local drug delivery in periodontics

Local drug delivery is simple to use and may conceivably in the future be delivered by the patients themselves, hence can be used as an adjunct to mechanical plaque removal.

1. GOOD MORNING 1

2. LOCAL DRUG DELIVERY Presented by Dr Sruthi K Nair

3. CONTENTS INTRODUCTION HISTORY CLASSIFICATION INDICATION &CONTRAINDICATION LOCAL DRUG DELIVERY AGENTS NEWER AGENTS IN LDD CONCLUSION

4. PERIODONTITIS Periodontal diseases are a heterogenous group of diseases, proven to be caused by pathologic microorganisms that organize to form a plaque associated biofilm on the tooth surface. The destruction of the periodontium is a result of interaction between microorganisms and specific host defense mechanism .

5. Removal of this biofilm by mechanical instrumentation is essential. Limitations of mechanical debridement In case of unfavorable anatomy of the tooth In situations like Intra oral microbial translocation In presence of tissue invasive organisms When there is bacterial invasion into dentinal tubules To overcome this, Antimicrobials both systemic and locally acting were used as adjuncts to mechanical therapy In case of unfavorable anatomy of the tooth In situations like Intra oral microbial translocation In presence of tissue invasive organisms When there is bacterial invasion into dentinal tubules Quirynen et al (2002)

6. Systemic antimicrobial agents may reduce or eliminate bacteria that cannot be removed by scaling and root planning. HOWEVER , ADVERSE EFFECTS SUCH AS limit the use of systemic antimicrobials ( Golomb G. et al 1984 ) drug toxicity acquired bacterial resistance patient’s compliance drug interaction inaccessible to pathogens in periodontal pocket

7. Local deliveries of antibacterial agents into periodontal pocket limiting the drug to its target site Achieve high concentration at target site Dr. Max Goodson in 1979 that championed and developed local delivery of therapeutic agents into a viable concept.

8. HISTORICAL PERSPECTIVE:

9. CLASSIFICATION OF LOCAL ANTIMICROBIAL THERAPY IN PERIODONTICS LANGER & PEPPAS (1988) based on their mechanism of action. 1. Diffusion controlled systems Reservoirs (membrane devices) Matrices( monoli hic device) 2. Chemically controlled systems 3. Swelling controlled systems 4 . Magnetically controlled systems Bio-erodible systems Pendant chain systems

10. Kornman2 classified controlled release delivery systems in Periodontics based on the release of the drug into: Reservoir without rate controlling system: Reservoir devices with rate controlling system: Includes devices such as hollow fibers filled with a therapeutic agent in which the agent is released simply by diffusion through the reservoir wall. The most common forms include solvent action on coated drug particles, microporous polymer membranes or monolithic matrices, or erodable polymeric matrices . Classification based on the rate controlling system Kornman

11. Based on duration of action (Greenstein & Tonetti 2000) A) SUSTAINED RELEASE DEVICES Drug delivery for less than 24 hrs require multiple applications follow first order kinetics B ) CONTROLLED DELIVERY DEVICES Duration of drug release exceeds 24hrs administered once follow zero order kinetics

12. 2.Rams & slots (1996): depending on the usage PERSONALLY APPLIED ( In patient home self-care) PROFESSIONALLY APPLIED (In dental office)

13. DRUG DELIVERY refers to approaches, formulations, technologies and systems for transporting pharmaceutical compound in the body as needed to safely achieve therapeutic effect. Local delivery has the advantage of achieving higher concentrations of the drug to the intended site of action using lower dosage with an associated reduction in side effects and toxic effects. For example dentrifices , mouthrinses , dental gels, irrigation devices and syringes.

14. Mouth rinses and dentrifices are considered in- efficent because of the short period of contact of the drug within the tissues and lack of adequate penetration into the periodontal pocket. Local agents used for irrigation includes chlorhexidine , povidine iodine, stannous fluoride hydrogen peroxide.

15. Drug Delivery Devices There are two possible approaches to improve the drug action: ( i ) Sustained and controlled drug release to reduce or eliminate side effects by improving the therapeutic index (ii) Site specific drug delivery to minimize systemic effects.

16. VARIOUS DRUG DELIVERY DEVICES ARE FIBERS FILM INJECTABLE SYSTEMS GELS STRIPS AND COMPACTS VESICULAR LIPOSOMAL SYSTEMS MICROPARTICLE SYSTEM NANOPARTICLE SYSTEM

17. Hollow and monolithic fibers are used Natural polymer like gelatin , chitosan ,collagen and synthetic polymers like polyvinyl alcohol (PVA), poly ( lactide coglycolide ) (PLGA), are commonly used to synthesize films. Bio degradable or non biodegradable

18. INDICATIONS: CONTRA-INDICATIONS: 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 Isolated periodontal pockets (>5mm), with successful phase 1 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.

19. Local delivery of antimicrobial therapy to periodontal pockets has the benefit of administering More drugs at the target site Minimizing the exposure of total body to the drug Sustained release of antimicrobial in the periodontal pockets

20. DISADVANTAGES: Difficulty in placing into deeper parts of pockets and furcation lesions. Patient compliance and manual dexterity Time consuming and labour intensive in-patients with numerous advanced lesions . 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.

21. Efficacy Of Local Drug Delivery Local application of pharmacological agents must fulfill the following criteria: 1. The medication must reach the intended site of action. 2. Remain at an adequate concentration. 3. Last for a sufficient duration of time. 4. Should have a sustained release .

22. Local route of drug delivery can attain 100-fold higher concentrations of an antimicrobial agent in subgingival sites compared with a systemic drug regimen thereby reducing the total patient dose by over 400 fold avoiding development of drug-resistant at non oral body sites . Goodson J. Antimicrobial strategies for treatment of periodontal diseases. Periodontol 2000: 1994; 5:142-168.

23. IDEAL REQUIREMENTS FOR LOCAL ANTIMICROBIAL AGENTS: Must deliver the drug to the base of pocket. Must have microbiologically effective concentrations in the pocket. Should sustain the concentration of the drug in the pocket for sufficient period of time & at a concentration to be clinically effective Less undesirable side effects (Goodson 1985)

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

25. Possible Drug Release Mechanisms For Drug Delivery The drug will be released over time either by diffusion out of the polymer matrix or by degradation of the polymer backbone. Desorption of surface bound/adsorbed drugs Diffusion through the carrier matrix; Diffusion through the carrier wall; Carrier matrix erosion; A combined erosion/diffusion process

26. Commercially Available Products 1. Tetracycline fibers ( Actisite , Alza Corp., Mountain view, California) 2. Metronidazole gel ( Elyzol , Dumex , Copenhagen, Denmark) 3 . Minocycline ointment ( Dentomycine , Lederle , UK & Periocline , Sunstar , Japan) 4. Chlorhexidine Chip ( Perio chip Peno Products Ltd., Jerusalem , Israel) 5. Doxycycline hyclate in a resorbable polymer ( Atridox , Atrix Labs, CO) 6 . Minocycline microspheres ( Arestin, Ora pharma, North Carolina, USA).

27. TETRACYCLINE Goodson et al in 1979 first proposed the concept of controlled delivery in the treatment of periodontitis. The first delivery devices involved hollow fibers of cellulose acetate filled with tetracycline. Tetracycline is a bacteriostatic antibiotic that interferes with bacterial protein synthesis and inhibits tissue collagenase activity ( Jain et al., 2008 ).

28. Tetracycline –containing fibers( Actisite ) FDA approved Non resorbable , biologically inert, safe plastic copolymer (ethylene &vinyl acetate) loaded with 25% w/w tetracycline hcl powder packed as thread of 0.5mm diameter &23cm length It maintains constant concentrations of active drug in the crevicular fluid in excess of 1000 μg / mL for a period of 10 days.( Maurizio S etal ) In contrast GCF conc. of only 4-8 microgram/ml were reported after systemic administration, 250 mg qid for 10 days.

29. Bioresorbable form is PERIODONTAL PLUS AB Biodegrade within 7 days ,so no 2 nd appointment Gel ( M aheshwari etal ) Tetracycline- Serratiopeptidase -Containing Periodontal Gel Formulation has shown statistically significant results along with scaling and root planing .

30. STUDIES Singh et al.(2009)- 3 months - No difference in the results achieved with local tetracycline hydrochloride or local metronidazole as adjuncts to mechanotherapy . However, both antibiotic therapies resulted in greater improvement in microbiological parameters when compared to mechano therapy alone.

31. Sadaf et al.(2012)- Tetracycline fibers - 3 months Higher reduction in plaque index, gingival index and in the clinical probing depths of the tested group than of the control group at all time intervals -15, 30, 60 and 90 days. Tetracycline fiber therapy enhances the benefits of SRP in the treatment of chronic periodontitis. ( Gupta Nidhi et al ,2015)

32. Subgingival doxycycline Doxycycline is a bacteriostatic agent Has the ability to down regulate MMP’s . The only FDA approved 10% Doxycycline in a gel system ATRIDOX (42.5 mg Doxycycline ) is a subgingival controlled-release product composed of a 2 syringe mixing system . It is the only local delivery system accepted by ADA

33. Doxycycline levels in GCF peaked to 1,500 - 2000 μg /ml in 2 hours following treatment with ATRIDOX. Local levels of Doxycycline have been found to remain well above the MIC for periodontal pathogens (6.0μg/ml) through Day 7. 95% of the polymer is bio absorbed or expelled from the pocket naturally within 28 days.

34. Locally applied controlled release DOX gel may partly counteract the negative effect of smoking on periodontal healing following no surgical therapy .( Tomasi C and Jan LW)

35. STUDIES The FDA has also approved doxycycline hyclate in a bioabsorbable polymer gel as a stand-alone therapy for the reduction of probing depths, bleeding upon probing, and gain of clinical attachment ( Kim TS etal,2002) Deo et al.(2011)- 6 months - Doxycycline hyclate 10% as an adjunct to SRP provided significant reductions in PPD and gains in CAL compared to SRP alone.

36. Subgingival Minocycline A bacteriostatic antibiotic has been tried clinically via in three different modes i.e . film, microspheres, and ointment. Film: Ethyl cellulose film containing 30% of Minocycline were tested as sustained release complete eradication of pathogenic flora from the pocket after 14 days

37. Microsphere: A new, locally delivered, sustained release form of minocycline microspheres (ARESTIN) for subgingival placement is available. The 2% minocycline is encapsulated into bio- resorbable microspheres (20-60μm in diameter) in a gel carrier and has resorption time of 21 days. Gingival crevicular fluid hydrolyses the polymer and releases minocycline for a period of 14 days or longer before resorbing completely.

38. Ointment: 2% minocycline hydrochloride in a matrix of hydroxyethyl -cellulose, amino alkyl- methacrylate , triacetine & glycerine. DENTOMYCIN – european union PERIOCLINE -JAPAN The concentration of minocycline in the periodontal pocket is about 1300μg/ml, 1 hr after single topical application of 0.05 ml ointment (1mg of minocycline ) and is reduced to 90μg/ml after 7 hrs.

39. STUDIES 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 Steenberghe et al (1999 ) that combined therapy provided a better result than SRP alone at sites >7 mm deep. Jung et al. ( 2012) - Minocycline hydrochloride2% -Reductions in PPD, BOP and gain in CAL were significantly greater at the minocycline ointment in association with flap surgery site than at the flap surgery site alone

40. Chlorhexidine Is available in the form of mouthrinses , Gels, varnishes, and chip to be used as a local drug delivery agent . MECHANISM OF ACTION ( Rolla and Melsen ) By binding to anionic acid groups on salivary glycoproteins thus reducing pellicle formation and plaque colonization. By binding to salivary bacteria and interfering with their adsorption to teeth.

41. Chlorhexidine has been shown to be an effective agent in plaque inhibition (Loe et al 1976) Because it is well retained in the oral cavity, Reacting reversibly with receptors in the mouth due to its affinity for hydroxyapetite and acidic salivary protein

42. Its antibacterial action is due to an increase of the cellular membrane permeability followed by the coagulation of intracellular cytoplasmic macromolecule

43. Periochip : small chip (4 5 3.5mm) composed of biodegradable hydrolyzed gelatin matrix, crosslinked with glutaral dehyde , also contains glycerine & water, into which 2.5mg chlorhexidine gluconate is incorporated Perio Chip releases chlorhexidine in vitro in a biphasic manner , Initially releasing approximately 40% of the chlorhexidine within the first 24 hours, and then releasing the remaining chlorhexidine in an almost linear fashion for 7–10 days.

44. Periocol -CG: Periocol CG is prepared by incorporating 2.5mg chlorhexidine from a 20% chlorhexidine solution in collagen membrane.Size of the chip is 4x5 mm and thickness is 0.25 - 0.32 mm and 10 mg wt. Chlo -Site is an agent containing 1.5% chlorhexidine of xanthan type . Xanthan gel is a saccharide polymer, which constitutes of a three-dimensional mesh mechanism, which is biocompatible with chlorhexidine .

45. STUDIES Medaiah et al.( 2014)- 3 months-Biodegradable chlorhexidine chip-No statistically significant differences between SRP and SRP + CHIP group in all clinical parameters.- Grover et al.( 2011)- 3 months - Chlorhexidine chip and SRP resulted in a clinically significant improvement in PPD and CAL compared with SRP alone.

46. Subgingival Metronidazole Elyzol 25% Metronidazole concentrations of above100 μ/ml were measurable in the periodontal pocket for at least 8 hours and concentrations above 1 μ/ml were found at 36 hours. Applied in viscous consistency to the pocket, where it is liquidized by the body heat and then hardens again, forming crystals in contact with water.

47. Griffiths et al.(2000)- 9 months- Metronidazole 25% dental gel-Combined therapy of SRP and metronidazole 25% dental gel was superior to the conventional treatment of SRP alone.

48. Riep et al.( 1999) - 3 months-PPD reduction and CAL gain were statistically significant after both treatments (SRP + subgingival application of metronidazole 25% dental gel and SRP alone). There were no statistically significant differences between the groups.

49. Newer Trends In Local Drug Delivery DRUGS FOR OSSEOUS DEFECTS Alendronate a novel bisphosphonate is a very potent inhibitor of bone resorption . local delivery of 1% ALN into periodontal pockets as an adjunct to SRP stimulated a significant increase in PD reduction, PAL gain, and improved bone fill (. Anuj Sharma etal,2011)

50. Simavastatin - Statins seem to modulate bone formation by increasing the expression of bone morphogenetic protein-2, inflammation, and angiogenesis Pardeep et al showed a greater decrease in gingival index and probing depth and a clinical attachment level gain with significant defect fill at sites treated with scaling and root planing plus locally delivered SMV gel in patients with chronic periodontitis.

51. Clarithromycin gel Adjunctive use of 0.5% clarithromycin as a controlled drug delivery system enhanced the clinical outcome in smokers( Agarwal E etal ) Okade etal - developed a new sub gingival release delivery system (PT-01) containing Ofloxacin for sub gingival therapy and found it to be effective in the reducing plaque scores and bleeding scores.

52. COLLOIDAL DRUG CARRIERS include micelles, emulsions, liposomes and nanoparticles ( nanospheres and nanocapsules ). The aim of using colloidal carriers is To increase the specificity towards cells or tissues, To improve the bioavailability of drugs by increasing their diffusion through biological membranes and To protect them against enzyme inactivation .

53. NANOPARTICLES . Due to their small size, penetrate regions that may be inaccessible to other delivery systems, such as the deep periodontal pockets Owing to its small size, it acquires a high disper sibility in an aqueous medium and controlled release rate.

54. The triclosan loaded polymeric (PLGA, polylacticacid and cellulose acetate phthalate) nanoparticles were prepared by emulsification–diffusion process. A preliminary in vivo study in dogs with induced periodontal defects suggested that triclosanloaded nanoparticles penetrate through the junctional epithelium ( PinonSegundo E etal )

55. LIPOSOMES A liposome is a spherical vesicle having at least one lipid bilayer . The liposome can be used as vehicle for administration of nutrients and pharmaceutical drugs. Liposomes can be prepared by disrupting biological membranes (such as by sonication ). Int J Immunopathol Pharmacol .  2012 Jul-Sep;25(3):657-70.

56. HERBS FOR PERIODONTITIS Eucalyptus Extract ( Saito MV,et al) Neem Leaf (M. Raveendra Pai,etal ) Bloodroot ( Chopra etal ) Chamomile Aloe vera , tulsi , propolis , Cocoa husk, pomegranate chamomile

57. Neem has also showed better efficacy in the treatment of oral infections and plaque growth inhibition in treating periodontal disorders. Neem has also shown good in vitro, broad range antibacterial activity .

58. Roobal Bahal et al -2% turmeric gel , significant reduction in the mean plaque index gingival index , sulcus bleeding index , probing pocket depth and significant reduction in trypsin like enzymes activity of “Red-Complex” microorganisms.

59. Aloe Vera Geeta Bhat et al in her study concluded that its use in local drug delivery results in significant reduction in pocket depth and resulted in reduction in the gingival index.

60. Along with individual herbs, herbal combinations can combat periodontitis. Mixture of peppermint oil , menthol , sage oil , chamomile , clove oil , caraway oil can reduce periodontitis symptoms World Journal of Pharmaceutical Research Vol 3, Issue 2, 2014.

61. LOCAL DELIVERY OF GROWTH FACTORS Fibroblast growth factor would be a very efficacious introduction in local drug delivery. To regenerate periodontal tissues, a sandwich membrane composed of a collagen sponge scaffold and gelatin microspheres containing basic fibroblast growthfactor ( bFGF ) in a controlled-release system was developed. ( Cooke JW etal 2006)

62. NOVEL CHITOSAN-PVA-BASED LOCAL DELIVERY Chitosan is a natural polysaccharide localized drug delivery system (LDDS) with chitosan and poly vinyl alcohol (PVA) for treating serve periodontitis has been designed ( Wang LC etal )

63. Conclusion: There is ample evidence to show that locally delivered antimicrobials can reduce clinical and microbial parameters to a level, if not better than, at least comparable to that of scaling and root planing. Mechanical instrumentation, can be technically demanding time consuming, and in some periodontal defects, ineffective or incomplete. Local drug delivery on the other hand is simple to use and may conceivably in the future be delivered by the patients themselves, hence can be used as an adjunct to mechanical plaque removal.

64. REFERENCES Clinical Periodontology - Carranza 9 th /10 th edition Clinical Periodontology & Implant Dentistry - Jan Lindhe 5 edition Drug delivery in treatment of periodontal disease - JP april 2006; 77 : 4 , 565 Local antimicrobial therapy - Perio 2000 vol 10,1996:139-159 Advanced Drug Delivery Systems in Treating Periodontal Diseases-A Review- IOSR Journal of Dental and Medical Sciences (IOSR-JDMS) LOCAL DRUG DELIVERY IN PERIODONTICS: A STRATEGIC INTERVENTION International Journal of Pharmacy and Pharmaceutical Sciences Vol 4, Issue 4, 2012 Local drug delivery in Periodontics: A tactical entreaty- Journal of Research in Pharmaceutical Science Volume 2 ~ Issue 1 (2014) pp: 06-11

65. REFERENCES Local Drug Delivery - ijpsi Volume 2 Issue 1 January 2013 PP.33-36 Recent advances in periodontal drug delivery systems International Journal of Drug Delivery 1(2009) 1-14 Local drug delivery agents as adjuncts to endodontic and periodontal therapy –Journal of medicine and life "Local Drug Delivery--- Periocol " In Periodontics LOCAL DRUG DELIVERY SYSTEMS IN THE TREATMENT OF PERIODONTITIS: A REVIEW Pharmacophore 2013, Vol. 4 (2), 39-49 Local Drug Delivery Systems in the Treatment of Periodontitis: A Literature Review - Journal of the International Academy of Periodontology 2015 17/3: 82–90

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67. Local delivery systems LIMITATIONS BENEFITS When used as monotherapy Allergic reaction Inability to disrupt biofilms , Failure to remove calculus. The ease of application Selectively targeting a limited number of diseased sites that were unresponsive to conventional therapy, Enhanced treatment results at specific locations.

68. as an adjunct to scaling and root planing for periodontal maintenance therapy. used in medically compromised patients for whom surgery is not an option or those who refuse surgical treatment. It is. highly contraindicated in patients with known hypersensitivity delivery of antimicrobial using ultrasonic devices is contraindicated in asthmatics and infective conditions such as AIDS, Tuberculosis

69. Locally applied antimicrobial agents should Safe Stable Substantive Efficaceous Cost effective Patient compliant Achieve effective concentrations.

70. Classification depending on the use: Rams & Slots 4classified drug delivery into: 1. Personally applied (in patient home self care) Non – sustained sub gingival drug delivery (Home oral irrigation) Sustained sub gingival drug delivery (None developed to date) Professionally applied (in dental office) Non – sustained sub gingival drug delivery (Professional pocket irrigation) Sustained sub gingival drug delivery (Controlled – release device).

71. 1. PERSONALLY APPLIED (In patient home self-care) A. Home oral irrigation devices: Devices with traditional jet tips Oral irrigator ( Water Pik , Fort Collins) Soft cone-rubber tip s (Pick pocket) Blunt tipped metal cannula connected to syringe or oral irrigator B. (none developed to date) NON-SUSTAINED SUBGINGIVAL DRUG DELIVERY SUSTAINED SUBGINGIVAL DRUG DELIVERY

72. PROFESSIONALLY APPLIED (In dental office) 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. 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 NON-SUSTAINED SUBGINGIVAL DRUG DELIVERY SUSTAINED SUBGINGIVAL DRUG DELIVERY

73. 3. OTHER LOCAL DELIVERY METHODS : Dentifrices, mouthrinses , chewing gum, Keyes technique, root biomodification .

74. Current strategies for the local delivery of antibiotics do not allow a complete clearance of bacteria filling dentinal tubules and this limits their therapeutic efficacy. The aim of the present study is to develop liposome-based delivery systems of sub-micron dimension, able to diffuse into the dentinal tubules.

75. Pik Pocket oral irrigation tip advanced into furcation involvement High-pressure pulsed oral irrigation at a 90" application angle provides 250% subgingival delivery of an aqueous solution. Ultrasonic scaler ( Piezon Master 400, EMS, Switzerland) with built-in reservoir for antimicrobial solution. Pocket delivery of povidone -iodine solution through ultrasonic scaling device.

76. For all these systems, the basic polymer can be of natural origin such as proteins or collagen, semi-synthetic such as cellulose derivatives or synthetic, all of which must preferably degrade during use. Natural polymers have been considered as biodegradable carriers Bio degradable or non biodegradable