Local Drug Delivery

Basic to recent advances in local drug delivery also covering the effects of GCF flow on local drugs as well as use of local drugs used in periimplantitis.

1. 1 GOOD MORNING

2. LOCAL DRUG DELIVERY Presented by: Ganesh Nair Guided by: Dr. Anita Panchal Dr. Bhaumik Nanavati Dr. Rahul Shah Dr. Riddhi Gandhi 2

3. INDEX: Introduction Periodontal pharmacokinetics Factors Affecting Local Delivery of Agents in Periodontal Pockets History and Development of periodontal local delivery devices Comparison of systemic vs local drug delivery Classification of LDD Antimicrobial effects of local delivery devices Efficacy of local delivery devices Clinical indications for treatment of periodontitis with adjunctive local delivery devices 3

4. Local conditions Special patient groups LDD in treatment of peri-implantitis Antimicrobial agents used for LDD: Tetracyclines Collagenase inhibitors Penicillins Clindamycin Azythromycin Metronidazole Chlorhexidine Ofloxacin Povidone iodine Other Agents Tried As LDD Conclusion. 4

5. Introduction: Treatment of periodontitis is routinely based on oral hygiene, root debridement, and risk factor modification. Localized therapy has received significant attention because of the site‐specific pattern of destruction of periodontal infections and the potential side effects of systemic antimicrobials and anti‐inflammatory agents. 5

6. There are three basic routes to localized adjunctive pharmacologic periodontal therapy: mouth rinses (toothpaste or varnishes), subgingival irrigation, and periodontal application of local delivery systems. 6

7. Drawback of rinses: Rinses are useful for supragingival biofilm control, modulation of gingival inflammation, and potentially for recolonization of the subgingival environment following periodontal treatment. Their major limitation, in the context of pharmacologic therapy of periodontitis , is that they do not gain access to the subgingival environment and therefore do not reach the desired site of action ( Pitcher et al . 1980 ). 7

8. Drawback of irrigation solution: Irrigation solutions placed directly into periodontal pockets initially reach effective concentrations in the area, but the flow of the gingival crevicular fluid (GCF) – which is replaced about 40 times per hour – leads to rapid clearance of subgingivally placed drugs. Clearance of a medication locally placed in a periodontal pocket follows exponential kinetics and it has been calculated that the concentration of a highly concentrated irrigating solution of a nonsubstantive (non‐binding) drug becomes ineffective about 15 minutes following application. 8

9. Goodson – a pharmacologist who in the early 1970s pioneered the field of local delivery to treat periodontitis pointed out that successful pharmacologic control of the periodontal microflora requires: (1) delivery of an intrinsically efficacious drug to the site of action (periodontal pocket and surrounding tissues); (2) a concentration of the drug higher than the minimum efficacious concentration ; and (3) maintenance of this concentration long enough for the effect to occur . 9

10. Periodontal pharmacokinetics: Pocket volume and clearance: Clearance of a drug placed into a periodontal pocket follows the exponential function: where C ( t ) is the concentration of the drug as a function of time ( t ), C (0)is the initial concentration obtained in the GCF, F is the GCF flow rate , and V is the resting fluid volume of the pocket. 10

11. Using an estimated periodontal pocket volume of 0.5 μL ( Binder et al . 1987 ) and a GCF flow rate of 20 μL /h ( Goodson et al . 1989 ), the half‐time (the time that it takes to reach half of the initial concentration) for a non‐substantive medication placed in the periodontal pocket will be 0.017 hours (or about 1 minute ). In the case of a substantive compound , the exponential function can be rewritten by introducing a multiplicative constant K into the denominator of the exponential term to account for binding of the drug to the root surface (and/or periodontal pocket wall): where K is the affinity constant, which is experimentally estimated from the determined clearance half‐time. 11

12. This equation can be conveniently rearranged to estimate the effect of the various parameters on the duration of the desired therapeutic effect: where C ( MIC ) is the minimum inhibitory concentration (MIC) and t ( MIC )is the time taken to reach the MIC or the expected time of antibacterial action. 12

13. From this relation, it is apparent that the time over which a therapeutic effect is observed ( t ( MIC ) ) will be longer when the: Volume of the pocket is large GCF flow rate is low Affinity constant for the drug is higher , that is a highly substantive drugs is used Initial concentration is very high , that is the drug has good solubility in the applied vehicle MIC is low , that is a very potent agent is used. 13

14. Factors Affecting Local Delivery of Agents in Periodontal Pockets: Site of Action Targets for these agents are bacteria residing in periodontal pocket and those in junctional epithelium, connective tissue, cementum and dentine. Concentration Drug should have a dose higher than Minimal Inhibitory Concentration (MIC). It is the in vitro concentration of drug that inhibits or kills 90% of target organisms in culture. 14

15. Time Once a drug reaches the site of action in an effective concentration, it must remain at the site enough for its pharmacological effect to occur . GCF clearance is very high. Drug concentration will be affected by this. Mode of Delivery Fibers , gel, microspheres and chip . 15

16. History and Development of periodontal local delivery devices: Goodson designed a first generation of local drug delivery devices for application into periodontal pockets. The concept was to constantly replenish the free drug in the periodontal pocket that is cleared by the GCF flow with the release of drug from a drug reservoir placed into the periodontal pocket ( Goodson et al . 1979 ). 16

17. These devices consisted of permeable hollow cellulose acetate fibers (with an internal thickness of 200 μm ) filled with a 20% tetracycline– HCl solution. The fiber was tied around the crevice of the pocket , pressed into the subgingival environment , and removed after 24 hours . Better release profiles were obtained with a second generation of devices characterized by a monolithic design (drug crystals interspersed within an inert matrix) such as acrylic strips or extruded ethylene vinyl acetate fibers ( Addy et al . 1982; Goodson et al . 1983 ). 17

18. In particular, following placement of 0.5‐mm diameter 25% tetracycline fibers , GCF concentrations in the order of 500–1500 μg / mL were reported ( Tonetti et al . 1989 ). Parallel efforts with bioresorbable matrices focused on chlorhexidine in cellulose acetate ( Soskolne et al . 1983 ) and on release platforms made of hydroxypropylcellulose ( Noguchi et al . 1984 ) or collagen matrices ( Minabe et al . 1989 ). 18

19. COMPARISON OF SYSTEMIC Vs LOCAL DRUG DELIVERY SYSTEMIC LOCAL Route of administration Oral or parenteral Site specific Pain, discomfort Not painful nil Drug dosage Higher drug dosage (milli-grams) Lower dosage (micro-grams) Peak levels Few hours in plasma Pharmacokinetics Distribution in various body compartments where antimicrobial effect may not be required Minimal distribution to different body compartments at delivered sites Frequency Once in 6-12 hrs Usually once a week Superinfection Present Limited Microbial resistance Present Limited Patient compliance Required for better efficacy Patient delivered-required Professional delivery-not required Time required Less time Loner time if many sites are involved Side effects More Limited Effects on connective tissue associated plaque Effective Limited 19

20. Classification of LDD: LANGER AND PEPPAS (1988) : Classified controlled drug release polymeric system based on their mechanism of action. I. Diffusion controlled systems A. Reservoirs (membrane devices) B. Matrices (monolithic device) II. Chemically controlled systems A. Bio-erodible systems B. Pendant chain systems III. Swelling controlled systems IV. Magnetically controlled systems 20

21. RAMS AND SLOTS (1996) : Depending on usage I. PERSONALLY APPLIED (In patient home self-care) A. NON-SUSTAINED SUBGINGIVAL DRUG DELIVERY Home oral irrigation Devices with traditional jet tips Oral irrigator (Water Pik , Fort Collins) Soft cone-rubber tips (Pick pocket) Blunt tipped mental cannula connected to syringe or oral irrigator B . SUSTAINED SUBGINGIVAL DRUG DELIVERY (none developed to date) 21

22. 22 Water pik Soft cone rubber tip

23. II.PROFESSIONALLY APPLIED (In dental office) A.NON-SUSTAINED SUBGINGIVAL DRUG DELIVERY Professional pocket irrigation Syringe with blunt end needle. Blunt-tipped cannula attached to oral irrigator Ultrasonic scaling devices Thin ultrasonic scaling inserts. B.SUSTAINED SUBGINGIVAL DRUG DELIVERY Controlled release devices: Reservoirs without a rate-controlling system : Hollow fibers, gels, dialysis tubing Reservoirs with a rate-controlling system : coated drug particles, microporous polymer membranes, monolithic matrices, erodible polymeric matrices. Hybrids 23

24. III. OTHER LOCAL DELIVERY METHODS: Dentifrices, mouthrinses , chewing gum, Keyes technique , root biomodification . 24

25. Antimicrobial effects of local delivery devices: A study by Johnson et al. showed that better clinical and microbiologic outcomes were obtained by combining mechanical debridement with local delivery of the antimicrobial . This established the key role of mechanical debridement in successful clinical strategies for application of local delivery devices ( Johnson et al . 1998 ). 25

26. With the most effective devices (those delivering high concentrations of intrinsically efficacious antimicrobials for >1 week ) , suppression of 99–99.9% of total microbial load was reported, leading to effective disinfection of the treated periodontal pocket. After exhaustion of the drug reservoir, however, rapid recolonization was observed. Three possible sources for this recolonization were hypothesized: (1) regrowth from the residual microbiota from within the periodontal pocket; (2 ) recolonization from other intraoral areas of infection; and/or (3) re‐infection of the patient from other subjects . 26

27. A pilot study conducted at the Forsyth Institute in 1988 by the Goodson group started to address the question of the source of recolonization ( Holborow et al . 1990; Niederman et al . 1990 ). The study employed tetracycline fibers and SRP with or without chlorhexidine mouth rinsing to complete the treatment of the subjects who had participated in the pivotal study leading to FDA approval of tetracycline fibers ( Goodson et al . 1991 ). 27

28. The hypothesis was that the intraoral antibacterial effect of chlorhexidine would modulate bacterial recolonization of tetracycline fiber ‐treated pockets. Results showed that chlorhexidine mouth rinsing over a 28‐day period led to significant depression of the bacterial recolonization profiles for three target pathogens . The data were interpreted as an indication that the overall oral ecology of the patient was a critical determinant of success with this therapeutic modality. 28

29. Persistent, stable suppression of bacterial levels was observed in the full‐mouth disinfection group. Interestingly, early recolonization kinetics predicted clinical (reduction of pocket depth and bleeding on probing) and radiographic (hard and soft tissue subtraction analysis) outcomes 3 and 6 months later ( Tonetti et al . 1995 ). 29

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31. Several important conclusions were drawn from these studies and these represent important strategic elements for the rationale use of local delivery devices:  1. Effective local delivery devices have the potential to dramatically change the microbial profile of treated periodontal pockets. Recolonization , however, is a critical phenomenon that may undermine clinical benefit .  31

32. 2. Bacteria present in other areas of the mouth are the major source of recolonization and need to be addressed by improved oral hygiene measures, treatment of the whole dentition, and – perhaps – antimicrobial mouth rinsing . 3.Local delivery devices are not a promising treatment for subjects who are unable or unwilling to achieve improved (optimal) oral hygiene levels . 32

33. Efficacy of local delivery devices: A systematic review and meta‐analysis by Hanes and Purvis (2003) along with a more recent one by Matesanz‐Pérez et al . (2013) represent the major evidence base for the use of local delivery devices. The 2003 review, conducted for the American Academy of Periodontology workshop , examined the clinical outcomes of 32 studies incorporating 3705 subjects and established that adjunctive local drug delivery resulted in significant reductions in gingival inflammation and probing depths , and improvements in clinical attachment level. 33

34. It observed clinical improvements for the adjunctive application of minocycline gel, microencapsulated minocycline , doxycycline gel , and chlorhexidine chips . Few studies have addressed the management of furcation defects with local delivery devices . Shortterm (3–6 months) adjunctive benefits in controlling gingival inflammation as well as improvements in probing depths and clinical attachment levels have been reported ( Tonetti et al . 1995; Dannewitz et al . 2009 ). 34

35. Another interesting and rapidly emerging area of application of local delivery devices relates to the control of peri ‐implant infections, particularly periimplantitis . Two independent systematic reviews on effective interventions for peri‐implantitis ( Esposito et al . 2012; Muthukuru et al . 2012 ) identified some initial evidence that local delivery combined with subgingival debridement may be of greater benefit than subgingival debridement alone. 35

36. Clinical indications for treatment of periodontitis with adjunctive local delivery devices: The majority of studies assessing the adjunctive benefit of local delivery devices to mechanical debridement have identified a range of clinical conditions where the addition of these devices leads to improved outcomes ( Tonetti et al . 1994; Tonetti 1998; Greenstein & Tonetti 2000 ). These include special local conditions and special patient groups . 36

37. Local conditions: As the majority of untreated shallow (4–5 mm) pockets are expected to heal with mechanical debridement alone, local delivery devices are of potential benefit for deeper pockets (6–8 mm range) or furcation involvements ( Tonetti et al . 1998; Dannewitz et al . 2009 ). In this respect, local delivery may be advantageous in the management of local non‐responding sites or disease recurrence during supportive periodontal care . 37

38. Another potentially important application is when residual pockets are present in the so‐called esthetic zone where a surgical intervention may compromise esthetics or phonetics. Application of local delivery devices seems to be a rationale choice at sites with deep pockets and persistent bleeding on probing that are associated with intrabony defects after completion of the cause‐related phase of therapy . 38

39. Special patient groups: From a clinical standpoint, important attenuations of the expected benefits of non‐surgical and surgical treatment have been observed in high‐risk groups . These include smokers and subjects with diabetes , significant co‐morbidities or erratic compliance with oral hygiene and/or long‐term adherence to the necessary supportive periodontal care program. 39

40. Studies have reported that the adjunctive effect of local drug delivery may not be adversely affected by cigarette smoking ( Ryder et al. 1999 ). In a planned secondary analysis of a multicenter trial assessing the adjunctive benefits of minocycline microspheres , the enhanced response to local delivery device application was greatest among smokers ( Paquette et al . 2003, 2004 ). 40

41. LDD in treatment of peri-implantitis : CIST protocol : Depending on the clinical and the radiographic diagnosis, a protocol of therapeutic measures, called cumulative interceptive supportive therapy (CIST), has been designed to head off the development of peri -implant lesions. 41

42. Antibiotic treatment (supportive therapy protocol C ) : the application of local antibiotics through the use of controlled delivery devices has emerged as a suitable treatment concept. However , only release devices with a dequate release kinetics may be used to ensure successful clinical outcomes . Tetracycline periodontal fibers ( Actisite® ; Alza, Palo Alto , CA, USA) have successfully been applied in some case studies. The therapeutic effect appears to be identical to the effect documented for the systemic administration of antibiotics.( Mombelli et al. 1998 ) 42

43. Control release device consists of microspheres containing minocycline hyclate ( Arestin ® ; Johnson & Johnson) which are applied to the peri -implant pocket using a syringe. These beads remain sticking to the implant surface and soft tissue walls for at least 10 days and, hence, provide an ideal profile for a high-dose application at the site. Several clinical studies have documented the efficacy of the product on both the clinicaland the microbiologic level. ( Renvert S et al 2006 & 2008, Salvi GE et al. 2007, P errson GR et al. 2006 ) 43

44. Antimicrobial agents used for LDD: Tetracyclines : Tetracycline- HCl , doxycycline hyclate and minocycline-HCl , are broad-spectrum antibiotics active against both gram-positive and gram-negative bacteria. Minor alterations in the molecular structure make both doxycycline and minocycline more lipophilic than the parent compound, resulting in better adsorption following systemic delivery and better penetration into the bacterial cell. 44

45. The tetracyclines bind to the bacterial 30S ribosomal subunit and inhibit protein synthesis in the bacterial cell. Thus, these are normally bacteriostatic antibiotics . At high concentrations , such as those achieved with localized delivery of the antibiotic directly into the periodontal pocket , the tetracyclines may exert a bactericidal effect due to their ability to cause alterations in the cytoplasmic membrane . This may result in leakage of nucleotides and other components from the bacterial cell and result in its death. 45

46. LDD systems like tetracycline, 12.7 mg tetracycline- HCl in an ethylene ⁄vinyl acetate copolymer fiber ( Actisite ® ), and doxycycline , 10% doxycycline hyclate in a gel delivery system ( Atridox ® ).Both systems, in a number of clinical trials , have been demonstrated to give statistically significant improvements in clinical (attachment level and probing pocket depth) and microbial parameters over those obtained with mechanical debridement alone [ Drisko CL et al 1998, Garret et al 1999,2000, Muller et al 1993 ]. Minocycline , the most lipophilic of the tetracyclines , has also been incorporated into a local delivery device consisting of minocycline-HCl microspheres ( Arestin ® ) and Periocline ® which is 2% minocycline gel use for local application. 46

47. 47 Armamentarium and application of tetracycline fibres. Minocycline microspheres

48. Collagenase inhibitors : A series of double-blind, placebo-controlled clinical trials has demonstrated that subantimicrobial dose doxycycline (SDD), 20 mg bid ( Periostat ® ), produces an improvement in clinical indices ( Ashley RA et al 1999,Caton JG et al 2000 & 2001, Crout RJ et al 1996, Golub in 1995 ), without causing any detectable effect on the subgingival flora or an increase in antibiotic resistance. Significant improvements in clinical attachment level and pocket probing depth were present at 3, 6, and 9 months of treatment in subjects that received SRP and SDD compared to SRP alone. 48

49. It is not surprising that SDD exerted no detectable effect on the normal flora at any of these sites. SDD at 20 mg bid yields peak serum levels of 0.7–0.8 µg of doxycycline per ml and steady state concentrations of around 0.4 µg ⁄ml . 49

50. Penicillins : The penicillins are a broad class of antibiotics that inhibit bacterial cell wall synthesis and directly result in the death of the cell. All penicillins consist of a β- lactam ring , a thiazolidine ring , and an acyl side chain . Amoxicillin , a semisynthetic penicillin, has excellent activity against both gram-negative and gram-positive bacteria, is absorbed well following oral administration, and penetrates into the gingival crevicular fluid . 50

51. Augmentin ® , introduced a little over a decade ago, combines the antibiotic amoxicillin with a β - lactamase inhibitor, clavulanic acid . Clavulanic acid exhibits no antimicrobial activity, but it does contain an unprotected β - lactam ring. Bacteria normally resistant to amoxicillin due to the production of β - lactamase may be susceptible to the combination of amoxicillin and clavulanic acid . 51

52. The efficacy of Augmentin ® has been tested in a few clinical trials with conflicting results. Magnusson et al. (1989) reported, for sites deemed clinically active, an average 2 mm gain in clinical attachment 3 months post-therapy and an average decrease of 2.5 mm probing pocket depth 6 months post-therapy . Winkel et al.(1999) in double-blind, placebo-controlled study with 21 patients with a diagnosis of generalized adult periodontitis found that, in comparison with placebo, Augmentin ® provided no additional clinical or microbiological benefits . 52

53. Clindamycin : Clindamycin is bacteriostatic and inhibits bacterial protein synthesis by binding to the 50S ribosomal subunit . Clindamycin-HCl has been shown, following normal oral dosage, to penetrate into the gingival crevicular fluid and to achieve and maintain concentrations that exceed the MICs of the periodontopathic gram-negative anaerobic bacteria.( Walker CB et al 1981 ) 53

54. Studies by Gordon J et al. (1985,1990), Magnusson et al. (1994), Ohta Y et al (1986) suggest clindamycin-HCl may be a useful adjunct in the treatment of truly refractory patients who have not responded favorably to other modes of periodontal therapy . Prior to initiating clindamycin therapy, culture and sensitivity testingis strongly recommended to screen for the presence of E. corrodens ( Walker CB et al. 1996 ) and A. actinomycetemcomitans ( Loesche WJ et al. 2002 ). Presence of either contraindicates clindamycin use. 54

55. Following clindamycin initiation , patients should be carefully monitored and advised of the possibility of adverse gastrointestinal events . Due to the potential serious adverse effects, the use of this drug should be reserved for those patients that have proven to be refractory to other modes of periodontal therapy . 55

56. Azithromycin : Azithromycin belongs to the same general class of macrolide antibiotics as erythromycin. Azithromycin has been reported to penetrate both healthy and diseased periodontal tissues and to maintain chemotherapeutic levels in excess of the MICs of the majority of periodontopathogens thought to be involved in chronic inflammatory periodontal diseases. Smith et al. (2000) conducted a double-blind, placebo-controlled clinical trial to evaluate the efficacy of azithromycin as an adjunct to SRP . 56

57. Metronidazole : A 5-nitroimidazole compound, specifically targets anaerobic microorganisms but has essentially no activity against aerobic or microaerophilic bacteria . Localized delivery of metronidazole to specific, diseased sites would allow minimal amounts of drug to achieve high concentrations . Elyzol ® , which is commercially available in many European countries but not in the United States. Elyzol ® is a 25% metronidazole dental gel consisting of metronidazole benzoate in a mixture of mono- and triglycerides . 57

58. Metronidazole benzoate gradually disintegrates into metronidazole and delivers high concentrations of the drug to the periodontal pocket for approximately 24 h after placement . Riep et al.(1999) compared the effects obtained with the dental gel plus SRP, to SRP alone, in 30 maintenance patients in a single-blind clinical study. Both treatments resulted in significant improvement in probing pocket depths and clinical attachment level . However, there were no significant differences between the two treatments. 58

59. 59

60. Chlorhexidine : Chlorhexidine has often been employed as an adjunct to mechanical debridement due to its broad-spectrum antimicrobial activity , substantivity in the oral cavity and ease of use during oral irrigation or gel placement. A biodegradable chlorhexidine containing gelatin chip ( PerioChip ® ) has received Food & Drug Administration approval in the United States for use as an adjunct to SRP. 60

61. The results of a multicenter clinical trial reported that the chip’s use resulted in a significant improvement in probing pocket depth relative to SRP alone but that no significant differences were noted in change in clinical attachment level ( Jeffcoat et al 1998, Soskolne WA et al 1997 ). Reductions in levels of P. gingivalis , P. intermedia , T. forsythia, and C. rectus were reported relative to SRP. However, Daneshmand et al.(2002) did not find any microbial benefit when the chlorhexidine chip was used as an adjunct to SRP compared to SRP alone. 61

62. The gelatin chip is placed directly into the periodontal pocket, releasing 2.5 mg of chlorhexidine over a period of 7–10 days . Chlorhexidine levels, within the pocket, reach an average concentration equivalent to 125 µg of chlorhexidine per ml of gingival crevice fluid . 62

63. Ofloxacin : Ofloxacin belongs to quinolone family which constitute a group of 1,8 naphthyridine derivatives and are synthetically produced drugs. They are considered to be bactericidal as they inhibit the enzyme DNA replication by acting on the enzyme DNA gyrase . PT-01 is a soluble insert , with both fast and sustained release parts containing 10% w/w ofloxacin , and showed a constant drug level of above 2 mg/ml , (minimum MIC for most pathogenic organisms) which could be sustained for up to 7 days . 63

64. The controlled release system exhibited a biphasic pattern with a rapid early release phase peaking at approximately 12µg/ml and stabilizing at approximately 2µg/ml from day 3 to 7 following insertion ( Higashi et al 1990 ). Initial investigations failed to any additional microbiological effect in a split mouth design ( Kimura et al 1991 ). Further investigations by Yamagami et al (1992) showed four weekly applications of the insert resulted in significant resolution of periodontal inflammation and improvement in other clinical parameters compared to controls. 64

65. Povidone -iodine : Povidone -iodine (PVP-iodine) is a bactericidal antiseptic whose mechanism of action includes oxidation of amino , thiol , and hydroxy moieties of amino acids and nucleotides . Greenstein et al in 1999 , in a recent review of the effects of PVP-iodine, found evidence indicating PVP-iodine irrigation, delivered to the periodontal pocket via ultrasonic scalers , achieved better results in deep pockets than water . 65

66. Rosling et al.in 1986 tested the efficacy of PVP-iodine as an adjunct to conventional, nonsurgical periodontal therapy and retreatment in 223 advanced periodontitis subjects. During the 12 years of maintenance therapy , a larger proportion of the PVP-iodine-treated subjects maintained shallow pockets , avoiding further loss of attachment relative to mechanical debridement alone. In conclusion, documented evidence indicates that a beneficial additive effect may be obtained utilizing PVP-iodine as an adjunct to mechanical periodontal therapy. 66

67. Other Agents Tried As LDD: Eucalyptus Extract : Nagata et al 2008 Neem Extract: Ravindra Pai et al 2004 Herbal Combinations : Reddy et al 2010 Simvastatin : Morris et al 2008 Growth Factors: Cooke et al 2006 Chitosan -PVA-based local delivery system: Wang LC et al 2010 Curcumin : Elavarasu S et al 2016 Atorvastatin : Garg S et al 2016 67

68. Conclusion: Local drug delivery into the periodontal pocket is an effective treatment adjunct to mechanical debridement . Clinical application requires the use of a well‐designed technology platform that is able to counteract GCF clearance of the locally applied antibiotic and maintain effective concentrations for long enough for the desired pharmacologic effect to occur . Pocket disinfection is feasible, but recolonization is a critical phenomenon that needs to be prevented with a specific clinical strategy: optimal supragingival hygiene, full‐mouth approach, and/or use of an antiseptic mouth rinse . 68

69. BIBLIOGRAPHY: Periodontology 2000:systemic & topical antimicrobial therapy in periodontics . February 1996 - vol. 10 issue 1 page 5-159 Periodontology 2000:‘nonsurgical periodontal therapy’ :October 2004, vol 36, issue 1, page no 9-204 Jan lindhe ; Clinical periodontology and implant dentistry: 6 th edition: chp 44; 891-97 Carranza 12 edition: Chp 89 . Stuart froum:Dental impalnt complications:etiology , prevention and treatment: Chp 7: 119-33 Arvind venkatesh :local drug delivery systems in the treatment of periodontitis – an overview; international journal of pharmacy and pharmaceutical sciences , vol 4, issue 1, 2012 ;30-7 Esha agarwal : Locally delivered 0.5% azithromycin , as an adjunct to non surgical treatment in chronic periodontitis with type 2 diabetes: A randomized controlled clinical trial:journal of periodontology ;2012:1-11 69