Skip to main content

Advertisement

Springer Nature Link
Log in

Understanding the Pharmacological and Nanotechnological Facets of Dipeptidyl Peptidase-4 Inhibitors in Type II Diabetes Mellitus: a Paradigm in Therapeutics

  • Published:
BioNanoScience Aims and scope Submit manuscript

Abstract

The worldwide incidence of type 2 diabetes mellitus (T2DM), a chronic metabolic disorder, is increasing rapidly. A newer category of oral hypoglycemic medications called dipeptidyl peptidases-4 (DPP-4) inhibitors has come into existence for the management of T2DM. DPP-4 inhibitors, i.e., linagliptin, saxagliptin, and sitagliptin, belong to BCS class III, while alogliptin belongs to BCS class I. These drugs have high aqueous solubility and, therefore, short elimination half-life which necessitates the need for multiple daily dosing. Furthermore, the unrestrained drug release from conventional tablets can cause elevation in systemic drug concentrations which might instigate gastrointestinal side effects. The poor membrane permeability of BCS class III drugs also results in their poor oral bioavailability. Therefore, clinical compliance and therapeutic efficacy of DPP-4 inhibitors can be enhanced by nanotechnology-based techniques. This research paper has described various risk factors and pathophysiology of T2DM and also explained about the mode of action of DPP-4 inhibitors. The main objectives and rationale of this review include the exploration of preclinical pharmacological investigations and the summarization of developed nanoformulations of DPP-4 inhibitors researched in previous decades. The nanoformulations which has been synthesized for DPP-4 inhibitors in the past few decades for the management of T2DM include polymeric nanoparticle, solid lipid nanoparticle, transferosomes, niosomes, mucoadhesive nanoparticle, and self-microemulsifying drug delivery systems.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Similar content being viewed by others

Explore related subjects

Discover the latest articles and news from researchers in related subjects, suggested using machine learning.

Availability of Data and Materials

Not applicable.

References

  1. Kaul, K., Tarr, J.M., Ahmad, S.I., Kohner, E.M., & Chibber, R. (2013). Introduction to diabetes mellitus. In S. I. Ahmad (Ed.), Diabetes. Advances in Experimental Medicine and Biology (vol. 771). Springer.

  2. Grewal, A. S., Thapa, K., Kanojia, N., Sharma, N., & Singh, S. (2020). Natural compounds as source of aldose reductase (Ar) inhibitors for the treatment of diabetic complications: A mini review. Current Drug Metabolism, 21(14), 1091–1116.

    CAS  PubMed  Google Scholar 

  3. Andukuri, R., Drincic, A., & Rendell, M. (2009). Alogliptin: A new addition to the class of DPP-4 inhibitors. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy, 2, 117–126.

  4. Forouhi, N. G., & Wareham, N. J. (2010). Epidemiology of diabetes. Medicine, 38(11), 602–606.

    Google Scholar 

  5. Mayer-Davis, E. J., Kahkoska, A. R., Jefferies, C., Dabelea, D., Balde, N., Gong, C. X., Aschner, P., & Craig, M. E. (2018). ISPAD Clinical Practice Consensus Guidelines 2018: Definition, epidemiology, and classification of diabetes in children and adolescents. Pediatric Diabetes, 19(Suppl 27), 7–19.

    PubMed  PubMed Central  Google Scholar 

  6. Bobiş, O., Dezmirean, D. S., & Moise, A. R. (2018). Honey and diabetes: The importance of natural simple sugars in diet for preventing and treating different type of diabetes. Oxidative Medicine and Cellular Longevity, 2018, 1–12.

    Google Scholar 

  7. Makrilakis, K. (2019). The role of DPP-4 inhibitors in the treatment algorithm of type 2 diabetes mellitus: When to select, what to expect. International Journal of Environmental Research and Public Health, 16(15), 2720.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. https://go.drugbank.com/

  9. https://pubchem.ncbi.nlm.nih.gov/

  10. Keating, G. M. (2015). Alogliptin: A review of its use in patients with type 2 diabetes mellitus. Drugs, 75, 777–796.

    CAS  PubMed  Google Scholar 

  11. de Abreu Engel, R. E., Barden, A. T., Campanharo, S. C., Olegário, N., Volpato, N. M., & Schapoval, E. E. S. (2019). Evaluation of linagliptin dissolution from tablets using HPLC and UV methods. Drug Analytical Research, 3(2), 46–50.

    Google Scholar 

  12. Lyseng-Williamson, K. A. (2007). Sitagliptin. Drugs, 67, 587–597.

    CAS  PubMed  Google Scholar 

  13. Wondmkun, Y. T. (2020). Obesity, insulin resistance, and type 2 diabetes: Associations and therapeutic implications. Diabetes, Metabolic Syndrome and Obesity, 13, 3611–3616.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Ozougwu, J. C., Obimba, K. C., Belonwu, C. D., & Unakalamba, C. B. (2013). The pathogenesis and pathophysiology of type 1 and type 2 diabetes mellitus. Journal of Physiology and Pathophysiology, 4(4), 46–57.

    Google Scholar 

  15. Dendup, T., Feng, X., Clingan, S., & Astell-Burt, T. (2018). Environmental risk factors for developing type 2 diabetes mellitus: A systematic review. International Journal of Environmental Research and Public Health, 15(1), 78.

    PubMed  PubMed Central  Google Scholar 

  16. Harding, J. L., Pavkov, M. E., Magliano, D. J., Shaw, J. E., & Gregg, E. W. (2019). Global trends in diabetes complications: A review of current evidence. Diabetologia, 62, 3–16.

    PubMed  Google Scholar 

  17. Mansour, A., Mousa, M., Abdelmannan, D., Tay, G., Hassoun, A., & Alsafar, H. (2023). Microvascular and macrovascular complications of type 2 diabetes mellitus: Exome wide association analyses. Frontiers in Endocrinology, 14, 1143067.

    PubMed  PubMed Central  Google Scholar 

  18. Rahman, S., Rahman, T., Ismail, A. A., & Rashid, A. R. A. (2007). Diabetes-associated macrovasculopathy: Pathophysiology and pathogenesis. Diabetes, Obesity and Metabolism, 9(6), 767–780.

    CAS  PubMed  Google Scholar 

  19. Oh, J.-W., Muthu, M., Haga, S. W., Anthonydhason, V., Paul, P., & Chun, S. (2020). Reckoning the dearth of bioinformatics in the arena of diabetic nephropathy (DN)—need to improvise. Processes, 8(7), 808.

    CAS  Google Scholar 

  20. Lankatillake, C., Huynh, T., & Dias, D. A. (2019). Understanding glycaemic control and current approaches for screening antidiabetic natural products from evidence-based medicinal plants. Plant Methods, 15(1), 1–35.

    CAS  Google Scholar 

  21. Beulens, J. W. J., Pinho, M. G. M., Abreu, T. C., den Braver, N. R., Lam, T. M., Huss, A., Vlaanderen, J., Sonnenschein, T., Siddiqui, N. Z., Yuan, Z., Kerckhoffs, J., Zhernakova, A., Gois, M. F. B., & Vermeulen, R. C. H. (2021). Environmental risk factors of type 2 diabetes-an exposome approach. Diabetologia, 65, 263–274.

    PubMed  Google Scholar 

  22. Association, A. D. (2010). Diagnosis and classification of diabetes mellitus. Diabetes care, 33(Supplement_1), S62–S69.

    Google Scholar 

  23. Khan, M. A. B., Hashim, M. J., King, J. K., Govender, R. D., Mustafa, H., & Al Kaabi, J. (2020). Epidemiology of type 2 diabetes–global burden of disease and forecasted trends. Journal of Epidemiology and Global Health, 10(1), 107.

    PubMed  PubMed Central  Google Scholar 

  24. Nithya, V., Sangavi, P., Srinithi, R., Nachammai, K. T., Gowtham Kumar, S., Prabu, D., & Langeswaran, K. (2023). Diabetes and other comorbidities: Microvascular and macrovascular diseases diabetes and cancer. In Rana Noor (Ed.), Advances in Diabetes Research and Management (pp. 21–39). Springer.

    Google Scholar 

  25. Baynes, H. W. (2015). Classification, pathophysiology, diagnosis and management of diabetes mellitus. Journal of Diabetes & Metabolism, 6(5), 1–9.

    Google Scholar 

  26. Glovaci, D., Fan, W., & Wong, N. D. (2019). Epidemiology of diabetes mellitus and cardiovascular disease. Current Cardiology Reports, 21, 1–8.

    Google Scholar 

  27. Burn, P. (2010). Type 1 diabetes. Nature Reviews Drug discovery, 9(3), 187.

    CAS  PubMed  Google Scholar 

  28. Cooke, D. W., & Plotnick, L. (2008). Type 1 diabetes mellitus in pediatrics. Pediatrics in Review, 29(11), 374–385.

    PubMed  Google Scholar 

  29. Boles, A., Kandimalla, R., & Reddy, P. H. (2017). Dynamics of diabetes and obesity: Epidemiological perspective. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, 1863(5), 1026–1036.

  30. Galicia-Garcia, U., Benito-Vicente, A., Jebari, S., Larrea-Sebal, A., Siddiqi, H., Uribe, K. B., Ostolaza, H., & Martín, C. (2020). Pathophysiology of type 2 diabetes mellitus. International Journal of Molecular Sciences, 21(17), 6275.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Olokoba, A. B., Obateru, O. A., & Olokoba, L. B. (2012). Type 2 diabetes mellitus: A review of current trends. Oman Medical Journal, 27(4), 269.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Stumvoll, M., Goldstein, B. J., & Van Haeften, T. W. (2005). Type 2 diabetes: Principles of pathogenesis and therapy. The Lancet, 365(9467), 1333–1346.

    CAS  Google Scholar 

  33. DeFronzo, R. A., Ferrannini, E., Groop, L., Henry, R. R., Herman, W. H., Holst, J. J., Hu, F. B., Kahn, C. R., Raz, I., Shulman, G. I., & Simonson, D. C. (2015). Type 2 diabetes mellitus. Nature reviews Disease Primers, 1(1), 1–22.

    Google Scholar 

  34. Chiefari, E., Arcidiacono, B., Foti, D., & Brunetti, A. (2017). Gestational diabetes mellitus: An updated overview. Journal of Endocrinological Investigation, 40, 899–909.

    CAS  PubMed  Google Scholar 

  35. Johns, E. C., Denison, F. C., Norman, J. E., & Reynolds, R. M. (2018). Gestational diabetes mellitus: Mechanisms, treatment, and complications. Trends in Endocrinology & Metabolism, 29(11), 743–754.

    CAS  Google Scholar 

  36. McIntyre, H. D., Catalano, P., Zhang, C., Desoye, G., Mathiesen, E. R., & Damm, P. (2019). Gestational diabetes mellitus. Nature Reviews Disease Primers, 5(1), 47.

    PubMed  Google Scholar 

  37. Ahmad, K. (2014). Insulin sources and types: A review of insulin in terms of its mode on diabetes mellitus. Journal of Traditional Chinese Medicine, 34(2), 234–237.

    PubMed  Google Scholar 

  38. Bastaki, S. (2005). Diabetes mellitus and its treatment. Dubai Diabetes and Endocrinology Journal, 13(3), 111–134.

    Google Scholar 

  39. Zahoor, I., Singh, S., Behl, T., Sharma, N., Naved, T., Subramaniyan, V., & Al-Harrasi, A. (2022). Emergence of microneedles as a potential therapeutics in diabetes mellitus. Environmental Science and Pollution Research, 29, 3302–3322.

    PubMed  Google Scholar 

  40. Grarup, N., Sandholt, C. H., Hansen, T., & Pedersen, O. (2014). Genetic susceptibility to type 2 diabetes and obesity: From genome-wide association studies to rare variants and beyond. Diabetologia, 57, 1528–1541.

    CAS  PubMed  Google Scholar 

  41. Zaccardi, F., Webb, D. R., Yates, T., & Davies, M. J. (2016). Pathophysiology of type 1 and type 2 diabetes mellitus: A 90-year perspective. Postgraduate Medical Journal, 92(1084), 63–69.

    CAS  PubMed  Google Scholar 

  42. Hu, F. B., Manson, J. E., Stampfer, M. J., Colditz, G., Liu, S., Solomon, C. G., & Willett, W. C. (2001). Diet, lifestyle, and the risk of type 2 diabetes mellitus in women. New England Journal of Medicine, 345(11), 790–797.

    CAS  PubMed  Google Scholar 

  43. Schellenberg, E. S., Dryden, D. M., Vandermeer, B., Ha, C., & Korownyk, C. (2013). Lifestyle interventions for patients with and at risk for type 2 diabetes: A systematic review and meta-analysis. Annals of Internal Medicine, 159(8), 543–551.

    PubMed  Google Scholar 

  44. Andersen, E. S., Deacon, C. F., & Holst, J. J. (2018). Do we know the true mechanism of action of the DPP-4 inhibitors? Diabetes, Obesity and Metabolism, 20(1), 34–41.

    CAS  PubMed  Google Scholar 

  45. Istrate, D., & Crisan, L. (2022). Natural compounds as DPP-4 inhibitors: 3D-similarity search, ADME toxicity, and molecular docking approaches. Symmetry, 14(9), 1842.

    ADS  CAS  Google Scholar 

  46. Mathur, V., Alam, O., Siddiqui, N., Jha, M., Manaithiya, A., Bawa, S., Sharma, N., Alshehri, S., Alam, P., & Shakeel, F. (2023). Insight into structure activity relationship of DPP-4 inhibitors for development of antidiabetic agents. Molecules, 28(15), 5860.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Cada, D. J., Levien, T. L., & Baker, D. E. (2013). Alogliptin. Hospital Pharmacy, 48(7), 580–592.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Boddu, R., Vadla, H. C., Prathap, V. R., Kothamasu, U., Rallabandi, B. C., & Gannu, R. (2021). Development of an in vitro-in vivo correlation for sitagliptin and metformin prolonged-release tablet formulations. Turkish Journal of Pharmaceutical Sciences, 18(2), 233.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Shrestha, N., Araujo, F., Shahbazi, M.-A., Mäkilä, E., Gomes, M. J., Airavaara, M., Kauppinen, E. I., Raula, J., Salonen, J., Hirvonen, J., & Sarmento, B. (2016). Oral hypoglycaemic effect of GLP-1 and DPP4 inhibitor based nanocomposites in a diabetic animal model. Journal of Controlled Release, 232, 113–119.

    CAS  PubMed  Google Scholar 

  50. Thondawada, M., Wadhwani, A. D., S. Palanisamy, D., Rathore, H. S., Gupta, R. C., Chintamaneni, P. K., Samanta, M.K., Dubala, A., Varma, S., Krishnamurthy, P.T., & Gowthamarajan, K. (2018). An effective treatment approach of DPP-IV inhibitor encapsulated polymeric nanoparticles conjugated with anti-CD-4 mAb for type 1 diabetes. Drug Development and Industrial Pharmacy, 44(7), 1120–1129.

  51. Dobnig, H., & Amrein, K. (2019). Best practice & research clinical endocrinology & metabolism.

  52. Dhillon, S. (2010). Sitagliptin: A review of its use in the management of type 2 diabetes mellitus. Drugs, 70, 489–512.

    CAS  PubMed  Google Scholar 

  53. Dave, D. J. (2011). Saxagliptin: A dipeptidyl peptidase-4 inhibitor in the treatment of type 2 diabetes mellitus. Journal of Pharmacology and Pharmacotherapeutics, 2(4), 230–235.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Rasul, A., Maheen, S., Khan, H. U., Rasool, M., Shah, S., Abbas, G., Afzal, K., Tariq, F., Shahzadi, I., & Asad, M. H. H. B. (2021). Formulation, optimization, in vitro and in vivo evaluation of saxagliptin-loaded lipospheres for an improved pharmacokinetic behavior. BioMed Research International, 2021, 1–17.

    Google Scholar 

  55. Plosker, G. L. (2014). Sitagliptin: A review of its use in patients with type 2 diabetes mellitus. Drugs, 74(2), 223–242.

    CAS  PubMed  Google Scholar 

  56. Scott, L. J. (2017). Sitagliptin: A review in type 2 diabetes. Drugs, 77, 209–224.

    CAS  PubMed  Google Scholar 

  57. Lyseng-Williamson, K. A., & Yang, L. P. H. (2014). Saxagliptin: A guide to its use in type 2 diabetes mellitus. Drugs & Therapy Perspectives, 30(3), 92–99.

    Google Scholar 

  58. Scheen, A. J. (2010). Pharmacokinetics of dipeptidylpeptidase-4 inhibitors. Diabetes, Obesity and Metabolism, 12(8), 648–658.

    CAS  PubMed  Google Scholar 

  59. Kania, D. S., Gonzalvo, J. D., & Weber, Z. A. (2011). Saxagliptin: A clinical review in the treatment of type 2 diabetes mellitus. Clinical Therapeutics, 33(8), 1005–1022.

    CAS  PubMed  Google Scholar 

  60. Dhillon, S., & Weber, J. (2009). Saxagliptin. Drugs, 69, 2103–2114.

    CAS  PubMed  Google Scholar 

  61. Scott, L. J. (2011). Linagliptin: In type 2 diabetes mellitus. Drugs, 71, 611–624.

    CAS  PubMed  Google Scholar 

  62. Graefe-Mody, U., Retlich, S., & Friedrich, C. (2012). Clinical pharmacokinetics and pharmacodynamics of linagliptin. Clinical Pharmacokinetics, 51, 411–427.

    CAS  PubMed  Google Scholar 

  63. Deeks, E. D. (2012). Linagliptin: A review of its use in the management of type 2 diabetes mellitus. Drugs, 72, 1793–1824.

    CAS  PubMed  Google Scholar 

  64. White, W. B., Cannon, C. P., Heller, S. R., Nissen, S. E., Bergenstal, R. M., Bakris, G. L., Perez, A. T., Fleck, P. R., Mehta, C. R., Kupfer, S., & Wilson, C. (2013). Alogliptin after acute coronary syndrome in patients with type 2 diabetes. New England Journal of Medicine, 369(14), 1327–1335.

    CAS  PubMed  Google Scholar 

  65. Kaku, K., Kisanuki, K., Shibata, M., & Oohira, T. (2019). Benefit-risk assessment of alogliptin for the treatment of type 2 diabetes mellitus. Drug Safety, 42, 1311–1327.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Waget, A., Cabou, C., Masseboeuf, M., Cattan, P., Armanet, M., Karaca, M., Castel, J., Garret, C., Payros, G., Maida, A., & Sulpice, T. (2011). Physiological and pharmacological mechanisms through which the DPP-4 inhibitor sitagliptin regulates glycemia in mice. Endocrinology, 152(8), 3018–3029.

    PubMed  Google Scholar 

  67. Eggadi, V., Sheshagiri, S. B. B., Devandla, A., Dasi, N., Kulundaivelu, U., Revoori, S. K., Kesireddy, S. R., Revoori, K., & Keshireddy, S. R. (2015). Effect of atorvastatin on pharmacology of sitagliptin in streptozotocin-nicotinamide induced type-II diabetes in rats. Biology and Medicine, 7(1), 1.

    Google Scholar 

  68. Eitah, H. E., Maklad, Y. A., Abdelkader, N. F., El Din, A. A. G., Badawi, M. A., & Kenawy, S. A. (2019). Modulating impacts of quercetin/sitagliptin combination on streptozotocin-induced diabetes mellitus in rats. Toxicology and Applied Pharmacology, 365, 30–40.

    CAS  PubMed  Google Scholar 

  69. Samaha, M. M., Said, E., & Salem, H. A. (2019). A comparative study of the role of crocin and sitagliptin in attenuation of STZ-induced diabetes mellitus and the associated inflammatory and apoptotic changes in pancreatic β-islets. Environmental Toxicology and Pharmacology, 72, 103238.

    CAS  PubMed  Google Scholar 

  70. Craig, S. L., Gault, V. A., Flatt, P. R., & Irwin, N. (2021). The methionine aminopeptidase 2 inhibitor, TNP-470, enhances the antidiabetic properties of sitagliptin in mice by upregulating xenin. Biochemical Pharmacology, 183, 114355.

    CAS  PubMed  Google Scholar 

  71. Hou, J., Zheng, D., Fan, K., Yu, B., Xiao, W., Ma, J., Jin, W., Tan, Y., & Wu, J. (2012). Combination of mangiferin and dipeptidyl peptidase-4 inhibitor sitagliptin improves impaired glucose tolerance in streptozotocin-diabetic rats. Pharmacology, 90(3–4), 177–182.

    CAS  PubMed  Google Scholar 

  72. Wang, J., Hu, L., Chen, Y., Fu, T., Jiang, T., Jiang, A., & You, X. (2019). Sitagliptin improves renal function in diabetic nephropathy in male Sprague Dawley rats through upregulating heme oxygenase-1 expression. Endocrine, 63, 70–78.

    CAS  PubMed  Google Scholar 

  73. Karabulut, S., Coskun, Z. M., & Bolkent, S. (2015). Immunohistochemical, apoptotic and biochemical changes by dipeptidyl peptidase-4 inhibitor-sitagliptin in type-2 diabetic rats. Pharmacological Reports, 67(5), 846–853.

    CAS  PubMed  Google Scholar 

  74. Al-Damry, N. T., Attia, H. A., Al-Rasheed, N. M., Al-Rasheed, N. M., Mohamad, R. A., Al-Amin, M. A., Dizmiri, N., & Atteya, M. (2018). Sitagliptin attenuates myocardial apoptosis via activating LKB-1/AMPK/Akt pathway and suppressing the activity of GSK-3β and p38α/MAPK in a rat model of diabetic cardiomyopathy. Biomedicine & Pharmacotherapy, 107, 347–358.

    CAS  Google Scholar 

  75. Reimer, R. A., Grover, G. J., Koetzner, L., Gahler, R. J., Juneja, P., Lyon, M. R., & Wood, S. (2012). Sitagliptin reduces hyperglycemia and increases satiety hormone secretion more effectively when used with a novel polysaccharide in obese Zucker rats. The Journal of Nutrition, 142(10), 1812–1820.

    CAS  PubMed  Google Scholar 

  76. Chang, Y., Sun, B., Han, Z., Han, F., Hu, S., Li, X., Xue, M., Yang, Y., Chen, L., Li, C. J., & Chen, L. M. (2017). Saxagliptin attenuates albuminuria by inhibiting podocyte epithelial-to-mesenchymal transition via SDF-1α in diabetic nephropathy. Frontiers in Pharmacology, 8, 780.

    PubMed  PubMed Central  Google Scholar 

  77. Schürmann, C., Linke, A., Engelmann-Pilger, K., Steinmetz, C., Mark, M., Pfeilschifter, J., Klein, T., & Frank, S. (2012). The dipeptidyl peptidase-4 inhibitor linagliptin attenuates inflammation and accelerates epithelialization in wounds of diabetic ob/ob mice. Journal of Pharmacology and Experimental Therapeutics, 342(1), 71–80.

    PubMed  Google Scholar 

  78. Dietrich, N., Kolibabka, M., Busch, S., Bugert, P., Kaiser, U., Lin, J., Fleming, T., Morcos, M., Klein, T., Schlotterer, A., & Hammes, H.P. (2016). The DPP4 inhibitor linagliptin protects from experimental diabetic retinopathy. PloS one, 11(12), e0167853

  79. Nakamura, Y., Inagaki, M., Shimizu, T., Fujita, K., Inoue, M., Gotoh, H., Oguchi, K., & Goto, Y. (2013). Long-term effects of alogliptin benzoate in hemodialysis patients with diabetes: A 2-year study. Nephron Clinical Practice, 123(1–2), 46–51.

    CAS  PubMed  Google Scholar 

  80. Jahangir, M. A., Khan, R., & Sarim Imam, S. (2018). Formulation of sitagliptin-loaded oral polymeric nano scaffold: Process parameters evaluation and enhanced anti-diabetic performance. Artificial Cells, Nanomedicine, and Biotechnology, 46(sup1), 66–78.

    CAS  PubMed  Google Scholar 

  81. Harsha, S., Attimard, M., Khan, T. A., Nair, A. B., Aldhubiab, B. E., Sangi, S., & Shariff, A. (2013). Design and formulation of mucoadhesive microspheres of sitagliptin. Journal of Microencapsulation, 30(3), 257–264.

    CAS  PubMed  Google Scholar 

  82. Kazi, M., Alqahtani, A., Ahmad, A., Noman, O. M., Aldughaim, M. S., Alqahtani, A. S., & Alanazi, F. K. (2021). Development and optimization of sitagliptin and dapagliflozin loaded oral self-nanoemulsifying formulation against type 2 diabetes mellitus. Drug Delivery, 28(1), 100–114.

    CAS  PubMed  Google Scholar 

  83. SreeHarsha, N., Ramnarayanan, C., Al-Dhubiab, B. E., Nair, A. B., Hiremath, J. G., Venugopala, K. N., Satish, R.T., Attimarad, M., & Shariff, A. (2019). Mucoadhesive particles: A novel, prolonged-release nanocarrier of sitagliptin for the treatment of diabetics. BioMed Research International, 2019.

  84. Prabahar, K., Udhumansha, U., & Qushawy, M. (2020). Optimization of thiolated chitosan nanoparticles for the enhancement of in vivo hypoglycemic efficacy of sitagliptin in streptozotocin-induced diabetic rats. Pharmaceutics, 12(4), 300.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Nair, A. B., Sreeharsha, N., Al-Dhubiab, B. E., Hiremath, J. G., Shinu, P., Attimarad, M., Venugopala, K. N., & Mutahar, M. (2019). HPMC-and PLGA-based nanoparticles for the mucoadhesive delivery of sitagliptin: Optimization and in vivo evaluation in rats. Materials, 12(24), 4239.

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  86. HaqAsif, A., Harsha, S., HodalurPuttaswamy, N., & Al-Dhubiab, E. B. (2018). An effective delivery system of sitagliptin using optimized mucoadhesive nanoparticles. Applied Sciences, 8(6), 861.

    Google Scholar 

  87. Rachel, K. F. (2022). Development and characterization of anti-diabetic liposomal formulation. International Journal of Green Pharmacy (IJGP), 16(1).

  88. Alhamhoom, Y., Ravi, G., Osmani, R. A. M., Hani, U., & Prakash, G. M. (2022). Formulation, characterization, and evaluation of eudragit-coated saxagliptin nanoparticles using 3 factorial design modules. Molecules, 27(21), 7510.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Maheen, S., Rasul, A., Hanif, M., & Khan, H. U. (2020). Lipospheres for simultaneous controlled release and improved pharmacokinetic profiles of saxagliptin-enalapril: Formulation, optimization, and comparative in vitro-in vivo evaluation. An Official Journal of the American Association of Pharmaceutical Scientists, 21, 1–16.

    Google Scholar 

  90. Shah, P., Chavda, K., Vyas, B., & Patel, S. (2021). Formulation development of linagliptin solid lipid nanoparticles for oral bioavailability enhancement: Role of P-gp inhibition. Drug Delivery and Translational Research, 11, 1166–1185.

    CAS  PubMed  Google Scholar 

  91. Veni, D. K., & Gupta, N. V. (2020). Development and evaluation of Eudragit coated environmental sensitive solid lipid nanoparticles using central composite design module for enhancement of oral bioavailability of linagliptin. International Journal of Polymeric Materials and Polymeric Biomaterials, 69(7), 407–418.

    CAS  Google Scholar 

  92. Navaneetha, K., Navya, A., Venkateshwara, B., Reddy, T., & Saritha, N. J. (2017). Formulation and in-vitro evaluation of nanoparticles of linagliptin. WJPR, 6(7), 1319–1328.

    CAS  Google Scholar 

  93. Nishu, S. B. N., Karmoker, J. R., Ali, F. F., Rafa, N. N., Hoque, O., & Dewan, I. (2018). In vitro and ex vivo studies of linagliptin loaded non-ionic surfactant vesicles using statistical optimization. Journal of Advances in Medical and Pharmaceutical Sciences, 18(2), 1–16.

    Google Scholar 

  94. Rahi, F. A., Ameen, M. S. M., & Fayyadh, M. S. (2021). Linagliptin and gliclazide di-loaded extended-release nanoparticles: Formulation and evaluation. Wiadomosci Lekarskie (Warsaw, Poland: 1960), 74(9 cz 2), 2315–2322.

    PubMed  Google Scholar 

  95. Mohanty, D., Gilani, S. J., Zafar, A., Imam, S. S., Kumar, L. A., Ahmed, M. M., Jahangir, M. A., Bakshi, V., Ahmad, W., & Eltayib, E. M. (2022). Formulation and optimization of alogliptin-loaded polymeric nanoparticles: In vitro to in vivo assessment. Molecules, 27(14), 4470.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Nagavarma, B. V. N., Yadav, H. K. S., Ayaz, A., Vasudha, L. S., & Shivakumar, H. G. (2012). Different techniques for preparation of polymeric nanoparticles-a review. Asian Journal of Pharmaceutical and Clinical Research, 5(3), 16–23.

    CAS  Google Scholar 

  97. Crucho, C. I. C., & Barros, M. T. (2017). Polymeric nanoparticles: A study on the preparation variables and characterization methods. Materials Science and Engineering: C, 80, 771–784.

    CAS  PubMed  Google Scholar 

  98. Rao, J. P., & Geckeler, K. E. (2011). Polymer nanoparticles: Preparation techniques and size-control parameters. Progress in Polymer Science, 36(7), 887–913.

    CAS  Google Scholar 

  99. Mukherjee, S., Ray, S., & Thakur, R. S. (2009). Solid lipid nanoparticles: A modern formulation approach in drug delivery system. Indian Journal of Pharmaceutical Sciences, 71(4), 349.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Ganesan, P., & Narayanasamy, D. (2017). Lipid nanoparticles: Different preparation techniques, characterization, hurdles, and strategies for the production of solid lipid nanoparticles and nanostructured lipid carriers for oral drug delivery. Sustainable Chemistry and Pharmacy, 6, 37–56.

    Google Scholar 

  101. Chauhan, N., Kumar, K., & Pant, N. C. (2017). An updated review on transfersomes: A novel vesicular system for transdermal drug delivery. Universal Journal of Pharmaceutical Research, 2(4), 42–45.

    Google Scholar 

  102. Rai, S., Pandey, V., & Rai, G. (2017). Transfersomes as versatile and flexible nano-vesicular carriers in skin cancer therapy: The state of the art. Nano Reviews & Experiments, 8(1), 1325708.

    Google Scholar 

  103. Solanki, D., Kushwah, L., Motiwale, M., & Chouhan, V. (2016). Transferosomes-a review. World Journal of Pharmacy and Pharmaceutical Sciences, 5(10), 435–449.

    CAS  Google Scholar 

  104. Bhardwaj, P., Tripathi, P., Gupta, R., & Pandey, S. (2020). Niosomes: A review on niosomal research in the last decade. Journal of Drug Delivery Science and Technology, 56, 101581.

    CAS  Google Scholar 

  105. Yeo, P. L., Lim, C. L., Chye, S. M., Ling, A. P. K., & Koh, R. Y. (2017). Niosomes: A review of their structure, properties, methods of preparation, and medical applications. Asian Biomedicine, 11(4), 301–314.

    Google Scholar 

  106. Tangri, P., & Khurana, S. (2011). Niosomes: Formulation and evaluation. International Journal of Biopharmaceutics, 2(1), 47–53.

    Google Scholar 

  107. Moghassemi, S., & Hadjizadeh, A. (2014). Nano-niosomes as nanoscale drug delivery systems: An illustrated review. Journal of Controlled Release, 185, 22–36.

    CAS  PubMed  Google Scholar 

  108. Das Neves, J., Bahia, M. F., Amiji, M. M., & Sarmento, B. (2011). Mucoadhesive nanomedicines: Characterization and modulation of mucoadhesion at the nanoscale. Expert Opinion on Drug Delivery, 8(8), 1085–1104.

    CAS  PubMed  Google Scholar 

  109. Sapre, A. S., & Parikh, R. K. (2012). Design of a buccal mucoadhesive, nanoparticles based delivery system of fluoxetine. JPSBR, 2(3), 148–161.

    Google Scholar 

  110. Takeuchi, H., Yamamoto, H., & Kawashima, Y. (2001). Mucoadhesive nanoparticulate systems for peptide drug delivery. Advanced Drug Delivery Reviews, 47(1), 39–54.

    CAS  PubMed  Google Scholar 

  111. Jaiswal, P., & Aggarwal, G. (2013). Bioavailability enhancdement of poorly soluble drugs by smedds: A review. Journal of Drug Delivery and Therapeutics, 3(1).

  112. Dokania, S., & Joshi, A. K. (2015). Self-microemulsifying drug delivery system (SMEDDS)–challenges and road ahead. Drug Delivery, 22(6), 675–690.

    CAS  PubMed  Google Scholar 

  113. Potphode, V. R., Deshmukh, A. S., & Mahajan, V. R. (2016). Self-micro emulsifying drug delivery system: An approach for enhancement of bioavailability of poorly water soluble drugs. Asian Journal of Pharmacy and Technology, 6(3), 159–168.

    Google Scholar 

  114. Maurya, S. D., Arya, R. K. K., Rajpal, G., & Dhakar, R. C. (2017). Self-micro emulsifying drug delivery systems (SMEDDS): A review on physico-chemical and biopharmaceutical aspects. Journal of Drug Delivery and Therapeutics, 7(3), 55–65.

    CAS  Google Scholar 

  115. Ersin, Y., Bayram, K., Fatma, Ö., Tansel, A., & Celil, Ü. (2022). Oral formulations comprising sitagliptin HCI monohydrate with improved pharmaceutical characteristics. EP4045048.

  116. Xufeng, W. U., Li, S., Dadong, S., Pengcheng, L. I. U., Haoling, G. A. O., Dengfeng, D., & Lingling, W. (2022). Purification method of sitagliptin intermediate. CN114644568.

  117. Anthony, R., & Stephen, M. (2022). Low-dose triple combination formulation. US20220184070.

  118. Hong, G. U. O., Hai, G. U. O., & Kelin, S. H. I. (2022). Chemical treatment device for sitagliptin phosphate raw material. CN216677141.

  119. Hong, G. U. O., Hai, G. U. O., & Kelin, S. H. I. (2022). Sitagliptin phosphate medicine raw material treatment and extraction device. CN216653466.

  120. Seval, A., & Muge, U. B. (2022). An effervescent tablet composition of sitagliptin. EP3999070.

  121. Christou, K. E., Christou, K. I., Leonida, K. A., Christou, S. V., Konstantinou, K. A., Andrea, K. E., & Stylianou, F. M. (2022). Pharmaceutical composition comprising a combination of sitagliptin and metformin and method of preparation thereof. GR1010234.

  122. Hui, L. I. U. (2022). Preparation method of low-cost sitagliptin phosphate. CN11450769.

  123. Sathyanarayana, V., & Pankaj, P. (2022). An immediate release composition of sitagliptin hydrochloride. WO2022074664.

  124. Evangelos, K., Efthymios, K., Vasiliki, S., Ioanna, K., Anastasia, K., Andreas, K., & Manolis, F. (2022). Solid dosage form comprising sitagliptin and method of preparation thereof. WO2022058044.

  125. Xiang, L. I., Jie, Z., Minmin, Y. U., & Hui, Y. A. O. (2022). Sitagliptin phosphate tablet and preparation method thereof. CN114159401.

  126. Seval, A., Muge, U. B., Fatih, S., Onur, M., Ezel, U., & Seda, A. (2022). A tablet formulation comprising sitagliptin and metformin. WO2022035400.

  127. Qihui, X. I. E., Chaoyu, Y., Tiantian, N. I. E., & Longlong, W. (2022). Pharmaceutical composition containing sitagliptin and metformin, and preparation method thereof. CN114042051.

  128. Yongjie, Z., & Ying, Z. (2022). Sitagliptin and metformin double-layer sustained release tablet and preparation method thereof. CN114010612.

  129. Yuyuan, W. U., Hui, Z., Tiantian, X. I. E., & Maojia, Y. (2022). Analysis method for detecting release rate of sitagliptin metformin hydrochloride sustained release tablet. CN113945661.

  130. Yusheng, P. A. N., Xinxin, X., Cenbo, C., Hao, L. I., & Haixiang, W. (2022). Compound sustained-release tablet of epalrestat and sitagliptin or pharmaceutically acceptable salt thereof and preparation method thereof. CN113925838A.

  131. Sik, K. I. M. B. O., Wook, T. A. K. J. I. N., Hyun, C. H. O. J., Taek, I. M. H. O., & IL, K. I. M. Y. (2022). Composite formulation comprising sitagliptin and dapagliflozin and preparation method therefor. WO2022010078A1.

  132. Xiaojie, W., Dingchao, Q. I., Baocheng, Z., Guokai, L. I. U., & Baoquan, Z. (2022). Preparation method of 3-hydroxy-1-adamantane methyl ketone and method for synthesizing saxagliptin. CN114621068.

  133. Kenji, N., Wataru, I., Ayane, N., & Daiki, B. (2022). Saxagliptin-containing preparation and its manufacturing method. JP2022003016.

  134. Aydan, O., Nur, P. A., & Fatih, S. (2022). A process for formulations of linagliptin or a pharmaceutically acceptable salt thereof. WO2022173406A1.

  135. Takahisa, S., & Yukiko, K. (2022). Linagliptin-containing pharmaceutical composition with excellent thermal stability. JP2022097335.

  136. Ali, T., Hasan, T. A. L. I., & Mehtap, S. (2022). Pharmaceutical formulations of linagliptin. EP4019003.

  137. Meinicke, T., & Eynatten, M. V. O. N. (2022). Combination of linagliptin and metformin. JP2022093381.

  138. Yasushi, F., & Katsuhiko, O. (2022). Linagliptin-containing orally disintegrating tablet. WO2022102457.

  139. Takuma, T., & Masaya, F. (2022). Linagliptin-containing granule and pharmaceutical composition. JP2022074105A.

  140. Georg, B., Julia, F. K., Venkata, V., & Tracy, W. (2022). Pharmaceutical composition, methods for treating and uses thereof. US20220105043A1.

  141. Rentaro, I., Satoshi, K., & Junichi, K. (2022). Pharmaceutical formulation containing linagliptin and photostabilizing ingredient. JP2022012138A.

  142. Sermet, B. S., Selin, K. U., Gulcin, T. O. K., & Fatih, S. (2022). Pharmaceutical compositions comprising alogliptin. WO2022146344A1.

  143. Sermet, B. S., Selin, K. U., Bulent, D., Gulcin, T. O. K., & Fatih, S. (2022). Pharmaceutical capsule compositions of alogliptine. WO2022146355.

  144. Gulcin, T. O. K., Ediz, Y., & Ali, T. (2022). A combination comprising alogliptin and metformin. EP3976014.

  145. Qing, Z., Weibo, G. U. O., Lili, D., Jing, L. U. O., & Xiaoqin, L. I. U. (2022). Preparation method of alogliptin benzoate with high yield. CN114057685.

Download references

Acknowledgements

The authors would like to thank the Department of Pharmaceutics, MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, Haryana, India, 133207 for providing facilities for the completion of this review.

Funding

None.

Author information

Authors and Affiliations

  1. Department of Pharmaceutics, MM College of Pharmacy, Maharishi Markandeshwar (Deemed to Be University), Mullana, Ambala, Haryana, India, 133207

    Neha Tiwary, Neelam Sharma, Sukhbir Singh & Ishrat Zahoor

  2. Amity School of Pharmaceutical Sciences, Amity University, Mohali, Punjab, India

    Tapan Behl

Authors
  1. Neha Tiwary
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Neelam Sharma
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Sukhbir Singh
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Tapan Behl
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Ishrat Zahoor
    View author publications

    You can also search for this author inPubMed Google Scholar

Contributions

Neha Tiwary (N.T.) and Neelam Sharma (N.S.) conceived this study and wrote the final manuscript; Sukhbir Singh (S.S.) and Tapan Behl (T.B.) revised and edited this manuscript; Ishrat Zahoor (I.Z.) prepared figures.

Corresponding authors

Correspondence to Neelam Sharma or Sukhbir Singh.

Ethics declarations

Competing interests

The authors declare no competing interests.

Research Involving Humans and Animals Statement

None.

Informed Consent

None.

Conflict of Interest

None.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tiwary, N., Sharma, N., Singh, S. et al. Understanding the Pharmacological and Nanotechnological Facets of Dipeptidyl Peptidase-4 Inhibitors in Type II Diabetes Mellitus: a Paradigm in Therapeutics. BioNanoSci. 14, 211–229 (2024). https://doi.org/10.1007/s12668-023-01234-7

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12668-023-01234-7

Keywords