Formulation and physicochemical characterization of azithromycin-loaded cubosomes

Hoorieh Zaker, Somayeh Taymouri , Abolfazl Mostafavi


Background and purpose: Azithromycin (AZ) is a macrolide antibiotic that is soluble in saliva pH; its bitter taste can be well sensed, decreasing the ability of the patient to get the drug. Thus, handling such a bitter taste is challenging in developing the oral formulation. A wide range of methods has been applied to tackle this problem. Cubosomes are considered nanoparticles forming cubic three-dimensional structures with a taste-masking effect. This research aimed to apply cubosomes to mask AZ's bitter taste.

Experimental approach: Cubosomes which contained AZ were obtained by applying the film hydration method. Design expert software (version 11) was then employed for optimizing cubosomes that contained the drug. The encapsulation efficiency, particle size as well as polydispersity index of drug-loaded cubosomes were then subjected to evaluation. Assessment of particle morphology was done through SEM. The antimicrobial qualities of AZ-loaded cubosomes were then assessed by utilizing the disc diffusion method. Then, the taste masking study was carried out by referring to human volunteers.

Finding/Results: AZ-loaded cubosomes were spherical in terms of shape and in the 166-272 nm range, with a polydispersity index of 0.17-0.33 and encapsulation efficiency of 80-92%. The results related to the microbial culture revealed that the antimicrobial qualities related to AZ-loaded cubosomes were like those of AZ. The results obtained by taste evaluation also revealed that the cubosomes could well mask the drug's bitter taste.

Conclusion and implications: These findings, thus, revealed that while the antimicrobial impact of AZ is not under the influence of loading in cubosomes, its taste could be well improved.


Azithromycin; Cubosomes; Oral delivery; Taste masking.

Full Text:



Khanmohamadi A, Valizadeh H, Azhdarzadeh M, Lotfipur F, Mohammadi G, Zakeri P. Antibacterial evaluation of azithromycin nanoparticles. Res Pharm Sci. 2012;7(5):14.

Arora SC, Sharma PK, Irchhaiya R, Khatkar A, Singh N, Gagoria J. Development, characterization and solubility study of solid dispersions of cefuroxime axetil by the solvent evaporation method. J Adv Pharm Technol Res. 2010;1(3):326-329.PMID: 22247865.

Abou Assi R, Abdulbaqi IM, Ming TS, Yee CS, Wahab HA, Asif SM, et al. Liquid and solid self-emulsifying drug delivery systems (SEDDs) as carriers for the oral delivery of azithromycin: optimization, in vitro characterization and stability assessment. Pharmaceutics. 2020;12(11):1052,1-29.DOI: 10.3390/pharmaceutics12111052.

Saberi A, Jafari AZ, Mortazavi S. Formulation and evaluation of domperidone fast disintegrating tablets and its taste masking using solid dispersion technology. Res Pharm Sci. 2012;7(5):341.

Amin F, Khan S, Shah SMH, Rahim H, Hussain Z, Sohail M, et al. A new strategy for taste masking of azithromycin antibiotic: development, characterization, and evaluation of azithromycin titanium nanohybrid for masking of bitter taste using physisorption and panel testing studies. Drug Des Devel Ther. 2018;12:3855-3866.DOI: 10.2147/DDDT.S183534.

Jijo A, Flowerlet M. Taste masking of peadiatric formulation: a review on technologies, recent trends and regulatory aspects. Int J Pharm Pharm Sci. 2014;6(1):12-19.

Panovska Z, Sediva A, Jedelska M, Pokorny J. Effect of ethanol on interactions of bitter and sweet tastes in aqueous solutions. Czech J Food Sci. 2008;26(2):139-145.

Abdel-Bar HM, Abd el Basset Sanad R. Endocytic pathways of optimized resveratrol cubosomes capturing into human hepatoma cells. Biomed Pharmacother. 2017;93:561-569.DOI: 10.1016/j.biopha.2017.06.093.

Lai J, Chen J, Lu Y, Sun J, Hu F, Yin Z, et al. Glyceryl monooleate/poloxamer 407 cubic nanoparticles as oral drug delivery systems: I. In vitro evaluation and enhanced oral bioavailability of the poorly water-soluble drug simvastatin. AAPS PharmsciTech. 2009;10(3):960-966.DOI: 10.1208/s12249-009-9292-4.

Lai J, Lu Y, Yin Z, Hu F, Wu W. Pharmacokinetics and enhanced oral bioavailability in beagle dogs of cyclosporine A encapsulated in glyceryl monooleate/poloxamer 407 cubic nanoparticles. Int J Nanomedicine. 2010;5:13-23.PMID: 20161984.

Jin X, Zhang ZH, Li SL, Sun E, Tan XB, Song J, et al. A nanostructured liquid crystalline formulation of 20 (S)-protopanaxadiol with improved oral absorption. Fitoterapia. 2013;84:64-71.DOI: 10.1016/j.fitote.2012.09.013.

Dian L, Yang Z, Li F, Wang Z, Pan X, Peng X, et al. Cubic phase nanoparticles for sustained release of ibuprofen: formulation, characterization, and enhanced bioavailability study. Int J Nanomedicine. 2013;8:845-854.DOI: 10.2147/IJN.S40547.

Muheem A, Shakeel F, Warsi MH, Jain GK, Ahmad FJ. A combinatorial statistical design approach to optimize the nanostructured cubosomal carrier system for oral delivery of ubidecarenone for management of doxorubicin-induced cardiotoxicity: in vitro-in vivo investigations. J Pharm Sci. 2017;106(10):3050-3065.DOI: 10.1016/j.xphs.2017.05.026.

Nasr M, Dawoud M. Sorbitol based powder precursor of cubosomes as an oral delivery system for improved bioavailability of poorly water soluble drugs. J Drug Deliv Sci Technol. 2016;35:106-113.DOI: 10.1016/j.jddst.2016.06.011.

Fan Y, Chen H, Huang Z, Zhu J, Wan F, Peng T, et al. Taste-masking and colloidal-stable cubosomes loaded with Cefpodoxime proxetil for pediatric oral delivery. Int J Pharm. 2020;575:118875,1-40.DOI: 10.1016/j.ijpharm.2019.118875.

Zheng J, Zhang Y, Zhang S. Sustained release of azithromycin from lipid liquid-crystalline nanoparticles laden in situ gel for the treatment of periodontitis: in vitro and efficacy study. J Biomater Appl. 2022:37(3):482-492. DOI: 10.1177/08853282221095395.

Mansour M, El Ezz TAA, Fattoh FN, AbouelFadl DM, Gad HA. Delineating the usage of dexamethasone-loaded cubosomes as a therapeutic armamentarium for hearing loss versus its protective effect: in-vitro and in-vivo animal study. J Drug Deliv Sci Technol. 2021;61:102244,1-10.DOI: 10.1016/j.jddst.2020.102244.

Sultana N, Arayne MS, Hussain F, Fatima A. Degradation studies of azithromycin and its spectrophotometric determination in pharmaceutical dosage forms. Pak J Pharm Sci. 2006;19(2):98-103.PMID: 16751118.

Khanmohamadi A, Valizadeh H, Azhdarzadeh M, Lotfipur F, Mohammadi G, Zakeri. Antibacterial evaluation of azithromycin nanoparticles. Res Pharm Sci. 2012;7(5):341.

Fellers PJ, de Jager G, Poole MJ, Hill EC, Mittal P. Quality of Florida‐packed retail grapefruit juices as determined by consumer sensory panels and chemical and physical analyses. J Food Sc. 1986;51(2):417-420.DOI:10.1111/j.1365-2621.1986.tb11145.x

Taymouri S, Varshosaz J, Hassanzadeh F, Javanmard SH, Dana N. Optimisation of processing variables effective on self-assembly of folate targeted Synpronic-based micelles for docetaxel delivery in melanoma cells. IET Nanobiotechnol. 2015; 9(5):306-313.DOI: 10.1049/iet-nbt.2014.0076.

Amanat S, Taymouri S, Varshosaz J, Minaiyan M, Talebi A. Carboxymethyl cellulose-based wafer enriched with resveratrol-loaded nanoparticles for enhanced wound healing. Drug Deliv Transl Res. 2020;10(5):1241-1254.DOI: 10.1007/s13346-020-00711-w.

Hamdi M, Nasri R, Li S, Nasri M. Design of blue crab chitosan responsive nanoparticles as controlled-release nanocarrier: physicochemical features, thermal stability and in vitro pH-dependent delivery properties. J Biol Macromol. 2020;145:1140-1154.DOI: 10.1016/j.ijbiomac.2019.10.039.

Mohsen AM, Younis MM, Salama A, Darwish AB. Cubosomes as a potential oral drug delivery system for enhancing the hepatoprotective effect of coenzyme Q10. J Pharm Sci. 2021;110(7):2677-2686.DOI: 10.1016/j.xphs.2021.02.007.

Tung NT, Tran CS, Nguyen TL, Hoang T, Trinh TD, Nguyen TN. Formulation and biopharmaceutical evaluation of bitter taste masking microparticles containing azithromycin loaded in dispersible tablets. Eur J Pharm Biopharm. 2018;126:187-200.DOI: 10.1016/j.ejpb.2017.03.017.

Lian R, Lu Y, Qi J, Tan Y, Niu M, Guan P, et al. Silymarin glyceryl monooleate/poloxamer 407 liquid crystalline matrices: physical characterization and enhanced oral bioavailability. AAPS Pharm Sci Tech. 2011;12(4):1234-1240.DOI: 10.1208/s12249-011-9666-2.

Otroj M, Taymouri S, Varshosaz J, Mirian M. Preparation and characterization of dry powder containing sunitinib loaded PHBV nanoparticles for enhanced pulmonary delivery. J Drug Deliv Sci Technol. 2020;56:101570,1-11.DOI: 10.1016/j.jddst.2020.101570.

Nasr M, Saber S, Bazeed AY, Ramadan HA, Ebada A, Ciorba AL, et al. Advantages of cubosomal formulation for gatifloxacin delivery in the treatment of bacterial keratitis: in vitro and in vivo approachusing clinical isolate of methicillin-resistant Staphylococcus aureus. Materials (Basel). 2022;15(9):3374,1-10.DOI: 10.3390/ma15093374.


  • There are currently no refbacks.

Creative Commons LicenseThis work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.