Abstract
Eudragit RS (ERS), a quaternary polyacrylate positively charged polymer, exhibits a very low permeability and swells in aqueous media independently of pH without dissolving. Owing to its high solubility in N-methyl pyrrolidone (NMP), it was interesting to apply as polymer matrix for solvent-exchanged in situ forming gel. The aim of this research was to prepare in situ forming gels from ERS to deliver the antimicrobial agents (doxycycline hyclate, metronidazole, and benzoyl peroxide) for periodontitis treatment. They were evaluated for viscosity and rheology, gel formation, syringeability, drug release, and antimicrobial activities. The solvent exchange between NMP and an external aqueous simulated gingival crevicular fluid stimulated the dissolved ERS transforming into the opaque rigid gel. Antimicrobial agent loaded ERS systems exhibited Newtonian flow with acceptable syringeability. The higher-loaded ERS promoted the more prolongation of drug release because of the retardation of water diffusion into the precipitated matrix. Antimicrobial activities against Staphylococcus aureus, Escherichia coli, Candida albicans, Streptococcus mutans, and Porphyromonas gingivalis depended on type of drugs and test microorganisms. Doxycycline hyclate loaded ERS systems showed these activities greater than the others; however, all of them could inhibit all test microorganisms. Thus, the solvent exchange-induced in situ forming gels comprising ERS-antimicrobial drugs exhibited potential use as localized delivery systems for periodontitis treatment.
Similar content being viewed by others
References
Rowe RC, Sheskey PJ, Quinn EM. Handbook of pharmaceutical excipients. The sixth ed. Washington, DC: Pharmaceutical Press and American Pharmaceutical Association; 2009.
Akhgari A, Farahmand F, Afrasiabi GH, Sadeghi F, Vandamme TF. Permeability and swelling studies on free films containing inulin in combination with different polymethacrylates aimed for colonic drug delivery. Eur J Pharm Sci. 2006;28(4):307–14.
Patel RR, Patel JK. Development and evaluation of in situ novel intragastric controlled-release formulation of hydrochlorothiazide. Acta Pharma. 2011;61:73–82.
Sawant PD, Luu D, Ye R, Buchta R. Drug release from hydroethanolic gels. Effect of drug’s lipophilicity (log P), polymer–drug interactions and solvent lipophilicity. Int J Pharm. 2010;396:45–52.
Addy M, Langeroudi M. Comparison of the immediate effects on the sub-gingival microflora of acrylic strips containing 40% chlorhexidine, metronidazole or tetracycline. J Clin Periodontol. 1984;1:379–86.
Addy M, Hassan H, Moran J, Wade W, Newcombe R. Use of antimicrobial containing acrylic strips in the treatment of chronic periodontal disease. A three month follow-up study. J Periodontol. 1988;59(9):557–64.
Higashi K, Matsushita M, Morisaki K, Hayashi SI, Mayumi T. Local drug delivery systems for the treatment of periodontal disease. J Pharmacobio-Dyn. 1991;14:72–81.
Xiong W, Gao X, Zhao Y, Xu H, Yang X. The dual temperature/pH-sensitive multiphase behavior of poly(N-isopropylacrylamide-co-acrylic acid) microgels for potential application in in situ gelling system. Colloids Surf, B: Bointerfaces. 2011;84:103–10.
Solorio L, Olear AM, Hamilton JI, Patel RB, Beiswenger AC, Wallace JE, et al. Noninvasive characterization of the effect of varying PLGA molecular weight blends on in situ forming implant behavior using ultrasound imaging. Theranostics. 2012;2(11):1064–77. doi:10.7150/thno.4181.
Phaechamud T, Mahadlek J, Chuenbarn T. In situ forming gel comprising bleached shellac loaded with antimicrobial drugs for periodontitis treatment. Mater Des. 2016;494:381–92. doi:10.1016/j.matdes.2015.09.138.
Phaechamud T, Mahadlek J. Solvent exchange-induced in situ forming gel comprising ethyl cellulose-antimicrobial drugs. Int J Pharm. 2015;494:381–92. doi:10.1016/j.msec.2015.09.083.
Schwach AK, Vivien CN, Gurny R. Local delivery of antimicrobial agents for the treatment of periodontal diseases. Eur J Pharm Biopharm. 2000;50:83–99.
Malik K, Singh I, Nagpal M, Arora S. Atrigel: a potential parenteral controlled drug delivery system. Der Pharm Sin. 2010;1(1):74–81.
Jain N, Jain GK, Javed S, Iqbal Z, Talegaonkar S, Ahmad FJ, et al. Recent approaches for the treatment of periodontitis. Drug Discov Today. 2008;13:932–43.
Sanghvi R, Narazaki R, Machatha SG, Yalkowsky SH. Solubility improvement of drugs using N-methyl pyrrolidone. AAPS PharmSciTech. 2008;9:366–76.
Engelhardt G, Fleig H. Methyl-2-pyrrolidinone (NMP) does not induce structural and numerical chromosomal aberrations in vivo. Mutat Res Genet Tox. 1993;298:149–55.
Heidari MR. Reference module in biomedical sciences, from encyclopedia of toxicology (3rd edition), 2014, pp. 588–593.
Liu Q, Zhang H, Zhou G, Xie S, Zou H, Yu Y, et al. In vitro and in vivo study of thymosin alpha1 biodegradable in situ forming poly(lactide-co-glycolide) implants. Int J Pharm. 2010;2010(397):122–9.
Strickley RG. Solubilizing excipients in oral and injectable formulations. Pharm Res. 2004;21:201–30.
Jouyban A, Fakhree MA, Shayanfar A. Review of pharmaceutical applications of N-methyl-2-pyrrolidone. J Pharm Pharm Sci. 2010;13(4):524–35.
Mahadlek J, Phaechamud T. Metrodidazole in situ forming eudragit RS gel comprising different solvents. Key Eng Mater. 2015;659:13–8.
Mahadlek J, Charoenteeraboon J, Phaechamud T. Benzoyl peroxide in situ forming antimicrobial gel for periodontitis treatment. Key Eng Mater. 2013;545:63–8.
Martin A. Physical pharmacy. Philadelphia: Lea and Febiger; 1993. p. 393–476.
Popa L, Ghica MV, Dinu-Pirvu C. Periodontal chitosan-gels designed for improved local intra-pocket drug delivery. Farmacia. 2013;61(2):240–9.
MicroMath Scientist Handbook Rev. 7EEF, MicroMath: Salt Lake City, 1995, p: 467.
Kogawa AC, Salgado HR. Doxycycline hyclate: a review of properties, applications and analytical methods. Int J Life Sci Pharm Res. 2012;2(4):11–25.
Alexander KS, Vangala SS, Dollimore D. The formulation development and stability of metronidazole suspension. Int J Pharm Compd. 1999;1(3):200–5.
Mayol L, Quaglia F, Borzacchiello A, Ambrosio L, Rotonda MIL. A novel poloxamers/hyaluronic acid in situ forming hydrogel for drug delivery: rheological, mucoadhesive and in vitro release properties. Eur J Pharm Biopharm. 2008;70:199–206.
Fresno MJC, Ramirez AD, Jimenez MM. Systematic study of the flow behavior and mechanical properties of carbopol® UltrezTM 10 hydroalcoholic gels. Eur J Pharm Biopharm. 2002;54:329–35.
Gad HA, El-Nabarawi MA, Abd El-Hady SS. Formulation and evaluation of PLA and PLGA in situ implants containing secnidazole and/or doxycycline for treatment of periodontitis. AAPS PharmSciTech. 2008;9(3):878–84. doi:10.1208/s12249-008-9126-9.
Chang JY, Oh Y-K, Choi H, Kim YB, Kim C-K. Rheological evaluation of thermosensitive and mucoadhesive vaginal gels in physiological conditions. Int J Pharm. 2002;241:155–63.
Miyazaki S, Kubo W, Itoh K, Konno Y, Fujiwara M, Dairaku M, et al. The effect of taste masking agents on in situ gelling pectin formulations for oral sustained delivery of paracetamol and ambroxol. Int J Pharm. 2005;297:38–49.
Rungseevijitprapa W, Bodmeier R. Injectability of biodegradable in situ forming microparticle systems (ISM). Eur J Pharm Sci. 2009;36:524–31.
Abashzadeh S, Dinarvand R, Sharifzadeh M, Hassanzadeh G, Amini M, Atyabi F. Formulation and evaluation of an in situ gel forming system for controlled delivery of triptorelin acetate. Eur J Pharm. 2011;44:514–21.
Yang L, Fassihi R. Examination of drug solubility, polymer types, hydrodynamics and loading dose on drug release behavior from a triple-layer asymmetric configuration delivery system. Int J Pharm. 1997;155:219–29.
Khuathan N, Pongjanyakul T. Modification of quaternary polymethacrylate films using sodium alginate: film characterization and drug permeability. Int J Pharm. 2014;460(1–2):63–72.
Sánchez-Lafuente C, Faucci MT, Fernández-Arévalo M, Álvarez-Fuentes J, Rabasco AM, Mura P. Development of sustained release matrix tablets of didanosine containing methacrylic and ethylcellulose polymers. Int J Pharm. 2002;234:213–21.
Yamamoto S, Saeki T, Inoshita T. Drying of gelled sugar solutions—water diffusion behavior. Chem Eng J. 2002;86:179–84.
Wang L, Wang A, Zhao X, Liu X, Wang D, Sun F, et al. Design of a long-term antipsychotic in situ forming implant and its release control method and mechanism. Int J Pharm. 2012;427:284–92.
Fu XC, Wang GP, Liang WQ, Chow MS. Prediction of drug release from HPMC matrices: effect of physicochemical properties of drug and polymer concentration. J Control Release. 2004;95:209–16.
Brodbeck KJ, DesNoyer JR, McHugh AJ. Phase inversion dynamics of PLGA solutions related to drug delivery: part II. The role of solution thermodynamics and bath-side mass transfer. J Control Release. 1999;62(3):333–44.
Wischke C, Schwendeman SP. Principles of encapsulating hydrophobic drugs in PLA/PLGA microparticles. Int J Pharm. 2008;364:298–327.
Mocanu G, Airinei A, Carpov A. Macromolecular drug conjugates II. Metronidazole-dextran prodrugs. J Bioact Compat Polym. 1993;8(4):383–92.
Kiortsis S, Kachrimanis K, Broussali T, Malamataris S. Drug release from tableted wet granulations comprising cellulosic (HPMC or HPC) and hydrophobic component. Eur J Pharm Biopharm. 2005;59:73–83.
Reza MS, Quadir MA, Haider SS. Comparative evaluation of plastic, hydrophobic and hydrophilic matrices for controlled-release drug delivery. J Pharm Phram Sci. 2003;6(2):282–91.
Siepmann J, Peppas NA. Modelling of drug release from delivery systems based on hydroxypropyl methylcellulose (HPMC). Adv Drug Deliv Rev. 2001;48:139–57.
Poursamar SA, Azami M, Mozafari M. Controllable synthesis and characterization of porous polyvinyl alcohol/hydroxyapatite nanocomposite scaffolds via an in situ colloidal technique. Colloid Surface B. 2011;84(2):310–6.
Ren D, Yi H, Zhang H, Xie W, Wang W, Ma X. A preliminary study on fabrication of nanoscale fibrous chitosan membranes in situ by biospecific degradation. J Membr Sci. 2006;280:99–107.
Hoffart V, Lamprecht A, Maincent P, Lecompte T, Vigneron C, Ubrich N. Oral bioavailability of a low molecular weight heparin using a polymeric delivery system. J Control Release. 2006;113:38–42.
Gargouri M, Sapin A, Bouali S, Becuwe P, Merlin JL, Maincent P. Optimization of a new non-viral vector for transfection: Eudragit nanoparticles for the delivery of DNA plasmid. Technol Cancer Res Treat. 2009;8:433–44.
Eidi H, Joubert O, Attik G, Duval RE, Bottin MC, Hamouia A, et al. Cytotoxicity assessment of heparin nanoparticles in NR8383 macrophages. Int J Pharm. 2010;396:156–65. doi:10.1016/j.ijpharm.2010.06.006.
Pignatello R, Bucolo C, Ferrara P, Maltese A, Puleo A, Puglisi G. Eudragit RS100 nanosuspensions for the ophthalmic controlled delivery of ibuprofen. Eur J Pharm Sci. 2002;16:53–61.
Ubrich N, Schmidt C, Bodmeier R, Hoffman M, Maincent P. Oral evaluation in rabbits of cyclosporin-loaded Eudragit RS or RL nanoparticles. Int J Pharm. 2005;288:169–75.
Vaquettea C, Babak VG, Baros F, Boulanouar O, Dumas D, Fievet P, et al. Zeta-potential and morphology of electrospun nano- and microfibers from biopolymers and their blends used as scaffolds in tissue engineering. Mendeleev Commun. 2008;18:38–41.
Valenze G, Veihelamann S, Peplies J, Tichy D, Roldan-Pareja MC, Schlagenhaul U, et al. Microbial changes in periodontitis successfully treated by mechanical plaque removal and systemic amoxicillin and metronidazole. Int J Med Microbiol. 2009;299:427–38.
Vitt A, Sofrata A, Slizen V, Sugars RV, Gustafsson A, Gudkova EI, et al. Antimicrobial activity of polyhexamethylene guanidine phosphate in comparison to chlorhexidine using the quantitative suspension method. Ann Clin Microbiol Antimicrob. 2015;14:36. doi:10.1186/s12941-015-0097-x.
Yue IC, Poff J, Cortés ME, Sinisterra RD, Faris CB, Hildgen P, et al. A novel polymeric chlorhexidine delivery device for the treatment of periodontal disease. Biomaterials. 2004;25:3743–50.
Contardo MS, Díaz N, Lobos O, Padilla C, Giacaman RA. Oral colonization by Streptococcus mutans and its association with the severity of periodontal disease in adults. Rev Clin Periodoncia Implantol Rehabil Oral. 2011;4:9–12.
Do MP, Neut C, Delcourt E, Certo TS, Siepmann J, Siepmann F. In situ forming implants for periodontitis treatment with improved adhesive properties. Eur J Pharm Biopharm. 2014;88:342–50.
Seymour RA, Heasman PA. Pharmacological control of periodontal disease. II. Antimicrobial agents. J Dent. 1995;23:5–14.
Amel Y, Bouziane D, Leila M, Ahmed B. Microbiological study of periodontitis in the West of Algeria. West J Med Sci. 2010;5:7–12.
Phaechamud T, Mahadlek J, Charoenteeraboon J, Choopun S. Analysis for texture and topography of doxycycline hyclate thermosensitive systems comprising zinc oxide. Indian J Pharm Sci. 2013;75(4):385–92.
Phaechamud T, Mahadlek J, Charoenteeraboon J, Choopun S. Characterization and antimicrobial activity of N-methyl-2-pyrrolidone-loaded ethylene oxide-propylene oxide block copolymer thermosensitive gel. Indian J Pharm Sci. 2013;74(6):498–504.
Seymour RA, Heasman PA. Tetracyclines in the management of periodontal diseases. A review. J Clin Periodontal. 1995;22(1):22–35.
Rizzo A, Paolillo R, Guida L, Annunziata M, Bevilacqua N, Tufano MA. Effect of metronidazole and modulation of cytokine production on human periodontal ligament cells. Int Immunol Pharmacol. 2010;10(7):744–50.
Reznikov M, Hakendorf PH, Matthews DB. Response of a ‘susceptible’ Escherichia coli to metronidazole therapy: an investigation using experimental subcutaneous abscesses. Chemotherapy. 1985;31(1):50–4.
Burkhart CG, Burkhart CN, Isham N. Synergistic antimicrobial activity by combining an allylamine with benzoyl peroxide with expanded coverage against yeast and bacterial species. Br J Dermatol. 2006;154:341–4.
Chellquist EM, Gorman WG. Benzoyl peroxide solubility and stability in hydric solvents. Pharm Res. 1992;9(10):1341–6.
Acknowledgments
This research work was supported by the Research and Development Institute, Silpakorn University (grant no. SURDI 57/01/42). We would like to thank Juree Charoenteeraboon for her comment and help. This research work was also facilitated by the Faculty of Pharmacy, Silpakorn University, Thailand.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Phaechamud, T., Jantadee, T., Mahadlek, J. et al. Characterization of Antimicrobial Agent Loaded Eudragit RS Solvent Exchange-Induced In Situ Forming Gels for Periodontitis Treatment. AAPS PharmSciTech 18, 494–508 (2017). https://doi.org/10.1208/s12249-016-0534-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1208/s12249-016-0534-y