Advertisement

Emerging role of polyethylene glycol on doxycycline hyclate-incorporated Eudragit RS in situ forming gel for periodontitis treatment

  • Wai Wai Lwin
  • Napaphol Puyathorn
  • Setthapong Senarat
  • Jongjan Mahadlek
  • Thawatchai PhaechamudEmail author
Original Article

Abstract

Phase separation with solvent exchange induced-in situ forming gel (ISG) is an attractive delivery system for periodontitis treatment. Eudragit® RS-PO (ERS) in N-methyl pyrrolidone (NMP) was used as polymer matrix for doxycycline hyclate (DH)-loaded solvent-exchanged ISG; however, a high burst drug release was evident. The present study revealed the role of PEG 1500 on physicochemical properties and modification of a burst release for DH-loaded ISG. DH-loaded ISG system comprising PEG 1500 exhibited the Newtonian flow with acceptable injectability with PEG 1500 concentration dependence and high in vitro degradation owing to NMP and PEG 1500 liberation. Solvent exchange between NMP with PBS pH 6.8 conveyed the rapid phase separation of ERS/PEG 1500 as a matrix which the entrapped DH diffused out gradually. Both dialysis membrane and membrane-less methods proved the slower drug release of DH-loaded ERS ISG comprising PEG than PEG 1500-free ISG. SEM revealed the porous matrix topography from polymeric phase separation especially for higher PEG 1500 loading. PEG 1500 incorporation significantly decreased the inhibition diameter against S. aureus, E. coli and S. mutans (P < 0.05) indicating the retardation of drug release owing to the high viscosity of the PEG 1500. PEG 1500-incorporated DH-loaded ERS ISG exhibited the potential use for periodontitis treatment.

Graphical abstract

PEG loading into solvent induced ERS in situ forming gel for doxycycline hyclate periodontal pocket delivery.

Keywords

In situ forming gel Solid-like matrix PEG 1500 Eudragit RS Doxycycline hyclate Burst release 

Notes

Acknowledgements

This research work was supported by the Research and Development Institute, Silpakorn University (Grant no. SURDI 57/01/42). This research work was also facilitated by the Faculty of Pharmacy, Silpakorn University, Thailand. We also would like to thank Anthony Phonpituck for valuable comments and help.

Compliance with ethical standards

Conflict of interest

Authors declare that there is no conflict of interest regarding the publication of this article.

Statement of human and animal rights

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

  1. Abashzadeh R, Dinarvand M, Sharifzadeh G, Hassanzadeh G, Amini M, Atyabi F (2011) Formulation and evaluation of an in situ gel forming system for controlled delivery of triptorelin acetate. Eur J Pharm Sci 44:514–521CrossRefGoogle Scholar
  2. Ahmed TA, Ibrahim HM, Ibrahim F, Samy AM, Kaseem A, Nutan MTH, Hussain MD (2012) Development of biodegradable in situ implant and microparticle injectable formulations for sustained delivery of haloperidol. J Pharm Sci 10:3753–3762CrossRefGoogle Scholar
  3. Arendt-Nielsen L, Egekvist H, Bjerring P (2006) Pain following controlled cutaneous insertion of needles with different diameters. Somatosens Mot Res 23:37–43CrossRefGoogle Scholar
  4. Bodmeier R, Paeratakul O (1997) Plasticizer uptake by aqueous colloidal polymer dispersions used for the coating of solid dosage forms. Int J Pharm 52:17–26CrossRefGoogle Scholar
  5. Brodbeck KJ, DesNoyer JR, McHugh J (1999) Phase inversion dynamics of PLGA solutions related to drug delivery. Part II. The role of solution thermodynamics and bathside mass transfer. J Control Release 62:333–344CrossRefGoogle Scholar
  6. Do MP, Neut C, Metz H, Delcourt E, Mäder K, Siepmann J, Siepmann F (2015) In-situ forming composite implants for periodontitis treatment: how the formulation determines system performance. Int J Pharm 486:38–51CrossRefGoogle Scholar
  7. Engelhardt G, Fleig H (1993) Methyl-2-pyrrolidinone (NMP) does not induce structural and numerical chromosomal aberrations in vivo. Mutat Res Genet Toxicol 298:149–155CrossRefGoogle Scholar
  8. Esposito E, Sebben S, Cortesi R, Menegatti E, Nastruzzi C (1999) Preparation and characterization of cationic microspheres for gene delivery. Int J Pharm 189:29–41CrossRefGoogle Scholar
  9. Hatefi A, Amsden B (2002) Biodegradable injectable in situ forming drug delivery systems. J Control Release 80:9–28CrossRefGoogle Scholar
  10. Heidari MR (2014) Reference module in biomedical sciences, Encyclopedia of Toxicology, 3rd edn. Elsevier, Amsterdam, pp 588–593Google Scholar
  11. Irimia-Vladu M, Głowacki ED, Schwabegger G, Leonat L, Akpinar HZ, Sitter H, Bauer S, Sariciftci NS (2013) Natural resin shellac as a substrate and a dielectric layer for organic field-effect transistors. Green Chem 15:1473–1476CrossRefGoogle Scholar
  12. Jaiswal J, Gupta SK, Kreuter J (2004) Preparation of biodegradable cyclosporine nanoparticles by high-pressure emulsification-solvent evaporation process. J Control Release 96:69–178CrossRefGoogle Scholar
  13. Jouyban A, Fakhree MA, Shayanfar A (2010) Reivew of pharmaceutical applications of N-methyl-2-pyrrolidone. J Pharm Sci 13:524–535Google Scholar
  14. Kempe S, Metz H, Mader K (2008) Do in situ forming PLG/NMP implants behave similar in vitro and in vivo: a non-invasive and quantitative EPR investigation on the mechanism of the implant formation process. J Control Release 130:220–225CrossRefGoogle Scholar
  15. Kogawa AC, Salgado HRN (2012) Doxycycline hyclate: a review of properties, applications and analytical methods. Int J Life Sci Pharm Res 2:11–25Google Scholar
  16. Kojima H, Yoshihara K, Sawada T, Kondo H, Sako K (2008) Extended release of a large amount of highly water-soluble diltiazem hydrochloride by utilizing counter polymer in polyethylene oxides (PEO)/polyethylene glycol (PEG) matrix tablets. Eur J Pharm Biopharm 70:556–562CrossRefGoogle Scholar
  17. Liu H, Venkatraman SS (2012) Cosolvent effects on the drug release and depot swelling in injectable in situ depot-forming systems. J Pharm Sci 101:1783–1793CrossRefGoogle Scholar
  18. Liu Q, Zhang H, Zhou G, Xie S, Zou H, Yu Y, Li G, Sun D, Zhang G, Lu Y, Zhong Y (2010) In vitro and in vivo study of thymosin alpha1 biodegradable in situ forming poly(lactide-co-glycolide) implants. Int J Pharm 397:122–129CrossRefGoogle Scholar
  19. Lopedota A, Trapani A, Cutrignelli A, Chiarantini L, Pantucci E, Curci R, Manuali E, Trapani G (2009) The use of ERS® RS 100/cyclodextrin nanoparticles for the transmucosal administration of glutathione. Eur J Pharm Biopharm 72:509–520CrossRefGoogle Scholar
  20. Mahadlek J, Charoenteeraboon J, Phaechamud T (2013) Benzoyl peroxide in situ forming antimicrobial gel for periodontitis treatment. Key Eng Mater 545:63–68CrossRefGoogle Scholar
  21. Martin A (1993) Physical pharmacy. Lea and Febiger, Philadelphia, pp 393–476Google Scholar
  22. McHugh AJ (2005) The role of polymer membrane formation in sustained release drug drlivery systems. J Control Release 109:211–221CrossRefGoogle Scholar
  23. Mohl S, Winter G (2004) Continuous release of the interferon alpha 2a from triglyceride matrices. J Control Release 97:67–78CrossRefGoogle Scholar
  24. Morcol T, Nagappan P, Nerenbaum L, Mitchell A, Bell SJD (2004) Calcium phosphate-PEG-insulin-casein (CAPIC) particles as oral delivery systems for insulin. Int J Pharm 277:91–97CrossRefGoogle Scholar
  25. Morishita M, Kamei N, Ehara J, Isowa K, Takayama K (2004) A novel approach using functional peptides for efficient intestinal absorption of insulin. J Control Release 118:177–184CrossRefGoogle Scholar
  26. Nirmal HB, Bakliwal SR, Pawar SP (2010) In-situ gel: new trends in controlled and sustained drug delivery system. Int J PharmTech Res 2:1398–1408Google Scholar
  27. Okarter TU, Singla K (2000) The effects of plasticizers on the release of metoprolol tartrate from granules coated with a polymethacrylate film. Drug Dev Ind Pharm 26:323–329CrossRefGoogle Scholar
  28. Pandya Y, Sisodiya D, Dashora K (2014) Atrigel, implants and controlled released drug delivery system. Int J Biopharm 5:208–213Google Scholar
  29. Parent M, Nouvel C, Koerber M, Sapin A, Maincent P, Boudier A (2013) PLGA in situ implants formed by phase inversion: critical physicochemical parameters to modulate drug release. J Control Release 172:292–304CrossRefGoogle Scholar
  30. Patel RR, Patel JK (2011) Development and evaluation of in situ novel intragastric controlled-release formulation of hydrochlorothiazide. Acta Pharm 61:73–82CrossRefGoogle Scholar
  31. Peppas NA (2004) Devices based on intelligent biopolymers for oral protein delivery. Int J Pharm 277:11–17CrossRefGoogle Scholar
  32. Phaechamud T, Mahadlek J, Charoenteeraboon J, Choopun S (2013)Characterization and antimicrobial activity of N-methyl-2-pyrrolidone-loaded ethylene oxide-propylene oxide block copolymer thermosensitive gel. Indian J Pharm Sci 74:498–504.CrossRefGoogle Scholar
  33. Phaechamud T, Jantadee T, Mahadlek J, Charoensuksai P, Pichayakorn W (2016) Characterization of antimicrobial agent loaded ERS solvent exchange-induced in situ forming gels of periodontitis treatment. AAPS PharmSciTech 18:494–508CrossRefGoogle Scholar
  34. Phaechamud T, Mahadlek J, Tuntarawongsa S (2017) Peppermint oil/doxycycline hyclate-loaded ERS in situ forming gel for periodontitis treatment. J Pharm Investig 48:451–464.  https://doi.org/10.1007/s40005-017-0340-x CrossRefGoogle Scholar
  35. Popa L, Ghica MV, Dinu-Pirvu C (2013) Periodontal chitosan-gels designed for improved local intra-pocket drug delivery. Farmacia 61:240–249Google Scholar
  36. Qiaoa M, Luo Y, Zhang L, Ma Y, Stephenson TS, Zhu J (2010) Sustained release coating of tablets with ERS® RS/RL using a novel electrostatic dry powder coating process. Int J Pharm 399:37–43CrossRefGoogle Scholar
  37. Rachakonda VK, Terramsetty KM, Madihally SV, Robinson RL, Gasem KA (2008) Screening of chemical penetration enhancers for transdermal drug delivery using electrical resistance of skin. Pharm Res 25:2697–2704CrossRefGoogle Scholar
  38. Rowe RC, Sheskey PJ, Quinn EM (2009) Handbook of pharmaceutical excipients, 6th edn. Pharmaceutical Press and American Pharmaceutical Association, Washington, DCGoogle Scholar
  39. Sanghvi R, Narazaki R, Machatha SG, Yalkowsky SH (2008) Solubility improvement of drugs using N-methyl pyrrolidone. AAPS PharmSciTech 9:366–376CrossRefGoogle Scholar
  40. Sangster J (1997) Octanol-water partition coefficients: fundamentals and physical chemistry. Wiley, New YorkGoogle Scholar
  41. Schwach AK, Vivien CN, Gurny R (2000) Local delivery of antimicrobial agents for the treatment of periodontal diseases. Eur J Pharm Biopharm 50:83–99CrossRefGoogle Scholar
  42. Seymour RA, Heasman PA (1995) Tetracyclines in the management of periodontal diseases. A review. J Clin Periodontal 22:22–35CrossRefGoogle Scholar
  43. Siepmann J, Siepmann F (2008) Mathematical modeling of drug delivery. Int J Pharm 364:328–343CrossRefGoogle Scholar
  44. Solouk A, Mirzadeh H, Amanpour S (2014) Injectable scaffold as minimally invasive technique for cartilage tissue engineering: in vitro and in vivo preliminary study. Prog Biomat 3:143–151CrossRefGoogle Scholar
  45. Srichan T, Phaechamud T (2017) Designing solvent exchange-induced in situ forming gel from aqueous insoluble polymers as matrix base for periodontitis treatment. AAPS PharmSciTech 18:195–201CrossRefGoogle Scholar
  46. Stickley RG (2004) Solubilizing excipients in oral and injectable formulations. Pharm Res 21:201–230CrossRefGoogle Scholar
  47. Tan LP, Venkatraman SS, Sung PF, Wang XT (2004) Effect of plasticization on heparin release from biodegradable matrices. Int J Pharm 283:89–96CrossRefGoogle Scholar
  48. Tang Y, Singh J (2008) Controlled delivery of aspirin: effect of aspirin on polymer degradation and in vitro release from PLGA based phase sensitive systems. Int J Pharm 357:119–125CrossRefGoogle Scholar
  49. Trapani G, Franco M, Latrofa A, Pantaleo MR, Provenzano MR, Sanna E, Maciocco E, Liso G(1999)Physicochemical characterization and in vivo properties of zolpidem in solid dispersions with polyethylene glycol 4000 and 6000. Int J Pharm 184:121–130.CrossRefGoogle Scholar
  50. Velasco-De-Paola MVR, Santoro MIRM, Gai MN (1999) Dissolution kinetics evaluation of controlled-release tablets containing propranolol hydrochloride. Drug Dev Ind Pharm 25:535–541CrossRefGoogle Scholar
  51. Wang J, Li D, Li T, Ding J, Liu J, Li B, Chen X (2015) Gelatin tight-coated poly(lactide-co-glycolide) scaffold incorporating rhBMP-2 for bone tissue engineering. Materials 8:1009–1026CrossRefGoogle Scholar
  52. Xiong W, Gao X, Zhao Y, Xu H, Yang X (2011) 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 84:103–110CrossRefGoogle Scholar

Copyright information

© The Korean Society of Pharmaceutical Sciences and Technology 2019

Authors and Affiliations

  • Wai Wai Lwin
    • 1
  • Napaphol Puyathorn
    • 2
  • Setthapong Senarat
    • 2
  • Jongjan Mahadlek
    • 3
  • Thawatchai Phaechamud
    • 2
    Email author
  1. 1.Department of PharmaceuticsUniversity of PharmacyMandalayMyanmar
  2. 2.Department of Pharmaceutical Technology, Faculty of PharmacySilpakorn UniversityNakhon PathomThailand
  3. 3.Pharmaceutical Intelligence Unit Prachote Plengwittaya, Faculty of PharmacySilpakorn UniversityNakhon PathomThailand

Personalised recommendations