DESIGN OF NABUMETONE-LOADED TEMPERATURE-RESPONSIVE GEL FOR COLORECTAL DELIVERY USING LIPID NANOCARRIERS IN VITRO/IN VIVO EVALUATION

MOHAMMED A. AMIN; MOSTAFA A. MOHAMED; DALIA A. GABER

doi:10.22159/ijap.2025v17i6.55367

Authors

MOHAMMED A. AMIN Department of Pharmaceutics, College of Pharmacy, Qassim University, Qassim-51452, Saudi Arabia
MOSTAFA A. MOHAMED Clinical Pharmacy Program, College of Health Sciences and Nursing, Al-Rayan National College, Madina, Saudi Arabia. Department of Pharmaceutics, College of Pharmacy, Al-Ahram Canadian University, Egypt
DALIA A. GABER Clinical Pharmacy Program, College of Health Sciences and Nursing, Al-Rayan National College, Madina, Saudi Arabia https://orcid.org/0000-0002-1129-1021

DOI:

https://doi.org/10.22159/ijap.2025v17i6.55367

Keywords:

Thermoresponsive gel, Nabumetone, Solid lipid nanoparticles, Rectal administration, Enhanced bioavailability

Abstract

Objective: This study aimed to develop a novel thermosensitive in situ gel incorporating nabumetone-loaded solid lipid nanoparticles (NAB-SLP-TSG) for rectal delivery to enhance bioavailability and sustain drug retention.

Methods: NAB-SLPs were prepared and optimized using Central Composite Design and evaluated for particle size, encapsulation efficiency, surface charge, and morphology. The optimized SLPs were incorporated into a temperature-sensitive gel and characterized for gelation behavior, rheology, mucoadhesiveness, in vitro drug release, pharmacokinetics, rectal mucosal safety, and retention.

Results: Optimized NAB-SLPs demonstrated an encapsulation efficiency of 89.62±1.34%, drug loading of 14.85±1.13%, mean particle size of 161.43±2.17 nm, PDI of 0.29±0.07, and zeta potential of −20.45±0.63 mV. FTIR and XRD confirmed drug encapsulation and its amorphous dispersion in the lipid matrix. The NAB-SLP-TSG exhibited a gelation temperature of 32.81±0.73 °C, gelation time of 15.32±2.37 s, and mucoadhesive strength of (11.09±0.42)×10² dyne/cm². In vitro, a biphasic release profile was observed. In vivo, the formulation significantly enhanced NAB absorption and bioavailability without causing rectal tissue irritation, while ensuring prolonged local retention.

Conclusion: Unlike previously reported thermosensitive rectal gels for drugs like diclofenac or insulin, this formulation uniquely combines γ-Polyglutamic acid (γ-PGA) to significantly enhance mucoadhesion and solid lipid nanoparticles (SLPs) to sustain rectal retention. This dual approach distinctly advances prior systems by improving both residence time and systemic availability of nabumetone, offering a novel and superior alternative for rectal NSAID delivery.

References

1. Matsumoto K, Hasegawa T, Ohara K, Takei C, Kamei T, Koyanagi J. A metabolic pathway for the prodrug nabumetone to the pharmacologically active metabolite 6-methoxy-2-naphthylacetic acid (6-MNA) by non-cytochrome P450 enzymes. Xenobiotica. 2020;50(7):783-92. doi: 10.1080/00498254.2019.1704097, PMID 31855101.

2. Jameel BK, Raauf AM, Abbas WA. Synthesis, characterization molecular docking in silico ADME study and in vitro cytotoxicity evaluation of new pyridine derivatives of nabumetone. Al Mustansiriyah J Pharm Sci. 2023;23(3):250-62. doi: 10.32947/ajps.v23i3.1042.

3. Jagdale SC, Deore GK, Chabukswar AR. Development of microemulsion-based nabumetone transdermal delivery for treatment of arthritis. Recent Pat Drug Deliv Formul. 2018;12(2):130-49. doi: 10.2174/1872211312666180227091059, PMID 29485013.

4. Grande F, Ragno G, Muzzalupo R, Occhiuzzi MA, Mazzotta E, Luca MD. Gel formulation of nabumetone and a newly synthesized analog: microemulsion as a photoprotective topical delivery system. Pharmaceutics. 2020;12(5):423. doi: 10.3390/pharmaceutics12050423, PMID 32380748.

5. Park YJ, Yong CS, Kim HM, Rhee JD, Oh YK, Kim CK. Effect of sodium chloride on the release, absorption and safety of diclofenac sodium delivered by poloxamer gel. Int J Pharm. 2003;263(1-2):105-11. doi: 10.1016/S0378-5173(03)00362-4, PMID 12954185.

6. El Leithy ES, Shaker DS, Ghorab MK, Abdel Rashid RS. Evaluation of mucoadhesive hydrogels loaded with diclofenac sodium chitosan microspheres for rectal administration. AAPS PharmSciTech. 2010;11(4):1695-702. doi: 10.1208/s12249-010-9544-3, PMID 21108027.

7. Kawish SM, Hasan N, Beg S, Qadir A, Jain GK, Aqil M. Docetaxel loaded borage seed oil nanoemulsion with improved antitumor activity for solid tumor treatment: formulation development in vitro in silico and in vivo evaluation. J Drug Deliv Sci Technol. 2022;75:103693. doi: 10.1016/j.jddst.2022.103693.

8. Alhalmi A, Amin S, Khan Z, Beg S, Al Kamaly O, Saleh A. Nanostructured lipid carrier-based codelivery of raloxifene and naringin: formulation optimization in vitro, ex vivo, in vivo assessment and acute toxicity studies. Pharmaceutics. 2022;14(9):1771. doi: 10.3390/pharmaceutics14091771, PMID 36145519.

9. Pivetta TP, Simoes S, Araujo MM, Carvalho T, Arruda C, Marcato PD. Development of nanoparticles from natural lipids for topical delivery of thymol: investigation of its anti-inflammatory properties. Colloids Surf B Biointerfaces. 2018;164:281-90. doi: 10.1016/j.colsurfb.2018.01.053, PMID 29413607.

10. He C, Kim SW, Lee DS. In situ gelling stimuli-sensitive block copolymer hydrogels for drug delivery. J Control Release. 2008;127(3):189-207. doi: 10.1016/j.jconrel.2008.01.005, PMID 18321604.

11. Park YJ, Yong CS, Kim HM, Rhee JD, Oh YK, Kim CK. Effect of sodium chloride on the release, absorption and safety of diclofenac sodium delivered by poloxamer gel. Int J Pharm. 2003;263(1-2):105-11. doi: 10.1016/S0378-5173(03)00362-4, PMID 12954185.

12. Shtay R, Tan CP, Schwarz K. Development and characterization of solid lipid nanoparticles (SLNs) made of cocoa butter: a factorial design study. J Food Eng. 2018;231:30-41. doi: 10.1016/j.jfoodeng.2018.03.006.

13. Singh A, Neupane YR, Mangla B, Kohli K. Nanostructured lipid carriers for oral bioavailability enhancement of exemestane: formulation design in vitro ex vivo and in vivo studies. J Pharm Sci. 2019;108(10):3382-95. doi: 10.1016/j.xphs.2019.06.003, PMID 31201904.

14. Alam T, Khan S, Gaba B, Haider MF, Baboota S, Ali J. Adaptation of quality by design-based development of isradipine nanostructured lipid carrier and its evaluation for in vitro gut permeation and in vivo solubilization fate. J Pharm Sci. 2018;107(11):2914-26. doi: 10.1016/j.xphs.2018.07.021, PMID 30076853.

15. Li L, Guo D, Guo J, Song J, Wu Q, Liu D. Thermosensitive in situ forming gels for ophthalmic delivery of tea polyphenols. J Drug Deliv Sci Technol. 2018;46:243-50. doi: 10.1016/j.jddst.2018.05.019.

16. Zafar S, Akhter S, Ahmad I, Hafeez Z, Alam Rizvi MM, Jain GK. Improved chemotherapeutic efficacy against resistant human breast cancer cells with co-delivery of docetaxel and thymoquinone by chitosan grafted lipid nanocapsules: formulation optimization in vitro and in vivo studies. Colloids Surf B Biointerfaces. 2020;186:110603. doi: 10.1016/j.colsurfb.2019.110603, PMID 31846892.

17. Patel A, Bell M, O Connor C, Inchley A, Wibawa J, Lane ME. Delivery of ibuprofen to the skin. Int J Pharm. 2013;457(1):9-13. doi: 10.1016/j.ijpharm.2013.09.019, PMID 24064201.

18. Rizwanullah M, Amin S, Ahmad J. Improved pharmacokinetics and antihyperlipidemic effiacy of rosuvastatin-loaded nanostructured lipid carriers. J Drug Target. 2017;25(1):58-74. doi: 10.1080/1061186X.2016.1191080, PMID 27186665.

19. Kawish SM, Ahmed S, Gull A, Aslam M, Pandit J, Aqil M. Development of nabumetone-loaded lipid nano-scaffold for the effective oral delivery; optimization characterization drug release and pharmacodynamic study. J Mol Liq. 2017;231:514-22. doi: 10.1016/j.molliq.2017.01.107.

20. Alam M, Ahmed S, N, Moon G, Aqil M, Sultana Y. Chemical engineering of a lipid nano-scaffold for the solubility enhancement of an antihyperlipidaemic drug simvastatin; preparation optimization, physicochemical characterization and pharmacodynamic study. Artif Cells Nanomed Biotechnol. 2017;46(8):1-12. doi: 10.1080/21691401.2017.1396223.

21. Rizwanullah M, Ahmad J, Amin S. Nanostructured lipid carriers: a novel platform for chemotherapeutics. Curr Drug Deliv. 2016;13(1):4-26. doi: 10.2174/1567201812666150817124133, PMID 26279117.

22. Negi LM, Jaggi M, Joshi V, Ronodip K, Talegaonkar S. Hyaluronic acid decorated lipid nanocarrier for MDR modulation and CD-44 targeting in colon adenocarcinoma. Int J Biol Macromol. 2015;72:569-74. doi: 10.1016/j.ijbiomac.2014.09.005, PMID 25220787.

23. Sartaj A, Annu, Alam M, Biswas L, Yar MS, Mir SR. Combinatorial delivery of ribociclib and green tea extract mediated nanostructured lipid carrier for oral delivery for the treatment of breast cancer, synchronising in silico in vitro and in vivo studies. J Drug Target. 2022;30(10):1113-34. doi: 10.1080/1061186X.2022.2104292.

24. Ivanova NA, Trapani A, Franco CD, Mandracchia D, Trapani G, Franchini C. In vitro and ex vivo studies on diltiazem hydrochloride-loaded microsponges in rectal gels for chronic anal fissures treatment. Int J Pharm. 2019;557:53-65. doi: 10.1016/j.ijpharm.2018.12.039, PMID 30580086.

25. Ahmed S, Mahmood S, Danish Ansari MD, Gull A, Sharma N, Sultana Y. Nanostructured lipid carrier to overcome stratum corneum barrier for the delivery of agomelatine in rat brain; formula optimization, characterization and brain distribution study. Int J Pharm. 2021;607:121006. doi: 10.1016/j.ijpharm.2021.121006, PMID 34391848.

26. Yuan Y, Cui Y, Zhang L, Zhu HP, Guo YS, Zhong B. Thermosensitive and mucoadhesive in situ gel based on poloxamer as new carrier for rectal administration of nimesulide. Int J Pharm. 2012;430(1-2):114-9. doi: 10.1016/j.ijpharm.2012.03.054, PMID 22503953.

27. Kolawole OM, Lau WM, Khutoryanskiy VV. Chitosan/β-glycerophosphate in situ gelling mucoadhesive systems for intravesical delivery of mitomycin-C. Int J Pharm X. 2019;1:100007. doi: 10.1016/j.ijpx.2019.100007, PMID 31517272.

28. Vigani B, Rossi S, Sandri G, Bonferoni MC, Caramella CM, Ferrari F. Recent advances in the development of in situ gelling drug delivery systems for non-parenteral administration routes. Pharmaceutics. 2020;12(9):859. doi: 10.3390/pharmaceutics12090859, PMID 32927595.

29. Zahir Jouzdani F, Wolf JD, Atyabi F, Bernkop Schnurch A. In situ gelling and mucoadhesive polymers: why do they need each other? Expert Opin Drug Deliv. 2018;15(10):1007-19. doi: 10.1080/17425247.2018.1517741, PMID 30173567.

30. Myers RH, Montgomery DC, Anderson Cook CM. Response surface methodology: process and product optimization using designed experiments. 4th ed. John Wiley & Sons; 2016.

31. Batool S, Zahid F, Ud Din F, Naz SS, Dar MJ, Khan MW. Macrophage targeting with the novel carbopol-based miltefosine-loaded transfersomal gel for the treatment of cutaneous leishmaniasis: in vitro and in vivo analyses. Drug Dev Ind Pharm. 2021;47(3):440-53. doi: 10.1080/03639045.2021.1890768, PMID 33615936.

32. Jagdale SC, Deore GK, Chabukswar AR. Development of microemulsion-based nabumetone transdermal delivery for treatment of arthritis. Recent Pat Drug Deliv Formul. 2018;12(2):130-49. doi: 10.2174/1872211312666180227091059, PMID 29485013.

33. Pham CV, Van MC, Thi HP, Thanh CD, Ngoc BT, Van BN. Development of ibuprofen loaded solid lipid nanoparticle-based hydrogels for enhanced in vitro dermal permeation and in vivo topical anti-inflammatory activity. J Drug Deliv Sci Technol. 2020;57:101758. doi: 10.1016/j.jddst.2020.101758.

34. Baig MS, Ahad A, Aslam M, Imam SS, Aqil M, Ali A. Application of box–behnken design for preparation of levofloxacin-loaded stearic acid solid lipid nanoparticles for ocular delivery: optimization in vitro release ocular tolerance and antibacterial activity. Int J Biol Macromol. 2016;85:258-70. doi: 10.1016/j.ijbiomac.2015.12.077, PMID 26740466.

35. Plosker GL, Faulds D. Epirubicin a review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in cancer chemotherapy. Drugs. 1993;45(5):788-856. doi: 10.2165/00003495-199345050-00011, PMID 7686469.

36. Zahir Jouzdani F, Wolf JD, Atyabi F, Bernkop Schnurch A. In situ gelling and mucoadhesive polymers: why do they need each other? Expert Opin Drug Deliv. 2018;15(10):1007-19. doi: 10.1080/17425247.2018.1517741, PMID 30173567.

37. Din FU, Choi JY, Kim DW, Mustapha O, Kim DS, Thapa RK. Irinotecan encapsulated double reverse thermosensitive nanocarrier system for rectal administration. Drug Deliv. 2017;24(1):502-10. doi: 10.1080/10717544.2016.1272651, PMID 28181835.

38. Wadetwar RN, Agrawal AR, Kanojiya PS. In situ gel containing Bimatoprost solid lipid nanoparticles for ocular delivery: in vitro and ex vivo evaluation. J Drug Deliv Sci Technol. 2020;56:101575. doi: 10.1016/j.jddst.2020.101575.

39. Ivanova NA, Trapani A, Franco CD, Mandracchia D, Trapani G, Franchini C. In vitro and ex vivo studies on diltiazem hydrochloride-loaded microsponges in rectal gels for chronic anal fissures treatment. Int J Pharm. 2019;557:53-65. doi: 10.1016/j.ijpharm.2018.12.039, PMID 30580086.

40. Kumar R, Singh A, Sharma K, Dhasmana D, Garg N, Siril PF. Preparation characterization and in vitro cytotoxicity of fenofibrate and nabumetone loaded solid lipid nanoparticles. Mater Sci Eng C Mater Biol Appl. 2020;106:110184. doi: 10.1016/j.msec.2019.110184, PMID 31753394.

41. Purohit TJ, Hanning SM, Wu Z. Advances in rectal drug delivery systems. Pharm Dev Technol. 2018;23(10):942-52. doi: 10.1080/10837450.2018.1484766, PMID 29888992.

42. Park H, Kim MH, Yoon YI, Park WH. One-pot synthesis of injectable methylcellulose hydrogel containing calcium phosphate nanoparticles. Carbohydr Polym. 2017;157:775-83. doi: 10.1016/j.carbpol.2016.10.055, PMID 27987990.

43. Bar Shalom D, Klaus R, editors. Pediatric formulations: a road map. AAPS Adv Pharm Sci. 2014. doi: 10.1007/978-1-4899-8011-3.

44. Li L, Guo D, Guo J, Song J, Wu Q, Liu D. Thermosensitive in situ forming gels for ophthalmic delivery of tea polyphenols. J Drug Deliv Sci Technol. 2018 Aug;46:243-50. doi: 10.1016/j.jddst.2018.05.019.

45. Chen L, Han X, Xu X, Zhang Q, Zeng Y, Su Q. Optimization and evaluation of the thermosensitive in situ and adhesive gel for rectal delivery of budesonide. AAPS PharmSciTech. 2020;21(3):97. doi: 10.1208/s12249-020-1631-5, PMID 32128636.

46. Ramadan EM, Borg TM, Elkayal MO. Formulation and evaluation of novel mucoadhesive ketorolac tromethamine liquid suppository. Asian J Pharm Pharmacol. 2016;3:124-32.

47. Din FU, Kim DW, Choi JY, Thapa RK, Mustapha O, Kim DS. Irinotecan-loaded double reversible thermogel with improved antitumor efficacy without initial burst effect and toxicity for intramuscular administration. Acta Biomater. 2017;54:239-48. doi: 10.1016/j.actbio.2017.03.007, PMID 28285074.

48. Xing R, Mustapha O, Ali T, Rehman M, Zaidi SS, Baseer A. Development characterization and evaluation of SLN-loaded thermoresponsive hydrogel system of topotecan as biological macromolecule for colorectal delivery. BioMed Res Int. 2021;2021:9968602. doi: 10.1155/2021/9968602, PMID 34285920.

49. Al Kinani AA, Zidan G, Elsaid N, Seyfoddin A, Alani AW, Alany RG. Ophthalmic gels: past present and future. Adv Drug Deliv Rev. 2018;126:113-26. doi: 10.1016/j.addr.2017.12.017, PMID 29288733.

50. Agibayeva LE, Kaldybekov DB, Porfiryeva NN, Garipova VR, Mangazbayeva RA, Moustafine RI. Gellan gum and its methacrylated derivatives as in situ gelling mucoadhesive formulations of pilocarpine: in vitro and in vivo studies. Int J Pharm. 2020;577:119093. doi: 10.1016/j.ijpharm.2020.119093, PMID 32004682.