Skip to main content

Advertisement

SpringerLink
Log in

Development of oral aprepitant-loaded chitosan–polyethylene glycol-coated cyclodextrin nanocapsules: formulation, characterization, and pharmacokinetic evaluation

  • Original Article
  • Published:
Journal of Pharmaceutical Investigation Aims and scope Submit manuscript

Abstract

Purpose

Aprepitant (APRT), a selective neurokinin 1 antagonist, is clinically used in the prevention of acute and delayed chemotherapy-induced nausea and vomiting. The low solubility of APRT, which limits its oral bioavailability, is overcome by nanonization. This study aimed to design and evaluate novel in vitro and in vivo chitosan (CS)–polyethylene glycol (PEG)-coated cyclodextrin (CD) nanoparticles and nanocapsules to enhance the solubility and oral bioavailability of APRT.

Methods

A novel amphiphilic CD derivative with alkyl chains of 9 carbons (ACD-C9) was synthesized to form nanoparticles and nanocapsules by using nanoprecipitation. The nanocarriers were coated with the CS–PEG conjugate to increase their biological interaction with cell membranes via the positive charge and penetration-enhancer properties of CS. The nanosystems were evaluated for particle size, surface charge, drug loading, imaging, release, cell culture, and oral bioavailability in an animal model.

Results

The CS–PEG-coated nanosystems had particle size of 400–550 nm, a narrow polydispersity index, positive zeta potential, and favorable drug loading (55 and 93% for nanoparticles and nanocapsules, respectively). Sustained release was observed within 24 h. Blank nanoparticles and nanocapsules were non-cytotoxic against the L929 cell line. The intestinal permeability of the nanocarriers was 2–threefold (2-3 fold) higher than that of the drug solution, and the nanocapsules afforded the highest APRT permeability through Caco-2 cells. Oral bioavailability studies in rats revealed comparable degree of drug absorption between nanocapsules and commercial APRT products.

Conclusion

Oral ACD-C9 nanocapsules have the potential for the treatment of chemotherapy-induced nausea and vomiting.

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
Fig. 6

Similar content being viewed by others

References

  • Adel N (2017) Overview of chemotherapy-induced nausea and vomiting and evidence-based therapies. Am J Manage Care 23:S259–S265

    Google Scholar 

  • Aktas Y, Andrieux K, Alonso MJ, Calvo P, Gursoy RN et al (2005) Preparation and in vitro evaluation of chitosan nanoparticles containing a caspase inhibitor. Int J Pharm 298:378–383

    Article  CAS  PubMed  Google Scholar 

  • Aktas Y, Yenice K, Bilensoy E, Hincal AA (2015) Amphiphilic cyclodextrins as enabling excipients for drug delivery and for decades of scientific collaboration: tribute to a distinguished scientist, French representative and friend—a historical perspective. J Drug Deliv Sci Technol 30:261–265

    Article  CAS  Google Scholar 

  • Attari Z, Kalvakuntla S, Reddy MS, Deshpande M, Rao CM et al (2015) Formulation and characterisation of nanosuspensions of BCS class II and IV drugs by combinative method. J Exp Nanosci 11:276–288

    Article  Google Scholar 

  • Bilensoy E, Hincal AA (2009) Recent advances and future directions in amphiphilic cyclodextrin nanoparticles. Expert Opin Drug Deliv 6:1161–1173

    Article  CAS  PubMed  Google Scholar 

  • Caliph SM, Charman WN, Porter CJ (2000) Effect of short-, medium-, and long-chain fatty acid-based vehicles on the absolute oral bioavailability and intestinal lymphatic transport of halofantrine and assessment of mass balance in lymph-cannulated and non-cannulated rats. J Pharm Sci 89:1073–1084

    Article  CAS  PubMed  Google Scholar 

  • Charman WN (2000) Lipids, lipophilic drugs, and oral drug delivery-some emerging concepts. J Pharm Sci 89:967–978

    Article  CAS  PubMed  Google Scholar 

  • Charmsaz S, Collins DM, Perry AS, Prencipe M (2019) Novel strategies for cancer treatment: highlights from the 55th IACR Annual Conference. Cancers (Basel) 11:1125

    Article  CAS  Google Scholar 

  • Chen X, Wang T, Lu M, Zhu L, Wang Y et al (2014) Preparation and evaluation of tilmicosin-loaded hydrogenated castor oil nanoparticle suspensions of different particle sizes. Int J Nanomed 9:2655–2664

    Google Scholar 

  • Chorny M, Fishbein I, Danenberg HD, Golomb G (2002) Lipophilic drug loaded nanospheres prepared by nanoprecipitation: effect of formulation variables on size, drug recovery and release kinetics. J Control Release 83:389–400

    Article  CAS  PubMed  Google Scholar 

  • des Rieux A, Fievez V, Garinot M, Schneider YJ, Preat V (2006) Nanoparticles as potential oral delivery systems of proteins and vaccines: a mechanistic approach. J Control Release 116:1–27

    Article  PubMed  Google Scholar 

  • Emami J, Boushehri MS, Varshosaz J (2014) Preparation, characterization and optimization of glipizide controlled release nanoparticles. Res Pharm Sci 9:301–314

    CAS  PubMed  PubMed Central  Google Scholar 

  • Fessi H, Puisieux F, Devissaguet JP, Ammoury N, Benita S (1989) Nanocapsule formation by interfacial polymer deposition following solvent displacement. Int J Pharm 55:R1–R4

    Article  CAS  Google Scholar 

  • Gharibzahedi SMT, Jafari SM (2017) Nanocapsule formation by cyclodextrins. In: Jafari SM (ed) Nanoencapsulation technologies for the food and nutraceutical industries. Academic Press, Cambridge, pp 187–261

    Chapter  Google Scholar 

  • Groo AC, Saulnier P, Gimel JC, Gravier J, Ailhas C et al (2013) Fate of paclitaxel lipid nanocapsules in intestinal mucus in view of their oral delivery. Int J Nanomed 8:4291–4302

    Google Scholar 

  • Hamidi M, Azadi A, Rafiei P (2008) Hydrogel nanoparticles in drug delivery. Adv Drug Deliv Rev 60:1638–1649

    Article  CAS  PubMed  Google Scholar 

  • He M, Zhong C, Hu H, Jin Y, Chen Y et al (2019) Cyclodextrin/chitosan nanoparticles for oral ovalbumin delivery: preparation, characterization and intestinal mucosal immunity in mice. Asian J Pharm Sci 14:193–203

    Article  PubMed  Google Scholar 

  • Ibrahim MA, Preuss CV (2020) Antiemetic Neurokinin-1 receptor blockers. StatPearls. StatPearls Publishing, Treasure Island, FL

    Google Scholar 

  • Kalaria DR, Sharma G, Beniwal V, Ravi Kumar MN (2009) Design of biodegradable nanoparticles for oral delivery of doxorubicin: in vivo pharmacokinetics and toxicity studies in rats. Pharm Res 26:492–501

    Article  CAS  PubMed  Google Scholar 

  • Kamboj S, Rana V (2016) Formulation optimization of aprepitant microemulsion-loaded silicated corn fiber gum particles for enhanced bioavailability. Drug Dev Ind Pharm 42:1267–1282

    Article  CAS  PubMed  Google Scholar 

  • Kamboj S, Sharma R, Singh K, Rana V (2015) Aprepitant loaded solid preconcentrated microemulsion for enhanced bioavailability: a comparison with micronized Aprepitant. Eur J Pharm Sci 78:90–102

    Article  CAS  PubMed  Google Scholar 

  • Karimi Z, Abbasi S, Shokrollahi H, Yousefi G, Fahham M et al (2017) Pegylated and amphiphilic chitosan coated manganese ferrite nanoparticles for pH-sensitive delivery of methotrexate: synthesis and characterization. Mater Sci Eng C Mater Biol Appl 71:504–511

    Article  CAS  PubMed  Google Scholar 

  • Khattab WM, Zein El-Dein EE, El-Gizawy SA (2020) Formulation of lyophilized oily-core poly-E-caprolactone nanocapsules to improve oral bioavailability of Olmesartan Medoxomil. Drug Dev Ind Pharm 46:795–805

    Article  CAS  PubMed  Google Scholar 

  • Loftsson T, Brewster ME (1996) Pharmaceutical applications of cyclodextrins. 1. Drug solubilization and stabilization. J Pharm Sci 85:1017–1025

    Article  CAS  PubMed  Google Scholar 

  • Loftsson T, Duchene D (2007) Cyclodextrins and their pharmaceutical applications. Int J Pharm 329:1–11

    Article  CAS  PubMed  Google Scholar 

  • Loftsson T, Brewster ME, Másson M (2004) Role of cyclodextrins in improving oral drug delivery. Am J Drug Deliv 2:261–275

    Article  CAS  Google Scholar 

  • Mora-Huertas CE, Fessi H, Elaissari A (2010) Polymer-based nanocapsules for drug delivery. Int J Pharm 385:113–142

    Article  CAS  PubMed  Google Scholar 

  • Nurgali K, Jagoe RT, Abalo R (2018) Editorial: adverse effects of cancer chemotherapy: anything new to improve tolerance and reduce sequelae? Front Pharmacol 9:245

    Article  PubMed  PubMed Central  Google Scholar 

  • Olver I, Shelukar S, Thompson KC (2007) Nanomedicines in the treatment of emesis during chemotherapy: focus on aprepitant. Int J Nanomed 2:13–18

    Article  CAS  Google Scholar 

  • Palacio J, Agudelo NA, Lopez BL (2016) PEGylation of PLA nanoparticles to improve mucus-penetration and colloidal stability for oral delivery systems. Curr Opin Chem Eng 11:14–19

    Article  Google Scholar 

  • Parrott N, Lukacova V, Fraczkiewicz G, Bolger MB (2009) Predicting pharmacokinetics of drugs using physiologically based modeling-application to food effects. Aaps J 11:45–53

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Peltier S, Oger JM, Lagarce F, Couet W, Benoit JP (2006) Enhanced oral paclitaxel bioavailability after administration of paclitaxel-loaded lipid nanocapsules. Pharm Res 23:1243–1250

    Article  CAS  PubMed  Google Scholar 

  • Penalva R, Esparza I, Morales-Gracia J, Gonzalez-Navarro CJ, Larraneta E et al (2019) Casein nanoparticles in combination with 2-hydroxypropyl-beta-cyclodextrin improves the oral bioavailability of quercetin. Int J Pharm 570:118652

    Article  CAS  PubMed  Google Scholar 

  • Presas E, McCartney F, Sultan E, Hunger C, Nellen S et al (2018) Physicochemical, pharmacokinetic and pharmacodynamic analyses of amphiphilic cyclodextrin-based nanoparticles designed to enhance intestinal delivery of insulin. J Control Release 286:402–414

    Article  CAS  PubMed  Google Scholar 

  • Ran F, Lei W, Cui Y, Jiao J, Mao Y et al (2018) Size effect on oral absorption in polymer-functionalized mesoporous carbon nanoparticles. J Colloid Interface Sci 511:57–66

    Article  CAS  PubMed  Google Scholar 

  • Ren L, Zhou Y, Wei P, Li M, Chen G (2014) Preparation and pharmacokinetic study of aprepitant-sulfobutyl ether-beta-cyclodextrin complex. AAPS PharmSciTech 15:121–130

    Article  CAS  PubMed  Google Scholar 

  • Ridhurkar DN, Ansari KA, Kumar D, Kaul NS, Krishnamurthy T et al (2013) Inclusion complex of aprepitant with cyclodextrin: evaluation of physico-chemical and pharmacokinetic properties. Drug Dev Ind Pharm 39:1783–1792

    Article  CAS  PubMed  Google Scholar 

  • Roos C, Dahlgren D, Berg S, Westergren J, Abrahamsson B et al (2017) In vivo mechanisms of intestinal drug absorption from aprepitant nanoformulations. Mol Pharm 14:4233–4242

    Article  CAS  PubMed  Google Scholar 

  • Roos C, Dahlgren D, Sjogren E, Sjoblom M, Hedeland M et al (2018a) Jejunal absorption of aprepitant from nanosuspensions: role of particle size, prandial state and mucus layer. Eur J Pharm Biopharm 132:222–230

    Article  CAS  PubMed  Google Scholar 

  • Roos C, Westergren J, Dahlgren D, Lennernas H, Sjogren E (2018b) Mechanistic modelling of intestinal drug absorption—the in vivo effects of nanoparticles, hydrodynamics, and colloidal structures. Eur J Pharm Biopharm 133:70–76

    Article  CAS  PubMed  Google Scholar 

  • Sallas F, Darcy R (2008) Amphiphilic cyclodextrins—advances in synthesis and supramolecular chemistry. Eur J Org Chem 2008:957–969

    Article  Google Scholar 

  • Salustio PJ, Pontes P, Conduto C, Sanches I, Carvalho C et al (2011) Advanced technologies for oral controlled release: cyclodextrins for oral controlled release. Aaps Pharmscitech 12:1276–1292

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shono Y, Jantratid E, Kesisoglou F, Reppas C, Dressman JB (2010) Forecasting in vivo oral absorption and food effect of micronized and nanosized aprepitant formulations in humans. Eur J Pharm Biopharm 76:95–104

    Article  CAS  PubMed  Google Scholar 

  • Singare DS, Marella S, Gowthamrajan K, Kulkarni GT, Vooturi R et al (2010) Optimization of formulation and process variable of nanosuspension: an industrial perspective. Int J Pharm 402:213–220

    Article  CAS  PubMed  Google Scholar 

  • Sodeifian G, Sajadian SA, Daneshyan S (2018) Preparation of aprepitant nanoparticles (efficient drug for coping with the effects of cancer treatment) by rapid expansion of supercritical solution with solid cosolvent (RESS-SC). J Supercrit Fluids 140:72–84

    Article  CAS  Google Scholar 

  • Sun J, Wang F, Sui Y, She Z, Zhai W et al (2012) Effect of particle size on solubility, dissolution rate, and oral bioavailability: Evaluation using coenzyme Q(1)(0) as naked nanocrystals. Int J Nanomed 7:5733–5744

    CAS  Google Scholar 

  • Tobio M, Sanchez A, Vila A, Soriano II, Evora C et al (2000) The role of PEG on the stability in digestive fluids and in vivo fate of PEG-PLA nanoparticles following oral administration. Colloids Surf B Biointerfaces 18:315–323

    Article  CAS  PubMed  Google Scholar 

  • Toziopoulou F, Malamatari M, Nikolakakis I, Kachrimanis K (2017) Production of aprepitant nanocrystals by wet media milling and subsequent solidification. Int J Pharm 533:324–334

    Article  CAS  PubMed  Google Scholar 

  • Ünal H, d’Angelo I, Pagano E, Borrelli F, Izzo A et al (2015) Core–shell hybrid nanocapsules for oral delivery of camptothecin: formulation development, in vitro and in vivo evaluation. J Nanopart Res 17:1–13

    Article  Google Scholar 

  • Unal H, Ozturk N, Bilensoy E (2015) Formulation development, stability and anticancer efficacy of core-shell cyclodextrin nanocapsules for oral chemotherapy with camptothecin. Beilstein J Org Chem 11:204–212

    Article  PubMed  PubMed Central  Google Scholar 

  • Unal S, Aktas Y, Benito JM, Bilensoy E (2020) Cyclodextrin nanoparticle bound oral camptothecin for colorectal cancer: Formulation development and optimization. Int J Pharm 584:119468

    Article  CAS  PubMed  Google Scholar 

  • Varan G, Varan C, Erdogar N, Hincal AA, Bilensoy E (2017) Amphiphilic cyclodextrin nanoparticles. Int J Pharm 531:457–469

    Article  CAS  PubMed  Google Scholar 

  • Vila A, Sanchez A, Tobio M, Calvo P, Alonso MJ (2002) Design of biodegradable particles for protein delivery. J Control Release 78:15–24

    Article  CAS  PubMed  Google Scholar 

  • Wang Y, Cui Y, Zhao Y, Zhao Q, He B et al (2018) Effects of surface modification and size on oral drug delivery of mesoporous silica formulation. J Colloid Interface Sci 513:736–747

    Article  CAS  PubMed  Google Scholar 

  • Wu Y, Loper A, Landis E, Hettrick L, Novak L et al (2004) The role of biopharmaceutics in the development of a clinical nanoparticle formulation of MK-0869: a Beagle dog model predicts improved bioavailability and diminished food effect on absorption in human. Int J Pharm 285:135–146

    Article  CAS  PubMed  Google Scholar 

  • Ye Y, Zhang T, Li W, Sun H, Lu D, Wu B, Zhang X (2016) Glucose-based mesoporous carbon nanospheres as functional carriers for oral delivery of amphiphobic raloxifene: Insights into the bioavailability enhancement and lymphatic transport. Pharm Res 33:792–803

    Article  CAS  PubMed  Google Scholar 

  • Zerkoune L, Angelova A, Lesieur S (2014) Nano-Assemblies of modified cyclodextrins and their complexes with guest molecules: Incorporation in nanostructured membranes and amphiphile nanoarchitectonics design. Nanomaterials 4:741–765

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhang M, Li XH, Gong YD, Zhao NM, Zhang XF (2002) Properties and biocompatibility of chitosan films modified by blending with PEG. Biomaterials 23:2641–2648

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was financially supported by the TUBITAK Scientific Research Project 216S773. Authors would like to thank Hacettepe Technology Transfer Center for advance editing.

Author information

Authors and Affiliations

  1. Faculty of Pharmacy, Department of Pharmaceutical Technology, Hacettepe University, Ankara, Turkey

    Nazlı Erdoğar, Safiye Akkın & Erem Bilensoy

  2. Department of Chemistry and Bioscience, University of Aalborg, Aalborg, Denmark

    Thorbjorn T. Nielsen

  3. Faculty of Medicine, Department of Hematology, Hacettepe University, Ankara, Turkey

    Batuhan Erdoğdu

  4. Faculty of Pharmacy, Department of Analytical Chemistry, Hacettepe University, Ankara, Turkey

    Emirhan Nemutlu

  5. Faculty of Medicine, Department of Pharmacology, Hacettepe University, Ankara, Turkey

    Esin Özçelebi & Alper B. İskit

Authors
  1. Nazlı Erdoğar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Safiye Akkın
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thorbjorn T. Nielsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Esin Özçelebi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Batuhan Erdoğdu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Emirhan Nemutlu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Alper B. İskit
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Erem Bilensoy
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nazlı Erdoğar.

Ethics declarations

Conflict of interest

The authors declare no conflicts of interest.

Research involving human and animal rights

This study was approved by the local ethics committee for animal experimentation of Hacettepe University. (Approval number, 2016/28–05).

Additional information

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

Erdoğar, N., Akkın, S., Nielsen, T.T. et al. Development of oral aprepitant-loaded chitosan–polyethylene glycol-coated cyclodextrin nanocapsules: formulation, characterization, and pharmacokinetic evaluation. J. Pharm. Investig. 51, 297–310 (2021). https://doi.org/10.1007/s40005-020-00511-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40005-020-00511-x

Keywords

Search

Navigation