FORMULATION AND OPTIMIZATION OF SOLUPLUS® /POLOXAMER 338-BASED REPAGLINIDE NANOMICELLES USING BOX-BEHNKEN DESIGN
DOI:
https://doi.org/10.22159/ijap.2026v18i4.58009Keywords:
Box-behnken design, Nanomicelles, Repaglinide, Soluplus®, Thin film hydrationAbstract
Objective: To design and optimize repaglinide-loaded nanomicelles using Soluplus® and Poloxamer 338 to enhance its aqueous solubility, dissolution rate, and entrapment efficiency.
Methods: Thin film hydration technique was used for the precipitation of Repaglinide nanomicelles. A four-factor, three-level Box–Behnken design (BBD) was employed to evaluate the effects of formulation variables, including Soluplus® amount (X1), Poloxamer amount (X2), hydration volume (X3), and stirring speed (X4), on particle size (Y1), polydispersity index (PDI, Y2), and entrapment efficiency (EE%, Y3). Dissolution in vitro was performed in phosphate buffer (pH 6.8) containing 1% SDS and similarity factor (f2) was calculated.
Results: The optimized formulation showed a particle size of 61.25 nm, PDI 0.085, and EE% 87%. Dissolution reached 100% within 30 minutes compared with 26.54% for pure repaglinide. The similarity factor (f₂ = 17.03) confirmed a substantial difference between profiles, indicating markedly improved dissolution performance.
Conclusion: The significant enhancement in dissolution rate and high entrapment efficiency suggests that Soluplus®/Poloxamer 338-based nanomicelles represent a promising delivery system for improving the oral bioavailability of poorly soluble drugs such as repaglinide.
References
1. Ali H, Qader IN. Nano Pharmaceuticals: A Comprehensive Review on Chemistry, Nanostructures, and Advanced in Drug Delivery Applications. J Phys Chem Funct Mater. 2025;8(1):23-42. doi: 10.54565/jphcfum.1630835
2. Kumari S, Pathak K. Biopolymeric Micelles. Adv Biopolymeric Syst Drug Deliv: Springer; 2020. p. 291-315. doi: 10.1007/978-3-030-46923-8_11
3. Negut I, Bita B. Polymeric micellar systems—a special emphasis on “smart” drug delivery. Pharmaceutics. 2023;15(3):976. doi: 10.3390/pharmaceutics15030976
4. Gupta MN, Roy I. How corona formation impacts nanomaterials as drug carriers. Mol Pharm. 2020;17(3):725-37. doi: 10.1021/acs.molpharmaceut.9b01111
5. Kapare HS, Metkar SR. Micellar drug delivery system: a review. Pharm Reson. 2020;2(2):21-6.
6. Perumal S, Atchudan R, Lee W. A review of polymeric micelles and their applications. Polymers. 2022;14(12):2510. doi: 10.3390/polym14122510
7. Baccile N, Poirier A, Seyrig C, Le Griel P, Perez J, Hermida-Merino D, et al. Chameleonic amphiphile: The unique multiple self-assembly properties of a natural glycolipid in excess of water. J Colloid Interface Sci. 2023;630:404–15
8. Abdulqader AA, Rajab NA. Bioavailability study of Posaconazole in rats after oral Poloxamer P188 Nano-micelles and oral Posaconazole pure drug. J Adv Pharm Educ Res. 2023;13(2):140-3. doi: 10.51847/Q59uyvRmY3
9. Li G, Lu Y, Fan Y, Ning Q, Li W. Enhanced oral bioavailability of magnolol via mixed micelles and nanosuspensions based on Soluplus®-Poloxamer 188. Drug Deliv. 2020;27(1):1010-7. doi: 10.1080/10717544.2020.1785582. doi: 10.1080/10717544.2020.1785582
10. Rada FH. Meglitinide Drugs Member as a Compendium. J Compr Health. 2025;13(1):12-5. doi: 10.25259/JCH_53_2024
11. Singh A, Shadangi S, Gupta PK, Rana S. Type 2 diabetes mellitus: A comprehensive review of pathophysiology, comorbidities, and emerging therapies. Compr Physiol. 2025;15(1):e70003. doi: 10.1002/cph4.70003
12. Desai MN. Study of Solid-State Transitions and Its Impact on Solubility and Stability of Repaglinide: University of the Sciences in Philadelphia; 2021.
13. Gadadare R, Mandpe L, Pokharkar V. Ultra rapidly dissolving repaglinide nanosized crystals prepared via bottom-up and top-down approach: influence of food on pharmacokinetics behavior. AAPS PharmSciTech. 2015;16(4):787-99.doi: 10.1208/s12249-014-0267-8
14. Albetawi S, Abdalhafez A, Abu-Zaid A, Matrouk A, Alhourani N. Recent solubility and dissolution enhancement techniques for repaglinide a BCS class II drug: A review. Pharmacia. 2021;68:573-83. doi: 10.3897/pharmacia.68.e66586
15. Fouad SA, Teaima MH, Gebril MI, et al. Formulation of novel niosomal repaglinide chewable tablets using coprocessed excipients: in vitro characterization, optimization and enhanced hypoglycemic activity in rats. Drug Deliv. 2023;30(1):2181747.doi: 10.1080/10717544.2023.2181747
16. Magdum R, et al. Design and evaluation of repaglinide nanosuspension for oral controlled drug delivery system by using 32 factorial design. Int J Drug Deliv Technol. 2025;15(2).doi:10.25258/ijddt.15.2.6
17. Hala Mohammed Fatih, Ahmed KK. Formulation and Evaluation of Lercanidipine HCL Loaded Nanomicelles. Iraqi Journal of Pharmaceutical Sciences. 2026;35(1):80-8.
18. Zhang J, Li Y, Fang X, Zhou D, Wang Y, Chen M. TPGS-g-PLGA/Pluronic F68 mixed micelles for tanshinone IIA delivery in cancer therapy. Int J Pharm. 2014;476(1-2):185-98. doi: 10.1016/j.ijpharm.2014.09.017
19. Abdulqader AA, Sultan NA. Preparation and characterization of posaconazole as a nano-micelle using d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS). Iraqi J Pharm Sci. 2023;32:26-32. doi: 10.31351/vol32issSuppl.pp26-32
20. Toma NM, Abdulrasool AA. Formulation and evaluation of montelukast sodium nanoparticles for transdermal delivery. Int J Drug Deliv Technol. 2021;11(2):530-8. doi: 10.25258/ijddt.11.2.52
21. Sameena Begum, Niranjan Panda, Ch. Praveena. Design And Development Of Enzalutamide-Encapsulated Polycaprolactone Nanoparticles For Prostate Cancer: A Box–Behnken Statistical Approach. Asian J Pharm Clin Res . 2026 ;19(1):203-10.
22. P.Bhaskararaoetal.Theindustrialimportanceoftechnologytransferforanalyticalmethoddevelopmentandvalidationapplicationtovilazodonehydrochloridedosageform. International Journal of Chemistry Research.2024 ;8(4):212-17
23. Mohsen AM, El-Hashemy HA, Salama A, Darwish AB. Formulation of tizanidine hydrochloride–loaded provesicular system for improved oral delivery and therapeutic activity employing a 23 full factorial design. Drug Deliv Transl Res. 2023;13(2):580-92.doi: 10.1007/s13346-022-01217-3
24. Wang J, Lv F, Sun T, et al. Sorafenib nanomicelles effectively shrink tumors by vaginal administration for preoperative chemotherapy of cervical cancer. Nanomaterials. 2021;11(12):3271. doi: 10.3390/nano11123271
25. Ahmed KK. Nanosuspension-Based Repaglinide Fast-Dissolving Buccal Film for Dissolution. AAPS PharmSciTech. 202X.doi:10.1208/s12249-024-02868-w
26. Emad H, Abd-Alhammid SN. Improvement of the solubility and dissolution characteristics of risperidone via nanosuspension formulations. Iraqi J Pharm Sci. 2022;31(1):43-56. doi: 10.31351/vol31iss1pp43-56
27. Alhagiesa AW, Ghareeb MM. The Formulation and Characterization of Nimodipine Nanoparticles for the Enhancement of solubility and dissolution rate. Iraqi J Pharm Sci. 2021;30(2):143-52. doi: 10.31351/vol30iss2pp143-152
28. Akila Rm, Nithin Mk. Design And Evaluation Of Ashwagandha Chitosan Nanoparticles For Enhanced Neuroprotection In Huntington’s Disease. Int J Pharm Pharm Sci . 2025;17(8):64-8.
29. Sonkambale KG, Katedeshmukh RG, Kumbhar AB, et al. Formulation and evaluation of nanosuspension for enhancing the solubility of poorly soluble antihyperlipidemic drugs. Eur J Mol Clin Med. 2021;8(3). doi: 10.53555/ecb.v11:i12.17844
30. Patra A, Satpathy S, Shenoy AK, et al. Formulation and evaluation of mixed polymeric micelles of quercetin for treatment of breast, ovarian, and multidrug resistant cancers. Int J Nanomedicine. 2018;13:2869-81.doi: 10.2147/IJN.S153094
31. Xu T, Li H, Xia Y, et al. Three-dimensional-printed oral films based on LCD: influence factors of the film printability and received qualities. Pharmaceutics. 2023;15(3):758. doi: 10.3390/pharmaceutics15030758
32. Lu P, Liang Z, Zhang Z, et al. Novel nanomicelle butenafine formulation for ocular drug delivery against fungal keratitis: In Vitro and In Vivo study. Eur J Pharm Sci. 2024;192:106629.doi: 10.1016/j.ejps.2023.106629
33. Abd-Alhammid SN, Kadhum RW. Process Factors Affecting the Preparation and Characterization of Dutasteride Nanosuspension. Iraqi J Pharm Sci. 2025;34(1):35-48. doi: 10.31351/vol34iss1pp35-48
34. Teaima MH, El Mohamady AM, El-Nabarawi MA, Mohamed AI. Formulation and evaluation of niosomal vesicles containing ondansetronHCL for trans-mucosal nasal drug delivery. Drug Dev Ind Pharm. 2020;46(5):751-61.doi: 10.1080/03639045.2020.1753061
35. Seary H, Barakat EH, Raslan MA, Samy AM. Development, characterization, and optimization of repaglinide loaded spanlastics along with investigation of drug solubility in various media. Univ J Pharm Res. 2024. doi: 10.22270/ujpr.v9i5.1221
36. Pignatello R, Corsaro R, Bonaccorso A, et al. Soluplus® polymeric nanomicelles improve solubility of BCS-class II drugs. Drug Deliv Transl Res. 2022;12(8):1991-2006. doi: 10.1007/s13346-022-01182-x
37. Drais HK, Hussein AA. Lipid-polymer hybrid nanocarriers for oral delivery of felodipine: formulation, characterization and ex vivo evaluation. Adv Pharm Bull. 2021;12(4):791. doi: 10.34172/apb.2022.081
38. Zawar L, Bari S. Microwave induced solid dispersion as a novel technique for enhancing dissolution rate of repaglinide. Adv Pharmacol Pharm. 2013;1(2):95-101. doi: 10.13189/app.2013.010208
39. Kumar Mahawar M, Bharimalla AK, Arputharaj A, et al. Optimization of process parameters for preparation of cellulose nanocrystal‑stabilized nanosulphur suspension using response surface methodology. Sci Rep. 2023;13:20678.doi: 10.1038/s41598-023-47164-y
40. Jassem NA, Abd Alhammid SN. Enhancement of the dissolution and solubility of canagliflozin using nanodispersion systems. Al-Rafidain J Med Sci. 2024;6(1):222-31. doi: 10.54133/ajms.v6i1.639
41. El-Nabarawi M, Khalil I, Saad R. Impact of hydrophilic polymer solubilization on bioavailability enhancement of repaglinide by solid dispersion. Inven Rapid Pharm Tech. 2016;3:1-12.
42. Abul Kalam M, Khan AA, Khan S, et al. Optimizing indomethacin loaded chitosan nanoparticle size encapsulation and release using box–behnken experimental design. Int J Biol Macromol. 2016;87:329-40. doi: 10.1016/j.ijbiomac.2016.02.033, PMID 26893052.
43. Zeeshan M, Ali H, Khan S, et al. Glycyrrhizic acid-loaded pH-sensitive poly-(lactic-co-glycolic acid) nanoparticles for the amelioration of inflammatory bowel disease. Nanomedicine. 2019;14(15):1945-69.doi: 10.2217/nnm-2018-0415
44. Muhesen RA, Rajab NA. Formulation and characterization of olmesartan medoxomil as a nanoparticle. Res J Pharm Technol. 2023;16(7):3314-20. doi: 10.52711/0974-360X.2023.00547
45. Al-Zheery WH, Kassab HJ. Effect of Different Type of Terpenes on Disulfiram Loaded Transdermal Invasomes Preparation and in-vitro Characterization. Iraqi J Pharm Sci. 2025;34(3):78-89. doi: 10.31351/vol34iss3pp78-89
46. Ali R, Qamar W, Kalam MA, Binkhathlan Z. Soluplus–TPGS Mixed Micelles as a Delivery System for Brigatinib: Characterization and In Vitro Evaluation. ACS Omega. 2024;9(40):41830-40.doi: 10.1021/acsomega.4c06264
47. Efthymiou C, Bergström LM, Pedersen JN, et al. Self-assembling properties of ionisable amphiphilic drugs in aqueous solution. J Colloid Interface Sci. 2021;600:701-10. doi: 10.1016/j.jcis.2021.05.049
48. Zeng YC, Li S, Liu C, et al. Soluplus micelles for improving the oral bioavailability of scopoletin and their hypouricemic effect in vivo. Acta Pharmacol Sin. 2017;38(3):424-33.doi: 10.1038/aps.2016.126
49. Takayama R, Ishizawa M, Yamada M, et al. Characterization of soluplus/ASC-DP nanoparticles encapsulated with minoxidil for skin targeting. ChemEngineering. 2021;5(3):44.doi:10.3390/chemengineering5030044
50. Alsafar ZA, Jawad FJ. Preparation and Evaluation of Lercanidipine HCl Nanosuspension to Improve the Dissolution Rate. Iraqi J Pharm Sci. 2024;33(4):20-30. doi:10.31351/vol33iss(4SI)pp20-30
51. Mothé C, Azevedo A, Drumond W, Wang S. Thermal properties of amphiphilic biodegradable triblock copolymer of L, L-lactide and ethylene glycol. J Therm Anal Calorim. 2010;101(1):229-33.
52. Kang JH, Jeong JH, Kwon YB, et al. Mucosal penetrative polymeric micelle formulations for insulin delivery to the respiratory tract. Int J Nanomedicine. 2024;19:9195-211. doi: 10.2147/IJN.S474287.
53. Jain A, Bhardwaj K, Bansal M. Polymeric micelles as drug delivery system: recent advances, approaches, applications and patents. Curr Drug Saf. 2024;19(2):163-71. doi: 10.2174/1574886318666230605120433.
54. Al-Lawati H, Binkhathlan Z. Polymeric micelles for oral drug delivery: progress and innovations in preclinical studies. Int J Pharm. 2026;687:126373. doi: 10.1016/j.ijpharm.2025.126373.
55. Zhang Z, Lu Y, Qi J, et al. An update on oral drug delivery via intestinal lymphatic transport. Acta Pharm Sin B. 2021;11(8):2449-68.doi: 10.1016/j.apsb.2020.12.022
56. Dinh L. Oral drug delivery via intestinal lymphatic systems: recent approaches targeting lymphatic transport. Pharmaceuticals. 2023.doi:10.3390/liquids3040029
57. Pignatello R, Corsaro R, Bonaccorso A, et al. Soluplus® polymeric nanomicelles improve solubility of BCS-class II drugs. Drug Deliv Transl Res. 2022;12(8):1991-2006.doi: 10.1007/s13346-022-01182-x
58. Li L, Huh KM, Lee YK, Kim SY. Biofunctional self-assembled nanoparticles of folate–PEG–heparin/PBLA copolymers for targeted delivery of doxorubicin. J Mater Chem. 2011;21(39):15288-97.
59. Pervez S, Nasir F, Hidayatullah T, et al. Transdermal Delivery of Glimepiride: A Novel Approach Using Nanomicelle-Embedded Microneedles. Pharmaceutics. 2023;15(8). doi:10.3390/pharmaceutics15082019
60. Rashid AM, Abdal-Hammid SN. Formulation and characterization of itraconazole as nanosuspension dosage form for enhancement of solubility. Iraqi J Pharm Sci. 2019;28(2):124-33. doi: 10.31351/vol28iss2pp124-133.
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