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image of Development and Evaluation of a pH-Triggered Aristoflex-Based In-Situ Gel for Sustained Acetazolamide Delivery in Glaucoma Management

Abstract

Introduction

Glaucoma is a common eye condition characterized by elevated intraocular pressure (IOP), which can lead to gradual vision loss or serious ocular issues. An effective dosage form is needed to address challenges, such as poor bioavailability and short retention time on the ocular surface. The current study aims to develop a sustained-release - gel formulation by modifying its polymeric composition, thereby overcoming the barriers of existing ocular drug delivery systems.

Methods

The formulations were prepared using the cold method and optimized with experimental design software to assess the effect of different concentrations, with viscosity as the dependent variable. The optimized formulation (S2) was tested for clarity, viscosity, pH, gelling capacity, rheological behavior, and drug–polymer interactions , , and .

Results

The gel was transparent, with a pH of 7.1, viscosity of 16327 CP, and transformed from sol to gel at ocular pH. Additionally, the formulation demonstrated sustained drug release in both and studies, yielding a favorable result in reducing IOP.

Discussion

Among all the polymers used in the formulation, Aristoflex and sodium alginate make an excellent formulation with a more extended gelling period and increased ocular residence.

Conclusion

The optimized formulation (S2), unlike traditional eye drops, may offer improved ocular delivery at lower doses and enhance patient compliance.

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2026-01-22
2026-02-02

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References

  1. Sharif N.A. Neuropathology and therapeutics addressing glaucoma, a prevalent retina-optic nerve-brain disease that causes eyesight impairment and blindness. OBM Neurobiol. 2022 6 1 1 51 10.21926/obm.neurobiol.2201116
    [Google Scholar]
  2. Patton G.N. Lee H.J. Chemical insights into topical agents in intraocular pressure management: from glaucoma etiopathology to therapeutic approaches. Pharmaceutics 2024 16 2 274 10.3390/pharmaceutics16020274 38399328
    [Google Scholar]
  3. Wagner I.V. Stewart M.W. Dorairaj S.K. Updates on the diagnosis and management of glaucoma. Mayo Clin. Proc. Innov. Qual. Outcomes 2022 6 6 618 635 10.1016/j.mayocpiqo.2022.09.007 36405987
    [Google Scholar]
  4. Schuster A.K. Erb C. Hoffmann E.M. Dietlein T. Pfeiffer N. The diagnosis and treatment of glaucoma. Dtsch. Arztebl. Int. 2020 117 13 225 234 10.3238/arztebl.2020.0225 32343668
    [Google Scholar]
  5. Zembala J. Forma A. Zembala R. Technological advances in therapy of primary open-angle glaucoma: insights into current nanotechnologies. J. Clin. Med. 2023 12 18 5798 10.3390/jcm12185798 37762739
    [Google Scholar]
  6. Mohan N. Chakrabarti A. Nazm N. Mehta R. Edward D.P. Newer advances in medical management of glaucoma. Indian J. Ophthalmol. 2022 70 6 1920 1930 10.4103/ijo.IJO_2239_21 35647957
    [Google Scholar]
  7. Qin M. Yu-Wai-Man C. Glaucoma: Novel antifibrotic therapeutics for the trabecular meshwork. Eur. J. Pharmacol. 2023 954 175882 10.1016/j.ejphar.2023.175882 37391006
    [Google Scholar]
  8. Paul S. Majumdar S. Chakraborty M. Revolutionizing ocular drug delivery: recent advancements in in situ gel technology. Bull. Natl. Res. Cent. 2023 47 1 154 10.1186/s42269‑023‑01123‑9
    [Google Scholar]
  9. Fea A.M. Novarese C. Caselgrandi P. Boscia G. Glaucoma treatment and hydrogel: current insights and state of the art. Gels 2022 8 8 510 10.3390/gels8080510 36005112
    [Google Scholar]
  10. Belamkar A. Harris A. Zukerman R. Sustained release glaucoma therapies: Novel modalities for overcoming key treatment barriers associated with topical medications. Ann. Med. 2022 54 1 343 358 10.1080/07853890.2021.1955146 35076329
    [Google Scholar]
  11. Weinreb R.N. Aung T. Medeiros F.A. The pathophysiology and treatment of glaucoma: a review. JAMA 2014 311 18 1901 1911 10.1001/jama.2014.3192 24825645
    [Google Scholar]
  12. Ahmed S. Amin M.M. Sayed S. Ocular drug delivery: a comprehensive review. AAPS PharmSciTech 2023 24 2 66 10.1208/s12249‑023‑02516‑9 36788150
    [Google Scholar]
  13. Akhter M.H. Ahmad I. Alshahrani M.Y. Drug delivery challenges and current progress in nanocarrier-based ocular therapeutic system. Gels 2022 8 2 82 10.3390/gels8020082 35200463
    [Google Scholar]
  14. Wu K.Y. Ashkar S. Jain S. Marchand M. Tran S.D. Breaking barriers in eye treatment: polymeric nano-based drug-delivery system for anterior segment diseases and glaucoma. Polymers (Basel) 2023 15 6 1373 10.3390/polym15061373 36987154
    [Google Scholar]
  15. Wang L. Zhang H. Ocular barriers as a double-edged sword: preventing and facilitating drug delivery to the retina. Drug Deliv. Transl. Res. 2023 13 2 547 567 10.1007/s13346‑022‑01231‑5 36129668
    [Google Scholar]
  16. Sharma Y. Patel P. Kurmi B.D. A mini-review on new developments in nanocarriers and polymers for ophthalmic drug delivery strategies. Curr. Drug Deliv. 2024 21 4 488 508 10.2174/1567201820666230504115446 37143264
    [Google Scholar]
  17. Wood C.M. Cerebrospinal fluid modulation for enhanced drug delivery in the brain. Doctoral dissertation, Rutgers University—School of Graduate Studies 2023 10.7282/t3‑vg2x‑ny66
    [Google Scholar]
  18. Shalaby W.S. Ahmed O.M. Waisbourd M. Katz L.J. A review of potential novel glaucoma therapeutic options independent of intraocular pressure. Surv. Ophthalmol. 2022 67 4 1062 1080 10.1016/j.survophthal.2021.12.003 34890600
    [Google Scholar]
  19. Vallejo R. Quinteros D. Gutiérrez J. Acetazolamide encapsulation in elastin like recombinamers using a supercritical antisolvent (SAS) process for glaucoma treatment. Int. J. Pharm. 2024 657 124098 10.1016/j.ijpharm.2024.124098 38621614
    [Google Scholar]
  20. da Silva P.H.R. de Castro M.A. Ribeiro M.C.S. Acetazolamide-loaded intravitreal implants for the treatment of glaucoma: formulation, physicochemical characterization and assessment of In vitro and in vivo safety. Int. J. Pharm. 2025 674 125507 10.1016/j.ijpharm.2025.125507 40132768
    [Google Scholar]
  21. Londhe V.Y. Sharma S. Formulation, characterization, optimization and in-vivo evaluation of methazolamide liposomal in-situ gel for treating glaucoma. J. Drug Deliv. Sci. Technol. 2022 67 102951 10.1016/j.jddst.2021.102951
    [Google Scholar]
  22. Storgaard L. Tran T.L. Freiberg J.C. Hauser A.S. Kolko M. Glaucoma clinical research: Trends in treatment strategies and drug development. Front. Med. (Lausanne) 2021 8 733080 10.3389/fmed.2021.733080 34589504
    [Google Scholar]
  23. Khallaf A.M. El-Moslemany R.M. Ahmed M.F. Morsi M.H. Khalafallah N.M. Exploring a novel fasudil–phospholipid complex formulated as a liposomal thermosensitive in situ gel for glaucoma. Int. J. Nanomedicine 2022 17 163 181 10.2147/IJN.S342975 35046652
    [Google Scholar]
  24. Kurniawansyah I.S. Rusdiana T. Sopyan I. Desy Arya I.F. Wahab H.A. Nurzanah D. Comparative study of in situ gel formulation based on the physico-chemical aspect: systematic review. Gels 2023 9 8 645 10.3390/gels9080645 37623100
    [Google Scholar]
  25. Fathalla Z. Mustafa W.W. Abdelkader H. Moharram H. Sabry A.M. Alany R.G. Hybrid thermosensitive-mucoadhesive in situ forming gels for enhanced corneal wound healing effect of L-carnosine. Drug Deliv. 2022 29 1 374 385 10.1080/10717544.2021.2023236 35068268
    [Google Scholar]
  26. Njoku C.N. Otisi S.K. Application of central composite design with design expert v13 in process optimization. Response Surface Methodology—Research Advances and Applications. Kayaroganam P. IntechOpen 2023 10.5772/intechopen.109704
    [Google Scholar]
  27. Challa T.R. Reshma K. Experimental design statistically by design expert software: a model poorly soluble drug with dissolution enhancement and optimization. INTERNATIONAL JOURNAL OF DRUG DELIVERY TECHNOLOGY 2022 12 3 1367 1375 10.25258/ijddt.12.3.72
    [Google Scholar]
  28. Mohammed N. Palaniandy P. Shaik F. Mewada H. Balakrishnan D. Comparative studies of RSM Box-Behnken and ANN-Anfis fuzzy statistical analysis for seawater biodegradability using TiO2 photocatalyst. Chemosphere 2023 314 137665 10.1016/j.chemosphere.2022.137665 36581118
    [Google Scholar]
  29. Biswal S. Parmanik A. Das D. Sahoo R.N. Nayak A.K. Gellan gum-based in-situ gel formulations for ocular drug delivery: A practical approach. Int. J. Biol. Macromol. 2024 138979 10.1016/j.ijbiomac.2024.138979 39708866
    [Google Scholar]
  30. Abdelmonem R. Elhabal S.F. Abdelmalak N.S. El-Nabarawi M.A. Teaima M.H. Formulation and characterization of acetazolamide/carvedilol liposomal gel for glaucoma treatment: In vitro and in vivo study. Pharmaceutics 2021 13 2 221 10.3390/pharmaceutics13020221 33562785
    [Google Scholar]
  31. El-Feky Y.A. Fares A.R. Zayed G. El-Telbany R.F.A. Ahmed K.A. El-Telbany D.F.A. Repurposing of nifedipine loaded in situ ophthalmic gel as a novel approach for glaucoma treatment. Biomed. Pharmacother. 2021 142 112008 10.1016/j.biopha.2021.112008 34385102
    [Google Scholar]
  32. Allam A. Elsabahy M. El Badry M. Eleraky N.E. Betaxolol‐loaded niosomes integrated within pH‐sensitive in situ forming gel for management of glaucoma. Int. J. Pharm. 2021 598 120380 10.1016/j.ijpharm.2021.120380 33609725
    [Google Scholar]
  33. Vijay M. Parjanya K. Formulation and evaluation of in-situ gel of bromhexine hydrochloride for nasal delivery. Pharm. Sin. 2012
    [Google Scholar]
  34. Dholakia M. Thakkar V. Patel N. Gandhi T. Development and characterisation of thermo reversible mucoadhesive moxifloxacin hydrochloride in situ ophthalmic gel. J. Pharm. Bioallied Sci. 2012 4 5 42 10.4103/0975‑7406.94138 23066202
    [Google Scholar]
  35. Ranch K.M. Maulvi F.A. Naik M.J. Koli A.R. Parikh R.K. Shah D.O. Optimization of a novel in situ gel for sustained ocular drug delivery using Box-Behnken design: In vitro, ex vivo, in vivo and human studies. Int. J. Pharm. 2019 554 264 275 10.1016/j.ijpharm.2018.11.016 30423418
    [Google Scholar]
  36. Youssef A.A.A. Dudhipala N. Majumdar S. Dual drug loaded lipid nanocarrier formulations for topical ocular applications. Int. J. Nanomedicine 2022 17 2283 2299 10.2147/IJN.S360740 35611213
    [Google Scholar]
  37. Ahirrao S.P. Bhambere D.S. Agiwale B. Algat S. Zoman D. Chaudhari V. pH sensitive in-situ gel for ophthalmic delivery of ofloxacin and dexamethasone sodium phosphate: Formulation, development, and evaluation. Mater. Today Proc. 2023 10.1016/j.matpr.2023.07.161
    [Google Scholar]
  38. Sadeq Z.A. Sabri L.A. Al-Kinani K.K. Natural polymer Effect on gelation and rheology of ketotifen-loaded pH-sensitive in situ ocular gel (Carbapol) ‎. J. Adv. Pharm. Educ. Res. 2022 12 2 45 50 10.51847/zOf4TcFeKT
    [Google Scholar]
  39. Gilani S.J. Jumah M.N. Zafar A. Formulation and evaluation of nano lipid carrier-based ocular gel system: optimization to antibacterial activity. Gels 2022 8 5 255 10.3390/gels8050255 35621552
    [Google Scholar]
  40. Polat H.K. Ünal S. Aytekin E. Formulation development of Lornoxicam loaded heat triggered ocular in-situ gel using factorial design. Drug Dev. Ind. Pharm. 2023 49 9 601 615 10.1080/03639045.2023.2264932 37788164
    [Google Scholar]
  41. Phan C.M. Ross M. Fahmy K. Evaluating viscosity and tear breakup time of contemporary commercial ocular lubricants on an In vitro eye model. Transl. Vis. Sci. Technol. 2023 12 6 29 10.1167/tvst.12.6.29 37382574
    [Google Scholar]
  42. Laddha U.D. Kshirsagar S.J. Formulation of nanoparticles loaded in situ gel for treatment of dry eye disease: In vitro, ex vivo and in vivo evidences. J. Drug Deliv. Sci. Technol. 2021 61 102112 10.1016/j.jddst.2020.102112
    [Google Scholar]
  43. Yadav N. Parashar A.K. Sethi V.A. Development and assessment of in-situ gel formulation for ocular pain and inflammation. Int J Newgen Res Pharm Healthc 2024 2 1 248 254 10.61554/ijnrph.v2i1.2024.71
    [Google Scholar]
  44. Shukr M.H. Ismail S. El-Hossary G.G. El-Shazly A.H. Design and evaluation of mucoadhesive in situ liposomal gel for sustained ocular delivery of travoprost using two steps factorial design. J. Drug Deliv. Sci. Technol. 2021 61 102333 10.1016/j.jddst.2021.102333
    [Google Scholar]
  45. Aldawsari M.F. Moglad E.H. Alotaibi H.F. Alkahtani H.M. Khafagy E.S. Ophthalmic bimatoprost-loaded niosomal in situ gel: preparation, optimization, and in vivo pharmacodynamics study. Polymers (Basel) 2023 15 21 4336 10.3390/polym15214336 37960016
    [Google Scholar]
  46. Mandal S. Prabhushankar G.L. Thimmasetty M.K.M.J. Geetha M.S. Formulation and evaluation of an in situ gel-forming ophthalmic formulation of moxifloxacin hydrochloride. Int. J. Pharm. Investig. 2012 2 2 78 82 10.4103/2230‑973X.100042 23119236
    [Google Scholar]
  47. Alsaidan O.A. Zafar A. Yasir M. Alzarea S.I. Alqinyah M. Khalid M. Development of ciprofloxacin-loaded bilosomes in-situ gel for ocular delivery: optimization, in-vitro characterization, ex-vivo permeation, and antimicrobial study. Gels 2022 8 11 687 10.3390/gels8110687 36354595
    [Google Scholar]
  48. Agha O.A. Girgis G.N.S. El-Sokkary M.M.A. Soliman O.A.E.A. Spanlastic-laden in situ gel as a promising approach for ocular delivery of Levofloxacin: In-vitro characterization, microbiological assessment, corneal permeability and in-vivo study. Int. J. Pharm. X 2023 6 100201 10.1016/j.ijpx.2023.100201 37560488
    [Google Scholar]
  49. Sipos B. Budai-Szűcs M. Kókai D. Erythromycin-loaded polymeric micelles: in situ gel development, In vitro and ex vivo ocular investigations. Eur. J. Pharm. Biopharm. 2022 180 81 90 10.1016/j.ejpb.2022.09.023 36183927
    [Google Scholar]
  50. Safan A. Youssef T. Zaazou M.H. Abd El-Moez S.I. El-Shinawy H. Sadony D.M. Antibacterial effect of silver and gold nanoparticles and diode laser against Lactobacillus acidophilus bacteria. Int. J. Adv. Res. (Indore) 2014 2 8 34 38
    [Google Scholar]
  51. Saka R. Jain H. Kommineni N. Chella N. Khan W. Enhanced penetration and improved therapeutic efficacy of bexarotene via topical liposomal gel in imiquimod induced psoriatic plaque model in BALB/c mice. J. Drug Deliv. Sci. Technol. 2020 58 101691 10.1016/j.jddst.2020.101691
    [Google Scholar]
  52. Ali F. Habibullah S. Giri Y. Behera A. Mohanty B. Formulation and evaluation of acetazolamide loaded in–situ gel for the treatment of glaucoma. Journal of Research in Pharmacy 2023 27 1 74 85 10.29228/jrp.291
    [Google Scholar]
  53. Pardeshi S.R. More M.P. Patil P.B. Mujumdar A. Naik J.B. Statistical optimization of voriconazole nanoparticles loaded carboxymethyl chitosan-poloxamer based in situ gel for ocular delivery: In vitro, ex vivo, and toxicity assessment. Drug Deliv. Transl. Res. 2022 12 12 3063 3082 10.1007/s13346‑022‑01171‑0 35525868
    [Google Scholar]
  54. Szalai B Budai-Szűcs M Kovács A The effect of mucoadhesive polymers on ocular permeation of thermoresponsive in situ gel containing dexamethasone–cyclodextrin complex. Int J Pharm 2024 667 Pt A 124848 10.1016/j.ijpharm.2024.124848 39447934
    [Google Scholar]
  55. Chaudhari P. Naik R. Sruthi Mallela L. A supramolecular thermosensitive gel of ketoconazole for ocular applications: In silico, In vitro, and ex vivo studies. Int. J. Pharm. 2022 613 121409 10.1016/j.ijpharm.2021.121409 34952148
    [Google Scholar]
  56. Patel D. Patel A. Patel M. Patel C. Formulation and evaluation of mixed matrix gastro-retentive drug delivery for famotidine. Int. J. Pharm. Investig. 2011 1 4 247 254 10.4103/2230‑973X.93006 23071951
    [Google Scholar]
  57. Ünal S. Polat H.K. Yuvalı D. Şafak E.K. Development of in situ gel containing CUR: HP-β-CD inclusion complex prepared for ocular diseases: formulation, characterization, anti-inflammatory, anti-oxidant evaluation and comprehensive release kinetic studies. Journal of Research in Pharmacy 2023 27 1 97 119 10.12991/jrp.2023.296
    [Google Scholar]
  58. Rawat P.S. Ravi P.R. Mir S.I. Design, characterization and pharmacokinetic–pharmacodynamic evaluation of poloxamer- and kappa-carrageenan-based dual-responsive in situ gel of nebivolol for treatment of open-angle glaucoma. Pharmaceutics 2023 15 2 405 10.3390/pharmaceutics15020405 36839727
    [Google Scholar]
  59. Kalaria V.J. Saisivam S. Alshishani A. Aljariri Alhesan J.S. Chakraborty S. Rahamathulla M. Design and evaluation of in situ gel eye drops containing nanoparticles of Gemifloxacin Mesylate. Drug Deliv. 2023 30 1 2185180 10.1080/10717544.2023.2185180 36876464
    [Google Scholar]
  60. Barse R. Kokare C. Tagalpallewar A. Influence of hydroxypropylmethylcellulose and poloxamer composite on developed ophthalmic in situ gel: Ex vivo and in vivo characterization. J. Drug Deliv. Sci. Technol. 2016 33 66 74 10.1016/j.jddst.2016.03.011
    [Google Scholar]
  61. Khan N. Aqil M. Imam S.S. Ali A. Development and evaluation of a novel in situ gel of sparfloxacin for sustained ocular drug delivery: In vitro and ex vivo characterization. Pharm. Dev. Technol. 2015 20 6 662 669 10.3109/10837450.2014.910807 24754411
    [Google Scholar]
  62. Stuart K.V. Madjedi K. Luben R.N. Modifiable Risk Factors for Glaucoma Collaboration. Alcohol, intraocular pressure, and open-angle glaucoma: a systematic review and meta-analysis. Ophthalmology 2022 129 6 637 652 10.1016/j.ophtha.2022.01.023 35101531
    [Google Scholar]
  63. Shi Y. Wang H. Oatts J.T. A prospective study of intraocular pressure spike and failure after gonioscopy-assisted transluminal trabeculotomy in juvenile open-angle glaucoma: a prospective study of GATT in JOAG. Am. J. Ophthalmol. 2022 236 79 88 10.1016/j.ajo.2021.10.009 34695398
    [Google Scholar]
  64. Pehlivan S.B. Yavuz B. Çalamak S. Preparation and In vitro/in vivo evaluation of cyclosporin A-loaded nanodecorated ocular implants for subconjunctival application. J. Pharm. Sci. 2015 104 5 1709 1720 10.1002/jps.24385 25716582
    [Google Scholar]
  65. Palei N.N. Mohanta B.C. Das M.K. Sabapathi M.L. Lornoxicam loaded nanostructured lipid carriers for topical delivery: Optimization, skin uptake and in vivo studies. J. Drug Deliv. Sci. Technol. 2017 39 490 500 10.1016/j.jddst.2017.05.001
    [Google Scholar]
  66. Gade S. Patel K.K. Gupta C. An ex vivo evaluation of moxifloxacin nanostructured lipid carrier enriched in situ gel for transcorneal permeation on goat cornea. J. Pharm. Sci. 2019 108 9 2905 2916 10.1016/j.xphs.2019.04.005 30978345
    [Google Scholar]
  67. Nair A.B. Shah J. Jacob S. Experimental design, formulation and in vivo evaluation of a novel topical in situ gel system to treat ocular infections. PLoS One 2021 16 3 e0248857 10.1371/journal.pone.0248857 33739996
    [Google Scholar]
  68. Maulvi F.A. Lakdawala D.H. Shaikh A.A. In vitro and in vivo evaluation of novel implantation technology in hydrogel contact lenses for controlled drug delivery. J. Control. Release 2016 226 47 56 10.1016/j.jconrel.2016.02.012 26860285
    [Google Scholar]
  69. Li R. Jiang S. Liu D. A potential new therapeutic system for glaucoma: solid lipid nanoparticles containing methazolamide. J. Microencapsul. 2011 28 2 134 141 10.3109/02652048.2010.539304 21142697
    [Google Scholar]
  70. Collier D.J. Wolff C.B. Hedges A.M. Benzolamide improves oxygenation and reduces acute mountain sickness during a high‐altitude trek and has fewer side effects than acetazolamide at sea level. Pharmacol. Res. Perspect. 2016 4 3 e00203 10.1002/prp2.203 27433337
    [Google Scholar]
  71. Kaur I.P. Smitha R. Aggarwal D. Kapil M. Acetazolamide: future perspective in topical glaucoma therapeutics. Int. J. Pharm. 2002 248 1-2 1 14 10.1016/S0378‑5173(02)00438‑6 12429455
    [Google Scholar]
  72. Rojek B. Wesolowski M. FTIR and TG analyses coupled with factor analysis in a compatibility study of acetazolamide with excipients. Spectrochim. Acta A Mol. Biomol. Spectrosc. 2019 208 285 293 10.1016/j.saa.2018.10.020 30340208
    [Google Scholar]
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Development and Evaluation of a pH-Triggered Aristoflex-Based In-Situ Gel for Sustained Acetazolamide Delivery in Glaucoma Management
Bentham Science Publishers ; https://doi.org/10.2174/0115748855425376251117071959
/content/journals/cdth/10.2174/0115748855425376251117071959
/content/journals/cdth/10.2174/0115748855425376251117071959
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  • Article Type:     Research Article
Keywords: ocular drug target ; Aristoflex ; glaucoma ; intraocular pressure ; bioavailability

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