Strategies to enhance oral delivery of curcumin using solid self-emulsifying drug delivery systems

Suchiwa Pan-On; Duy Toan Pham; Waree Tiyaboonchai

doi:10.7324/JAPS.2024.168338

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Abstract

Curcumin is a phenolic compound of turmeric with remarkable pharmacological properties. However, curcumin’s inherent poor water solubility, permeability, and instability in the gastrointestinal tract hinder its therapeutic use. Herein, curcumin-loaded solid self-micro- and nanoemulsifying drug delivery systems (C-SSMEDDS and C-SSNEDDS) were developed using Neusilin®UFL2 as a solid carrier. All developed formulations significantly showed improvement in curcumin water solubility, >100-fold as compared to the free curcumin. In both the simulated stomach (pH 1.2) and intestinal (pH 6.8) conditions, C-SSMEDDS and C-SSNEDDS enhanced the dissolution profiles of curcumin with 60%–70% release within 5 minutes and possessed an average droplet diameter of ~100 and ~150 nm, correspondingly. Moreover, permeation studies in the Caco-2 cell monolayer revealed that both formulations provided significantly greater cellular accumulation and absorption compared with the free curcumin. Finally, the C-SSMEDDS and C-SSNEDDS were physicochemically stable for at least 1 year at ambient temperature (25°C ± 0.5°C). In summary, the findings indicated that C-SSMEDDS and C-SSNEDDS are potential strategies for improving curcumin oral bioavailability.

Keyword: Absorption curcumin dissolution self-emulsifying drug delivery system oral administration

Citation:

Pan-On S, Pham DT, Tiyaboonchai W. Strategies to enhance oral delivery of curcumin using solid self-emulsifying drug delivery systems. J Appl Pharm Sci. 2024. Online first. http://doi.org/10.7324/JAPS.2024.168338

Copyright: © The Author(s). This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Reference

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3. Kulkarni S, Dhir A, Akula KK. Potentials of curcumin as an antidepressant. ScientificWorldJournal. 2009 Nov 1;9:1233-41. https://doi.org/10.1100/tsw.2009.137
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5. Sanmukhani J, Anovadiya A, Tripathi CB. Evaluation of antidepressant like activity of curcumin and its combination with fluoxetine and imipramine: an acute and chronic study. Acta Pol Pharm. 2011 Sep-Oct;68(5):769-75.
6. Kurien BT, D'Souza A, Scofield RH. Heat-solubilized curry spice curcumin inhibits antibody-antigen interaction in in vitro studies: a possible therapy to alleviate autoimmune disorders. Mol Nutr Food Res. 2010 Aug;54(8):1202-9. https://doi.org/10.1002/mnfr.200900106
7. Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB. Bioavailability of curcumin: problems and promises. Mol Pharm. 2007 Nov-Dec;4(6):807-18. https://doi.org/10.1021/mp700113r
8. Tønnesen HH, Karlsen J. Studies on curcumin and curcuminoids. VI. Kinetics of curcumin degradation in aqueous solution. Z Lebensm Unters Forsch. 1985 May;180(5):402-4. https://doi.org/10.1007/BF01027775
9. Tønnesen HH, Másson M, Loftsson T. Studies of curcumin and curcuminoids. XXVII. Cyclodextrin complexation: solubility, chemical and photochemical stability. Int J Pharm. 2002 Sep 5;244(1-2):127-35. https://doi.org/10.1016/S0378-5173(02)00323-X
10. Sadegh Malvajerd S, Azadi A, Izadi Z, Kurd M, Dara T, Dibaei M, et al. Brain delivery of curcumin using solid lipid nanoparticles and nanostructured lipid carriers: preparation, optimization, and pharmacokinetic evaluation. ACS Chem Neurosci. 2019 Jan 16;10(1):728-9. https://doi.org/10.1021/acschemneuro.8b00510
11. Karimi N, Ghanbarzadeh B, Hamishehkar H, Mehramuz B, Kafil HS. Antioxidant, antimicrobial and physicochemical properties of turmeric extract-loaded nanostructured lipid carrier (NLC). Colloid Interface Sci Commun. 2018 Jan 1;22:18-24. https://doi.org/10.1016/j.colcom.2017.11.006
12. Ganesan P, Narayanasamy D. Lipid nanoparticles: different preparation techniques, characterization, hurdles, and strategies for the production of solid lipid nanoparticles and nanostructured lipid carriers for oral drug delivery. Sustain Chem Pharm. 2017 Dec 1;6:37-56. https://doi.org/10.1016/j.scp.2017.07.002
13. Sermkaew N, Ketjinda W, Boonme P, Phadoongsombut N, Wiwattanapatapee R. Liquid and solid self-microemulsifying drug delivery systems for improving the oral bioavailability of andrographolide from a crude extract of Andrographis paniculata. Eur J Pharm Sci. 2013 Nov 20;50(3-4):459-66. https://doi.org/10.1016/j.ejps.2013.08.006
14. Kang BK, Lee JS, Chon SK, Jeong SY, Yuk SH, Khang G, et al. Development of self-microemulsifying drug delivery systems (SMEDDS) for oral bioavailability enhancement of simvastatin in beagle dogs. Int J Pharm. 2004 Apr 15;274(1-2):65-73. https://doi.org/10.1016/j.ijpharm.2003.12.028
15. Zhang P, Liu Y, Feng N, Xu J. Preparation and evaluation of self-microemulsifying drug delivery system of oridonin. Int J Pharm. 2008 May 1;355(1-2):269-76. https://doi.org/10.1016/j.ijpharm.2007.12.026
16. Gursoy RN, Benita S. Self-emulsifying drug delivery systems (SEDDS) for improved oral delivery of lipophilic drugs. Biomed Pharmacother. 2004 Apr;58(3):173-82. https://doi.org/10.1016/j.biopha.2004.02.001
17. Chatterjee B, Hamed Almurisi S, Ahmed Mahdi Dukhan A, Mandal UK, Sengupta P. Controversies with self-emulsifying drug delivery system from pharmacokinetic point of view. Drug Deliv. 2016 Nov;23(9):3639-52. https://doi.org/10.1080/10717544.2016.1214990
18. Tuleu C, Newton M, Rose J, Euler D, Saklatvala R, Clarke A, et al. Comparative bioavailability study in dogs of a self-emulsifying formulation of progesterone presented in a pellet and liquid form compared with an aqueous suspension of progesterone. J Pharm Sci. 2004 Jun;93(6):1495-502. https://doi.org/10.1002/jps.20068
19. Franceschinis E, Voinovich D, Grassi M, Perissutti B, Filipovic- Grcic J, Martinac A, et al. Self-emulsifying pellets prepared by wet granulation in high-shear mixer: influence of formulation variables and preliminary study on the in vitro absorption. Int J Pharm. 2005 Mar 3;291(1-2):87-97. https://doi.org/10.1016/j.ijpharm.2004.07.046
20. Beg S, Jena SS, Patra CN, Rizwan M, Swain S, Sruti J, et al. Development of solid self-nanoemulsifying granules (SSNEGs) of ondansetron hydrochloride with enhanced bioavailability potential. Colloids Surf B Biointerfaces. 2013 Jan 1;101:414-23. https://doi.org/10.1016/j.colsurfb.2012.06.031
21. Acharya B, Guru PS, Dash S. Tween-80-n-butanol-diesel-water microemulsion system-a class of alternative diesel fuel. J Dispers Sci Technol. 2014 Oct 3;35(10):1492-501. https://doi.org/10.1080/01932691.2013.858348
22. Bhandari S, Rana V, Tiwary AK. Antimalarial solid self-emulsifying system for oral use: in vitro investigation. Ther Deliv. 2017 Apr;8(4):201-13. https://doi.org/10.4155/tde-2016-0092
23. Kharat M, Zhang G, McClements DJ. Stability of curcumin in oil-in-water emulsions: impact of emulsifier type and concentration on chemical degradation. Food Res Int. 2018 Sep 1;111:178-86. https://doi.org/10.1016/j.foodres.2018.05.021
24. Sinha Babu SP, Sarkar D, Ghosh NK, Saha A, Sukul NC, Bhattacharya S. Enhancement of membrane damage by saponins isolated from Acacia auriculiformis. Jpn J Pharmacol. 1997 Dec;75(4):451-4. https://doi.org/10.1254/jjp.75.451
25. Craig DQ, Barker SA, Banning D, Booth SW. An investigation into the mechanisms of self-emulsification using particle size analysis and low frequency dielectric spectroscopy. Int J Pharm. 1995 Jan 31;114(1):103-10. https://doi.org/10.1016/0378-5173(94)00222-Q
26. Constantinides PP, Lancaster CM, Marcello J, Chiossone DC, Orner D, Hidalgo I, et al. Enhanced intestinal absorption of an RGD peptide from water-in-oil microemulsions of different composition and particle size. J Controlled Release. 1995 May 1;34(2):109-16. https://doi.org/10.1016/0168-3659(94)00129-I
27. Gupta MK, Vanwert A, Bogner RH. Formation of physically stable amorphous drugs by milling with Neusilin. J Pharm Sci. 2003 Mar 1;92(3):536-51. https://doi.org/10.1002/jps.10308
28. Fuji Chemical Industries. Neusilin®. [cited 2020 Apr 28]. Available from: http://www.neusilin.com/product/pharmacopoeia.php
29. Wang YJ, Pan MH, Cheng AL, Lin LI, Ho YS, Hsieh CY, et al. Stability of curcumin in buffer solutions and characterization of its degradation products. J Pharm Biomed Anal. 1997 Aug 1;15(12):1867-76. https://doi.org/10.1016/S0731-7085(96)02024-9
30. Artursson P, Karlsson J. Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells. Biochem Biophys Res Commun. 1991 Mar 29;175(3):880-5. https://doi.org/10.1016/0006-291X(91)91647-U
31. Yee S. In vitro permeability across Caco-2 cells (colonic) can predict in vivo (small intestinal) absorption in man-fact or myth. Pharm Res. 1997 Jun;14(6):763-6.
32. Maher S, Heade J, McCartney F, Waters S, Bleiel SB, Brayden DJ. Effects of surfactant-based permeation enhancers on mannitol permeability, histology, and electrogenic ion transport responses in excised rat colonic mucosae. Int J Pharm. 2018 Mar 25;539(1-2):11- 22. https://doi.org/10.1016/j.ijpharm.2018.01.008
33. Srinivasan B, Kolli AR, Esch MB, Abaci HE, Shuler ML, Hickman JJ. TEER measurement techniques for in vitro barrier model systems. J Lab Autom. 2015 Apr;20(2):107-26. https://doi.org/10.1177/2211068214561025
34. Dahan A, Lennernäs H, Amidon GL. The fraction dose absorbed, in humans, and high jejunal human permeability relationship. Mol Pharm. 2012 Jun 4;9(6):1847-51. https://doi.org/10.1021/mp300140h
35. Mehnert W, Mäder K. Solid lipid nanoparticles: production, characterization and applications. Adv Drug Deliv Rev. 2001 Apr 25;47(2-3):165-96. https://doi.org/10.1016/S0169-409X(01)00105-3
36. Aji Alex MR, Chacko AJ, Jose S, Souto EB. Lopinavir loaded solid lipid nanoparticles (SLN) for intestinal lymphatic targeting. Eur J Pharm Sci. 2011 Jan 18;42(1-2):11-8. https://doi.org/10.1016/j.ejps.2010.10.002

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1. Kotha RR, Luthria DL. Curcumin: biological, pharmaceutical, nutraceutical, and analytical aspects. Molecules. 2019 Aug 13;24(16):2930. https://doi.org/10.3390/molecules24162930

2. Ringman JM, Frautschy SA, Cole GM, Masterman DL, Cummings JL. A potential role of the curry spice curcumin in Alzheimer's disease. Curr Alzheimer Res. 2005 Apr;2(2):131-6. https://doi.org/10.2174/1567205053585882

3. Kulkarni S, Dhir A, Akula KK. Potentials of curcumin as an antidepressant. ScientificWorldJournal. 2009 Nov 1;9:1233-41. https://doi.org/10.1100/tsw.2009.137

4. Xie L, Li XK, Funeshima-Fuji N, Kimura H, Matsumoto Y, Isaka Y, et al. Amelioration of experimental autoimmune encephalomyelitis by curcumin treatment through inhibition of IL-17 production. Int Immunopharmacol. 2009 May;9(5):575-81. https://doi.org/10.1016/j.intimp.2009.01.025

5. Sanmukhani J, Anovadiya A, Tripathi CB. Evaluation of antidepressant like activity of curcumin and its combination with fluoxetine and imipramine: an acute and chronic study. Acta Pol Pharm. 2011 Sep-Oct;68(5):769-75.

6. Kurien BT, D'Souza A, Scofield RH. Heat-solubilized curry spice curcumin inhibits antibody-antigen interaction in in vitro studies: a possible therapy to alleviate autoimmune disorders. Mol Nutr Food Res. 2010 Aug;54(8):1202-9. https://doi.org/10.1002/mnfr.200900106

7. Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB. Bioavailability of curcumin: problems and promises. Mol Pharm. 2007 Nov-Dec;4(6):807-18. https://doi.org/10.1021/mp700113r

8. Tønnesen HH, Karlsen J. Studies on curcumin and curcuminoids. VI. Kinetics of curcumin degradation in aqueous solution. Z Lebensm Unters Forsch. 1985 May;180(5):402-4. https://doi.org/10.1007/BF01027775

9. Tønnesen HH, Másson M, Loftsson T. Studies of curcumin and curcuminoids. XXVII. Cyclodextrin complexation: solubility, chemical and photochemical stability. Int J Pharm. 2002 Sep 5;244(1-2):127-35. https://doi.org/10.1016/S0378-5173(02)00323-X

10. Sadegh Malvajerd S, Azadi A, Izadi Z, Kurd M, Dara T, Dibaei M, et al. Brain delivery of curcumin using solid lipid nanoparticles and nanostructured lipid carriers: preparation, optimization, and pharmacokinetic evaluation. ACS Chem Neurosci. 2019 Jan 16;10(1):728-9. https://doi.org/10.1021/acschemneuro.8b00510

11. Karimi N, Ghanbarzadeh B, Hamishehkar H, Mehramuz B, Kafil HS. Antioxidant, antimicrobial and physicochemical properties of turmeric extract-loaded nanostructured lipid carrier (NLC). Colloid Interface Sci Commun. 2018 Jan 1;22:18-24. https://doi.org/10.1016/j.colcom.2017.11.006

12. Ganesan P, Narayanasamy D. Lipid nanoparticles: different preparation techniques, characterization, hurdles, and strategies for the production of solid lipid nanoparticles and nanostructured lipid carriers for oral drug delivery. Sustain Chem Pharm. 2017 Dec 1;6:37-56. https://doi.org/10.1016/j.scp.2017.07.002

13. Sermkaew N, Ketjinda W, Boonme P, Phadoongsombut N, Wiwattanapatapee R. Liquid and solid self-microemulsifying drug delivery systems for improving the oral bioavailability of andrographolide from a crude extract of Andrographis paniculata. Eur J Pharm Sci. 2013 Nov 20;50(3-4):459-66. https://doi.org/10.1016/j.ejps.2013.08.006

14. Kang BK, Lee JS, Chon SK, Jeong SY, Yuk SH, Khang G, et al. Development of self-microemulsifying drug delivery systems (SMEDDS) for oral bioavailability enhancement of simvastatin in beagle dogs. Int J Pharm. 2004 Apr 15;274(1-2):65-73. https://doi.org/10.1016/j.ijpharm.2003.12.028

15. Zhang P, Liu Y, Feng N, Xu J. Preparation and evaluation of self-microemulsifying drug delivery system of oridonin. Int J Pharm. 2008 May 1;355(1-2):269-76. https://doi.org/10.1016/j.ijpharm.2007.12.026

16. Gursoy RN, Benita S. Self-emulsifying drug delivery systems (SEDDS) for improved oral delivery of lipophilic drugs. Biomed Pharmacother. 2004 Apr;58(3):173-82. https://doi.org/10.1016/j.biopha.2004.02.001

17. Chatterjee B, Hamed Almurisi S, Ahmed Mahdi Dukhan A, Mandal UK, Sengupta P. Controversies with self-emulsifying drug delivery system from pharmacokinetic point of view. Drug Deliv. 2016 Nov;23(9):3639-52. https://doi.org/10.1080/10717544.2016.1214990

18. Tuleu C, Newton M, Rose J, Euler D, Saklatvala R, Clarke A, et al. Comparative bioavailability study in dogs of a self-emulsifying formulation of progesterone presented in a pellet and liquid form compared with an aqueous suspension of progesterone. J Pharm Sci. 2004 Jun;93(6):1495-502. https://doi.org/10.1002/jps.20068

19. Franceschinis E, Voinovich D, Grassi M, Perissutti B, Filipovic- Grcic J, Martinac A, et al. Self-emulsifying pellets prepared by wet granulation in high-shear mixer: influence of formulation variables and preliminary study on the in vitro absorption. Int J Pharm. 2005 Mar 3;291(1-2):87-97. https://doi.org/10.1016/j.ijpharm.2004.07.046

20. Beg S, Jena SS, Patra CN, Rizwan M, Swain S, Sruti J, et al. Development of solid self-nanoemulsifying granules (SSNEGs) of ondansetron hydrochloride with enhanced bioavailability potential. Colloids Surf B Biointerfaces. 2013 Jan 1;101:414-23. https://doi.org/10.1016/j.colsurfb.2012.06.031

21. Acharya B, Guru PS, Dash S. Tween-80-n-butanol-diesel-water microemulsion system-a class of alternative diesel fuel. J Dispers Sci Technol. 2014 Oct 3;35(10):1492-501. https://doi.org/10.1080/01932691.2013.858348

22. Bhandari S, Rana V, Tiwary AK. Antimalarial solid self-emulsifying system for oral use: in vitro investigation. Ther Deliv. 2017 Apr;8(4):201-13. https://doi.org/10.4155/tde-2016-0092

23. Kharat M, Zhang G, McClements DJ. Stability of curcumin in oil-in-water emulsions: impact of emulsifier type and concentration on chemical degradation. Food Res Int. 2018 Sep 1;111:178-86. https://doi.org/10.1016/j.foodres.2018.05.021

24. Sinha Babu SP, Sarkar D, Ghosh NK, Saha A, Sukul NC, Bhattacharya S. Enhancement of membrane damage by saponins isolated from Acacia auriculiformis. Jpn J Pharmacol. 1997 Dec;75(4):451-4. https://doi.org/10.1254/jjp.75.451

25. Craig DQ, Barker SA, Banning D, Booth SW. An investigation into the mechanisms of self-emulsification using particle size analysis and low frequency dielectric spectroscopy. Int J Pharm. 1995 Jan 31;114(1):103-10. https://doi.org/10.1016/0378-5173(94)00222-Q

26. Constantinides PP, Lancaster CM, Marcello J, Chiossone DC, Orner D, Hidalgo I, et al. Enhanced intestinal absorption of an RGD peptide from water-in-oil microemulsions of different composition and particle size. J Controlled Release. 1995 May 1;34(2):109-16. https://doi.org/10.1016/0168-3659(94)00129-I

27. Gupta MK, Vanwert A, Bogner RH. Formation of physically stable amorphous drugs by milling with Neusilin. J Pharm Sci. 2003 Mar 1;92(3):536-51. https://doi.org/10.1002/jps.10308

28. Fuji Chemical Industries. Neusilin®. [cited 2020 Apr 28]. Available from: http://www.neusilin.com/product/pharmacopoeia.php

29. Wang YJ, Pan MH, Cheng AL, Lin LI, Ho YS, Hsieh CY, et al. Stability of curcumin in buffer solutions and characterization of its degradation products. J Pharm Biomed Anal. 1997 Aug 1;15(12):1867-76. https://doi.org/10.1016/S0731-7085(96)02024-9

30. Artursson P, Karlsson J. Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells. Biochem Biophys Res Commun. 1991 Mar 29;175(3):880-5. https://doi.org/10.1016/0006-291X(91)91647-U

31. Yee S. In vitro permeability across Caco-2 cells (colonic) can predict in vivo (small intestinal) absorption in man-fact or myth. Pharm Res. 1997 Jun;14(6):763-6.

32. Maher S, Heade J, McCartney F, Waters S, Bleiel SB, Brayden DJ. Effects of surfactant-based permeation enhancers on mannitol permeability, histology, and electrogenic ion transport responses in excised rat colonic mucosae. Int J Pharm. 2018 Mar 25;539(1-2):11- 22. https://doi.org/10.1016/j.ijpharm.2018.01.008

33. Srinivasan B, Kolli AR, Esch MB, Abaci HE, Shuler ML, Hickman JJ. TEER measurement techniques for in vitro barrier model systems. J Lab Autom. 2015 Apr;20(2):107-26. https://doi.org/10.1177/2211068214561025

34. Dahan A, Lennernäs H, Amidon GL. The fraction dose absorbed, in humans, and high jejunal human permeability relationship. Mol Pharm. 2012 Jun 4;9(6):1847-51. https://doi.org/10.1021/mp300140h

35. Mehnert W, Mäder K. Solid lipid nanoparticles: production, characterization and applications. Adv Drug Deliv Rev. 2001 Apr 25;47(2-3):165-96. https://doi.org/10.1016/S0169-409X(01)00105-3

36. Aji Alex MR, Chacko AJ, Jose S, Souto EB. Lopinavir loaded solid lipid nanoparticles (SLN) for intestinal lymphatic targeting. Eur J Pharm Sci. 2011 Jan 18;42(1-2):11-8. https://doi.org/10.1016/j.ejps.2010.10.002