Investigation of Cyclodextrin-Based Nanosponges for Solubility and Bioavailability Enhancement of Rilpivirine
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Rilpivrine is BCS class II drug used for treatment of HIV infection. The drug has low aqueous solubility (0.0166 mg/ml) and dissolution rate leading to low bioavailability (32%). Aim of this work was to enhance solubility and dissolution of rilpivirine using beta-cyclodextrin-based nanosponges. These nanosponges are biocompatible nanoporous particles having high loading capacity to form supramolecular inclusion and non-inclusion complexes with hydrophilic and lipophilic drugs for solubility enhancement. Beta-cyclodextrin was crosslinked with carbonyl diimidazole and pyromellitic dianhydride to prepare nanosponges. The nanosponges were loaded with rilpivirine by solvent evaporation method. Binary and ternary complexes of drug with β-CD, HP-β-CD, nanosponges, and tocopherol polyethylene glycol succinate were prepared and characterized by phase solubility, saturation solubility in different media, in vitro dissolution, and in vivo pharmacokinetics. Spectral analysis by Fourier transform infrared spectroscopy, powder X-ray diffraction, and differential scanning calorimetry was performed. Results obtained from spectral characterization confirmed inclusion complexation. Phase solubility studies indicated stable complex formation. Saturation solubility was found to be 10–13-folds higher with ternary complexes in distilled water and 12–14-fold higher in 0.1 N HCl. Solubility enhancement was evident in biorelevant media. Molecular modeling studies revealed possible mode of entrapment of rilpivirine within β-CD cavities. A 3-fold increase in dissolution with ternary complexes was observed. Animal studies revealed nearly 2-fold increase in oral bioavailability of rilpivirine. It was inferred that electronic interactions, hydrogen bonding, and van der Waals forces are involved in the supramolecular interactions.
KEY WORDSbioavailability nanosponges beta-cyclodextrin inclusion complex rilpivirine
The authors would like to thank Dr. Ashwini Madgulkar Principal, AISSMS College of Pharmacy, Pune-01, Maharashtra (India) for providing necessary help and facilities to carry out the research work and also thankful to Mylan Laboratories, Hyderabad (India) for providing drug as gift sample.
Compliance with Ethical Standards
Approval to carry out in vivo studies was obtained from Institutional Animal Ethics Committee, AISSMS College of Pharmacy (Approval from: AISSMS/CPCSEA/IAEC/PT-01/02/2K17) and their guidelines were followed for the studies.
Conflict of Interest
The authors declare that they have no conflict of interest.
- 13.Christian F, Mehrdad Y, Claudio O. Inclusion and functionalization of polymers with cyclodextrins: current applications and future prospects. Molecules. 2014;19:1466–79.Google Scholar
- 14.Gidwani B, Vyas A. A comprehensive review on cyclodextrin based carriers for delivery of chemotherapeutic cytotoxic anticancer drugs. Bio Med Res Int. 2015;15:1–15.Google Scholar
- 17.Shende P, Gaud R, Bakal R, Patil D. Effect of inclusion complexation of meloxicam with betacyclodextrin-and beta-cyclodextrin-based nanosponges on solubility, in vitro release and stability studies. Colloids Surf, B. 2015;15:1–26.Google Scholar
- 20.Rao M, Shirsath C. Enhancement of bioavailability of non-nucleoside reverse transcriptase inhibitor using nanosponges. AAPS PharmSciTech. 2016;10:1–11.Google Scholar
- 21.Rao M, Bajaj A, Pardeshi A, Aghav S. Investigation of nanoporous colloidal carrier for solubility enhancement of Cefpodoxime proxetil. J Pharm Res. 2012;5(5):2496–9.Google Scholar
- 24.Sevukaranjan M, Bachala T, Nair R. Novel inclusion complex of oseltamivir phosphate with beta cyclodextrin physic-chemical characterization. J Pharma Sci Res. 2010;2(9):583–9.Google Scholar
- 26.Safwat M, Soliman G, Sayed D, Attia M. Gold nanoparticles capped with benzalkonium chloride and poly (ethylene imine) for enhanced loading and skin permeability of 5-fluorouracil. Drug Dev Ind Pharm. 2017;(11):1–16.Google Scholar
- 29.Kommavarpupu M, Sunkara M. Preparation and characterization of rilpivirine solid dispersions with the application of enhanced solubility and dissolution rate. J Basic Appl Sci. 2015;4:71–9.Google Scholar
- 30.Kumar V, Raja J, Bhikshapathi D. Enhancement of solubility and oral bioavailability of poorly soluble drug Rilpivirine by novel self-emulsifying drug delivery system. Am J Pharma Tech Res. 2015;5(3):1–18.Google Scholar
- 32.Dora CP, Trotta F, Kushwah V, Devasari N, Singh C, Suresh S, et al. Potential of erlotinib cyclodextrin nanosponge complex to enhance solubility, dissolution rate, in vitro cytotoxicity and oral bioavailability. Carbohydr Polym. 2015;5:1–19.Google Scholar
- 33.Shankar G, Agrawal Y. Formulation and evaluation of β-cyclodextrin based nanosponges of a poorly water soluble drug. J Chem Pharm Res. 2015;7(4):595–604.Google Scholar
- 34.Trotta F, Shende P, Biasizzo M. Influence of different techniques on formulation and comparative characterization of inclusion complexes of ASA with b-cyclodextrin and inclusion complexes of ASA with PMDA cross-linked b-cyclodextrin. J Inclusion Phenom Macrocyclic Chem. 2015;3:14–27.Google Scholar
- 35.Ghosh S, Bomma S, Prasanna L, Vidyadhar S. Method development and validation of Rilpivirine in bulk and tablet doses form by RP-HPLC method. Res J PharmTech. 2013;6(3):1–8.Google Scholar
- 38.Darandale S, Shevalkar G, Vavia P. Effect of lipid composition in propofol formulations: decisive component in reducing the free propofol content and improving pharmacodynamic profiles. AAPS PharmSciTech. 2016:1–10.Google Scholar
- 41.Panikumar A, Venkat R, Sunitha G, Babu S, Subrahmanyam C. Development of biorelevant and discriminating method for dissolution of efavirenz and its formulations. Asian J Pharm Clin Res. 2012;5(3):220–3.Google Scholar
- 43.Rao M, Shivpuje S, Godbole R, Shirsath C. Design and evaluation of sustained release matrix tablets using sintered technique. Int J Pharm Sci. 2015;8(2):115–21.Google Scholar
- 45.Cozzia V, Charbe N, Baldelli M, Castoldia S. Development and validation of a chromatographic UV method for the simultaneous quantification of dolutegravir and rilpivirine in human plasma. Drug Monit. 2016:1–8.Google Scholar
- 48.Prasasty V, Yulandi A. Structure based design of novel rilpivirine analogues as HIV-1 non- nucleoside reverse transcriptase inhibitors through QSPR and molecular docking. Int J Pharm Sci. 2015;7(11):340–5.Google Scholar
- 49.Sagawa N, Shikata T. All are polar molecules hydrophilic? Hydration numbers of nitro compounds and nitriles in aqueous solution. Phys Chem Chem Phy. 2014;16(26):1–18.Google Scholar
- 53.Sherje A, Dravyakar B, Kadam D, Jadhav M. Cyclodextrin-based nanosponges: a critical review. Carbohydr Polym. 2017;17:1–45.Google Scholar
- 55.Sharma N, Madan P, Lin S. Effect of process and formulation variables on the preparation of parenteral paclitaxel-loaded biodegradable polymeric nanoparticles: a cosurfactant study. As J Pharm Sci. 2016;11(3):404–16.Google Scholar
- 56.Takahashi A, Veiga F, Ferraz H. Cyclodextrins inclusion complexes characterization—part II: X-ray diffraction, infrared spectroscopy and nuclear magnetic resonance. Int J Pharm Sci Rev Res. 2012;12(1):9–15.Google Scholar
- 57.Kumar V, Raju J. Solubility enhancement of poorly soluble antiretrovirals by novel self-emulsifying drug delivery system. Int J Pharm Anal Res. 2016;5(2):245–56.Google Scholar
- 58.Shrinivas P, Sreeja K. Formulation and evaluation of voriconazole loaded nanosponges for oral and topical delivery. Int J Drug Dev Res. 2013;5(1):55–69.Google Scholar
- 60.Janet C, Olatunji A, Godwin A, Xia W, Khan I. Preparation and characterization of β sitosterol/ β-cyclodextrin crystalline inclusion complexes. J Inclusion Phenom Macrocyclic Chem. 2015;83(1):141–8.Google Scholar
- 61.Baghel S, Cathcart H, O’Reilly NJ. Polymeric amorphous solid dispersions: a review of amorphization, crystallization, stabilization, solid-state characterization, and aqueous solubilization of biopharmaceutical classification system class II drugs. J Pharm Sci. 2016;105:2527–44.CrossRefPubMedGoogle Scholar
- 63.James MR. Influence of vitamin E TPGS on the properties of hydrophilic films produced by hot melt extrusion. Int J Pharm. 2000;202(2):63–70.Google Scholar
- 67.www.jaNSen.com/newzealand/sites/www_jaNSen_com.../edurant_data_sheet.pd (Date of access 13.05.17).