Generic placeholder image

Drug Delivery Letters

Author(s): Deepak Sharma*, Amit Sharma and Rajeev Garg

DOI: 10.2174/2210303109666190529123029

DownloadDownload PDF Flyer Cite As
Preparation, Physicochemical Evaluation and Characterization of Mucoadhesive Buccal Gels Impregnated with Benzydamine Hydrochloride for the Effective Treatment of Aphthous Stomatitis: Effect of Different Grades of HPMC Polymer on In vitro and Ex vivo Performance

Page: [341 - 357] Pages: 17

  • * (Excluding Mailing and Handling)

Abstract

Background: Drug delivery across the buccal mucosal epithelium membrane is one of the promising routes to treat various recurrent ailments of the oral cavity. Aphthous stomatitis is an inflammatory oro-mucosal disorder associated with mucous membranes of mouth, cheek, lips, tongue or gingival region. Benzydamine Hydrochloride was designated as a drug of choice by virtue of its anesthetic, antimicrobial, analgesic, anti-inflammatory and antibacterial action. The medication administration through the buccal route is very testing because of restricted absorption area, shorter residence time and movements of the target region.

Objective: To prepare mucoadhesive buccal gel of Benzydamine Hydrochloride and assess the effects of various HPMC polymer on in vitro and ex vivo performance with the assumption to extend the residence period and achieve maximum drug release in a sustained manner at the target region.

Methods: Mucoadhesive buccal gels were formulated by utilizing various HPMC grades that served as rate controlling and mucoadhesive polymer. A total of 24 preparations were formulated and subjected to physicochemical evaluation and characterization.

Results: It was found that the physicochemical parameters varied according to the polymer type and concentration used. Eight formulations were exposed to ex vivo study by virtue of maximum in vitro permeation and mucoadhesion properties. Because of higher ex vivo drug permeation and mucoadhesion, F24 was considered as the final optimized formulation. FTIR and DSC established compatibility between the drug and excipient. The amorphous nature of the drug within the optimized formulation was further unveiled by XRD study.

Conclusion: The developed buccal gel has a great prospective in contrast to marketed conventional preparation for treating aphthous stomatitis.

Keywords: Benzydamine hydrochloride, aphthous stomatitis, mucoadhesive buccal gel, ex vivo drug permeation, in vitro drug permeation, ex vivo mucoadhesive force, sustained drug delivery.

Graphical Abstract

[1]
Zeng, N.; Dumortier, G.; Maury, M.; Mignet, N.; Boudy, V. Influence of additives on a thermosensitive hydrogel for buccal delivery of salbutamol: relation between micellization, gelation, mechanic and release properties. Int. J. Pharm., 2014, 467(1-2), 70-83.
[http://dx.doi.org/10.1016/j.ijpharm.2014.03.055] [PMID: 24699353]
[2]
Zeng, N.; Seguin, J.; Destruel, P.L.; Dumortier, G.; Maury, M.; Dhotel, H.; Bessodes, M.; Scherman, D.; Mignet, N.; Boudy, V. Cyanine derivative as a suitable marker for thermosensitive in situ gelling delivery systems: In vitro and in vivo validation of a sustained buccal drug delivery. Int. J. Pharm., 2017, 534(1-2), 128-135.
[http://dx.doi.org/10.1016/j.ijpharm.2017.09.073] [PMID: 28982548]
[3]
Hauptstein, S.; Hintzen, F.; Müller, C.; Ohm, M.; Bernkop-Schnürch, A. Development and in vitro evaluation of a buccal drug delivery system based on preactivated thiolated pectin. Drug Dev. Ind. Pharm., 2014, 40(11), 1530-1537.
[http://dx.doi.org/10.3109/03639045.2013.836213] [PMID: 24025071]
[4]
Morales, J.O.; McConville, J.T. Manufacture and characterization of mucoadhesive buccal films. Eur. J. Pharm. Biopharm., 2011, 77(2), 187-199.
[http://dx.doi.org/10.1016/j.ejpb.2010.11.023] [PMID: 21130875]
[5]
Choi, S.G.; Lee, S.E.; Kang, B.S.; Ng, C.L.; Davaa, E.; Park, J.S. Thermosensitive and mucoadhesive sol-gel composites of paclitaxel/dimethyl-β-cyclodextrin for buccal delivery. PLoS One, 2014, 9(9)e109090
[http://dx.doi.org/10.1371/journal.pone.0109090] [PMID: 25275485]
[6]
Nair, A.B.; Kumria, R.; Harsha, S.; Attimarad, M.; Al-Dhubiab, B.E.; Alhaider, I.A. In vitro techniques to evaluate buccal films. J. Control. Release, 2013, 166(1), 10-21.
[http://dx.doi.org/10.1016/j.jconrel.2012.11.019] [PMID: 23219961]
[7]
Ikinci, G.; Şenel, S.; Wilson, C.G.; Şumnu, M. Development of a buccal bioadhesive nicotine tablet formulation for smoking cessation. Int. J. Pharm., 2004, 277(1-2), 173-178.
[http://dx.doi.org/10.1016/j.ijpharm.2003.10.040] [PMID: 15158980]
[8]
Amasya, G.; Karavana, S.Y.; Şen, T.; Baloglu, E.; Tarimci, N. Bioadhesive and mechanical properties of triamcinolone ace-tonide buccal gels. Turk. J. Pharm. Sci., 2012, 9(1), 1-12.
[9]
Pandey, P.; Cabot, P.J.; Wallwork, B.; Panizza, B.J.; Parekh, H.S. Formulation, functional evaluation and ex vivo performance of thermoresponsive soluble gels - A platform for therapeutic delivery to mucosal sinus tissue. Eur. J. Pharm. Sci., 2017, 96, 499-507.
[http://dx.doi.org/10.1016/j.ejps.2016.10.017] [PMID: 27771516]
[10]
Cavallari, C.; Brigidi, P.; Fini, A. Ex-vivoand in-vitro assessment of mucoadhesive patches containing the gel-forming polysaccharide psyllium for buccal delivery of chlorhexidine base. Int. J. Pharm., 2015, 496(2), 593-600.
[http://dx.doi.org/10.1016/j.ijpharm.2015.10.077] [PMID: 26541304]
[11]
Russo, E.; Selmin, F.; Baldassari, S.; Gennari, C.G.M.; Cavigl-ioli, G.; Cilurzo, F.; Minghetti, P.; Parod, B. A focus on muco-adhesive polymers and their application in buccal dosage forms. J. Drug Deliv. Sci. Technol., 2016, 32, 113-125.
[http://dx.doi.org/10.1016/j.jddst.2015.06.016]
[12]
Li, C.L.; Martini, L.G.; Ford, J.L.; Roberts, M. The use of hypromellose in oral drug delivery. J. Pharm. Pharmacol., 2005, 57(5), 533-546.
[http://dx.doi.org/10.1211/0022357055957] [PMID: 15901342]
[13]
Phadtare, D.; Phadtare, N.B.G.; Asawat, M. Hypromellose: A choice of polymer in extended release tablet formulation. World J. Pharm. Pharm. Sci., 2014, 3(9), 551-566.
[14]
Edgar, N.R.; Saleh, D.; Miller, R.A. Recurrent aphthous sto-matitis: A Review. J. Clin. Aesthet. Dermatol., 2017, 10(3), 26-36.
[PMID: 28360966]
[15]
Pfeiffer, D.F.; Powala, C. Methods of treating recurrent aphthous stomatitis. U.S. Patent 20060252731A1 2006.
[16]
Shashy, R.G.; Ridley, M.B. Aphthous ulcers: a difficult clinical entity. Am. J. Otolaryngol., 2000, 21(6), 389-393.
[http://dx.doi.org/10.1053/ajot.2000.18872] [PMID: 11115523]
[17]
Wadhawan, R.; Sharma, S.; Solanki, G.; Vaishnav, R. Alterna-tive medicine for aphthous stomatitis: A review. Int. J. A A Case Rep., 2014, 1(1), 5-10.
[18]
Muñoz-Corcuera, M.; Esparza-Gómez, G.; González-Moles, M.A.; Bascones-Martínez, A. Oral ulcers: clinical aspects. A tool for dermatologists. Part I. Acute ulcers. Clin. Exp. Dermatol., 2009, 34(3), 289-294.
[http://dx.doi.org/10.1111/j.1365-2230.2009.03220.x] [PMID: 19309371]
[19]
Tarakji, B.; Gazal, G.; Al-Maweri, S.A.; Azzeghaiby, S.N.; Alaizari, N. Guideline for the diagnosis and treatment of recurrent aphthous stomatitis for dental practitioners. J. Int. Oral Health, 2015, 7(5), 74-80.
[PMID: 26028911]
[20]
Swain, N.; Pathak, J.; Poonja, L.S.; Penkar, Y. Etiological factors of recurrent aphthous stomatitis: A common perplexi-ty. J. Contemp. Dent., 2012, 2(3), 96-100.
[http://dx.doi.org/10.5005/jp-journals-10031-1019]
[21]
Slebioda, Z.; Szponar, E.; Kowalska, A. Etiopathogenesis of recurrent aphthous stomatitis and the role of immunologic aspects: literature review. Arch. Immunol. Ther. Exp. (Warsz.), 2014, 62(3), 205-215.
[http://dx.doi.org/10.1007/s00005-013-0261-y] [PMID: 24217985]
[22]
Puri, N.; Gill, J.K.; Kaur, H.; Kaur, N.; Kaur, J. Recurrent aphthous stomatitis: Therapeutic management from topicals to systemics. J. Adv. Med. Dent. Sci. Res., 2015, 3(2), 165-170.
[23]
Yildirim, E.; Işik, M.M.; Jain, S.; Sezgin, A.; Karaer, O.; Karasu, T.R.; Yilmaz, K. Stable pharmaceutical combination containing benzydamine. W.O. Patent 2016126217Al 2016.
[24]
Francese, F.; Olden, D. Pharmaceutical compositions containing a benzydamine or its salt and an antimicrobial agent. E. Patent 0812193B1 2002.
[25]
Baloğlu, E.; Karavana, S.Y.; Hyusein, I.Y.; Köse, T. Design and formulation of mebeverine HCl semisolid formulations for intraorally administration. AAPS PharmSciTech, 2010, 11(1), 181-188.
[http://dx.doi.org/10.1208/s12249-009-9374-3] [PMID: 20101482]
[26]
Parashar, B.; Kabra, A.; Chandel, A. Formulation and evalua-tion of gel containing miconazole nitrate an antifungal agent. Int. J. Pharm. Res. Rev., 2013, 2(6), 18-28.
[27]
Suresh, P.K.; Manhar, S. Bioadhesive buccal gels impregnated with fluconazole: formulation; in vitro and ex vivo characterization. J. Appl. Pharm. Sci, 2014, 4(3), 015-019.
[28]
Rai, V.K.; Yadav, N.P.; Sinha, P.; Mishra, N.; Luqman, S.; Dwivedi, H.; Kymonil, K.M.; Saraf, S.A. Development of cellulosic polymer based gel of novel ternary mixture of miconazole nitrate for buccal delivery. Carbohydr. Polym., 2014, 103, 126-133.
[http://dx.doi.org/10.1016/j.carbpol.2013.12.019] [PMID: 24528709]
[29]
Karade, P.G.; Shah, R.R.; Chougule, D.D.; Bhise, S.B. Formu-lation and evaluation of celecoxib gel. J. Drug Deliv. Thera-peut., 2012, 2(3), 132-135.
[30]
Harish, N.M.; Prabhu, P.; Charyulu, R.N.; Gulzar, M.A.; Subrahmanyam, E.V.S. Formulation and evaluation of in situ gels containing clotrimazole for oral candidiasis. Indian J. Pharm. Sci., 2009, 71(4), 421-427.
[http://dx.doi.org/10.4103/0250-474X.57291] [PMID: 20502548]
[31]
Chatterjee, A.; Bhowmik, B.B.; Thakur, Y.S. Formulation; In vitro and in vivo pharmacokinetics of anti-HIV vaginal bio-adhesive gel. J. Young Pharm., 2011, 3(2), 83-89.
[http://dx.doi.org/10.4103/0975-1483.80290] [PMID: 21731351]
[32]
Sharma, D.; Singh, R.; Garg, R. Development and validation of stability indicating UV spectro-photometric method for the estimation of benzydamine hydrochloride in bulk and in pharmaceutical dosage form: A novel analytical technique for conducting in-vitro quality control tests. Int. J. Pharm. Sci. Res., 2018, 9(2), 678-686.
[33]
Helal, D.A.; El-Rhman, D.A.B.D.; Abdel-Halim, S.A.; El-Nabarawi, M.A. Formulation and evaluation of fluconazole topical gel. Int. J. Pharm. Pharm. Sci., 2012, 4(5), 176-183.
[34]
Kumar, L.; Verma, R. In vitro evaluation of topical gel pre-pared using natural polymer. Int. J. Drug Deliv., 2010, 2, 58-63.
[http://dx.doi.org/10.5138/ijdd.2010.0975.0215.02012]
[35]
Baibhav, J.; Singh, G.; Rana, A.C.; Saini, S.; Singla, V. Emulgel: A comprehensive review on the recent advances in topical drug delivery. Int. Res. J. Pharm., 2011, 2(1), 66-70.
[36]
Shelke, S.; Shahi, S.; Jalalpure, S.; Dhamecha, D.; Shengule, S. Formulation and evaluation of thermoreversible mucoad-hesive in-situ gel for intranasal delivery of naratriptan hydro-chloride. J. Drug Deliv. Sci. Technol., 2015, 29, 238-244.
[http://dx.doi.org/10.1016/j.jddst.2015.08.003]
[37]
Galgatte, U.C.; Kumbhar, A.B.; Chaudhari, P.D. Development of in situ gel for nasal delivery: design, optimization, in vitro and in vivo evaluation. Drug Deliv., 2014, 21(1), 62-73.
[http://dx.doi.org/10.3109/10717544.2013.849778] [PMID: 24191774]
[38]
Shah, R.A.; Mehta, M.R.; Patel, D.M.; Patel, C.N. Design and optimization of mucoadhesive nasal in situ gel containing so-dium cromoglycate using factorial design. Asian J. Pharm., 2011, 5(2), 65-74.
[http://dx.doi.org/10.4103/0973-8398.84546]
[39]
Parmar, V.J.; Lumbhani, A.N. Formulation and development of thermoreversible mucoadhesive intranasal in situ Hydrogel by using a combination of polymers. Bullet. Pharm. Res., 2012, 2(3), 167-174.
[40]
Chaudhary, B.; Verma, S. Preparation and evaluation of novel in situ gels containing acyclovir for the treatment of oral herpes simplex virus infections. ScientificWorldJournal, 2014.2014280928
[http://dx.doi.org/10.1155/2014/280928] [PMID: 24790559]
[41]
Kaur, P.; Garg, V.; Bawa, P.; Sharma, R.; Singh, S.K.; Kumar, B.; Gulati, M.; Pandey, N.K.; Narang, R.; Wadhwa, S.; Mohan-ta, S.; Jyoti, J.; Som, S. Formulation; systematic optimization; in vitro; ex vivo; and stability assessment of transethosome based gel of curcumin. Asian J. Pharm. Clin. Res., 2018, 11(2), 41-47.
[http://dx.doi.org/10.22159/ajpcr.2018.v11s2.28563]
[42]
Pandya, K.; Agrawal, P.; Dashora, A.; Sahu, D.; Garg, R.; Pareta, K.L.; Menaria, M.; Joshi, B. Formulation and evalua-tion of oral floatable in-situ gel of ranitidine hydrochloride. J. Drug Deliv. Ther., 2013, 3(3), 90-97.
[http://dx.doi.org/10.22270/jddt.v3i3.516]
[43]
Bhoyar, B.S.; Patil, A.T. Formulation and evaluation of oph-thalmic gel based on drug-polymer-polymer ternary interac-tion. Asian J. Pharm. Clin. Res., 2015, 8(3), 283-288.
[44]
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.
[http://dx.doi.org/10.4103/2230-973X.108961] [PMID: 23799203]
[45]
Dhiman, M.; Yedurkar, P.; Sawant, K.K. Formulation, characterization, and in vitro evaluation of bioadhesive gels containing 5-Fluorouracil. Pharm. Dev. Technol., 2008, 13(1), 15-25.
[http://dx.doi.org/10.1080/10837450701702438] [PMID: 18300096]
[46]
Bhabani Shankar, N.; Prasant Kumar, R.; Udaya Kumar, N.; Benoy Brata, B. Development and characterization of bioadhesive gel of microencapsulated metronidazole for vaginal use. Iran. J. Pharm. Res., 2010, 9(3), 209-219.
[PMID: 24363730]
[47]
Singh, K.P.; Chhabra, G.; Sharma, V.; Pathak, K. Thermosensitive periodontal sol of ciprofloxacin hydrochloride and serratiopeptidase: Pharmaceutical and mechanical analysis. Int. J. Pharm. Investig., 2014, 4(1), 5-14.
[http://dx.doi.org/10.4103/2230-973X.127734] [PMID: 24678456]
[48]
Yadav, J.D.; Kunjwani, H.K.; Suryawanshi, S.S. Formulation and evaluation of thermosensitive in situ gel of salbutamol sulphate for nasal drug delivery system. Int. J. Pharm. Pharm. Sci., 2012, 4(4), 188-194.
[49]
Pandit, A.P.; Vaibhav, V. Pol; Vinit S. Kulkarni, V.S. Xyloglu-can based in situ gel of lidocaine HCl for the treatment of periodontosis. J. Pharm. (Cairo), 2016, 1-9.
[http://dx.doi.org/10.1155/2016/3054321]
[50]
Ghori, M.U.; Grover, L.M.; Asare-Addo, K.; Smith, A.M.; Conway, B.R. Evaluating the swelling, erosion, and compaction properties of cellulose ethers. Pharm. Dev. Technol., 2018, 23(2), 183-197.
[http://dx.doi.org/10.1080/10837450.2017.1389958] [PMID: 28985687]
[51]
Peh, K.K.; Wong, C.F. Polymeric films as vehicle for buccal delivery: Swelling, mechanical, and bioadhesive properties. J. Pharm. Pharm. Sci., 1999, 2(2), 53-61.
[PMID: 10952770]
[52]
Abu-Huwaij, R.; Assaf, S.; Salem, M.; Sallam, A. Mucoadhesive dosage form of lidocaine hydrochloride: I. Mucoadhesive and physicochemical characterization. Drug Dev. Ind. Pharm., 2007, 33(8), 855-864.
[http://dx.doi.org/10.1080/03639040701377516] [PMID: 17729103]
[53]
Peddapalli, H.; Ganta, R.P.; Boggula, N. Formulation and evaluation of transdermal patches for antianxiety drug. Asian J. Pharm., 2018, 12(2), 127-136.
[54]
Bodmeier, R.; Paeratakul, O. Evaluation of drug-containing polymer films prepared from aqueous latexes. Pharm. Res., 1989, 6(8), 725-730.
[http://dx.doi.org/10.1023/A:1015950825398] [PMID: 2813266]
[55]
Trastullo, R.; Abruzzo, A.; Saladini, B.; Gallucci, M.C.; Cerchiara, T.; Luppi, B.; Bigucci, F. Design and evaluation of buccal films as paediatric dosage form for transmucosal delivery of ondansetron. Eur. J. Pharm. Biopharm., 2016, 105, 115-121.
[http://dx.doi.org/10.1016/j.ejpb.2016.05.026] [PMID: 27267732]
[56]
Pathan, I.B.; Mene, H.; Bairagi, S. Quality by design (QbD) approach to formulate in situ gelling system for nose to brain delivery of fluoxetine hydrochloride: Ex-vivo and In-vivo study. Ars Pharm., 2017, 58(3), 107-114.
[57]
Meher, J.G.; Tarai, M.; Patnaik, A.; Mishra, P.; Yadav, N.P. Cellulose buccoadhesive film bearing glimepiride: Physi-comechanical characterization and biophysics of buccoadhe-sion. AAPS PharmSciTech, 2016, 17(4), 940-950.
[http://dx.doi.org/10.1208/s12249-015-0419-5] [PMID: 26831445]
[58]
Patel, D.P.; Setty, C.M.; Mistry, G.N.; Patel, S.L.; Patel, T.J.; Mistry, P.C.; Rana, A.K.; Patel, P.K.; Mishra, R.S. Development and evaluation of ethyl cellulose-based transdermal films of furosemide for improved in vitro skin permeation. AAPS PharmSciTech, 2009, 10(2), 437-442.
[http://dx.doi.org/10.1208/s12249-009-9224-3] [PMID: 19381831]
[59]
Bose, P.S.C.; Reddy, P.S.; Ravi, V.; Sarita, D.; Kumar, T.M.P. Formulation and evaluation of sustained release floating tab-lets of diltiazem HCl using xanthan gum. Res. J. Pharm. Biol. Chem. Sci., 2011, 2, 319-328.
[60]
Rana, P.; Murthy, R.S.R. Formulation and evaluation of mucoadhesive buccal films impregnated with carvedilol nanosuspension: a potential approach for delivery of drugs having high first-pass metabolism. Drug Deliv., 2013, 20(5), 224-235.
[http://dx.doi.org/10.3109/10717544.2013.779331] [PMID: 23651066]
[61]
Nath, J. Veda, Hari, B.N.; Devi, D.R. Implantable vaginal drug delivery system of zidovudine for site specific activity. Asian J Pharm., 2013, 7(3), 140-150.
[http://dx.doi.org/10.4103/0973-8398.120089]