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Metronidazole-Loaded BioabsorbableFilms as Local Antibacterial Treatment

of Infected Periodontal PocketsYael Shifrovitch,* Itzhak Binderman,* Hila Bahar,* Israela Berdicevsky, and Meital Zilberman*

Background: Periodontal disease is infectious in nature andleads to an inflammatory response. It arises from the accu-mulation of subgingival bacterial plaque and leads to the lossof attachment, increased probing depth, and bone loss. It isone of the worlds most prevalent chronic diseases. In thisstudy we developed and studied metronidazole-loaded 50/50poly(DL-lactide-co-glycolide) (PDLGA), 75/25 PDLGA, and

poly(DL-lactic acid) (PDLLA) films. These films are designedto be inserted into the periodontal pocket and treat infectionswith controlled-release metronidazole for 1 month.

Methods: The structured films were prepared using the solu-tion-casting technique. Concentrated solutions and high sol-vent-evaporation rates were used to get most of the druglocated in the bulk, i.e., in whole films volume. The effects ofcopolymer composition and drug content on the release profile,cell growth, and bacterial inhibition were investigated.

Results: The PDLLA and 75/25 PDLGA films generallyexhibited a low- or medium-burst release followed by a moder-ate release at an approximately constant rate, whereas the 50/50 PDLGA films exhibited a biphasic release profile. The drugreleased from films loaded with 10% weight/weight metronida-zoleresulted in a significant decrease in bacterial viability withinseveral days. When exposed to human gingival fibroblasts incell culture conditions, these films maintained their normal fi-broblastic features.

Conclusions: This study enabled the understanding of met-ronidazole-release kinetics from bioabsorbable polymericfilms. The developed systems demonstrated good biocom-patibility and the ability to inhibit Bacteroides fragilis growth;therefore, they may be useful in the treatment of periodontaldiseases. J Periodontol 2009;80:330-337.

KEY WORDS

Biocompatibility; drug delivery; metronidazole.

Periodontal disease, a localized in-

flammatory response due to infec-tion of a periodontal pocket arisingfrom the accumulation of subgingivalplaque, is one of the worlds most prev-alent chronic diseases. With 36.8% ofAmerican adults estimated to havethe disease, the prevalence of periodon-tal disease is greater than cancer, heartdisease, arthritis, obesity, acquired im-munodeficiency syndrome, and manyother diseases.1 The topical administra-tion of antibacterial agents in the form ofmouthwashes is ineffective in controllingdisease progression because a limitedamount of the drugs actually reach theperiodontal pocket. Moreover, the drugsare constantly flushed because of a veryhigh fluid-clearance rate (an estimated40 replacements of the fluid per hourwithin a 5-mm pocket).2

There are numerous benefits for localdrug delivery to the pocket in the formof subgingivally placed systems. Fortu-nately, periodontal diseases are localizedin the immediate environment of the

pocket, which is easily accessible forthe insertion of a delivery device by sy-ringe or tweezers, depending on thephys-ical form of the delivery system. Thecritical period of exposure of the pocketto the antibacterial drug is between 7and 10 days.3 Intrapocket delivery sys-tems can be divided into bioabsorbableand non-bioabsorbable systems. Non-bioabsorbable systems must be removedor discharged from the pocket after their

* Department of Biomedical Engineering, Tel Aviv University, Tel Aviv, Israel. Department of Microbiology, Technion Israel Institute of Technology, Haifa, Israel.

doi: 10.1902/jop.2009.080216

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drug-release function has been accomplished. Exam-ples of non-bioabsorbable systems include celluloseacetate fibers loaded with tetracycline,4-6 chlorhexi-dine,7 or metronidazole8 and film- or slab-baseddevices madeof poly(methyl methactylate)and ethyl-cellulose loaded with the three aforementioned

drugs.9-13 The most studied systems showed promis-ing clinical results in the maintenance of periodontalpockets over a 2-year period.12,13

Bioabsorbable systems are usually polymeric orprotein in nature and undergo natural degradationin response to gingival fluid components. The first bio-absorbable systems to be developed were based onhydroxypropylcellulose loaded with various agents:tetracycline, chlorhexidine, and ofloxacin.14 The re-searchers reported on the fast drug release from thefilm within 2 hours with tetracycline remaining withinthe pocket for 24 hours after insertion. Several mod-

ifications have been made to overcome the rapid deg-radation and short duration of drug release, e.g.,incorporating methacrylic acid copolymer particlesinto the film to get ofloxacin release for 7 days.14

A bioabsorbable device based on hydrolyzed gelatincross-linked by formaldehyde, as reported by Stein-berg et al.,15 has evolved to the commercial chlorhex-idine in a gelatin matrix. This United States Food andDrug Administrationapproved device releases chlor-hexidine. A different system is based on a water-freemixture of melted glycerol mono-oleate and metroni-dazole to which sesame oil was added to improve its

flow properties in the syringe. The gel flows deeply intothe periodontalpocketsand readilyadaptsto rootmor-phology.Itsetsinaliquidcrystallinestatewhenitcomesin contact with water. The matrix is degraded as a resultof neutrophil and bacterial activity within the pocket.16

Effective doses of metronidazole within the pocket aremaintained for 24 to 36 hours.

Metronidazole-loaded poly(vinyl alcohol) filmsdemonstrated a biphasic release profile, but the drugwas released within several hours because of thehigh hydrophilic nature of the host polymer.17 Metro-nidazole and amoxicillin were loaded in poly(DL-lactide-co-glycolide) (PDLGA) and poly(DL-lacticacid) (PDLLA) films.18 The drug-release study18

showed that during the first 16 days, thereleased quan-tities of drugs were higher than the minimum inhibitoryconcentration (MIC) needed against various microbescausing periodontal diseases.

Metronidazole is a partially hydrophilic drug, whicheffectively inhibits anaerobic microorganisms andprotozoan infections.19,20 This drug is used for thetreatment of many infections, including periodontaland vaginal infections.12,21,22 This drug was incorpo-rated in drug-delivery systems for various applica-tions, such as tablets for the treatment of peptic

ulcers,23 microspheres for the treatment of diseases

associated with the colon and the gastric mucosa,24

alginate gel beads for gastric applications,25 and var-ious systems for the treatment of periodontal dis-eases, as described above.

Solution casting of polymers is a well-knownmethod for preparing polymer films. To incorporate

a drug using this method, the polymer is dissolvedin a solvent and mixed with the drug prior to casting.Then the solvent is evaporated, and the polymer/drugfilm is created. We reported a method for controllingdrug location/dispersion within the film.26,27 In thisprocess, the solvent evaporation rate determinesthe kinetics of drug and polymer solidification and,thus, the drug dispersion/location within the film. Sol-ubility effects in the starting solution also contribute tothe postcasting diffusion processes and occur con-comitantly with the drying step. In general, two typesof polymer/drug film structures were created and

studied: a polymer film with large drug crystals lo-cated on the film surface (A type) and a polymer filmwith small drug particles and crystals distributedwithin the bulk (B type). This structure enables controlof the drug-release profile and results in desired re-lease behavior. The two types of films, A and B, weredeveloped and studied for two types of drugs: highlyhydrophobic drugs, such as dexamethasone,26 andhighly hydrophilic drugs, such as gentamicin.27 Metro-nidazole has moderate hydrophilicity (10 mg/ml).Therefore, it is of interest to study the controlled-releasecharacteristics of polymer/metronidazole-loaded films.

The aim of the present study was to develop andevaluate metronidazole-loaded bioabsorbable films,designed to be inserted into the periodontal pocketand treat infections during metronidazole con-trolled-release phase. This study focused on the ef-fects of drug content and the type of host polymeron the drug-release profile. Selected films were stud-ied for cell growth and bacterial inhibition. We believethat a relatively long release time (4 weeks) would bebeneficial for the healing process.

MATERIALS AND METHODS

All experiments and analyses were conducted in theBiomaterials Laboratory at Tel-Aviv University.

Materials

Bioabsorbable polymers. The following three bioab-sorbable polymers were used: PDLLAi with an inher-ent viscosity (IV) of 0.62 dl/g in ChCl3 at 30C, whichcorresponds to a molecular weight (MW) of 90,177Da; 75/25 PDLGA with an IV of 0.65 dl/g in ChCl3at 30C, which corresponds to a MW of 100,050 Da;

PerioChip, Perio Products, Jerusalem, Israel. Elyzol, Dumex, Copenhagen, Denmark.i Absorbable Polymers International, Pelham, AL. Absorbable Polymers International.

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50/50 PDLGA# with an IV of 0.57 dl/g in ChCl3 at30C, which corresponds to a MW of 71,500 Da.

The drug used in the study was metronidazole.**Microorganisms. A clinical isolate ofBacteroides fra-

giliswas used in this study. Centers for Disease Controland Prevention (CDC) anaerobic blood agar was used

to grow the microorganisms.This medium is highlyrec-ommended for the anaerobic growth of bacteria.

Film PreparationPolymer films (0.12 to 0.15 mm thick) consisting ofPDLLA, 75/25 PDLGA, or 50/50 PDLGA and metro-nidazole were prepared by a three-step solution-processing method. The polymer (1 g) was mixedwith a relatively small volume of methylene chloride(20 ml) at room temperature until it was totally dis-solved, giving a clear solution; metronidazole wasadded to the polymer solution to give a relatively con-centrated solution. Two constant drug loadingswere used: 20 mg metronidazole (2% weight/weight[w/w]) and 100 mg metronidazole (10% w/w). Thedrug was fully dissolved in both solutions. The follow-ing steps were solution casting into a petri dish andsolvent drying under atmospheric pressure at roomtemperature. The petri dish was not covered, so asto enable a relatively fast evaporation rate of 10 to20 ml/hour. Afterwards, the solution was cast into apetri dish, and the solvent was dried under atmo-spheric pressure at room temperature. Following thisstep, the film underwent isothermal heat treatment at33C for 23 hours in a vacuum oven. This heat treat-

ment enabled disposal of residual solvent.

Morphologic CharacterizationPolarized light microscopy was performed using a mi-croscope (transmission mode).

In Vitro Weight-Loss StudiesThe polymer films (1 1 cm) were weighed and thenimmersed in phosphate buffered saline (PBS; 50 mlin a petri dish) at 37C for 20 weeks to determine theirweight-loss profiles. Samples (also those broken intosmallpieces)wereremovedeveryweek,driedinavac-uum oven, and weighed. The weight loss was calcu-

lated as follows:

weight loss % 100Xw0 wf

w0;

where w0 and wfare the weights of the dried films be-fore and after exposure to water, respectively. Foursamples were tested at each point. The means andSD values are presented in the relevant figures.

In Vitro Metronidazole Release StudyPolymer/metronidazole films with a diameter of 10 cmwere immersed in 40 ml PBS at37C for 7 weeks (50/50 PDLGA films were immersed for 5 weeks) in semi-

static conditions to determine the kinetics of metroni-

dazole release from the films. The films were weighedbefore the experiment to permit determination of100% release. Sodium azide (0.05% weight/volume)wasaddedtopreventcontaminationbyvariousmicro-organisms. At the following times, 1.5-ml sampleswere collected: 1, 6, and 24 hours; 2, 3, and 8 days;

and 2, 3, 4, 5, and 7 weeks. The maximum metronida-zole concentration in the release medium was 10times less than its water solubility so as not to affectthe release kinetics. The amount removed was re-placed with fresh PBS, and the correction factor wasapplied as follows:

correction factor 40

40 1:5

n1;

where nis the sequential sample number. The metro-nidazole content in each sample was determined withan ultraviolet/visible scanning spectrophotometer

at 320 nm. The metronidazole working range was10 to 140 mg/ml; therefore, the samples were diluted.A calibration curve was prepared for each set of mea-surements, with a correlation coefficient >0.99. Threesamples were examined for each film type. The meansand SD values are presented in the relevant figures.

Preparation of BacteriaB. fragilis was grown overnight on CDC anaerobicblood agar at 37C under anaerobic conditions. Thebacterialcells werecollectedandresuspended in salineandadjustedto1108/mlbyvisualcomparisontoa0.5

McFarlandstandard.Ten-folddilutionswereperformedin Eppendorf tubes. Aliquots of 100 ml were spread onCDC agar, and three repetitions were conducted.

Evaluation of Residual BacteriaSamples of 10 or 100 ml were collected or diluted toa final concentration, at the appropriate time, andspread on CDCanaerobic agar plates. Colonyformingunits (CFU)/ml were counted after 24 hours of incuba-tion at 37C.

MICThe MICof metronidazole against B. fragiliswas deter-

mined using the E-test method, and it was found to be1 mg/ml. Special stripsii for detecting MIC values (us-ing the E-test method) were used.

Microbiologic Experiment DesignThe microbiologic study, i.e., the kinetics of residualbacteria, was performed as follows. The effect of met-ronidazole releasedfrom thefilms(in PBS) on bacterialinhibition was studied. The release medium samples

# Absorbable Polymers International.** Sigma, St. Louis, MO. Difco Microbiology, Detroit, MI. Leica, Wetzlar, Germany. Zenyth 200rt, Anthos, Eugendorf, Australia.ii Biodisk, Salna, Sweden.

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were collected after 0, 5, and 48 hours and 1, 2, and 3weeks.The organismswereaddedto a final concentra-tion of 1 107 CFU/ml. The samples were collected(after 0 and 24 hours and 2 and 7 days in the case of50/50 PDLGA films and after 0 and 24 hours and 3and 8 daysin the caseof PDLLA films) for viablecount-

ing and were expressed as CFU/ml. Bacteria in PBSserved as the control. CDC anaerobic blood agarplates were used for counting the residual bacterial.The calculation established the residual number ofbacteria in the presence of metronidazole.

Because B. fragilisis an obligatory anaerobe, all in-cubations were performed in anaerobic jars in thepresence of anaerobic bags.

Biocompatibility ExperimentFilms of5 5 mm, which were loaded with 2% w/w and10% w/w of metronidazole, were placed in 35-mm cell

culture dishes and covered with 70% alcohol solutionfor 30 minutes to achieve sterilization of the films. Thealcohol wasdecanted and replaced by three washes ofsterile PBS and left to dry in the laminar flow hood,blowing sterile air. Human gingival fibroblasts (HGFs;three to four subcultures of human gingival explants)were seeded at 1 105 cells/dish, with 2 ml growthmedium covering the films. The cells were culturedin minimum essential medium supplemented with10% newborn bovine serum. The medium was re-placed every 4 days. After 4 to 6 days, subconfluentcultures were observed under phase-contrast micros-

copy. The medium was decanted, and the cells werewashed with PBS and fixed with 5% formalin in PBS.Two hours later, the formalin was removed, and thecells were washed in PBS and stained with Coomassieblue to expose the cytoskeleton F-actin. Cells on thefilms and the culture dish exhibited normal fibroblasticmorphologic features.

RESULTS

Microstructure of Polymer/Metronidazole FilmsBioabsorbable polymeric films containing metronida-zole were prepared using solution processing, ac-companied by a postpreparation isothermal heattreatment. Our structuring technique enabled us tocontrol the drug location/dispersion in the film. Usingthis technique, the films were prepared from concen-trated solutions using a fast evaporation rate to getfilms with the most drug molecules located in the bulk,i.e., in whole films volume, rather than on the surface.The microstructure of the metronidazole-loaded 50/50PDLGA, 75/25 PDLGA, and PDLLA films is presentedin Figure 1. In the 50/50 and 75/25 PDLGA-basedfilms, drug crystals, particles, and aggregates (2 to100 mm) are dispersed in the bulk. Only a small

amount of the drug is located on the surface of the film.

Conversely, in the PDLLA-basedfilms, more drugcrys-tals and particles are located on the surface of the film.The effect of this difference in microstructure on thedrug-release profile is described in the next section.

Figure 1.Light photomicrographs of polymer/metronidazole 10% w/w films. Hostpolymer: 50/50 PDLGA (A), 75/25 PDLGA (B), and PDLLA (C).

Oxoid, Cambridge, U.K.


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Metronidazole Release From Bioabsorbable Filmsand Their Weight-Loss ProfileThe effects of polymer type and drug loading on themetronidazole-release profile were examined. The cu-mulative metronidazole-release profiles from variouspolymer/metronidazole films loaded with 2% w/w met-ronidazole and 10% w/w metronidazole are presentedin Figure 2. A small or moderate burst release (duringthe first 48 hour) was observed for all six studied films.The films loaded with 2% w/w metronidazole released10% to 20% of their drug within the first 48 hours (Fig.2A), whereas the films loaded with 10% w/w metroni-dazole released 20% to 38% of their drug (Fig. 2B).

The PDLLA/metronidazole and 75/25 PDLGA/met-ronidazole films exhibited a constant rate of releaseduring the first 2 to 3 weeks; thereafter, only a smallamount of drug was released through week 7. Con-versely, the 50/50 PDLGA/metronidazole film ex-hibited a two-phase release: the first release occurredduring the first 3 days for the 2% w/w loaded filmsand during the first 7 days forthe 10% w/wloaded films,and the second phase started after 14 days for the 2%w/w loaded films and after 20 days for the 10% w/wloaded films. All encapsulated drug was released by

35 days.

The weight-loss (erosion) profile of PDLLA and 50/50 PDLGA is presented in Figure 3. Although thePDLLA films lost only 2% of their initial weight duringthe first 7 weeks of degradation, the 50/50 PDLGAfilms lost 18% of their initial weight.

Microbiologic Evaluation of the Effect ofMetronidazole Release on Bacterial ViabilityThe purpose of these experiments was to monitor theeffectiveness of various concentrations of the antibi-otic released from the films in terms of the residualbacteria compared to the initial number of bacteria.Bacteria present in PBS only served as the control.We chose the following two types of films with different

release profiles: 50/50 PDLGA films loaded with 2%w/w metronidazole, which demonstrated a biphasicrelease profile with a relatively highburst release of20% (compared to the other samples containing 2%w/w drug), and PDLLA films loaded with 10% w/wmetronidazole, which demonstrated the highest burstrelease of;38% and the highest release rate duringthe first 2 weeks of release.

Figure 4 presents the two profiles for comparison.The profiles are expressed as the percentage of thetotal drug encapsulated (Fig. 4A) and as the drugamount (milligrams; Fig. 4B). The samples were col-lected after 5 and 48 hours and after 7 and 21 days for50/50 PDLGA film containing 2% w/w metronidazoleand after 5 and 48 hours and 7 and 14 days for PDLLAloaded with 10% w/w metronidazole. B. fragilis wasadded to the tubes containing previously releaseddrug, and thenumber of bacterial cells wasmonitored.The initial bacterial concentrations used in our exper-iment were 1 107 CFU/ml, which is relatively high.Most infections involve lower concentrations (usuallynot more than 1105CFU/ml). Therefore, we assumethat if our metronidazole-eluting films were effectiveagainst such concentrations, they will be effectiveagainst serious infections. The results (bacterial inhi-

bition kinetics) for 50/50 PDLGA film containing 2%

Figure 2.In vitro cumulative metronidazole release from polymer/metronidazolefilms: A) films containing 2% w/w metronidazole, B) films containing10% w/w metronidazole. Blue diamonds = 50/50 PDLGA; redsquares = 75/25 PDLGA; green triangles = PDLLA.

Figure 3.Weight loss of polymer films as a function of degradation time. Bluediamonds = 50/50 PDLGA; green triangles = PDLLA.


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w/w metronidazole are presented in Figure 5A, andthe results for PDLLA loaded with 10% w/w metroni-dazole are presented in Figure 5B.

Our results showed that, when B. fragilis was ex-posed to 50/50 PDLGA film loaded with 2% w/w met-ronidazole, the quantity of drug released during thefirst 7 days (

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PDLGA and PDLLAfilms (Fig. 2). The former films ex-

hibited a constant rate of release during the first 2 to 3weeks, and then only a very small amount of drug wasreleased until week 7. This first phase of release isgoverned mainly by diffusion. We expected a secondphase of release to occur after 7 weeks because of acombination of diffusion and erosion of the host poly-mer. In the case of 50/50 PDLGA films, we observedthe two phases of release because that film exhibitedthe fastest degradation rate, and massive erosion oc-curred during the first 4 weeks of exposure to aqueousmedium (Fig. 3). The release profiles of the filmsloaded with 10% w/w drug showed that larger drugquantities were released from the PDLLA films thanfrom the 75/25 PDLGA films (Fig. 2B). This probablyresulted from differences in the drugs location in thefilm, i.e., in the former, larger drug quantities werelocated near the films surface (Fig. 1). Our resultsalso showed that the drug loading affected the burstrelease. The higher burst release from films loadedwith 10% w/w drug resulted from higher driving forcefor diffusion of drug molecules from polymer domainsclose to the surface.

Metronidazole is a relatively hydrophilic drug (10mg/ml); therefore, we expected higher burst releaseandhigher rates of release. Theslow-moderate burst-re-

lease values and moderate drug-release rate observed

in the current study resulted fromthe film structuring, i.e., most drugmolecules were located in the filmrather than on its surface. Also, spe-cific interactions, such as hydrogenbonding, may exist between the

metronidazole molecules andthebi-oabsorbable polyester chains.These may decrease the releaserate. Our metronidazole-releaseprofiles showedlonger periods of re-lease than those obtained for othermetronidazole-eluting bioabsorb-able systems (several hours to sev-eral days).14,17,18

Our microbiologic experimentsshowed that metronidazole was ef-fective in the tested samples. The

films collection and preparationmethod did not affect metroni-dazoles antibiotic potency. Also,our results indicated that moderatedrug contents (such as 10% w/w)were very effective and could erad-icate the bacterial growth withinseveral days, even when a largeinoculum (1 107 CFU/ml) wascreated. The release profile ofmetronidazole from PDLLA films

loaded with 10% drug was more suitable than that ob-

tained from 50/50 PDLGA films loaded with 2% drug.In addition to their effectiveness against the relevantbacterial strain, our new structured bioabsorbablepoly-mer/metronidazole films were biocompatible withHGFs and, therefore, may be used to treat periodontaldiseases.

CONCLUSIONS

Bioabsorbable films containing metronidazole wereprepared by solution processing. These films are de-signed to be inserted into the periodontal pockets andtreat infections with controlled-release metronidazolefor 1 month. PDLLA and 75/25 PDLGA films gener-ally exhibited a low or medium burst release followedby a moderate release at an approximately constantrate, whereas the 50/50 PDLGA films exhibited a bi-phasicreleaseprofiledue to therelatively high degrada-tion rate of the host polymer. This study demonstratedthatthe release profileof metronidazole was determinedmainlybythehostpolymertype.Drugloadinghadami-nor effect on the release profile.

The drug contents in the surrounding medium ex-ceededtherequiredminimumeffectiveconcentration.When relatively high drug loading was used (10%w/w), the released metronidazole resulted in a signifi-

cantdecrease in bacterial viability within several days,

Figure 6.HGF growth on PDLLA/metronidazole (2% w/w) films (A), on plate at the vicinity of PDLLA/metronidazole (2% w/w) films (B), on PDLLA/metronidazole (10% w/w) films (C), on plate at thevicinity of PDLLA/metronidazole (10% w/w) films (D). (Original magnification 10).


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even with relatively high bacterial concentrations (1 107/ml CFU). When relatively low drug loading wasused (2% w/w), the kinetics of bacterial inhibitionwas relatively slow, and1 week was required to erad-icate bacterial growth. The film preparation did notaffect metronidazoles potency as an antibacterial

agent. Our results indicated that the drug-loaded filmsexhibited biocompatible properties with regard toHGFs. Hence, our new metronidazole-eluting filmsmaybe usefulin thetreatment of periodontal diseases.

ACKNOWLEDGMENTS

A clinical isolate ofB. fragiliswas kindly provided bythe Microbiology Department, Haddassah Ein KaremHospital, Jerusalem, Israel. The authors report noconflicts of interest related to this study.

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14. Deasy PB, Collins AEM, MacCarthy DJ, Russell RJ. Useof strips containing tetracycline hydrochloride or met-ronidazole for the treatment of advanced periodontal

disease. J Pharm Pharmacol1989;41:694-699.15. Steinberg D, Friedman M, Soskolne A, Sela MN. A new

degradable controlled release device for treatment ofperiodontal disease: In vitro release study. J Periodon-tol 1990;61:393-398.

16. Norling T, Lading P, Engstrom S, Larsson K, Krog N,Nissen SS. Formulation of a drug delivery systembased on a mixture of monoglycerides and triglycer-ides for use in the treatment of periodontal disease.J Clin Periodontol 1992;19:687-692.

17. Mallapragada SK, Peppas NA, Colombo P. Crystaldissolution-controlled release systems. II. Metronida-zole release from semicrystalline poly(vinyl alcohol)systems. J Biomed Mater Res 1997;36:125-130.

18. Ahuja A, Ali J, Rachman S. Biodegradable periodontalintrapocket device containing metronidazole andamoxicillin: Formulation and characterization. Phar-mazie 2006;61:25-29.

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20. Lamp KC, Freeman CD, Klutman NE, Lacy MK.Pharmacokinetics and pharmacodynamics of nitro-imidazole antimicrobials. Clin Pharmacokinet 1999;36:353-373.

21. Perioli L, Ambrogi V, Rubini D, et al. Novel mucoad-hesive buccal formulation containing metronidazolefor the treatment of periodontal disease. J Control

Release2004;95:521-533.22. Austin MN, Meyn LA, Hillier SL. Susceptibility of

vaginal bacteria to metronidazole and tinidazole. An-aerobe 2006;12:227-230.

23. Wu Y, Fassihi R. Stability of metronidazole, tetracy-cline HCl and famotidine alone and in combination. IntJ Pharm 2005;290:1-13.

24. Chourasia MK, Jain SK. Design and development ofmultiparticulate system for targeted drug delivery tocolon. Drug Deliv 2004;11:201-207.

25. Murata Y, Kofuji K, Kawashima S. Preparation offloating alginate gel beads for drug delivery to thegastric mucosa. J Biomater Sci Polym Ed 2003;14:581-588.

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films used in medical support devices: Structure,degradation, crystallinity and drug release. Acta Bio-mater 2005;1:615-625.

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Correspondence: Dr. Meital Zilberman, Department of Bio-medical Engineering, Faculty of Engineering, Tel AvivUniversity, Tel Aviv 69978, Israel. Fax: 972-3-6407939;e-mail: [email protected].

Submitted April 23, 2008; accepted for publication July

30, 2008.


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