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Lipopolysaccharide Polyelectrolyte Complex for Oral Delivery of an Anti-tubercular Drug

  • Research Article
  • Theme: Lipid-Based Drug Delivery Strategies for Oral Drug Delivery
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Abstract

Anti-tuberculosis drug delivery has remained a challenge due to inconsistent bioavailability and inadequate sustained-release properties leading to treatment failure. To resolve these drawbacks, a lipopolysaccharide polyelectrolyte complex (PEC) encapsulated with rifampicin (RIF) (as the model drug) was fabricated, using the solvent injection technique (SIT), with soy lecithin (SLCT), and low-molecular-weight chitosan (LWCT). The average particle size and surface charge of RIF-loaded PEC particulates was 151.6 nm and + 33.0 nm, respectively, with noted decreased particle size and surface charge following increase in SLCT-LWCT mass ratio. Encapsulation efficiency (%EE) and drug-loading capacity (%LC) was 64.25% and 5.84%, respectively. Increase in SLCT-LWCT mass ratio significantly increased %EE with a marginal reduction in %LC. In vitro release studies showed a sustained-release profile for the PEC particulate tablet over 24 h (11.4% cumulative release) where the dominant release mechanism involved non-Fickian anomalous transport shifting towards super case II release as SLCT ratios increased (6.4% cumulative release). PEC-tablets prepared without SIT presented with rapid Fickian-diffusion-based drug release with up to 90% RIF release within 4 h. Ex vivo permeability studies revealed that lipopolysaccharide PEComplexation significantly increased the permeability of RIF by ~ 2-fold within the 8-h study period. These results suggest successful encapsulation of RIF within a PEC structure while imparting increased amorphic regions, as indicated by x-ray diffraction, for potential benefits in improved drug dissolution, bioavailability, and dosing.

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References

  1. Costa A, Pinheiro M, Magalhães J, Ribeiro R, Seabra V, Reis S, et al. The formulation of nanomedicines for treating tuberculosis. Adv Drug Deliv Rev. 2016;102:102–15. https://doi.org/10.1016/j.addr.2016.04.012.

    Article  CAS  PubMed  Google Scholar 

  2. Rappuoli R, Aderem A. A 2020 vision for vaccines against HIV tuberculosis and malaria. Nature. 2011;473(7348):463–9. https://doi.org/10.1038/nature10124.

    Article  CAS  PubMed  Google Scholar 

  3. Sosnik A, Carcaboso ÁM, Glisoni RJ, Moretton MA, Chiappetta DA. New old challenges in tuberculosis: potentially effective nanotechnologies in drug delivery ☆. Adv Drug Deliv Rev. 2010;62(4–5):547–59. https://doi.org/10.1016/j.addr.2009.11.023.

    Article  CAS  PubMed  Google Scholar 

  4. Pinheiro M, Reis S. Liposomes as drug delivery systems for the treatment of TB. Review. Nanomedicine (Lond). 2011;6:1413–28.

    Article  CAS  Google Scholar 

  5. Bachhav SS, Dighe VD, Kotak D, Devarajan PV. Erratum to ‘Rifampicin Lipid-Polymer hybrid nanoparticles (LIPOMER) for enhanced Peyer’s patch uptake’ (International Journal of Pharmaceutics (2017) 532 (612–622) (S0378517317309067) (10.1016/j.ijpharm.2017.09.040)). Int J Pharm. 2017;534(1–2):387–90. https://doi.org/10.1016/j.ijpharm.2017.09.040.

    Article  CAS  PubMed  Google Scholar 

  6. Petkar KC, Chavhan S, Kunda N, Saleem I, Somavarapu S, Taylor KMG, et al. Development of novel octanoyl chitosan nanoparticles for improved rifampicin pulmonary delivery: optimization by factorial design. AAPS PharmSciTech. 2018;19(4):1758–72. https://doi.org/10.1208/s12249-018-0972-9.

    Article  CAS  PubMed  Google Scholar 

  7. Patil J, Devi VK, Devi K, Sarasija S. A novel approach for lung delivery of rifampicin-loaded liposomes in dry powder form for the treatment of tuberculosis. Lung India. 2015;32(4):331 Available from: http://www.lungindia.com/text.asp?2015/32/4/331/159559. Accessed 19 Aug 2018.

    Article  PubMed  PubMed Central  Google Scholar 

  8. El-ridy MS, Mostafa DM, Shehab A, Nasr EA, El-alim SA. Biological evaluation of pyrazinamide liposomes for treatment of Mycobacterium tuberculosis. Int J Pharm. 2007;330:82–8.

    Article  CAS  PubMed  Google Scholar 

  9. Devi N, Maji TK. Preparation and evaluation of gelatin/sodium carboxymethyl cellulose polyelectrolyte complex microparticles for controlled delivery of isoniazid. AAPS PharmSciTech. 2009;10(4):1412–9. https://doi.org/10.1208/s12249-009-9344-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Singh C, Koduri LVSK, Bhatt TD, Jhamb SS, Mishra V, Gill MS, et al. In vitro-in vivo evaluation of novel co-spray dried rifampicin phospholipid lipospheres for oral delivery. AAPS PharmSciTech. 2017;18(1):138–46. https://doi.org/10.1208/s12249-016-0491-5.

    Article  CAS  PubMed  Google Scholar 

  11. Ohashi K, Kabasawa T, Ozeki T, Okada H. One-step preparation of rifampicin/poly (lactic-co-glycolic acid) nanoparticle-containing mannitol microspheres using a four-fluid nozzle spray drier for inhalation therapy of tuberculosis. J Control Release. 2009;135(1):19–24. https://doi.org/10.1016/j.jconrel.2008.11.027.

    Article  CAS  PubMed  Google Scholar 

  12. Esmaeili F, Hosseini-nasr M, Rad-malekshahi M. Preparation and antibacterial activity evaluation of rifampicin-loaded poly lactide-co-glycolide nanoparticles. Nanomedicine. 2007;3:161–7.

    Article  CAS  PubMed  Google Scholar 

  13. Costa A, Sarmento B, Seabra V. European journal of pharmaceutical sciences mannose-functionalized solid lipid nanoparticles are effective in targeting alveolar macrophages. Eur J Pharm Sci. 2018;114(October 2017):103–13. https://doi.org/10.1016/j.ejps.2017.12.006.

    Article  CAS  PubMed  Google Scholar 

  14. Amarnath R, Munusamy MA, Kumar K, Rajan M. Targeted delivery of rifampicin to tuberculosis-infected macrophages: design, in-vitro, and in-vivo performance of rifampicin-loaded poly (ester amide) s nanocarriers. Int J Pharm. 2016;513(1–2):628–35. https://doi.org/10.1016/j.ijpharm.2016.09.080.

    Article  CAS  Google Scholar 

  15. Rawal T, Mishra N, Jha A, Bhatt A, Tyagi RK, Panchal S, et al. Chitosan nanoparticles of gamma-Oryzanol: formulation, optimization, and in vivo evaluation of anti-hyperlipidemic activity. AAPS PharmSciTech. 2018;19(4):1894–907 Available from: http://www.ncbi.nlm.nih.gov/pubmed/29663289. Accessed 19 Aug 2018.

    Article  CAS  PubMed  Google Scholar 

  16. Nagpal K, Singh SK, Mishra DN. Chitosan nanoparticles: a promising system in novel drug delivery. Chem Pharm Bull (Tokyo). 2010;58(11):1423–30 Available from: https://www.jstage.jst.go.jp/article/cpb/58/11/58_11_1423/_article. Accessed 20 Aug 2018

    Article  CAS  Google Scholar 

  17. Patidar A, Thakur DS, Kumar P, Verma J. A review on novel lipid based nanocarriers. Int J Pharm and Pharm Sci. 2010;2(4)30–35. Available from: https://innovareacademics.in/journal/ijpps/Vol2Issue4/806.pdf.

  18. Salomon C, Goycoolea FM, Moerschbacher B. Recent trends in the development of chitosan-based drug delivery systems. AAPS PharmSciTech. 2017;18(4):933–5. https://doi.org/10.1208/s12249-017-0764-7.

    Article  PubMed  Google Scholar 

  19. Bhise KS, Dhumal RS, Chauhan B, Paradkar A, Kadam SS. Effect of oppositely charged polymer and dissolution medium on swelling, erosion, and drug release from chitosan matrices. AAPS PharmSciTech. 2007;8(2):Article 44.

    Article  PubMed  Google Scholar 

  20. Bawa P, Pillay V, Choonara YE, Claire L, Methaius V, Ndesendo K, et al. Research article a composite polyelectrolytic matrix for controlled oral drug delivery. 2011;12(1)227–238. https://doi.org/10.1208/s12249-010-9576-8.

  21. Barbieri S, Sonvico F, Como C, Colombo G, Zani F, Buttini F, et al. Lecithin/chitosan controlled release nanopreparations of tamoxifen citrate: loading, enzyme-trigger release and cell uptake. J Control Release. 2013;167(3):276–83. https://doi.org/10.1016/j.jconrel.2013.02.009.

    Article  CAS  PubMed  Google Scholar 

  22. Pepic I, Hafner A, Lovric J. Lecithin/chitosan nanoparticles for transdermal delivery of melatonin. J Microencapsul. 2011;28(8):807–15.

    Article  PubMed  Google Scholar 

  23. Al-Remawi M, Elsayed A, Maghrabi I, Hamaidi M, Jaber N. Chitosan/lecithin liposomal nanovesicles as an oral insulin delivery system. Pharm Dev Technol. 2017;22(3):390–8.

    Article  CAS  PubMed  Google Scholar 

  24. Sahoo D, Sahoo S, Mohanty P, Sasmal S, Nayak PL. Chitosan: a new versatile bio-polymer for various applications. Des Monomers Polym. 2009;12(5):377–404.

    Article  CAS  Google Scholar 

  25. Siyawamwaya M, Choonara YE, Bijukumar D, Kumar P, Du Toit LC, Pillay V. A review: overview of novel polyelectrolyte complexes as prospective drug bioavailability enhancers. Int J Polym Mater Polym Biomater. 2015;64(18):955–68.

    Article  CAS  Google Scholar 

  26. Heinen C, Reuss S, Saaler-Reinhardt S, Langguth P. Mechanistic basis for unexpected bioavailability enhancement of polyelectrolyte complexes incorporating BCS class III drugs and carrageenans. Eur J Pharm Biopharm. 2013;85(1):26–33. https://doi.org/10.1016/j.ejpb.2013.03.010.

    Article  CAS  PubMed  Google Scholar 

  27. Cheow WS, Hadinoto K. Self-assembled amorphous drug-polyelectrolyte nanoparticle complex with enhanced dissolution rate and saturation solubility. J Colloid Interface Sci. 2012;367(1):518–26. https://doi.org/10.1016/j.jcis.2011.10.011.

    Article  CAS  PubMed  Google Scholar 

  28. Sonvico F, Cagnani A, Rossi A, Motta S, Di Bari MT, Cavatorta F, et al. Formation of self-organized nanoparticles by lecithin/chitosan ionic interaction. Int J Pharm. 2006;324:67–73.

    Article  CAS  PubMed  Google Scholar 

  29. Pawar H, Douroumis D, Boateng JS. Colloids and surfaces B: biointerfaces preparation and optimization of PMAA–chitosan–PEG nanoparticles for oral drug delivery. Colloids Surf B Biointerfaces. 2012;90:102–8. https://doi.org/10.1016/j.colsurfb.2011.10.005.

    Article  CAS  PubMed  Google Scholar 

  30. Ceccaldi C, Strandman S, Hui E, Montagnon E, Schmitt C, Hadj Henni A, et al. Validation and application of a nondestructive and contactless method for rheological evaluation of biomaterials. J Biomed Mater Res B Appl Biomater. 2017;105(8):2565–73.

    Article  CAS  PubMed  Google Scholar 

  31. Norris DA, Sinko PJ. Effect of size, surface charge, and hydrophobicity on the translocation of polystyrene microspheres through gastrointestinal mucin. J Appl Polym Sci. 1997;63(11):1481–92.

    Article  CAS  Google Scholar 

  32. Liu M, Zhang J, Shan W, Huang Y. Developments of mucus penetrating nanoparticles. Asian J Pharm Sci. 2014;10(4):275–82. https://doi.org/10.1016/j.ajps.2014.12.007.

    Article  Google Scholar 

  33. Jain S, Reddy CSK, Swami R, Kushwah V. Amphotericin B loaded chitosan nanoparticles: implication of bile salt stabilization on gastrointestinal stability, permeability and oral bioavailability. AAPS PharmSciTech. 2018;(10). https://doi.org/10.1208/s12249-018-1153-6.

  34. Laridi R, Kheadr EE, Benech RO, Vuillemard JC, Lacroix C, Fliss I. Liposome encapsulated nisin Z: optimization, stability and release during milk fermentation. Int Dairy J. 2003;13(4):325–36.

    Article  CAS  Google Scholar 

  35. Javed I, Hussain SZ, Ullah I, Khan I, Ateeq M, Shahnaz G, et al. Synthesis, characterization and evaluation of lecithin-based nanocarriers for the enhanced pharmacological and oral pharmacokinetic profile of amphotericin B. Journal of Materials Chemistry B. 2015;3(42):8359–65. https://doi.org/10.1039/c5tb01258a.

  36. Cevher E, Taha MAM, Orlu M, Araman A. Evaluation of mechanical and mucoadhesive properties of clomiphene citrate gel formulations containing carbomers and their thiolated derivatives. Drug Delivery. 2008;15(1):57–67. https://doi.org/10.1080/10717540701829234

  37. Chowdary KPR, Srinivasa Rao, Y. Mucoadhesive microspheres for controlled drug delivery. Biol Pharm Bull 2004;27(11):1717–24. https://doi.org/10.1248/bpb.27.1717

  38. Smart J. The basics and underlying mechanisms of mucoadhesion. Adv Drug Deliv Rev. 2005;57(11):1556–68. https://doi.org/10.1016/j.addr.2005.07.001

  39. 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. https://doi.org/10.1016/j.ijpharm.2017.07.060.

    Article  CAS  PubMed  Google Scholar 

  40. Date PV, Samad A, Devarajan PV. Freeze thaw: a simple approach for prediction of optimal cryoprotectant for freeze drying. AAPS PharmSciTech. 2010;11(1):304–13. https://doi.org/10.1208/s12249-010-9382-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. 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. https://doi.org/10.1016/j.ijpharm.2013.10.043.

    Article  CAS  PubMed  Google Scholar 

  42. Alkhader E, Billa N, Roberts CJ. Mucoadhesive chitosan-pectinate nanoparticles for the delivery of curcumin to the colon. AAPS PharmSciTech. 2016;18(4):1009–18. https://doi.org/10.1208/s12249-016-0623-y.

  43. Kumar S, Dutta PK, Koh J. International journal of biological macromolecules a physico-chemical and biological study of novel chitosan—chloroquinoline derivative for biomedical applications. Int J Biol Macromol. 2011;49(3):356–61. https://doi.org/10.1016/j.ijbiomac.2011.05.017.

    Article  CAS  PubMed  Google Scholar 

  44. Formariz TP, Chiavacci LA, Sarmento VH V, Franzini CM, Jr AAS-, Scarpa M V, et al. Structural changes of biocompatible neutral microemulsions stabilized by mixed surfactant containing soya phosphatidylcholine and their relationship with doxorubicin release. Colloids Surf B Biointerfaces. 2008;63:287–95. https://doi.org/10.1016/j.colsurfb.2007.12.021.

  45. Cheng W, Luo Z, Li L, Fu X. Preparation and characterization of debranched-starch/phosphatidylcholine inclusion complexes. J Agric Food Chem. 2015;63(2):634–41. https://doi.org/10.1021/jf504133c.

  46. Celia C, Trapasso E, Cosco D, Paolino D, Fresta M. Turbiscan lab® expert analysis of the stability of Ethosomes® and ultradeformable liposomes containing a bilayer fluidizing agent. Colloids Surf B Biointerfaces. 2009;72(1):155–60.

    Article  CAS  PubMed  Google Scholar 

  47. Gan LJ, Wang XY, Yang D, Zhang H, Shin JA, Hong ST, et al. Emulsifying properties of lecithin containing different fatty acids obtained by immobilized lecitase ultra-catalyzed reaction. J Am Oil Chem Soc. 2014;91(4):579–90.

    Article  CAS  Google Scholar 

  48. Hörter D, Dressman JB. Influence of physicochemical properties on dissolution of drugs in the gastrointestinal tract. Adv Drug Deliv Rev. 1997;25(1):3–14.

    Article  Google Scholar 

  49. Vårum KM, Myhr MM, Hjerde RJN, Smidsrød O. In vitro degradation rates of partially N-acetylated chitosans in human serum. Carbohydr Res. 1997;299(1–2):99–101. https://doi.org/10.1016/s0008-6215(96)00332-1.

  50. Agoram B, Woltosz WS, Bolger MB. Predicting the impact of physiological and biochemical processes on oral drug bioavailability. Adv Drug Deliv Rev. 2001;50. S41–S67. https://doi.org/10.1016/s0169-409x(01)00179-x.

  51. Eduardo J, Ballerini M, Chiann C, Nella M. Effect of pH, mucin and bovine serum on rifampicin permeability through Caco-2 cells. Biopharm Drug Dispos. 2012;323(August):316–23. https://doi.org/10.1002/bdd.1802.

    Article  CAS  Google Scholar 

  52. Mariappan TT, Singh S. Positioning of rifampicin in the biopharmaceutics classification system (BCS). Clin Res Regul Aff. 2006;23(1):1–10. https://doi.org/10.1080/10601330500533990.

    Article  Google Scholar 

  53. Collett A, Tanianis-hughes J, Warhurst G. Rapid induction of P-glycoprotein expression by high permeability compounds in colonic cells in vitro: a possible source of transporter mediated drug interactions. Biochem Pharmacol. 2004;68:783–90. https://doi.org/10.1016/j.bcp.2004.05.006.

    Article  CAS  PubMed  Google Scholar 

  54. Buckley ST, Fischer SM, Fricker G, Brandl M. European journal of pharmaceutical sciences in vitro models to evaluate the permeability of poorly soluble drug entities: challenges and perspectives. Eur J Pharm Sci. 2012;45(3):235–50. https://doi.org/10.1016/j.ejps.2011.12.007.

    Article  CAS  PubMed  Google Scholar 

  55. Hamalainen M, Frostell-Karlsson A. Predicting the intestinal absorption potential of hits and leads. Drug Discov Today Technol. 2004;1(4):397–405. https://doi.org/10.1016/j.ddtec.2004.09.004.

    Article  CAS  PubMed  Google Scholar 

  56. Danaei M, Dehghankhold M, Ataei S, Hasanzadeh Davarani F, Javanmard R, Dokhani A, et al. Impact of particle size and polydispersity index on the clinical applications of lipidic nanocarrier systems. Pharmaceutics. 2018;10(2):1–17.

    Article  Google Scholar 

  57. Were LM, Bruce BD, Davidson PM, Weiss J. Size, stability, and entrapment efficiency of phospholipid nanocapsules containing polypeptide antimicrobials. J Agric Food Chem. 2003;51(27):8073–9.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the National Research Foundation (NRF) of South Africa.

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  1. Mumuni Sumaila and Poornima Ramburrun contributed equally to the research.

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  1. Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 2193, South Africa

    Mumuni Sumaila, Poornima Ramburrun, Pradeep Kumar, Yahya E. Choonara & Viness Pillay

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Sumaila, M., Ramburrun, P., Kumar, P. et al. Lipopolysaccharide Polyelectrolyte Complex for Oral Delivery of an Anti-tubercular Drug. AAPS PharmSciTech 20, 107 (2019). https://doi.org/10.1208/s12249-019-1310-6

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