Skip to main content
SpringerLink
Log in

Improved Oral Absorption of Poorly Soluble Curcumin via the Concomitant Use of Borneol

  • Research Article
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

In this study, borneol, a natural active compound was applied to improve the bioavailability of curcumin (CUR). In order to increase CUR solubility and dissolution, solid dispersions (SDs) were prepared with the matrix of polyvinylpyrrolidone (PVP) at various ratios by solvent evaporation method. CUR was evidenced to exist as amorphous state in solid dispersion by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). Fourier-transform infrared spectroscopy (FT-IR) was utilized to confirm intermolecular hydrogen bonding. The SD at the ratio of 1:3 (CUR:PVP) exhibited the optimal solubility and dissolution rate in various media. The results of ex vivo permeability studies by everted gut sac method showed that the apparent permeability coefficients (Papp) of CUR in SD across the duodenum, jejunum, and ileum had been significantly improved by co-incubation of borneol, and the improvement degree relied on the concentration of borneol. The pharmacokinetic results in rats indicated that the AUC0-t of CUR-SD (40 mg/kg) co-administration of borneol (90 mg/kg) were 2.53-fold higher than CUR-SD alone, and 19.41-fold higher than pure CUR (200 mg/kg) with borneol (90 mg/kg). Therefore, the combination of borneol and solid dispersion strategy provide a potential approach to enhance the oral bioavailability of CUR.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Bhattacharyya S, Mandal D, Sen GS, Pal S, Banerjee S, Lahiry L, et al. Tumor-induced oxidative stress perturbs nuclear factor-κB activity-augmenting tumor necrosis factor-α–mediated T-cell death: protection by curcumin. Cancer Res. 2007;67(1):362–70. https://doi.org/10.1158/0008-5472.CAN-06-2583.

    Article  CAS  PubMed  Google Scholar 

  2. Joe B, Lokesh BR. Role of capsaicin, curcumin and dietary n-3 fatty acids in lowering the generation of reactive oxygen species in rat peritoneal macrophages. Biochim Biophys Acta. 1994;1224(2):255–63.

    Article  CAS  Google Scholar 

  3. Joe B, Vijaykumar M, Lokesh BR. Biological properties of curcumin-cellular and molecular mechanisms of action. Crit Rev Food Sci Nutr. 2004;44(2):97–111. https://doi.org/10.1080/10408690490424702.

    Article  CAS  PubMed  Google Scholar 

  4. Basnet P, Skalko-Basnet N. Curcumin: an anti-inflammatory molecule from a curry spice on the path to cancer treatment. Molecules. 2011;16(6):4567–98. https://doi.org/10.3390/molecules16064567.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Begum AN, Jones MR, Lim GP, Morihara T, Kim P, Heath DD, et al. Curcumin structure-function, bioavailability, and efficacy in models of neuroinflammation and Alzheimer’s disease. J Pharmacol Exp Ther. 2008;326(1):196–208. https://doi.org/10.1124/jpet.108.137455.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. DiSilvestro RA, Joseph E, Zhao S, Bomser J. Diverse effects of a low dose supplement of lipidated curcumin in healthy middle aged people. Nutr J. 2012;11:79. https://doi.org/10.1186/1475-2891-11-79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Wahlang B, Pawar YB, Bansal AK. Identification of permeability-related hurdles in oral delivery of curcumin using the Caco-2 cell model. Eur J Pharm Biopharm. 2011;77(2):275–82. https://doi.org/10.1016/j.ejpb.2010.12.006.

    Article  CAS  PubMed  Google Scholar 

  8. 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(8):694–702. https://doi.org/10.3109/1061186X.2016.1157883.

    Article  CAS  PubMed  Google Scholar 

  9. Yang KY, Lin LC, Tseng TY, Wang SC, Tsai TH. Oral bioavailability of curcumin in rat and the herbal analysis from Curcuma longa by LC-MS/MS. J Chromatogr B Anal Technol Biomed Life Sci. 2007;853(1–2):183–9. https://doi.org/10.1016/j.jchromb.2007.03.010.

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  11. Maiti K, Mukherjee K, Gantait A, Saha BP, Mukherjee PK. Curcumin-phospholipid complex: preparation, therapeutic evaluation and pharmacokinetic study in rats. Int J Pharm. 2007;330(1–2):155–63. https://doi.org/10.1016/j.ijpharm.2006.09.025.

    Article  CAS  PubMed  Google Scholar 

  12. Jang DJ, Kim ST, Oh E, Lee K. Enhanced oral bioavailability and antiasthmatic efficacy of curcumin using redispersible dry emulsion. Biomed Mater Eng. 2014;24(1):917–30. https://doi.org/10.3233/bme-130886.

    Article  CAS  PubMed  Google Scholar 

  13. Schiborr C, Kocher A, Behnam D, Jandasek J, Toelstede S, Frank J. The oral bioavailability of curcumin from micronized powder and liquid micelles is significantly increased in healthy humans and differs between sexes. Mol Nutr Food Res. 2014;58(3):516–27. https://doi.org/10.1002/mnfr.201300724.

    Article  CAS  PubMed  Google Scholar 

  14. Jang SW, Kang MJ. Improved oral absorption and chemical stability of everolimus via preparation of solid dispersion using solvent wetting technique. Int J Pharm. 2014;473(1–2):187–93. https://doi.org/10.1016/j.ijpharm.2014.06.006.

    Article  CAS  PubMed  Google Scholar 

  15. Chen J, Li L, Su J, Chen T. Natural borneol enhances bisdemethoxycurcumin-induced cell cycle arrest in the G2/M phase through up-regulation of intracellular ROS in HepG2 cells. Food Funct. 2015;6(3):740–8. https://doi.org/10.1039/c4fo00807c.

    Article  CAS  PubMed  Google Scholar 

  16. Cui Y, Li L, Zhang L, Li J, Gu J, Gong H, et al. Enhancement and mechanism of transdermal absorption of terpene-induced propranolol hydrochloride. Arch Pharm Res. 2011;34(9):1477–85. https://doi.org/10.1007/s12272-011-0909-2.

    Article  CAS  PubMed  Google Scholar 

  17. Liu J, Fu S, Wei N, Hou Y, Zhang X, Cui H. The effects of combined menthol and borneol on fluconazole permeation through the cornea ex vivo. Eur J Pharmacol. 2012;688(1–3):1–5. https://doi.org/10.1016/j.ejphar.2011.12.007.

    Article  CAS  PubMed  Google Scholar 

  18. Lu Y, Chen X, Du S, Wu Q, Yao Z, Zhai Y. The in situ and in vivo study on enhancing effect of borneol in nasal absorption of Geniposide in rats. Arch Pharm Res. 2010;33(5):691–6. https://doi.org/10.1007/s12272-010-0507-8.

    Article  CAS  PubMed  Google Scholar 

  19. Yi T, Tang D, Wang F, Zhang J, Zhang J, Wang J, et al. Enhancing both oral bioavailability and brain penetration of puerarin using borneol in combination with preparation technologies. Drug Deliv. 2017;24(1):422–9. https://doi.org/10.1080/10717544.2016.1259372.

    Article  CAS  PubMed  Google Scholar 

  20. Zhou Y, Li W, Chen L, Ma S, Ping L, Yang Z. Enhancement of intestinal absorption of akebia saponin D by borneol and probenecid in situ and in vitro. Environ Toxicol Pharmacol. 2010;29(3):229–34. https://doi.org/10.1016/j.etap.2010.01.004.

    Article  CAS  PubMed  Google Scholar 

  21. Tang B, Fang GH, Gao Y, Liu Y, Liu JW, Zou MJ, et al. Co-encapsulation of borneol and paclitaxel by liprosomes improved anti-tumor effect in a xenografted glioma model. RSC Adv. 2015;5(129):106613–20. https://doi.org/10.1039/c5ra22233h.

    Article  CAS  Google Scholar 

  22. Chen J, Li L, Su J, Li B, Chen T, Wong YS. Synergistic apoptosis-inducing effects on A375 human melanoma cells of natural borneol and curcumin. PLoS One. 2014;9(6):e101277. https://doi.org/10.1371/journal.pone.0101277.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Sadeghi F, Ashofteh M, Homayouni A, Abbaspour M, Nokhodchi A, Garekani HA. Antisolvent precipitation technique: a very promising approach to crystallize curcumin in presence of polyvinyl pyrrolidon for solubility and dissolution enhancement. Colloids Surf B Biointerfaces. 2016;147:258–64. https://doi.org/10.1016/j.colsurfb.2016.08.004.

    Article  CAS  PubMed  Google Scholar 

  24. Costa P, Sousa Lobo JM. Modeling and comparison of dissolution profiles. Eur J Pharm Sci. 2001;13(2):123–33.

    Article  CAS  Google Scholar 

  25. Wang Y, Zou M, Zhao N, Ren J, Zhou H, Cheng G. Effect of diallyl trisulfide on the pharmacokinetics of dipyridamole in rats. Arch Pharm Res. 2011;34(11):1957–64. https://doi.org/10.1007/s12272-011-1116-x.

    Article  CAS  PubMed  Google Scholar 

  26. Frizon F, Eloy JD, Donaduzzi CM, Mitsui ML, Marchetti JM. Dissolution rate enhancement of loratadine in polyvinylpyrrolidone K-30 solid dispersions by solvent methods. Powder Technol. 2013;235:532–9. https://doi.org/10.1016/j.powtec.2012.10.019.

    Article  CAS  Google Scholar 

  27. Tantishaiyakul V, Kaewnopparat N, Ingkatawornwong S. Properties of solid dispersions of piroxicam in polyvinylpyrrolidone. Int J Pharm. 1999;181(2):143–51.

    Article  CAS  Google Scholar 

  28. Paradkar A, Ambike AA, Jadhav BK, Mahadik KR. Characterization of curcumin–PVP solid dispersion obtained by spray drying. Int J Pharm. 2004;271(1–2):281–6. https://doi.org/10.1016/j.ijpharm.2003.11.014.

    Article  CAS  PubMed  Google Scholar 

  29. Zhang Q, Polyakov NE, Chistyachenko YS, Khvostov MV, Frolova TS, Tolstikova TG, et al. Preparation of curcumin self-micelle solid dispersion with enhanced bioavailability and cytotoxic activity by mechanochemistry. Drug Deliv. 2018;25(1):198–209. https://doi.org/10.1080/10717544.2017.1422298.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Barzegar-Jalali M, Alaei-Beirami M, Javadzadeh Y, Mohammadi G, Hamidi A, Andalib S, et al. Comparison of physicochemical characteristics and drug release of diclofenac sodium-eudragit (R) RS100 nanoparticles and solid dispersions. Powder Technol. 2012;219:211–6. https://doi.org/10.1016/j.powtec.2011.12.046.

    Article  CAS  Google Scholar 

  31. Wang C, Ma C, Wu Z, Liang H, Yan P, Song J, et al. Enhanced bioavailability and anticancer effect of curcumin-loaded electrospun nanofiber: in vitro and in vivo study. Nanoscale Res Lett. 2015;10(1):439. https://doi.org/10.1186/s11671-015-1146-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Sethia S, Squillante E. Solid dispersion of carbamazepine in PVP K30 by conventional solvent evaporation and supercritical methods. Int J Pharm. 2004;272(1–2):1–10. https://doi.org/10.1016/j.ijpharm.2003.11.025.

    Article  CAS  PubMed  Google Scholar 

  33. Chen S, Zhu J, Ma F, Fang Q, Li Y. Preparation and characterization of solid dispersions of dipyridarmole with a carrier “copolywidonum plasdone (R) S-630”. Drug Dev Ind Pharm. 2007;33(8):888–99. https://doi.org/10.1080/03639040701199209.

    Article  CAS  PubMed  Google Scholar 

  34. Leuner C, Dressman J. Improving drug solubility for oral delivery using solid dispersions. Eur J Pharm Biopharm. 2000;50(1):47–60.

    Article  CAS  Google Scholar 

  35. Tran TT, Tran KA, Tran PH. Modulation of particle size and molecular interactions by sonoprecipitation method for enhancing dissolution rate of poorly water-soluble drug. Ultrason Sonochem. 2015;24:256–63. https://doi.org/10.1016/j.ultsonch.2014.11.020.

    Article  CAS  PubMed  Google Scholar 

  36. Khemiss F, Massoudi R, Ahmadi S, Ghoul-Mazgar S, Safta S, Moshtaghie AA, et al. Aeromonas hydrophila disturbs water and electrolyte transport in Mugil cephalus L. intestine. Afr J Biotechnol. 2008;7(4):373–80.

    CAS  Google Scholar 

  37. Gao Y, He L, Katsumi H, Sakane T, Fujita T, Yamamoto A. Improvement of intestinal absorption of water-soluble macromolecules by various polyamines: intestinal mucosal toxicity and absorption-enhancing mechanism of spermine. Int J Pharm. 2008;354(1–2):126–34. https://doi.org/10.1016/j.ijpharm.2007.11.061.

    Article  CAS  PubMed  Google Scholar 

  38. Duan M, Xing Y, Guo J, Chen H, Zhang R. Borneol increases blood-tumour barrier permeability by regulating the expression levels of tight junction-associated proteins. Pharm Biol. 2016;54(12):3009–18. https://doi.org/10.1080/13880209.2016.1199044.

    Article  CAS  PubMed  Google Scholar 

  39. Wang S, Tan N, Ma C, Wang J, Jia P, Liu J, et al. Inhibitory effects of benzaldehyde, vanillin, muscone and borneol on P-glycoprotein in Caco-2 cells and everted gut sac. Pharmacology. 2018;101(5–6):269–77. https://doi.org/10.1159/000487144.

    Article  CAS  PubMed  Google Scholar 

  40. Yu B, Ruan M, Dong X, Yu Y, Cheng H. The mechanism of the opening of the blood-brain barrier by borneol: a pharmacodynamics and pharmacokinetics combination study. J Ethnopharmacol. 2013;150:1096–108. https://doi.org/10.1016/j.jep.2013.10.028.

    Article  CAS  PubMed  Google Scholar 

  41. He H, Shen Q, Li J. Effects of borneol on the intestinal transport and absorption of two P-glycoprotein substrates in rats. Arch Pharm Res. 2011;34(7):1161–70. https://doi.org/10.1007/s12272-011-0714-y.

    Article  CAS  PubMed  Google Scholar 

  42. Wang R, Wu Z, Yang S, Guo S, Dai X, Qiao Y, et al. A molecular interpretation on the different penetration enhancement effect of borneol and menthol towards 5-fluorouracil. Int J Mol Sci. 2017;18(12). https://doi.org/10.3390/ijms18122747.

    Article  Google Scholar 

Download references

Funding

This work was supported by the disruptive technologies innovation fund of Shenyang Pharmaceutical University (DFJJ2018208) and the Natural Science Foundation of Liaoning Province of China (Grant No. 201602706).

Author information

Authors and Affiliations

  1. Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, China

    Ying Gao, Guo Chen, Xiaojiao Luan, Meijuan Zou, Hongyu Piao & Gang Cheng

Authors
  1. Ying Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Guo Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiaojiao Luan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Meijuan Zou
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hongyu Piao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gang Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gang Cheng.

Ethics declarations

All animal experiments were carried out in accordance with the Guidelines for the Use of Laboratory Animals and approved by the Shenyang Pharmaceutical University Ethics Committee.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gao, Y., Chen, G., Luan, X. et al. Improved Oral Absorption of Poorly Soluble Curcumin via the Concomitant Use of Borneol. AAPS PharmSciTech 20, 150 (2019). https://doi.org/10.1208/s12249-019-1364-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1208/s12249-019-1364-5

Key Words

Search

Navigation