Introduction

Antihistamines of the first generation were formerly used to treat allergic disorders.^1,2 Second-generation antihistamines, such as Terfenadine, Fexofenadine HCl etc were next being prescribed owing to avoid the sedative side effects observed with first generation drugs.^3–5 Terfenadine’s carboxylic acid metabolite is Fexofendine HCl. There are no sedative impacts of fexofenadine HCl. ^2,6,7 It has no sedative or electrocardiographic effects, according to reports. Fexofenadine HCl is available in pill, capsule, and oral suspension dosage forms. It has been established that they are bioequivalent.^6,8,9 Fexofenadine is quickly absorbed after consumption and has a lengthy duration of action (half-life 14.4 hours), making it suitable for once-daily use. Adults and children over the age of 12 should take 60 mg twice a day, 120 mg once a day, or 180 mg orally once a day of fexofenadine HCl. The suggested dose for children aged 6 to 11 years is 30mg twice day.^10–12 Oral suspension is indicated for children aged six months and above, with a suggested dose of 15 mg twice day for children aged six months to two years and 30 mg twice daily for children aged two to eleven years.^12,13

In our study, we suggest that microspheres can be the perfect dosage form of Fexofenadine HCl to treat allergic disorders. In microcapsules, the active drug molecule is encapsulated and enclosed by a distinct polymeric wall, while in microspheres, the drug is evenly diffused all through the polymeric material.^10,13 Microspheres provide a variety of benefits over traditional drug delivery systems, including the ability to transport therapeutic active ingredients to the region of interest of the body in a regulated and sustained way, resulting in better therapeutic effects. Microspheres are novel drug delivery systems with particle sizes 1-1000μm.¹⁴  Conventional sustained release dosage forms like tablets and capsules have the risk of dose dumping. ¹⁵ Besides, the drugs which has lower bioavailability are eliminated from the physiological system with lower degree of absorption.^16,17 Thus the total drug administered is not utilized, and the drug passes through the metabolism organs like kidney or liver and have harmful effects.¹⁸ With the use of sustained release microspheres, we can avoid dose dumping risks and thus increase safety profile. We will need lower dose than the conventional ones to reach the minimum effective concentration (MIC).¹⁹ Fexofenadine HCl microspheres is suitable for making the best use of the given dose with less side effects. 

Comparison of Current Treatment Approaches

One of the most frequent kinds of allergies is allergic rhinitis or hay fever.^20,21 According to recent research, its frequency has risen from 1.4 to 45 percent in the last several decades.⁷ Allergic rhinitis has both direct and indirect consequences on one’s quality of life, and it’s often paired by asthma, middle ear irritation, nasal polyps, sinusitis, and respiratory tract infections. Allergic disorder is a common condition that affects millions of people in the world.^22,23 For moderate to severe allergic condition, intranasal corticosteroids (INCs) are frequently recommended as first-line treatment. Beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone furoate, fluticasone propionate, mometasone, and triamcinolone are among the most commonly used INCs.²⁴  Their anti-inflammatory properties reduce inflammation, edema, and vascular leakage, which helps to relieve rhinorrhea and congestion.^25–27 INCs reduce the amount of histamine-producing mast cells in the nasal mucosa, which reduces itchiness and sneezing.  INCS has longer onset of action.^28,29 Although these medications have comparable safety and effectiveness, systemic steroids usually have major side effects.^30–32 INCs have a low risk of systemic adverse events (AEs), such as hypothalamic-pituitary-adrenal axis suppression or growth suppression, when administered at prescribed dosages and durations.^33,34 Researchers are suggesting intranasal corticosteroids (INCs) due to their greater efficacy over antihistamines.^33,35,36

While not a cure, Allergen-Specific Immunotherapy (ASIT) remains the only treatment that can modify the natural course of an allergic illness. But the danger of allergic immunotherapy-related systemic responses (SRs), which are estimated to occur in 1% to 4% of patients and can vary from moderate to lethal in severity, is a significant obstacle to applying this unique and successful therapeutic option.^4,7,37,38

An allergic patient is given a constantly higher dosage of an allergen immunotherapy in order to reduce their symptoms when they come into contact with the allergen they are allergic to. Despite the fact that ASIT is not a remedy, it is the only therapy that might potentially modify the natural path of an allergic condition.^27,39 For those with atopy, which is characterized as a heightened predisposition toward IgE-based sensitivity, which results in the formation of particular IgE antibodies to common environmental allergens—about 40% of the overall population is believed to be IgE-based sensitive.^20,39 The therapeutic arsenal should be expanded to include any treatment that can alleviate symptoms without inflicting intolerable side-effects.

Fexofenadine HCl microspheres- Can it be first line therapy?

But in the perspective of safety, antihistamines are more accepted globally^36,40,41. So, this is chosen as the first-line therapy. It has also been offered in a sustained release dosage form of tablet or capsule to make the medication dose more convenient for patients. Microspheres are used to increase dose efficiency while reducing the likelihood of adverse effects. Pharmaceutical firms may develop the most optimal release patterns using microspheres of active pharmaceutical ingredients (API).^14,18 Polymeric microspheres containing fexofenadine HCl may assist achieve the optimum absorption profile and bioavailability. Furthermore, microspheres give a large margin of safety by eliminating the risk of dosage burst.^10,13 Fexofenadine HCl is absorbed at a rate of 30-40 percent. The remainder is eliminated via the kidneys without being absorbed. Side effects would be lessened if Fexofenadine HCl sustained-release microspheres of polymer blends were utilized since less medicine would be supplied and the kidney would clear out less drug.¹⁴ The needed dosage might be given to the patient based on his or her particular needs, pathophysiology, and physical condition. The needed dosage in microspheres may also be supplied as a capsule, and the dose can be determined based on drug entrapment efficiency and microsphere drug loading. It would also assist to lower manufacturing costs by requiring less medicine to be included into the pharmaceutical formulations. As a consequence, patients are likely to get treatments at a reduced cost. To balance its lengthy half-life and low absorption, the polymer concentration should be maintained moderate. Microspheres dosage forms are coming into light day by day. When drug is a blessing, it can do the most harm to the body. Now-a –days the main challenge is not to find out the drug for a treatment, but the challenge is how to deliver the drug for its maximum safety and effectiveness.  Fexofenadine HCl is obviously safer than steroids and immunotherapy. If we can modify and optimize the dosage form, it can be used as the first line therapy for the allergic disorders. 

Conclusion

Effective treatment options for allergic disorders may help the patients achieve a higher quality of life. Researchers are always attempting to identify methods to lessen the side effects of drugs by altering the molecule, site specific targeted medication release, and dosage forms and dosage forms with cost-effectiveness. Due to the reduced effectiveness of Fexofenadine HCl, i.e. its lesser bioavailability, intranasal corticosteroids (INCS), subcutaneous, and sublingual immunotherapy have been recommended as current therapeutic options. If Fexofenadine HCl efficacy can be increased by boosting bioavailability, it might be the ‘state of art’ alternative for patients in every way: convenience, cost effectiveness, and a large margin of safety. 

Acknowledgement

We are grateful to Bangladesh Council of Scientific and Industrial Research. 

Conflict of Interest

This research has no conflict of interest.

Funding Sources

There is no funding source.

References

1. Simon FER, Simons KJ. H1 Antihistamines: Current Status and Future Directions. World Allergy Organ J. 2008;1(9):145-155. doi:10.1186/1939-4551-1-9-145
   CrossRef
2. Fein MN, Fischer DA, O’Keefe AW, Sussman GL. CSACI position statement: Newer generation H1-antihistamines are safer than first-generation H1-antihistamines and should be the first-line antihistamines for the treatment of allergic rhinitis and urticaria. Allergy, Asthma Clin Immunol. 2019;15(1):1-6. doi:10.1186/s13223-019-0375-9
   CrossRef
3. Randall KL, Hawkins CA. Antihistamines and allergy. Aust Prescr. 2018;41(2):42-45. doi:10.18773/austprescr.2018.013
   CrossRef
4. Simons FER, Simons KJ. Histamine and H1-antihistamines: Celebrating a century of progress. J Allergy Clin Immunol. 2011;128(6):1139-1150.e4. doi:10.1016/j.jaci.2011.09.005
   CrossRef
5. Maeda T, Babazono A, Nishi T. Surveillance of First-Generation H1-Antihistamine Use for Older Patients with Dementia in Japan: A Retrospective Cohort Study. Curr Gerontol Geriatr Res. 2018;2018:1-6. doi:10.1155/2018/3406210
   CrossRef
6. Ahn JH, Kim J, Rehman NU, Kim HJ, Ahn MJ, Chung HJ. Effect of rumex acetosa extract, a herbal drug, on the absorption of fexofenadine. Pharmaceutics. 2020;12(6):1-14. doi:10.3390/pharmaceutics12060547
   CrossRef
7. Slavin RG. Treating rhinitis in the older population: Special considerations. Allergy, Asthma Clin Immunol. 2009;5(1):1-4. doi:10.1186/1710-1492-5-9
   CrossRef
8. Bernstein DI, Schoenwetter WF, Nathan RA, Storms W, Ahlbrandt R, Mason J. Efficacy and Safety of Fexofenadine Hydrochloride for Treatment of Seasonal Allergic Rhinitis. Ann Allergy, Asthma Immunol. 1997;79(5):443-448. doi:10.1016/S1081-1206(10)63041-4
   CrossRef
9. Kaiser HB, Rooklin A, Spangler D, Capano D. Efficacy of Loratadine Compared with Fexofenadine or Placebo for the Treatment of Seasonal Allergic Rhinitis. Clin Drug Investig. 2001;21(8):571-578. doi:10.2165/00044011-200121080-00006
   CrossRef
10. Arefin P, Hasan I, Reza MS. Design, characterization and in vitro evaluation of HPMC K100 M CR loaded Fexofenadine HCl microspheres. Springerplus. 2016;5(1). doi:10.1186/s40064-016-2322-2
    CrossRef
11. Huh Y, Cho H-J, Yoon I-S, et al. Preparation and evaluation of spray-dried hyaluronic acid microspheres for intranasal delivery of fexofenadine hydrochloride. Eur J Pharm Sci. 2010;40(1):9-15. doi:10.1016/j.ejps.2010.02.002
    CrossRef
12. Shasho H, Sakur AA, Trefi S. SEPARATION AND ASSAY OF FOUR ANTIHISTAMINE DRUGS DIPHENHYDRAMINE, CHLORPHENIRAMINE, CYPROHEPTADINE AND FEXOFENADINE IN PHARMACEUTICAL FORMS BY A SINGLE HPLC METHOD. Int J Pharm Pharm Sci. 2018;10(4):53. doi:10.22159/ijpps.2018v10i4.24819
    CrossRef
13. Arefin P, Hasan I, Islam MS, Reza MS. Formulation and In vitro Evaluation of Eudragit RL 100 Loaded Fexofenadine HCl Microspheres. Bangladesh Pharm J. 2016;19(1):58-67. doi:10.3329/bpj.v19i1.29240
    CrossRef
14. Arefin P, Habib MS, Ahmed NU, et al. Microspheres and microcapsules: A review of their manufacturing techniques for Pharmaceutical industries. Indian J Nov Drug Deliv. 2020;12(4):177-185.
15. Arefin P, Habib MS, Chakraborty D, Bhattacharjee SC, Das S. An overview of microcapsule dosage form. Int J Pharm Chem Anal. 2020;7(4):155-160. doi:10.18231/j.ijpca.2020.025
    CrossRef
16. Wang J, Cheng X, Li Y, You J. Microsphere with narrow nanopores: Fabrication in PVDF/PMMA/PLLA blend and enhanced adsorption/separation performances. Appl Surf Sci. 2021;566:150673. doi:10.1016/j.apsusc.2021.150673
    CrossRef
17. Wenzhi S, Dezhou W, Min G, Chunyu H, Lanlan Z, Peibiao Z. Assessment of nano-hydroxyapatite and poly (lactide-co-glycolide) nanocomposite microspheres fabricated by novel airflow shearing technique for in vivo bone repair. Mater Sci Eng C. 2021;128:112299. doi:10.1016/j.msec.2021.112299
    CrossRef
18. Arefin P, Habib MS, Mostafa M, et al. Evaluation of the Influence of Stirring Speed on the Release Kinetics of Fexofenadine HCl Polymeric Microspheres. Biosci Biotechnol Res Asia. 2021;18(4).
    CrossRef
19. Arefin P, Ahmed R, Habib MS, et al. Evaluation of Critical Quality Attributes of Immediate Release Ciprofloxacin Tablets of Different Pharmaceutical Companies in Bangladesh. Biosci Biotechnol Res Asia. 2021;17(4):781-788. doi:10.13005/bbra/2883
20. Oktemer T, Altintoprak N, Muluk NB, et al. Clinical Efficacy of Immunotherapy in Allergic Rhinitis. Am J Rhinol Allergy. 2016;30(5_suppl):S4-S7. doi:10.2500/ajra.2016.30.4368
    CrossRef
21. Hossenbaccus L, Linton S, Garvey S, Ellis AK. Towards definitive management of allergic rhinitis: best use of new and established therapies. Allergy, Asthma Clin Immunol. 2020;16(1):39. doi:10.1186/s13223-020-00436-y
    CrossRef
22. Baraniuk JN. Pathogenesis of allergic rhinitis. Am J Rhinol. 1997;11(3):245.
    CrossRef
23. Skoner DP. Allergic rhinitis: Definition, epidemiology, pathophysiology, detection, and diagnosis. J Allergy Clin Immunol. 2001;108(1):S2-S8. doi:10.1067/mai.2001.115569
    CrossRef
24. Mir E, Panjabi C, Shah A. Impact of allergic rhinitis in school going children. Asia Pac Allergy. 2012;2(2):93. doi:10.5415/apallergy.2012.2.2.93
    CrossRef
25. Moote W, Kim H, Ellis AK. Allergen-specific immunotherapy. Allergy, Asthma Clin Immunol. 2018;14(S2):53. doi:10.1186/s13223-018-0282-5
    CrossRef
26. Gu Y, Liu Y, Cao X. Evolving strategies for tumor immunotherapy: Enhancing the enhancer and suppressing the suppressor. Natl Sci Rev. 2017;4(2):161-163. doi:10.1093/nsr/nwx032
    CrossRef
27. Ellis AK, Gagnon R, Hammerby E, Lau A. Sublingual immunotherapy tablet for the treatment of house dust mite allergic rhinitis in Canada: an alternative to minimize treatment costs? Allergy, Asthma Clin Immunol. 2019;15(1):27. doi:10.1186/s13223-019-0344-3
    CrossRef
28. Bernstein DI, Bardelas JA, Svanholm Fogh B, Kaur A, Li Z, Nolte H. A practical guide to the sublingual immunotherapy tablet adverse event profile: implications for clinical practice. Postgrad Med. 2017;129(6):590-597. doi:10.1080/00325481.2017.1302306
    CrossRef
29. Wahn U, Bachert C, Heinrich J, Richter H, Zielen S. Real-world benefits of allergen immunotherapy for birch pollen-associated allergic rhinitis and asthma. Allergy. 2019;74(3):594-604. doi:10.1111/all.13598
    CrossRef
30. Sur DK, Scandale S. Treatment of allergic rhinitis. Am Fam Physician. 2010;81(12):1440-1446. doi:10.4102/safp.v52i5.1656
31. Khan NU, Begum KS. Allergic Rhinitis during Pregnancy -an Update of Management. Med Today. 2017;28(2):83-88. doi:10.3329/medtoday.v28i2.32933
    CrossRef
32. Petersen TH, Agertoft L. Corticosteroids for Allergic Rhinitis. Curr Treat Options Allergy. 2016;3(1):18-30. doi:10.1007/s40521-016-0075-3
    CrossRef
33. Varshney J, Varshney H. Allergic rhinitis: An overview. Indian J Otolaryngol Head Neck Surg. 2015;67(2):143-149. doi:10.1007/s12070-015-0828-5
    CrossRef
34. Titulaer J, Arefian H, Hartmann M, Younis MZ, Guntinas-Lichius O. Cost-effectiveness of allergic rhinitis treatment: An exploratory study. SAGE Open Med. 2018;6:205031211879458. doi:10.1177/2050312118794588
    CrossRef
35. Kim H, Bouchard J, Renzi PM. The link between allergic rhinitis and asthma: A role for antileukotrienes? Can Respir J. 2008;15(2):91-98. doi:10.1155/2008/416095
    CrossRef
36. Juel-Berg N, Darling P, Bolvig J, et al. Intranasal Corticosteroids Compared with Oral Antihistamines in Allergic Rhinitis: A Systematic Review and Meta-Analysis. Am J Rhinol Allergy. 2017;31(1):e19-e28. doi:10.2500/ajra.2016.30.4397
    CrossRef
37. Hox V, Lourijsen E, Jordens A, et al. Benefits and harm of systemic steroids for short- And long-term use in rhinitis and rhinosinusitis: An EAACI position paper. Clin Transl Allergy. 2020;10(1):1-27. doi:10.1186/s13601-019-0303-6
    CrossRef
38. Nadel JA. Modulation of neurogenic inflammation by peptidases. Neuropeptides Respir Med. 2017;372(5):351-372. doi:10.1201/9780203745915
    CrossRef
39. Valovirta E, Petersen TH, Piotrowska T, et al. Results from the 5-year SQ grass sublingual immunotherapy tablet asthma prevention (GAP) trial in children with grass pollen allergy. J Allergy Clin Immunol. 2018;141(2):529-538.e13. doi:10.1016/j.jaci.2017.06.014
    CrossRef
40. Okubo K, Suzuki T, Tanaka A, Aoki H. Efficacy and safety of rupatadine in Japanese patients with seasonal allergic rhinitis: A double-blind, randomized, multicenter, placebo-controlled clinical trial. Allergol Int. 2019;68(2):207-215. doi:10.1016/j.alit.2018.08.011
    CrossRef
41. Church M, Church D. Pharmacology of antihistamines. Indian J Dermatol. 2013;58(3):219. doi:10.4103/0019-5154.110832
    CrossRef