Novel mucoadhesive buccal formulation containing metronidazole for the treatment of periodontal disease

doi:10.1016/j.jconrel.2003.12.018

Journal of Controlled Release

Volume 95, Issue 3, 24 March 2004, Pages 521-533

https://doi.org/10.1016/j.jconrel.2003.12.018 Get rights and content

Abstract

Mucoadhesive tablets using different mixture of cellulose and polyacrylic derivatives were prepared in order to obtain new formulations containing metronidazole for periodontal disease treatment. All tablets were characterized by swelling studies, ex vivo and in vivo mucoadhesive time, ex vivo mucoadhesion force, in vitro and in vivo release. The best mucoadhesive performance and the best in vitro drug release profile were achieved by using hydroxyethyl cellulose (HEC) and carbomer 940 2:2 ratio. The chosen tablet, containing 20 mg of metronidazole, performed 12 h drug sustained release with buccal concentrations always higher than its MIC.

Introduction

Periodontal diseases are groups of infections and inflammatory conditions, including gingivitis and periodontitis that affect teeth-supporting structures. These diseases occur when bacteria from dental plaque invade surrounding tissues and accumulation of plaque at the gingival margin induces inflammatory response. The result is the formation of pockets between gingiva and tooth that causes gingival margin retraction and the development of an ideal environment for anaerobic bacteria growth responsible for the disease. The progression of this destructive process can cause tooth loss [1], [2], [3]. The therapeutic goal is the removing of bacteria responsible for the infection by mechanical cleaning and topical application of antimicrobial agents, such as tetracycline, metronidazole, clindamycin, ofloxacin, chlorexidine and cetylpyridinium. Tetracyclines, in particular doxycycline, are used extensively in the treatment of periodontal disease, but the development of bacterial resistance induces to prefer the use of metronidazole, very selective agent against anaerobic bacteria [4].

Antimicrobial agents are orally administered to produce a systemical effect, but this application induces some side effects like hypersensitivity, gastrointestinal intolerance, development of bacterial resistance [5], [6]. Furthermore, it is reported that this kind of administration does not guarantee an adequate concentration at the action site because the active product is not retained locally for a sufficient period of time [7]. A solution to these problems could be the local administration of the drug formulated in a controlled release delivery system to be placed directly on the action site.

The first delivery devices were hollow polymeric fibers filled with tetracycline [8], [9]. They were not adhesive and the application required surgical procedure sometimes supported by the use of cyanoacrylate glue [10]. Surgical removal was necessary as well. Successively, attempts were done with doxycycline and bioabsorbable materials [11], however surgical application was still required.

The mucoadhesive system which can be applied and removed directly by patients, represents a good recent alternative. Appropriate materials for bioadhesion are mainly hydrogel-forming polymers [12], [13] which are called wet adhesives because they require moisture to exhibit adhesive property [14]. Examples of bioadhesive polymers are cellulose derivatives, natural gums, sodium alginate, polyoxyethylenes and polyacrylates.

The aim of this study is the preparation of mucoadhesive tablets in order to obtain buccal sustained release of metronidazole. In planning this kind of formulation, the following characteristics are required: (i) small size, (ii) flexibility and adaptability to the mucosa, (iii) no irritation, no discomfort, no bad taste, (iv) no dry mouth, (v) no excessive salivation and heaviness in buccal cavity.

In this study, we developed a new mucoadhesive tablet using different mixtures of cellulose derivates (Hydroxypropylcellulose—HPC, Hydroxyethylcellulose—HEC, Hydroxypropylmethylcellulose K4M—HPMC K4M, Hydroxypropylmethylcellulose K4M—HPMC K15M, Sodium Carboxymethylcellulose—NaCMC) and polyacrylic derivatives (Carbomer 940, Carbopol 971, Polycarbophil). Polyacrilic acids show better bioadhesive properties than cellulose derivatives however, since may cause irritation to the mucosa due to the high presence of carboxyl groups, their mixture was preferred because it could offer acceptable adhesion and biocompatibility properties [15], [16], [17], [18].

The investigation consisted of the following steps: (a) preparation of non-medicated tablets by compression of different mixtures of polymers, (b) in vitro characterization and ex vivo and in vivo studies, (c) choice of mucoadhesive tablets showing the best performances, (d) preparation of medicated tablets with metronidazole, (e) evaluation of in vitro drug release, (f) evaluation of in vivo drug release, (g) investigation of the release modality from the matrix.

Section snippets

Materials

HPC (Klucel HF) and HEC (Natrosol-250HHX), were obtained by Aqualon (Hercules incorporated, USA). HPMC (Methocel K4M and Methocel K15M) were supplied by Colorcon (England). NaCMC was obtained by Aldrich (USA). Carbopol 971 and polycarbophil were obtained by Noveon (USA). Carbomer 940 was purchased by Galeno (Italy). Metronidazole was obtained by Farchemia (Italy). Pig buccal mucosa was furnished by Istituto Zooprofilattico Sperimentale dell'Umbria e delle Marche (IZS), Perugia (Italy).

Manufacture of non-medicated tablets

Swelling studies

The % of hydration (Fig. 1) showed that all the tablets were characterized by very similar hydration profiles, as they hydrated quickly reaching a plateau after 8 h, and remained almost constant until the end of the experiment (24 h). Most of the tablets reached 70% hydration within the first hour, with the exception of group II that hydrated faster reaching the 70% of hydration in half an hour. Moreover, tablets 12, 15 and 18 having 3:1 HEC/acrylic polymer ratio showed the highest hydration

Conclusion

The new mucoadhesive tablet formulated allows a good metronidazole local sustained release in the oral cavity for 12 h together with a remarkable reduction of the daily drug dosage (more than 15 folds) if compared to traditional systemic therapies (40 mg pro-die vs. 600 mg). These results guarantee the achievement of therapeutic concentration in the action site, the decrease of drug side effects and the improvement of patient's compliance. Therefore, such formulation looks very promising for

Acknowledgements

The authors are very much grateful to Prof. Virgilio Gallai and Potito D'Errico, from the Neuroscience Department of the University of Perugia, for their valuable suggestions, Dr. Marinella Capuccella, from IZS, for collaboration in ex vivo experiments and Mr. Marco Marani for the precious collaboration and technical assistance.

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Novel mucoadhesive buccal formulation containing metronidazole for the treatment of periodontal disease

Abstract

Introduction

Section snippets

Materials

Manufacture of non-medicated tablets

Swelling studies

Conclusion

Acknowledgements

Adv. Drug Deliv. Rev.

Eur. J. Pharm. Biopharm.

Int. J. Pharm.

J. Control. Release

Int. J. Pharm.

Int. J. Pharm.

Untreated periodontal disease: a longitudinal study

J. Periodontol.

Progression of periodontal disease in adult subjects in the absence of periodontal therapy

J. Clin. Periodontol.

Nature of periodontal disease: pathogenic mechanisms

J. Periodontol. Res.

A clinical and microbiological evaluation of systemic and local metronidazole delivery in adult periodontis patients

J. Clin. Periodontol.

The systemic use of antibiotics in periodontal therapy

Microbiological response to mechanical treatment in combination whit adjunctive therapy. A review of the literature

J. Periodontol.

The use of tetracycline-containing controlled release fibers in the treatment of refractory periodontis

J. Periodontol.

Periodontal therapy by local delivery of tetracycline

J. Clin. Periodontol.