Local drug delivery system

CONTENTS
• Introduction
• Historical perspective
• Terminology
• Objectives
• Indications
• Contraindications
• Advantages
• Disadvantages
• Systemic Versus Local Drug Delivery
• Requirements For Local Antimicrobial Agents
• Factors Affecting the Bio-availability of an antimicrobial agent
• Classification of local antimicrobial therapy in periodontics
• Drug delivery systems
• 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
• Future trends
• Conclusion 3

addition of antimicrobials (systemic and local)
adjuncts to mechanical therapy.
5
Systemic
antimicrobial
agents
Adverse
effects
Local drug
deliveries

HISTORICAL PERSPECTIVE:
 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’.
 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, efficacy to side effects.
 Dr. Max GoodSon (1979) first proposed the concept of
controlled release local delivery of therapeutic agents for
the treatment of periodontitis.
6

TERMINOLOGY:
• Antimicrobial agents are chemotherapeutic agents that reduce
the amount of bacteria present either by superficially targeting
certain organisms or by nonspecifically reducing all bacteria.
• Targeted drug delivery: refers to delivery of medication to a
patient in a manner that increases the concentration of the
medication in some parts of the body relative to others.
• Local delivery of antimicrobial agents in
periodontics Implies antimicrobial therapy placed directly in the
subgingival region. The term local delivery is usually used to
suggest more specific or targeted delivery of an agent.
• Non-sustained subgingival drug delivery Provides high
pocket concentrations of the antimicrobial agent for only short
time periods. 7

• 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.
8

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.
9

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 such as various broad spectrum
antiseptic solutions e.g. chlorhexidine.
• 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.
• Local antimicrobial delivery reduces the dangers associated
with systemic administration such as toxicity, adverse
reactions, resistant strains and superimposed infections. 10

INDICATIONS:
• Isolated periodontal pockets (>5mm), with successful phase I
therapy.
• Periodontal patients who are medically compromised where
surgical therapy is contraindicated.
• In combination with mechanical debridement or alone.
• In patients who are suffering from recurrent or refractory
periodontitis.
• During periodontal regenerative procedures.
• Where periodontal surgery is to be avoided or the patient is
on supportive periodontal treatment.
11

DISADVANTAGES:
• Difficulty in placing antimicrobial agents into deeper parts
of pockets and furcation lesions.
• Patient compliance and manual dexterity.
• Time consuming in patients with numerous advanced
lesions.
• Do not markedly affect pathogens residing on other oral
surfaces.
• Non-sustained drug delivery provides only a brief
exposure of the target microorganism to the applied
antimicrobial agent.
12

Systemic Local
1. Route of administration
2. Pain/Discomfort
3. Drug dosage
4. Peak levels
5. Pharmacokinetics
6. Frequency
7. Super infection
8. Microbial resistance
Oral or Parental
Not painful
Higher drug dosage
(in mg)
Few hours in plasma
Distribution in various
compartments where
antimicrobial effect may
not be required.
Once in 6-12 hours
Present
Present
Site Specific
Nil
Lower dosage
(in micrograms)
Within few minutes in GCF
Minimal body distribution
to different compartments
with maximum concentration
at delivered sites.
Usually once a week
Limited
Limited
13

Systemic Local
9.Patients compliance
10.Time required
11. Side effects
12. Effects on connective
tissue associated
plaque
Required for better
efficacy
Less time
More
Effective
Patient delivered -
compliance required
Professional Delivered -
not required
Longer time if many sites
are involved
Limited
Limited
14

REQUIREMENTS FOR LOCAL ANTIMICROBIAL AGENTS
• Safety
• Stability
• Substantivity
• Efficacy
• Adequate subgingival delivery
• Achievement of effective concentrations
• Biodegradable
• Retention after placement
• No emergence of bacterial resistance
• Should be effective only against periodontal pathogens
and not on commensal microflora.
• Cost-effectiveness and patient compliance.
15

CLASSIFICATION OF LOCAL ANTIMICROBIAL
THERAPY IN PERIODONTICS
LANGER AND PEPPAS (1988)
- 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 16

2. RAMS AND SLOTS (1996)
- depending on usage
I. PERSONALLY APPLIED
by patient at home (self-care)
A. NON-SUSTAINED SUBGINGIVAL DRUG DELIVERY
Home oral irrigation
Home oral irrigation devices:
 Devices with traditional jet tips
 Oral irrigator
 Soft cone-rubber tips
 Blunt tipped metal cannula connected to syringe or
oral irrigator
B.SUSTAINED SUBGINGIVAL DRUG DELIVERY
(none developed to date)
20

II. PROFESSIONALLY APPLIED (In dental office)
A. NON-SUSTAINED SUBGINGIVAL DRUG
DELIVERY
Professional pocket irrigation devices :
 Syringe with blunt end needle
 Blunt-tipped cannula attached to oral irrigator
 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 21

Fibers
• Fibers, or thread-like devices, are reservoir-type systems, placed
circumferentially into the pockets with an applicator and secured
with cyanoacrylate adhesive for the sustained release of the
trapped drug into the periodontal pocket.
• Several polymers such as
– poly(ecaprolactone) (PCL),
– polyurethane,
– polypropylene,
– cellulose acetate propionate and
– ethyl vinyl acetate (EVA)
have been investigated as
matrices for the delivery of drug
to the periodontal pocket.
• Examples are Chlorhexidine fibers and tetracycline fibers. 22

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.
• Film is prepared either by solvent casting or direct milling.
23

• Bigger films either could be
applied within the cavity
onto the cheek mucosa or
gingival surface or could be
cut or punched into
appropriate sizes so as to
be inserted into the site of
action.
24

• Sustained release devices composed of cross-linked fish
gelatin (bycoprotein) containing chlorhexidine diacetate or
chlorhexidine hydrochloride have been developed by
Steinberg.
• Films based on synthetic biodegradable polymers such as
poly (lactide-co-glycolide) (PLGA) containing tetracycline
have been developed for modulated-release of drug in the
periodontal pocket as slab like device.
25

Injectable System
• The application can be easily and
rapidly carried out, without pain,
by using a syringe.
• Thus, the cost of the therapy is
considerably reduced compared
to devices that need time to be
placed and secured.
• Moreover, an injectable delivery
system should be able to fill the
pocket, thus reaching a large
proportion of pathogens.
26

Gels
• Mucoadhesive, metronidazole (MTZ) containing gel
systems based on hydroxyethyl cellulose, corbopol 974,
and polycarbophil have been made.
• Gel is applied sublingually with the help of blunt cannula
and syringe.
• Locally applied controlled release DOX gel may partly
counteract the negative effect of smoking on periodontal
healing following no surgical therapy.
27

• Tetracycline containing copolymer gels represents a safe
and effective bioerodible therapy for periodontitis due to
 Safety profile,
 Longer-term retention,
 Antimicrobial activity.
• Comparative analysis of tetracycline containing dental gels:
poloxamer and monoglyceride based formulations have
been done which shows that poloxamer and monoglyceride
gels, when applied subgingivally, produce a significant
improved outcome in moderate to deep periodontal
pockets.
28

Injectable Gels
• Gels can be more easily prepared and administered.
• Moreover, they possess
 A higher biocompatibility and bioadhesivity, allowing adhesion to the
mucosa in the dental pocket and, finally,
 They can be rapidly eliminated through normal catabolic pathways,
decreasing the risk of irritative or allergic host reactions at the
application site.
29

• Various oleogels and hydrogels for the delivery of
tetracycline (2.5%), metronidazole (25%), metronidazole
benzoate (40%), as well as a combination of tetracycline
(2.5%) and metronidazole benzoate (40%), have been
tested and satisfactory results have been achieved.
30

Strips and Compacts
• Acrylic strips have been fabricated using a mixture of
polymers, monomers and different concentrations of
antimicrobial agents.
• Strips were fabricated either by solvent casting or pressure
melt method.
• 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.
31

• 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 structure of a
biodegradable local drug delivery device.
32

Vesicular Systems
• Vesicular liposomal systems are designed to mimic the bio-
membranes in terms of structure and biobehaviour, and hence
are investigated intensively for targeting periodontal biofilms.
33

• 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.
• Succinylated Concanavalin-A (lectin)-bearing liposomes
(proteoliposomes) have been found to be effective for the
delivery of triclosan to periodontal biofilms.
• In vitro and in vivo studies have revealed that, even after
a very short exposure, the proteoliposomes are retained
by the bacteria eventually delivering triclosan into the
cellular interiors.
34

Microparticle System
• Microparticles based system of biodegradable poly alpha
hydroxy acids such as poly lactide (PLA) or poly (lactide –
co-glycolide) PLGA containing tetracycline has been
designed for periodontal disease therapy.
• PLGA microspheres containing minocycline have been
formulated and have been used for the elimination of
Porphyromonas gingivalis from the periodontal pocket .
35

• Microparticles of poly (dl-lactic-coglycolic acid) (PLGA)
containing chlorhexidine free base, chlorhexidine di
gluconate and their association or inclusion complex with
methylated-beta-cyclodextrin (HPBCD) were prepared
with single emulsion, solvent evaporation technique.
• Non-biodegradable as well as biodegradable materials for
the preparation of microspheres include the polymers of
natural origin, modified natural substances and synthetic
polymers.
36

• They could preferably be formulated as a chip or could be
part of a dental paste formulation, or otherwise be
directly injected into the periodontal cavity.
• Tetracycline-containing microcapsules in Pluronic F127
were reported to form gel at body temperature and hold
the microcapsules in the periodontal pocket for the
duration of treatment.
37

• PLGA microcapsules and microspheres have been proposed
for the delivery of tetracycline and histatins.
• These microparticulate systems provide stability to the
encapsulated drug.
• The in vitro drug release from such systems depends upon
the polymer (lactide:glycolide) ratio, molecular weight,
crystallinity and pH of the medium.
38

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.
• Nanoparticles, owing to their small size, penetrate regions
that may be inaccessible to other delivery systems, such
as the periodontal pocket areas below the gum line.
39

• These systems
 Reduce the frequency of administration and
 Provide a uniform distribution of the active agent over an extended
period of time.
• Biocompatible nanoparticles composed of 2-hydroxyethyl
methacrylate (HEMA) and polyethyleneglycol
dimethacrylate (PEGDMA) could be used as a drug delivery
system for dental applications.
40

• Three preliminary studies have been conducted to assess
the efficacy of nanoparticles in periodontal drug delivery.
a) Dung et al used 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.
b) Pinon et al conducted a preliminary 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.
41

c) Moulari et. al, investigated 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.
HLE-loaded PLGA nanoparticles were prepared using
interfacial polymer deposition following the solvent
diffusion method.
Incorporation of the HLE into a colloidal carrier improved its
antibacterial performance and diminution of the
bactericidal concentration was observed.
42

Some of the recently developed drug
delivery vehicles are briefed here :
• Nanomaterials
• Nanoparticles
• Lipid core micelles and polymeric micelles
• Liposomes
• Nanowires
• Nanoshells
• Nanotubes
• Nanobots
• Nanoneedles
• Nanorods
• Nanocantilevers
43

• Nanopores
• Bucky balls (Fullerene)
• Gold Nanoparticles
• Quantum Dots
• Nanorobots
• Dendrimers
• Hydrogels
• Colloidosomes
• Thin film drug delivery vehicles
• Fast dissolving tablet
• Implantable drug delivery vehicles
• Controlled release formulations
• Drug loaded erythrocytes
• Self-emulsifying drug delivery systems
44

TETRACYCLINE
• The tetracyclines were introduced into clinical practice in
the late 1940s.
• They are primarily bacteriostatic agents that are
effective against many Gram negative species including
putative pathogens such as Aggregatibacter
actinomycetemcomitans.
• They interfere with bacterial protein synthesis and also
inhibit tissue collagenase activity.
45

• Tetracyclines are used extensively in the management of
periodontal diseases and the agents used commonly are
• Tetracycline HCl,
• Doxycycline HCl,
• Minocycline HCl.
• Tetracycline solutions also exhibited high substantivity in
the periodontal environment.
 This property could be related to the formation of less soluble
calcium-tetracycline complexes as a result of partial dissolution of
the hydroxyapatite of cementum or dentin at lower pH levels.
46
•Exhibit greater oral absorption,
•Have more prolonged half-lives, and
•Show enhanced lipid solubility,
Which is important for their antibacterial action.

• Most of the subgingival microorganisms are susceptible to
tetracycline at a minimum inhibitory concentration (MIC)
of ≤ 1-2 µg/ml.
• However, species such as Eikenella corrodens, Prevotella
oralis, Selenomonas sputigena and some strains of
Campylobacter and Veillonella exhibited intrinsic
tetracycline resistance (MIC ≥ 16 µg/ml)
47

Actisite (US ; Switzerland )
• The first delivery devices involved hollow fibers of
cellulose acetate filled with tetracycline.
• These are non-resorbable biologically inert, generally
considered as safe, plastic copolymer (ethylene and vinyl-
acetate) loaded with 25% w/w tetracycline HCl powder
packaged as a thread of 0.5 mm in diameter and 23 cm in
length.
• Fiber is packed into pocket and secured with a thin layer
of cyanoacrylate adhesive, left in place for 7-12 days.
48

• Recently bioresorbable tetracycline fiber has been
developed with base of collagen film, which is commercially
available as PERIODONTAL PLUS AB.
• It offers the advantage of no second appointment for
removal as it biodegrades within 7 days.
51

Tetracycline
fiber
Systemic
adm
GCF
Conc
1590 µg/ml 4-8 µg/ml
Serum
conc
0.4 µg/ml 2-4 µg/ml
52

Gel
• Tetracycline-Serratiopeptidase-Containing Periodontal Gel
Formulation has shown statistically significant results
along with scaling and root planing.
• Bioerodible Injectable Poly (ortho ester) for Tetracycline
Controlled Delivery formulations loaded with tetracycline
10% or 20% showed complete in vitro degradation
concomitant with drug release.
53

• In a 60-day multicenter study - 107 periodontitis patients
after supragingival scaling, (Goodson et al 1991)
 Four non-adjacent teeth with pockets in the range of 6-
10mm was selected
 Randomly assigned to-
Tetracycline fiber
Placebo fiber
Scaling
Untreated
Analysis: fiber therapy significantly had
Probing depth, BOP
Attachment levels
54

• Newman et al (1994)
• Conducted a 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.
55

MINOCYCLINE
• Semisynthetic tetracycline - was first introduced in
1967
• Minocycline hydrochloride has in vitro antibacterial
activity against a wide range of gram-ve and gram+ve
microorganisms thought to be related to periodontal
disease.
• Local delivery of minocycline has been tried clinically
via three different modes i.e. film, microspheres, and
ointment.
56

Film
• Ethyl cellulose film containing 30% of Minocycline were
tested as sustained release devices.
• The results indicated that the use of this device may
cause complete eradication of pathogenic flora from the
pocket after 14 days.
57

Microsphere
• The FDA recently approved a new, locally delivered,
sustained release form of minocycline microspheres
(ARESTIN) for subgingival placement.
• The 2% minocycline is encapsulated into bioresorbable
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.
58

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
An electron photomicrograph
of the minocycline
microspheres, and a
photomicrograph of the
microspheres in cross-
section.
59

• Williams et al 2001 – multicenter trial
-748 pts with moderate to advanced
periodontitis
• Locally administered microencapsulated
spheres of minocycline.
• Results – test sites showed significantly
more PD reduction than either SRP
alone.
61

Ointment
• Minocycline ointment is a bioabsorbable sustained delivery
system consisting of 2% minocycline hydrochloride in a
matrix of hydroxyethyl-cellulose, aminoalkyl-methacrylate,
triacetine and glycerine.
• Dentomycin (2% Minocycline gel) has received regulatory
approval for the treatment of periodontitis in the
European Union.
• The same product is available in Japan with the name
Periocline.
62

• 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.
• It has shown that the combination of ointment with scaling
and root planing was significantly better than scaling and
root planing alone in pockets > 7mm.
63

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

• Van Steenberghe et al.1993 –
randomized double-blind study - 103 adults
with moderate to severe periodontitis
• SRP done at baseline
• Patients received either the test or a control
minocycline ointment in four sessions at an
interval of 4 weeks
• Assessment – a significantly greater
reduction of PD in test group.
65

DOXYCYCLINE
• Doxycycline is a broad-spectrum semi synthetic
tetracycline.
• Doxycycline is bacteriostatic, inhibiting bacterial
protein synthesis due to disruption of transfer RNA
and messenger RNA at ribosomal sites.
• In vitro testing has shown that Porphyromonas
gingivalis, Prevotella intermedia, Campylobacter
rectus, and Fusobacterium nucleatum, which are
associated with periodontal disease, are susceptible
to doxycycline at concentrations of 6.0 µg/ml.
66

• Doxycycline has the ability to downregulate MMP’s a family
of zinc dependent enzymes that are capable of degrading a
variety extracellular matrix molecules including collagens.
• Such activity relates to the drug's ability to bind
with calcium and zinc ions.
67

Biodegradable formulation contains:
• 10% by weight Doxycycline
• 33% by weight poly (DL- lactide)
• 57% by weight NMP (N-methyl-2-
pyrrolidone)
68

The ATRIDOX® product(US) is a subgingival controlled-
release product composed of a 2 syringe mixing system.
69
Syringe A contains 450 mg of the
ATRIGEL® Delivery System, which is a
bioabsorbable, flowable polymeric
formulation composed of 36.7% poly (DL-
lactide) dissolved in 63.3% N-methyl-2-
pyrrolidone

70
Syringe B contains doxycycline
hyclate which is equivalent to 42.5
mg doxycycline.

The constituted product is a pale yellow to yellow viscous
liquid with a concentration of 10% of doxycycline hyclate
71

Upon contact with the crevicular fluid, the liquid product solidifies
and quickly hardens to a wax-like substance, then allows for
controlled release of drug for a period of 7 days
72

Doxycycline levels in GCF Time
1,500 - 2000 μg/mL 2 hours
> 1000 μg/mL 18 hours
Well above the minimum inhibitory
concentration for
periodontal pathogens (6.0 μg/mL)
Day 7
95% of the polymer is bio absorbed
or expelled from the pocket
naturally
Day 28
73

• Garrett et al 1999, 2000 – 411 pts with moderate to
severe adult periodontitis.
• Atridox was compared to placebo control and oral
hygiene and SRP.
• Result : Treatment to be statistically superior to
placebo control and oral hygiene and equally effective
as SRP.
74

CHLORHEXIDINE
• Chlorhexidine gluconate is an antimicrobial agent
active against a wide spectrum of gram-positive and
gram-negative organisms, yeast, fungi, facultative
anaerobes and aerobes.
• In 1970, Loe and Schiott reported 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.
 In order to affect the subgingival microbiota,
sustained release devices (SRD) were developed.
Such devices used ethylcellulose and polyethylene
glycol as polymers and chlorhexidine as solvent.
75

• Its mechanism of action relates to
 Reduction in pellicle formation,
 Alteration of bacterial adherence to teeth, and
 An alteration of bacterial cell walls, causing lysis.
• Its antibacterial action is due to an increase of the cellular
membrane permeability, followed by the coagulation of
intracellular cytoplasmic macromolecules.
• Because chlorhexidine is highly cationic, it exhibits high
substantivity.
• Its chemical structure allows it to remain in the oral cavity
for a prolonged period after a single rinse and thereby
function in a slow release type manner.
76

PERIO-CHIP
 Unique patented “targeted
controlled release” bio
degradable polymer containing
chlorhexidine (Israel).
 Small, bullet-shaped or baby’s
finger nail like thin film,
weighing 7.4mg.
 Measures 5x4 mm in size and
0.35 mm thickness.
 The chip contains 2.5 mg
chlorhexidine gluconate
incorporated in a
biodegradable matrix of
cross-linked hydrolyzed
gelatin.
77

Advantages of the Perio-chip
• Very easy and convenient to use. Takes seconds to place in
any pocket.
• Highly effective, safe and well tolerated. Painless to the
patient. In some instances there may be minor discomfort
in the first 24 hrs.
• No restrictions on eating or oral hygiene after chip
insertion.
• All quadrants 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 - 125µg/ml ( Soskolne 1997).
• Delivers effective dosage even to the base of the pocket.
• Reduces amount of pathogenic bacteria up to 100 days –
99% of subgingival microflora( Soskolne 1990).
79

• Soskolne et al 1997, Jeffcoat et al
1998 – split mouth design to compare
the treatment outcomes of SRP alone
with the combined use of SRP &
PerioChip in pocket depth of 5-8mm.
• Results – average PD reduction in
treated sites with chip was significantly
greater than in the sites receiving
mechanical treatment only.
80

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.
• It has been shown to resorb after 30 days; however their
coronal edge degrades within 10 days.
81

Chlo-Site
• Chlo-Site is an agent containing 1.5% chlorhexidine of
xanthan type (Ghimas Company, Italy).
• Xanthan gel is a saccharide polymer, which constitutes of a
three-dimensional mesh mechanism, which is biocompatible
with chlorhexidine.
• The gel gets vanished from the pocket within l0-30 days
of injection and effective concentration of chlorhexidine
against microorganisms is established for at least 15 days
in the region.
82

• Both chlorhexidine and gel matrix are mucoadhesive so
that they stick inside the pockets and are not easily
washed out by gingival fluid or saliva.
• It degrades spontaneously at the site of application, is
well tolerated and is efficient in treatment of periodontal
pockets & periimplantitis.
83

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.
• In the recent past, 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.
84

METROGENE (SEPTODENT, FRANCE)
• It is a new combination of two known substances;
bovine collagen (Type I) sponges 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).
85

Elyzol (Copenhagen, Denmark)
• Metronidazole benzoate 25% in a mixture of glyceryl
mono-oleate and sesame oil.
• The gel disintegrates in the pocket and releases
Metronidazole.
• Estimated dose of Metronidazole per treated tooth
was 3mg and drug concentration in GCF after one day
was 1g/ml.
86

• Ainamo et al 1992 – two randomly selected
quadrants were treated with the gel twice a week;
other two – 2 episodes of subgingival scaling.
• Differences were considered insignificant by the
authors.
• Using similar design, the microbiological outcome of 2
gel applications Vs scaling was compared by Pedrazolli
et al 1992 (6-month period).
• Total bacterial cultivable count and proportions of
anaerobic bacteria were affected in a similar way in
both groups, and no difference was seen in PD
reduction & BOP.
87

• Grossi et al 1995 – 164 pts
no significant difference between metronidazol gel
application and SRP
 Opened the question of equivalence between the two
treatment modalities.
 From a practical standpoint, one form of treatment
may be preferred to another of equal efficacy if it
offers better tolerability for the patient or lower
costs.
88

Sanguinarine
• Sanguinarine, a benzophenanthridine alkaloid with a wide-
spectrum antiseptic activity in vitro, was obtained from
the bloodroot plant (Sanguinaria canadensis).
• Short-term studies have shown some plaque and gingivitis
reduction.
• However, the results of long-term studies are conflicting:
some showed no reduction in plaque or gingivitis, whereas
others demonstrated a significant reduction when patients
used both mouth-rinse and dentifrice forms.
89

• The proposed mechanism of action is an alteration of the
bacterial wall, so that aggregation and attachment are
reduced.
• The product may be cationic and the degree of
substantivity is unclear.
• Adverse effects include a burning sensation of the mouth.
• Its MIC against periodontal pathogens has been reported
to range from 1 to 32 µg/ml compared to 0.06±32 µg/ml
for tetracyclines.
90

• Local application of sanguinarine via a controlled release
system showed low clinical efficacy.
• The reason for this may be due to its conversion to the
pseudobase form. This conversion has been shown to occur
above pH 6.0 leading to increased insolubility and resulting
in reduced bioavailability.
• With the pH of gingival crevicular fluid (GCF) in a
periodontal pocket being in the range of 7.5±7.9, it is the
likely cause of the sanguinarine conversion to its less
bioavailable form.
91

Histatins
• The histatins are a group of small, cationic histidine-rich
peptides secreted by human parotid and submandibular
salivary glands.
• These endogenous peptides have been shown to bind to
hydroxyapatite, suggesting a role in the formation of the
acquired enamel pellicle.
• The histatins play a major role in protecting the host oral
cavity from etiologic pathogens.
92

• In particular, the histatins are antifungal and also
demonstrate bactericidal and bacteriostatic effects
against periodontal pathogens such as Porphyromonas
gingivalis, Prevotella intermedia and Bacteroides
forsythus.
• However, one common problem encountered with most
peptides is their relatively low stability.
• The physicochemical properties of many peptides make it
difficult to obtain satisfactory formulations, in particular,
since inactivation is possible during their incorporation into
the controlled release system.
93

Ofloxacin
• Ofloxacin is a newly developed synthetic pyridone
carboxylic acid (PCA) derivative.
• Although the earlier PCA derivatives were not active
against Gram positive bacteria and anaerobes, ofloxacin
can kill Gram positive bacteria and anaerobic bacteria.
• This action is absent or very weak in the earlier antibiotic,
i.e. erythromycin, tetracycline and clindamycin.
• Ofloxacin showed marked antibacterial activity against
Bacteroides species, Fusobacterium species and
Aa.comitans.
94

• Furthermore, ofloxacin has high chemical stability and
adverse effects have rarely been reported.
• Okade and co-workers
developed a new sub gingival release delivery system (PT-01)
containing Ofloxacin for sub gingival therapy.
• The PT-01 was found to be effective in the reduction of
supra gingival plaque, reduction in the plaque index,
reduction in bleeding on probing.
95

Clindamycin
• Systemic clindamycin therapy, as an adjunct to scaling,
decreased the incidence of active disease from an annual
rate of 8.0 to 0.5% of sites per patient.
• However, clindamycin did not permanently suppress
subgingival Porphyromonas gingivalis, which may explain the
recurrence of disease activity in some patients.
96

• Following gel insertion of clindamycin in conjunction with
subgingival scaling, motile rods and spirochetes were not
detected after 1 month.
• Prevotella intermedia and Porphyromonas gingivalis were
eliminated or below detectable levels after 1 week post-
therapy but were again detected at 12 weeks.
97

SPIRULINA
• A study was done to assess the clinical effects of Spirulina in-situ gel as an
adjunct to Scaling And Root Planning (SRP) in the treatment of chronic
periodontitis subjects.
• 64 sites were selected with probing pocket depth of ≥5mm and they were
divided into 2 groups; 33 sites were treated with SRP along with spirulina gel
(Group A) and 31 sites were treated with SRP alone (Group B).
• Results: Group A (SRP along with spirulina) showed statistically significant
decrease in mean probing pocket depth and gain in the clinical attachment
level after 120 days as compared to Group B SRP alone.
• It exerts strong anti-inflammatory effects which are closely connected with
its antioxidative activity.
– Jaideep Mahendra et al. Clinical Effects of Subgingivally Delivered Spirulina Gel in Chronic
Periodontitis Cases: A Placebo Controlled Clinical Trial. Journal of clinical and diagnostic
research Year : 2013 | Month : 10 | Volume : 7 | Issue : 10 | Page : 2330 - 2333
98

ALENDRONATE
• Alendronate (ALN), an aminobisphosphonate, is known to inhibit
osteoclastic bone resorption and was proposed to have osteostimulative
properties in vivo and in vitro as shown by an increase in matrix formation.
• A study was done to explore the efficacy of a 1% ALN gel compared to a
placebo gel as a local drug delivery system in adjunct to scaling and root
planing (SRP) for the treatment of intrabony defects in patients with
chronic periodontitis.
• A total of 66 intrabony defects were treated with a 1%ALN or placebo gel.
• Results: The mean PD reduction and CAL gain were greater in the ALN
group than in the placebo group at 2 and 6 months. Furthermore, a
significantly greater mean percentage of bone fill was found in the ALN
group (40.4% – 11.71%) than in the placebo group (2.5% – 1.02%).
– Anuj Sharma and A.R. Pradeep. Clinical Efficacy of 1% Alendronate Gel as a Local Drug
Delivery System in the Treatment of Chronic Periodontitis: A Randomized, Controlled
Clinical Trial. 2012 Volume 83.
99

STATINS
• Simvastatin is derived from the product of the
fermentation of Aspergillus terreus, which belongs to the
Statin family.
• Statins such as SMV, are specific competitive inhibitors of
3-hydroxy-2-methyl-glutaryl coenzyme A (HMG- CoA)
reductase.
• These agents are widely used to lower cholesterol, and
treat hyperlipidemia and arteriosclerosis.
100

• Statins also seem to modulate bone formation by
increasing the expression of bone morphogenetic protein,
inflammation, and angiogenesis, thus providing a new
direction in the field of periodontal therapy.
• Various studies showed that SMV assists in bone
regeneration as well as the anti-inflammatory effect when
delivered or applied locally
101

AZITHROMYCIN
• Aim : to investigate the adjunctive effects of subgingivally
delivered Azithromycin (AZM) (0.5% concentration) as an adjunct
to scaling and root planing (SRP) for treating chronic periodontitis
in patients with type 2 diabetes.
• Methods : 63 patients were categorized into two treatment groups:
Group 1: SRP plus placebo gel and Group 2: SRP plus 0.5% AZM.
• Results : patients in Group 2 treated with SRP + 0.5 %AZM showed
enhanced reductions in PI, GI, PD and gains in CAL (p <0.05) over a
period of 9 months as compared to Group 1.
– Esha Agarwal et al. Locally Delivered 0.5% Azithromycin, as an Adjunct to Non
Surgical Treatment in Chronic Periodontitis With Type 2 Diabetes: A
Randomized Controlled Clinical Trial. Journal of Periodontology, 06/2012.
102

• Aim : to evaluate the adjunctive effects of subgingivally delivered
0.5% azithromycin (AZM) as an adjunct to scaling and root planing
(SRP) in the treatment of chronic periodontitis in smokers.
• METHODS: Fifty-four patients were randomized and categorized into
two treatment groups: Group 1 - 26 subjects who received (SRP) plus
placebo gel and Group 2 - 28 subjects who received (SRP) plus 0.5%
azithromycin.
• RESULTS: A single application of AZM resulted in attachment gain at
9 months of 2.44 ± 0.64 mm as compared to 0.18 ± 0.68 mm for the
placebo. Similarly, pocket depth and PI were significantly reduced but
no change in the mSBI was noted.
– Pradeep AR et al. Local drug delivery of 0.5% azithromycin in the treatment
of chronic periodontitis among smokers. Aust Dent J. 2013 Mar;58(1):34-40.
103

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.
104

• 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.
105

Inhibition of Periodontal Disease Progression
• Garrett et al 1999 compared 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.
106

Impact of Local Drug Delivery on Furcations
• Tonetti et al. (1998) reported that tetracycline
fibers in conjunction with SRP initially provided a
better result than SRP alone at molar furcations;
however, after 6 months, there were no statistically
significant differences with respect to mean probing
depth reduction or gain of clinical attachment.
• In contrast, Williams et al. and Meimberg et al.(2002)
noted a statistically significant greater probing depth
reduction in molar furcation when SRP plus minocycline
microspheres were compared to SRP alone.
• Additional studies are needed to assess the effect of
local delivery in a variety of defects to include
furcations and intrabony lesions. 107

Repair of Osseous Defects
• Bone deposition in infrabony defects is a desirable
treatment outcome; however, the amount of bone fill
that occurred after local drug delivery is limited.
• Aimetti et al.(2004) reported that tetracycline
fibers plus SRP resulted in 0.94 mm bone deposition
in osseous defects versus 0.09 mm after SRP
alone.
• In general, results regarding bone fill need to be
interpreted in light of the fact that other clinical
procedures provide better bone repair in osseous
defects.
108

Future trends in local drug
delivery
1. Clarithromycin gel
• A study has been conducted to investigate the adjunctive
effects of subgingivally delivered 0.5 % clarithromycin as
an adjunct to scaling and root planing for treating chronic
periodontitis smoker subjects.
• It was observed that the adjunctive use of 0.5%
clarithromycin as a controlled drug delivery system
enhanced the clinical outcome.
• This product is still under investigation and yet to be
patented.
109

2. Herbal products
• Various herbal formulations like aloe vera, neem, tulsi,
propolis, cocoa husk, pomegranate, cranberry etc. are
being used widely these days.
• These products have shown promising results with no side
effects and are economical as well.
110

Aloe vera
• The medicinal value of the plant lies in a gel like pulp‑
obtained on peeling the leaves.
• These substances include
 Lignins : Cellulose based substances which have the capacity to‑
penetrate the tissue and carry elements with it.
 Saponins : Glycosides that promote cleansing and provide an
antiseptic quality.
 Vitamins : Vit A which is necessary for integrity of epithelial cells,
Vit C which helps in connective tissue regeneration (collagen
synthesis), and Vit E which is an antioxidant and neutralises free
radicals by donating one of their electrons, ending the electron
stealing reaction.
111

 Minerals : increase tensile strength of wound, so helpful in
early wound healing.
 Amino acids : building blocks for repair and regeneration of
traumatized tissue.
 Anthroquinones : similar to alkaloids & produce analgesia and
have healing, antibacterial, antiviral, and antifungal
properties.
 Sugars : such as polymannose, glucose, and fructose which
have immune modulating and anti inflammatory actions.‑
 Enzymes.
• Aloe vera gel improves wound healing by
 Increasing blood supply, which increased oxygenation as a result.
 Has a positive influence on the collagen content and stability.
112

• Yagi et al. in 2002 in a study found that three aloesin
derivatives from aloe (namely isorabaichromione,
feruloylaloesin, and p coumaroylaloesin) have potent free‑
radical and superoxide anion scavenging properties.
• It was found that aloesin compounds inhibited
cyclooxygenase 2 (COX 2) and thromboxane (TX) A2‑ ‑
synthase, which explains the healing effects of aloe vera.
• Due to some chemical structural similarity between aloins
and tetracyclines, aloe derivatives could inhibit the MMP’s
through a mechanism similar to that of inhibitory
tetracyclines such as doxycycline.
113

• Aim : To evaluate the effect of aloe vera gel as an adjunct
to scaling and root planing (SRP) in the management of
• SRP ALOE group showed significantly better results than‑
SRP alone.
– Harjit Kaur Virdi et al. Effect of locally delivered aloe vera gel as
an adjunct to scaling and root planing in the treatment of chronic
periodontitis: A clinical study. Indian Journal of Oral Sciences Vol.
3 Issue 2 May-Aug 2012
114

• Geetha Bhat et al. concluded that subgingival
administration of Aloe vera gel results in improvement of
periodontal condition.
– Geetha Bhat et al. Aloe vera: Nature's soothing healer
to periodontal disease. J Indian Soc Periodontol. 2011 Jul-
Sep; 15(3): 205–209.
115

Neem
• Neem extract contains
(i) Azadiractin - the active principle,
(ii) Glycosides -antimicrobial,
(iii) Sterols
(iv) Luminols-anti-inflammatory and
(v) Flavenoids.
• Neem has showed better efficacy in the treatment of oral
infections and plaque growth inhibition in treating
periodontal disorders.
116

• Neem has multivarious actions like
 Antibacterial,
 Astringent,
 Antiseptic,
 Anti-inflammatory,
 Antiviral and
 Antimicrobial properties.
• It removes toxins from the body, purifies the blood and
neutralizes damaging free radicals. So, locally it may also
have an effect in enhancing healing.
• It is easily available and has no known adverse reactions.
117

• Neem extract gel produced more improvements in clinical
as well as microbiological parameters than the control. The
approach of local delivery of a natural extract with no
known side effects has proved promising results.
– Dr. Verdine Virginia Antony et al. “Evaluation of the Efficacy of
Azadirachta Indica (Neem) Extract Gel as a Local Drug Delivery in
the Treatment of Patients with Chronic Periodontitis. ” A Double
Blind Randomised Clinical Trial. IOSR Journal Of Pharmacy Volume
3, Issue 4 (May 2013), Pp 15-21
118

Turmeric
• It has proven properties like
 Anti-inflammatory,
 Antioxidant,
 Antimicrobial,
 Hepatoprotective,
 Immunostimulant,
 Antiseptic,
 Antimutagenic, and
 It also accelerates wound healing.
119

• A study was done to 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. Comparative evaluation of the efficacy of turmeric
and curcumin as a local drug delivery system: a clinicomicrobiological
study. Gen Dent. 2012 Sep-Oct;60(5):e283-7
120

• 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. Evaluation of local drug-delivery system
containing 2% whole turmeric gel used as an adjunct to
scaling and root planing in chronic periodontitis: A clinical and
microbiological study. J Indian Soc Periodontol. 2011 Jan-
Mar; 15(1): 35–38.
121

Propolis
• Propolis is a resinous mixture that honey bees collect from
tree buds, sap flows, or other botanical sources.
• It is used as a sealant for unwanted open spaces in
the hive.
• Its actions are :
 Antimicrobial : due to active constituents
including flavonoids like galangin and hydroxycinnamic
acids like caffeic acid.
122

 Immunomodulator : Propolis exhibit
both immunosuppressive and immunostimulant effects.
 As an oral hygiene product : protect against dental
caries and periodontal diseases, due to its antimicrobial
properties.
Propolis is also being investigated for its efficacy in the
treatment of canker sores and in reducing the
inflammation associated with canal debridement
and endodontic procedures.
 Antioxidant.
123

• The study indicated a potentially useful role of Semisolid
systems containing propolis in the treatment of
periodontitis and suggest they are worthy of clinical
evaluation.
– Marcos L. Bruschi et al. Semisolid systems containing propolis for
the treatment of periodontal disease: In Vitro release kinetics,
syringeability, rheological, textural, and mucoadhesive properties.
Journal of Pharmaceutical Sciences Volume 96, Issue 8, pages
2074-2089, August 2007
124

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
• 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.
125

3. 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 growth factor
(bFGF) in a controlled-release system was developed.
• This sandwich membrane induced successful regeneration
of the periodontal tissues in a short period of time
(4weeks ).
126

The strategic approaches with associated
challenges and achievements towards the
formation of periodontal drug delivery system :
Strategy 1: systemic delivery devices
• Low benefit to risk ratio, ingestion of large drug doses
• Inadequate drug concentration at periodontal site
• Rapid/non-sustained drug release
• Poor patient compliance: frequent administration
• No penetration of delivery system
• No adhesion/retention into periodontal pocket
• High incidence of bacterial resistance
127

Strategy 2: local mouth rinses and dental irrigation
• Inadequate drug concentration at periodontal site
• Drug dose is reduced
• Rapid/non-sustained drug release
• Systemic toxicity is decreased
• Poor patient compliance: frequent administration
• No penetration of delivery system
• No adhesion/retention into periodontal pocket
• High incidence of bacterial resistance
128

Strategy 3: non-biodegradable, intrapocket fibres, strips,
films and microparticles
• Poor patient compliance: discomfort during the placement
of device, at least two visits to therapist is required and
development of foreign body response, if left in situ
• Adequate drug concentration at periodontal site
• Poor penetration of system/drug
• Prolonged/sustain drug release
• Poor retention of system into periodontal pocket
• Less frequent administration
• Low incidence of bacterial resistance
129

Strategy 4: biodegradable, intra-pocket fibres, strips,
films and microparticles
• Poor patient compliance: discomfort during placement
• Visit to therapist is reduced
• Poor penetration of system/drug
• No foreign body response
130

Strategy 5: biodegradable nanoparticles
• Placement is easier
• Good penetration due to nano-sized particles
131

Strategy 6: Mucoadhesive, biodegradable nanoparticles
• Good retention of system
Strategy 7: antibiotic-free, mucoadhesive, biodegradable
nanoparticles
• Bacterial resistance does not develop
132

• Evidence suggests that compared with SRP alone, when SRP is
combined with certain anti-infective agents in sustained-release
vehicles, statistically significant adjunctive effects on PD reduction
and a decreased percentage of sites with BOP can be anticipated.
Statistically significant effects of PD reduction were seen with
CHX chip.
• 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.
• Meta-analysis has revealed a 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.
• Use of anti-infective sustained-release systems as adjuncts to SRP
does not result in significant patient-centered adverse events or
morbidity.
– Rupali Kalsi et al. Effect of local drug delivery in chronic periodontitis patients: A
meta-analysis. J Indian Soc Periodontol. 2011 Oct-Dec; 15(4): 304–309.
133

CONCLUSION
• Local drug delivery often appears to be as effective
as scaling and root planing with regards to reducing
signs of periodontal inflammatory disease.
• 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 and in isolated pockets also. Therefore,
their routine utilization is unnecessary.
134

• 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.
• 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.
135

REFERENCES
• Carranza’s Clinical Periodontology 10th
Ed.
• Pramod Vishwanath Prasad et al. Bird’s Eye View on the
Recent Advances in Drug Delivery Systems. Journal of
Biomaterials and Nanobiotechnology, 2011, 2, 544-556
• Vidya Dodwad et al. Magic Bullet to treat Periodontitis: A
targeted approach. JPBMS, 2012, 20 (19)
• Amit Bhardwaj et al. Advances in periodontal drug delivery
systems. International Journal of Novel Drug Delivery
Technology. Jan-Mar 2012, Vol-2, Issue-1
136

• Vidya Dodwad et al. Local Drug Delivery In Periodontics: A
Strategic Intervention. International Journal of Pharmacy
and Pharmaceutical Sciences. Vol 4, Issue 4, 2012
• Pragati S et al. Recent advances in periodontal drug
delivery systems. International Journal of Drug Delivery
1(2009) 1-14
• K. Schwach-Abdellaoui et al. Local delivery of antimicrobial
agents for the treatment of periodontal diseases.
European Journal of Pharmaceutics and Biopharmaceutics
50 (2000) 83-99
137

• RAMS & SLOTS. Local delivery of antimicrobial agents in
the periodontal pocket. Perio 2000, Vol. 10, 1996, 139-159
• Internet sources.
138

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