Skip to main content

Advertisement

SpringerLink
Log in

Drug-Phospholipid Complex—a Go Through Strategy for Enhanced Oral Bioavailability

  • Review Article
  • Theme: Lipid-Based Drug Delivery Strategies for Oral Drug Delivery
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

Among many, the oral route of delivery is considered to be the most favorable route with the highest patient compliance. The main issue with oral delivery is the environmental vulnerability of gastro intestinal tract (G.I.T). The bioavailability could further decrease when drug has poor aqueous solubility and permeability through biological membrane. This drawback could be resolved by employing drug-phospholipid complex strategy, as they utilize mechanism which is similar to the absorption mechanism of nutritional constituents form G.I.T. The drug-phospholipid complexes are considered ideal for oral delivery as they are biodegradable and non-toxic, which enable them to be employed as solubilizer, emulsifier, and as a matrix forming excipient for dugs with poor solubility and/or permeability. The present review compiles the basic know how about the phospholipids and the mechanism through which it improves the bioavailability of drugs. Further, it also compiles the crucial formulation aspects and methods of preparations of drug-phospholipid complex along with its physical and in silico characterization techniques. The increase in number of recent reports involving the utilization of drug-phospholipid complex to improve oral bioavailability of drugs thus explains how vital the strategy is for a successful oral delivery.

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

Similar content being viewed by others

References

  1. Veber DF, Johnson SR, Cheng H-Y, Smith BR, Ward KW, Kopple KD. Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem. 2002;45(12):2615–23.

    Article  CAS  PubMed  Google Scholar 

  2. Kuche K, Maheshwari R, Tambe V, Mak K-K, Jogi H, Raval N, et al. Carbon nanotubes (CNTs) based advanced dermal therapeutics: current trends and future potential. Nanoscale. 2018;10(19):8911–37.

    Article  CAS  PubMed  Google Scholar 

  3. Yan C, Gu J, Lv Y, Shi W, Jing H. Improved intestinal absorption of water-soluble drugs by acetylation of G2 PAMAM dendrimer nanocomplexes in rat. Drug Deliv Transl Res. 2017;7(3):408–15.

  4. Kirtane AR, Narayan P, Liu G, Panyam J. Polymer-surfactant nanoparticles for improving oral bioavailability of doxorubicin. J Pharm Investig. 2017;47(1):65–73.

    Article  CAS  Google Scholar 

  5. Pandey SC, Kaur R, Gangadharapp H, Sachin J. Self-emulsifying drug delivery system: a review. RJPT. 2018;1(4):313–23.

  6. Vilas PC, Gujarathi NA, Rane BR, Pawar SP. A Review on self microemulsifying drug delivery system. Pharma Sci Monit. 2013;4(1):3628–48.

  7. Andonova V, Peneva P. Characterization methods for solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC). Curr Pharm Des. 2017;23(43):6630–42.

    Article  CAS  Google Scholar 

  8. Semalty A, Semalty M, Rawat BS, Singh D, Rawat M. Pharmacosomes: the lipid-based new drug delivery system. Expert Opin Drug Deliv. 2009;6(6):599–612.

    Article  CAS  PubMed  Google Scholar 

  9. J-n Y, Zhu Y, Wang L, Peng M, S-s T, Cao X, et al. Enhancement of oral bioavailability of the poorly water-soluble drug silybin by sodium cholate/phospholipid-mixed micelles. Acta Pharmacol Sin. 2010;31(6):759.

    Article  CAS  Google Scholar 

  10. Gnananath K, Nataraj KS, Rao BG. Phospholipid complex technique for superior bioavailability of Phytoconstituents. Adv Pharm Bull. 2017;7(1):35–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Singh RP, Gangadharappa H, Mruthunjaya K. Phospholipids: unique carriers for drug delivery systems. J Drug Deliv Sci Technol. 2017;39:166–79.

    Article  CAS  Google Scholar 

  12. Marsh D. General features of phospholipid phase transitions. Chem Phys Lipids. 1991;57(2–3):109–20.

    Article  CAS  PubMed  Google Scholar 

  13. Seimiya T, Ohki S. Ionic structure of phospholipid membranes, and binding of calcium ions. Biochim Biophys Acta (BBA)-Biomembr. 1973;298(3):546–61.

    Article  CAS  Google Scholar 

  14. Sosenko IR, Innis SM, Frank L. Intralipid increases lung polyunsaturated fatty acids and protects newborn rats from oxygen toxicity. Pediatr Res. 1991;30(5):413–7.

    Article  CAS  PubMed  Google Scholar 

  15. de Boer JF, Kuipers F, Groen AK. Cholesterol transport revisited: A new Turbo mechanism to drive cholesterol excretion. Trends Endocrin Met. 2017;29(2):123–33.

  16. Mills PC, Chen Y, Hills YC, Hills BA. Comparison of surfactant lipids between pleural and pulmonary lining fluids. Pulm Pharmacol Ther. 2006;19(4):292–6.

  17. Cevc G. Phospholipids handbook: CRC press; 1993.

    Google Scholar 

  18. Li J, Wang X, Zhang T, Wang C, Huang Z, Luo X, et al. A review on phospholipids and their main applications in drug delivery systems. Asian J Pharm Sci. 2015;10(2):81–98.

    Article  Google Scholar 

  19. Intermolecular JI. Surface forces. San Diego: Academic press; 1992.

    Google Scholar 

  20. McMahon HT, Gallop JL. Membrane curvature and mechanisms of dynamic cell membrane remodelling. Nature. 2005;438(7068):590–6.

    Article  CAS  PubMed  Google Scholar 

  21. Phillips R, Theriot J, Kondev J, Garcia H. Physical biology of the cell: Garland. Science. 2012.

  22. Sharma S, Roy RK. Phytosomes: an emerging technology. Int J Pharm Res Dev. 2010;2(5):1–7.

    Google Scholar 

  23. Kapoor B, Gupta R, Singh SK, Gulati M, Singh S. Prodrugs, phospholipids and vesicular delivery-an effective triumvirate of pharmacosomes. Adv Colloid Interf Sci. 2018;253:35–65.

    Article  CAS  Google Scholar 

  24. Carey MC, Small DM. The characteristics of mixed micellar solutions with particular reference to bile. Am J Med. 1970;49(5):590–608.

    Article  CAS  PubMed  Google Scholar 

  25. Gangwar M, Singh R, Goel R, Nath G. Recent advances in various emerging vescicular systems: an overview. Asian Pac J Trop Biomed. 2012;2(2):S1176–S88.

    Article  Google Scholar 

  26. Bhingare U, Khadabadi S, Shinde N. Pharmacosomes: A novel drug delivery system. Int J. 2014;3(1):14–20.

    Google Scholar 

  27. Gavhane YN, Yadav AV. Loss of orally administered drugs in GI tract. Saudi Pharm J. 2012;20(4):331–44.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Jena SK, Singh C, Dora CP, Suresh S. Development of tamoxifen-phospholipid complex: novel approach for improving solubility and bioavailability. Int J Pharm. 2014;473(1–2):1–9.

    Article  CAS  PubMed  Google Scholar 

  29. van Hoogevest P. Review–an update on the use of oral phospholipid excipients. Eur J Pharm Sci. 2017;108:1–12.

    Article  PubMed  CAS  Google Scholar 

  30. Chaudhri O, Small C, Bloom S. Gastrointestinal hormones regulating appetite. Phil Trans R Soc London B: Biol Sci. 2006;361(1471):1187–209.

    Article  CAS  Google Scholar 

  31. Marieb EN, Hoehn K. Human anatomy and physiology. 8e éd ed. San Francisco: Benjamin Cummings; 2010.

    Google Scholar 

  32. Kossena GA, Charman WN, Wilson CG, O’Mahony B, Lindsay B, Hempenstall JM, et al. Low dose lipid formulations: effects on gastric emptying and biliary secretion. Pharm Res. 2007;24(11):2084–96.

    Article  CAS  PubMed  Google Scholar 

  33. Higgins J, Fielding C. Lipoprotein lipase. Mechanism of formation of triglyceride-rich remnant particles from very low density lipoproteins and chylomicrons. Biochemistry. 1975;14(11):2288–93.

    Article  CAS  PubMed  Google Scholar 

  34. Harde H, Das M, Jain S. Solid lipid nanoparticles: an oral bioavailability enhancer vehicle. Expert Opin Drug Deliv. 2011;8(11):1407–24.

    Article  CAS  PubMed  Google Scholar 

  35. Nestel P, Havel R, Bezman A. Sites of initial removal of chylomicron triglyceride fatty acids from the blood. J Clin Invest. 1962;41(10):1915–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Semalty A, Semalty M, Singh D, Rawat M. Phyto-phospholipid complex of catechin in value added herbal drug delivery. J Incl Phenom Macrocycl Chem. 2012;73(1–4):377–86.

    Article  CAS  Google Scholar 

  37. Alexander A, Ajazuddin S, Verma T, Swarna MJ, Patel S. Mechanism responsible for mucoadhesion of mucoadhesive drug delivery system: a review. Int J Appl Biol Pharm Technol. 2011;2(1):434–45.

    Google Scholar 

  38. Behra A, Giri TK, Tripathi DK, Ajazuddin AA. An exhaustive review on recent advancement in pharmaceutical bioadhesive used for systemic drug delivery through oral mucosa for achieving maximum pharmacological response and effect. Int J Pharmacol. 2012;8(5):283–305.

    Article  CAS  Google Scholar 

  39. Afanas’eva YG, Fakhretdinova E, Spirikhin L, Nasibullin R. Mechanism of interaction of certain flavonoids with phosphatidylcholine of cellular membranes. Pharm Chem J. 2007;41(7):354–6.

    Article  CAS  Google Scholar 

  40. Li N, Ye Y, Yang M, Jiang X, Ma J. Pharmacokinetics of baicalin-phospholipid complex in rat plasma and brain tissues after intranasal and intravenous administration. Die Pharmazie-an international. J Pharm Sci. 2011;66(5):374–7.

    CAS  Google Scholar 

  41. Yue P-F, Yuan H-L, Li X-Y, Yang M, Zhu W-F. Process optimization, characterization and evaluation in vivo of oxymatrine–phospholipid complex. Int J Pharm. 2010;387(1–2):139–46.

    Article  CAS  PubMed  Google Scholar 

  42. Maryana W, Rachmawati H, Mudhakir D. Formation of Phytosome containing Silymarin using thin layer-hydration technique aimed for Oral delivery. Mater Today Proc. 2016;3(3):855–66.

    Article  Google Scholar 

  43. Qin X, Yang Y, T-t F, Gong T, X-n Z, Huang Y. Preparation, characterization and in vivo evaluation of bergenin-phospholipid complex. Acta Pharmacol Sin. 2010;31(1):127–36.

    Article  CAS  PubMed  Google Scholar 

  44. Guo B, Liu H, Li Y, Zhao J, Yang D, Wang X, et al. Application of phospholipid complex technique to improve the dissolution and pharmacokinetic of probucol by solvent-evaporation and co-grinding methods. Int J Pharm. 2014;474(1–2):50–6.

    Article  CAS  PubMed  Google Scholar 

  45. Sikarwar MS, Sharma S, Jain AK, Parial S. Preparation, characterization and evaluation of marsupsin–phospholipid complex. AAPS PharmSciTech. 2008;9(1):129–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Li Y, Yang D-J, Chen S-L, Chen S-B, AS-C C. Comparative physicochemical characterization of phospholipids complex of puerarin formulated by conventional and supercritical methods. Pharm Res. 2008;25(3):563–77.

    Article  CAS  PubMed  Google Scholar 

  47. Dora CP, Kushwah V, Katiyar SS, Kumar P, Pillay V, Suresh S, et al. Improved oral bioavailability and therapeutic efficacy of erlotinib through molecular complexation with phospholipid. Int J Pharm. 2017;534(1–2):1–13.

    Article  CAS  PubMed  Google Scholar 

  48. Cui F, Shi K, Zhang L, Tao A, Kawashima Y. Biodegradable nanoparticles loaded with insulin–phospholipid complex for oral delivery: preparation, in vitro characterization and in vivo evaluation. J Control Release. 2006;114(2):242–50.

    Article  CAS  PubMed  Google Scholar 

  49. Murugan V, Mukherjee K, Maiti K, Mukherjee PK. Enhanced oral bioavailability and antioxidant profile of ellagic acid by phospholipids. J Agric Food Chem. 2009;57(11):4559–65.

    Article  CAS  PubMed  Google Scholar 

  50. Dora CP, Kushwah V, Katiyar SS, Kumar P, Pillay V, Suresh S, et al. Improved metabolic stability and therapeutic efficacy of a novel molecular gemcitabine phospholipid complex. Int J Pharm. 2017;530(1–2):113–27.

    Article  CAS  PubMed  Google Scholar 

  51. Kumar P, Choonara YE, Pillay V. In silico affinity profiling of neuroactive polyphenols for post-traumatic calpain inactivation: a molecular docking and atomistic simulation sensitivity analysis. Molecules. 2014;20(1):135–68.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Larkin P. Infrared and Raman spectroscopy: principles and spectral interpretation. Amsterdam: Elsevier; 2017.

    Google Scholar 

  53. Singh C, Bhatt TD, Gill MS, Suresh S. Novel rifampicin–phospholipid complex for tubercular therapy: synthesis, physicochemical characterization and in-vivo evaluation. Int J Pharm. 2014;460(1–2):220–7.

    Article  CAS  PubMed  Google Scholar 

  54. Rajan S, Kang S-Y, Gutowsky HS, Oldfield E. Phosphorus nuclear magnetic resonance study of membrane structure. Interactions of lipids with protein, polypeptide, and cholesterol. J Biol Chem. 1981;256(3):1160–6.

    Article  CAS  PubMed  Google Scholar 

  55. Jin Y, Wunderlich B. Single-run heat capacity measurement by DSC: principle, experimental and data analysis. Thermochim Acta. 1993;226:155–61.

    Article  CAS  Google Scholar 

  56. Chandrasekaran B, Abed SN, Al-Attraqchi O, Kuche K, Tekade RK. Computer-aided prediction of pharmacokinetic (ADMET) properties. In: Dosage Form Design Parameters. Amsterdam: Elsevier; 2018. p. 731–55.

    Chapter  Google Scholar 

  57. Ngwuluka NC, Choonara YE, Kumar P, du Toit LC, Khan RA, Pillay V. A novel pH-responsive interpolyelectrolyte hydrogel complex for the oral delivery of levodopa. Part I. IPEC modeling and synthesis. J Biomed Mater Res A. 2015;103(3):1077–84.

    Article  PubMed  CAS  Google Scholar 

  58. Wang L, Hao Y, Liu N, Ma M, Yin Z, Zhang X. Enhance the dissolution rate and oral bioavailability of pranlukast by preparing nanosuspensions with high-pressure homogenizing method. Drug Dev Ind Pharm. 2012;38(11):1381–9.

    Article  CAS  PubMed  Google Scholar 

  59. Hao Y, Wang L, Li J, Liu N, Feng J, Zhao M, et al. Enhancement of solubility, transport across Madin-Darby canine kidney monolayers and oral absorption of pranlukast through preparation of a pranlukast-phospholipid complex. J Biomed Nanotechnol. 2015;11(3):469–77.

    Article  CAS  PubMed  Google Scholar 

  60. Schuetz EG, Schinkel AH, Relling MV, Schuetz JD. P-glycoprotein: a major determinant of rifampicin-inducible expression of cytochrome P4503A in mice and humans. Proc Natl Acad Sci. 1996;93(9):4001–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Qin L, Niu Y, Wang Y, Chen X. Combination of phospholipid complex and submicron emulsion techniques for improving Oral bioavailability and therapeutic efficacy of water-insoluble drug. Mol Pharm. 2018;15(3):1238–47.

    Article  CAS  PubMed  Google Scholar 

  62. Immordino ML, Brusa P, Rocco F, Arpicco S, Ceruti M, Cattel L. Preparation, characterization, cytotoxicity and pharmacokinetics of liposomes containing lipophilic gemcitabine prodrugs. J Control Release. 2004;100(3):331–46.

    Article  CAS  PubMed  Google Scholar 

  63. Elnaggar YS, Shehata EM, Galal S, Abdallah OY. Self-emulsifying preconcentrates of daidzein–phospholipid complex: design, in vitro and in vivo appraisal. Nanomedicine. 2017;12(8):893–910.

    Article  CAS  PubMed  Google Scholar 

  64. Ma H, Chen H, Sun L, Tong L, Zhang T. Improving permeability and oral absorption of mangiferin by phospholipid complexation. Fitoterapia. 2014;93:54–61.

    Article  CAS  PubMed  Google Scholar 

  65. Zhou H, Han Y-m, Zheng Y-m, Xu X-y, Fu S-q, Wang L-I, et al. Preparative procedure of inclusion compound of mangiferin-HP-β-CD. J Chongqing Inst Technol (Nat Sci). 2009;9:011.

    Google Scholar 

  66. Li Y, Ren X, Lio C, Sun W, Lai K, Liu Y, et al. A chlorogenic acid-phospholipid complex ameliorates post-myocardial infarction inflammatory response mediated by mitochondrial reactive oxygen species in SAMP8 mice. Pharmacol Res. 2018;130:110–22.

    Article  CAS  PubMed  Google Scholar 

  67. Maheshwari R, Kuche KN, Advankar A, Soni N, Raval N, Sharma PA, et al. Natural Ingredients/Botanical Extracts for the Nutraceutical Industry. In: Flavors for Nutraceutical and Functional Foods. Boca Raton: CRC Press; 2018. p. 95–142.

    Google Scholar 

  68. Wu J-Y, Li Y-J, Han M, Hu X-B, Yang L, Wang J-M, et al. A microemulsion of puerarin–phospholipid complex for improving bioavailability: preparation, in vitro and in vivo evaluations. Drug Dev Ind Pharm. 2018;44(8):1336–41.

    Article  CAS  PubMed  Google Scholar 

  69. Ge L, He X, Zhang Y, Zhang Y, Chai F, Jiang L, et al. A dabigatran etexilate phospholipid complex nanoemulsion system for further oral bioavailability by reducing drug-leakage in the gastrointestinal tract. Nanomedicine. 2018;14(4):1455–64.

    Article  CAS  Google Scholar 

  70. Pouton CW, Porter CJ. Formulation of lipid-based delivery systems for oral administration: materials, methods and strategies. Adv Drug Deliv Rev. 2008;60(6):625–37.

    Article  CAS  PubMed  Google Scholar 

  71. Constantinides PP. Lipid microemulsions for improving drug dissolution and oral absorption: physical and biopharmaceutical aspects. Pharm Res. 1995;12(11):1561–72.

    Article  CAS  PubMed  Google Scholar 

  72. Pouton CW. Formulation of poorly water-soluble drugs for oral administration: physicochemical and physiological issues and the lipid formulation classification system. Eur J Pharm Sci. 2006;29(3–4):278–87.

    Article  CAS  PubMed  Google Scholar 

  73. Čerpnjak K, Zvonar A, Gašperlin M, Vrečer F. Lipid-based systems as promising approach for enhancing the bioavailability of poorly water-soluble drugs. Acta Pharma. 2013;63(4):427–45.

    Article  CAS  Google Scholar 

  74. Walstra P. Principles of emulsion formation. Chem Eng Sci. 1993;48(2):333–49.

    Article  CAS  Google Scholar 

  75. Ruan J, Liu J, Zhu D, Gong T, Yang F, Hao X, et al. Preparation and evaluation of self-nanoemulsified drug delivery systems (SNEDDSs) of matrine based on drug–phospholipid complex technique. Int J Pharm. 2010;386(1–2):282–90.

    Article  CAS  PubMed  Google Scholar 

  76. Wu H, Long X, Yuan F, Chen L, Pan S, Liu Y, et al. Combined use of phospholipid complexes and self-emulsifying microemulsions for improving the oral absorption of a BCS class IV compound, baicalin. Acta Pharm Sin B. 2014;4(3):217–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Wei D, Zhang X. Solubility of puerarin in the binary system of methanol and acetic acid solvent mixtures. Fluid Phase Equilib. 2013;339:67–71.

    Article  CAS  Google Scholar 

  78. Xia H-j, Zhang Z-h, Jin X, Hu Q, Chen X-y, Jia X-b. A novel drug–phospholipid complex enriched with micelles: preparation and evaluation in vitro and in vivo. Int J Nanomedicine. 2013;8:545.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Munyendo WL, Zhang Z, Abbad S, Waddad AY, Lv H, Baraza LD, et al. Micelles of TPGS modified apigenin phospholipid complex for oral administration: preparation, in vitro and in vivo evaluation. J Biomed Nanotechnol. 2013;9(12):2034–47.

    Article  CAS  PubMed  Google Scholar 

  80. Jin X, Zhang Z-h, Sun E, Qian Q, X-b T, X-b J. Preparation of a nanoscale baohuoside I-phospholipid complex and determination of its absorption: in vivo and in vitro evaluations. Int J Nanomedicine. 2012;7:4907.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Beg S, Raza K, Kumar R, Chadha R, Katare O, Singh B. Improved intestinal lymphatic drug targeting via phospholipid complex-loaded nanolipospheres of rosuvastatin calcium. RSC Adv. 2016;6(10):8173–87.

    Article  CAS  Google Scholar 

Download references

Author information

Author notes

  1. Kaushik Kuche and Nallamothu Bhargavi contributed equally to this work.

Authors and Affiliations

  1. Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Sec-67, S.A.S., Nagar, Punjab, 160062, India

    Kaushik Kuche, Nallamothu Bhargavi, Chander Parkash Dora & Sanyog Jain

Authors
  1. Kaushik Kuche
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nallamothu Bhargavi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chander Parkash Dora
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sanyog Jain
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sanyog Jain.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Guest Editor: Sanyog Jain

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

Kuche, K., Bhargavi, N., Dora, C.P. et al. Drug-Phospholipid Complex—a Go Through Strategy for Enhanced Oral Bioavailability. AAPS PharmSciTech 20, 43 (2019). https://doi.org/10.1208/s12249-018-1252-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1208/s12249-018-1252-4

KEY WORDS

Search

Navigation