Local drug delivery

1. LOCAL DRUG DELIVERY

2. INTRODUCTION
Treatment of
periodontitis
is routinely
based on oral
hygiene, root
debridement,
and risk factor
modification
LOCALIZED
THERAPY
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
The adjunctive use
of locally applied or systemic
administration of antimicrobials
and/or host
response‐modulating
medications has been
proposed.

3. • Chronic periodontitis is a bacterial infection. The focus of almost all
nonsurgical periodontal therapy, including mechanical therapy such
as scaling and root planing (SRP), is directed to combat that infection.
• With regard to chemical antibacterial therapies, a number of
treatment strategies have been considered including systemic
delivery, oral rinses or toothpastes, and irrigating devices.
• As a potential treatment strategy for chronic periodontitis, none of
these therapies ultimately seemed to have resulted in a significant
clinical benefit to reduce signs of periodontitis.

4. There are three basic routes to localized adjunctive
pharmacologic periodontal therapy:
Mouth rinses
(toothpaste
varnishes)
Subgingival
irrigation
Periodontal
application
of local
delivery
systems.

5. RINSES
• Rinses are useful for:
supragingival biofilm control,
modulation of gingival inflammation,
and potentially for recolonization of the
subgingival environment following periodontal
treatment.
LIMITATION: they do not gain access to the subgingival
environment and therefore do not reach the desired
site of action (Pitcher et al. 1980).

6. Irrigation solutions
• 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.

7. • This time can be prolonged by the application of substantive
drugs such as tetracyclines or chlorhexidine that bind to the
root surface and/or the soft tissue wall of the periodontal
pocket and thus establish a drug reservoir that can be slowly
released to counteract the clearance by the GCF flow.
Irrigation solutions
• Limitations on reservoir volume, however, limit the duration
of the possible pharmacologic effect.

8. » W.D. Miller (1880’s) -- the use of an antimicrobial mouthrinse (Listerine)
to aid in fighting what was then known as ‘Pyorrhea alveolaris’.
» Dr. Max GoodSon (1979… championed and developed controlled release
local delivery of therapeutic agents…
HISTORY

9. 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-resistance at non oral body
sites.
(Goodson J., 1994).

12. Based on the application [Rams and Slots] 1996
1. Personally applied (in patient
home self-care )
A. Nonsustained subgingival drug
delivery
Home oral irrigation
Home oral irrigation jet tips
Traditional jet tips
Oral irrigation (water pick)
Soft cone rubber tips (pick
pocket)
B. Sustained subgingival drug
delivery
2. Professionally applied (in
dental office)
A. Nonsustained subgingival drug
delivery
Professional pocket irrigation
B. Sustained subgingival drug
delivery
Controlled release devices
Hollow fibres
Dialysis tubing
Strips
8 Films

13. II Based on the duration of medicament release
(Greenstein and Tonetti 2000)
A. Sustained release devices – Designed to provide drug delivery for
less than 24 hours
B. Controlled release devices – Designed to provide drug release that
at least exceeds 1 day or for at least 3 days following application
III Depending on degradability. (Kornman1993)
1. Nondegradable devices (first generation)
2. Degradable devices (second generation)

14. Based on their mechanism of action (Langer &
Peppas (1988) --
Diffusion controlled systems
Chemically controlled systems
Solvent activated System
Release induced by external forces

15. Solvent activated
system
Osmotic system
Swelling controlled
system
Release induced by
external forces
Magnetically
controlled systems

16. Based on the rate controlling system:
Kornman1993
Reservoir without
rate controlling
system:
hollow fibers filled with a
therapeutic agent in which
the agent is released simply
by diffusion through the
reservoir wall.
Reservoir devices
with rate
controlling system:
solvent action on coated
drug particles, microporous
polymer membrane or
erodable polymeric
matrices.

17. Based on duration of action (Greenstein &
Tonetti 2000)
SUSTAINED RELEASE
DEVICES
Drug delivery for less than 24 hrs require
multiple applications
CONTROLLED DELIVERY
DEVICES
Duration of drug release exceeds 24hrs
administered once

18. Periodontal pharmacokinetics
The action of an intrinsically efficacious drug in a
body site is dependent upon the bioavailability of
free active medication at the desired location; here
specifically the periodontal pocket and the
neighboring soft and hard tissues.

19. • From a pharmacologic standpoint, the
periodontal pocket is a challenging
microenvironment:
• It is characterized by the rapid flow of
GCF, has a small resting volume, and
has an uneven topography.
• Periodontal pockets are uneven in
terms of depth, width, presence of
furcation involvements, composition
and amounts of subgingival biofilm,
and calculus deposits.
• These characteristics translate into
specific difficulties for the design of
periodontal local delivery devices.
Periodontal pharmacokinetics

20. Developmentofperiodontal
localdeliverydevices
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).
• 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.
• A subsequent
clinical study
compared
hollow fibers
left in place for
2 days with
scaling and
root planning
(SRP).
• Microbial and
clinical
parameters
improved, but
less than in the
SRP group
(Lindhe et al.
1979).

21. 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).
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. 1989a, b).

22. • The pivotal trial required for regulatory clearance by the US Food and
Drug Administration (FDA) of 25% tetracycline–HCl ethylene vinyl
acetate fibers was the first multicenter trial in the field of
periodontology to be conducted under stringent quality control and was
a stepping stone towards modern clinical trial design and execution in
dentistry.
(Goodson et al. 1991a, b).

23. 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.

24. 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.
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.

25. 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.

26. 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 general, adjunctive treatment with local delivery devices is favored
when there are relatively few residual pockets and systemic delivery
of the antimicrobial may not be warranted.
• In this respect, local delivery may be advantageous in the
management of local non‐responding sites or disease recurrence
during supportive periodontal care.

27. • 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.
• Lastly, 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.

28. Special patient groups
• 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.
• 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 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).

29. • Older patients as well as those with concomitant self‐reported
cardiovascular disease have also been reported to respond better to
adjunctive local delivery than to mechanical debridement alone.
• Local drug delivery may contribute to better control of periodontitis
in subjects with relative or absolute contraindications to surgical
intervention.
• Lastly, in patients with diabetes and periodontitis, recent randomized
controlled clinical trials have shown benefits in the control of gingival
inflammation and better clinical outcomes from the application of
adjunctive local drug delivery with respect to subgingival
debridement alone (Agarwal et al. 2012).

30. INDICATIONS
1. Isolated periodontal pockets
(>5mm), with successful phase 1
therapy.
2. Periodontal patients who are
medically compromised where
surgical therapy is
contraindicated.
3. In combination with mechanical
debridement.
4. Who are suffering from
recurrent periodontitis.
5. During periodontal regenerative
procedures.
CONTRAINDICATIONS
1. With known Hypersensitivity
reaction to antimicrobials
2. Those requiring multiple
areas of treatment.
3. As replacement or SRP,
replacement for surgical
therapy.
4. Asthmatics, Infective
conditions (AIDS, TB)

31. ADVANTAGES
1. limit drug at the target site.
2. No risk of emergence of
resistant microorganism.
3. Minimizing the exposure of
total body to the drug.
4. Sustained release of
antimicrobial in the
periodontal pockets.
DISADVANTAGES
1. Difficulty in placing into deeper
parts of pockets and furcation
lesions.
2. Patient compliance and manual
dexterity.
3. Time consuming and labour
intensive inpatients with
numerous advanced lesions.
4. Do not markedly affect pathogens
residing on extra-pocket oral
surfaces.
5. Non-sustained drug delivery
provides only a brief exposure of
the target microorganism to the
applied antimicrobial agent.

32. 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 :
(3)
maintenance
of this
concentration
long enough for
the
effect to occur
These three principles – site, concentration, and time – are the key parameters
in the optimization of local pharmacologic treatment (Goodson 1989, 1996).
(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;

33. varnishes
(chlorhexidine),
gels (doxycycline,
metronidazole,
minocycline,
azithromycin),
nonresorbable
polymer fibers
(tetracycline),
gelatin chips
(chlorhexidine;)
ointments
(tetracycline),
and resorbable
polymer
microspheres
(minocycline).
• The drugs investigated for local application include tetracycline,
minocycline, doxycycline, metronidazole, azithromycin, and
chlorhexidine.
• The agents were administered using the following devices:

34. VARIOUS DRUG DELIVERY DEVICES
FIBERS
FILMS
INJECTABLE GELS
STRIPS AND COMPACTS
VESICULAR LIPOSOMAL SYSTEMS
MICROPARTICLE SYSTEM
NANOPARTICLE SYSTEM

35. FIBERS
Hollow- reserviours without rate control
system- drug release--- diffusion.Eg:
tetracycline in hollow fibres of cellulose
acetate. (1979)
monolithic fibres of EVA with 25%
tetracycline HCl.
Fibers, or thread-like devices,
are reservoir-type systems,
placed circumferentially into
the pockets with an
applicator and secured with
an adhesive for the sustained
release of the trapped drug
into the periodontal pocket.
Several polymers… Polyethylene, Polypropylene, Polycaprolactone, Polyurethane,
Cellulose acetate propionate and Ethylene vinyl acetate (EVA) have been investigated as
matrices for LDD.
Eg: Chlorhexidine fibres, tetracycline fibres

36. FILMS
• Films are matrix delivery systems in which drugs are distributed
throughout the polymer and release occurs by drug diffusion and/or
matrix dissolution or erosion.
• Bigger films could be applied within
the cavity onto the cheek mucosa or
gingival surface.
• Both degradable and non- degradable films are available.
Advantages- Could be cut or punched into appropriate sizes so as to be inserted into the
site of action.
Can be easily inserted
Minimal discomfort to the patient
Sufficient adhesiveness is present

37. • Addy et al., (1982) described the film or slab form
intrapocket delivery devices.
• They described the use of slabs of – made of methyl
methacrylate for the intrapocket delivery of
tetracycline, metronidazole, chlorhexidine.
Non
degradable
films
• Periochip
• controlled subgingival delivery of
chlorhexidine
Degradable
devices

38. INJECTABLE SYSTEM
It is relatively simple procedure.
Fluid nature of the formulations would allow the drug to gain access to the entire pocket.
The application can be easily and rapidly carried out, without pain, by using a syringe.
The formulation undergo a change in to a sticky semisolid or solid phase so as to prevent it from
being washed out.
A higher biocompatibility and bioadhesivity, allowing adhesion to the mucosa in the dental pocket.
They can be rapidly eliminated through normal catabolic pathways, decreasing the risk of irritative or
allergic host reactions at the application site.
Eg: gel formulations of tetracycline (2.5%), metronidazole (25%), metronidazole benzoate
(40%), combination of tetracycline (2.5%) and metronidazole benzoate (40%).

39. STRIPS AND COMPACTS
• Acrylic strips have been fabricated using a mixture of polymers,
monomers and different concentrations of antimicrobial agents.
• Strips containing tetracycline, metronidazole or chlorhexidine
demonstrated a decrease in number of motile rods, notably
spirochetes.
• In a later development, the evaluation of amoxycillin-clavulanic acid
loaded acrylic strips is reported.
• Highest level of antibacterial agent was released during the first 24
hours period followed by release of therapeutic level of drugs for a
subsequent 9 days period.
• Effect persisted even after 3 week of removal of acrylic strips.
• Tissue adhesive implants were made using n-butyl-2-cyanoacrylate as
a drug trapping material and slowly release drug when used in the
form of a biodegradable local drug delivery device.

40. VESICULAR SYSTEMS
• Designed to mimic the bio-membranes in terms
of structure and biobehaviour, and hence are
investigated intensively for targeting periodontal biofilms.
• The targeting of liposomes was thought to be because of the interaction of
the polyhydroxy groups of liposomes with surface polymers of the bacterial
glycol-calyx.
• Proteoliposomes (Succinylated Concanavalin-A (lectin)-bearing
liposomes)have been found to be effective for the delivery of triclosan to
periodontal biofilms.
• Studies.. Even after a very short exposure, liposomes were retained in the
bacteria delivering the drug into cellular interiors. (Robinson et al.)

41. MICROPARTICLE SYSTEM
Non-biodegradable and biodegradable materials for the preparation of
microspheres include the polymers of natural origin, modified natural
substances and synthetic polymers.
Biodegradable polymers such as poly lactide (PLA) or poly (lactide – co-
glycolide) PLGA has been designed for periodontal disease therapy.
PLGA microspheres containing minocycline … have been used for the
elimination of Porphyromonas gingivalis from the periodontal pocket.
• .. provide stability to the encapsulated drug.
• The in vitro drug release in these systems depends upon the polymer
(lactide:glycolide) ratio, molecular weight, crystallinity and pH of the
medium

42. NANOPARTICLE SYSTEM
• The nanoparticulate system provides several advantages as
compared with microspheres, microparticles and emulsion-based
delivery systems, including high dispersibility in an aqueous medium,
controlled release rate and increased stability.
• Penetrate regions that may be inaccessible to other delivery systems,
such as the periodontal pocket areas below the gum line.

43. Biocompatible nanoparticles composed of 2-hydroxyethyl methacrylate
(HEMA) and polyethyleneglycol dimethacrylate (PEGDMA) could be used as
a drug delivery system for dental applications.
These systems
• Reduce the frequency of administration and
• Provide a uniform distribution of the active agent over an extended
period of time.

44. a) Antisense oligonucleotide-
loaded chitosan
tripolyphosphate (TPP)
nanoparticles and showed the
sustained release of
oligonucleotides which is
suitable for the local
therapeutic application in
periodontal diseases. (Dung et
al.)
b) An in vivo study in dogs
with induced periodontal
defects using Triclosan-loaded
polymeric (PLGA, PLA and
cellulose acetate phthalate)
nanoparticles and suggested
that triclosan-loaded
nanoparticles penetrate
through the junctional
epithelium. (Pinon et al)
c) the in vitro bactericidal
activity of the Harungana
madagascariensis leaf extract
(HLE) on the oral bacterial
strains largely implicated in
dental caries and gingivitis
infections. Moulari et.
Al.Incorporation of the HLE
into a colloidal carrier
improved its antibacterial
performance and diminution
of the bactericidal
concentration was observed.

45. Commercially Available Products
Tetracycline fibers
(Actisite, Alza Corp.,
Mountain view,
California)
Minocycline ointment
(Dentomycine,
Lederle, UK &
Periocline, Sunstar,
Japan)
Doxycycline hyclate in
a resorbable polymer
(Atridox, Atrix Labs,
CO)
Metronidazole gel
(Elyzol, Dumex,
Copenhagen,
Denmark)
Chlorhexidine Chip
(Perio chip Peno
Products Ltd.,
Jerusalem, Israel)

46. TETRACYCLINE
• Tetracycline is a bacteriostatic antibiotic that interferes with bacterial
protein synthesis and inhibits tissue collagenase activity.
• Agents used commonly are: Tetracycline HCl, Doxycycline HCl,
Minocycline HCl.
• 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.

47. Tetracycline-containing fibers(Actisite)
FDA approved.
• Non resorbable, biologically inert, safe polymer (ethylene vinyl
acetate) loaded with 25% w/w tetracycline HCl powder.
• Packed as flexible yellow fibres of 0.5mm d, 23cm length (2.7 mg
TTC).
• 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.

48. PLACEMENT OF ACTISITE FIBRE

49. • … study in periodontal maintenance patients needing treatment of
localized recurrent periodontitis…Effect of fiber therapy was evaluated as
an adjunct to SRP.
• Results – sites treated with fiber and SRP showed significantly higher
attachment level, pocket depth reduction and less BOP (Newman et al
(1994)
• In a 60-day multicenter study - 107 periodontitis patients after
supragingival scaling,…
• Four non-adjacent teeth (pockets in the range of 6-10mm) was
selected and randomly assigned to 4 groups-
• Tetracycline fiber, Placebo fiber, Scaling and Untreated.
• Results-fiber therapy significantly had reduction in probing depth,
BOP,and gain in attachment levels. Goodson et al )

50. Other forms:
Bioresorbable form is PERIODONTAL PLUS AB formulation containing
TTC (2 mg of Tetracycline) in 25 mg of collagen fibrils.
dual mode of action by…...
enables the active agent and vehicle to be able to work positively
towards the repair of the periodontal lesion.
Each vial contains 25 mg (Total 100 mg in 4 vials)

51. Tetracycline-Serratiopeptidase-
Containing Periodontal Gel
• Study- - Serratiopeptidase tetra gel with aerosol (colloidal silica) used.
• ….Aimed to decrease polymer concentration and to obtain reasonable
vicocity at a lower concentration of pluronic gel by adding a viscocity
modifier.
• Results…- Formulation has shown statistically significant results along
with scaling and root planing(Maheshwa ri etal)

53. SUBGINGIVAL DOXYCYCLINE
• Broad-spectrum antibiotic
• Bacteriostatic, inhibiting bacterial protein synthesis
• Ability to downregulate MMPs.
• The only FDA approved 10% Doxycycline – ATRIDOX gel (42.5 mg
Doxycycline)

54. Subgingival controlled-release product composed of a
2 syringe mixing system
• Syringe A -- 450 mg of the ATRIGEL® Delivery System, which is a
bioabsorbable, flowable polymeric formulation.
• Syringe B- doxycycline hyclate which is equivalent to 42.5 mg
doxycycline.

55. • The constituted product is a pale yellow to yellow viscous liquid with
a concentration of 10% of doxycycline hyclate.
• Upon contact with the crevicular fluid, the liquid product solidifies
and quickly hardens to a waxlike substance, then allows for
controlled release of drug for a period of 7 days.

58. SUBGINGIVAL MINOCYCLINE
Semisynthetic tetracycline - first introduced in 1967
• In vitro antibacterial activity against a wide range of gram-ve and
gram+ve microorganisms
• LDD minocycline -- tried clinically via in three different modes i.e.
film, microspheres, and ointment.
1. Film:
• Ethyl cellulose film containing 30% of Minocycline were tested as
sustained release
• complete eradication of pathogenic flora from the pocket after 14
days.

59. MICROSPHERE
• Locally delivered, sustained release form of minocycline microspheres
(ARESTIN) for subgingival placement is available.
• Arestin-- 2% minocycline 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.

60. Electron photomicrograph
and CS view of microsphere
showing minocycline
HCL particles
The microspheres is dispensed subgingivally to
the base of the periodontal pocket by means of a
disposable plastic cartridge affixed to a
stainless-steel handle .

61. OINTMENT
• 2% minocycline hydrochloride in a matrix of hydroxyethyl-cellulose,
aminoalkyl-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.

62. The Dentomycin gel has been reported to be effective in periodontal
disease because of:
• Its power to eliminate key periodontal pathogens.
• Minimal risk of bacterial resistance.
• Inhibits harmful bacterial collagenase without effecting normal
collagen turnover and regeneration of gingival tissues.

64. SUBGINGIVAL 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.
• Metronidazole has been incorporated as collagen sponges, dialysis
tubing, acrylic strips, films and gel forms for sustained subgingival delivery
in the treatment of periodontal disease.

65. ELYZOL
• Metronidazole 25% in a mixture of glyceryl mono-oleate and sesame oil.
Contains metronidazole benzoate- active agent.
• flows freely on application.. on contact with gingival crevicular fluid,
becomes more viscous and stays in the periodontal pocket… gel disintegrates
in the pocket and releases metronidazole..for at least 24 hours.
• Can be administered quickly and easily and high periodontal pocket levels of
metronidazole are maintained.
• Administered twice- with an interval of one week.

67. CHLORHEXIDINE
• Available as 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.

68. • Chlorhexidine has been shown to be an effective agent in plaque
inhibition (Loe et al 1976)as…
• well retained in the oral cavity.
• Reacting reversibly with receptors in the mouth due to its affinity for
hydroxyapetite and acidic salivary protein.
• Its antibacterial action is due to an increase of the cellular membrane
permeability followed by the coagulation of intracellular cytoplasmic
macromolecule

69. PERIOCHIP
• Small chip (4.5× 3.5mm) composed of biodegradable hydrolyzed
gelatin matrix, crosslinked with glutaraldehyde, also contains glycerine
&water into which chlorhexidine gluconate (2.5mg) 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.

70. • Unique patented “targeted controlled release” bio degradable
polymer containing chlorhexidine.
• Small, bullet-shaped or baby’s finger nail like thin film, weighing
7.4mg.

71. 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.

72. Chlo-Site
• 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.

74. • Meta-analysis on four studies including SRP and local sustained
release agents compared with SRP alone….
• Compared with SRP alone, no evidence was found for the adjunctive
effects on reduction of PI with
ATRIDOX and MINO microspheres. BOP reductions were not significant
with ATRIDOX and TET fibres.
• large effect of adjunctive therapy in pocket depth reduction, with a
moderate effect on reduction of bleeding scores and mild effect on
reduction of plaque scores.

75. NEWER TRENDS IN LOCAL DRUG DELIVERY-DRUGS
FOR OSSEOUS DEFECTS
Alendronate
• - a novel bisphosphonate; 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, CAL gain, and
improved bone fill (Anuj Sharma et al, 2011)
Statins– Simvastatin, Atorvastatin, Rosuvastatin –
• Lipid lowering drugs-- an effective approach for the treatment of
hyperlipidemia and arteriosclerosis.
• Statins are specific competitive inhibitors of HMG-CoA reductase.
• modulate bone formation by increasing the expression of bone
morphogenetic protein-2, inflammation, and angiogenesis.

77. Metformin
• --effectiveness of MF 1% in an indigenously prepared, biodegradable,
controlled-release gel, as an adjunct to scaling and root planing (SRP)
in treatment of vertical defects in smokers with generalized chronic
periodontitis (CP) was investigated….greater decrease in mSBI and PD
and more CAL gain with significant IBD fill at vertical defect sites
treated with SRP plus locally delivered MF, versus SRP plus placebo, in
smokers with generalized CP. (Rao. NS et al, 2013)

78. Satranidazole
• Study.. effectiveness of subgingivally delivered satranidazole (SZ) gel
as an adjunct to scaling and root planing (SRP) in the treatment of
chronic periodontitis.
• Results….greater mean reduction of PD, mean CAL gain and number
of sites harbouring periodontopathogens….
• The use of 3% SZ gel, when used as an adjunct to nonsurgical
periodontal therapy in subjects with periodontitis, achieved better
results than initial periodontal treatment alone.(N Priyanka, 2015)

79. Clarithromycin gel
• Clarithromycin has been used in periodontal treatment as an adjunct
to SRP in gel form as LDD.
• Study-- investigate the adjunctive effects of subgingivally delivered
0.5% clarithromycin (CLM) as an adjunct to scaling and root planing
for treating chronic periodontitis in smokers.
• Adjunctive use of 0.5% clarithromycin as a controlled drug delivery
system …enhanced the clinical outcome in smokers (Agarwal E etal,
2012.).

80. HERBAL PRODUCTS FOR PERIODONTITIS
Eucalyptus
Extract
Neem Leaf Bloodroot Chamomile
Liquorice Propolis Aloevera

81. Eucalyptus extract Ethanol extracts (60% ethanol) from
Euclyptus globulus leaves reportedly possess antibacterial
activity against various bacteria, including oral bacteria.
• displayed antibacterial activity against several
periodontopathic bacteria, (Porphyromonas gingivalis and
Prevotella intermedia)
The growth of P. gingivalis was strongly inhibited even with
a low concentration (10 mg/ml) of eucalyptus extracts.
Neem Neem leaf extract can help reduce bacteria and
plaque levels that cause the progression of periodontitis.
bioactive materials found in neem leads to the presence of
gallotannins during the early stages of plaque formation
that could effectively reduce the number of bacteria
available for binding to the tooth surface by increasing their
physical removal from the oral cavity through aggregate
formation. potential anti-plaque activity -- reduced bacterial
adhesion to saliva coated hydroxyapetite.

82. Bloodroot Sanguinaria canadensis (bloodroot) --
herbaceous flowering plant native to eastern North
America.The FDA has approved the inclusion of
sanguinarine in toothpastes as an antibacterial or anti-
plaque agent. Due to its natural alkaloids, bloodroot
can curb the growth of bacteria responsible for
periodontal disease.reduce inflammation and prevent
deepening of periodontal pockets, thereby preventing
bone loss & tooth loss.(Reddy PD, 2010)
Chamomile (Matricaria Recutita)an age-old medicinal
herb known in ancient Egypt, Greece and which are a
member of the Asteraceae family. With its anti-
inflammatory and antibacterial properties, chamomile
helps in reducing the inflammation in periodontal
tissues and reduces the bacterial load in the oral cavity.
(Reddy PD,Chopra RN et al)

83. LiquoriceLiquorice (Glycyrrhiza glabra),-- sweet wood (native to
the Mediterranean and certain areas of Asia). a perennial herb
with sweet taste; widespread pharmacological
effects.)antioxidant and hepatoprotective properties… inhibit
the generation of reactive oxygen species (ROS) by neutrophils
at the site of inflammation. (Racková L) The ability of liquorice to
reduce formation of dental plaque contributes to its role in
periodontitis management
Propolis generic name for a complex resinous mixture collected
by honey bee from the buds and exudates of various plants used
for the treatment of aphthous ulcer, Candidiasis, gingivitis,
periodontitis, and pulpitis due to its antimicrobial and anti-
inflammatory activities.Studies have evaluated the antibacterial
action of propolis against certain anaerobic oral pathogens and
found it to be very effective against Peptostreptococcus
anaerobius, Lactobacillus acidophilus, Actinomyces naeslundii,
;Prevotella sp., Porphyromonas gingivalis, Fusobacterium
nucleatum and Veillonella parvula. (Gebara EC)

84. • A study was aimed at the clinical and microbiological evaluation of the efficacy of
subgingivally delivered Indian propolis extract as an adjunct to scaling and root
planing (SRP) in the treatment of periodontitis.
• Twenty patients diagnosed with chronic periodontitis presenting a minimum of
two pockets (probing depth ≥5 mm) were selected.
• Sites were assigned randomly into control sites (n=20) which received SRP alone or
test sites (n=20) which received SRP and locally delivered propolis. At selected
sites, the clinical parameters were assessed and subgingival plaque samples were
collected at baseline, 15 days and one month.
• The samples were cultured 76 anerobically for periodontal pathogens.
• The results indicated that there was a significant improvement in both clinical and
microbiological parameters (p<0.01) in the test sites compared to the control sites
at the end of the study.
• Subgingival delivery of propolis showed promising results as an adjunct to SRP in
patients with chronic periodontitis when assessed by clinical and microbiological
parameters.

85. STUDIES:
• Aim : To evaluate the effect of aloe vera gel as an adjunct to scaling and root planing (SRP) in the
management of chronic periodontitis.
• SRP-ALOE group showed significantly better results than SRP alone. (Harjit Kaur ,2012)
• Geeta Bhat et al, 2011) 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.
ALOE VERA-The medicinal value of the plant lies in a
gel-like pulp obtained on peeling the leaves. These
substances include …. Lignins, Saponins, Vitamins,
aminoacids, anthraquinones etc.. improves wound
healing by Increasing blood supply, which increased
oxygenation as a result.potent free radical and
superoxide anion scavenging properties. (Yagi et al.
in 2002 )

86. STUDIES:
The experimental local drug-delivery system containing 2% whole turmeric gel can be effectively
used as an adjunct to scaling and root planing and is more effective than scaling and root planing
alone in the treatment of periodontal pockets. (Roobal Behal et al. 2011)
TURMERIC-It has proven properties like Anti-inflammatory,
antioxidant, antimicrobial, hepatoprotective, antiseptic,
accelerates wound healing.study … evaluate the adjunctive
efficacy of turmeric, curcumin, and traditional nonsurgical
methods for treating periodontal pockets.Plaque index and
gingival index scores showed significant improvement from
baseline through the end of the study. Kudva P et al,2012

87. POMEGRANATE-A clinical study conducted by Sastracaha
et al (2003) concluded that extracts of Punica granatum
plus scaling and root planning significantly reduced the
clinical signs of chronic periodontitis. Vasconcelos et al
(2006) investigated the antimicrobial effect of Punica
granatum Linn (pomegranate) phytotherapeutic gel and
concluded that Punica granatum L. gel had greater
efficiency in inhibiting microbial adherence in oral cavity.
HERBAL COMBINATIONS
• Along with individual herbs, herbal combinations can combat periodontitis.
• Mixture of peppermint oil, menthol, chamomile, clove oil.. can reduce
periodontitis symptoms.
World Journal of Pharmaceutical Research Vol 3, Issue 2, 2014.

88. LOCAL DELIVERY OF GROWTH FACTORS
• Fibroblast growth factor was found to 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.(Nakahara T et al.2003)

89. NOVEL CHITOSAN-PVA-BASED LOCAL DELIVERY
• Chitosan is a natural polysaccharide.
• ..physically or chemically crosslinked to prepare microspheres, films
and gels.
• These stable chitosan-based depot systems have been investigated
for treatment of various diseases including cancer and bacterial
infection.
• Localized drug delivery system with chitosan and poly vinyl alcohol
(PVA) for treating severe periodontitis has been designed that
delivered antibacterial agent ornidazole into gingival crevicular fluid.
(Wang LC etal) …

90. SUMMARY
• As a monotherapy, LDD 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.
• LDD often appears to be as effective as scaling and root planing with
regards to reducing signs of periodontal inflammatory disease.
• Local delivery may be an adjunct to 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 o instrument root surfaces.

91. CONCLUSION

92. THANK YOU