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AAPS PharmSciTech

, 20:97 | Cite as

Ultrasound-Assisted Facile Synthesis of Nanostructured Hybrid Vesicle for the Nasal Delivery of Indomethacin: Response Surface Optimization, Microstructure, and Stability

  • Suraj S. Patil
  • Dipak D. KumbharEmail author
  • Jagdish V. Manwar
  • Rajesh G. Jadhao
  • Ravindra L. Bakal
  • Sharad Wakode
Research Article
  • 22 Downloads

Abstract

This work is devoted to design a novel nanostructured hybrid vesicle (NHV) made of lecithin and an acrylate/C10-C30 alkyl acrylate for the nasal delivery of a model active indomethacin (IND), and further to probe its microstructure, intermolecular interactions, drug release behavior, ex vivo permeation, and stability. NHVs were prepared by cavitation technology employing RSM-based central composite design (CCD). Amount of lecithin (X1), power of ultrasound (X2), and sonication time (X3) were selected as three independent variables while the studied response included Z-Avg (nm), polydispersity index (PDI), and zeta potential (mV). The designed system (NHV) was investigated through dynamic (DLS) and electrophoretic light scattering (ELS), attenuated total reflectance (ATR-FTIR), oscillatory measurement (stress and frequency sweep), and transmission electron microscopy (TEM). CCD was found useful in optimizing NHV. An optimized formulation (S6) had Z-Avg 80 nm, PDI 0.2, and zeta potential of − 43.26 mV. Morphology investigation revealed spherical vesicles with smaller TEM diameters (the largest particle being 52.26 nm). ATR analysis demonstrated significant intermolecular interactions among the drug (IND) and the components of vesicles. The designed vesicles had an elastic predominance and displayed supercase II (n > 1) type of drug release. Besides, the vesicles possessed potential to transport IND across the nasal mucosa with the steady-state flux (μg/cm2/h) and permeability coefficient (cm/h) of 26.61 and 13.30 × 10−3, respectively. NHV exhibited an exceptional stability involving a combination of electrostatic and steric interactions while the histopathology investigation confirmed their safety for nasal administration.

KEY WORDS

indomethacin hybrid vesicle microstructure supercase II transport nasal delivery 

Notes

Acknowledgements

Authors wish to acknowledge North Maharashtra University (NMU), Jalgaon, for providing Zetasizer facility, HR Patel College of Pharmacy Shirpur for NanoPlus facility, and Indian Institute of Technology (IIT), Mumbai, India, for TEM analysis.

Supplementary material

12249_2018_1247_MOESM1_ESM.docx (70 kb)
ESM 1 (DOCX 70 kb)
12249_2018_1247_MOESM2_ESM.docx (2.4 mb)
ESM 2 (DOCX 2482 kb)

References

  1. 1.
    Dao TPT, Brûlet A, Fernandes F, Er-Rafik M, Ferji K, Schweins R, et al. Mixing block copolymers with phospholipids at the nanoscale: from hybrid polymer/lipid worm-like micelles to vesicles presenting lipid nanodomains. Langmuir. 2017;33:1705–15.CrossRefGoogle Scholar
  2. 2.
    Bixner O, Bello G, Virk M, Kurzhals S, Scheberl A, Gal N, et al. Magneto-thermal release from nanoscale unilamellar hybrid vesicles. ChemNanoMat. 2016;2:1111–20.CrossRefGoogle Scholar
  3. 3.
    Chemin M, Brun PM, Lecommandoux S, Sandre O, Le Meins JF. Hybrid polymer/lipid vesicles: fine control of the lipid and polymer distribution in the binary membrane. Soft Matter. 2012;8:2867–74.CrossRefGoogle Scholar
  4. 4.
    Cheng Z, Elias DR, Kamat NP, Johnston ED, Poloukhtine A, Popik V, et al. Improved tumor targeting of polymer-based nanovesicles using polymer-lipid blends. Bioconjug Chem. 2011;22:2021–9.CrossRefGoogle Scholar
  5. 5.
    Dao TPT, Fernandes F, Er-Rafik M, Salva R, Schmutz M, Brulet A, et al. Phase separation and nanodomain formation in hybrid polymer/ lipid vesicles. ACS Macro Lett. 2015;4:182–6.CrossRefGoogle Scholar
  6. 6.
    Henderson IM, Paxton WF. Salt, shake, fuse-giant hybrid polymer/lipid vesicles through mechanically activated fusion. Angew Chem Int Ed. 2014;53:3372–6.CrossRefGoogle Scholar
  7. 7.
    Lim SK, de Hoog HP, Parikh AN, Nallani M, Liedberg B. Hybrid, nanoscale phospholipid/block copolymer vesicles. Polymers. 2013;5:1102–14.CrossRefGoogle Scholar
  8. 8.
    Morimoto N, Sasaki Y, Mitsunushi K, Korchagina E, Wazawa T, Qiu XP, et al. Temperature-responsive telechelic dipalmitoylglyceryl poly (N-isopropylacrylamide) vesicles: real-time morphology observation in aqueous suspension and in the presence of giant liposomes. Chem Commun. 2014;50:8350–2.CrossRefGoogle Scholar
  9. 9.
    Nam J, Beales PA, Vanderlick TK. Giant phospholipid/block copolymer hybrid vesicles: mixing behavior and domain formation. Langmuir. 2011;27(1):1–6.CrossRefGoogle Scholar
  10. 10.
    Olubummo A, Schulz M, Schöps R, Kressler J, Binder WH. Phase changes in mixed lipid/polymer membranes by multivalent nanoparticle recognition. Langmuir. 2014;30:259–67.CrossRefGoogle Scholar
  11. 11.
    Pippa N, Kaditi E, Pispas S, Demetzos C. PEO-b-PCL–DPPC chimeric nanocarriers: self-assembly aspects in aqueous and biological media and drug incorporation. Soft Matter. 2013;9:4073–82.CrossRefGoogle Scholar
  12. 12.
    Pippa N, Stellas D, Skandalis A, Pispas S, Demetzos C, Libera M, et al. Chimeric lipid/block copolymer nanovesicles: physico-chemical and biocompatibility evaluation. Eur J Pharm Biopharm. 2016;107:295–309.CrossRefGoogle Scholar
  13. 13.
    Ruysschaert T, Sonnen AFP, Haefele T, Meier W, Winterhalter M, Fournier D. Hybrid nanocapsules: interactions of ABA block copolymers with liposomes. J Am Chem Soc. 2005;127:6242–7.CrossRefGoogle Scholar
  14. 14.
    Schulz M, Glatte D, Meister A, Scholtysek P, Kerth A, Blume A, et al. Hybrid lipid/polymer giant unilamellar vesicles: effects of incorporated biocompatible PIB–PEO block copolymers on vesicle properties. Soft Matter. 2011;7:8100–10.CrossRefGoogle Scholar
  15. 15.
    Shen W, Hua J, Hu X. Impact of amphiphilic triblock copolymers on stability and permeability of phospholipid/polymer hybrid vesicles. Chem Phys Lett. 2014;600:56–61.CrossRefGoogle Scholar
  16. 16.
    Su X, Mohamed Moinuddeen SK, Mori L, Nallani M. Hybrid polymersomes: facile manipulation of vesicular surfaces for enhancing cellular interaction. J Mater Chem B. 2013;1:5751–5.CrossRefGoogle Scholar
  17. 17.
    Winzen S, Bernhardt M, Schaeffel D, Koch A, Kappl M, Koynov K, et al. Submicron hybrid vesicles consisting of polymer–lipid and polymer–cholesterol blends. Soft Matter. 2013;9:5883–90.CrossRefGoogle Scholar
  18. 18.
    Kumbhar DD, Pokharkar VB. Physicochemical investigations on an engineered lipid–polymer hybrid nanoparticle containing a model hydrophilic active, zidovudine. Colloids Surf A Physicochem Eng Asp. 2013a;436:714–25.CrossRefGoogle Scholar
  19. 19.
    Pokharkar VB, Jolly MR, Kumbhar DD. Engineering of a hybrid polymer–lipid nanocarrier for the nasal delivery of tenofovir disoproxil fumarate: physicochemical, molecular, microstructural, and stability evaluation. Eur J Pharm Sci. 2015;71:99–111.CrossRefGoogle Scholar
  20. 20.
    Le Meins JF, Schatz C, Lecommandoux S, Sandre O. Hybrid polymer/lipid vesicles: state of the art and future perspectives. Mater Today. 2013;16:397–402.CrossRefGoogle Scholar
  21. 21.
    Schulz M, Binder WH. Mixed hybrid lipid/polymer vesicles as a novel membrane platform. Macromol Rapid Commun. 2015;36:2031–41.CrossRefGoogle Scholar
  22. 22.
    Sivakumar M, Tang SY, Tan KW. Cavitation technology—a greener processing technique for the generation of pharmaceutical nanoemulsions. Ultrason Sonochem. 2014;21:2069–83.CrossRefGoogle Scholar
  23. 23.
    Gonzalez-Mira E, Egea MA, Garcia ML, Souto EB. Design and ocular tolerance of flurbiprofen loaded ultrasound-engineered NLC. Colloids Surf B: Biointerfaces. 2010;81:412–21.CrossRefGoogle Scholar
  24. 24.
    Muller RH, Mader K, Gohla S. Solid lipid nanoparticles (SLN) for controlled drug delivery - a review of the state of the art. Eur J Pharm Biopharm. 2000;50:161–77.CrossRefGoogle Scholar
  25. 25.
    Pelletier JP, Martel-Pelletier J, Rannou F, Cooper C. Efficacy and safety of oral NSAIDs and analgesics in the management of osteoarthritis: evidence from real-life setting trials and surveys. Semin Arthritis Rheum. 2016;45:S22–7.CrossRefGoogle Scholar
  26. 26.
    Takeuch K. Prostaglandin EP receptors and their roles in mucosal protection and ulcer healing in the gastrointestinal tract. Adv Clin Chem. 2010;51:121–44.CrossRefGoogle Scholar
  27. 27.
    Kalra J, Khan A. Reducing Aβ load and tau phosphorylation: emerging perspective for treating Alzheimer’s disease. Eur J Pharmacol. 2015;764:571–81.CrossRefGoogle Scholar
  28. 28.
    Tomita T. Secretase inhibitors and modulators for Alzheimer’s disease treatment. Expert Rev Neurother. 2009;9:661–79.CrossRefGoogle Scholar
  29. 29.
    Bhugra C, Shmeis R, Pikal MJ. Role of mechanical stress in crystallization and relaxation behavior of amorphous indomethacin. J Pharm Sci. 2008;97:4446–58.CrossRefGoogle Scholar
  30. 30.
    Choi KO, Choe J, Suh S, Ko S. Positively charged nanostructured lipid carriers and their effect on the dissolution of poorly soluble drugs. Molecules. 2016;21:672–84.CrossRefGoogle Scholar
  31. 31.
    Okumura T, Ishida M, Takayama K, Otsuka M. Polymorphic transformation of indomethacin under high pressures. J Pharm Sci. 2006;95:689–700.CrossRefGoogle Scholar
  32. 32.
    Surwase SA, Boetker JP, Saville D, Boyd BJ, Gordon KC, Peltonen L, et al. Indomethacin: new polymorphs of an old drug. Mol Pharm. 2013;10:4472–80.CrossRefGoogle Scholar
  33. 33.
    Aidarova S, Sharipova A, Krägel J, Miller R. Polyelectrolyte/surfactant mixtures in the bulk and at water/oil interfaces. Adv Colloid Interf Sci. 2014;205:87–93.CrossRefGoogle Scholar
  34. 34.
    Behbahani ES, Ghaedi M, Abbaspour M, Rostamizadeh K. Optimization and characterization of ultrasound assisted preparation of curcumin-loaded solid lipid nanoparticles: application of central composite design, thermal analysis and X-ray diffraction techniques. Ultrason Sonochem. 2017;38:271–80.CrossRefGoogle Scholar
  35. 35.
    Jiang HL, Yang JL, Shi YP. Optimization of ultrasonic cell grinder extraction of anthocyanins from blueberry using response surface methodology. Ultrason Sonochem. 2017;34:325–31.CrossRefGoogle Scholar
  36. 36.
    Song CK, Balakrishnan P, Shim CK, Chung SJ, Chong S, Kim DD. A novel vesicular carrier, transethosome, for enhanced skin delivery of voriconazole: characterization and in vitro/in vivo evaluation. Colloids Surf B: Biointerfaces. 2012;92:299–304.CrossRefGoogle Scholar
  37. 37.
    Dubey V, Mishra D, Dutta T, Nahar M, Saraf DK, Jain NK. Dermal and transdermal delivery of an anti-psoriatic agent via ethanolic liposomes. J Control Release. 2013;123:148–54.CrossRefGoogle Scholar
  38. 38.
    Kumbhar DD, Pokharkar VB. Engineering of a nanostructured lipid carrier for the poorly water-soluble drug, bicalutamide: physicochemical investigations. Colloids Surf A Physicochem Eng Asp. 2013b;416:32–42.CrossRefGoogle Scholar
  39. 39.
    Pund S, Rasve G, Borade G. Ex vivo permeation characteristics of venlafaxine through sheep nasal mucosa. Eur J Pharm Sci. 2013;48:195–201.CrossRefGoogle Scholar
  40. 40.
    Samson G, Calera AG, Girod SD, Faure F, Decullier E, Paintaud G, et al. Ex vivo study of bevacizumab transport through porcine nasal mucosa. Eur J Pharm Biopharm. 2012;80:465–9.CrossRefGoogle Scholar
  41. 41.
    Giannola LI, Caro VD, Giandalia G, Siragusa MG, Tripodo C, Florena AM, et al. Release of naltrexone on buccal mucosa: permeation studies, histological aspects and matrix system design. Eur J Pharm Biopharm. 2007;67:425–33.CrossRefGoogle Scholar
  42. 42.
    Gupta BC, Guttman I. Statistics and probability with applications for engineers and scientists. Hoboken: Wiley; 2013.Google Scholar
  43. 43.
    Yolmeh M, Najafzadeh M. Optimization and modelling green bean's ultrasound blanching. Int J Food Sci Technol. 2014;49:2678–84.CrossRefGoogle Scholar
  44. 44.
    O’Sullivan J, Murray B, Flynn C, Norton I. Comparison of batch and continuous ultrasonic emulsification processes. J Food Eng. 2015;167:114–21.CrossRefGoogle Scholar
  45. 45.
    Kovalchuk NM, Starov VM. Aggregation in colloidal suspensions: effect of colloidal forces and hydrodynamic interactions. Adv Colloid Interf Sci. 2012;179–182:99–106.CrossRefGoogle Scholar
  46. 46.
    Valenta C, Auner BG. The use of polymers for dermal and transdermal delivery. Eur J Pharm Biopharm. 2004;58:279–89.CrossRefGoogle Scholar
  47. 47.
    Miastkowska MA, Banach M, Pulit-Prociak J, Sikora ES, Glogowska A, Zielina M. Statistical analysis of optimal ultrasound emulsification parameters in thistle oil nanoemulsions. J Surfactant Deterg. 2017;20:233–46.CrossRefGoogle Scholar
  48. 48.
    Vincent B. Early (pre-DLVO) studies of particle aggregation. Adv Colloid Interf Sci. 2012;170:56–67.CrossRefGoogle Scholar
  49. 49.
    Chang DP, Jankunec M, Barauskas J, Tiberg F, Nylander T. Adsorption of lipid liquid crystalline nanoparticles on cationic, hydrophilic, and hydrophobic surfaces. ACS Appl Mater Interfaces. 2012;4:2643–51.CrossRefGoogle Scholar
  50. 50.
    Karthik P, Anandharamakrishnan C. Enhancing omega-3 fatty acids nanoemulsion stability and in-vitro digestibility through emulsifiers. J Food Eng. 2016;187:92–105.CrossRefGoogle Scholar
  51. 51.
    Bhattacharjee S. DLS and zeta potential—what they are and what they are not? J Control Release. 2016;235:337–51.CrossRefGoogle Scholar
  52. 52.
    Greene AC, Zhu J, Pochan DJ, Jia X, Kiick KL. Poly (acrylic acid-b-styrene) amphiphilic multiblock copolymers as building blocks for the assembly of discrete nanoparticles. Macromolecules. 2011;44:1942–51.CrossRefGoogle Scholar
  53. 53.
    Xuan J, Pelletier M, Xia H, Zhao Y. Ultrasound-induced disruption of amphiphilic block copolymer micelles. Macromol Chem Phys. 2011;212:498–506.CrossRefGoogle Scholar
  54. 54.
    Sharma P, Denny WA, Garg S. Effect of wet milling process on the solid state of indomethacin and simvastatin. Int J Pharm. 2009;380:40–8.CrossRefGoogle Scholar
  55. 55.
    Güler G, Gärtner RM, Ziegler C, Mäntele W. Lipid-protein interactions in the regulated betaine symporter BetP probed by infrared spectroscopy. J Biol Chem. 2016;291:4295–307.CrossRefGoogle Scholar
  56. 56.
    Mashaan NS, Karim MR. Investigating the rheological properties of crumb rubber modified bitumen and its correlation with temperature susceptibility. Mater Res. 2013;16:116–27.CrossRefGoogle Scholar
  57. 57.
    Shahin M, Hady SA, Hammad M, Mortada N. Optimized formulation for topical administration of clotrimazole using pemulen polymeric emulsifier. Drug Dev Ind Pharm. 2011;37:559–68.CrossRefGoogle Scholar
  58. 58.
    Bonacucina G, Martelli S, Palmieri GF. Rheological, mucoadhesive and release properties of carbopol gels in hydrophilic cosolvents. Int J Pharm. 2004;282:115–30.CrossRefGoogle Scholar
  59. 59.
    Torres LG, Iturbe R, Snowden MJ, Chowdhry BZ, Leharne SA. Preparation of o/w emulsion stabilized by solid particles and their characterization by oscillatory rheology. Colloids Surf A Physicochem Eng Asp. 2007;302:439–48.CrossRefGoogle Scholar
  60. 60.
    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;10:81–98.CrossRefGoogle Scholar
  61. 61.
    Szucs M, Sandri G, Bonferoni MC, Caramella CM, Vaghi P, Szabo-Revesz P, et al. Mucoadhesive behaviour of emulsions containing polymeric emulsifier. Eur J Pharm Sci. 2008;34(4–5):226–35.CrossRefGoogle Scholar
  62. 62.
    Kosmidis K, Rinaki E, Argyrakis P, Macheras P. Analysis of case II drug transport with radial and axial release from cylinders. Int J Pharm. 2003;254:183–8.CrossRefGoogle Scholar
  63. 63.
    Kalogeras IM, Neagu ER. Interplay of surface and confinement effects on the molecular relaxation dynamics of nanoconfined poly (methyl methacrylate) chains. Eur Phys J E. 2004;14:193–204.CrossRefGoogle Scholar
  64. 64.
    Shaw CL, Dymock RB, Cowin A, Wormald PJ. Effect of packing on nasal mucosa of sheep. J Laryngol Otol. 2000;114:506–9.Google Scholar
  65. 65.
    Donovan MD, Huang Y. Large molecule and particulate uptake in the nasal cavity: the effect of size on nasal absorption. Adv Drug Deliv Rev. 1998;29:147–55.CrossRefGoogle Scholar
  66. 66.
    Callens C, Remon JP. Evaluation of starch–maltodextrin–Carbopol 974 P mixtures for the nasal delivery of insulin in rabbits. J Control Release. 2000;66:215–20.CrossRefGoogle Scholar
  67. 67.
    Hayashi K, Shimanouchi T, Kato K, Miyazaki T, Nakamura A, Umakoshi H. Span 80 vesicles have a more fluid, flexible and wet surface than phospholipid liposomes. Colloids Surf Biointerfaces. 2011;87:28–35.CrossRefGoogle Scholar
  68. 68.
    Kato K, Walde P, Koine N, Ichikawa S, Ishikawa T, Nagahama R, et al. Temperature sensitive nonionic vesicles prepared from span 80 (sorbitan monoloeate). Langmuir. 2008;24:10762–70.CrossRefGoogle Scholar
  69. 69.
    Jacobs C, Muller RH. Production and characterization of a budesonide nanosuspension for pulmonary administration. Pharm Res. 2002;19:189–94.CrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  • Suraj S. Patil
    • 1
  • Dipak D. Kumbhar
    • 1
    Email author
  • Jagdish V. Manwar
    • 1
  • Rajesh G. Jadhao
    • 1
    • 2
  • Ravindra L. Bakal
    • 1
  • Sharad Wakode
    • 2
  1. 1.KYDSCT’s College of PharmacyJalgaonIndia
  2. 2.Delhi Institute of Pharmaceutical Sciences and Research (DIPSAR)New DelhiIndia

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