HYDROXOCOBALAMIN NASAL DELIVERY FOR VITAMIN B12 DEFICIENCY: OVERCOMING INSTABILITY WITH MICROENCAPSULATION
Main Article Content
Keywords
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Abstract
Vitamin B12 deficiency is a large scale global health issue which traditional delivery methods like intramuscular injections and oral supplements have little success in which we see poor patient compliance and very variable absorption. Hydroxocobalamin as a form of B12 has pharmacological benefits over other cobalamin forms in that it has a greater half life, more plasma protein binding, and better conversion into active coenzymes which makes it a very good option for alternate delivery systems. Also we see from clinical studies that the intranasal route of hydroxocobalamin is doable which reports in very quick and clinically relevant increases in serum B12 levels. But at present there is no marketed nasal formulation of this and we also have issues of hydroxocobalamin’s instability to light, temperature, pH and oxidative and reducing agents. By using microencapsulation we may see to overcome these issues of stability, residence time, and absorption through the nasal mucosa. In order to potentially improve the treatment of vitamin B12 deficiency, future research should concentrate on creating reliable nasal delivery systems for hydroxocobalamin that combine pharmacological advantages with enhanced patient adherence.
References
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3. Bender DA (2003). Nutritional biochemistry of the vitamins. Cambridge, U.K.: Cambridge University Press. ISBN 978-0-521-80388-5.
4. Ofoedu, C. E., Iwouno, J. O., Ofoedu, E. O., Ogueke, C. C., Igwe, V. S., Agunwah, I. M., Okorie, S. U., Chikwendu, C. I., Chacha, J. S., & Okpala, C. O. R. (2021). Revisiting food-sourced vitamins for consumer diet and health needs: A perspective review, from vitamin classification, metabolic functions, absorption, utilization, to balancing nutritional requirements. PeerJ, 9, e11940. (https://doi.org/10.7717/peerj.11940)
5. Green R., Allen L.H., Bjørke-Monsen A.L., Brito A., Guéant J.L., Miller J.W., Molloy A.M., Nexo E., Stabler S., Toh B.H., et al. Vitamin B12 Deficiency. Nat. Rev. Dis. Primers. 2017;3:17040. doi: 10.1038/nrdp.2017.40. (https://doi.org/10.1038/nrdp.2017.40)
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8. Dubascoux S., Payot J.R., Sylvain P., Nicolas M., Gimenez E.C. Vitamin B12 Quantification in Human Milk–Beyond Current Limitations Using Liquid Chromatography and Inductively Coupled Plasma–Mass Spectrometry. Food Chem. 2021;362:130197. doi: 10.1016/j.foodchem.2021.130197 (https://doi.org/10.1016/j.foodchem.2021.130197)
9. Hygum, K.; Lildballe, D.L.; Greibe, E.H.; Morkbak, A.L.; Poulsen, S.S.; Sorensen, B.S.; Petersen, T.E.; Nexo, E. Mouse Transcobalamin Has Features Resembling Both Human Transcobalamin and Haptocorrin. PLoS ONE 2011, 6, e20638. (https://doi.org/10.1371/journal.pone.0020638)
10. Fyfe, J.C.; Madsen, M.; Højrup, P.; Christensen, E.I.; Tanner, S.M.; de la Chapelle, A.; He, Q.; Moestrup, S.K. The Functional Cobalamin (Vitamin B12)–Intrinsic Factor Receptor Is a Novel Complex of Cubilin and Amnionless. Blood 2004, 103, 1573–1579. (https://doi.org/10.1182/blood-2003-08-2852)
11. Coelho, D.; Kim, J.C.; Miousse, I.R.; Fung, S.; Du Moulin, M.; Buers, I.; Suormala, T.; Burda, P.; Frapolli, M.; Stucki, M.; et al. Mutations in ABCD4 Cause a New Inborn Error of Vitamin B12 Metabolism. Nat. Genet. 2012, 44, 1152–1155. (https://doi.org/10.1038/ng.2386)
12. Rizzo, G.; Laganà, A.S. A Review of Vitamin B12. Mol. Nutr. Vitam. 2020, 105–129. (https://doi.org/10.1016/B978-0-12-811907-5.00005-1)
13. Nielsen, M.J.; Rasmussen, M.R.; Andersen, C.B.F.; Nexø, E.; Moestrup, S.K. Vitamin B 12 Transport from Food to the Body’s Cells—A Sophisticated, Multistep Pathway. Nat. Rev. Gastroenterol. Hepatol. 2012, 9, 345–354. (https://doi.org/10.1038/nrgastro.2012.76)
14. Ankar A and Kumar A (2025) Vitamin B12 Deficiency. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing. Updated 10 Sept 2024. (https://www.ncbi.nlm.nih.gov/books/NBK441923/)
15. Watanabe, F., Yabuta, Y., Bito, T. & Teng, F., 2014. Vitamin B₁₂-containing plant food sources for vegetarians. Nutrients, 6(5), pp.1861–1873. DOI: 10.3390/nu6051861 (https://doi.org/10.3390/nu6051861)
16. Semeco, A., 2024. Top 12 foods that are high in vitamin B₁₂. Healthline. (https://www.healthline.com/nutrition/vitamin-b12-foods)
17. Obeid, R., Fedosov, S.N. & Nexo, E., 2015. Comparative bioavailability and utilization of particular forms of B12 supplements with potential to mitigate B12-related genetic polymorphisms. Molecular Nutrition & Food Research,59(7),pp.1364–1374.(https://www.researchgate.net/publication/320876233)
18. Temova Rakuša, Ž., Roškar, R., Hickey, N. & Geremia, S.(2023)‘Vitamin B₁₂ in Foods, Food Supplements, and Medicines—A Review of Its Role and Properties with a Focus on Its Stability’, Molecules,28(1),article240.doi:10.3390/molecules280102(https://doi.org/10.3390/molecules28010240)
19. Seth, T., et al. "Comparative Efficacy of NASO B12 Versus Sublingual Methylcobalamin in Treating Vitamin B12 Deficiency: A Randomised Open-Label Clinical Trial." International Journal of Endocrinology and Metabolic Disorders, vol. 7, no. 1, 2021, (https://journalibrr.com/index.php/IBRR/article/view/352).
20. U.S. Food and Drug Administration (FDA). (2014) Nascobal® (cyanocobalamin) nasal spray: prescribing information. Silver Spring, MD: FDA. (https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021642s020lbl.pdf)
21. Ahangar, E. R., & Annamaraju, P. (2025). Hydroxocobalamin. In StatPearls [Internet]. StatPearls Publishing.(https://www.ncbi.nlm.nih.gov/books/NBK557632/)
22. Moravcová, M., Siatka, T., Kujovská Krčmová, L., and Matoušová, K. (2025) ‘Biological properties of vitamin B₁₂’, Nutrition Research Reviews, published online 8 October 2024 (accepted manuscript). Available at: Cambridge University Press (https://doi.org/10.1017/S0954422424000210)
23. Ahmad I, Qadeer K, Zahid S, et al. Effect of Ascorbic Acid on the Degradation of Cyanocobalamin and Hydroxocobalamin in Aqueous Solution: A Kinetic Study. AAPS PharmSciTech. 2014;15(5):1324-1333. doi:10.1208/s12249-014-0160-5. (https://doi.org/10.1208/s12249-014-0160-5)
24. Martens, J., Gast, R., & Pfeiffer, C. (2020) ‘Alternative delivery routes of vitamin B12 for improved patient adherence: nasal and sublingual administration’, Nutrition Reviews, 78(8), pp. 675–689. doi:10.1093/nutrit/nuaa012 (https://doi.org/10.1093/nutrit/nuaa012)
25. Köhler, W., Paul, M., & Seewald, M. (1998) ‘Pharmacokinetics of intranasal hydroxocobalamin administration in elderly subjects’, British Journal of Clinical Pharmacology, 45(6), pp. 601–604. doi:10.1046/j.1365-2125.1998.00642.x (https://doi.org/10.1046/j.1365-2125.1998.00642.x)
26. Butler, C.C., Vidal-Alaball, J., Cannings-John, R., McCaddon, A., Hood, K., & Goringe, A. (2006) ‘Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency: a systematic review of randomized controlled trials’, Family Practice, 23(3), pp. 279–285. (https://doi.org/10.1093/fampra/cml008)
27. Allen, L.H. (2009) ‘Causes of vitamin B12 and folate deficiency’, Food and Nutrition Bulletin, 29(2 Suppl), pp.S20–S34.doi:10.1177/15648265080292S105 (https://doi.org/10.1177/15648265080292s105)
28. Lederle, F.A. (1991) ‘Oral cobalamin for pernicious anemia: medicine’s best kept secret?’, Journal of the American Medical Association (JAMA), 265(1), pp. 94–95. (https://doi.org/10.1001/jama.1991.03460010094039)
29. Temova Rakuša Ž., Grobin A., Roškar R. A Comprehensive Approach for the Simultaneous Analysis of All Main Water-Soluble Vitamins in Multivitamin Preparations by a Stability-Indicating HPLC-DAD Method. Food Chem. 2021;337:127768. (https://doi.org/10.1016/j.foodchem.2020.127768)
30. CYANOKIT® (Hydroxocobalamin for Injection) for Intravenous Infusion. Highlights of Prescribing Information. Merck Santé s.a.s.; Semoy, France: 2018 (https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/022041s019,%20020lbl.pdf)
31. Mander L., Liu H.W. Comprehensive Natural Products II: Chemistry and Biology, Volumes 1−10. J. Am. Chem. Soc. 2010;132:9929.(https://doi.org/10.1021/ja105512f ).
32. Combs G.F. The Vitamins: Fundamental Aspects in Nutrition and Health. 3rd ed. Elsevier Academic Press; Amsterdam, The Netherlands: 2008. Poglavje 1: Chemical and Physiological Properties of Vitamins. V; pp. 503–514.
33. Hadinata Lie A., Chandra-Hioe M.V., Arcot J. Sorbitol Enhances the Physicochemical Stability of B12 Vitamers. Int. J. Vitam. Nutr. Res. 2020;90:439–447. (https://doi.org/10.1024/0300-9831/a000578 ).
34. Demerre L.J., Wilson C. Photolysis of Vitamin B12. J. Am. Pharm. Assoc. 1956;45:129–134. (https://doi.org/10.1002/jps.3030450302).
35. Bonnett R. The Chemistry of the Vitamin B12 Group. Chem. Rev. 1963;63:573–605. (https://doi.org/10.1021/cr60226a002).
36. Gakenheimer W.C., Feller B.A. A Note on a Preliminary Observation of the Incompatibility of Vitamin B12 and Ascorbic Acid. J. Am. Pharm. Assoc. 1949;38:660. (https://doi.org/10.1002/jps.3030381213).
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Oct 03, 2025
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Patel Rushil, Dr. Shweta Paroha, & Dr. Pragnesh Patani. (2025). HYDROXOCOBALAMIN NASAL DELIVERY FOR VITAMIN B12 DEFICIENCY: OVERCOMING INSTABILITY WITH MICROENCAPSULATION. Journal of Population Therapeutics and Clinical Pharmacology, 32(7), 1808-1824. https://doi.org/10.53555/mjj3ey13
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Author Biographies
Patel Rushil
Khyati College of Pharmacy, Palodia, Ahmedabad
Dr. Shweta Paroha
Khyati College of Pharmacy, Palodia, Ahmedabad
Dr. Pragnesh Patani
Khyati College of Pharmacy, Palodia, Ahmedabad
How to Cite
Patel Rushil, Dr. Shweta Paroha, & Dr. Pragnesh Patani. (2025). HYDROXOCOBALAMIN NASAL DELIVERY FOR VITAMIN B12 DEFICIENCY: OVERCOMING INSTABILITY WITH MICROENCAPSULATION. Journal of Population Therapeutics and Clinical Pharmacology, 32(7), 1808-1824. https://doi.org/10.53555/mjj3ey13