Rationalized Approach for Formulation and Optimization of Ebastine Microemulsion Using Design Expert for Solubility Enhancement
Ebastine is available as an oral antihistamine formula for allergic disorders such as tablets and syrup. Oral ebastine causes unfavorable effects on heart like QT prolongation, severe gastric distress, decreased tear production, resulting in dryness of the ocular surface, which exacerbates ocular discomfort and increasing susceptibility of eye to irritation. To avoid systemic side effects and ocular discomfort, topical ocular therapy could prove to be superior to systemic therapy in treating ocular allergies. Hence, topical formulation was developed to achieve onsite exposure of ebastine for ocular allergies. Moreover, conjunctiva is more accessible to hydrophilic molecules than lipophilic molecules. This creates challenge for a lipophilic molecule such as ebastine for topical ocular development. Successful dissolution of ebastine in o/w microemulsion allows its use in more convenient soluble form. Initially, solubility of drug in various oils, surfactant and cosurfactant was determined, followed by pseudo-ternary phase diagram to find microemulsion area. The D-optimal mixture design was employed for optimization of formulation. The optimized microemulsion formulation was characterized for its transparency, drug content, droplet size, zeta potential, viscosity, isotonicity, osmolarity and surface tension etc. The optimum physicochemical properties were observed to be eye-fitting. Carboxy methyl cellulose and sodium hyaluronate were used as gelling agents at different concentrations to increase residential time at the site of action. In vitro drug release study revealed that ebastine release from microemulsion gel in a sustained manner up to 24 hrs. for the purpose of providing prolonged therapy for ocular allergy. Hence, prepared microemulsion had great potential as an alternative to customary oral formulations of poorly soluble drug.
Keywords: Ebastine, Microemulsion, D-optimal mixture design, Solubility
2. Kawakami K, Yoshikawa T, Hayashi T, Nishihara Y, Masuda K. Microemulsion formulation for enhanced absorption of poorly soluble drugs II. In vivo study. J Control Release. 2002; 8(1):75-82.
3. Kalam MA, Alshamsan A, Aljuffali IA, Mishra AK, Sultana Y. Delivery of gatifloxacin using microemulsion as vehicle: formulation, evaluation, transcorneal permeation and aqueous humor drug determination. Drug delivery. 2016; 23(3):886-97.
4. Nair R, Chakrapani M, Kaza R. Preparation and evaluation of vancomycin microemulsion for ocular drug delivery. Drug Delivery Letters. 2012; 2(1):26-34.
5. Mohan K, Pravin S, Atul B. Ophthalmic microemulsion: a comprehensive review. Int J Pharm Bio Sci. 2012; 3(3):1-3.
6. Rico S, Antonijoan RM, Barbanoj MJ. Ebastine in the light of CONGA recommendations for the development of third-generation antihistamines. Journal of asthma and allergy. 2009; 2:73.
7. Mashige KP. Ocular allergy. Health sa gesondheid. 2017; 22(1):112-22.
8. Sánchez MC, Fernández Parra B, Matheu V, Navarro A, Ibáñez MD, Dávila I, Dordal MT, Lluch Bernal M, Rondón C, Montoro J, Antón E. Allergic conjunctivitis. J Investig Allergol Clin Immunol. 2011; 21(2 Suppl):1-9.
9. Abelson MB, Chapin MJ, Gomes P, Minno G, Nice J, inventors; Aciex Therapeutics Inc, assignee. Ophthalmic formulations of cetirizine and methods of use. United States patent US 8,569,273. 2013 Oct 29.
10. Azeem A, Rizwan M, Ahmad FJ, Iqbal Z, Khar RK, Aqil M, Talegaonkar S. Nanoemulsion components screening and selection: a technical note. AAPS Pharmscitech. 2009; 10 (1):69-76.
11. Gohel M, Patel A, Patel A, Hingorani L. Optimization of Bacoside, a loaded SNEDDS, using D-optimal mixture design for enhancement in solubility and bio- availability. Int J Pharm Pharm Sci. 2016; 8 (12):213-220.
12. Chouhan P, Saini TR. D-optimal design and development of microemulsion based transungual drug delivery formulation of ciclopirox olamine for treatment of onychomycosis. Indian Journal of Pharmaceutical Sciences. 2016; 78(4):498-511.
13. Duangjit S, Chairat W, Opanasopit P, Rojanarata T, Ngawhirunpat T. Application of Design Expert for the investigation of capsaicin-loaded microemulsions for transdermal delivery. Pharmaceutical development and technology. 2016; 21(6):698-705.
14. She Y, Li J, Xiao B, Lu H, Liu H, Simmons PA, Vehige JG, Chen W. Evaluation of a novel artificial tear in the prevention and treatment of dry eye in an animal model. Journal of Ocular Pharmacology and Therapeutics. 2015; 31(9):525-30.
15. Shah DP, Chhatrani BM. A Review on Microemulsion Based Gel: A Novel Approach for Enhancing Topical Delivery of Hydrophobic Drug. 2017; 8(4):19-35.
16. Fialho SL, da Silva-Cunha A. New vehicle based on a microemulsion for topical ocular administration of dexamethasone. Clin. Experiment. Ophthalmol. 2004; 32(6):626–632.
17. Üstündag-Okur N, Gökçe EH, Eğrilmez S, Özer Ö, Ertan G. Novel ofloxacin-loaded microemulsion formulations for ocular delivery. Journal of Ocular Pharmacology and Therapeutics. 2014; 30(4):319-32.
18. Ince I, Karasulu E, Ates H, Yavasoglu A, Kirilmaz L. A novel pilocarpine microemulsion as an ocular delivery system: in vitro and in vivo studies. J. Clin. Exp. Ophthalmol. 2015; 6: 408.
19. Kesavan K, Kant S, Singh PN, Pandit JK. Mucoadhesive chitosan-coated cationic microemulsion of dexamethasone for ocular delivery: in vitro and in vivo evaluation. Current eye research. 2013; 38(3):342-52.
20. Jain J, Fernandes C, Patravale V. Formulation development of parenteral phospholipid-based microemulsion of etoposide. Aaps Pharmscitech. 2010;11(2):826-31.
21. Kalam MA, Alshamsan A, Aljuffali IA et al. Delivery of gatifloxacin using microemulsion as vehicle: formulation, evaluation, transcorneal permeation and aqueous humor drug determination, Drug Deliv. 2016; 23(3):896–907.
22. Gohil R, Patel A, Pandya T, Dharamsi A. Optimization of Brinzolamide Loaded Microemulsion using Formulation by Design Approach: Characterization and In-vitro Evaluation. Current Drug Therapy. 2019; 14:1-18.
23. Grassi M, Coceani N, Magarotto L. Mathematical modeling of drug release from microemulsions: theory in comparison with experiments. Journal of colloid and interface science. 2000; 228(1):141-50.
24. Sandle T. Sterile ophthalmic preparations and contamination control. J GXP Compliance. 2014; 18 (3):1-5.
25. Brime B, Moreno MA, Frutos G, Ballesteros MP, Frutos P. Amphotericin B in oil–water lecithin-based microemulsions: formulation and toxicity evaluation. Journal of pharmaceutical sciences. 2002; 91(4):1178-85.
26. Han K, Woghiren OE, Priefer R. Surface tension examination of various liquid oral, nasal, and ophthalmic dosage forms. Chemistry Central Journal. 2016;10(1):31.
27. Kesavan K, Pandit JK, Kant S, Positively charged microemulsions of dexamethasone: comparative effects of two cosurfactants on ocular drug delivery and bioavailability. Ther. Delivery. 2013; 4(11):1385–1395.
28. Habib F, El-Mahdy M, Maher S. Microemulsions for ocular delivery: evaluation and characterization. Journal of Drug Delivery Science and Technology. 2011; 21(6):485-9.
29. Mainardes RM, Urban MC, Cinto PO. Colloidal carriers for ophthalmic drug delivery. Curr Drug Targets. 2005; 6:363–371.
30. Ali YA, Lehmussaari K. Industrial perspective in ocular drug delivery. Advanced Drug Delivery Reviews. 2006; 58:1258–1268.
31. Rathore KS, Nema RK, Sisodia SS. An overview and advancement in ocular drug delivery systems. International Journal of Pharmaceutical Sciences and Research. 2010; 1(10):11.
32. Del Amo EM, Urtti A. Current and future ophthalmic drug delivery systems: a shift to the posterior segment. Drug discovery today. 2008; 13 (3-4):135-43.
33. Pattarino F, Marengo E, Gasco MR, Carpignano R. Experimental design and partial least squares in the study of complex mixtures: microemulsions as drug carriers. International journal of pharmaceutics. 1993; 91(2-3):157-65.
34. Chen H, Chang X, Du D, Li J, Xu H, Yang X. Microemulsion-based hydrogel formulation of ibuprofen for topical delivery. International Journal of Pharmaceutics. 2006; 315(1-2):52-8.
35. Lawrence MJ, Rees GD. Microemulsion-based media as novel drug delivery systems. Advanced drug delivery reviews. 2012; 64:175-93.
36. Wilson CG. Topical drug delivery in the eye. Experimental eye research. 2004; 78 (3):737-43.
37. Hosoya K, Lee VH, Kim KJ ,Kwang Jin et al. Roles of the conjunctiva in ocular drug delivery: a review of conjunctival transport mechanisms and their regulation. European Journal of Pharmaceutics and Biopharmaceutics. 2005; 60(2):227–240.
38. Jiao J. Polyoxyethylated nonionic surfactants and their applications in topical ocular drug delivery. Advanced drug delivery reviews. 2008; 60 (15):1663-73.
39. Chandrakar S, Roy A, Choudhury A, Saha S, Bahadur S, Prasad P. Microemulsion: A Versatile Tool for Ocular Drug Delivery. Asian Journal of Pharmacy and Technology. 2014; 4(3):147-50.
40. Vandamme TH. Microemulsions as ocular drug delivery systems: recent developments and future challenges. Prog. Retin. Eye Res. 2002; 21:15–34.
41. Kaur IP, Kanwar M, Ocular preparations: the formulation approach. Drug Dev Ind Pharm. 2002; 28(5): 473-493.
42. Gautam N, Kesavan K. Development of microemulsions for ocular delivery. Therapeutic delivery. 2017; (5):313-30.
43. Habib F, El-Mahdy M, Maher S. Microemulsions for ocular delivery: evaluation and characterization. Journal of Drug Delivery Science and Technology. 2011; 21 (6):485-9.
44. Gaudana R, Jwala J, Boddu SH, Mitra AK. Recent perspectives in ocular drug delivery. Pharmaceutical research. 2009; 26 (5):1197.
45. Gan L, Wang J, Jiang M, Bartlett H, Ouyang D, Eperjesi F, Liu J, Gan Y. Recent advances in topical ophthalmic drug delivery with lipid-based nanocarriers. Drug discovery today. 2013; 18 (5-6):290-7.
46. Gan L, Gan Y, Zhu C et al, Novel microemulsion in situ electrolyte-triggered gelling system for ophthalmic delivery of lipophilic cyclosporine A: in vitro and in vivo results. Int. J. Pharm. 2009; 365(1–2):143–149.
47. Hegde RR, Verma A, Ghosh A. Microemulsion: new Insights into the ocular drug delivery. ISRN Pharm. 2013; 27:1–11.
48. Acharya DP, Hartley PG. Progress in microemulsion characterization. Curr. Opin. Colloid Interface Sci. 2012; 17(5):274–228.
49. Bharti SK, Kesavan K. Phase-transition W/O Microemulsions for ocular delivery: Evaluation of antibacterial activity in the treatment of bacterial keratitis. Ocular immunology and inflammation. 2017; 25(4):463-74.
50. Malmsten M, Kumar P, Mittal KL. Microemulsions in pharmaceuticals. In: Handbook of Microemulsion, Science and Technology. Marcel Dekker, Inc., NY, USA; 1999, P. 755–771.
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Authors who publish with this journal agree to the following terms:
- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. that allows others to share the work with an acknowledgment of the work's authorship and initial publication in this journal.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgment of its initial publication in this journal.
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (SeeÂ The Effect of Open Access).