Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Article
  • Published:
Journal of Pharmaceutical Investigation Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • 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 44:514–521

    CAS  PubMed  Google Scholar 

  • 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 10:3753–3762

    Google Scholar 

  • Arendt-Nielsen L, Egekvist H, Bjerring P (2006) Pain following controlled cutaneous insertion of needles with different diameters. Somatosens Mot Res 23:37–43

    PubMed  Google Scholar 

  • Bodmeier R, Paeratakul O (1997) Plasticizer uptake by aqueous colloidal polymer dispersions used for the coating of solid dosage forms. Int J Pharm 52:17–26

    Google Scholar 

  • 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 62:333–344

    CAS  PubMed  Google Scholar 

  • 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 486:38–51

    CAS  PubMed  Google Scholar 

  • Engelhardt G, Fleig H (1993) Methyl-2-pyrrolidinone (NMP) does not induce structural and numerical chromosomal aberrations in vivo. Mutat Res Genet Toxicol 298:149–155

    CAS  Google Scholar 

  • Esposito E, Sebben S, Cortesi R, Menegatti E, Nastruzzi C (1999) Preparation and characterization of cationic microspheres for gene delivery. Int J Pharm 189:29–41

    CAS  PubMed  Google Scholar 

  • Hatefi A, Amsden B (2002) Biodegradable injectable in situ forming drug delivery systems. J Control Release 80:9–28

    CAS  PubMed  Google Scholar 

  • Heidari MR (2014) Reference module in biomedical sciences, Encyclopedia of Toxicology, 3rd edn. Elsevier, Amsterdam, pp 588–593

    Google Scholar 

  • Irimia-Vladu M, GÅ‚owacki 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 15:1473–1476

    CAS  Google Scholar 

  • Jaiswal J, Gupta SK, Kreuter J (2004) Preparation of biodegradable cyclosporine nanoparticles by high-pressure emulsification-solvent evaporation process. J Control Release 96:69–178

    Google Scholar 

  • Jouyban A, Fakhree MA, Shayanfar A (2010) Reivew of pharmaceutical applications of N-methyl-2-pyrrolidone. J Pharm Sci 13:524–535

    CAS  Google Scholar 

  • 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 130:220–225

    CAS  PubMed  Google Scholar 

  • Kogawa AC, Salgado HRN (2012) Doxycycline hyclate: a review of properties, applications and analytical methods. Int J Life Sci Pharm Res 2:11–25

    CAS  Google Scholar 

  • 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 70:556–562

    CAS  PubMed  Google Scholar 

  • Liu H, Venkatraman SS (2012) Cosolvent effects on the drug release and depot swelling in injectable in situ depot-forming systems. J Pharm Sci 101:1783–1793

    CAS  PubMed  Google Scholar 

  • 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 397:122–129

    CAS  PubMed  Google Scholar 

  • 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 72:509–520

    CAS  PubMed  Google Scholar 

  • Mahadlek J, Charoenteeraboon J, Phaechamud T (2013) Benzoyl peroxide in situ forming antimicrobial gel for periodontitis treatment. Key Eng Mater 545:63–68

    Google Scholar 

  • Martin A (1993) Physical pharmacy. Lea and Febiger, Philadelphia, pp 393–476

    Google Scholar 

  • McHugh AJ (2005) The role of polymer membrane formation in sustained release drug drlivery systems. J Control Release 109:211–221

    CAS  PubMed  Google Scholar 

  • Mohl S, Winter G (2004) Continuous release of the interferon alpha 2a from triglyceride matrices. J Control Release 97:67–78

    CAS  PubMed  Google Scholar 

  • 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 277:91–97

    CAS  PubMed  Google Scholar 

  • 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 118:177–184

    Google Scholar 

  • Nirmal HB, Bakliwal SR, Pawar SP (2010) In-situ gel: new trends in controlled and sustained drug delivery system. Int J PharmTech Res 2:1398–1408

    CAS  Google Scholar 

  • 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 26:323–329

    CAS  PubMed  Google Scholar 

  • Pandya Y, Sisodiya D, Dashora K (2014) Atrigel, implants and controlled released drug delivery system. Int J Biopharm 5:208–213

    Google Scholar 

  • 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 172:292–304

    CAS  PubMed  Google Scholar 

  • Patel RR, Patel JK (2011) Development and evaluation of in situ novel intragastric controlled-release formulation of hydrochlorothiazide. Acta Pharm 61:73–82

    CAS  PubMed  Google Scholar 

  • Peppas NA (2004) Devices based on intelligent biopolymers for oral protein delivery. Int J Pharm 277:11–17

    CAS  PubMed  Google Scholar 

  • 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.

    Google Scholar 

  • 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 18:494–508

    PubMed  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

  • Popa L, Ghica MV, Dinu-Pirvu C (2013) Periodontal chitosan-gels designed for improved local intra-pocket drug delivery. Farmacia 61:240–249

    CAS  Google Scholar 

  • 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 399:37–43

    Google Scholar 

  • 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 25:2697–2704

    CAS  PubMed  Google Scholar 

  • Rowe RC, Sheskey PJ, Quinn EM (2009) Handbook of pharmaceutical excipients, 6th edn. Pharmaceutical Press and American Pharmaceutical Association, Washington, DC

    Google Scholar 

  • Sanghvi R, Narazaki R, Machatha SG, Yalkowsky SH (2008) Solubility improvement of drugs using N-methyl pyrrolidone. AAPS PharmSciTech 9:366–376

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sangster J (1997) Octanol-water partition coefficients: fundamentals and physical chemistry. Wiley, New York

    Google Scholar 

  • Schwach AK, Vivien CN, Gurny R (2000) Local delivery of antimicrobial agents for the treatment of periodontal diseases. Eur J Pharm Biopharm 50:83–99

    Google Scholar 

  • Seymour RA, Heasman PA (1995) Tetracyclines in the management of periodontal diseases. A review. J Clin Periodontal 22:22–35

    CAS  Google Scholar 

  • Siepmann J, Siepmann F (2008) Mathematical modeling of drug delivery. Int J Pharm 364:328–343

    CAS  PubMed  Google Scholar 

  • 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 3:143–151

    Google Scholar 

  • 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 18:195–201

    Google Scholar 

  • Stickley RG (2004) Solubilizing excipients in oral and injectable formulations. Pharm Res 21:201–230

    Google Scholar 

  • Tan LP, Venkatraman SS, Sung PF, Wang XT (2004) Effect of plasticization on heparin release from biodegradable matrices. Int J Pharm 283:89–96

    CAS  PubMed  Google Scholar 

  • 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 357:119–125

    CAS  PubMed  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • Velasco-De-Paola MVR, Santoro MIRM, Gai MN (1999) Dissolution kinetics evaluation of controlled-release tablets containing propranolol hydrochloride. Drug Dev Ind Pharm 25:535–541

    CAS  PubMed  Google Scholar 

  • 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 8:1009–1026

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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 84:103–110

    CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. Department of Pharmaceutics, University of Pharmacy, Mandalay, Myanmar

    Wai Wai Lwin

  2. Department of Pharmaceutical Technology, Faculty of Pharmacy, Silpakorn University, Nakhon Pathom, 73000, Thailand

    Napaphol Puyathorn, Setthapong Senarat & Thawatchai Phaechamud

  3. Pharmaceutical Intelligence Unit Prachote Plengwittaya, Faculty of Pharmacy, Silpakorn University, Nakhon Pathom, 73000, Thailand

    Jongjan Mahadlek

Authors
  1. Wai Wai Lwin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Napaphol Puyathorn
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Setthapong Senarat
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jongjan Mahadlek
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Thawatchai Phaechamud
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Thawatchai Phaechamud.

Ethics declarations

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.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lwin, W.W., Puyathorn, N., Senarat, S. et al. Emerging role of polyethylene glycol on doxycycline hyclate-incorporated Eudragit RS in situ forming gel for periodontitis treatment. J. Pharm. Investig. 50, 81–94 (2020). https://doi.org/10.1007/s40005-019-00430-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40005-019-00430-6

Keywords

Search

Navigation