Novel nanomicelle formulation to enhance bioavailability and stability of curcuminoids

Document Type: Original Article

Authors

1 Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran

2 Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

3 Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran

4 Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

5 Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

Abstract

Objective(s): Curcuminoids, comprising curcumin, demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC), are bioactive phytochemicals with numerous pharmacological effects. Oral biological availability of curcuminoids is low due to the low aqueous solubility and rapid metabolism. This study aimed at fabricating a nanomicellar curcuminoid formula with enhanced pharmacokinetic properties.
Materials and Methods: Curcuminoids nanomicelles were prepared and characterized regarding particle properties, stability, release profile and pharmacokinetic parameters.
Results: Encapsulation efficiency of curcuminoids in nanomicelles were 100%. Particle size analysis demonstrated a mean size of around 10 nm that remained stable for 24 months. Dissolution test showed the complete dissolution of encapsulated curcuminoids from nanomicelles within 20 min while the free curcuminoids were poorly dissolved (approximately 7% after 60 min). The results of long-term (24 months) and accelerated (6 months) stability studies showed no changes in the size and content of nanomicelles. The release studies in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) showed no release of curcuminoids for at least 4 hours. In vivo study in BALB/c mice showed improved pharmacokinetic parameters including maximum plasma concentration (Cmax) and time to reach the maximum concentration (Tmax) with nanomicelles as compared to free curcuminoids and two other commercial products. Tmax for all the three curcuminoid components was observed 30 min following oral administration. AUC of nanomicellar curcuminoids was 59.2 times more than free  curcuminoids.
Conclusion: These data indicated that nanomicelles could improve solubility, oral bioavailability and also the stability of curcuminoids. Thus, they merit further investigation for enhancing pharmacological effects of curcuminoids.

Keywords

Main Subjects


1. Pulido-Moran M, Moreno-Fernandez J, Ramirez-Tortosa C, Ramirez-Tortosa M. Curcumin and health. Molecules 2016; 21:264.
2. Gupta SC, Kismali G, Aggarwal BB. Curcumin, a component of turmeric: from farm to pharmacy. Biofactors 2013; 39:2-13.
3. Prasad S, Gupta SC, Tyagi AK, Aggarwal BB. Curcumin, a component of golden spice: from bedside to bench and back. Biotechnol Adv 2014; 32:1053-1064.
4. Sahebkar A. Are curcuminoids effective C-reactive protein-lowering agents in clinical practice? Evidence from a meta-analysis. Phytother Res 2014; 28:633-642.
5. Panahi Y, Sahebkar A, Parvin S, Saadat A. A randomized controlled trial on the anti-inflammatory effects of curcumin in patients with chronic sulphur mustard-induced cutaneous complications. Ann Clin Biochem 2012; 49:580-588.
6. Panahi Y, Hosseini MS, Khalili N, Naimi E, Majeed M, Sahebkar A. Antioxidant and anti-inflammatory effects of curcuminoid-piperine combination in subjects with metabolic syndrome: A randomized controlled trial and an updated meta-analysis. Clin Nutr 2015; 34:1101-1108.
7. Mirzaei H, Naseri G, Rezaee R, Mohammadi M, Banikazemi Z, Mirzaei HR, et al. Curcumin: A new candidate for melanoma therapy? Int J Cancer 2016; 139:1683-1695.
8. Momtazi AA, Shahabipour F, Khatibi S, Johnston TP, Pirro M, Sahebkar A. Curcumin as a microRNA regulator in cancer: A review. Rev Physiol Biochem Pharmacol 2016; 17:1-38.
9. Liu W, Zhai Y, Heng X, Che FY, Chen W, Sun D, et al. Oral bioavailability of curcumin: problems and advancements. J Drug Target 2016; 24:694-702.
10. Dawidczyk C, Kim C, Park J, Russell L, Lee K, Pomper M, et al. State-of-the-art in design rules for drug delivery platforms: lessons learned from FDA-approved nanomedicines. J Control Release 2014; 187:133-144.
11. Mobasheri M, Attar H, Rezayat Sorkhabadi SM, Khamesipour A, Jaafari MR. Solubilization behavior of polyene antibiotics in nanomicellar system: Insights from molecular dynamics simulation of the amphotericin B and nystatin interactions with polysorbate 80. Molecules 2015; 21:E6.
12. Shakeri A, Sahebkar A. Opinion Paper: Nanotechnology: A Successful Approach to Improve Oral Bioavailability of Phytochemicals. Recent Pat Drug Deliv Formul 2016; 10:4-6.
13. Patent Cooperation Treaty: 2018 MRJ, curcumin nanomicelles for oral administration, International application No. PCT/IB2018/051370; International filing date: March 4, 2018.
14. Ahmadi M, Agah E, Nafissi S, Jaafari MR, Harirchian MH, Sarraf P, et al. Safety and efficacy of nanocurcumin as add-on therapy to riluzole in patients with amyotrophic lateral sclerosis: A pilot randomized clinical trial. Neurotherapeutics 2018; 15:430-438.
15. Rahimi HR, Mohammadpour AH, Dastani M, Jaafari MR, Abnous K, Mobarhan MG, et al. The effect of nano-curcumin on HbA1c, fasting blood glucose, and lipid profile in diabetic subjects: a randomized clinical trial. Avicenna J Phytomed 2016; 6:567-577.
16. Charbgoo F, Alibolandi M, Taghdisi S, Abnous K, Soltani F, Ramezani M. MUC1 aptamer-targeted DNA micelles for dual tumor therapy using doxorubicin and KLA peptide. Nanomedicine 2018; 14:685-697.
17. Khodaverdi E, Tekie FSM, Mohajeri SA, Ganji F, Zohuri G, Hadizadeh F. Preparation and investigation of sustained drug delivery systems using an injectable, thermosensitive, in situ forming hydrogel composed of PLGA–PEG–PLGA. AAPS Pharm Sci Tech 2012; 13:590-600.
18. Gao J, Sun J, Li H, Liu W, Zhang Y, Li B, et al. Lyophilized HER2-specific PEGylated immunoliposomes for active siRNA gene silencing. Biomaterials 2010; 31:2655-2664.
19. Sahay G, Alakhova DY, Kabanov AV. Endocytosis of nanomedicines. J Control Release 2010; 145:182-195.
20. Letchford K, Liggins R, Burt H. Solubilization of hydrophobic drugs by methoxy poly(ethylene glycol)-block-polycaprolactone diblock copolymer micelles: theoretical and experimental data and correlations. J Pharm Sci 2008; 97:1179-1190.
21. Zhao L, Du J, Duan Y, Zang Y, Zhang H, Yang C, et al. Curcumin loaded mixed micelles composed of Pluronic P123 and F68: preparation, optimization and in vitro characterization. Colloids Surf B Biointerfaces 2012; 97:101-108.
22. Erfani-Moghadam V, Nomani A, Zamani M, Yazdani Y, Najafi F, Sadeghizadeh M. A novel diblock of copolymer of (monomethoxy poly [ethylene glycol]-oleate) with a small hydrophobic fraction to make stable micelles/polymersomes for curcumin delivery to cancer cells. Int J Nanomedicine 2014; 9:5541-5554.
23. Sahu A, Kasoju N, Goswami P, Bora U. Encapsulation of curcumin in pluronic block copolymer micelles for drug delivery applications. J Biomater Appl 2011; 25:619-639.
24. Hussain N, Jaitley V, Florence AT. Recent advances in the understanding of uptake of microparticulates across the gastrointestinal lymphatics. Adv Drug Deliv Rev 2001; 50:107-142.
25. Bao Y, Guo Y, Zhuang X, Li D, Cheng B, Tan S, et al. D-α-tocopherol polyethylene glycol succinate-based redox-sensitive paclitaxel prodrug for overcoming multidrug resistance in cancer cells. Mol Pharm 2014; 11:3196-3209.
26. Yodkeeree S, Chaiwangyen W, Garbisa S, Limtrakul P. Curcumin, demethoxycurcumin and bisdemethoxycurcumin differentially inhibit cancer cell invasion through the down-regulation of MMPs and uPA. J Nutr Biochem 2009; 20:87-95.