Efficacy and potentiality of vitamins and micronutrients oral sprays supplementation (review)

Introduction. Modern pharmaceutical development enables to introduce into practice more than ever new active ingredients delivery systems and forms enhancing actives activity compared to traditional approach (methods). A nowadays pace of life often providing improper feeding and micronutrients intake imbalance leads to necessary administration of micronutrient additional doses in the form of different pharmacies. Over the last years vitamins and minor nutrient elements spray forms are becoming more attractive for introduction into pharmaceutical practice. These dosage forms are characterized by the production availability, usability, easy dosage and sufficiently high bioavailability for both normal patients and ones having gastrointestinal tract diseases and other problems connecting with the food consumption and digestion.

Text. Drug delivery by oral mucosa attracts more attention due to its potential advantages compared to other methods. Until recently this administration way was considered mainly for topical application. However, in recent years number of developments connecting with oral cavity application as a portal for delivery of drugs active ingredients, vitamins and micronutrients into systemic blood has kept steadily growing. Diverse forms of oral drugs for sublingual and buccal administration have been developed by many scientific and clinical teams. Spray forms among them are of particular interest as the most economically viable and easy to use. Most of these developments deal with vitamins D and B₁₂, which arises from the acutest problems of their deficiency among global population, on the one hand, and low bioavailability due to negative effects by dietary intake, gastrointestinal tract health condition and other factors, on the other hand. Other micronutrients such as thiamin, niacin, pyridoxin, ascorbic acid, coenzyme Q and iron are examined and launched into the market in an oral spray form for sublingual application.

Conclusion. The current results of development and comparison study of micronutrients oral forms, in particular, randomized controlled trial data indicate a sublingual administration efficiency which either is similar to or exceeds traditional administration ways.

1. Puratchikody A., Prasanth V.V., Mathew S., Balaraman A. K. Buccal Drug Delivery: Past, Present and Future. International Journal of Drug Delivery. 2011;3(2):171–184.

2. Kianfar F., Chowdhry B. Z., Antonijevic M. D., Boateng J. S. Novel films for drug delivery via the buccal mucosa using model soluble and insoluble drugs. Drug Development and Industrial Pharmacy. 2012;38(10):1207–1220. DOI: 10.3109/03639045.2011.644294.

3. Patel K. V., Patel N. D., Dodiya H. D., Shelat P. K. Buccal bioadhesive drug delivery system: an overview. International Journal of Pharmaceutical & Biological Archives. 2011;2(2):600–609.

4. Kumar Sharma G., Kumar Sharma P., Bansal M. A review on mucoadhesive buccal patch as a novel drug delivery system. Pharma Science Monitor. 2012;3(2):30.

5. Kamimori G. H., Karyekar C. S., Otterstetter R., Cox D. S., Balkin T. J., Belenky G. L., Eddington N. D. The rate of absorption and relative bioavailability of caffeine administered in chewing gum versus capsules to normal healthy volunteers. International Journal of Pharmaceutics. 2002;234(1–2):159–167. DOI: 10.1016/S0378-5173(01)00958-9.

6. Modi P., Mihic M., Lewin A. The evolving role of oral insulin in the treatment of diabetes using a novel RapidMist system. Diabetes/Metabolism Research and Reviews. 2002;18(1):38–42. DOI: 10.1002/dmrr.208.

7. Rizk El Maalouf I., Capoccia K., Priefer R. Non-invasive ways of administering insulin. Diabetes & Metabolic Syndrome: Clinical Research & Reviews. 2022;16(4):102478. DOI: 10.1016/j.dsx.2022.102478.

8. Chaturvedi A., Srivastava P., Yadav S., Bansal M., Garg G., Kumar Sharma P. Fast dissolving films: a review. Current Drug Delivery. 2011;8(4):373–380. DOI: 10.2174/156720111795768022.

9. Boateng J., Mani J., Kianfar F. Improving drug loading of mucosal solvent cast films using a combination of hydrophilic polymers with amoxicillin and paracetamol as model drugs. BioMed Research International. 2013;198137. DOI: 10.1155/2013/198137.

10. Abd El Azim H., Nafee N., Ramadan A., Khalafallah N. Liposomal buccal mucoadhesive film for improved delivery and permeation of water-soluble vitamins. International Journal of Pharmaceutics. 2015;488(1–2):78–85. DOI: 10.1016/j.ijpharm.2015.04.052.

11. Tan Y.-l., Liu C.-G. Preparation and characterization of self-assemblied nanoparticles based on folic acid modified carboxymethyl chitosan. Journal of Materials Science: Materials in Medicine. 2011;22(5):1213–1220. DOI: 10.1007/s10856-011-4302-y.

12. Yang T.-Z., Wang X.-T., Yan X.-Y., Zhang Q. Phospholipid deformable vesicles for buccal delivery of insulin. Chemical and Pharmaceutical Bulletin. 2002;50(6):749–753. DOI: 10.1248/cpb.50.749.

13. Parmar K., Patel M. B. A review on sublingual spray: novel drug delivery system. International Journal of Pharmaceutical Sciences and Research. 2017;8(11):4533-4539. DOI: 10.13040/IJPSR.0975-8232.8(11).4533-39.

14. Khadzhieva Z. D., Pozdnyakova A. E., Zagorskaya N. S., Pozdnyakov D. I. Analysis of the sprays range on the Russian pharmaceutical market. Health and Education Millennium. 2019;21(5):42–46. (In Russ.) DOI: 10.26787/nydha-2226-7425-2019-21-5-42-46.

15. Sharma N., Jain S., Sardana S. Buccoadhesive drug delivery system. Journal of Advanced Pharmacy Education & Research. 2013;3(1):1–15.

16. Patel V. F., Liu F., Brown M. B. Advances in oral transmucosal drug delivery. Journal of Controlled Release. 2011;153(2):106–116. DOI: 10.1016/j.jconrel.2011.01.027.

17. Thosar M. Intra oral sprays – An overview. International Journal of Pharmacy & Life Sciences. 2011;2(10):1203.

18. Narang N., Sharma J. Sublingual mucosa as a route for systemic drug delivery. International Journal of Pharmacy & Life Sciences. 2011;3:18–22.

19. Kurosaki Y., Takatori T., Nishimura H., Nakayama T., Kimura T. Regional variation in oral mucosal drug absorption: permeability and degree of keratinization in hamster oral cavity. Pharmaceutical Research. 1991;8(10):1297–1301. DOI: 10.1023/a:1015812114843.

20. Grammatikopoulou M. G., Gkiouras K., Nigdelis M. P., Bogdanos D. P., Goulis D. G. Efficacy of Vitamin D3 Buccal Spray Supplementation Compared to Other Delivery Methods: A Systematic Review of Superiority Randomized Controlled Trials. Nutrients. 2020;12(3):691. DOI: 10.3390/nu12030691.

21. Pritchard L., Lewis S., Hickson M. Comparative effectiveness of vitamin D supplementation via buccal spray versus oral supplements on serum 25-hydroxyvitamin D concentrations in humans: a systematic review protocol. JBI Database of Systematic Reviews and Implementation Reports. 2019;17(4):487–499. DOI: 10.11124/JBISRIR-2017-003907.

22. Unsur E. K. Vitamin D levels of the healthy infants using oral spray or drop form of vitamin D supplement in the first year of life. Northern Clinics of Istanbul. 2021;8(1):31–36. DOI: 10.14744/nci.2020.09471.

23. Bakr I. S., Zaki A. M., El-Moslemany R. M., Elsaka R. O. Vitamin D oral gel for prevention of radiation-induced oral mucositis: A randomized clinical trial. Oral Diseases. 2021;27:1197–1204. DOI: 10.1111/odi.13650.

24. Nalbantoğlu Ö., Acar S., Arslan G., Köprülü Ö., Özkan B. Investigating the Efficiency of Vitamin D Administration with Buccal Spray in the Treatment of Vitamin D Deficiency in Children and Adolescents. Journal of Clinical Research in Pediatric Endocrinology. 2021;13(4):426–432. DOI: 10.4274/jcrpe.galenos.2021.2021.0047.

25. Satia M. C., Mukim A. G., Tibrewala K. D., Bhavsar M. S. A randomized two way cross over study for comparison of absorption of vitamin D3 buccal spray and soft gelatin capsule formulation in healthy subjects and in patients with intestinal malabsorption. Nutrition Journal. 2015;14:114. DOI: 10.1186/s12937-015-0105-1.

26. McCullough P., Heaney R. Correction of vitamin D deficiency using sublingually administered vitamin D2 in a Crohn’s disease patient with mal-absorption and a new ileostomy. The Journal of Steroid Biochemistry and Molecular Biology. 2017;173:211–214. DOI: 10.1016/j.jsbmb.2016.12.021.

27. Todd J. J., McSorley E. M., Pourshahidi L. K., Madigan S. M., Laird E., Healy M., Magee P. J. Vitamin D₃ supplementation in healthy adults: a comparison between capsule and oral spray solution as a method of delivery in a wintertime, randomised, open-label, cross-over study. British Journal of Nutrition. 2016;116(8):1402–1408. DOI: 10.1017/S0007114516003470.

28. Todd J. J., McSorley E. M., Pourshahidi L. K., Madigan S. M., Laird E., Healy M., Magee P. J. Vitamin D₃ supplementation using an oral spray solution resolves deficiency but has no effect on VO₂ max in Gaelic footballers: results from a randomised, double-blind, placebo-controlled trial. European Journal of Nutrition. 2017;56(4):1577–1587. DOI: 10.1007/s00394-016-1202-4.

29. Williams C. E., Williams E. A., Corfe B. M. Rate of change of circulating 25-hydroxyvitamin D following sublingual and capsular vitamin D preparations. European Journal of Clinical Nutrition. 2019;73:1630–1635. DOI: 10.1038/s41430-019-0503-0.

30. Penagini F., Borsani B., Maruca K., Giosia V., Bova S., Mastrangelo M., Zuccotti G. V., Mora S. Short-Term Vitamin D Supplementation in Children with Neurodisabilities: Comparison of Two Delivery Methods. Hormone Research in Paediatrics. 2017;88(3–4):281–284. DOI: 10.1159/000479690.

31. Ma’ali A., Naseef H., Qurt M., Abukhalil A. D., Rabba A. K., Sabri I. The Preparation and Evaluation of Cyanocobalamin Mucoadhesive Sublingual Tablets. Pharmaceuticals. 2023;16(10):1412. DOI: 10.3390/ph16101412.

32. Vitetta L., Zhou J., Manuel R., Dal Forno S., Hall S., Rutolo D. Route and Type of Formulation Administered Influences the Absorption and Disposition of Vitamin B12 Levels in Serum. Journal of Functional Biomaterials. 2018;9(1):12. DOI: 10.3390/jfb9010012.

33. Yadav R. K., Mishra S., Jain D. Methylcobalamine (Vitamin B12): Water Soluble Vitamin with Various Pharmacological Aspect. Journal of Drug Delivery and Therapeutics. 2021;11(1):130–137. DOI: 10.22270/jddt.v11i1.4488.

34. Kiliç B. O., Kiliç S., Eroğlu E. Ş., Gül E., Apak F. B. B. Sublingual Methylcobalamin Treatment Is as Effective as Intramuscular and Peroral Cyanocobalamin in Children Age 0–3 Years. Hematology. 2021;26(1):1013–1017. DOI: 10.1080/16078454.2021.2010877.

35. Varkal M. A., Karabocuoglu M. Efficiency of the Sublingual Route in Treating B12 Deficiency in Infants. International Journal for Vitamin and Nutrition Research. 2023;93(3):226–232. DOI: 10.1024/0300-9831/a000724.

36. Tugba-Kartal A., Cagla-Mutlu Z. Comparison of Sublingual and Intramuscular Administration of Vitamin B12 for the Treatment of Vitamin B12 Deficiency in Children. Revista de investigación clínica. 2020;72(6):380–385. DOI: 10.24875/RIC.20000208.

37. Bensky M. J., Ayalon-Dangur I., Ayalon-Dangur R., Naamany E., Gafter-Gvili A., Koren G., Shiber S. Comparison of Sublingual vs. Intramuscular Administration of Vitamin B12 for the Treatment of Patients with Vitamin B12 Deficiency. Drug Delivery and Translational Research. 2019;9(3):625–630. DOI: 10.1007/s13346-018-00613-y.

38. Parry-Strong A., Langdana F., Haeusler S., Weatherall M., Krebs J. Sublingual Vitamin B12 Compared to Intramuscular Injection in Patients with Type 2 Diabetes Treated with Metformin: A Randomised Trial. The New Zealand Medical Journal. 2016;129(1436):67–75.

39. Del Bo' C., Riso P., Gardana C., Brusamolino A., Battezzati A., Ciappellano S. Effect of Two Different Sublingual Dosages of Vitamin B₁₂ on Cobalamin Nutritional Status in Vegans and Vegetarians with a Marginal Deficiency: A Randomized Controlled Trial. Clinical Nutrition. 2019;38(2):575–583. DOI: 10.1016/j.clnu.2018.02.008.

40. Eleftheriadis G., Monou P. K., Andriotis E., Mitsouli E., Moutafidou N., Markopoulou C., Bouropoulos N., Fatouros D. Development and Characterization of Inkjet Printed Edible Films for Buccal Delivery of B-Complex Vitamins. Pharmaceuticals. 2020;13(9):203. DOI: 10.3390/ph13090203.

41. Jacobson B. H., Smith D. B., Warren A. J., Glass R. G., Kline C., Fedick J. L., Stemm J. Assessment of the Effectiveness of a Sublingual, Ergogenic Spray on Muscle Strength and Power. Journal of Strength and Conditioning Research. 2009;23(8):2326–2330. DOI: 10.1519/JSC.0b013e3181bab481.

42. Enzmann F. Spray containing ubiquinone Qn. United States patent US 20050019268A1. Available at: https://patents.google.com/patent/US20050019268A1/en. Accessed: 27.01.2005.

43. Maciejewska-Stupska K., Czarnecka K., Szymański P. Bioavailability enhancement of coenzyme Q₁₀: An update of novel approaches. Archiv der Pharmazie. 2024;29:e2300676. DOI: 10.1002/ardp.202300676.

44. Vitetta L., Leong A., Zhou J., Dal Forno S., Hall S., Rutolo D. The Plasma Bioavailability of Coenzyme Q10 Absorbed from the Gut and the Oral Mucosa. Journal of Functional Biomaterials. 2018;9(4):73. DOI: 10.3390/jfb9040073.

45. Leonhardt C. G., Busby J. C. Oral hygiene products containing ascorbic acid and method of using the same. United States patent US 20080057007A1. Available at: https://patents.google.com/patent/US20080057007A1/en. Accessed: 06.03.2008.

46. Montgomery R. E. Topical oral care compositions. United States patent US 20020137728A1. Available at: https://patents.google.com/patent/WO2002058662A2/en. Accessed: 26.09.2002.

47. Leonhardt C. G., Busby J. C. Oral hygiene products and method of using the same. United States patent US 8163271B2. Accessed: 24.04.2012.

48. Murererehe J., Uwitonze A. M., Nikuze P., Patel J., Razzaque M. S. Beneficial Effects of Vitamin C in Maintaining Optimal Oral Health. Frontiers in Nutrition. 2022:8:805809. DOI: 10.3389/fnut.2021.805809.

49. Hersh T. Intra-oral antioxidant preparations. United States patent US 5906811A. Available at: https://patents.google.com/patent/US5906811A/en. Accessed: 25.05.1999.

50. Kristó K., Módra S., Hornok V., Süvegh K., Ludasi K., Aigner Z., Kelemen A., Sovány T., Pintye-Hódi K., Regdon G. Investigation of Surface Properties and Free Volumes of Chitosan-Based Buccal Mucoadhesive Drug Delivery Films Containing Ascorbic Acid. Pharmaceutics. 2022;14(2):345. DOI: 10.3390/pharmaceutics14020345.

51. Atri A. Formulation and characterization of oral dissolving films with ascorbic acid. Selected Full-Text Master Theses. Available at: https://digitalcommons.liu.edu/brooklyn_fulltext_master_theses/8. Accessed: 19.07.2024.

52. Maciel V. B. V., Remedio L. N., Yoshida C. M. P., Carvalho R. A. Carboxymethyl cellulose-based orally disintegrating films enriched with natural plant extract for oral iron delivery. Journal of Drug Delivery Science and Technology. 2021;66:102852. DOI: 10.1016/j.jddst.2021.102852.

53. Bosi S. P., Lapin D., Sacchetti, Marchi A., Cristina E. P. New methods of iron administration and new formulations suitable for this purpose. Japan patent JP 2016523954A. Accessed: 12.08.2016.