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Good morning. LOCAL DRUG DELIVERY. PRESENTED BY Dr. SONAL GANJI. CONTENTS:. Introduction Historical perspective Terminology Classification of local antimicrobial therapy in periodontics Objectives Indications Contraindications Advantages Disadvantages

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  1. Good morning

  2. LOCAL DRUG DELIVERY PRESENTED BY Dr. SONAL GANJI

  3. CONTENTS: • Introduction • Historical perspective • Terminology • Classification of local antimicrobial therapy in periodontics • Objectives • Indications • Contraindications • Advantages • Disadvantages • Systemic Versus Local Drug Delivery • Requirements For Local Antimicrobial Agents • Factors Affecting the Bio-availability of an antimicrobial agent • Local Drug Delivery’s Impact on Deep Probing Depths (7 mm) • Inhibition of Periodontal Disease Progression • Impact of Local Drug Delivery on Furcations • Repair of Osseous Defects • Conclusion • References

  4. INTRODUCTION: • Periodontitis is an infection of the periodontium. It is considered an infection because there is a bacterial etiology and an immune response. Once destruction of tissue occurs, the condition is referred to as a disease. • Non-surgical and surgical therapy is both applicable in the treatment of periodontal disease. However, mechanical therapy itself may not always reduce or eliminate the anaerobic infection at the base of pocket, with in the gingival tissues and in both structures inaccessible to periodontal instruments.

  5. To overcome this, addition of antimicrobials both systemic and locally would enhance a treatment protocol and serve as adjuncts to mechanical therapy. Systemic antimicrobial agents may reduce or eliminate bacteria that cannot be removed by scaling and root planning. However, adverse effects such as drug toxicity, acquired bacterial resistance, drug interaction and patient’s compliance limit the use of systemic antimicrobials (Golomb G. et al 1984) • Therefore to override these short comings, local deliveries of antibacterial agents into periodontal pockets have been extensively studied.

  6. HISTORICAL PERSPECTIVE: The concept of targeted drug delivery had its origin in the 1970’s based on the theory that if one could substantially improve the cellular specificity of a drug there would be an accompanying significant improvement in the therapeutic index; i.e, the efficacy to side effects. W.D. Miller in the 1880’s suggested the use of an antimicrobial mouthrinse (Listerine) to aid in fighting what was then known as ‘Pyorrhea alveolaris’. It was Dr. Max GoodSon (1979) who championed and developed controlled release local delivery of therapeutic agents into a viable concept.

  7. TERMINOLOGY: • Antimicrobialagentsare chemotherapeutic agents that reduce the amount of bacteria present either by superficially targeting certain organisms or by nonspecifically reducing all bacteria. • Targeted drug delivery:Truly refers to delivery of agents to specific cells. • Local delivery of antimicrobial agents in periodnticsImplies antimicrobial therapy placed directly in the subgingival region. The term local delivery is usually used to suggest more specific or trageted delivery of an agent. • Non-sustained subgingival drug deliveryProvides high pocket concentrations of the antimicrobial agent for only short time periods.

  8. Sustained subgingival drug delivery/ Controlled release delivery (CRD) Synonyms: Sustained release, Prolonged release, timed release, slow release, sustained action, prolonged action or extended action. CRD’s are designed to release a drug slowly and to retain therapeutic level for a prolonged period of time Controlled release local delivery: Implies release of chemotherapeutic agents into the periodontal pockets over an extended period of time, provides prolonged drug availability, and sustained drug action.

  9. CLASSIFICATION OF LOCAL ANTIMICROBIAL THERAPY IN PERIODONTICS: • 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

  10. 2. RAMS AND SLOTS (1996)Depending on usage I. PERSONALLY APPLIED (In patient home self-care) A. NON-SUSTAINED SUBGINGIVAL DRUG DELIVERY Home oral irrigation Home oral irrigation devices: • 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)

  11. II. PROFESSIONALLY APPLIED (In dental office) A. NON-SUSTAINED SUBGINGIVAL DRUG DELIVERY Professional pocket irrigation Professional irrigation devices : • 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

  12. III. OTHER LOCAL DELIVERY METHODS: Dentifrices, mouthrinses, chewing gum, Keyes technique, root biomodification. OBJECTIVES: • The use of a local antimicrobial is to prevent or control microbial induced inflammation in an effective concentration and be maintained there long enough for the desired effect to be accomplished without causing any side effects. • Use of antimicrobials as part of regenerative periodontal therapy to assist in periodontal regeneration.

  13. INDICATIONS: • Periodontal patients with successful phase I therapy • Periodontal patients who are medically compromised where surgical therapy is contraindicative. • In combination with mechanical debridement or alone. • In-patients who are suffering from recurrent or refractory periodontitis. • During periodontal regenerative procedures. CONTRAINDICATIONS: • Periodontal patients with known hypersensitivity reaction to any of the antimicrobials used for periodontal therapy. • With local delivery of Metronidazole preparations, contraindicated in alcoholics. • Patients susceptible to infective endocarditis are contraindicated for irrigation devices to avoid the risk of bacteremia. • Delivery of antimicrobial agents using ultrasonic scalers is contraindicated in asthmatics, infective conditions (AIDS, TB) and those with cardiac pacemakers.

  14. ADVANTAGES: • Local drug delivery can attain 100 folds higher concentrations of the agent in subgingival sites compared with a systemic drug regimen. • Local delivery may employ antimicrobial agents not suitable for systemic administration. • Personally applied antimicrobial regimens offer the potential of daily placement into pockets, for compliant patients. • Professionally applied antimicrobial regimens reduce potential problems with patient compliance that place the use of systemic drug regimens. • Local antimicrobial delivery reduces the dangers associated with systemic administration such as toxicity, adverse reactions, resistant strains and superimposed infections.

  15. DISADVANTAGES: • Difficulty in placing antimicrobial agents into deeper parts of pockets and furcation lesions. • Patient compliance and manual dexterity are limiting factors in the case of personally applied antimicrobial regimens. • Professionally applied antimicrobial therapy is time consuming and labour intensive in-patients with numerous advanced lesions. • Locally applied antimicrobial agents do not markedly affect pathogens residing on extra-pocket oral surfaces. • Non-sustained drug delivery provides only a brief exposure of the target microorganism to the applied antimicrobial agent.

  16. SYSTEMIC VERSUS LOCAL DRUG DELIVERY:

  17. REQUIREMENTS FOR LOCAL ANTIMICROBIAL AGENTS: • Safety • Stability • Substantivity • Efficacy • Adequate subgingival delivery • Achievement of effective concentrations. • Cost-effectiveness and patient compliance.

  18. FACTORS AFFECTING THE BIO-AVAILABILITY OF AN ANTIMICROBIAL AGENT: • Solubility • pH and ion-binding capacity • Delivery vehicle-drug interaction • Metabolism

  19. TETRACYCLINE • The tetracyclines are primarily bacteriostatic agents that are effective against many Gram negative species including putative pathogens such as Actinobacillusactinomycetemcomitans (A a). • Tetracyclines are used extensively in the management of periodontal diseases and the agents used commonly are tetracycline HCl, DoxycyclineHCl and MinocyclineHCl.

  20. Description: The Actisite (tetracycline impregnated) fiber, available as flexible monofilament in 23 cms length(9 inch) monofilament of ethylene vinyl acetate copolymer, and 0.5 mm thickness contains 12.7 mg of evenly dispersed tetracycline. During the 10 day intra-pocket placement and retention, Actisite releases 25% of the available tetracycline and produce a sustained high level of tetracyline ranging 1590 ug/ml in gingival crevicular fluid (Tonetti et al 1990). This is in contrast with the typical 4-8 ug/ml tetracycline concentration in GCF reported after the oral rinsing (1000mg/day) and greatly exceeds the bacteriostatic level of pathogens susceptible to tetracycline.

  21. Dosage And Administration : Actisite (tetracycline hydrochloride) periodontal fiber for 10 days is indicated as an adjunct to scaling and root planning. Repeated fiber applications have not been studied. Actisite fiber should be inserted into the periodontal pocket the pocket is completely filled. The length of fiber used will vary with pocket depth and contour. The fiber should be placed to closely approximate the pocket anatomy and should be in contact with the base of the pocket. An appropriate cyanoacrylate adhesive should be used to help secure the fiber in the pocket. When placed within a periodontal pocket, Actisite fiber provides continuous release of tetracycline for 10 days. At the end of 10 days of treatment, all fibers must be removed. Fibers lost before 7 days should be replaced.

  22. These anticipated therapeutic benefits with tetracycline (Actisite) fiber therapy should be weighed against the possible side/adverse effects of tetracycline and the fiber insertion into the pocket like allergy, gingival erythema, pain, discomfort, periodontal abscess and oral candidiasis (Goodson 1966). • The placement of tetracycline (Actisite) fiber in the periodontal pockets, in conjunction with scaling and root planing offers great promise in the treatment of chronic adult periodontitis. Also this mode of drug delivery (controlled release drug delivery system) appears to be safe for the periodontal tissues and is well tolerated by the patients.

  23. OFLOXACIN • The development of fluoroquinolone derivatives over the past decade has renewed interest in this group of antibiotics. • Ofloxacin has been used as an antibacterial agent and has shown to be effective against gram positive and anaerobic bacteria. The concentration of ofloxacin has been found to be higher in the GCF and suggests that ofloxacin is a suitable agent in periodontal chemotherapy. • Annie Mathew, Vandana., Mehta D.S.:Suggested that there was significant reduction in plaque index sulcus bleeding index, gingival index and probing pocket depth in both tetracycline and ofloxacin groups at different intervals from the baseline. On comparison between tetracycline and ofloxacin suggested that both are closely parallel with that of clinical parameter.

  24. CHLORHEXIDINE • Chlorhexidine gluconate is an antimicrobial agent active against a wide spectrum of gram-positive and gram-negative organisisms, yeast, fungi, facultative anaerobes and aerobes. • In1970,Loe and Schiottreported a total inhibition of new plaque formation and prevention of the development of gingivitis by an aqueous solution of 0.2% chlorhexidine digluconate in the form of a mouthrinse.

  25. CLINICAL APPLICATIONS:: • Oral irrigators: Studies have demostrated that 100 ml of 0.02% solution of chlorhexidine digluconate, applied once daily in an oral irrigator, gave complete plaque inhibition. • Gels: Chlorhexidine digluconate has also been ircorporated in gels. Gels applied for a period of 5 minutes once or twice a day in individual trays or acrylic stents have proved to be effective in the treatment of denture stomatitis and oral candidiasis. • Chlorhexidine Dentifrices: • Sustained release devices: In order to affect the subgingival microbiota, sustained release devices (SRD) were developed. Such devices used ethylcellulose and polyethylene glycol as polymers and chlorhexidine and ethanol as solvents.

  26. PERIO-CHIP: The perio-chip is a unique patented “targeted controlled release” bio degradable polymer containing chlorhexidine. It is a small, bullet-shaped, thin film, weighing 7.4mg. It measures 5x4 mm in size and 0.35 mm thickness. The chip contains 2.5 mg chlorehexidine gluconate incorporated in a biodegradable matrix of cross-linked hydrolyzed gelatin.

  27. Advantages of the Perio-chip: • Very easy and convenient to use. Takes seconds to place in any pocket. • Chlorhexidine is highly effective, safe and well tolerated. • Painless to the patient. In some instances there may be minor discomfort in the first 24 hrs. • There are no restrictions on eating or oral hygiene after chip insertion. • All quandrants can be treated at the same visit. • Does not affect taste or stain teeth. • Maintains effective concentration of chlorhexidine in the pocket up to 10 days. • Delivers effective dosage even to the base of the pocket. • Reduces amount of pathogenic bacteria up to 100 days.

  28. Srinivas Reddy N., Shobha Prakash, Mehta D.SSuggested a significant reduction in clinical parameters like plaque index, gingival index, gingival bleeding index, probing pocket depth when used in combination of SRP and perio-chip 2.5 mg chlorhexidine gluconate, than perio-chip or SRP alone. • Jeffcoat et al (1997)who studied the SRP alone and SRP+periochip, in which SRP+periochip showed significant reduction in probing depth when compared to SRP alone. • Finally it can be suggested that subgingival delivery of biodegradable 2.5mg chlorhexidine gluconate chip form can be effective when associated with mechanical debridement in the treatment of chronic adult periodontitis.

  29. METRONIDAZOLE • Metronidazole is particularly attractive as an antimicrobial because of its selective efficacy against obligate anaerobes. Both systemic and local applications are effective against periodontal pathogens. Therefore, local application would be preferred. A Metronidazole 25% dental gel marketed as Elyzol has been developed by Dumex Ltd Copenhagen, Denmark for application locally into the periodontal pocket. The gel disintegrates in the pocket and releases Metronidazole. • In the recent past, Metronidazole has been incorporated as collagen sponges (Hitzig C. et al, 1997), dialysis tubing (Wan Yusof WZA et al 1984), zinc oxide eugenol paste, acrylic strips (Yeung FIS et al 1983), films (Golomb G. et al 1984) and gel (Klinge B et al 1992) forms for sustained subgingival delivery in the treatment of periodontal disease.

  30. Collagen sponges containing 5% metronidazole with tradenameMETROGENE (SEPTODENT, FRANCE) which is intended to be inserted into periodontal pocket. It is a new combination of two known substances; bovine collagen (Type I) into which Metronidazole is incorporated at a concentration of 5 percent in the finished product. In contact with human gingival fluid, this collagen rapidly forms a resorbable gel which is non-irritant as it is virtually devoid of any immunogenicity (Hugly 1983, Stein 1985). • Tony P. Paul, Vandana K.L., Mehta D.S.suggested that significant improvement in clinical parameter such as plaque index, gingival index, pocket depth used in combination of SRP and metrogene, than metrogene, SRP alone.

  31. MINOCYCLINE • It is a semisynthetic tetracycline which was first introduced in 1967. • Minocycline hydrochloride has in vitro antibacterial activity against a wide range of gram-negative and gram positive microorganisms thought to be related to periodontal disease. • A subgingival delivery system of 2% Minocycline HCl marketed as 2% Dentomycin gel (Lederle – U.K) was recently approved in Great Britain and other European countries for use as an adjunct to subgingival debridement.

  32. The Dentomycin (2%) gel has been reported to be effective in periodontal disease because of (i) its power to eliminate key periodontal pathogens. (ii) Greater all round activity than Metronidazole or Tetracycline. (iii) Minimal risk of bacterial resistance developing. (iv) Inhibits harmful bacterial collagenase without effecting normal collagen turnover and regeneration of gingival tissues. Musalaiah, vandana K.L., Mehta D.S. suggestedthat excellent improvement in clinical parameters such as plaque index, gingival index, pocket depth used in combination of SRP and dentomycin 2% gel, than dentomycin 2% gel, SRP alone.

  33. The ATRIDOX subgingival antibiotic product combines the ATRIGEL system with the generic antibiotic doxycycline to form a product designed to control the bacteria that cause periodontal disease. ATRIDOX is intended to add a new, less invasive pharmaceutical maintenance procedure to current periodontal treatment. The liquid ATRIDOX product is administered by a periodontist or a general dentist by filling the periodontal pocket with ATRIDOX using a syringe with a blunt needle.

  34. Upon contact with the gingival crevicular fluid in the pocket, the liquid drug delivery system converts into a solid within the pocket and releases doxycycline over a period of several days (9 days). As the polymer biodegrades, the implant becomes fragmented and the pieces are flushed out of the pocket by the outward flow of gingival crevicular fluid.

  35. Local Drug Delivery’s Impact on Deep Probing Depths (7 mm) • As probing depths increase, SRP becomes less efficient; therefore investigators evaluated the potential benefit of employing local drug delivery at deep sites (7 mm). • Timmerman et al.(1996)reported that there was no benefit of employing 2% minocycline gel as an adjunct to SRP to reduce probing depths at deep sites, whereas van Steenberghe et al.(1999) noted that combined therapy provided a better result than SRP alone at sites 7 mm deep.

  36. In summary, sites with deep probing depths provide an opportunity to attain greater probing depth reductions than shallow pockets. However, there are limited data related to the ability of individual drug delivery systems to enhance probing depth reductions at pockets 7 mm, Therefore, this facet of therapy requires further study.

  37. Inhibition of Periodontal Disease Progression • Garrett et al 1999compared doxycycline gel versus SRP, and found that there was no statistically significant benefit regarding inhibition of disease progression associated with drug therapy. • Jeffcoat et al 2000, after employing chlorhexidine chips plus SRP, noted that these sites achieved a mean 0.1 mm gain of bone, whereas 15% of the sites administered SRP alone lost bone (0.04mm) during a 9-month clinical trial. Overall, it is difficult to project outcomes regarding the ability of local drug delivery to inhibit disease progression because a limited number of studies, diverse study protocols, and different thresholds for disease progression were used.

  38. CONCLUSION: • As a monotherapy, local drug delivery systems incorporating a variety of drugs can improve periodontal health. • There is no single universal drug that would be effective in all situations. Therefore, at non-responsive sites, bacterial and antibiotic sensitivity testing may be necessary to determine putative pathogens and their susceptibility to specific antimicrobial agents. • Local drug delivery often appears to be as effective as scaling and root planing with regards to reducing signs of periodontal inflammatory disease : redness, bleeding upon probing, probing depth, and loss of clinical attachment.

  39. Local drug delivery systems usually do not provide a benefit beyond what is achievable with conventional scaling and root planing in the treatment of adult periodontitis. Therefore, their routine utilization is unnecessary. • Local delivery may be an adjunct to the conventional therapy. The sites most likely to be responsive to this adjunctive treatment method may have refractory or recurrent periodontitis, or specific locations where it is difficult to instrument root surfaces. However, the data are limited to support this concept. • At present, there are insufficient data to indicate that one local drug delivery device is clearly superior to all the other systems. However, desired characteristics include ease of placement, controlled release of drugs and resorbability.

  40. In conjunction with conventional treatment, systemically administered drugs appear to be as effective as local drug delivery. • To date, results from studies assessing local drug delivery systems have not justified extending the time interval between supportive periodontal maintenance visits. • There are preliminary, but very limited data, regarding the ability of local delivery to help suppress future disease progression. • There are insufficient data to indicate that local drug delivery induces bacterial resistance to antimicrobial agents. Long term studies are needed to address this important issue. • There are limited term data (5 years) evaluating the efficacy of local drug delivery.

  41. Additional studies are needed to evaluate if local delivery is effective against tissue invasive organisms. • There is a lack of data to support the impression that local drug delivery in conjunction with root planning reduces the need for periodontal surgery more than scaling and root planing alone. • Further study should be directed towards comparison of clinical and microbiologic parameters after the local delivery system in the treatment of chronic adult periodontitis. • Prudent administration of antimicrobial agents following judicious pharmacologic principles will preclude the abuse of chemotherapeutic agents and reduce the potential of developing or selecting drug resistant bacterial strains. Local drug delivery systems with controlled release properties have the potential to be used as a therapeuic component in the management of periodontal diseases.

  42. REFERENCES: • Clinical Peridontology. Carranza., 8th edn • Clinical Peridontology 9th edn. • Clinical practice of the Dental Hygienist, E.M. Wilkins, 9th edn. • Annals of periodontology 1996: 1: 491-566 • Goodson J.M. et al Periodontal disease treatment by local drug delivery JP : 1985, 56, 265-272. • Kenneth S. Control Released Local delivery Antimicrobials in periodontics.Prospects for the future. JP 1993: 64, 782-791. • Periodontology 2000 Vol 10: 1996, 139-159. • J Periodontol 2006;77:565-578

  43. Thank you

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