QUALITY-BY-DESIGN ASSISTED DEVELOPMENT AND EVALUATION OF A MICROBALLOON-BASED GASTRORETENTIVE DRUG DELIVERY SYSTEM
DOI:
https://doi.org/10.22159/ijap.2026v18i2.56652Keywords:
Levofloxacin, Floating microballoons, Gastroretentive drug delivery system, Eudragit RS100, Ethyl cellulose, Quality by design, Plackett-burman, Central composite designAbstract
Objective: To develop and optimize levofloxacin-loaded floating microballoons for gastroretentive delivery to improve local antibiotic concentrations against Helicobacter pylori (H. pylori), prolong gastric residence, and achieve extended release using a Quality by Design (QbD) approach.
Methods: Microballoons were prepared by a modified emulsion solvent diffusion technique using levofloxacin hemihydrate, eudragit RS100 (Eu RS100) and ethyl cellulose (EC) in ethanol: dichloromethane (1:1 v/v) and stabilized with 0.75% PVA. A Plackett–Burman design screened formulation and process variables; significant factors were optimized by a central composite design (CCD). Characterization included entrapment efficiency (EE), percentage yield, particle size and zeta potential, in vitro buoyancy, dissolution testing, fourier transform infrared spectroscopy, powder x-ray diffraction, differential scanning calorimetry, scanning electron microscopy and ICH Q1A (R2) stability testing at 25 °C/60% RH and 40 °C/75% RH. Data were modelled in Design-Expert® and kinetics evaluated.
Results: Plackett–Burman screening identified EC, Eu RS100 and stirring speed as critical. CCD optimization selected EC 400 mg and Eu RS100 392 mg (desirability 0.789) at fixed stirring (300 rpm). The validated optimized formulation showed a percentage yield of ≈85%, EE of 74.7%±1.2%, a mean particle size of 266.3±4.2 µm, a zeta potential between −15 and −25 mV, and a buoyancy of 79.1%±2.4% at 12 h. Twelve-hour cumulative release was 64.7 %±1.9 % with sustained, controlled release. Fourier transform infrared spectroscopy spectroscopy showed small changes in the spectrum that were consistent with hydrogen-bonding interactions (the drug did not break down). Powder x-ray diffraction and differential scanning calorimetry showed that levofloxacin lost its crystalline structure (from partial to complete amorphization) in the polymer matrix. Scanning electron microscopy verified the presence of spherical, hollow, porous microballoons characterised by distinct internal cavities. In terms of appearance, drug content, buoyancy, or release profile, stability testing revealed no significant changes.
Conclusion: Levofloxacin-loaded floating microballoons, developed using a QbD framework, provided high entrapment, prolonged gastric buoyancy and controlled release with robust stability. The formulation is a promising gastroretentive platform to enhance local gastric drug concentration and potentially improve H. pylori eradication.
References
1. Hooi JK, Lai WY, Ng WK, Suen MM, Underwood FE, Tanyingoh D. Global prevalence of Helicobacter pylori infection: systematic review and meta-analysis. Gastroenterology. 2017 Aug;153(2):420-9. doi: 10.1053/j.gastro.2017.04.022, PMID 28456631.
2. Malfertheiner P, Megraud F, Rokkas T, Gisbert JP, Liou JM, Schulz C. Management of Helicobacter pylori infection: the Maastricht VI/Florence consensus report. Gut. 2022 Sep;71(9):1724-62. doi: 10.1136/gutjnl-2022-327745, PMID 35944925.
3. Savoldi A, Carrara E, Graham DY, Conti M, Tacconelli E. Preva-lence of antibiotic resistance in Helicobacter pylori: a systematic review and meta-analysis in world health organization regions. Gastroenterology. 2018 Nov;155(5):1372-82.e17. doi: 10.1053/j.gastro.2018.07.007, PMID 29990487.
4. Chey WD, Howden CW, Moss SF, Morgan DR, Greer KB, Grover S. ACG clinical guideline: treatment of Helicobacter pylori infection. Am J Gastroenterol. 2024 Sep;119(9):1730-53. doi: 10.14309/ajg.0000000000002968, PMID 39626064.
5. Hu Y, Zhu Y, Lu NH. Recent progress in Helicobacter pylori treatment. Chin Med J (Engl). 2020 Feb 5;133(3):335-43. doi: 10.1097/CM9.0000000000000618, PMID 31929363.
6. Umamaheshwari RB, Ramteke S, Jain NK. Anti-Helicobacter py-lori effect of mucoadhesive nanoparticles bearing amoxicillin in experimental gerbils model. AAPS PharmSciTech. 2004 Jun;5(2):e32. doi: 10.1208/pt050232, PMID 15760090.
7. Kim DH, Lee SW, Lee JH, Park JW, Park SM, Maeng HJ. Develop-ment of gastroretentive floating combination tablets containing amoxicillin trihydrate 500 mg and levofloxacin 125 mg for eradicating resistant helicobacter pylori. Pharmaceutics. 2024 Sep 24;16(10):1242. doi: 10.3390/pharmaceutics16101242, PMID 39458574.
8. Azab ET, Thabit AK, McKee S, Al Qiraiqiri A. Levofloxacin versus clarithromycin for Helicobacter pylori eradication: are 14 d regimens better than 10 d regimens? Gut Pathog. 2022 Dec 6;14(1):24. doi: 10.1186/s13099-022-00502-3, PMID 35668511.
9. Streubel A, Siepmann J, Bodmeier R. Gastroretentive drug deliv-ery systems. Expert Opin Drug Deliv. 2006 Mar 28;3(2):217-33. doi: 10.1517/17425247.3.2.217, PMID 16506949.
10. Arora S, Ali J, Ahuja A, Khar RK, Baboota S. Floating drug deliv-ery systems: a review. AAPS PharmSciTech. 2005 Oct 19;6(3):E372-90. doi: 10.1208/pt060347, PMID 16353995.
11. Korsmeyer RW, Gurny R, Doelker E, Buri P, Peppas NA. Mecha-nisms of solute release from porous hydrophilic polymers. Int J Pharm. 1983 May;15(1):25-35. doi: 10.1016/0378-5173(83)90064-9.
12. Bolton S, Bon C. Pharmaceutical statistics. 5th ed Bolton S, Bon C, editors. Boca Raton: CRC Press; 2009. p. 670. doi: 10.3109/9781420074239.
13. Gohel MC, Parikh RK, Nagori SA, Jena DG. Fabrication of modi-fied release tablet formulation of metoprolol succinate using hydroxypropyl methylcellulose and xanthan gum. AAPS Pharm-SciTech. 2009 Mar 16;10(1):62-8. doi: 10.1208/s12249-008-9174-1, PMID 19148762.
14. Gannu R, Palem CR, Yamsani SK, Yamsani VV, Yamsani MR. En-hanced bioavailability of buspirone from reservoir-based transdermal therapeutic system optimization of formulation employing box–behnken statistical design. AAPS PharmSciTech. 2010 Jun 2;11(2):976-85. doi: 10.1208/s12249-010-9451-7, PMID 20517714.
15. Kawashima Y, Niwa T, Takeuchi H, Hino T, Itoh Y. Hollow microspheres for use as a floating controlled drug delivery system in the stomach. J Pharm Sci. 1992 Feb;81(2):135-40. doi: 10.1002/jps.2600810207, PMID 1372046.
16. Yadav A, Jain DK. In vitro characterization of gastroretentive microballoons prepared by the emulsion solvent diffusion method. J Adv Pharm Technol Res. 2010;1(1):56-67. doi: 10.4103/2231-4040.70524, PMID 22247832.
17. Vanaja K, Shobha Rani RH. Design of experiments: concept and applications of plackett burman design. Clin Res Regul Aff. 2007 Jan 10;24(1):1-23. doi: 10.1080/10601330701220520.
18. Kharb M, Tanwar YS. Development and statistical optimization of Gastroretantive floating microspheres of pregabalin prepared by W/O/O multiple emulsion method. Int J Appl Pharm. 2021 May 7;13(3):199-206. doi: 10.22159/ijap.2021v13i3.41001.
19. Awasthi R, Kulkarni GT. Development and characterization of amoxicillin loaded floating microballoons for the treatment of Helicobacter pylori induced gastric ulcer. Asian J Pharm Sci. 2013 Jun;8(3):174-80. doi: 10.1016/j.ajps.2013.07.023.
20. Awasthi R, Kulkarni GT, Pawar VK, Garg G. Optimization studies on gastroretentive floating system using response surface methodology. AAPS PharmSciTech. 2012 Mar 2;13(1):85-93. doi: 10.1208/s12249-011-9730-y, PMID 22135108.
21. Alnaqbi AY, Bhongade BA, Azzawi AA. New validated diffuse re-flectance infrared fourier transform spectroscopic method for the quantification of levofloxacin in pharmaceutical dosage form. Indian J Pharm Sci. 2021;83(3):430-6. doi: 10.36468/pharmaceutical-sciences.791.
22. Kadri L, Carta M, Lampronti G, Delogu F, Tajber L. Mechano-chemically induced solid-state transformations of levofloxacin. Mol Pharm. 2024 Jun 3;21(6):2838-53. doi: 10.1021/acs.molpharmaceut.4c00008, PMID 38662637.
23. Kumar V, Sodavat RK, Rathore GS. Formulation and evaluation of gastroretentive floating tablets of lovastatin using natural polymers. J Drug Deliv Ther. 2025 Jul 15;15(7):71-9. doi: 10.22270/jddt.v15i7.7280.
24. Varshosaz J, Tabbakhian M, Zahrooni M. Development and char-acterization of floating microballoons for oral delivery of cin-narizine by a factorial design. J Microencapsul. 2007 May;24(3):253-62. doi: 10.1080/02652040601162723, PMID 17454436.
25. Choudhary S, Jain A, Amin MC, Mishra V, Agrawal GP, Keshar-wani P. Stomach specific polymeric low density microballoons as a vector for extended delivery of rabeprazole and amoxicillin for treatment of peptic ulcer. Colloids Surf B Biointerfaces. 2016 May;141:268-77. doi: 10.1016/j.colsurfb.2016.01.048, PMID 26859118.
26. Jain A, Pandey V, Ganeshpurkar A, Dubey N, Bansal D. Formula-tion and characterization of floating microballoons of nizatidine for effective treatment of gastric ulcers in murine model. Drug Deliv. 2015 Apr 3;22(3):306-11. doi: 10.3109/10717544.2014.891273, PMID 24601855.
27. Sato Y, Kawashima Y, Takeuchi H, Yamamoto H. In vitro and in vivo evaluation of riboflavin-containing microballoons for a floating controlled drug delivery system in healthy humans. Int J Pharm. 2004 May;275(1-2):97-107. doi: 10.1016/j.ijpharm.2004.01.036, PMID 15081141.
28. Ramachandran S, Shaheedha SM, Thirumurugan G, Dhanaraju MD. Floating controlled drug delivery system of famotidine loaded hollow microspheres (microballoons) in the stomach. Curr Drug Deliv. 2010 Jan 1;7(1):93-7. doi: 10.2174/156720110790396436, PMID 20044907.
29. International Conference on Harmonisation of Technical Re-quirements for Registration of Pharmaceuticals for Human Use (ICH). Stability testing of new drug substances and products. ICH Q1A (R2). Geneva: ICH; 2003 Feb 6.
30. Boorugu R, Gadela RV. Eplerenone floating microspheres: radiographic and pharmacokinetic studies in rabbits. Int J Appl Pharm. 2024;16(2):231–6. doi: 10.22159/ijap.2024v16i2.49798.
31. Krishna SR, Ramu A, Vidyadhara S, Rani AP. Bioavailability en-hancement by floating microballoons of dipyridamole and clopidogrel: in vivo pharmacokinetic study. Int J Appl Pharm. 2021;13(6):216–20. doi: 10.22159/ijap.2021v13i6.42316.
32. Mc Hugh ML. Multiple comparison analysis testing in ANOVA. Biochem Med (Zagreb). 2011;21(3):203-9. doi: 10.11613/BM.2011.029, PMID 22420233.
33. Maurya S, Malik JK, Kumar GP, Kumar S, Singh G, Singh SP. Preparation and evaluation of chitosan microspheres containing levofloxacin. Saudi J Med Pharm Sci. 2024 Feb 1;10(2):99-104. doi: 10.36348/sjmps.2024.v10i02.006.
34. Spizzirri UG, Hampel S, Cirillo G, Mauro MV, Vittorio O, Caval-canti P. Functional gelatin-carbon nanotubes nanohybrids with enhanced antibacterial activity. Int J Polym Mater Polym Biomater. 2015 Sep 22;64(9):439-47. doi: 10.1080/00914037.2014.958833.
35. Perissutti B, Rubessa F, Moneghini M, Voinovich D. Formulation design of carbamazepine fast-release tablets prepared by melt granulation technique. Int J Pharm. 2003 Apr;256(1-2):53-63. doi: 10.1016/S0378-5173(03)00062-0, PMID 12695011.
36. Mozayad AN, Fouad MA, Elkady EF. Utilizing experimental de-sign and desirability function in optimizing RP-HPLC method for simultaneous determination of some skeletal muscle relaxants and analgesics. Sci Rep. 2024 May 6;14(1):10360. doi: 10.1038/s41598-024-58381-4, PMID 38710733.
37. Krishna KA, Srivastava R. In vitro-in vivo studies on floating mi-crospheres for gastroretentive drug delivery system: a review. Asian J Pharm Clin Res. 2021 Jan 5;14(1):13-26. doi: 10.22159/ajpcr.2021.v14i1.39183.
38. Beg S, Kaur R, Khurana RK, Rana V, Sharma T, Singh B. QbD-based development of cationic self-nanoemulsifying drug deliv-ery systems of paclitaxel with improved biopharmaceutical at-tributes. AAPS PharmSciTech. 2019 Apr 21;20(3):118. doi: 10.1208/s12249-019-1319-x, PMID 30790136.
39. Parmar A, Kaur G, Kapil S, Sharma V, Sharma S. Central compos-ite design-based optimization and fabrication of benzylisothio-cynate-loaded PLGA nanoparticles for enhanced antimicrobial attributes. Appl Nanosci. 2020 Feb 23;10(2):379-89. doi: 10.1007/s13204-019-01185-0.
40. Senthilnathan B, Maheswaran A, Gopalasatheeskumar K, Masi-lamani K, Edros RZ. Formulation and evaluation of pregabalin loaded Eudragit S100 nanoparticles. Int J Eng Technol Sci. 2016 Dec 30;3(2):64-70. doi: 10.15282/ijets.6.2016.1.9.1059.
41. Hasan AA, Madkor H, Wageh S. Formulation and evaluation of metformin hydrochloride-loaded niosomes as controlled release drug delivery system. Drug Deliv. 2013 Apr 8;20(3-4):120-6. doi: 10.3109/10717544.2013.779332, PMID 23651102.
42. Reddy LH, Murthy RS. Floating dosage systems in drug delivery. Crit Rev Ther Drug Carrier Syst. 2002;19(6):553-85. doi: 10.1615/CritRevTherDrugCarrierSyst.v19.i6.20, PMID 12822735.
43. Saini S, Bhardwaj BY, Chhabra J, Kumar M, Pahwa R. In vivo monitoring strategies for evaluation of floating drug delivery systems. Int J Appl Pharm. 2022 Nov 7;14(6):28-33. doi: 10.22159/ijap.2022v14i6.45906.
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