10.1007/s40097-022-00515-z

Chitosan conjugated-ordered mesoporous silica: a biocompatible dissolution enhancer for promoting the antidiabetic effect of a poorly water-soluble drug of repaglinide

  • Aziz Maleki1,
  • Shayesteh Bochani2,
  • Mehraneh Kermanian3,
  • Pooyan Makvandi4,
  • Mir-Jamal Hosseini*5,
  • Mehrdad Hamidi6,
  • Ali Kalantari-Hesari7,
  • Hamid Reza Kheiri8,
  • Mohammad Reza Eskandari9,
  • Maryam Rosta9,
  • Virgilio Mattoli4,
  • Seyed Hojjat Hosseini10,
  1. Zanjan Pharmaceutical Nanotechnology Research Center (ZPNRC), Zanjan University of Medical Sciences, Zanjan, 45139-56184, IR Department of Pharmaceutical Nanotechnology, School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, 45139-56184, IR
  2. Department of Pharmaceutical Nanotechnology, School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, 45139-56184, IR
  3. Zanjan Pharmaceutical Nanotechnology Research Center (ZPNRC), Zanjan University of Medical Sciences, Zanjan, 45139-56184, IR
  4. Centre for Materials Interfaces, Istituto Italiano Di Tecnologia, Pisa, 56025, IT
  5. Zanjan Applied Pharmacology Research Center, Zanjan University of Medical Sciences, Zanjan, 45139-56184, IR
  6. Zanjan Pharmaceutical Nanotechnology Research Center (ZPNRC), Zanjan University of Medical Sciences, Zanjan, 45139-56184, IR Trita Nanomedicine Research and Technology Development Center (TNRTC), Zanjan, 45156-13191, IR
  7. Department of Pathobiology, Faculty of Veterinary Science, Bu-Ali Sina University, Hamadan, IR
  8. Zanjan Pharmaceutical Nanotechnology Research Center (ZPNRC), Zanjan University of Medical Sciences, Zanjan, 45139-56184, IR Department of Biotechnology, Faculty of Pharmacy, Zanjan University of Medical Sciences, Zanjan, 45139-56184, IR
  9. Department of Pharmacology and Toxicology, School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, IR
  10. Department of Physiology and Pharmacology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, IR
Chitosan conjugated-ordered mesoporous silica: a biocompatible dissolution enhancer for promoting

Published in Issue 20-09-2022

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

How to Cite

Maleki, A., Bochani, S., Kermanian, M., Makvandi, P., Hosseini, M.-J., Hamidi, M., Kalantari-Hesari, A., Kheiri, H. R., Eskandari, M. R., Rosta, M., Mattoli, V., & Hosseini, S. H. (2022). Chitosan conjugated-ordered mesoporous silica: a biocompatible dissolution enhancer for promoting the antidiabetic effect of a poorly water-soluble drug of repaglinide. Journal of Nanostructure in Chemistry, 14(4 (August 2024). https://doi.org/10.1007/s40097-022-00515-z
Crossref
Scopus
Google Scholar
Europe PMC

Abstract

Abstract The oral pathway is the preferred drug administration route in pharmaceutical sciences, however, the most employed ‘highly active’ drug candidates suffer from poor water solubility. The aim of this study was to develop repaglinide (RL)-loaded chitosan-grafted mesoporous silica material (MSM) to enhance drug dissolution. Such enhanced dissolution was investigated in in vitro and in vivo conditions. Our results showed successful grafting of chitosan (CN) on the surface of the MSM and the loading of RL into the mesopores of the silica host. Furthermore, the obtained drug dissolution profiles were fitted to mathematical models to characterize and compare drug dissolution profiles. Cytotoxicity evaluation against the human colorectal adenocarcinoma (Caco-2) cell line showed concentration-dependent toxicity for the MSN-based particles. Various liver and kidney mitochondrial functional parameters including lipid peroxidation assay, complex II activity, mitochondrial glutathione (GSH) level assay, ferric reducing antioxidant power (FRAP) assay, protein carbonyl level, and reactive oxygen species (ROS) formation, were used to investigate the biosafety of the silica-based dissolution enhancer. A significant reduction in blood glucose was observed after oral administration of the biocomposites for 24 h. The histopathological studies of the kidney and liver indicated no MSM-related adverse effects. We believed that our achievements can help the use of the hybrid organic–inorganic MSMs in improving the bioavailability of PWSDs in the one hand and, on the other hand, open a novel avenue to develop biocompatible and nontoxic MSMs in oral bioavailability of PWSDs. Graphical abstract

Keywords

  • Repaglinide,
  • Dissolution rate,
  • Drug dissolution kinetic,
  • Poorly water-soluble drug,
  • Chitosan-grafted mesoporous silica

References

  1. Budiman and Aulifa (2022) Characterization of drugs with good glass formers in loaded-mesoporous silica and its theoretical value relevance with mesopores surface and pore-filling capacity https://doi.org/10.3390/ph15010093
  2. Kawabata et al. (2011) Formulation design for poorly water-soluble drugs based on biopharmaceutics classification system: basic approaches and practical applications (pp. 1-10) https://doi.org/10.1016/j.ijpharm.2011.08.032
  3. Charalabidis et al. (2019) The biopharmaceutics classification system (BCS) and the biopharmaceutics drug disposition classification system (BDDCS): beyond guidelines (pp. 264-281) https://doi.org/10.1016/j.ijpharm.2019.05.041
  4. Hatorp (2002) Clinical pharmacokinetics and pharmacodynamics of repaglinide (pp. 471-483) https://doi.org/10.2165/00003088-200241070-00002
  5. Zawar and Bari (2012) Preparation, characterization and in vivo evaluation of antihyperglycemic activity of microwave generated repaglinide solid dispersion (pp. 482-487) https://doi.org/10.1248/cpb.60.482
  6. Simos et al. (2021) Trends of nanotechnology in type 2 diabetes mellitus treatment (pp. 62-76) https://doi.org/10.1016/j.ajps.2020.05.001
  7. Dunn and Faulds (2000) Nateglinide (pp. 607-615) https://doi.org/10.2165/00003495-200060030-00007
  8. Jain et al. (2005) Calcium silicate based microspheres of repaglinide for gastroretentive floating drug delivery: preparation and in vitro characterization (pp. 300-309) https://doi.org/10.1016/j.jconrel.2005.06.007
  9. Hatorp et al. (1998) Bioavailabitity of repaglinide, a novel antidiabetic agent, administered orally in tablet or solution form or intravenously in healthy male volunteers (pp. 636-641)
  10. Liu et al. (2014) Preparation, characterization and in vivo evaluation of formulation of repaglinide with hydroxypropyl-β-cyclodextrin (pp. 159-166) https://doi.org/10.1016/j.ijpharm.2014.10.038
  11. Manvi et al. (2011) Preparation, characterization and in vitro evaluation of repaglinide binary solid dispersions with hydrophilic polymers (pp. 111-121)
  12. Sinswat et al. (2007) Dissolution rates and supersaturation behavior of amorphous repaglinide particles produced by controlled precipitation (pp. 18-27) https://doi.org/10.1166/jbn.2007.001
  13. Purvis et al. (2007) Rapidly dissolving repaglinide powders produced by the ultra-rapid freezing process (pp. 52-60) https://doi.org/10.1208/pt0803058
  14. Seedher and Kanojia (2008) Micellar solubilization of some poorly soluble antidiabetic drugs: a technical note (pp. 431-436) https://doi.org/10.1208/s12249-008-9057-5
  15. Gao et al. (2013) Coamorphous repaglinide-saccharin with enhanced dissolution (pp. 290-295) https://doi.org/10.1016/j.ijpharm.2013.04.032
  16. Nicolescu et al. (2010) Phase solubility studies of the inclusion complexes of repaglinide with β-cyclodextrin and β-cyclodextrin derivatives (pp. 620-628)
  17. Gaud and Prabhakar (2014) Recent advances in drug delivery systems (pp. 444-457)
  18. Bernardos et al. (2019) Mesoporous silica-based materials with bactericidal properties https://doi.org/10.1002/smll.201900669
  19. Maleki et al. (2017) Mesoporous silica materials: from physico-chemical properties to enhanced dissolution of poorly water-soluble drugs (pp. 329-347) https://doi.org/10.1016/j.jconrel.2017.07.047
  20. Manzano and Vallet-Regí (2020) Mesoporous silica nanoparticles for drug delivery https://doi.org/10.1002/adfm.201902634
  21. Rahmati et al. (2021) Cu–curcumin/MCM-41 as an efficient catalyst for in situ conversion of carbazole to fuel oxygenates a DOE approach https://doi.org/10.1007/s40097-021-00417-6
  22. McCarthy et al. (2016) Mesoporous silica formulation strategies for drug dissolution enhancement: a review (pp. 93-108) https://doi.org/10.1517/17425247.2016.1100165
  23. Ibrahim et al. (2020) Formulation and optimization of drug-loaded mesoporous silica nanoparticle-based tablets to improve the dissolution rate of the poorly water-soluble drug silymarin https://doi.org/10.1016/j.ejps.2019.105103
  24. Hancock and Parks (2000) What is the true solubility advantage for amorphous pharmaceuticals? (pp. 397-404) https://doi.org/10.1023/A:1007516718048
  25. Wang et al. (2014) The investigation of MCM-48-type and MCM-41-type mesoporous silica as oral solid dispersion carriers for water insoluble cilostazol (pp. 819-828) https://doi.org/10.3109/03639045.2013.788013
  26. Wang et al. (2013) Ordered nanoporous silica as carriers for improved delivery of water insoluble drugs: a comparative study between three dimensional and two dimensional macroporous silica (pp. 4015-4031) https://doi.org/10.2147/IJN.S52605
  27. Guo et al. (2019) Enlarged pore size chiral mesoporous silica nanoparticles loaded poorly water-soluble drug perform superior delivery effect https://doi.org/10.3390/molecules24193552
  28. Basharzad et al. (2022) Polysorbate-coated mesoporous silica nanoparticles as an efficient carrier for improved rivastigmine brain delivery https://doi.org/10.1016/j.brainres.2022.147786
  29. Sharifi et al. (2022) Mesoporous bioactive glasses in cancer diagnosis and therapy: stimuli-responsive, toxicity, immunogenicity, and clinical translation https://doi.org/10.1002/advs.202102678
  30. Shen et al. (2011) Physical state and dissolution of ibuprofen formulated by co-spray drying with mesoporous silica: effect of pore and particle size (pp. 188-195) https://doi.org/10.1016/j.ijpharm.2011.03.018
  31. Khanfar et al. (2013) Mesoporous silica based macromolecules for dissolution enhancement of Irbesartan drug using pre-adjusted pH method (pp. 22-28) https://doi.org/10.1016/j.micromeso.2013.02.007
  32. Waters et al. (2013) Inclusion of fenofibrate in a series of mesoporous silicas using microwave irradiation (pp. 936-941) https://doi.org/10.1016/j.ejpb.2013.08.002
  33. Kamal et al. (2021) Chemotherapeutic and chemopreventive potentials of ρ-coumaric acid–squid chitosan nanogel loaded with Syzygium aromaticum essential oil (pp. 523-533) https://doi.org/10.1016/j.ijbiomac.2021.08.038
  34. Kahya (2018) Water soluble chitosan derivatives and their biological activities: a review (pp. 1-16)
  35. Hassan et al. (2021) Co-delivery of imidazolium Zn (II) salen and OriganumSyriacum essential oil by shrimp chitosan nanoparticles for antimicrobial applications https://doi.org/10.1016/j.carbpol.2021.117834
  36. Sofy et al. (2019) Polyphosphonium-oligochitosans decorated with nanosilver as new prospective inhibitors for common human enteric viruses https://doi.org/10.1016/j.carbpol.2019.115261
  37. Elbehairi et al. (2020) Chitosan nano-vehicles as biocompatible delivering tools for a new Ag (I) curcuminoid-Gboxin analog complex in cancer and inflammation therapy (pp. 2750-2764) https://doi.org/10.1016/j.ijbiomac.2020.10.153
  38. Elshaarawy et al. (2020) Inhibitory activity of biofunctionalized silver-capped N-methylated water-soluble chitosan thiomer for microbial and biofilm infections (pp. 709-717) https://doi.org/10.1016/j.ijbiomac.2020.02.284
  39. Rabiee et al. (2021) Calcium-based nanomaterials and their interrelation with chitosan: optimization for pCRISPR delivery https://doi.org/10.1007/s40097-021-00446-1
  40. Ashrafi et al. (2020) Antimicrobial effect of chitosan–silver–copper nanocomposite on Candida albicans (pp. 87-95) https://doi.org/10.1007/s40097-020-00331-3
  41. Bui et al. (2017) Chitosan combined with ZnO, TiO2 and Ag nanoparticles for antimicrobial wound healing applications: a mini review of the research trends https://doi.org/10.3390/polym9010021
  42. Zhao et al. (1998) Nonionic triblock and star diblock copolymer and oligomeric surfactant syntheses of highly ordered, hydrothermally stable, mesoporous silica structures (pp. 6024-6036) https://doi.org/10.1021/ja974025i
  43. Deng et al. (2011) Hollow chitosan–silica nanospheres as pH-sensitive targeted delivery carriers in breast cancer therapy (pp. 4976-4986) https://doi.org/10.1016/j.biomaterials.2011.03.050
  44. Akaike (1974) A new look at the statistical model identification (pp. 716-723) https://doi.org/10.1109/TAC.1974.1100705
  45. Zhang et al. (2010) Ddsolver: an add-in program for modeling and comparison of drug dissolution profiles (pp. 263-271) https://doi.org/10.1208/s12248-010-9185-1
  46. Costa and Lobo (2001) Modeling and comparison of dissolution profiles (pp. 123-133) https://doi.org/10.1016/S0928-0987(01)00095-1
  47. Khan (1975) The concept of dissolution efficiency (pp. 48-49) https://doi.org/10.1111/j.2042-7158.1975.tb09378.x
  48. Brockmeier (1986) In vitro/in vivo correlation of dissolution using moments of dissolution and transit times (pp. 164-174)
  49. Sadighian et al. (2017) Magnetic nanogels as dual triggered anticancer drug delivery: toxicity evaluation on isolated rat liver mitochondria (pp. 18-29) https://doi.org/10.1016/j.toxlet.2017.06.004
  50. Hosseini et al. (2014) Toxicity of copper on isolated liver mitochondria: impairment at complexes I, II, and IV leads to increased ros production (pp. 367-381) https://doi.org/10.1007/s12013-014-9922-7
  51. Bradford (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding (pp. 248-254) https://doi.org/10.1016/0003-2697(76)90527-3
  52. Ahmadi et al. (2021) Investigation of therapeutic effect of curcumin α and β glucoside anomers against Alzheimer’s disease by the nose to brain drug delivery https://doi.org/10.1016/j.brainres.2021.147517
  53. Benzie and Strain (1996) The ferric reducing ability of plasma (FRAP) as a measure of “antioxidant power”: the FRAP assay (pp. 70-76) https://doi.org/10.1006/abio.1996.0292
  54. Hesari et al. (2015) Crocin prevention of anemia-induced changes in structural and functional parameters of mice testes (pp. 213-223) https://doi.org/10.1016/j.jab.2015.02.001
  55. Nosrati et al. (2018) Anticancer activity of tamoxifen loaded tyrosine decorated biocompatible Fe 3 O 4 magnetic nanoparticles against breast cancer cell lines (pp. 1178-1186) https://doi.org/10.1007/s10904-017-0758-7
  56. Abedimanesh et al. (2021) The anti-diabetic effects of betanin in streptozotocin-induced diabetic rats through modulating AMPK/SIRT1/NF-κB signaling pathway (pp. 1-13) https://doi.org/10.1186/s12986-021-00621-9
  57. Podust et al. (2014) Chitosan-nanosilica hybrid materials: preparation and properties (pp. 563-569) https://doi.org/10.1016/j.apsusc.2014.09.038
  58. Lee et al. (2009) Membrane of hybrid chitosan–silica xerogel for guided bone regeneration (pp. 743-750) https://doi.org/10.1016/j.biomaterials.2008.10.025
  59. Sevimli and Yilmaz (2012) Surface functionalization of SBA-15 particles for amoxicillin delivery (pp. 281-291) https://doi.org/10.1016/j.micromeso.2012.02.037
  60. Zu et al. (2016) Preparation and in vitro/in vivo evaluation of resveratrol-loaded carboxymethyl chitosan nanoparticles (pp. 971-981) https://doi.org/10.3109/10717544.2014.924167
  61. Gao et al. (2014) Preparation, characterization, and adsorption evaluation of chitosan-functionalized mesoporous composites (pp. 15-26) https://doi.org/10.1016/j.micromeso.2014.02.025
  62. Gan et al. (2015) A dual-delivery system of pH-responsive chitosan-functionalized mesoporous silica nanoparticles bearing BMP-2 and dexamethasone for enhanced bone regeneration (pp. 2056-2066) https://doi.org/10.1039/C4TB01897D
  63. Dhana lekshmi et al. (2010) In vitro characterization and in vivo toxicity study of repaglinide loaded poly (methyl methacrylate) nanoparticles (pp. 194-203) https://doi.org/10.1016/j.ijpharm.2010.06.023
  64. Gao et al. (2010) Synthesis, characterization, and in vitro pH-controllable drug release from mesoporous silica spheres with switchable gates (pp. 17133-17138) https://doi.org/10.1021/la102952n
  65. Horcajada et al. (2004) Influence of pore size of MCM-41 matrices on drug delivery rate (pp. 105-109) https://doi.org/10.1016/j.micromeso.2003.12.012
  66. Maleki and Hamidi (2016) Dissolution enhancement of a model poorly water-soluble drug, atorvastatin, with ordered mesoporous silica: comparison of MSF with SBA-15 as drug carriers (pp. 171-181) https://doi.org/10.1517/17425247.2015.1111335
  67. Mellaerts et al. (2007) Enhanced release of itraconazole from ordered mesoporous SBA-15 silica materials https://doi.org/10.1039/b616746b
  68. Shen et al. (2010) Stabilized amorphous state of ibuprofen by co-spray drying with mesoporous SBA-15 to enhance dissolution properties (pp. 1997-2007) https://doi.org/10.1002/jps.21967
  69. Argyo et al. (2014) Multifunctional mesoporous silica nanoparticles as a universal platform for drug delivery 26(1) (pp. 435-451) https://doi.org/10.1021/cm402592t
  70. Li et al. (2012) Mesoporous silica nanoparticles in biomedical applications (pp. 2590-2605) https://doi.org/10.1039/c1cs15246g
  71. Wan and Zhao (2007) On the controllable soft-templating approach to mesoporous silicates (pp. 2821-2860) https://doi.org/10.1021/cr068020s
  72. Douroumis et al. (2011) Mesoporous silica nanoparticles as a drug delivery system (pp. 115-146)
  73. Zhang et al. (2010) Inclusion of telmisartan in mesocellular foam nanoparticles: drug loading and release property (pp. 17-23) https://doi.org/10.1016/j.ejpb.2010.05.010
  74. Zhang et al. (2011) Inclusion of the poorly water-soluble drug simvastatin in mesocellular foam nanoparticles: drug loading and release properties (pp. 118-124) https://doi.org/10.1016/j.ijpharm.2010.07.040
  75. Li et al. (2014) Synthesis of SBA-15/polyaniline mesoporous composite for removal of resorcinol from aqueous solution (pp. 260-266) https://doi.org/10.1016/j.apsusc.2013.11.065
  76. Tang et al. (2011) Facile synthesis of pH sensitive polymer-coated mesoporous silica nanoparticles and their application in drug delivery (pp. 388-396) https://doi.org/10.1016/j.ijpharm.2011.10.013
  77. Guo et al. (2013) Effects of particle morphology, pore size and surface coating of mesoporous silica on Naproxen dissolution rate enhancement (pp. 228-235) https://doi.org/10.1016/j.colsurfb.2012.06.026
  78. Marsac et al. (2008) Recrystallization of nifedipine and felodipine from amorphous molecular level solid dispersions containing poly(vinylpyrrolidone) and sorbed water (pp. 647-656) https://doi.org/10.1007/s11095-007-9420-3
  79. Martinez-Oharriz et al. (2002) Solid dispersions of diflunisal–PVP: polymorphic and amorphous states of the drug (pp. 717-725) https://doi.org/10.1081/DDC-120003864
  80. Wong et al. (2006) Enhancement of the dissolution rate and oral absorption of a poorly water soluble drug by formation of surfactant-containing microparticles (pp. 61-68) https://doi.org/10.1016/j.ijpharm.2006.03.001
  81. Kosuge et al. (2004) Morphological control of rod-and fiberlike SBA-15 type mesoporous silica using water-soluble sodium silicate (pp. 899-905) https://doi.org/10.1021/cm030622u
  82. Yu et al. (2003) Morphological control of highly ordered mesoporous carbon (pp. 45-48) https://doi.org/10.1016/S0167-2991(03)80323-3
  83. Lin et al. (2017) Redox-responsive nanocarriers for drug and gene co-delivery based on chitosan derivatives modified mesoporous silica nanoparticles (pp. 41-50) https://doi.org/10.1016/j.colsurfb.2017.04.002
  84. Zhu et al. (2009) Magnetic SBA-15/poly(N-isopropylacrylamide) composite: preparation, characterization and temperature-responsive drug release property (pp. 107-112) https://doi.org/10.1016/j.micromeso.2009.03.031
  85. Popat et al. (2012) A pH-responsive drug delivery system based on chitosan coated mesoporous silica nanoparticles (pp. 11173-11178) https://doi.org/10.1039/c2jm30501a
  86. Xu et al. (2013) Mesoporous systems for poorly soluble drugs (pp. 181-197) https://doi.org/10.1016/j.ijpharm.2012.09.008
  87. Dash et al. (2010) Kinetic modeling on drug release from controlled drug delivery systems (pp. 217-223)
  88. Kumar et al. (2014) Impact of surface area of silica particles on dissolution rate and oral bioavailability of poorly water soluble drugs: a case study with aceclofenac (pp. 459-468) https://doi.org/10.1016/j.ijpharm.2013.12.017
  89. Asare-Addo et al. (2015) Triboelectrification and dissolution property enhancements of solid dispersions (pp. 306-316) https://doi.org/10.1016/j.ijpharm.2015.03.013
  90. Stoker et al. (2019) Impact of pharmacological agents on mitochondrial function: a growing opportunity? (pp. 1757-1772) https://doi.org/10.1042/BST20190280
  91. Schwall et al. (2012) The stability and activity of respiratory complex II is cardiolipin-dependent (pp. 1588-1596) https://doi.org/10.1016/j.bbabio.2012.04.015
  92. Dröse (2013) Differential effects of complex II on mitochondrial ROS production and their relation to cardioprotective pre-and postconditioning (pp. 578-587) https://doi.org/10.1016/j.bbabio.2013.01.004
  93. Cheng et al. (2011) The cytotoxic mechanism of malondialdehyde and protective effect of carnosine via protein cross-linking/mitochondrial dysfunction/reactive oxygen species/MAPK pathway in neurons (pp. 184-194) https://doi.org/10.1016/j.ejphar.2010.09.033
  94. Suzuki et al. (2010) Protein carbonylation (pp. 323-325) https://doi.org/10.1089/ars.2009.2887
  95. Marí et al. (2020) Mitochondrial glutathione: recent insights and role in disease https://doi.org/10.3390/antiox9100909
  96. Shahidi, F.: Handbook of antioxidants for food preservation. Woodhead Publishing (2015).
  97. Benzie and Strain (1999) Ferric reducing (antioxidant) power as a measure of antioxidant capacity: The FRAP assay and its modification for measurement of ascorbic acid (FRASC) (pp. 15-27) https://doi.org/10.1016/S0076-6879(99)99005-5
  98. Li et al. (2015) Biodistribution, excretion, and toxicity of mesoporous silica nanoparticles after oral administration depend on their shape (pp. 1915-1924) https://doi.org/10.1016/j.nano.2015.07.004
  99. Lee et al. (2008) Synthesis and characterization of positive-charge functionalized mesoporous silica nanoparticles for oral drug delivery of an anti-inflammatory drug (pp. 3283-3292) https://doi.org/10.1002/adfm.200800521
  100. Kassem et al. (2017) Phospholipid complex enriched micelles: a novel drug delivery approach for promoting the antidiabetic effect of repaglinide (pp. 75-84) https://doi.org/10.1016/j.ejps.2016.12.005
  101. Uppal et al. (2018) Nanoparticulate-based drug delivery systems for small molecule anti-diabetic drugs: an emerging paradigm for effective therapy (pp. 20-42) https://doi.org/10.1016/j.actbio.2018.09.049
  102. Jain and Saraf (2009) Repaglinide-loaded long-circulating biodegradable nanoparticles: rational approach for the management of type 2 diabetes mellitus (pp. 29-35) https://doi.org/10.1111/j.1753-0407.2008.00001.x