new localDRUG DELIVERY hashim.pptx for dental

Dental

1. LOCAL DRUG DELIVERY DEPARTMENT OF PERIODONTICS GUIDED BY , DR. AJEY BHAT DR. SHILVANA ANSARI DR. RENJITH MADHAVAN DR. SUNEETHI M DEY SUBMITTED BY , Hashim e 180021982

2. CONTENTS INTRODUCTION LOCAL DRUG DELIVERY SYSTEM INTRODUCTION GOALS OF LOCAL DRUG DELIVERY HISTORY PRINCIPLES INDICATIONS CONTRAINDICATIONS CLASSIFICATIONS IDEAL REQUISITES ADVANTAGES DISADVANTAGES SUBSTANTIVITY COMPARISON OF DRUG DELIVERY FOR MANAGEMENT OF PERIODONTITIS . VEHICLES FOR LOCAL DRUG DELIVERY SYSTEMS

3. LOCAL DELIVERY DIVICES TETRACYCLINE FIBERS CHLORHEXIDINE BASED PRODUCTS SUBGINGIVAL DOXYCYCLINES SUBGINGIVAL MINOCYCLINES SUBGINGIVAL METRONIDASOLE SUBGINGIVAL MOXIFLOXACINE FUTURE TRENDS FUTURE REQUIREMENTS CONCLUSION REFFERENCE

4. INTRODUCTION PERIODONTITIS Periodontitis is defined as an inflammatory disease of supporting tissue of teeth initiated by specific microorganism or group of specific microorganism , resulting in progressive destruction of the periodontium with periodontal pocket formation , gingival recession , or combination of both .

5. The traditional mechanical therapy alone is not sufficient for the treatment of moderate to severe periodontitis with deeper pockets . To overcome this , local drug delivery into periodontal pocket is recommended . Systemic administration of medications results in local concentrations of free, active drug in the periodontal pocket and surrounding tissues.

6. LOCAL DRUG DELIVERY SYSTEM Aim is targeting an anti infective agent to infection sites and sustaining its localized concentration at effective levels for a sufficient time with minimal or no side effects. 3 basic routes to localized adjunctive pharmacologic periodontic therapy: mouth rinses , subgingival irrigation and local delivery systems .

7. Rinses are useful for supragingival biofilm control, modulation of gingival Inflammation . They do not gain access to the subgingival environment . Irrigation solutions placed directly in to periodontal pockets A highly concentrated irrigating solution of a non substantive ( non binding) drug becomes ineffective about 15 min following application

8. This time can be prolonged by application of substantive drugs that bind to the root surface and / or the soft tissue wall of the periodontal pocket and establish a drug reservoir that can be slowly released . Goodson- in 1970s pointed out that successful pharmacologic control of the periodontal microflora requires; Site Concentration Time

9. GOALS OF LOCAL DRUG DELIVERY The primary goal in using an intra pocket device for the delivery of an antibacterial agent is the achievement and maintenance of the therapeutic levels of the drug for the required period of time . This inhibits or kills the pathogens , without any harm to the tissues .

10. HISTORY GOODSON et al 1979 – Tetracycline fibers D.STEINBERG et al 1990 – chlorhexidine as LDD NAKAGAWA et al – 1991 – minocycline Stoller et al 1998 – doxycycline hyclate Ainamo et al 1992 -25% metronidazole gel

11. PRINCIPLES The periodontal pocket Natural reservoir Easily accessible for insertion of devices GCF is the leaching medium Gets distributed from pockets

12. INDICATIONS In medically compromised patients where surgical procedures are not recommended . Periodontal abscess . Periodontal maintenance therapy . Patient with GI intolerance to systemic drug medication . In failing implant cases .

13. CONTRAINDICATIONS In patients with history of allergy to a particular antimicrobial agent . In pregnancy and lactating periods . Children under the age of 12 years . Patient with complete renal failure . Patients susceptible to infective endocarditis .

14. CLASSIFICATION OF LOCAL DRUG DELIVERY . Based on the application - Rams & slots ( 1996 ) Personally applied Nonsustained subgingival drug delivery Home oral irrigation Traditional jet tips Oral irrigations Soft cone rubber tips ( pickpockets ) Sustained local drug delivery .

15. Professionally applied in Dental office . Nonsustained subgingival drug delivery . Professional pocket irrigation . Sustained subgingival drug delivery . Controlled release devices Hollow fibers Dialysis tubing Strips Films

16. (B) . Based on the duration – Greenstein and Tonetti ( 2000) Sustained release device Device with drug delivery less than 24 h Require multiple applications . Follow first order drug kinetics Controlled release device Drug release more than 24 h Administration only once Follow zero order drug kinetics

17. (C) . Depending on degradability Non degradable devices ( First generation ) Degradable devices ( Second generation ) (D) . Langer and peppas Diffusion controlled system Matrices Reservoirs Chemically controlled systems Pendant chain system Osmotic system Swelling controlled systems

18. (E) . Kornman classification of controlled release local drug delivery systems Reservoirs without a rate controlling system Reservoirs with a rate controlling system Eg : hollow fibers , gels Eg : Polymeric matrices

19. (F) . Depending on the origin . Allopathic / chemical Herbal / Ayurvedic (G) . Based on the type of local drug delivery system Fibers Films Gels Strips Vesicular liposomal systems Microparticle systems Nanoparticle systems

20. IDEAL REQUISITES It should deliver drugs to the connective tissue apically and laterally of the periodontal pockets . Maintain a microbiologically effective concentration . It should maintain the drug concentration in the periodontal pocket for sufficient time . Easy to deliver into the pockets It should be biodegradable It should not develop bacterial resistance Minimal or no adverse effects It should not affect commensal microflora of pockets .

21. ADVANTAGES High concentration in subgingival sites . Independent of patient compliance . Does not harm the useful microflora of GI tract . Systemic intolerance is bypassed . Improved pharmacokinetics

22. DISADVANTAGES Difficulty in placing deeper sites . Has to be professionally placed . Complete drug penetration is not possible . Time consuming .

23. SUBSTANTIVITY It is refers to the property of a substance to bind to soft and / hard tissue of the pockets , thereby establishing a drug reservoir . Incorporation of a drug into various vehicles or device , prior to placement into periodontal pocket enhance sustantively . It is influenced by series of parameters like ; concentration of the medium length of time of contact of the solution with the oral structures . Ph temperature

24. COMPARISON OF DRUG DELIVERY SYSTEM FOR THE MANAGEMENT OF PERIODONTITIS PHARMACO KINETIC VARIABLES MOUTH RINSE SUBGINGIVAL IRRIGATIONS SYSTEMIC DELIVERY CONTROLLED DELIVERY SITE DELIVERY POOR GOOD GOOD GOOD CONCENTRATION GOOD GOOD FAIR GOOD DURATION POOR POOR FAIR GOOD

25. VEHICLES FOR LOCAL DELIVERY Dentifrices Mouthrinses Chewing gum Slow release devices

26. VARIOUS DRUGS / AGENTS USED TETRACYCLINE CHLORHEXIDINE DOXYCYCLINE MINOCYCLINE METRONIDAZOLE MOXIFLOXACIN OTHER DRUGS LIKE CLARITHROMYCIN , ALENDRONATES , OFLOXACIN , CLINDAMYCIN etc.

27. Tetracycline Containing Fibers The first local delivery product , was ethylene /vinyl acetate copolymer fiber (diameter,  0.5 mm) that contained tetracycline(12.7 mg per 9 inches ) . Tolerated by oral tissues and for 10 days its sustained concentration exceeding 1300 microgrms / ml TETRACYCLINE BASED PRODUCTS GCF concentrations of only 4 to 8 µg/ml reported after systemic tetracycline administration( 250mg 4 times daily for 10 days for total oral dose of 10 g)

28. Tetracycline fibers reduces probing depth, bleeding on probing, and periodontal pathogens and provided gains in clinical attachment level. These fibers are no longer commercially available. Disadvantages included time required for placement (≥ 10 min per tooth), and a second patient appointment . Placement of fibers around 12 or more teeth resulted in oral candidiasis in few patients

29. PerioCol –TC is another tetracycline based product Each PerioCol- TC contains fish type 1 collagen (approximately 25 mg) impregnated with approximately 2 mg of tetracycline hydrochloride PerioCol – TC releases tetracycline in vitro for 8 to 10 days. A periodontal dressing should be placed to avoid dislodging the fibers. Indicated for adult periodontitis with pocket deeper than 5mm . PerioCol - TC

30. The fibers are moistened with saline and placed in to the periodontal pocket to a depth of the pocket base; they are biodegradable PerioCol -TC is stored in a dry place between 5° C (41° F) and 25° C (77° F) and has a shelf life of 2 years with proper storage. Periodontal Plus AB PERIODONTAL PLUS AB

31. Periodontal Plus AB is a bioresorbable tetracycline fiber. It is 25 mg of pure fibrillar collagen evenly impregnated with approximately 2 mg of tetracycline hydrochloride . Packed as a strip containing four individually packed and separable sterile product packs. The fiber biodegrades in the periodontal pocket within 7 days. The fiber should be retained with a periodontal dressing or covered with a dental adhesive for 10 days.

32. CHLORHEXIDINE BASED PRODUCTS Chlorhexidine is active against a broad range of microbes . It disrupts the cell membrane and causes precipitation of the cytoplasm, resulting in cell death. The chip is stored at 20° to 25° C (68 to 77° F), with excursions permitted to 15° to 30° C (59 o to 86 o F) The chlorhexidine chip is placed into the pocket directly from the foil container using a forceps.

33. Subgingival Chlorhexidine in Chip Form PerioChip PerioChip is a small chip (4.0 x 5.0 x 0.35 mm) that is composed of a biodegradable hydrolyzed gelatin matrix. Cross linked with glutaraldehyde , and contains glycerin and water into which 2.5 mg of chlorhexidine gluconate has been incorporated per chip.

34. Maintains drug concentrations in the GCF more than 100 µg/mL for at least 7 days. Since the chip biodegrades within 7-10 days, a second appointment for removal is not needed . Dental floss should be avoided for 10 days to avoid dislodging it. PLACEMENT 0F PERIO CHIP

35. PerioCol -CG PerioCol -CG is a small, 10-mg chip (4 x 5 x 0.25-0.32 mm )designed as a collagen matrix into which chlorhexidine gluconate (2.5 mg) is incorporated from a 20% chlorhexidine solution . PERIOCOL CG Resorb after 30 days but coronal edge will degrades within 10 days . It releases chlorhexidine at a rate of approximately 40% to 45% in the first 24 hours, followed by a linear release for 7 to 8 days

36. Subgingival Chlorhexidine in Gel Form Chlo -Site is a xanthan gel, consisting of a saccharide polymer as a three-dimensional mesh containing 1.5% chlorhexidine in 0.5 mL of gel Individually packed for delivery in 0.25ml prefilled syringes fitted with a blunt side-exit needle. The gel contains two types : a slow-release chlorhexidine digluconate ( 0.5% ) and a rapid-release chlorhexidine dihydrochloride ( 1.0% )

37. CHLORHEXIDINE GEL – CHLO SITE The gel disappear from the pocket in 10 to 30 days and chlorhexidine concentration in GCF of more than 100 µg/ml for an average of 6-9 days.

38. Subgingival Chlorhexidine in Gel Form Chlo -Site is a xanthan gel, consisting of a saccharide polymer as a three-dimensional mesh containing 1.5% chlorhexidine in 0.5 mL of gel Individually packed for delivery in 0.25ml prefilled syringes fitted with a blunt side-exit needle. The gel contains two types : a slow-release chlorhexidine digluconate ( 0.5% ) and a rapid-release chlorhexidine dihydrochloride ( 1.0% )

39. DOXYCYCLINE BASED PRODUCTS Doxycycline in gel form A gel system involving the use of a syringe with 10% doxycyclineAtridox Doxycycline gel is a subgingival , controlled-release delivery product composed of a two-syringe mixing system .

40. Syringe A contains  450 mg of a bioabsorbable polymeric formulation of 36.7% poly (D,L,-lactide) dissolved in 63.3% N-methyl-2-pyrrolidone Syringe B contains 50 mg of doxycycline hyclate , equivalent to 42.5 mg of doxycycline . Atridox two syringe system

41. The two syringes are stored at 2° to 30° C (36° to 86° F). When mixed, the product is a viscous liquid of  500  mg, which contains 50 mg (10%) of doxycycline hyclate . Indicated for the treatment of chronic adult periodontitis for a gain in clinical attachment , reduction in probing depth and reduction of bleeding on probing. Inhibit bacterial protein biosynthesis by interfering with transfer RNA( tRNA ) and messenger RNA(mRNA) at the ribosome Used by injecting the mixed contents of the two syringes directly into the pocket The pocket contents are then covered with a periodontal dressing or a cyanoacrylate dental adhesive.

42. If not used immediately, the mixed contents in syringe A can be stored in an airtight container at room temperature for a maximum of 3 days. The gel release doxycycline in the GCF over 7 days. The doxycycline gel is biodegradable and does not require removal.

43. Ligosan Slow Release Resorbable doxycycline gel provided in a laminate pouch and stored under refrigeration. It contains 1, 2, 4, 8, 10, or 16 single application cylinder cartridges, each containing  260  mg of Ligosan Slow Release .

44. Used by inserting the cartridge in to the caulking gun ,opening the spray nozzle and then discharging the gel to the bottom of the pocket. Concentrations in the GCF remained above 16 µg/mL for at least 12 days. Mechanical hygiene should be avoided for 7 days. Ligosan slow release

45. SUBGINGIVAL MINOCYCLINE A locally delivered, sustained-release form of minocycline microspheres (Arestin) Contain minocycline hydrochloride incorporated into a bioresorbable poly ( glycolide -co-D,L- lactide ) polymer in unit-dose cartridges.

46. Each cartridge delivers minocycline hydrochloride equivalent to 1 mg of minocycline free base . Indicated for the reduction of pocket depth in patients with adult periodontitis and as part of a periodontal maintenance program. Its bacteriostatic , antimicrobial activity results from the inhibition of protein biosynthesis. Patients should avoid hard or sticky foods at the treated teeth for 1 week and interproximal cleaning devices for about 10 days.

47. The cartridges are stored at 20° to 25° C (68% to 77° F), with excursions permitted to 15° to 30° C (59° to 86° F). Used by injecting the contents of a unit-dose cartridge into the pocket. Neither a periodontal dressing nor an adhesive is needed. It is biodegradable and does not require removal.

48. PLACEMENT OF MINOCYCLINES MINOCYCLINES

49. SUBGINGIVAL METRONIDAZOLE A topical medication that contains an oil-based metronidazole 25% dental gel (glyceryl mono oleate and sesame oil) . As a precursor, the preparation contains metronidazole-benzoate, which is converted into the active substance by esterases in GCF.

50. It is applied in a viscous consistency to the pocket, where it is liquidized by the body heat and then hardens again, forming crystals when it comes in contact with water. Two 25% gel applications at a 1-week interval have been used.

51. Subgingival metronidazole placement

52. SUBGINGIVAL MOXIFLOXACIN This antibiotic inhibits cell replication by modifying the actions of DNA gyrase and topoisomerase IV. Since moxifloxacin have antimicrobial activity against aerobic and anaerobic bacteria, it has been introduced as a local delivery agent for the treatment of destructive periodontal diseases.

53. Administration of moxifloxacin

54. CLINICAL INDICATIONS FOR TREATMENT OF PERIODONTITIS WITH ADJUNCTIVE LOCAL DELIVERY DEVICES These include Local conditions Special patient groups

55. LOCAL CONDITIONS Deeper pockets (6-8mm range) or furcation involvement Management of local non responding sites or disease recurrence during supportive periodontal care When residual pockets are present in the esthetic zone where a surgical intervention may compromise esthetics or phonetics. Sites with deep pockets and persistent bleeding on probing that are associated with intra bony defects Pocket disinfection before regenerative periodontal surgery

56. SPECIAL PATIENT GROUPS Smokers Diabetic patient Cardiovascular patients Older patients Subjects with relative or absolute contraindications to surgical intervention

57. FUTURE TRENDS IN LOCAL DRUG DELIVERY The requirements for treating periodontal disease include a means for targeting anti infective agent to infection sites and sustaining its localized concentration at effective levels for a sufficient time while concurrently evoking minimal or no side effects . Various newer agents are being investigated in the field of local drug delivery to ensure maximum benefits .

58. FUTURE REQUIREMENTS Various drug delivery and drug targeting systems are currently under development to obtain so that better and effective administration of desired and newer drug can be done through the best possible system . Increased dissolution velocity Increased saturation solubility Improved bioadhesivity and Versatility in surface modifications . Long term longitudinal studies to be done to know the durability of these drugs on long term basis .

59. CONCLUSION When systemic antibiotics( eg:metronidazole , tetracycline) are used as adjuncts to scaling and root planing ,provide improvements in attachment levels (0.35 mm for metronidazole; 0.40 mm for tetracycline) Improvements in clinical attachment levels also occur with the chlorhexidine chip (0.16 mm) and doxycycline gel (0.34 mm).

60. When scaling and root planing are combined with the subgingival placement of sustained-release vehicles, further reduction of pocket depths, additional gains in clinical attachment levels (e.g., 0.39 mm with minocycline gel), and further decreases in inflammation. The decision regarding when to use local or systemic antimicrobials should be made on the basis of the clinician's consideration of the clinical findings, the patient's medical and dental history, the patient's preferences and the benefits of adjunctive therapy with these agents

61. REFERENCE CARRANZA - CLINICAL PERIODONTOLOGY - 10 TH EDITION CARRANZA - CLINICAL PERIODONTOLOGY - 11 TH EDITION CLINICAL PERIODONTOLOGY AND IMPLANT DENTISTRY - JAN LINDHE – 6 TH EDITION RICHARD D. FINKELMAN, HECTOR L. SARMIENTO, ALAN M.POLSON LINDHE 4TH EDITION, THE USE OF ANTIBIOTICS IN PERIODONTAL THERAPY 496-498)9 GOODSON JM, HAFFAJEE A, SOCRANSKY SS. PERIODONTAL THERAPY BY LOCAL DELIVERY OF TETRACYCLINE. J CLIN PERIODONTOL. 1979 APR;6(2):83-92. DOI: 10.1111/J.1600-051X.1979.TB02186.X. PMID: 379050 P ANARTH R, KALE P, MANI A AND KENDRE S: LOCAL DRUG DELIVERY IN PERIODONTITIS: AN INNOVATIVE TREATMENT MODALITY. INT J PHARM SCI & RES 2021; 12(9): 4616-25. DOI: 10.13040/IPSR.0975-8232.12(9).4616-25. ALLO 2021 ARE RESERVED BY INTEMATIONAL JOURNAL OF PHARMACEUTICA SCRENCES AND KESEARCH. THIS JOURAL LICENSED UNDER A CREATIVE COMMONS ATTRIBUTION-NON COMMERCIAL -SHAREA NE 3.0 UNPORTED LICENS

62. THANK YOU