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AAPS PharmSciTech

, 20:106 | Cite as

Solid Dispersion of Kaempferol: Formulation Development, Characterization, and Oral Bioavailability Assessment

  • Mariana Colombo
  • Gabriela de Lima Melchiades
  • Luana Roberta Michels
  • Fabrício Figueiró
  • Valquiria Linck Bassani
  • Helder Ferreira Teixeira
  • Letícia Scherer KoesterEmail author
Research Article
First Online:

Abstract

Kaempferol (KPF), an important flavonoid, has been reported to exert antioxidant, anti-inflammatory, and anticancer activity. However, this compound has low water solubility and hence poor oral bioavailability. This work aims to prepare a solid dispersion (SD) of KPF using Poloxamer 407 in order to improve the water solubility, dissolution rate, and pharmacokinetic properties KPF. After optimization, SDs were prepared at a 1:5 weight ratio of KPF:carrier using the solvent method (SDSM) and melting method (SDMM). Formulations were characterized by Fourier transform infrared spectroscopy (FTIR), X-ray diffractometry (XRD) analysis, differential scanning calorimetry (DSC), and scanning electron microscopy (SEM). The solubility in water of carried-KPF was about 4000-fold greater than that of free KPF. Compared with free KPF or the physical mixture, solid dispersions significantly increased the extent of drug release (approximately 100% within 120 min) and the dissolution rate. Furthermore, after oral administration of SDMM in rats, the area under the curve (AUC) and the peak plasma concentration (Cmax) of KPF from SDMM were twofold greater than those of free KPF (p < 0.05). In conclusion, SD with Poloxamer 407 is a feasible pharmacotechnical strategy to ameliorate the dissolution and bioavailability of KPF.

KEY WORDS

kaempferol Poloxamer 407 solid dispersion dissolution bioavailability 
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Notes

Funding Information

This study was financially supported by CAPES-MEC, Brazil (Network Nanobiotec—grant no. 902/2009 and PROCAD—grant no. 552457/2011-6), CNPq (grant no. 453927/2014-9), and FAPERGS (Edital PqG 2017-T.O. 17/2551-0001043-4 and 17/2551-0000 970-3). M.C. thanks CAPES for her scholarship.

References

  1. 1.
    Calderon-Montano JM, Burgos-Moron E, Perez-Guerrero C, Lopez-Lazaro M. A review on the dietary flavonoid kaempferol. Mini-Rev Med Chem. 2011;11:298–344.CrossRefGoogle Scholar
  2. 2.
    Devi KP, Malar DS, Nabavi SF, Sureda A, Xiao J, Nabavi SM, et al. Kaempferol and inflammation: from chemistry to medicine. Pharmacol Res. 2015;99:1–10.CrossRefGoogle Scholar
  3. 3.
    Chen AY, Chen YC. A review of the dietary flavonoid, kaempferol on human health and cancer chemoprevention. Food Chem. 2013;138:2099–107.  https://doi.org/10.1016/j.foodchem.2012.11.139.CrossRefPubMedGoogle Scholar
  4. 4.
    Rothwell JA, Day AJ, Morgan MR. Experimental determination of octanol-water partition coefficients of quercetin and related flavonoids. J Agric Food Chem. 2005;53:4355–60.CrossRefGoogle Scholar
  5. 5.
    Xie Y, Luo H, Duan J, Hong C, Ma P, Li G, et al. Phytic acid enhances the oral absorption of isorhamnetin, quercetin, and kaempferol in total flavones of Hippophae rhamnoides L. Fitoterapia. 2014;93:216–25.  https://doi.org/10.1016/j.fitote.2014.01.013S0367-326X(14)00019-7.CrossRefPubMedGoogle Scholar
  6. 6.
    Vo CL, Park C, Lee BJ. Current trends and future perspectives of solid dispersions containing poorly water-soluble drugs. Eur J Pharm Biopharm. 2013;85:799–813.CrossRefGoogle Scholar
  7. 7.
    Chiou WL, Riegelman S. Pharmaceutical applications of solid dispersion systems. J Pharm Sci. 1971;60:1281–302.CrossRefGoogle Scholar
  8. 8.
    Leuner C, Dressman J. Improving drug solubility for oral delivery using solid dispersions. Eur J Pharm Biopharm. 2000;50:47–60.  https://doi.org/10.1016/S0939-6411(00)00076-X.CrossRefPubMedGoogle Scholar
  9. 9.
    Meng F, Gala U, Chauhan H. Classification of solid dispersions: correlation to (i) stability and solubility (ii) preparation and characterization techniques. Drug Dev Ind Pharm. 2015;41:1401–15.CrossRefGoogle Scholar
  10. 10.
    Vasconcelos T, Marques S, das Neves J, Sarmento B. Amorphous solid dispersions: rational selection of a manufacturing process. Adv Drug Deliv Rev. 2016;100:85–101.  https://doi.org/10.1016/j.addr.2016.01.012.CrossRefPubMedGoogle Scholar
  11. 11.
    Mustapha O, Kim KS, Shafique S, Kim DS, Jin SG, Seo YG, et al. Comparison of three different types of cilostazol-loaded solid dispersion: physicochemical characterization and pharmacokinetics in rats. Colloids Surf B Biointerfaces. 2017;154:89–95.CrossRefGoogle Scholar
  12. 12.
    Chen ZP, Sun J, Chen HX, Xiao YY, Liu D, Chen J, et al. Comparative pharmacokinetics and bioavailability studies of quercetin, kaempferol and isorhamnetin after oral administration of Ginkgo biloba extracts, Ginkgo biloba extract phospholipid complexes and Ginkgo biloba extract solid dispersions in rats. Fitoterapia. 2010;81:1045–52.CrossRefGoogle Scholar
  13. 13.
    Wang W, Kang Q, Liu N, Zhang Q, Zhang Y, Li H, et al. Enhanced dissolution rate and oral bioavailability of Ginkgo biloba extract by preparing solid dispersion via hot-melt extrusion. Fitoterapia. 2015;102:189–97.CrossRefGoogle Scholar
  14. 14.
    Li W, Yi S, Wang Z, Chen S, Xin S, Xie J, et al. Self-nanoemulsifying drug delivery system of persimmon leaf extract: optimization and bioavailability studies. Int J Pharm. 2011;420:161–71.  https://doi.org/10.1016/j.ijpharm.2011.08.024S0378-5173(11)00786-1.CrossRefPubMedGoogle Scholar
  15. 15.
    Zhao G, Duan J, Xie Y, Lin G, Luo H, Li G, et al. Effects of solid dispersion and self-emulsifying formulations on the solubility, dissolution, permeability and pharmacokinetics of isorhamnetin, quercetin and kaempferol in total flavones of Hippophae rhamnoides L. Drug Dev Ind Pharm. 2013;39:1037–45.  https://doi.org/10.3109/03639045.2012.699066.CrossRefPubMedGoogle Scholar
  16. 16.
    Duan J, Dang Y, Meng H, Wang H, Ma P, Li G, et al. A comparison of the pharmacokinetics of three different preparations of total flavones of Hippophae rhamnoides in beagle dogs after oral administration. Eur J Drug Metab Pharmacokinet. 2016;41:239–49.CrossRefGoogle Scholar
  17. 17.
    Tzeng CW, Yen FL, Wu TH, Ko HH, Lee CW, Tzeng WS, et al. Enhancement of dissolution and antioxidant activity of kaempferol using a nanoparticle engineering process. J Agric Food Chem. 2011;59:5073–80.CrossRefGoogle Scholar
  18. 18.
    Kumar A, Gupta GK, Khedgikar V, Gautam J, Kushwaha P, Changkija B, et al. In vivo efficacy studies of layer-by-layer nano-matrix bearing kaempferol for the conditions of osteoporosis: a study in ovariectomized rat model. Eur J Pharm Biopharm. 2012;82:508–17.CrossRefGoogle Scholar
  19. 19.
    Zhang K, Gu L, Chen J, Zhang Y, Jiang Y, Zhao L, et al. Preparation and evaluation of kaempferol-phospholipid complex for pharmacokinetics and bioavailability in SD rats. J Pharm Biomed Anal. 2015;114:168–75.CrossRefGoogle Scholar
  20. 20.
    Telange D, Patil A, Pethe A, Tatode A, Sridhar A, Dave V. Kaempferol-phospholipid complex: formulation, and evaluation of improved solubility, in vivo bioavailability, and antioxidant potential of kaempferol. 2016.Google Scholar
  21. 21.
    Colombo M, Melchiades GL, Figueiró F, Battastini AMO, Teixeira HF, Koester LS. Validation of an HPLC-UV method for analysis of Kaempferol-loaded nanoemulsion and its application to in vitro and in vivo tests. J Pharm Biomed Anal. 2017;145:831–7.  https://doi.org/10.1016/j.jpba.2017.07.046.CrossRefPubMedGoogle Scholar
  22. 22.
    Nemitz MC, Yatsu FK, Bidone J, Koester LS, Bassani VL, Garcia CV, et al. A versatile, stability-indicating and high-throughput ultra-fast liquid chromatography method for the determination of isoflavone aglycones in soybeans, topical formulations, and permeation assays. Talanta. 2015;134:183–93.CrossRefGoogle Scholar
  23. 23.
    Higuchi T, Connors KA. Phase solubility techniques. Adv Anal Chem Instrum. 1965;4:117–212.Google Scholar
  24. 24.
    Khan KA. The concept of dissolution efficiency. J Pharm Pharmacol. 1975;27:48–9.CrossRefGoogle Scholar
  25. 25.
    Moore JW, Flanner HH. Mathematical comparison of dissolution profiles. Pharm Technol. 1996;20:64–74.Google Scholar
  26. 26.
    Zhang Y, Huo M, Zhou J, Xie S. PKSolver: an add-in program for pharmacokinetic and pharmacodynamic data analysis in Microsoft Excel. Comput Methods Prog Biomed. 2010;99:306–14.CrossRefGoogle Scholar
  27. 27.
    Eloy JO, Marchetti JM. Solid dispersions containing ursolic acid in Poloxamer 407 and PEG 6000: a comparative study of fusion and solvent methods. Powder Technol. 2014;253:98–106.  https://doi.org/10.1016/j.powtec.2013.11.017.CrossRefGoogle Scholar
  28. 28.
    Simonazzi A, Davies C, Cid AG, Gonzo E, Parada L, Bermudez JM. Preparation and characterization of Poloxamer 407 solid dispersions as an alternative strategy to improve benznidazole bioperformance. J Pharm Sci. 2018;107:2829–36.CrossRefGoogle Scholar
  29. 29.
    Dugar RP, Gajera BY, Dave RH. Fusion method for solubility and dissolution rate enhancement of ibuprofen using block copolymer poloxamer 407. AAPS PharmSciTech. 2016;17:1428–40.  https://doi.org/10.1208/s12249-016-0482-6.CrossRefPubMedGoogle Scholar
  30. 30.
    Chaudhari SP, Dugar RP. Application of surfactants in solid dispersion technology for improving solubility of poorly water soluble drugs. J Drug Delivery Sci Technol. 2017;41:68–77.  https://doi.org/10.1016/j.jddst.2017.06.010.CrossRefGoogle Scholar
  31. 31.
    Tambe A, Pandita N. Enhanced solubility and drug release profile of boswellic acid using a poloxamer-based solid dispersion technique. J Drug Delivery Sci Technol. 2018;44:172–80.  https://doi.org/10.1016/j.jddst.2017.11.025.CrossRefGoogle Scholar
  32. 32.
    Dumortier G, Grossiord JL, Agnely F, Chaumeil JC. A review of poloxamer 407 pharmaceutical and pharmacological characteristics. Pharm Res. 2006;23:2709–28.CrossRefGoogle Scholar
  33. 33.
    Rowe RC, Sheskey PJ, Owen SC. Handbook of pharmaceutical excipients. London: Pharmaceutical Press London; 2006.Google Scholar
  34. 34.
    Li B, Konecke S, Harich K, Wegiel L, Taylor LS, Edgar KJ. Solid dispersion of quercetin in cellulose derivative matrices influences both solubility and stability. Carbohydr Polym. 2013;92:2033–40.CrossRefGoogle Scholar
  35. 35.
    Mehanna MM, Motawaa AM, Samaha MW. In sight into tadalafil - block copolymer binary solid dispersion: mechanistic investigation of dissolution enhancement. Int J Pharm. 2010;402:78–88.CrossRefGoogle Scholar
  36. 36.
    Ali W, Williams AC, Rawlinson CF. Stochiometrically governed molecular interactions in drug: poloxamer solid dispersions. Int J Pharm. 2010;391:162–8.CrossRefGoogle Scholar
  37. 37.
    Khan AW, Kotta S, Ansari SH, Sharma RK, Ali J. Enhanced dissolution and bioavailability of grapefruit flavonoid Naringenin by solid dispersion utilizing fourth generation carrier. Drug Dev Ind Pharm. 2015;41:772–9.CrossRefGoogle Scholar
  38. 38.
    Cavallari C, Gonzalez-Rodriguez M, Tarterini F, Fini A. Image analysis of lutrol/gelucire/olanzapine microspheres prepared by ultrasound-assisted spray congealing. Eur J Pharm Biopharm. 2014;88:909–18.  https://doi.org/10.1016/j.ejpb.2014.08.014.CrossRefPubMedGoogle Scholar
  39. 39.
    Kawabata Y, Wada K, Nakatani M, Yamada S, Onoue S. Formulation design for poorly water-soluble drugs based on biopharmaceutics classification system: basic approaches and practical applications. Int J Pharm. 2011;420:1–10.  https://doi.org/10.1016/j.ijpharm.2011.08.032.CrossRefPubMedGoogle Scholar
  40. 40.
    FDA. Guidance for industry: dissolution testing of immediate release solid oral dosage forms. Rockville, MD. 1997.Google Scholar
  41. 41.
    FDA. Guidance for industry: SUPAC-MR: modified release solid oral dosage forms scale-up and postapproval changes: chemistry, manufacturing, and controls; in vitro dissolution testing and in vivo bioequivalence documentation. Rockville, MD. 1997.Google Scholar
  42. 42.
    FDA. Guidance for industry: waiver of in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms based on a biopharmaceutics classification system. Rockville, MD. 2000.Google Scholar
  43. 43.
    Xing J, Chen X, Zhong D. Absorption and enterohepatic circulation of baicalin in rats. Life Sci. 2005;78:140–6.CrossRefGoogle Scholar
  44. 44.
    DuPont MS, Day AJ, Bennett RN, Mellon FA, Kroon PA. Absorption of kaempferol from endive, a source of kaempferol-3-glucuronide, in humans. Eur J Clin Nutr. 2004;58:947–54.CrossRefGoogle Scholar
  45. 45.
    Zhang WD, Wang XJ, Zhou SY, Gu Y, Wang R, Zhang TL, et al. Determination of free and glucuronidated kaempferol in rat plasma by LC-MS/MS: application to pharmacokinetic study. J Chromatogr B Analyt Technol Biomed Life Sci. 2010;878:2137–40.CrossRefGoogle Scholar
  46. 46.
    Zhang Q, Zhang Y, Zhang Z, Lu Z. Sensitive determination of kaempferol in rat plasma by high-performance liquid chromatography with chemiluminescence detection and application to a pharmacokinetic study. J Chromatogr B. 2009;877:3595–600.  https://doi.org/10.1016/j.jchromb.2009.08.046.CrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  • Mariana Colombo
    • 1
  • Gabriela de Lima Melchiades
    • 1
  • Luana Roberta Michels
    • 1
  • Fabrício Figueiró
    • 2
    • 3
  • Valquiria Linck Bassani
    • 1
  • Helder Ferreira Teixeira
    • 1
  • Letícia Scherer Koester
    • 1
    Email author
  1. 1.Laboratório de Desenvolvimento Galênico, Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de FarmáciaUniversidade Federal do Rio Grande do SulPorto AlegreBrazil
  2. 2.Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da SaúdeUniversidade Federal do Rio Grande do SulPorto AlegreBrazil
  3. 3.Departamento de Bioquímica, Instituto de Ciências Básicas da SaúdeUniversidade Federal do Rio Grande do SulPorto AlegreBrazil

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