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Development of Nanostructured Liquid Crystalline Formulation of Anti-Cancer Drug as a New Drug Delivery System

  • Hadel A. Abo El-EninEmail author
Original Article
  • 23 Downloads

Abstract

Purpose

This study is concerned with encapsulation of the anti-cancer drug (berberine hydrochloride (BH)) in nanocarriers as cubosomes, which is, then, formulated in solid form to ease its incorporation into different drug delivery systems, improve its solubility, and improve its anti-cancer activity.

Methods

BH cubosomes were prepared using glyceryl mono-oleate (GMO) and poloxamer 407 (PF127). Polyvinyl alcohol (PVA) was added as a stabilizer. The well-characterized cubosome formula via particle size, entrapment efficiency, and in vitro release study was converted into free-flowing powder (S-BH) using sugar carriers at different mass ratios. The prepared powdered cubosome S-BH was subjected to in vitro characterization, such as flowability, compressibility, drug solubility, and drug release studies. The prepared formula’s cytotoxic effects on human breast cancer cell line (MCF-7) were studied.

Results and Discussion

The prepared cubosome formula has an average particle size of 220.8 nm with a polydispersity index (PdI) < 1 and a high drug EE value (64.75%). The BH release rate begins relatively fast followed by a slower release rate. S-BH has good flowability and compressibility as evidenced by decreased repose angle (31.53 ± 0.31) and lowered required pressure for compression (60.07 ± 6.16). Enhanced dissolution rate and increased drug solubility relate to the increased particle surface area as a result of decreased particle size. It also provides high anti-proliferative and apoptotic activities against breast cancer cells.

Conclusion

The prepared solid cubosomal BH can be utilized for the preparation of different solid dosage forms, like tablets and capsules.

Keywords

Cubosomes Natural arachidonic acid inhibitory Berberine hydrochloride Cytotoxicity Solid cubosome 

Abbreviations

GMO

Glycerol-mono-oleate

PF127

Poloxamer 407

Cubs

Cubosomes

Et

Ethanol

EE

Entrapping efficiency

PS

Particle size

BH

Berberine hydrochloride

AA

Arachidonic acid

BH-cubs

Cubosomal berberine hydrochloride

S-BH

Solid BH-cubosome

NDDS

New drug delivery systems

PBS

Phosphate-buffered saline

PdI

Polydispersity index

MCF-7

Human breast cancer cell line

Malt

Maltodextrin

PVA

Polyvinyl alcohol

Notes

Acknowledgments

The author thanks the Taif University-Deanship of research for its financial support to complete this project. The author also thanks Dr. Reem El Namary and Mrs. Rabab for their help to complete this project.

References

  1. 1.
    Kushwaha SKS, Rastogl A, Rai AK, Singh S. Novel drug delivery system for anticancer drug: a review. Int J PharmTech Res. 2012;4(2):542–53.Google Scholar
  2. 2.
    Samadi AK, Bilsland A, Georgakilas AG, Amedei A, Amin A, Bishayee A, et al. editors. A multi-targeted approach to suppress tumor-promoting inflammation. Elsevier; 2015.Google Scholar
  3. 3.
    Geldenhuys WJ, Bishayee A, Darvesh AS, Carroll RT. Natural products of dietary origin as lead compounds in virtual screening and drug design. Curr Pharm Biotechnol. 2012;13(1):117–24.Google Scholar
  4. 4.
    Yarla NS, Bishayee A, Sethi G, Reddanna P, Kalle AM, Dhananjaya BL, et al. editors. Targeting arachidonic acid pathway by natural products for cancer prevention and therapy. Elsevier; 2016.Google Scholar
  5. 5.
    Alhazmi FG. Comparison of breast and colorectal cancer screening programs in the Netherlands and the Kingdom of Saudi Arabia. Cancer. 2016;4(1):157–65.Google Scholar
  6. 6.
    Patil JB, Kim J, Jayaprakasha GK. Berberine induces apoptosis in breast cancer cells (MCF-7) through mitochondrial-dependent pathway. Eur J Pharmacol. 2010;645(1):70–8.Google Scholar
  7. 7.
    Wang L, Li H, Wang S, Liu R, Wu Z, Wang C, et al. Enhancing the antitumor activity of berberine hydrochloride by solid lipid nanoparticle encapsulation. AAPS PharmSciTech. 2014;15(4):834–44.Google Scholar
  8. 8.
    Shen R, Kim JJ, Yao M, Elbayoumi TA. Development and evaluation of vitamin E D-α-tocopheryl polyethylene glycol 1000 succinate-mixed polymeric phospholipid micelles of berberine as an anticancer nanopharmaceutical. Int J Nanomedicine. 2016;11:1687.Google Scholar
  9. 9.
    Xue M, Yang M-X, Zhang W, Li X-M, Gao D-H, Ou Z-M, et al. Characterization, pharmacokinetics, and hypoglycemic effect of berberine loaded solid lipid nanoparticles. Int J Nanomedicine. 2013;8:4677.Google Scholar
  10. 10.
    Battu SK, Repka MA, Maddineni S, Chittiboyina AG, Avery MA, Majumdar S. Physicochemical characterization of berberine chloride: a perspective in the development of a solution dosage form for oral delivery. AAPS PharmSciTech. 2010;11(3):1466–75.Google Scholar
  11. 11.
    Roger E, Lagarce F, Garcion E, Benoit JP. Lipid nanocarriers improve paclitaxel transport throughout human intestinal epithelial cells by using vesicle-mediated transcytosis. J Control Release. 2009;140(2):174–81.Google Scholar
  12. 12.
    Boyd BJ, Khoo S-M, Whittaker DV, Davey G, Porter CJH. A lipid-based liquid crystalline matrix that provides sustained release and enhanced oral bioavailability for a model poorly water soluble drug in rats. Int J Pharm. 2007;340(1):52–60.Google Scholar
  13. 13.
    Lai J, Chen J, Lu Y, Sun J, Hu F, Yin Z, et al. Glyceryl monooleate/poloxamer 407 cubic nanoparticles as oral drug delivery systems: I. In vitro evaluation and enhanced oral bioavailability of the poorly water-soluble drug simvastatin. AAPS PharmSciTech. 2009;10(3):960–6.Google Scholar
  14. 14.
    Dian L, Yang Z, Li F, Wang Z, Pan X, Peng X, et al. Cubic phase nanoparticles for sustained release of ibuprofen: formulation, characterization, and enhanced bioavailability study. Int J Nanomedicine. 2013;8:845.Google Scholar
  15. 15.
    Azhari H, Strauss M, Hook S, Boyd BJ, Rizwan SB. Stabilising cubosomes with Tween 80 as a step towards targeting lipid nanocarriers to the blood–brain barrier. Eur J Pharm Biopharm. 2016;104:148–55.Google Scholar
  16. 16.
    Cabral H, Matsumoto Y, Mizuno K, Chen Q, Murakami M, Kimura M, et al. Accumulation of sub-100 nm polymeric micelles in poorly permeable tumours depends on size. Nat Nanotechnol. 2011;6(12):815–23.Google Scholar
  17. 17.
    Ali MA, Kataoka N, Ranneh A-H, Iwao Y, Noguchi S, Oka T, et al. Enhancing the solubility and oral bioavailability of poorly water-soluble drugs using monoolein cubosomes. Chem Pharm Bull. 2017;65(1):42–8.Google Scholar
  18. 18.
    Barman RK, Iwao Y, Funakoshi Y, Ranneh A-H, Noguchi S, Wahed MII, et al. Development of highly stable nifedipine solid–lipid nanoparticles. Chem Pharm Bull. 2014;62(5):399–406.Google Scholar
  19. 19.
    Rizwan SB, McBurney WT, Young K, Hanley T, Boyd BJ, Rades T, et al. Cubosomes containing the adjuvants imiquimod and monophosphoryl lipid A stimulate robust cellular and humoral immune responses. J Control Release. 2013;165(1):16–21.Google Scholar
  20. 20.
    Murgia S, Falchi AM, Meli V, Schillén K, Lippolis V, Monduzzi M, et al. Cubosome formulations stabilized by a dansyl-conjugated block copolymer for possible nanomedicine applications. Colloids Surf B: Biointerfaces. 2015;129:87–94.Google Scholar
  21. 21.
    Moebus K, Siepmann J, Bodmeier R. Cubic phase-forming dry powders for controlled drug delivery on mucosal surfaces. J Control Release. 2012;157(2):206–15.Google Scholar
  22. 22.
    Jain V, Swarnakar NK, Mishra PR, Verma A, Kaul A, Mishra AK, et al. Paclitaxel loaded PEGylated gleceryl monooleate based nanoparticulate carriers in chemotherapy. Biomaterials. 2012;33(29):7206–20.Google Scholar
  23. 23.
    Guo S, Wang G, Wu T, Bai F, Xu J, Zhang X. Solid dispersion of berberine hydrochloride and Eudragit® S100: formulation, physicochemical characterization and cytotoxicity evaluation. J Drug Delivery Sci Technol. 2017;40:21–7.Google Scholar
  24. 24.
    Luo X, Li J, Guo L, Cheng X, Zhang T, Deng Y. Preparation of berberine hydrochloride long-circulating liposomes by ionophore A23187-mediated ZnSO4 gradient method. Asian J Pharm Sci. 2013;8(4):261–6.Google Scholar
  25. 25.
    Kwon M, Choi YA, Choi M-K, Song I-S. Mixed micelle formulation of berberine using common excipients with P-gp modulation potential for the enhanced oral bioavailability of berberine. Drug Metab Pharmacokinet. 2017;32(1):S101.Google Scholar
  26. 26.
    Luo Q, Lin T, Zhang CY, Zhu T, Wang L, Ji Z, et al. A novel glyceryl monoolein-bearing cubosomes for gambogenic acid: preparation, cytotoxicity and intracellular uptake. Int J Pharm. 2015;493(1):30–9.Google Scholar
  27. 27.
    Garg NK, Singh B, Jain A, Nirbhavane P, Sharma R, Tyagi RK, et al. Fucose decorated solid-lipid nanocarriers mediate efficient delivery of methotrexate in breast cancer therapeutics. Colloids Surf B: Biointerfaces. 2016;146:114–26.Google Scholar
  28. 28.
    Enin HAA, El Nabarawy NA, Elmonem RAA. Treatment of radiation-induced oral mucositis using a novel accepted taste of prolonged release mucoadhesive bi-medicated double-layer buccal films. AAPS PharmSciTech. 2016;1–13.Google Scholar
  29. 29.
    Gandhi A, Jana S, Sen KK. In-vitro release of acyclovir loaded Eudragit RLPO® nanoparticles for sustained drug delivery. Int J Biol Macromol. 2014;67:478–82.Google Scholar
  30. 30.
    Akhlaghi SP, Loh W. Interactions and release of two palmitoyl peptides from phytantriol cubosomes. Eur J Pharm Biopharm. 2017;117:60–7.Google Scholar
  31. 31.
    Goyal R, Macri L, Kohn J. Formulation strategy for the delivery of cyclosporine A: comparison of two polymeric nanospheres. Sci Rep. 2015;5.Google Scholar
  32. 32.
    Ekambaram P, Sathali AAH. Formulation and evaluation of solid lipid nanoparticles of ramipril. J Young Pharm. 2011;3(3):216–20.Google Scholar
  33. 33.
    Patra CN, Pandit HK, Singh SP, Devi MV. Applicability and comparative evaluation of wet granulation and direct compression technology to Rauwolfia serpentina root powder: a technical note. AAPS PharmSciTech. 2008;9(1):100–4.Google Scholar
  34. 34.
    Al-Achi A, Patel B. Formulation and optimization of potassium iodide tablets. Saudi Pharm J. 2015;23(1):95–101.Google Scholar
  35. 35.
    Heckel RW. Density-pressure relationships in powder compaction. Trans Metall Soc AIME. 1961;221(4):671–5.Google Scholar
  36. 36.
    Singh D, Rawat MSM, Semalty A, Semalty M. Chrysophanol–phospholipid complex. J Therm Anal Calorim. 2013;111(3):2069–77.Google Scholar
  37. 37.
    Abo Enin HA, Abdel-Bar HM. Solid super saturated self-nanoemulsifying drug delivery system (sat-SNEDDS) as a promising alternative to conventional SNEDDS for improvement rosuvastatin calcium oral bioavailability. Exp Opin Drug Deliv. 2016;13(11):1513–21.Google Scholar
  38. 38.
    Hou Z, Li Y, Huang Y, Zhou C, Lin J, Wang Y, et al. Phytosomes loaded with mitomycin C–soybean phosphatidylcholine complex developed for drug delivery. Mol Pharm. 2012;10(1):90–101.Google Scholar
  39. 39.
    Namasivayam S, Robin A. Preparation of nano albumin-flutamide (Nab-flu) conjugate and evaluation of its in vitro drug control release, anticancer activity and genotoxicity. 2018.Google Scholar
  40. 40.
    D’Souza S, Faraj JA, Giovagnoli S, DeLuca PP. In vitro–in vivo correlation from lactide-co-glycolide polymeric dosage forms. Progress in Biomaterials. 2014;3(2–4):131–42.Google Scholar
  41. 41.
    Dash S, Murthy PN, Nath L, Chowdhury P. Kinetic modeling on drug release from controlled drug delivery systems. Acta Pol Pharm. 2010;67(3):217–23.Google Scholar
  42. 42.
    Wang J, Liu Q, Yang Q. Radiosensitization effects of berberine on human breast cancer cells. Int J Mol Med. 2012;30(5):1166–72.Google Scholar
  43. 43.
    Alam F, Mezhal F, El Hasasna H, Nair VA, Aravind SR, Saber Ayad M, et al. The role of p53-microRNA 200-Moesin axis in invasion and drug resistance of breast cancer cells. Tumor Biol. 2017;39(9):1010428317714634.Google Scholar
  44. 44.
    Gautam A, Singh G, Ram S. A simple polyol synthesis of silver metal nanopowder of uniform particles. Synth Met. 2007;157(1):5–10.Google Scholar
  45. 45.
    Zhang P, Gao W, Zhang L, Chen L, Shen Q, Wang X, et al. In vitro evaluation of topical microemulsion of capsaicin free of surfactant. Biol Pharm Bull. 2008;31(12):2316–20.Google Scholar
  46. 46.
    Zhuang C-Y, Li N, Wang M, Zhang X-N, Pan W-S, Peng J-J, et al. Preparation and characterization of vinpocetine loaded nanostructured lipid carriers (NLC) for improved oral bioavailability. Int J Pharm. 2010;394(1):179–85.Google Scholar
  47. 47.
    Nguyen HTP, Soucé M, Perse X, Vial F, Perrier T, Yvergnaux F, et al. Lipid-based submicron capsules as a strategy to include high concentrations of a hydrophobic lightening agent in a hydrogel. Int J Cosmet Sci. 2017;39:450–6.Google Scholar
  48. 48.
    Esposito E, Eblovi N, Rasi S, Drechsler M, Di Gregorio GM, Menegatti E, et al. Lipid-based supramolecular systems for topical application: a preformulatory study. AAPS J. 2003;5(4):62–76.Google Scholar
  49. 49.
    Fonte P, Araújo F, Seabra V, Reis S, van de Weert M, Sarmento B. Co-encapsulation of lyoprotectants improves the stability of protein-loaded PLGA nanoparticles upon lyophilization. Int J Pharm. 2015;496(2):850–62.Google Scholar
  50. 50.
    Khan MI, Madni A, Peltonen L. Development and in-vitro characterization of sorbitan monolaurate and poloxamer 184 based niosomes for oral delivery of diacerein. Eur J Pharm Sci. 2016;95:88–95.Google Scholar
  51. 51.
    Tavano L, Muzzalupo R, Trombino S, Cassano R, Pingitore A, Picci N. Effect of formulations variables on the in vitro percutaneous permeation of sodium diclofenac from new vesicular systems obtained from Pluronic triblock copolymers. Colloids Surf B: Biointerfaces. 2010;79(1):227–34.Google Scholar
  52. 52.
    Li S, Ji Z, Zou M, Nie X, Shi Y, Cheng G. Preparation, characterization, pharmacokinetics and tissue distribution of solid lipid nanoparticles loaded with tetrandrine. AAPS PharmSciTech. 2011;12(3):1011–8.Google Scholar
  53. 53.
    Shah RB, Tawakkul MA, Khan MA. Comparative evaluation of flow for pharmaceutical powders and granules. AAPS PharmSciTech. 2008;9(1):250–8.Google Scholar
  54. 54.
    Liebermann HA, Lachman L, Schwartz JB. Pharmaceutical dosage forms: tablets, vol. 2. New York: Marcel Dekker; 1990.Google Scholar
  55. 55.
    USP. The United States pharmacopeial convention. Headquarters C, editor. Rockville, MD 20852 12601 Twinbrook Pkwy; 2014.Google Scholar
  56. 56.
    Kim MH, Kim T-H, Ko JA, Ko S, Oh J-M, Park HJ. Kinetic and thermodynamic studies of silver migration from nanocomposites. J Food Eng. 2019;243:1–8.Google Scholar
  57. 57.
    Hiremath PS, Soppimath KS, Betageri GV. Proliposomes of exemestane for improved oral delivery: formulation and in vitro evaluation using PAMPA, Caco-2 and rat intestine. Int J Pharm. 2009;380(1–2):96–104.Google Scholar
  58. 58.
    Tan A, Rao S, Prestidge CA. Transforming lipid-based oral drug delivery systems into solid dosage forms: an overview of solid carriers, physicochemical properties, and biopharmaceutical performance. Pharm Res. 2013;30(12):2993–3017.Google Scholar
  59. 59.
    Brophy MR, Deasy PB. Application of the Higuchi model for drug release from dispersed matrices to particles of general shape. Int J Pharm. 1987;37(1):41–7.Google Scholar
  60. 60.
    Noyes AA, Whitney WR. The rate of solution of solid substances in their own solutions. J Am Chem Soc. 1897;19(12):930–4.Google Scholar
  61. 61.
    McLendon R, Friedman A, Bigner D, Van Meir EG, Brat DJ, Mastrogianakis GM, et al. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008;455(7216):1061–8.Google Scholar
  62. 62.
    Larsson K. Aqueous dispersions of cubic lipid–water phases. Curr Opin Colloid Interface Sci. 2000;5(1–2):64–9.Google Scholar
  63. 63.
    Katneni K, Charman SA, Porter CJ. An evaluation of the relative roles of the unstirred water layer and receptor sink in limiting the in-vitro intestinal permeability of drug compounds of varying lipophilicity. J Pharm Pharmacol. 2008;60(10):1311–9.Google Scholar
  64. 64.
    Elnaggar YS, Etman SM, Abdelmonsif DA, Abdallah OY. Novel piperine-loaded Tween-integrated monoolein cubosomes as brain-targeted oral nanomedicine in Alzheimer’s disease: pharmaceutical, biological, and toxicological studies. Int J Nanomedicine. 2015;10:5459.Google Scholar
  65. 65.
    Um JY, Chung H, Kim KS, Kwon IC, Jeong SY. In vitro cellular interaction and absorption of dispersed cubic particles. Int J Pharm. 2003;253(1–2):71–80.Google Scholar
  66. 66.
    Barreto JA, O’Malley W, Kubeil M, Graham B, Stephan H, Spiccia L. Nanomaterials: applications in cancer imaging and therapy. Adv Mater. 2011;23(12):H18–40.Google Scholar
  67. 67.
    Murgia S, Falchi AM, Mano M, Lampis S, Angius R, Carnerup AM, et al. Nanoparticles from lipid-based liquid crystals: emulsifier influence on morphology and cytotoxicity. J Phys Chem B. 2010;114(10):3518–25.Google Scholar

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Authors and Affiliations

  1. 1.Pharmaceutics Department, Faculty of PharmacyTaif UniversityTaifSaudi Arabia
  2. 2.Pharmaceutics DepartmentNational Organization of Drug Control and Research (NODCAR)PyramidsEgypt

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