Research Article
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Polymeric Nanoparticle Formulation, Characterization and Penetration Study for Topical Delivery of Timolol Maleate

Year 2025, Volume: 12 Issue: 2, 117 - 128, 31.05.2025

Muhammad Sulaiman , Endang Lukitaningsih , Ronny Martien , Retno Danarti , Yohanes Widodo Wirohadidjojo

Abstract

Infantile hemangioma (IH), while usually not life-threatening, often carries the risk of complications and causes anxiety due to changes in appearance. While regarded as an effective therapeutic choice, timolol maleate (TM) is mostly effective for mild and superficial lesions due to its limited absorption. The goal of this study was to examine the potency of natural polymers to be utilized as main ingredients in nanoparticle formulations to be used as a potential alternative for treating IH. The major ingredients chosen for nanoparticle production were chitosan and acacia gum. Different combinations of polymer concentrations were examined to improve the characteristics of an optimal formula. The nanoparticles obtained were assessed in terms of their physical properties, encapsulation efficiency, and skin permeation. The resulting nanoparticles (TMNP) exhibited a spherical morphology, had diameters of 175.417 ± 3.144 nm, a PDI of 0.346 ± 0.031 and ZP of 31.95 ± 1.09 mV. An encapsulation efficiency value of 17.42 ± 0.02% was considerably adequate to promote desirable activity towards IH. The nanoparticle exhibited enhanced penetration of drug compared to the unencapsulated form. This research is hoped to contribute to the expanding application of nanoparticle technology, particularly in the treatment of infantile hemangioma utilizing nanoparticles derived from natural sources.

Keywords

Nanoparticles Pharmaceutical preparations Biopolymer Penetration study Infantile hemangioma

Thanks

We expressed our gratitude for the implementation of this research which was carried out through a funding by The Final Project Recognition Grant Gadjah Mada University (Number 5075/UN1.P.II/Dit-Lit/PT.01.01/2023) in 2023

References

  • 1. Satterfield KR, Chambers CB. Current treatment and management of infantile hemangiomas. Surv Ophthalmol [Internet]. 2019 Sep 1;64(5):608–18. Available from: <URL>.
  • 2. Cuggino JC, Tártara LI, Gugliotta LM, Palma SD, Alvarez Igarzabal CI. Mucoadhesive and responsive nanogels as carriers for sustainable delivery of timolol for glaucoma therapy. Mater Sci Eng C [Internet]. 2021 Jan 1;118:111383. Available from: <URL>.
  • 3. Negri L, Ferreras A, Iester M. Timolol 0.1% in Glaucomatous Patients: Efficacy, Tolerance, and Quality of Life. J Ophthalmol [Internet]. 2019 May 2;2019(1):4146124. Available from: <URL>.
  • 4. Wu HW, Wang X, Zhang L, Zheng JW, Liu C, Wang YA. Topical timolol vs. oral propranolol for the treatment of superficial infantile hemangiomas. Front Oncol [Internet]. 2018 Dec 18;8(DEC):605. Available from: <URL>.
  • 5. Tiemann L, Hein S. Infantile hemangioma: A review of current pharmacotherapy treatment and practice pearls. J Pediatr Pharmacol Ther [Internet]. 2020 Sep 1;25(7):586–99. Available from: <URL>.
  • 6. Liviskie CJ, Brennan CC, McPherson CC, Vesoulis ZA. Propranolol for the treatment of lymphatic malformations in a neonate – A case report and review of literature. J Pediatr Pharmacol Ther [Internet]. 2020 Mar 1;25(2):155–62. Available from: <URL>.
  • 7. Macca L, Altavilla D, Di Bartolomeo L, Irrera N, Borgia F, Li Pomi F, et al. Update on treatment of infantile hemangiomas: What’s new in the last five years? Front Pharmacol [Internet]. 2022 May 26;13:879602. Available from: <URL>.
  • 8. Morsi NM, Aboelwafa AA, Dawoud MHS. Improved bioavailability of timolol maleate via transdermal transfersomal gel: Statistical optimization, characterization, and pharmacokinetic assessment. J Adv Res [Internet]. 2016 Sep 1;7(5):691–701. Available from: <URL>.
  • 9. Danarti R, Ariwibowo L, Radiono S, Budiyanto A. Topical timolol maleate 0.5% for infantile hemangioma: Its effectiveness compared to ultrapotent topical corticosteroids - A single-center experience of 278 cases. Dermatology [Internet]. 2016 Jan 10;232(5):566–71. Available from: <URL>.
  • 10. Gong H, Xu D peng, Li Y xiao, Cheng C, Li G, Wang XK. Evaluation of the efficacy and safety of propranolol, timolol maleate, and the combination of the two, in the treatment of superficial infantile haemangiomas. Br J Oral Maxillofac Surg [Internet]. 2015 Nov 1;53(9):836–40. Available from: <URL>.
  • 11. Chen ZY, Wang QN, Zhu YH, Zhou LY, Xu T, He ZY, et al. Progress in the treatment of infantile hemangioma. Ann Transl Med [Internet]. 2019 Nov;7(22):692–692. Available from: <URL>.
  • 12. Benson HAE, Grice JE, Mohammed Y, Namjoshi S, Roberts MS. Topical and transdermal drug delivery: From simple potions to smart technologies. Curr Drug Deliv [Internet]. 2019 May 29;16(5):444–60. Available from: <URL>.
  • 13. Ghasemiyeh P, Mohammadi-Samani S. Potential of nanoparticles as permeation enhancers and targeted delivery options for skin: Advantages and disadvantages. Drug Des Devel Ther [Internet]. 2020 Aug 12;Volume 14:3271–89. Available from: <URL>.
  • 14. Püttgen K, Lucky A, Adams D, Pope E, McCuaig C, Powell J, et al. Topical timolol maleate treatment of infantile hemangiomas. Pediatrics [Internet]. 2016 Sep 1;138(3):e20160355. Available from: <URL>.
  • 15. Wu HW, Liu C, Wang X, Zhang L, Yuan W, Zheng JW, et al. Topical application of 0.5% timolol maleate hydrogel for the treatment of superficial infantile hemangioma. Front Oncol [Internet]. 2017 Jun 27;7:137. Available from: <URL>.
  • 16. Zanela da Silva Marques T, Santos-Oliveira R, Betzler de Oliveira de Siqueira L, da Silva Cardoso V, Maria Faria de Freitas Z, Barros RCSA, et al. Development and characterization of a nanoemulsion containing propranolol for topical delivery. Int J Nanomedicine [Internet]. 2018 May 14;13:2827–37. Available from: <URL>.
  • 17. Ma J, Wang Y, Lu R. Mechanism and application of chitosan and its derivatives in promoting permeation in transdermal drug delivery systems: A review. Pharmaceuticals [Internet]. 2022 Apr 10;15(4):459. Available from: <URL>.
  • 18. Neupane R, Boddu SHS, Renukuntla J, Babu RJ, Tiwari AK. Alternatives to biological skin in permeation studies: Current trends and possibilities. Pharmaceutics [Internet]. 2020 Feb 13;12(2):152. Available from: <URL>.
  • 19. Muhtadi WK, Novitasari L, Danarti R, Martien R. Development of polymeric nanoparticle gel prepared with the combination of ionic pre-gelation and polyelectrolyte complexation as a novel drug delivery of timolol maleate. Drug Dev Ind Pharm [Internet]. 2020 Nov 1;46(11):1844–52. Available from: <URL>.
  • 20. Vuillemin ME, Michaux F, Muniglia L, Linder M, Jasniewski J. Gum Arabic and chitosan self-assembly: Thermodynamic and mechanism aspects. Food Hydrocoll [Internet]. 2019 Nov 1;96:463–74. Available from: <URL>.
  • 21. Schafer N, Balwierz R, Biernat P, Ochędzan-Siodłak W, Lipok J. Natural ingredients of transdermal drug delivery systems as permeation enhancers of active substances through the Stratum Corneum. Mol Pharm [Internet]. 2023 Jul 3;20(7):3278–97. Available from: <URL>.
  • 22. Modena MM, Rühle B, Burg TP, Wuttke S. Nanoparticle characterization: What to measure? Adv Mater [Internet]. 2019 Aug 30;31(32):1901556. Available from: <URL>.
  • 23. Dukhin AS, Xu R. Zeta-potential measurements. In: Characterization of Nanoparticles [Internet]. Elsevier; 2020. p. 213–24. Available from: <URL>.
  • 24. Akinluwade K, Oyatogun G, Alebiowu G, Adeyemi I, Akinwole I. Synthesis and characterization of polymeric nanoparticles formed from cowry shells and acacia gum extracts. J Adv Biol Biotechnol [Internet]. 2017 Jan 10;14(1):1–8. Available from: <URL>.
  • 25. Ta Q, Ting J, Harwood S, Browning N, Simm A, Ross K, et al. Chitosan nanoparticles for enhancing drugs and cosmetic components penetration through the skin. Eur J Pharm Sci [Internet]. 2021 May 1;160:105765. Available from: <URL>.
  • 26. de Oliveira JL, Campos EVR, Pereira AES, Nunes LES, da Silva CCL, Pasquoto T, et al. Geraniol encapsulated in chitosan/gum arabic nanoparticles: A promising system for pest management in sustainable agriculture. J Agric Food Chem [Internet]. 2018 May 30;66(21):5325–34. Available from: <URL>.
  • 27. Chavda D, Thakkar V, Soni T, Gandhi T. Formulation and in vitro-in vivo evaluations of timolol maleate viscous eye drops for the treatment of glaucoma. Eur J Biomed Pharm Sci [Internet]. 2016;3(9):573–85. Available from: <URL>.
  • 28. Rahma A, Lane ME, Sinkó B. A comparative study of the in vitro permeation of 2-phenoxyethanol in the skin PAMPA model and mammalian skin. Int J Pharm [Internet]. 2023 Mar 25;635:122692. Available from: <URL>.
  • 29. Todo H. Transdermal permeation of drugs in various animal species. Pharmaceutics [Internet]. 2017 Sep 6;9(3):33. Available from: <URL>.
  • 30. Praça FSG, Medina WSG, Eloy JO, Petrilli R, Campos PM, Ascenso A, et al. Evaluation of critical parameters for in vitro skin permeation and penetration studies using animal skin models. Eur J Pharm Sci [Internet]. 2018 Jan 1;111:121–32. Available from: <URL>.
  • 31. Chantasart D, Hao J, Li SK. Evaluation of skin permeation of β-blockers for topical drug delivery. Pharm Res [Internet]. 2013 Mar 4;30(3):866–77. Available from: <URL>.
  • 32. Soni S, Jain SK, Jain NK. Effect of penetration enhancers on transdermal delivery of timolol maleate. Drug Dev Ind Pharm [Internet]. 1992 Jan 20;18(10):1127–35. Available from: <URL>.
  • 33. Iyer A, Jyothi VGSS, Agrawal A, Khatri DK, Srivastava S, Singh SB, et al. Does skin permeation kinetics influence efficacy of topical dermal drug delivery system? J Adv Pharm Technol Res [Internet]. 2021 Oct 1;12(4):345–55. Available from: <URL>.
  • 34. Supe S, Takudage P. Methods for evaluating penetration of drug into the skin: A review. Ski Res Technol [Internet]. 2021 May 23;27(3):299–308. Available from: <URL>.

Year 2025, Volume: 12 Issue: 2, 117 - 128, 31.05.2025

Muhammad Sulaiman , Endang Lukitaningsih , Ronny Martien , Retno Danarti , Yohanes Widodo Wirohadidjojo

Abstract

References

  • 1. Satterfield KR, Chambers CB. Current treatment and management of infantile hemangiomas. Surv Ophthalmol [Internet]. 2019 Sep 1;64(5):608–18. Available from: <URL>.
  • 2. Cuggino JC, Tártara LI, Gugliotta LM, Palma SD, Alvarez Igarzabal CI. Mucoadhesive and responsive nanogels as carriers for sustainable delivery of timolol for glaucoma therapy. Mater Sci Eng C [Internet]. 2021 Jan 1;118:111383. Available from: <URL>.
  • 3. Negri L, Ferreras A, Iester M. Timolol 0.1% in Glaucomatous Patients: Efficacy, Tolerance, and Quality of Life. J Ophthalmol [Internet]. 2019 May 2;2019(1):4146124. Available from: <URL>.
  • 4. Wu HW, Wang X, Zhang L, Zheng JW, Liu C, Wang YA. Topical timolol vs. oral propranolol for the treatment of superficial infantile hemangiomas. Front Oncol [Internet]. 2018 Dec 18;8(DEC):605. Available from: <URL>.
  • 5. Tiemann L, Hein S. Infantile hemangioma: A review of current pharmacotherapy treatment and practice pearls. J Pediatr Pharmacol Ther [Internet]. 2020 Sep 1;25(7):586–99. Available from: <URL>.
  • 6. Liviskie CJ, Brennan CC, McPherson CC, Vesoulis ZA. Propranolol for the treatment of lymphatic malformations in a neonate – A case report and review of literature. J Pediatr Pharmacol Ther [Internet]. 2020 Mar 1;25(2):155–62. Available from: <URL>.
  • 7. Macca L, Altavilla D, Di Bartolomeo L, Irrera N, Borgia F, Li Pomi F, et al. Update on treatment of infantile hemangiomas: What’s new in the last five years? Front Pharmacol [Internet]. 2022 May 26;13:879602. Available from: <URL>.
  • 8. Morsi NM, Aboelwafa AA, Dawoud MHS. Improved bioavailability of timolol maleate via transdermal transfersomal gel: Statistical optimization, characterization, and pharmacokinetic assessment. J Adv Res [Internet]. 2016 Sep 1;7(5):691–701. Available from: <URL>.
  • 9. Danarti R, Ariwibowo L, Radiono S, Budiyanto A. Topical timolol maleate 0.5% for infantile hemangioma: Its effectiveness compared to ultrapotent topical corticosteroids - A single-center experience of 278 cases. Dermatology [Internet]. 2016 Jan 10;232(5):566–71. Available from: <URL>.
  • 10. Gong H, Xu D peng, Li Y xiao, Cheng C, Li G, Wang XK. Evaluation of the efficacy and safety of propranolol, timolol maleate, and the combination of the two, in the treatment of superficial infantile haemangiomas. Br J Oral Maxillofac Surg [Internet]. 2015 Nov 1;53(9):836–40. Available from: <URL>.
  • 11. Chen ZY, Wang QN, Zhu YH, Zhou LY, Xu T, He ZY, et al. Progress in the treatment of infantile hemangioma. Ann Transl Med [Internet]. 2019 Nov;7(22):692–692. Available from: <URL>.
  • 12. Benson HAE, Grice JE, Mohammed Y, Namjoshi S, Roberts MS. Topical and transdermal drug delivery: From simple potions to smart technologies. Curr Drug Deliv [Internet]. 2019 May 29;16(5):444–60. Available from: <URL>.
  • 13. Ghasemiyeh P, Mohammadi-Samani S. Potential of nanoparticles as permeation enhancers and targeted delivery options for skin: Advantages and disadvantages. Drug Des Devel Ther [Internet]. 2020 Aug 12;Volume 14:3271–89. Available from: <URL>.
  • 14. Püttgen K, Lucky A, Adams D, Pope E, McCuaig C, Powell J, et al. Topical timolol maleate treatment of infantile hemangiomas. Pediatrics [Internet]. 2016 Sep 1;138(3):e20160355. Available from: <URL>.
  • 15. Wu HW, Liu C, Wang X, Zhang L, Yuan W, Zheng JW, et al. Topical application of 0.5% timolol maleate hydrogel for the treatment of superficial infantile hemangioma. Front Oncol [Internet]. 2017 Jun 27;7:137. Available from: <URL>.
  • 16. Zanela da Silva Marques T, Santos-Oliveira R, Betzler de Oliveira de Siqueira L, da Silva Cardoso V, Maria Faria de Freitas Z, Barros RCSA, et al. Development and characterization of a nanoemulsion containing propranolol for topical delivery. Int J Nanomedicine [Internet]. 2018 May 14;13:2827–37. Available from: <URL>.
  • 17. Ma J, Wang Y, Lu R. Mechanism and application of chitosan and its derivatives in promoting permeation in transdermal drug delivery systems: A review. Pharmaceuticals [Internet]. 2022 Apr 10;15(4):459. Available from: <URL>.
  • 18. Neupane R, Boddu SHS, Renukuntla J, Babu RJ, Tiwari AK. Alternatives to biological skin in permeation studies: Current trends and possibilities. Pharmaceutics [Internet]. 2020 Feb 13;12(2):152. Available from: <URL>.
  • 19. Muhtadi WK, Novitasari L, Danarti R, Martien R. Development of polymeric nanoparticle gel prepared with the combination of ionic pre-gelation and polyelectrolyte complexation as a novel drug delivery of timolol maleate. Drug Dev Ind Pharm [Internet]. 2020 Nov 1;46(11):1844–52. Available from: <URL>.
  • 20. Vuillemin ME, Michaux F, Muniglia L, Linder M, Jasniewski J. Gum Arabic and chitosan self-assembly: Thermodynamic and mechanism aspects. Food Hydrocoll [Internet]. 2019 Nov 1;96:463–74. Available from: <URL>.
  • 21. Schafer N, Balwierz R, Biernat P, Ochędzan-Siodłak W, Lipok J. Natural ingredients of transdermal drug delivery systems as permeation enhancers of active substances through the Stratum Corneum. Mol Pharm [Internet]. 2023 Jul 3;20(7):3278–97. Available from: <URL>.
  • 22. Modena MM, Rühle B, Burg TP, Wuttke S. Nanoparticle characterization: What to measure? Adv Mater [Internet]. 2019 Aug 30;31(32):1901556. Available from: <URL>.
  • 23. Dukhin AS, Xu R. Zeta-potential measurements. In: Characterization of Nanoparticles [Internet]. Elsevier; 2020. p. 213–24. Available from: <URL>.
  • 24. Akinluwade K, Oyatogun G, Alebiowu G, Adeyemi I, Akinwole I. Synthesis and characterization of polymeric nanoparticles formed from cowry shells and acacia gum extracts. J Adv Biol Biotechnol [Internet]. 2017 Jan 10;14(1):1–8. Available from: <URL>.
  • 25. Ta Q, Ting J, Harwood S, Browning N, Simm A, Ross K, et al. Chitosan nanoparticles for enhancing drugs and cosmetic components penetration through the skin. Eur J Pharm Sci [Internet]. 2021 May 1;160:105765. Available from: <URL>.
  • 26. de Oliveira JL, Campos EVR, Pereira AES, Nunes LES, da Silva CCL, Pasquoto T, et al. Geraniol encapsulated in chitosan/gum arabic nanoparticles: A promising system for pest management in sustainable agriculture. J Agric Food Chem [Internet]. 2018 May 30;66(21):5325–34. Available from: <URL>.
  • 27. Chavda D, Thakkar V, Soni T, Gandhi T. Formulation and in vitro-in vivo evaluations of timolol maleate viscous eye drops for the treatment of glaucoma. Eur J Biomed Pharm Sci [Internet]. 2016;3(9):573–85. Available from: <URL>.
  • 28. Rahma A, Lane ME, Sinkó B. A comparative study of the in vitro permeation of 2-phenoxyethanol in the skin PAMPA model and mammalian skin. Int J Pharm [Internet]. 2023 Mar 25;635:122692. Available from: <URL>.
  • 29. Todo H. Transdermal permeation of drugs in various animal species. Pharmaceutics [Internet]. 2017 Sep 6;9(3):33. Available from: <URL>.
  • 30. Praça FSG, Medina WSG, Eloy JO, Petrilli R, Campos PM, Ascenso A, et al. Evaluation of critical parameters for in vitro skin permeation and penetration studies using animal skin models. Eur J Pharm Sci [Internet]. 2018 Jan 1;111:121–32. Available from: <URL>.
  • 31. Chantasart D, Hao J, Li SK. Evaluation of skin permeation of β-blockers for topical drug delivery. Pharm Res [Internet]. 2013 Mar 4;30(3):866–77. Available from: <URL>.
  • 32. Soni S, Jain SK, Jain NK. Effect of penetration enhancers on transdermal delivery of timolol maleate. Drug Dev Ind Pharm [Internet]. 1992 Jan 20;18(10):1127–35. Available from: <URL>.
  • 33. Iyer A, Jyothi VGSS, Agrawal A, Khatri DK, Srivastava S, Singh SB, et al. Does skin permeation kinetics influence efficacy of topical dermal drug delivery system? J Adv Pharm Technol Res [Internet]. 2021 Oct 1;12(4):345–55. Available from: <URL>.
  • 34. Supe S, Takudage P. Methods for evaluating penetration of drug into the skin: A review. Ski Res Technol [Internet]. 2021 May 23;27(3):299–308. Available from: <URL>.
There are 34 citations in total.

Details

Primary Language English
Subjects Medicinal and Biomolecular Chemistry (Other)
Journal Section RESEARCH ARTICLES
Authors

Muhammad Sulaiman 0000-0001-5131-6249

Endang Lukitaningsih 0000-0002-4969-5128

Ronny Martien 0000-0001-7291-6497

Retno Danarti 0000-0001-7594-184X

Yohanes Widodo Wirohadidjojo 0000-0001-5248-9029

Publication Date May 31, 2025
Submission Date November 26, 2024
Acceptance Date April 7, 2025
Published in Issue Year 2025 Volume: 12 Issue: 2

Cite

Vancouver Sulaiman M, Lukitaningsih E, Martien R, Danarti R, Widodo Wirohadidjojo Y. Polymeric Nanoparticle Formulation, Characterization and Penetration Study for Topical Delivery of Timolol Maleate. JOTCSA. 2025;12(2):117-28.
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