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Optimization of In Situ Gel-Forming Chlorhexidine-Encapsulated Polymeric Nanoparticles Using Design of Experiment for Periodontitis

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Abstract

Periodontitis is a chronic inflammatory disease of the gums caused by pathogenic microorganisms damaging and destroying periodontal tissues. Chlorhexidine digluconate (CHX) is a commonly used antimicrobial agent for the treatment of periodontitis. However, it has many drawbacks, such as toxicity due to the high dosage required, low prolonged release, and low adhesion in the periodontal pocket. The objective of this study was to develop and optimize CHX-encapsulated polymeric nanoparticles (NPs) loaded into in situ gel-forming (ISGF) using design of experiment (DoE) to improve the treatment of periodontitis and overcome these limitations. CHX-NPs were optimized from 0.046%w/v chitosan, 0.05%w/w gelatin, and 0.25%w/w CHX. After that, the optimized of CHX-NPs was loaded into a thermosensitive ISGF, which was a mixture of 15%w/v Poloxamer 407 and 1% hydroxypropyl methylcellulose (HPMC). The optimized CHX-NPs, loaded into ISGF, was evaluated by measuring gelling temperature and time, pH, viscosity, compatibility, in vitro drug release, antibacterial activity, cytotoxicity, and stability. The results showed that the size, PDI, and zeta potential of optimized CHX-NPs were 53.07±10.17 nm, 0.36±0.02, and 27.63±4.16 mV, respectively. Moreover, the optimized ISGF loading CHX-NPs showed a gelling temperature at 34.3±1.2°C within 120.00±17.32 s with a pH value of 4.06. The viscosity of the formulations at 4°C was 54.33±0.99 cP. The DSC and FTIR showed no interaction between ingredients. The optimal formulations showed a prolonged release of up to 7 days while providing potential antibacterial activity and were safe for normal gingival fibroblast cells. Moreover, the formulations had high stability at 4°C and 25°C for 3 months. In conclusion, the study achieved the successful development of ISGF loading CHX-NPs formulations for effectiveness use in periodontal treatment.

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References

  1. Martínez-García M, Hernández-Lemus E. Periodontal inflammation and systemic diseases: an overview. Front Physiol. 2021;12. https://doi.org/10.3389/fphys.2021.709438.

  2. Arigbede AO, Babatope BO, Bamidele MK. Periodontitis and systemic diseases: a literature review. J Indian Soc Periodontol. 2012;16(4):487–91. https://doi.org/10.4103/0972-124X.106878.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Banjar W, Alshammari MH. Genetic factors in pathogenesis of chronic periodontitis. J Taibah Univ Med Sci. 2014;9(3):245–7. https://doi.org/10.1016/j.jtumed.2014.04.003.

    Article  Google Scholar 

  4. Yadav R, Kanwar IL, Haider T, Pandey V, Gour V, Soni V. In situ gel drug delivery system for periodontitis: an insight review. Future J Pharm Sci. 2020;6(1):33. https://doi.org/10.1186/s43094-020-00053-x.

    Article  Google Scholar 

  5. Könönen E, Gursoy M, Gursoy UK. Periodontitis: a multifaceted disease of tooth-supporting tissues. J Clin Med. 2019;8(8):1135. https://doi.org/10.3390/jcm8081135.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Silva-Boghossian CM, Neves AB, Resende FA, Colombo AP. Suppuration-associated bacteria in patients with chronic and aggressive periodontitis. J Periodontol. 2013;84(9):e9–16. https://doi.org/10.1902/jop.2013.120639.

    Article  PubMed  Google Scholar 

  7. Juvekar S, Kathpalia H. Solvent removal precipitation based in situ forming implant for controlled drug delivery in periodontitis. J Control Release. 2017;251:75–81. https://doi.org/10.1016/j.jconrel.2017.02.022.

    Article  CAS  PubMed  Google Scholar 

  8. Pihlstrom BL. Periodontal risk assessment, diagnosis and treatment planning. Periodontol. 2000;2001(25):37–58. https://doi.org/10.1034/j.1600-0757.2001.22250104.x.

    Article  Google Scholar 

  9. Pihlstrom BL, Michalowicz BS, Johnson NW. Periodontal diseases. Lancet. 2005;366(9499):1809–20. https://doi.org/10.1016/s0140-6736(05)67728-8.

    Article  PubMed  Google Scholar 

  10. Juvekar S, Kathpalia H. Solvent removal precipitation based in situ forming implant for controlled drug delivery in periodontitis. J Control Release. 2017;251:75–81. https://doi.org/10.1016/j.jconrel.2017.02.022.

    Article  CAS  PubMed  Google Scholar 

  11. Bromberg LE, Buxton DK, Friden PM. Novel periodontal drug delivery system for treatment of periodontitis. J Control Release. 2001;71(3):251–9. https://doi.org/10.1016/s0168-3659(01)00226-7.

    Article  CAS  PubMed  Google Scholar 

  12. Raheja I, Kohli K, Drabu S. Periodontal drug delivery system containing antimicrobial agents. Int J Pharm Pharm Sci. 2013;5:11–6.

    CAS  Google Scholar 

  13. Joshi D, Garg T, Goyal AK, Rath G. Advanced drug delivery approaches against periodontitis. Drug Delivery. 2016;23(2):363–77. https://doi.org/10.3109/10717544.2014.935531.

    Article  CAS  PubMed  Google Scholar 

  14. Do MP, Neut C, Delcourt E, Seixas Certo T, Siepmann J, Siepmann F. In situ forming implants for periodontitis treatment with improved adhesive properties. Eur J Pharm Biopharm. 2014;88(2):342–50. https://doi.org/10.1016/j.ejpb.2014.05.006.

    Article  CAS  PubMed  Google Scholar 

  15. Varoni E, Tarce M, Lodi G, Carrassi A. Chlorhexidine (CHX) in dentistry: state of the art. Minerva Stomatol. 2012;61(9):399–419.

    CAS  PubMed  Google Scholar 

  16. Horner C, Mawer D, Wilcox M. Reduced susceptibility to chlorhexidine in staphylococci: is it increasing and does it matter? J Antimicrob Chemother. 2012;67(11):2547–59. https://doi.org/10.1093/jac/dks284.

    Article  CAS  PubMed  Google Scholar 

  17. Koburger T, Hübner NO, Braun M, Siebert J, Kramer A. Standardized comparison of antiseptic efficacy of triclosan, PVP-iodine, octenidine dihydrochloride, polyhexanide and chlorhexidine digluconate. J Antimicrob Chemother. 2010;65(8):1712–9. https://doi.org/10.1093/jac/dkq212.

    Article  CAS  PubMed  Google Scholar 

  18. Babich H, Wurzburger BJ, Rubin YL, Sinensky MC, Blau L. Anin vitro study on the cytotoxicity of chlorhexidine digluconate to human gingival cells. Cell Biol Toxicol. 1995;11(2):79–88. https://doi.org/10.1007/BF00767493.

    Article  CAS  PubMed  Google Scholar 

  19. Helgeland K, Heyden G, Rölla G. Effect of chlorhexidine on animal cells in vitro. Scand J Dent Res. 1971;79(3):209–15. https://doi.org/10.1111/j.1600-0722.1971.tb02011.x.

    Article  CAS  PubMed  Google Scholar 

  20. Barbour ME, Maddocks SE, Wood NJ, Collins AM. Synthesis, characterization, and efficacy of antimicrobial chlorhexidine hexametaphosphate nanoparticles for applications in biomedical materials and consumer products. Int J Nanomedicine. 2013;8:3507–19. https://doi.org/10.2147/ijn.S50140.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Li L, Pan H, Tao J, Xu X, Mao C, Gu X, et al. Repair of enamel by using hydroxyapatite nanoparticles as the building blocks. J Mater Chem. 2008;18(34):4079–84.

    Article  CAS  Google Scholar 

  22. Zielińska A, Carreiró F, Oliveira AM, Neves A, Pires B, Venkatesh DN, et al. Polymeric nanoparticles: production, characterization, toxicology and ecotoxicology. Molecules. 2020;25(16):3731. https://doi.org/10.3390/molecules25163731.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Pragati S, Ashok S, Singh K. Recent advances in periodontal drug delivery systems. Int J Drug Del. 2011;1:1–14. https://doi.org/10.5138/ijdd.2009.0975.0215.01001.

    Article  CAS  Google Scholar 

  24. Al-Obaidy SSM, Greenway GM, Paunov VN. Enhanced antimicrobial action of chlorhexidine loaded in shellac nanoparticles with cationic surface functionality. Pharmaceutics. 2021;13(9):1389. https://doi.org/10.3390/pharmaceutics13091389.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Steckiewicz KP, Cieciórski P, Barcińska E, Jaśkiewicz M, Narajczyk M, Bauer M, et al. Silver nanoparticles as chlorhexidine and metronidazole drug delivery platforms: their potential use in treating periodontitis. Int J Nanomed. 2022;17:495–517. https://doi.org/10.2147/IJN.S339046.

    Article  CAS  Google Scholar 

  26. Vikman A, Kozlova D, Ganesan K, Biewald C, Seipold N, Gaengler P, et al. Chlorhexidine-loaded calcium phosphate nanoparticles for dental maintenance treatment: combination of mineralising and antibacterial effects. RSC Advances. 2012;2:870–5. https://doi.org/10.1039/C1RA00955A.

    Article  Google Scholar 

  27. Garala K, Joshi P, Shah M, Ramkishan A, Patel J. Formulation and evaluation of periodontal in situ gel. Int J Pharm Investig. 2013;3(1):29–41. https://doi.org/10.4103/2230-973x.108961.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kulkarni AP, Aslam Khan SK, Dehghan MH. Evaluation of polaxomer-based in situ gelling system of articaine as a drug delivery system for anesthetizing periodontal pockets – an in vitro study. Indian J Dent. 2012;3(4):201–8. https://doi.org/10.1016/j.ijd.2012.07.006.

    Article  Google Scholar 

  29. Ruel-Gariépy E, Leroux JC. In situ-forming hydrogels–review of temperature-sensitive systems. Eur J Pharm Biopharm. 2004;58(2):409–26. https://doi.org/10.1016/j.ejpb.2004.03.019.

    Article  CAS  PubMed  Google Scholar 

  30. Ji QX, Zhao QS, Deng J, Lü R. A novel injectable chlorhexidine thermosensitive hydrogel for periodontal application: preparation, antibacterial activity and toxicity evaluation. J Mater Sci Mater Med. 2010;21(8):2435–42. https://doi.org/10.1007/s10856-010-4098-1.

    Article  CAS  PubMed  Google Scholar 

  31. Zhou D, Xu Z, Li Y, Chen L, Liu Y, Xu Y, et al. Preparation and characterization of thermosensitive hydrogel system for dual sustained-release of chlorhexidine and bovine serum albumin. Materials Letters. 2021;300:130121. https://doi.org/10.1016/j.matlet.2021.130121.

  32. Jain M, Dave D, Jain P, Manohar B, Yadav B, Shetty N. Efficacy of xanthan based chlorhexidine gel as an adjunct to scaling and root planing in treatment of the chronic periodontitis. J Indian Soc Periodontol. 2013;17(4):439–43. https://doi.org/10.4103/0972-124x.118313.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Suriyaamporn P, Opanasopit P, Ngawhirunpat T, Rangsimawong W. Computer-aided rational design for optimally Gantrez® S-97 and hyaluronic acid-based dissolving microneedles as a potential ocular delivery system. Journal of Drug Delivery Science and Technology. 2021;61. https://doi.org/10.1016/j.jddst.2020.102319.

  34. Azizian S, Hadjizadeh A, Niknejad H. Chitosan-gelatin porous scaffold incorporated with chitosan nanoparticles for growth factor delivery in tissue engineering. Carbohydrate Polymers. 2018;202:315–22. https://doi.org/10.1016/j.carbpol.2018.07.023.

    Article  CAS  PubMed  Google Scholar 

  35. Sahatsapan N, Ngawhirunpat T, Rojanarata T, Opanasopit P, Patrojanasophon P. Catechol-functionalized alginate nanoparticles as mucoadhesive carriers for intravesical chemotherapy. AAPS PharmSciTech. 2020;21(6):212. https://doi.org/10.1208/s12249-020-01752-7.

    Article  CAS  PubMed  Google Scholar 

  36. Oktay AN, Karakucuk A, Ilbasmis-Tamer S, Celebi N. Dermal flurbiprofen nanosuspensions: optimization with design of experiment approach and in vitro evaluation. Eur J Pharm Sci. 2018;122:254–63. https://doi.org/10.1016/j.ejps.2018.07.009.

    Article  CAS  PubMed  Google Scholar 

  37. Danaei M, Dehghankhold M, Ataei S, Hasanzadeh Davarani F, Javanmard R, Dokhani A, et al. Impact of particle size and polydispersity index on the clinical applications of lipidic nanocarrier systems. Pharmaceutics. 2018;10(2):57. https://doi.org/10.3390/pharmaceutics10020057.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Shivam U U, Siddhi K C, Devarshi U G, Umeshkumar M U, Jayvadan K P. Nanoparticles laden in situ gel for sustained drug release after topical ocular administration. J Drug Del Sci Technol. 2020;57:101736. https://doi.org/10.1016/j.jddst.2020.101736.

  39. Wang Q, Zhang L, Ding W, Zhang D, Reed K, Zhang B. Orthogonal optimization and physicochemical characterization of water-soluble gelatin-chitosan nanoparticles with encapsulated alcohol-soluble eugenol. Food and Bioproc Technol. 2020;13(6):1024–34. https://doi.org/10.1007/s11947-020-02448-3.

    Article  CAS  Google Scholar 

  40. Convention USP. USP 43 / NF 38. United States Pharmacopeial Convention: Rockville, MD; 2020.

  41. Cardoso MA, Fávero M, Gasparetto J, Hess B, Stremel D, Pontarolo R. Development and validation of an RP-HPLC method for the determination of chlorhexidine and p-chloroaniline in various pharmaceutical formulations. J Liq ChromatogrRelat Technol. 2011;34:1556–67. https://doi.org/10.1080/10826076.2011.575979.

    Article  CAS  Google Scholar 

  42. Sobaih A, Abd El Aziz L, Nassif N. HPLC Method for determination of chlorhexidine in pharmaceutical formulations alone and in presence of hexamidine and p-chlorocresol, and in spiked human saliva. Arch Pharm Sci Ain Shams Univ. 2022;6(1):45-59. https://doi.org/10.21608/aps.2022.108801.1075.

  43. Sahatsapan N, Pamornpathomkul B, Rojanarata T, Ngawhirunpat T, Poonkhum R, Opanasopit P, et al. Feasibility of mucoadhesive chitosan maleimide-coated liposomes for improved buccal delivery of a protein drug. J Drug Del Sci Technol. 2022;69. https://doi.org/10.1016/j.jddst.2022.103173.

  44. Abdelwahed W, Degobert G, Stainmesse S, Fessi H. Freeze-drying of nanoparticles: formulation, process and storage considerations. Adv Drug Deliv Rev. 2006;58(15):1688–713. https://doi.org/10.1016/j.addr.2006.09.017.

    Article  CAS  PubMed  Google Scholar 

  45. Swain GP, Patel S, Gandhi J, Shah P. Development of moxifloxacin hydrochloride loaded in-situ gel for the treatment of periodontitis: in-vitro drug release study and antibacterial activity. J Oral Biol Craniofac Res. 2019;9(3):190–200. https://doi.org/10.1016/j.jobcr.2019.04.001.

    Article  PubMed  PubMed Central  Google Scholar 

  46. da Silva JB, Cook MT, Bruschi ML. Thermoresponsive systems composed of poloxamer 407 and HPMC or NaCMC: mechanical, rheological and sol-gel transition analysis. Carbohydrate Polymers. 2020;240:116268. https://doi.org/10.1016/j.carbpol.2020.116268.

  47. Gupta H, Sharma A, Shrivastava B. Pluronic and chitosan based in situ gel system for periodontal application. Asian J Pharm. 2014;3.

  48. Nasra MM, Khiri HM, Hazzah HA, Abdallah OY. Formulation, in-vitro characterization and clinical evaluation of curcumin in-situ gel for treatment of periodontitis. Drug Deliv. 2017;24(1):133–42. https://doi.org/10.1080/10717544.2016.1233591.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Sahatsapan N, Rojanarata T, Ngawhirunpat T, Opanasopit P, Tonglairoum P. 6-Maleimidohexanoic acid-grafted chitosan: a new generation mucoadhesive polymer. Carbohydr Polym. 2018;202:258–64. https://doi.org/10.1016/j.carbpol.2018.08.119.

    Article  CAS  PubMed  Google Scholar 

  50. Chantadee T, Santimaleeworagun W, Phorom Y, Chuenbarn T, Phaechamud T. Vancomycin HCl-loaded lauric acid in situ-forming gel with phase inversion for periodontitis treatment. Journal of Drug Delivery Science and Technology. 2020;57:101615. https://doi.org/10.1016/j.jddst.2020.101615.

  51. Lertsuphotvanit N, Santimaleeworagun W, Narakornwit W, Chuenbarn T, Mahadlek J, Chantadee T, et al. Borneol-based antisolvent-induced in situ forming matrix for crevicular pocket delivery of vancomycin hydrochloride. International Journal of Pharmaceutics. 2022;617:121603. https://doi.org/10.1016/j.ijpharm.2022.121603.

  52. Beg S, Dhiman S, Sharma T, Jain A, Sharma RK, Jain A, et al. Stimuli responsive in situ gelling systems loaded with PLGA nanoparticles of moxifloxacin hydrochloride for effective treatment of periodontitis. AAPS PharmSciTech. 2020;21(3):76. https://doi.org/10.1208/s12249-019-1613-7.

    Article  CAS  PubMed  Google Scholar 

  53. Xue K, Zhao X, Zhang Z, Qiu B, Tan Q, Ong KH, et al. Sustained delivery of anti-VEGFs from thermogel depots inhibits angiogenesis without the need for multiple injections. Biomater Sci. 2019;7(11):4603–14. https://doi.org/10.1039/C9BM01049A.

    Article  CAS  PubMed  Google Scholar 

  54. Maheshwari M, Miglani G, Mali A, Paradkar A, Yamamura S, Kadam S. Development of tetracycline-serratiopeptidase-containing periodontal gel: formulation and preliminary clinical study. AAPS PharmSciTech. 2006;7(3):76. https://doi.org/10.1208/pt070376.

    Article  PubMed  Google Scholar 

  55. Shaikh HK, Kshirsagar R, Patil SG. MATHEMATICAL MODELS FOR DRUG RELEASE CHARACTERIZATION: A REVIEW. 2015.

  56. Moore DS, Notz W, Fligner MA. The basic practice of statistics. 6th ed. New York: W.H. Freeman and Co.; 2013.

    Google Scholar 

  57. Slavin YN, Asnis J, Häfeli UO, Bach H. Metal nanoparticles: understanding the mechanisms behind antibacterial activity. J Nanobiotechnology. 2017;15(1):65. https://doi.org/10.1186/s12951-017-0308-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Katuwavila NP, Perera ADLC, Samarakoon SR, Soysa P, Karunaratne V, Amaratunga GAJ, et al. Chitosan-alginate nanoparticle system efficiently delivers doxorubicin to MCF-7 cells. J Nanomat. 2016;2016:3178904. https://doi.org/10.1155/2016/3178904.

    Article  CAS  Google Scholar 

  59. Baliga S, Muglikar S, Kale R. Salivary pH: a diagnostic biomarker. J Indian Soc Periodontol. 2013;17(4):461–5. https://doi.org/10.4103/0972-124x.118317.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Barclay CW, Spence D, Laird WR. Intra-oral temperatures during function. J Oral Rehabil. 2005;32(12):886–94. https://doi.org/10.1111/j.1365-2842.2005.01509.x.

    Article  CAS  PubMed  Google Scholar 

  61. Chen Y, Lee JH, Meng M, Cui N, Dai CY, Jia Q, et al. An overview on thermosensitive oral gel based on Poloxamer 407. Materials (Basel). 2021;14(16):4522. https://doi.org/10.3390/ma14164522.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Uppuluri CT, Ravi PR, Dalvi AV, Shaikh SS, Kale SR. Piribedil loaded thermo-responsive nasal in situ gelling system for enhanced delivery to the brain: formulation optimization, physical characterization, and in vitro and in vivo evaluation. Drug Del Trans Res. 2021;11(3):909–26. https://doi.org/10.1007/s13346-020-00800-w.

    Article  CAS  Google Scholar 

  63. Fakhari A, Corcoran M, Schwarz A. Thermogelling properties of purified poloxamer 407. Heliyon. 2017;3(8):e00390. https://doi.org/10.1016/j.heliyon.2017.e00390.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Freitas M, Farah M, Bretas R, E R-J, Marchetti J. Rheological characterization of Poloxamer 407 nimesulide gels. Revista de Ciências Farmacêuticas Básica e Aplicada. 2009;27.

  65. Patel P, Gajera B, Dave R. A quality-by-design study to develop nifedipine nanosuspension: examining the relative impact of formulation variables, wet media milling process parameters, and excipient variability on drug product quality attributes. Drug Dev Ind Pharm. 2018;44:1–33. https://doi.org/10.1080/03639045.2018.1503296.

    Article  CAS  Google Scholar 

  66. Priyadarshini BM, Selvan ST, Narayanan K, Fawzy AS. Characterization of chlorhexidine-loaded calcium-hydroxide microparticles as a potential dental pulp-capping material. Bioengineering (Basel). 2017;4(3):59. https://doi.org/10.3390/bioengineering4030059.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Pupe C, Villardi M, Rodrigues C, Rocha H, Maia L, Sousa V, et al. Preparation and evaluation of antimicrobial activity of nanosystems for the control of oral pathogens Streptococcus mutans and Candida albicans. Int J Nanomed. 2011;6:2581–90. https://doi.org/10.2147/IJN.S25667.

    Article  CAS  Google Scholar 

  68. Vidal-Romero G, Zambrano-Zaragoza ML, Martínez-Acevedo L, Leyva-Gómez G, Mendoza-Elvira SE, Quintanar-Guerrero D. Design and evaluation of pH-dependent nanosystems based on cellulose acetate phthalate, nanoparticles loaded with chlorhexidine for periodontal treatment. Pharmaceutics. 2019;11(11):604. https://doi.org/10.3390/pharmaceutics11110604.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Hosseini S, Kassaee M, Elahi SH, Bolhari B. A novel binary chlorhexidine-chitosan irrigant with high permeability, and long lasting synergic antibacterial effect. Nanochem Res. 2018;3(1):92–8. https://doi.org/10.22036/ncr.2018.01.010.

    Article  CAS  Google Scholar 

  70. Saluja H, Mehanna A, Panicucci R, Atef E. Hydrogen bonding: between strengthening the crystal packing and improving solubility of three haloperidol derivatives. Molecules. 2016;21(6):719.

    Article  PubMed  PubMed Central  Google Scholar 

  71. 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. https://doi.org/10.3390/pharmaceutics12090859.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Dutta K, Das R, Ling J, Monibas RM, Carballo-Jane E, Kekec A, et al. In situ forming injectable thermoresponsive hydrogels for controlled delivery of biomacromolecules. ACS Omega. 2020;5(28):17531–42. https://doi.org/10.1021/acsomega.0c02009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Kapoor A, Malhotra R, Grover V, Grover D. Systemic antibiotic therapy in periodontics. Dent Res J (Isfahan). 2012;9(5):505–15. https://doi.org/10.4103/1735-3327.104866.

    Article  CAS  PubMed  Google Scholar 

  74. Bartold PM. Turnover in periodontal connective tissues: dynamic homeostasis of cells, collagen and ground substances. Oral Dis. 1995;1(4):238–53. https://doi.org/10.1111/j.1601-0825.1995.tb00189.x.

    Article  CAS  PubMed  Google Scholar 

  75. Brizuela M, Winters R. Histology, oral mucosa. StatPearls. Treasure Island (FL): StatPearls Publishing Copyright © 2023, StatPearls Publishing LLC.; 2023.

  76. Paarakh MP, Jose PA, Setty CM, Christoper GVP. RELEASE KINETICS – CONCEPTS AND APPLICATIONS. Int J Phar Res Technol. 2019.

  77. Karpiński TM, Szkaradkiewicz AK. Chlorhexidine–pharmaco-biological activity and application. Eur Rev Med Pharmacol Sci. 2015;19(7):1321–6.

    PubMed  Google Scholar 

  78. Seneviratne CJ, Leung KCF, Wong CH, Lee SF, Li X, Leung PC, et al. Nanoparticle-encapsulated chlorhexidine against oral bacterial biofilms. PLOS ONE. 2014;9(8):e103234. https://doi.org/10.1371/journal.pone.0103234.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Poppolo Deus F, Ouanounou A. Chlorhexidine in dentistry: pharmacology, uses, and adverse effects. Int Den J. 2022;72(3):269–77. https://doi.org/10.1016/j.identj.2022.01.005.

    Article  Google Scholar 

  80. Hidalgo E, Dominguez C. Mechanisms underlying chlorhexidine-induced cytotoxicity. Toxicol In Vitro. 2001;15(4–5):271–6. https://doi.org/10.1016/s0887-2333(01)00020-0.

    Article  CAS  PubMed  Google Scholar 

  81. Pucher JJ, Daniel JC. The effects of chlorhexidine digluconate on human fibroblasts in vitro. J Periodontol. 1992;63(6):526–32. https://doi.org/10.1902/jop.1992.63.6.526.

    Article  CAS  PubMed  Google Scholar 

  82. Mariotti AJ, Rumpf DA. Chlorhexidine-induced changes to human gingival fibroblast collagen and non-collagen protein production. J Periodontol. 1999;70(12):1443–8. https://doi.org/10.1902/jop.1999.70.12.1443.

    Article  CAS  PubMed  Google Scholar 

  83. Chang YC, Huang FM, Tai KW, Chou MY. The effect of sodium hypochlorite and chlorhexidine on cultured human periodontal ligament cells. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2001;92(4):446–50. https://doi.org/10.1067/moe.2001.116812.

    Article  CAS  PubMed  Google Scholar 

  84. Yeung SY, Huang CS, Chan CP, Lin CP, Lin HN, Lee PH, et al. Antioxidant and pro-oxidant properties of chlorhexidine and its interaction with calcium hydroxide solutions. Int Endod J. 2007;40(11):837–44. https://doi.org/10.1111/j.1365-2591.2007.01271.x.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors would like to thank Mr. Paul Mines for proofreading.

Funding

This research was financially supported by the National Research Council of Thailand (N42A650551), the Faculty of Pharmacy, Silpakorn University, and the Department of Pharmaceutical Technology, University of Applied Sciences (BHT), Germany.

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Authors and Affiliations

  1. Pharmaceutical Development of Green Innovations Group (PDGIG), Faculty of Pharmacy, Silpakorn University, Nakhon Pathom, 73000, Thailand

    Phuvamin Suriyaamporn, Nitjawan Sahatsapan, Prasopchai Patrojanasophon, Praneet Opanasopit & Tanasait Ngawhirunpat

  2. Department of Pharmaceutical Technology, University of Applied Sciences (BHT), Luxemburger Street 10, 13353, Berlin, Germany

    Mont Kumpugdee-Vollrath

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  2. Nitjawan Sahatsapan
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  3. Prasopchai Patrojanasophon
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  4. Praneet Opanasopit
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  5. Mont Kumpugdee-Vollrath
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  6. Tanasait Ngawhirunpat
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Contributions

Phuvamin Suriyaamporn: methodology, software, validation, formal analysis, investigation, data curation, and writing—original draft preparation. Nitjawan Sahatsapan: methodology, validation, formal analysis, investigation, and data curation. Prasopchai Patrojanasophon: writing-review and editing. Praneet Opanasopit: conceptualization, resources, visualization, and funding acquisition. Mont Kumpugdee-Vollrath: conceptualization, resources, visualization, project administration, and funding acquisition. Tanasait Ngawhirunpat: visualization, supervision, and project administration. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Tanasait Ngawhirunpat.

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Suriyaamporn, P., Sahatsapan, N., Patrojanasophon, P. et al. Optimization of In Situ Gel-Forming Chlorhexidine-Encapsulated Polymeric Nanoparticles Using Design of Experiment for Periodontitis. AAPS PharmSciTech 24, 161 (2023). https://doi.org/10.1208/s12249-023-02600-0

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