations | B1 | B3 | B2 | B1 | B3 | B2 | B1 | B3 | B2 |
Cmax (ng/mL) | 101.1 | 81.3 | 194.9 | 340.3 | 249.7 | 594.2 | 1013.3 | 678.1 | 955.3 |
(41.3) | (30.3) * | (84.6) | (104.9) | (60.5) * | (230.8) | (224.3) ^ | (89.2) * | (133.9) | |
Tmax (h) | 9.3 | 2.3 | 1.9 | 9.3 | 3.3 | 1.9 | 9.3 | 7.3 | 3.2 |
(3.3) *^ | (1.9) | (0.6) | (3.3) * | (2.9) | (0.6) | (3.3) * | (1.0) * | (0.8) | |
AUC0-12h (h.ng/mL) | 566.7 | 500.3 | 593.7 | 1895.1 | 1640.5 | 1832.0 | 5745.3 | 5624.8 | 5684.5 |
(254.0) | (140.6) | (107.6) | (675.1) | (399.5) | (266.2) | (1951.1) | (852.5) | (396.4) | |
C.I. Cmax | 0.36–0.91 | 0.33–0.63 | 0.40–0.93 | 0.35–0.59 | 0.87–1.36 | 0.61–0.83 | |||
C.I. AUC0-12h | 0.66–1.28 | 0.74–0.99 | 0.77–1.36 | 0.80–1.01 | 0.83–1.18 | 0.92–1.07 |
Delta-Tocotrienol | Gamma-Tocotrienol | Alpha-Tocotrienol | |||||||
---|---|---|---|---|---|---|---|---|---|
Formulations | B2 | Tocovid | TRF | B2 | Tocovid | TRF | B2 | Tocovid | TRF |
Cmax (ng/mL) | 133.5 | 498.3 | 57.5 | 424.3 | 648.8 | 192.0 | 1126.4 | 1089.7 | 394.7 |
(55.1) ^ | (86.3) * | (53.8) | (155.4) | (114.5) | (171.5) | (173.5) # | (123.6) # | (159.3) | |
Tmax (h) | 4.4 | 1.8 | 6.6 | 4.4 | 1.8 | 6.7 | 6.2 | 3.0 | 7.2 |
(3.3) | (0.3) | (5.3) | (3.3) | (0.3) | (5.1) | (4.0) | (0.0) | (4.6) | |
AUC0-12h (h.ng/mL) | 665.5 | 1583.2 | 228.4 | 2128.6 | 2301.3 | 759.4 | 7913.4 | 7509.3 | 2639.2 |
(144.0) *^ | (242.0) * | (137.6) | (428.6) * | (252.1) * | (401.6) | (1253.7) * | (571.7) * | (1342.2) | |
C.I. Cmax | 2.25–4.91 | 8.46–15.62 | 2.09–4.61 | 3.24–5.71 | 2.61–3.32 | 2.48–3.50 | |||
C.I. AUC0-12h | 2.57–5.02 | 6.61–10.50 | 2.40–4.59 | 2.78–4.32 | 2.77–4.09 | 2.71–3.96 |
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Lee, Y.Z.; Seow, E.K.; Lim, S.C.; Yuen, K.H.; Abdul Karim Khan, N. Formulation and In Vivo Evaluation of a Solid Self-Emulsifying Drug Delivery System Using Oily Liquid Tocotrienols as Model Active Substance. Pharmaceutics 2021, 13, 1777. https://doi.org/10.3390/pharmaceutics13111777
Lee YZ, Seow EK, Lim SC, Yuen KH, Abdul Karim Khan N. Formulation and In Vivo Evaluation of a Solid Self-Emulsifying Drug Delivery System Using Oily Liquid Tocotrienols as Model Active Substance. Pharmaceutics. 2021; 13(11):1777. https://doi.org/10.3390/pharmaceutics13111777
Chicago/Turabian StyleLee, You Zhuan, Eng Kwong Seow, Sheau Chin Lim, Kah Hay Yuen, and Nurzalina Abdul Karim Khan. 2021. "Formulation and In Vivo Evaluation of a Solid Self-Emulsifying Drug Delivery System Using Oily Liquid Tocotrienols as Model Active Substance" Pharmaceutics 13, no. 11: 1777. https://doi.org/10.3390/pharmaceutics13111777
APA StyleLee, Y. Z., Seow, E. K., Lim, S. C., Yuen, K. H., & Abdul Karim Khan, N. (2021). Formulation and In Vivo Evaluation of a Solid Self-Emulsifying Drug Delivery System Using Oily Liquid Tocotrienols as Model Active Substance. Pharmaceutics, 13(11), 1777. https://doi.org/10.3390/pharmaceutics13111777