• Dalia M. Elbehairy Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Ain Shams University, Egypt, PO box: 11566
  • Rihab Osman
  • Omaima Sammour


Objective: Preparation and characterization of inhalable taste masked microparticles (MPs) loaded with the anti-asthmatic bitter drug, ketotifen (KT).

Methods: MPs were prepared by a spray-drying technique. The effects of addition of different excipients namely: mannitol, leucine and hyaluronic acid (HA) on the physicochemical properties of KT spray dried powders were determined. Powder taste was evaluated on volunteers. DSC and x-ray diffraction were done to investigate thermal and crystallographic properties of the powders. The surface morphology and shape of KT-loaded hyaluronic acid MPs were examined using scanning electron microscope, in vitro pulmonary deposition and inhalation indices were determined using a twin stage glass impinger (TSI).

Results: Leucine improved the powder flow properties. Mannitol, at all tested ratios, produced brownish discoloration in spray dried powders (SDP) upon storage even in dessicator. At a drug to HA ratio of 1:2, the bitter taste of KT had significantly improved besides obtaining a high respirable particle fraction. This selected ratio showed good physicochemical stability for up to 9 mo.

Conclusion: The developed KT spray dried particles may offer a good platform for the targeted pulmonary delivery of the drug overcoming the major biological barriers.

Keywords: Ketotifen, Microparticles, Pulmonary delivery, Hyaluronic acid, Taste masking, Spray drying


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Byron P, Patton J. Drug delivery via the respiratory tract. J Aerosol Med 1994;7:49-75.

Clarke C, May C. A comparison of the efficacy of ketotifen (HC 20-511) with sodium cromoglycate (SCG) in skin test positive asthma. Br J Clin Pharmacol 1980;10:473-6.

Jayaram L, Pizzichini M, Cook RJ, Boulet LP, Lemiere C, Pizzichini E, et al. Determining asthma treatment by monitoring sputum cell counts effect on exacerbations. Eur Respir J 2006;27:483-94.

Dyson A, Mackay A. Ketotifen in adult asthma. Br Med J 1980;280:360-1.

Bustos G, Bustos D, Romero O. Prevention of asthma with ketotifen in preasthmatic children: a three-year follow-up study. Clin Exp Allergy 1995;25:568-73.

Guerrero S, Muniz E, Teijon C, Olmo R, Teijon J, Blanco M. Ketotifen-loaded microspheres prepared by spray-drying poly(D,L-lactide) and poly(D,L-lactide-co-glycolide) polymers: characterization and in vivo evaluation. J Pharm Sci 2008;97:3153-69.

Tinkelman D, Moss B, Bukantz S, Sheffer A, Dobken J, Chodosh S, et al. A multicenter trial of the prophylactic effect of ketotifen, theophylline, and placebo in atopic asthma. J Allergy Clin Immunol 1985;76:487-97.

Schwarzer G, Bassler D, Mitra A, Ducharme F, Forster J. Ketotifen alone or as additional medication for long-term control of asthma and wheeze in children. Cochrane Database Systematic Rev 2004:CD001384.

Daniher D, Zhu J. Dry powder platform for pulmonary drug delivery. Particuology 2008;6:225-38.

Zhu B, Haghi M, Nguyen A, Goud M, Yeung S, Young PM, et al. Delivery of theophylline as dry powder for inhalation. Asian J Pharm Sci 2015;10:520-7.

Yang W, Peters J, Williams R. Inhaled nanoparticles--a current review. Int J Pharm 2008;356:239-47.

Hewett P. The particle size distribution, density, and specific surface area of welding fumes from SMAW and GMAW mild and stainless steel consumables. Am Ind Hyg Assoc J 1995;56:128-35.

Qian Y, Willeke K, Grinshpun S, Donnelly J, Coffey C. Performance of N95 respirators: filtration efficiency for airborne microbial and inert particles. Am Ind Hyg Assoc J 1998;59:128-32.

Mobley C, Hochhaus G. Methods used to assess pulmonary deposition and absorption of drugs. Drug Discovery Today 2001;6:367-75.

Roa W, Azarmi S, Al-Hallak M, Finlay W, Magliocco A, Lobenberg R. Inhalable nanoparticles, a non-invasive approach to treat lung cancer in a mouse model. J Controlled Release 2011;150:49-55.

Evora C, Soriano I, Rogers R, Shakesheff K, Hanes J, Langer R. Relating the phagocytosis of microparticles by alveolar macrophages to surface chemistry: the effect of 1,2-dipalmitoylphosphatidylcholine. J Controlled Release 1998;51:143-52.

Weingart J, Vabbilisetty P, Sun X. Membrane-mimetic surface functionalization of nanoparticles: Methods and applications. Adv Colloid Interface Sci 2013;197:68-84.

Roa WH, Azarmi S, Al-Hallak M, Finlay W, Magliocco A, Lobenberg R. Inhalable nanoparticles, a non-invasive approach to treat lung cancer in a mouse model. J Controlled Release 2011;150:49-55.

Ito M, Ikehama K, Yoshida K, Haraguchi T, Yoshida M, Wada K, et al. Bitterness prediction of H1-antihistamines and prediction of masking effects of artificial sweeteners using an electronic tongue. Int J Pharm 2013;441:121-7.

Wu L, Miao X, Shan Z, Huang Y, Li L, Pan X, et al. Studies on the spray dried lactose as carrier for dry powder inhalation. Asian J Pharm Sci 2014;9:336-41.

Mishra M, Mishra B. Mucoadhesive microparticles as potential carriers in inhalation delivery of doxycycline hyclate: a comparative study. Acta Pharm Sin B 2012;2:518-26.

Fatnassi M, Jacquart S, Brouillet F, Rey C, Combes C, Girod S. Optimization of spray-dried hyaluronic acid microspheres to formulate drug-loaded bone substitute materials. Powder Technol 2014;255:44-51.

Polexe R, Delair T. Elaboration of stable and antibody functionalized positively charged colloids by polyelectrolyte complexation between chitosan and hyaluronic acid. Molecules 2013;18:8563-78.

Iskandar F, Nandiyanto A, Widiyastuti W, Young L, Okuyama K, Gradon L. Production of morphology-controllable porous hyaluronic acid particles using a spray-drying method. Acta Biomater 2009;5:1027-34.

Cantor J. Potential therapeutic applications of hyaluronan in the lung. Int J Chronic Obstruct Pulm Dis 2007;2:283-8.

Osman R, Kan P, Awad G, Mortada N, El-Shamy A, Alpar O. Spray dried inhalable ciprofloxacin powder with improved aerosolization and antimicrobial activity. Int J Pharm 2013;449:44-58.

Puttewar T, Kshirsagar M, Chandewar A, Chikhale R. Formulation and evaluation of orodispersible tablet of taste masked doxylamine succinate using ion exchange resin. J King Saud Univ Sci 2010;22:229-40.

Awasthi R, Kulkarni G. Development, and characterization of amoxicillin loaded floating micro balloons for the treatment of Helicobacter pylori-induced gastric ulcer. Asian J Pharmacol 2013;8:174-80.

Shah P, Mashru R. Formulation and evaluation of taste masked oral reconstitute suspension of primaquine phosphate. AAPS PharmSciTech 2008;9:1025-30.

Oskouie A, Noll K, Wang H. Minimizing the effect of density in the determination of aerodynamic particle diameter using a time of flight instrument. J Aerosol Sci 2003;34:501-6.

Sung J, Pulliam B, Edwards D. Nanoparticles for drug delivery to the lungs. Trends Biotechnol 2007;25:563-70.

Gervelas C, Serandour A, Geiger S, Grillon G, Fritsch P, Taulelle C, et al. Direct lung delivery of a dry powder formulation of DTPA with improved aerosolization properties: effect on lung and systemic decorporation of plutonium. J Controlled Release 2007;118:78-86.

Kawashima Y, Serigano T, Hino T, Yamamoto H, Takeuchi H. Effect of surface morphology of carrier lactose on dry powder inhalation property of pranlukast hydrate. Int J Pharm 1998;172:179-88.

Moreira G, Maia M, Souza A, Brito E, Medeiros M, Azeredo H. Physical properties of spray dried acerola pomace extract as affected by temperature and drying aids. LWT-Food Sci Technol 2009;42:641-5.

Wu Y, Levons J, Narang A, Raghavan K, Rao V. Reactive impurities in excipients: profiling, identification and mitigation of drug–excipient incompatibility. AAPS PharmSciTech 2011;12:1248-63.

Sinsuebpol C, Chatchawalsaisin J, Kulvanich P. Preparation and in vivo absorption evaluation of spray-dried powders containing salmon calcitonin loaded chitosan nanoparticles for pulmonary delivery. Drug Des Dev Ther 2013;7:861-73.

Seville P, Learoyd T, Li H, Williamson I, Birchall J. Amino acid-modified spray-dried powders with enhanced aerosolisation properties for pulmonary drug delivery. Powder Technol 2007;178:40-50.

Ros M, Casciaro R, Lucca F, Troiani P, Salonini E, Favilli F, et al. Hyaluronic acid improves the tolerability of hypertonic saline in the chronic treatment of cystic fibrosis patients: a multicenter, randomized, controlled clinical trial. J Aerosol Med Pulm Drug Delivery 2014;27:133-7.

Maiz Carro L, Lamas Ferreiro A, Ruiz de Valbuena Maiz M, Wagner Struwing C, Gabilondo Alvarez G, Suarez Cortina L. [Tolerance of two inhaled hypertonic saline solutions in patients with cystic fibrosis]. Med Clin (Barc) 2012;138:57-9.

Fernandez Tena A, Casan Clara P. Deposition of inhaled particles in the lungs. Arch Bronconeumol 2012;48:240-6.

Hastedt J, Cabot K, Gong D, Hester D. Storage stable powder compositions of the interleukin-4 receptor. US Google Patents US7449201, B2; 2008.

Woo JS, Piao MG, Li DX, Ryu DS, Choi JY, Kim JA, et al. Development of cyclosporin A-loaded hyaluronic microsphere with enhanced oral bioavailability. Int J Pharm 2007;345:134-41.

Piao MG, Kim JH, Kim JO, Lyoo WS, Lee MH, Yong CS, et al. Enhanced oral bioavailability of piroxicam in rats by hyaluronate microspheres. Drug Dev Ind Pharm 2007;33:485-91.

Abd El-Bary A, Salem H, Kharshoum R. 2-Hydroxypropyl-ß-Cyclodextrin complex with ketotifen fumarate for eye drops preparations. Drug Delivery 2011;3:13.

Fahmy R, Badr-Eldin S. Novel delivery approach for ketotifen fumarate: dissofilms formulation using 3 experimental design: in vitro/in vivo evaluation. Pharm Dev Technol 2014;19:521-30.

Luo Y, Kirker K, Prestwich G. Cross-linked hyaluronic acid hydrogel films: new biomaterials for drug delivery. J Controlled Release 2000;69:169-84.

Adhikari S, Kar T. Bulk single crystal growth and characterization of l-leucine–A nonlinear optical material. Mater Chem Phys 2012;133:1055-9.

El-Gendy N, Gorman E, Munson E, Berkland C. Budesonide nanoparticle agglomerates as dry powder aerosols with rapid dissolution. J Pharm Sci 2009;98:2731-46.



How to Cite

Elbehairy, D. M., R. Osman, and O. Sammour. “INHALED TASTE MASKED SPRAY DRIED KETOTIFEN MICROPARTICLES: FORMULATION, CHARACTERIZATION AND IN VITRO PULMONARY DEPOSITION”. International Journal of Pharmacy and Pharmaceutical Sciences, vol. 8, no. 6, June 2016, pp. 166-74,



Original Article(s)