Ldd

local drug delivery

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Overview • Introduction• Rationale • Advantage • Limitation • Local Delivery Devices

– Fibers – Strips and compacts– Films– Injectable systems– Gels

• Clinical consideration• Conclusion• References

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Introduction • Periodontal disease is associated with bacteria

and treatment by chemotherapeutic agents appears to be appropriate

• Chemotherapeutic agents may be administered – systemically or – delivered locally

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• Pocket irrigation –– Reduce microbial levels and provide some

improvement in clinical parameters– Response to therapy - mixed– Requires daily professional or patient administration

for best results - (Greenstein - 1991)

• lack of drug retention in the periodontal pocket – chief reason for these mixed results

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• Controlled release local delivery systems

– Antimicrobial is available at therapeutic levels for several days

– Evaluated in several forms and using different antimicrobials

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Rationale• Early 1970s - concern emerged with respect to

systemic antibiotic therapy for chronic infections such as periodontal disease

Side effects including – hypersensitivity, – gastrointestinal intolerance and the – development of bacterial resistance

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• severe or aggressive forms of periodontitis in young subjects often cannot be arrested by mechanical treatment alone

• Some patients or sites where even repeated treatment fails to stop the disease– referred as refractory subjects or non-responding

sites

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• Related to the persistence of pathogens in the pocket after treatment or to the production by the bacteria of specific virulence factors interfering with the host defense (e.g. leukotoxin production, encapsulation, etc.)

• Could be due to the recolonization of treated sites from bacterial reservoirs such as dentinal tubules and soft tissues – In this context - antimicrobial agents are of great interest

and may be valuable as adjuncts to mechanical therapy

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Advantage • Show improve patient acceptance and compliance

• More possible for direct access to target diseases/various periodontal diseases

• Reduce oral healthcare treatment cost

• Offers avoidance of GI tract with problems of oral drug administration

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• Serve as a reliable route for drug administration in very ill patient who are not able to swallow

• Bypasses the first pass metabolism by the liver

• Can offer increase therapeutic efficacy of the drug

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• Route is safe and convenient route

• Can produce longer duration of action

• Offers noninvasive, painless, and simple application

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Limitation • Not feasible for local irritants

– Drug and other excipients used in the formulation processing either erythema, itching, or local arrhythmia cannot be delivered by this route

• Dose is limited because of relatively small area

• Presystemic metabolism may occur by the enzymes like peptidase and esterase

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• Should be devoid of irritancy or a sensitization

• Manufacturing cost of the patches or devices should be taken in consideration

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Local Delivery Devices1. Fibers2. Strips and compacts3. Films4. Injectable systems5. Gels

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Fibers – • Hollow fibers• Ethylene vinyl acetate fibers

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Hollow fibers

• Released tetracycline at a first order rate with 95% of the drug released in the first 2 h– GCF - remained in the therapeutic range for 24 h

and some effects on spirochetes

• Study should be viewed primarily as an evaluation of drug delivery

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Ethylene vinyl acetate fibers

Tetracycline incorporated into different polymers • Polyethylene, • Polypropylene, • Polycaprolactone, • Polyurethane, • Cellulose acetate propionate and • Ethylene vinyl acetate (EVA)

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• EVA fibers – Tetracycline– maintained constant drug levels in GCF of periodontal

pockets above 600 mg/ml throughout day 10 – • M. Tonetti et al. - 1990

• GCF - equilibrium with the same binding sites occupied by tetracycline following 1% irrigation

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• Tetracycline fibers• with the exception of

Porphyromonas gingivalis

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R.A. Lowenguth et.al. Evaluation of periodontal treatments using controlled release tetracycline fibers. Microbiological response, J. Periodontol. 66 (1995) 700 -707.

Strips and compacts

• Larsen – studied in vitro release of doxycycline from

different bioabsorbable materials and acrylic strips

• Acrylic strip and Colla Cote decreased to low levels of both concentration and residual antibacterial activity in a few days

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• 25% tetracycline hydrochloride or metronidazole in poly(hydroxybutyric acid) (PHBA) as a biodegradable polymer matrix showed sustained release over 4-5 days with a significant burst effect at day 1

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• may involve the risk of leaving injurious acrylic material in the periodontal pocket upon removal of the strip

• Removal of the strip - may cause damage to regenerating tissue

• Showed sustained release over 4 - days with a significant burst effect at day 1

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Compacts • Compacts based on PHBA containing

tetracycline hydrochloride • 50% (w/w) of tetracycline, the mean drug

concentration obtained was in the therapeutic range over the 10 days

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• controlled release strip coded PT-01 and made of poly (methacrylic acid) and hydroxypropyl-cellulose containing 10% ofloxacin - Kimura et al. (1991)– found in higher concentrations than the MIC of most

periodontopathic bacteria in GCF over 7 days by a single application in the human periodontal pocket

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Films

• Made of – Eudragit L and Eudragit S, two water soluble

poly(methacrylic acid-co-methyl methacrylate), and – Eudragit RL - non-water soluble polymer poly(ethyl

methacrylate-co-chlorotrimethyl ammonium methyl methacrylate),

• developed by Higashi et al. (1991) for the delivery of clindamycin

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• Total drug release varies from 1 to 100 h• concentration in the GCF – maintained at a constant level for 24-72 h

• Time of drug release - too low for further clinical studies

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• Sustained release devices composed of a cross-linked fish gelatin containing chlorhexidine diacetate or chlorhexidine hydrochloride– developed by Steinberg et al. (1990)

• In vitro release profile of chlorhexidine from such degradable films is - – dependent on the amount of CHX incorporated into the

film (cross-link density of the polymer and chlorhexidine salt used)

• Time of total drug release is short & varies from 4 - 80 h

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• Films based on synthetic biodegradable polymers – poly(lactide-co-glycolide) (PLGA) containing tetracycline

• Incomplete release of tetracycline;– only 30-60% of total tetracycline - released

- R.K. Agarwal et al. 1993

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• Atelocollagen preparations with immobilized tetracycline

• Collagen film treated by cross-linking and containing tetracycline – showed an amount of tetracycline exceeding the

effective dose (≥ 8 mg/ml) in the GCF, even on day 10 after insertion of the preparation

- M. Minabe et al.1989

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• Ethyl cellulose films - 20% metronidazole or 20% chlorhexidine – compared to short-term use of systemic antibiotic therapy

in patients with advanced forms of periodontal disease in order to prevent the normally necessary access surgery

• All teeth - scaled just before the insertion of the films• 93% reduction in the need for periodontal surgery for

individual teeth and an 81% reduction in the need for tooth extractions– W.J. Loesche et al. Oral Surg. Oral Med. Oral Pathol. Endod.

81 (1996) 533-543.

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• New film composed of cross-linked hydrolyzed gelatin and glycerin for local delivery of chlorhexidine digluconate has been developed and commercialized under the trademark Periochip

- G. Goffin (1998)

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• biodegradable film • showed an initial burst effect in the first 24 h,

whereby 40% of chlorhexidine was released, probably due to diffusion,

• Constant slower release over about 7 days, occurring partially in parallel with enzymatic degradation of the film

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Insertion of a chlorhexidine chip into a residual pocket mesial to an upper molar with a furcation involvement

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• in vivo study on 12 patients reported - – chlorhexidine concentrations of 800-1000 mg/ml in the

GCF in the first 48 h after the Periochip placement– Followed by lower concentrations of 100 - 500 mg/ml

over the next 6 days

• Concentrations above the MIC for most pathogens (150 mg/ml) were seen for at least 7 days

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• Compared to scaling and root planing alone– Periochip treatment adjunctive to scaling and root

planing showed significant reduction in the probing pocket depth, a gain in attachment level for pockets > 7 mm at 6 months

– decrease in the GI & in BOP at 3 months

• Advantage– Remains inside the pocket with no additional aids for

retention because of the adhesive nature of the Periochip components

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Injectable systems• Attractive for the delivery of antibiotic agents into

the periodontal pocket• Easily and rapidly carried out, without pain, by

using a syringe• Cost of the therapy is considerably reduced

compared to devices that need time to be placed and secured

• Biodegradable micro particles and gels

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Microparticles

• Based on biodegradable poly(a-hydroxyacids) • poly(lactide) (PLA) or • poly(lactide-co-glycolide) (PLGA)

• containing tetracycline - designed for periodontal disease therapy – P. Esposito et al. (1997)

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• Tetracycline release rate is influenced by the – polymer choice (lactide/glycolide ratio)– polymer molecular weight and crystallinity) – pH of the medium

• Tetracycline release rate is increased as the pH increases

• PLGA microspheres - proposed for delivery of histatins

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• PLGA microspheres containing minocycline were evaluated alone or as an adjunct to scaling and root planing, in comparison to scaling and root planing alone or to no subgingival treatment in adult periodontitis – A.A. Jones et al-1994

• Data - probing depth reduction with treatment plus scaling and root planing was significantly greater than all other groups at 1 month

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• No differences in probing depth reduction - at 6 months

• Significant reduction in Porphyromonas gingivalis 1 month after therapy

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Minocycline microsphere: unit dose cartridge and handle

Electron photomicrograph of minocycline microsphere

Right – cross-sectional photomicrograph of microsphere showing minocyclin HCL particles

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Gels1. Metronidazole- containing gel 2. Tetracycline containing gel3. Gel containing 1% clindamycin hydrochloride4. gel formulation based on 2.5% hydroxy

propylmethyl cellulose containing 0.125% histatin

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Metronidazole-containing gel• based on hydroxyethylcellulose, Carbopol 974P and

Polycarbophil

• In vitro drug release was significantly decreased – as the concentration of each polymeric component was

increased, due to both the concomitant increased viscosity of the formulation and additionally, the swelling kinetics of polycarbophil following contact with dissolution fluid

– D.S. Jones et al. 199745

• Increasing the concentrations of each polymeric component – significantly increased formulation hardness,– compressibility, – adhesiveness and syringeability due to polymeric

effects on formulation viscosity.

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Elyzol

• Injectable lipid-like vehicle based on glycerol monooleate and sesame oil containing 25% metronidazole

• Initially thixotropic carrier thickens into a gel

• According to the manufacturer,– formation of highly viscous liquid crystals when the

formulation is in contact with water is responsible for this effect

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• Therapeutic levels of metronidazole are reported – for a period of 2-3 days and the agent should be used

twice in 3 weeks

Data indicate that -• local metronidazole gel in combination with SRP seems

to be more effective in terms of producing both clinical and microbiological improvements – compared to pure mechanical and pure metronidazole

treatments

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• Controversial results reported in another study do not support the routine use of adjunctive Elyzol in the non-surgical treatment of periodontitis because of the poor clinical and microbiological efficacy compared to scaling and root planing alone– R.M. Palmer - 1998

• Probably due to the rapid elimination of Elyzol gel from the periodontal pocket – K. Stoltze, Elimination of Elyzol 25% Dentalgel matrix from

periodontal pockets, J. Clin. Periodontol. 22 (1995) 185-187.

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Probing depth reduction with metronidazole gel

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Tetracycline gel

• Bioadhesive semi-solid systems based on – Hydroxyethyl cellulose (HEC) – Polyvinyl pyrrolidone (PVP)

• Increased concentrations of HEC decreased the rate of release of tetracycline, due to the concomitant increase in product viscosity and the subsequent decreased rate of penetration of dissolution fluid into the formulation

• Conversely, an increased PVP concentration increased tetracycline release rates, due to an increased formulation porosity

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• Increased concentrations of HEC and PVP – increased the hardness, – compressibility – work of syringeability of semi-solid formulations

and – Adhesiveness

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• Two other semi-solid lipid-like formulations based on -– poly(oxyethylene-co-oxypropylene) (poloxamer) and – glycerol monooleate developed for tetracycline released - Esposito et al. (1996)

• Characterized by a solid-gel transition and become semi-solid once in the periodontal pocket

• After 7 h, in vitro tetracycline release - 18% and 65% of the entrapped drug for monoglyceride and poloxamer gels, respectively

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• persistence of monoglyceride gel is more prolonged than that of poloxamer gel

– Poloxamer disappeared after 1 h while – monoglyceride gel - still retained after 8 h

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• A short-term split mouth clinical trial - – subgingival application of both gels in conjunction with

scaling and root planing produced – clinically and statistically significant improvement outcome

in moderate to deep periodontal pockets

• Surprisingly, in spite of the rapid drug release and the poor retention of such gels, – positive clinical results were obtained

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• 2% minocycline have been commercialized under several trademarks

• Periocline – T. Nakagawa et al- 1991– K. Hayashi et al -1998

• Dentomycin – M.A. Graca et al (1997)

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• Gel is composed of – Hydroxyethylcellulose, – Aminoalkyl-methacrylate copolymer, – triacetine, – Magnesium chloride and – Glycerynum concentratum

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• Administration of periocline - once a week for 4 consecutive weeks

• At week 4, proportions of P. gingivalis & A. actinomycetemcomitans - significantly decreased in treated sites

• Prevotella intermedia was detected – from 7 of 22 sites at week 4 and – 16 sites at week 12 in treated sites

• Minocycline treated sites – associated with a significant decrease in probing depth and

bleeding on probing compared with those of control sites at week 4

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Dentomycin gel • Adjunctive formulation provided a more advantageous

outcome for non-surgical periodontal treatment in terms of attachment level and bleeding on probing– M.A. Graca, T.L.P. Watts, R.F. Wilson, R.M. Palmer, A

randomized controlled trial of a 2%minocycline gel as an adjunct to non-surgical periodontal treatment, using a design with multiple matching criteria, J. Clin. Periodontol. 24 (1997) 249-253.

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• study - 54 patients with four pockets ≥5 mm and bleeding on probing, the efficacy of three commercialized available periodontal systems for local delivery of antibiotics as adjuncts to scaling and root planing was evaluated – M. Radvar, N. Pourtaghi, D.F. Kinane, Comparison of 3

periodontal local antibiotic therapies in persistent periodontal pockets, J. Periodontol. 67 (1996) 860-865.

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• Four treatment groups included

1. scaling and root planing alone, 2. scaling and root planing plus application of 25%

tetracycline fiber (Actisite), 3. scaling and root planing plus application of 2%

minocycline gel (Dentomycin) and 4. scaling and root planing plus application of 25%

metronidazole gel (Elyzol)

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• Clinical measurements - baseline and 6 weeks after the end of treatment periods

• improvements in clinical parameters › scaling and root planing alone in all three adjunctive treatment groups

• probing depth reduction - significantly greater in the scaling plus tetracycline fiber group (1.35 mm) than the scaling and root planing alone group (0.6 mm)

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• improvement of the attachment level or bleeding on probing - not significant

• Scaling plus tetracycline fiber treatment - greatest reduction in the gingival index scores

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• Considering the time and cost involved in using different locally delivered antimicrobial systems, using these agents does not seem justified as part of initial periodontal therapy

• suggested - following initial phase therapy, tetracycline fibers could be used in place of surgery for sites with remaining severe disease, whereas the other systems might be applicable in less severe cases

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• Injectable biodegradable delivery system containing 10% doxycycline hyclate (Atrigel

• based on a biodegradable polyester poly(DL-lactide) dissolved in a biocompatible solvent N-methyl-2-pyrrolidone (NMP)

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Atridos injection

• can pass through a cannula into a periodontal pocket where it solidifies in situ to deliver the therapeutic agent over 7 days

• Analyses of the bioactive doxycycline levels into the GCF showed a level of 250 mg/ml during a period of 7 days

• levels of 10-20 mg/ml were still present for 3-5 days after the polymer had been removed– G.L. Yewey et al (1997)

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• A comparative study using the same Atrigel delivery system containing either 10% doxycycline hyclate or 5% sanguinarine hydrochloride – clinical and statistical superiority were observed in the

doxycycline group for all parameters when compared to the formulation containing sanguinarine and the vehicle alone

– A.M. Polson et al.(1997)

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Gel containing 1% clindamycin hydrochloride

• mucoadhesive gel formulation based on 4% Carbopol

• evaluated in vivo on microbial flora of periodontal pockets deeper than 5 mm - E. Sauvetre et al. 1993

• Active and placebo gels were inserted once a week for 2 weeks in sites that received subgingival scaling and root planing

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• Changes in the microbial content of the periodontal pockets treated by subgingival scaling and 1% clindamycin gel were significant, compared with negative controls, particularly with respect to anaerobic blackpigmented bacteria and the motile gram-negative flora

• after 3 months, most of the treated cases were recolonized by the same initial species

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Gel containing 0.125% histatin

• based on 2.5% hydroxy propyl methylcellulose• Studied in vivo in beagle dogs - Paquette et al. (1997) • Active and placebo formulations were tested for 10 weeks

and applied twice daily around premolar teeth

• Reported that beagles treated with active gel demonstrated – significantly lower plaque index scores at day 42, – significantly lower gingival index scores from day 21 through 42– significantly lower percentage of bleeding on probing scores at

days 14 and 28 compared to beagles treated with placebo gel

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Clinical consideration• The following medications are the most often

prescribed – Actisite– Atridox – FDA approved– Arestin– PerioChip– Periostat

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Susceptibility of suspected pathogens to various antimicrobials agents

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• Atrigel delivery system – Maintained in the pocket by the addition of periodontal

adhesive (Octyldente) or periodontal dressing (Coe-Pack or Periocare)

• Poor retention of oil-based delivery systems within the aqueous environment of the periodontal pocket as in the case of Elyzol

• Deleterious effects of plasticizers leached from solid polymeric drug delivery systems on the periodontal tissues

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25% metronidazole dental gel

doxycycline hyclate in Biodegradable polymer

Tetracycline fiber

Local drug delivery at deep pocket depth

• Greater than 7 mm pocket• SRP become less efficient

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When to administer ?• Patient may respond to conventional therapy

– so routine local drug therapy is not advocated

• Not indicated in aggressive form of periodontitis

• Indicated in non responding to SRP alone– Localised recurrent disease

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Conclusion • Effectiveness of SRP may be enhanced with

antiseptics and antibiotics

• Medication - released over 1 to 3 weeks and helps eliminate the disease causing bacteria with a high concentration of a drug or antiseptic– Gives the gum tissue more time and a better chance

to heal without the disease causing bacteria present

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• Useful adjunct to conventional surgical or non-surgical treatments, – but are no substitute for these measures

• Controlled delivery systems are of interest as an adjunct for recurrent and refractory periodontitis

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References 1. K. Schwach-Abdellaouia, N. Vivien-Castionib, R. Gurny. Local delivery of

antimicrobial agents for the treatment of periodontal diseases. European Journal of Pharmaceutics and Biopharmaceutics 50 (2000) 83-99.

2. Mahesh R. Dabhi et.al. Formulation development of smart gel periodontal drug delivery system for local delivery of chemotherapeutic agents with application of experimental design. Drug Delivery, 2010; 17(7): 520–531.

3. Arthur J. Bonito et al. Impact of local adjuncts to scaling and root planing in periodontal disease therapy: A systematic review. J Periodontol 2005;76:1227-1236.

4. R.J, Oringer et.al.effect of locally delivered Minocyclin microsphere on marker of bone resorption. J Periodontol 2002;73:835-842.

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5. Maria Pavia,Carmelo G.A. Nobile, and Italo F. Angelillo. Meta-analysis of local tetracycllin in treating chronic periodontitis. J Periodontol 2003;74:916-932.

6. Maria Emanuel Ryan. Nonsurgical Approaches for the Treatment of Periodontal Diseases. Dent Clin N Am 49 (2005) 611–636

7. Pragati S, Ashok S., Kuldeep S. Recent advances in periodontal drug delivery systems . International Journal of Drug Delivery 1(2009) 1-14

8. Gary Greenstein. Local drug delivery in the treatment of periodontal disease: assessing the clinical significance of the results. . J Periodontol 2006;77:565-578.

9. Killoy WJ: The clinical significance of local chemotherapies. J Clin Periodontol 2002; 29 (Suppl 2): 22–29.

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Thank you !

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