Formulation and optimization of gellan gum-poloxamer based dexamethasone mucoadhesive in situ gel

Abstract

The main objective of the present study was to formulate and evaluate mucoadhesive in situ buccal gels of dexamethasone based on gellan gum-poloxamer 407. Formulations were characterized for gelling capacity, drug content, pH, viscosity, rheological studies, mechanical studies and in vitro drug release. The drug content, clarity and pH of the formulations were found to be satisfactory. Mucoadhesive in situ gels showed thermoresponsive behavior, existing as a liquid at room temperature and gel at 30–37ºC. Formulations exhibited pseudoplastic flow and typical gel-type mechanical spectra (G′ > G″) at different frequecy values and 37ºC. Prepared gels resulted in preparations with desirable rheological features as well as texture (appropriate hardness, compressibility, adhesiveness, cohesiveness and elasticity) properties, which could benefit the therapeutic efficacy, by increasing the residence time and easiness for local application on the buccal mucosa. Additionally, the developed preparations exhibited sustained drug release up to 72 h as intended for these systems. Optimized formulation containing 14% w/v poloxamer 407 and 0.4% w/v gellan gum exhibited desired characteristics (mechanical and rheological properties) for developing buccal drug delivery systems. Thus, buccal dexamethasone loaded mucoadhesive in situ gel was found to be a promising formulation.

Keywords

• Dexamethasone
• gellan gum
• poloxamer
• in situ gel
• buccal drug delivery

References

1. [1] Yakubov GE, Gibbins H, Proctor GB, Carpenter GH. Oral mucosa: physiological and physicochemical aspects. In: Khutoryanskiy VV. (Eds). Mucoadhesive Materials and Drug Delivery Systems. John Wiley & Sons. 35, Chichester, West Sussex, UK, 2014, chapter 1. [CrossRef]
2. [2] Sankar V, Hearnden V, Hull K, Juras DV, Greenberg M, Kerr A, Lockhart PB, Patton LL, Porter S, Thornhill M. Local drug delivery for oral mucosal diseases: Challenges and opportunities. Oral Dis. 2011; 17(1): 73-84. [CrossRef]
3. [3] Silva AC, Santos D, Ferreira D, Lopes CM. Lipid-based nanocarriers as an alternative for oral delivery of poorly water-soluble drugs: Peroral and mucosal routes. Curr Med Chem. 2012; 19: 4495-4510. [CrossRef]
4. [4] Shojaei AH. Buccal mucosa as a route for systemic drug delivery: A review. J Pharm Pharm Sci. 1998; 1: 15–30.
5. [5] Hearnden V, Sankar V, Hull K, Juras DV, Greenberg M, Kerr AR, Lockhart PB, Patton LL, Porter S, Thornhill MH. New developments and opportunities in oral mucosal drug delivery for local and systemic disease. Adv Drug Deliv Rev. 2012; 64(1): 16–28. [CrossRef]
6. [6] Almeida H, Amaral MH, Lobao P, Sousa Lobo JM. In situ gelling systems: a strategy to improve the bioavailability of ophthalmic pharmaceutical formulations. Drug Discov Today. 2014; 19(4): 400-412. [CrossRef]
7. [7] Dhir S, Saffi KA, Kamalpuria N, Mishra D. An overview of in situ gelling system. Int J Pharm Life Sci. 2016; 7(8): 5135-5156.
8. [8] Saviola G, Bonazzi S, Comini L, Abdi-Ali L. Dexamethasone is an “essential medicine”. It is time to consider this drug in the treatment of rheumatic diseases. A narrative review. Acta Medica Mediterr. 2020; 36: 107-114. [CrossRef]

9. [9] Ruan JY, Li D, Tao H, Chunni D. Effects of dexamethasone on the EGF mRNA levels and inflammatory factors in rabbits with oral ulcers. Pharm Bioprocess. 2018; 6(3): 119-125.
10. [10] Zhang C, Liu Y, Li W, Gao P, Xiang D, Ren X, Liu D. Mucoadhesive buccal film containing ornidazole and dexamethasone for oral ulcers: In vitro and in vivo studies. Pharm Dev Tech. 2019; 24(1): 118-126. [CrossRef]
11. [11] Miyazaki S, Tobiyama T, Takada M, Attwood D. Percutaneous absorption of indomethacin from pluronic F-127 gels in rats. J Pharm Pharmacol. 1995; 47: 455-457. [CrossRef]
12. [12] Üstündağ Okur N, Yoltaş A, Yozgatlı V. Development and characterization of voriconazole loaded in situ gel formulations for ophthalmic application. Turk J Pharm Sci. 2016; 13(3): 311-317.
13. [13] Desai SD, Blanchard J. Evaluation of pluronic F127-based sustained-release ocular delivery systems for pilocarpine using the albino rabbit eye model. J Pharm Sci. 1998; 87: 1190-1195. [CrossRef]
14. [14] Osmałek T, Froelich A, Tasarek S. Application of gellan gum in pharmacy and medicine. Int J Pharm. 2014; 466(1-2): 328–340. [CrossRef]
15. [15] Oliveira JT, Martins L, Picciochi R, Malafaya PB, Sousa RA, Neves NM, Mano JF, Reis RL. Gellan gum: A new biomaterial for cartilage tissue engineering applications. J Biomed Mater Res A. 2010; 93: 852-863. [CrossRef]
16. [16] Silva-Correia J, Oliveira JM, Caridade SG, Oliveira JT, Sousa RA, Mano JF, Reis RL. Gellan gum-based hydrogels for intervertebral disc tissueengineering applications. J Tissue Eng Regen Med. 2011; 5(6): e97-e107. [CrossRef]
17. [17] Rençber S, Aydın Köse F, Karavana SY. Dexamethasone loaded PLGA nanoparticles for potential local treatment of oral precancerous lesions. Pharm Dev Tech. 2020; 25(2): 149-158. [CrossRef]
18. [18] Elmowafy E, Cespi M, Bonacucina G, Soliman ME. In situ composite ion-triggered gellan gum gel incorporating amino methacrylate copolymer microparticles: A therapeutic modality for buccal applicability. Pharm Dev Tech. 2019; 24(10): 1258-1271. [CrossRef]
19. [19] Baloglu E, Karavana SY, Ay Senyigit Z, Guneri T. Rheological and mechanical properties of poloxamer mixtures as a mucoadhesive gel base. Pharm Dev Tech. 2011; 16(6): 627-636. [CrossRef]
20. [20] Garala K, Joshi P, Shah M, Ramkishan A, Patel J. Formulation and evaluation of periodontal in situ gel. Int J Pharm Investig. 2013; 3(1): 29-41. [CrossRef]
21. [21] Gousia Begum S, Sekar M. Formulation and evaluation of tinidazole mucoadhesive buccal gels. Int J Pharm Bio Sci. 2017; 8(2): 48-55. [CrossRef]
22. [22] Rençber S, Karavana SY, Ay Şenyigit Z, Eraç B, Hoşgör Limoncu M, Baloğlu E. Mucoadhesive in situ gel formulation for vaginal delivery of clotrimazole: Formulation, preparation and in vitro/in vivo evaluation. Pharm Dev Tech. 2017; 22(4): 551-561. [CrossRef]
23. [23] Chang JY, Oh YK, Choi H, Kim YB, Kim CK. Rheological evaluation of thermosensitive and mucoadhesive vaginal gels in physiological conditions. Int J Pharm. 2002; 241: 155-163. [CrossRef]
24. [24] Estanqueiro M, Amaral MH, Sousa Lobo JM. Comparison between sensory and instrumental characterization of topical formulations: Impact of thickening agents. Int J Cosmet Sci. 2016; 38: 389-398. [CrossRef]
25. [25] Silva AC, Amaral MH, Gonzalez-Mira E, Santos D, Ferreira D. Solid lipid nanoparticles (SLN)–based hydrogels as potential carriers for oral transmucosal delivery of risperidone: preparation and characterization studies. Colloids Surf B Biointerfaces. 2012; 93: 241-248. [CrossRef]
26. [26] Sapra P, Patel D, Soniwala M, Chavda J. Development and optimization of in situ periodontal gel containing Levofloxacin for the treatment of periodontal diseases. J Sci Innov Res. 2013; 2(3): 607-626.
27. [27] Jones DS, Woolfson AD, Brown AF, Coulter WA, McClelland C, Irwin CR. Design, characterisation and preliminary clinical evaluation of a novel mucoadhesive topical formulation containing tetracycline for the treatment of periodontal disease. J Control Release. 2000; 67: 357-368. [CrossRef]
28. [28] Stein GE, Mummaw N. Placebo-controlled trial of itraconazole for treatment of acute vaginal candidiasis. Antimicrob Agents Chemother. 1993; 37: 89-92. [CrossRef]
29. [29] Ustundag Okur N., Yozgatlı V., Senyigit Z. Formulation and detailed characterization of voriconazole loaded in situ gels for ocular application. J Fac Pharm Ankara. 2020; 44(1): 33-49. [CrossRef]
30. [30] Karavana SY, Gökçe EH, Rençber S, Özbal S, Pekçetin Ç, Güneri P, Ertan G.A new approach to the treatment of recurrent aphthous stomatitis with bioadhesive gels containing cyclosporine a solid lipid nanoparticles: In Vivo/in vitro examinations. Int J Nanomedicine. 2012; 7: 5693-5704. [CrossRef]
31. [31] Swain GP, Patel S, Gandhi J, Shah P. Development of moxifloxacin hydrochloride loaded in-situ gel for the treatment of periodontitis: in-vitro drug release study and antibacterial activity. J Oral Biol Craniofac Res. 2019; 9: 190-200. [CrossRef]
32. [32] De Souza Ferreira SB, Moço TD, Borghi-Pangoni FB, Junqueira MV, Bruschi ML. Rheological, mucoadhesive and textural properties of thermoresponsive polymer blends for biomedical applications. J Mech Behav Biomed Mater. 2015; 55: 164-178. [CrossRef]
33. [33] Carvalho FC, Bruschi ML, Evangelista RC, Gremião MPD. Mucoadhesive drug delivery systems. Braz J Pharm Sci. 2010; 46: 1-18. [CrossRef]
34. [34] Jones DS, Woolfson AD, Brown AF. Textural, viscoelastic and mucoadhesive properties of pharmaceutical gels composed of cellulose polymers. Int J Pharm. 1997; 151: 223-233. [CrossRef]
35. [35] Bruschi ML, Jones DS, Panzeri H, Gremião MPD, Freitas O, Lara EHG. Semisolid systems containing propolis for the treatment of periodontal disease: In vitro realease kinetics, syringeability, rheological, textural and mucoadhesive properties. J Pharm Sci. 2007; 99: 4215–4227. [CrossRef]
36. [36] De Souza Ferreira SB, Bassi da Silva J, Borghi-Pangoni FB, Junqueira MV, Bruschi ML. Linear correlation between rheological, mucoadhesive and textural properties of thermoresponsive polymer blends for biomedical applications. J Mech Behav Biomed Mater. 2017; 68: 265-275. [CrossRef]
37. [37] Jones DS, Woolfson AD, Djokic J, Coulter WA. Development and mechanical characterization of bioadhesive semisolid, polymeric systems containing tetracycline for the treatment of periodontal diseases. Pharm Res. 1996; 13: 1734-1738. [CrossRef]
38. [38] Cevher E, Taha MAM, Orlu M, Araman A. Evaluation of mechanical and mucoadhesive properties of clomiphene citrate gel formulations containing carbomers and their thiolated derivatives. Drug Deliv. 2008, 15(1): 57-67. [CrossRef]
39. [39] Tan YTF, Peh KK, Al-Hanbali O. Effect of carbopol and polyvinylpyrrolidone on the mechanical, rheological and release properties of bioadhesive polyethylene glycol gels. AAPS PharmSciTech. 2000; 1: 1-10. [CrossRef]
40. [40] Esposito E, Menegatti E, Cortesi R. Hyaluronan-based microspheres as tools for drug delivery: A comparative study. Int J Pharm. 2005; 288: 35-49. [CrossRef]
41. [41] Karavana SY, Ay Senyigit Z, Hilmioglu-Polat S, Metin DY, Zekioglu O, Baloglu E. Mucoadhesive in situ gel formulations of miconazole nitrate for the treatment of mucosal candidiasis. Lat Am J Pharm. 2012; 31: 821–829.
42. [42] Ay Senyigit Z, Karavana SY, Eraç B, Gursel O, Hosgor Limoncu M, Baloglu E. Evaluation of chitosan based vaginal bioadhesive gel formulations for antifungal drugs. Acta Pharm. 2014; 64: 139–156. [CrossRef]
43. [43] Tas C, Özkan Y, Savaser A, Baykara T. In vitro release studies of chlorpheniramine maleate from gels prepared by different cellulose derivatives. Il Farmaco. 2003; 58: 605-611. [CrossRef]
44. [44] Cavallari C, Fini A, Ospitali F. Mucoadhesive multiparticulate patch for the intrabuccal controlled delivery of lidocaine. Eur J Pharm Biopharm. 2013; 83(3): 405-14. [CrossRef]
45. [45] Cao SL, Zhang QZ, Jiang XG. Preparation of ion-activated in situ gel systems of scopolamine hydrobromide and evaluation of its antimotion sickness efficacy. Acta Pharmacol Sin. 2007; 28(4): 584-90. [CrossRef]
46. [46] Karavana SY, Rençber S, Ay Şenyiğit Z, Baloğlu E. A new in-situ gel formulation of itraconazole for vaginal administration. Pharmacol Pharm. 2012; 3: 417-426. [CrossRef]
47. [47] Goyal RN, Gupta VK, Chatterjee S. Fullerene-C60-modified edge plane pyrolytic graphite electrode for the determination of dexamethasone in pharmaceutical formulations and human biological fluids. Biosens Bioelectron. 2009; 24(6): 1649-1654. [CrossRef]
48. [48] Desai UH, Patwari AH, Maradiya JK, Sathawara MK, Suhagia BN, Rathod IS. RP-HPLC method for simultaneous estimation of ciprofloxacin and dexamethasone in eye/ear drops. Int J Pharm Sci Res. 2013; 5(2): 62-66.
49. [49] International Conference on Harmonisation (ICH) (2005) [Online] http://www.ich.org/LOB/media/MEDIA417.pdf.
50. [50] Sandri G, Rossi S, Ferrari F, Bonferonia MC, Muzzarelli C, Caramella C. Assessment of chitosan derivatives as buccal and vaginal penetration enhancers. Eur J Pharm Sci. 2004; 21: 351-359. [CrossRef]
51. [51] Andrews GP, Gorman SP, Jones DS. Rheological characterisation of primary and binary interactive bioadhesive gels composed of cellulose derivatives designed as ophthalmic viscosurgical devices. Biomater. 2005; 26(5): 571-580. [CrossRef]
52. [52] Andrews GP, Jones DS. Rheological characterization of bioadhesive binary polymeric systems designed as platforms for drug delivery implants. Biomacromolecules. 2006; 7: 899-906. [CrossRef]