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1. LOCAL DRUG DELIVERY
Dr. S. K. Balaji
Additional Professor

2. INTRODUCTION
 Periodontal diseases are poly microbial infections
 Periodontitis is a multifactorial disease
 Sub gingival environment – Ideal for pathogenic bacteria
 Sub gingival microorganisms – Principle etiologic factor
MICROBES
SYSTEMIC
FACTORS
HORMONES
STRESS
HOST
RESPONSE
GENETIC
SUSEPTIBILITY

3. INTRODUCTION
 The role of microorganisms in initiation and progression of
periodontal infections was confirmed by numerous authors
Loe et al, 1965
Thiladhe et al, 1966
Socransky et al, 1994
 Removal of this biofilm by mechanical instrumentation is
essential
 Also prudent use of chemotherapeutic agents becomes
mandatory to produce ideal results

4. LIMITATIONS OF MECHANICAL
DEBRIDEMENT - Quirynen et al (2002)
 Tooth / Root anatomy unfavourable
 Intra oral microbial
translocation

5.  Bacterial invasion into dentinal tubules
 Tissue invasive organisms

6. USE OF ANTIBIOTICS FOR THE TREATMENT
OF PERIODONTAL DISEASES
 Biofilm cells – 1000 to 1500 times resistant to antibiotics
 Antibiotics cannot penetrate the depth and do not reach
colonies at the depth of the matured biofilm
 PENICILLIN
 TETRACYCLINE
 CLINDAMYCIN
 CIPROFLOXACIN
 METRONIDAZOLE

7. LOCAL DRUG DELIVERY
 Local delivery of antimicrobial agents in periodontics
implies antimicrobial therapy placed directly in the
sub gingival region
 The term local delivery is usually used to suggest
more specific or targeted delivery of an agent

8. ISSUE SYSTEMIC LOCAL
Route of administration Oral/ parentral Site specific
Drug distribution Wide distribution Narrow range
Therapeutic potential May reach widely
distributed micro
organisms better
May act better locally on
biofilm associated bacteria
Problem Systemic side effects Reinfection from nontreated
sites
Clinical Limitations Requires good patient
compliance
Reinfections limited to the
treated site
Diagnostic problems Identification of
pathogens, choice of
drug
Distribution pattern of lesion &
pathogens, identification of
sites to be treated
Pain/discomfort Not painful Nil
Drug Dosage Higher drug dosage (mg) Lower Dosage

9. Peaklevels Few hours in plasma Within few minutes in GCF
Frequency Once in 6-12 hrs Once a week
Super infection Present Limited
Microbial resistance Present Limited
Time required Less time Longer if many sites are treated
Effects on connective tissue
Associated plaque
Effective Limited

10. IDEAL REQUIREMENTS
 The drug must reach to the base of pocket
 Must have microbiologically effective concentrations in the
pocket.
 Substantively little or no effect on host tissue
(Goodson 1985)
 Ease of placement and cost effective
 Biodegradable (Greenstein and Polson 1998)

11. CLASSIFICATION
 I ] Based on application [Rams and Slots]
A ] Personally applied
i ] Nonsustained sub gingival drug delivery
Home oral irrigation
Home oral irrigation jet tips
Traditional jet tips
Oral irrigator (water pick)
Soft cone rubber tips (pick pocket)
ii ] Sustained sub gingival drug delivery
None developed

12. CLASSIFICATION
 B ] Professionally applied (in dental office)
i ] Nonsustained sub gingival drug delivery
Pocket irrigation
ii ] Sustained sub gingival drug delivery
Controlled release devices
hollow fibres
dialysis tubing
Strips
Film

13. CLASSIFICATION
 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
(Kornman1993)

14. CLASSIFICATION
 III ] Based on degradation
A ] Biodegradable
B ] Non biodegradable
 IV ] Based on physical form

15. FIBRES
Hollow
Monofilament
Tetracycline
Chlorhexidine
FILMS
Matrix delivery systems
Biodegradable –
Soluble films
Fish collagen
Dissolution
Steinberg et al
Non biodegradable –
Insoluble films
Ethyl cellulose
diffusion
CHX, tetracyclines,
metronidazole
INJECTABLE
SYSTEMS
Easy & effective
Cost saving
GELS
Solid/semisolid
formulations
Base – Methyl
cellulose
CHX,
metronidazole,
tetracycline etc

16. STRIPS &
COMPACTS
Polymers and
monomers
impregnated with
drug
Metronidazole
CHX, Augmentin,
Tetracycline,
Doxycycline
VESICULAR
SYSTEMS
Mimic
biomembranes
Triclosan., CHX
MICROPARTICLE
SYSTEM
Biodegradable PLA
or PGLA
Tetracycline &
doxycycline
microspheres
NANOPARTICULATE
SYSTEM
Targeted controlled
slow drug release
Bioadhesive &
increases stability

17. COMPARISON OF DRUG DELIVERY SYSTEMS
FOR THE MANAGEMENT OF
PERIODONTITIS

18. ADVANTAGES OF CONTROLLED DRUG
DELIVERY SYSTEMS
 Can attain 100 fold higher concentrations
 Can employ agents that are not suitable for systemic administration
 Patient compliance
 Alternative for patients predisposed to adverse reactions from systemic
antibiotic administration
 Reduced risk for drug resistant microbe development at non oral body sites
(Rams and Slots)
 Increased access to the site
 Lower total drug dosage
(Goodson 1989)

19. DISADVANTAGES OF CONTROLLED DRUG
DELIVERY SYSTEMS
 Difficulty in placing therapeutic concentrations into
deeper part of periodontal pockets and furcation
lesions
 Time consuming and labour intensive
 Do not have effect on bacteria residing on extra pocket
oral niches
 Cannot be used for aggressive periodontal diseases

20. INDICATIONS AND CONTRAINDICATIONS
INDICATIONS
 As an adjunct to root
surface instrumentation in
pockets of 5 mm or greater
 Localized recurrent
pockets in patients under
supportive periodontal
therapy
 Non responding sites to
conventional therapy in
well motivated patients
CONTRAINDICATIONS
 Allergic to particular drug used
 In pregnant and lactating
mothers (for tetracycline group
of drugs)
 To be used with caution in
patients with history of immune
deficiency (to prevent the
overgrowth of candida or other
resistant organisms)

21. ADVERSE EFFECTS
 Allergic reactions
 Might produce resistant strains or overgrowth of intrinsically resistant
organisms
 Occurrence of candidiasis especially
 Pain on insertion
 Burning sensation on insertion (with Chlorhexidine)
 Development of abscesses
 Interference with taste
Tonetti (2000)

22. DRUG SELECTION
 Identification of periodontal pathogens
 Is advisable to do bacterial culture and sensitivity testing -
Magnusson 1989
e.g., Tetracyclines often administered, as they are broad
spectrum antibiotics. However studies also showed
patients previously treated with tetracycline responded not
well and other antibiotics were beneficial
 No single drug is the universal drug of choice.

23. VARIOUS DRUGS USED AS CONTROLLED
RELEASED SYSTEMS
TETRACYCLINE :
 Broad spectrum antibiotics with activity against both gram
positive and gram negative organisms
 Consist of four fused cyclic rings and the various
derivatives consist of only minor alterations of the
chemical constituents attached to this basic ring structure
 Tetracycline, Doxycycline and Minocycline are commonly
used with similar spectrum of activity. Hence resistance to
one indicates resistance to all the three

24.  They are bacteriostatic agents but may have a
bactericidal effects in high concentrations (Walker
1996). These drugs principally acts by inhibiting
protein synthesis
 In addition to its antibacterial action, it also possess
the following function
Demineralizes dentin cementum and dentin,
when applied topically thereby enhancing
attachment of fibroblasts to the tooth surface
(Wikesjo et al 1986; Morrison et al 1992)

25. ADVANTAGES :
 Has high substantivity
ie . after local delivery, it has been detected at
1-20µm within epithelial tissues
(Ciancio et al 1992)
 Detectable in crevicular fluid several weeks following
application (Wikesjo et al 1986)
 Attains high concentration in crevicular fluid

26. SERUM AND GCF CONCENTRATION OF
COMMONLY USED ANTIBIOTICS

27. TETRACYCLINE fibres (ACTISITE)
 They are non-resorbable cylindrical drug delivery
devices made of a biologically inert, plastic co-polymer
loaded with 25% tetracycline HCL powder
(Goodson et al 1983)
 23 cm in length and 0.5 mm in diameter. The fibre is flexible
and can be folded on itself to nearly fill the pocket
 Able to release and maintain tetracycline for a period of 7 days
(Tonetti et al 1990) with mean concentrations of 43µg/ml in the
superficial portions of the pocket wall
 At a concentration more than 150 times achieved by systemic
tetracycline, these fibres provide bactericidal concentration of
tetracycline.

28. TYPES OF FIBRES
 Hollow fibres:
Cellulose acetate fibres are filled with tetracycline and they
provide only sustained release system
 Monolithic fibres:
Prepared by melt extrusion technique, wherein, a mixture of 25%
tetracycline HCl and 75% ethylene vinyl acetate was heated to 214 C
and extruded as 0.5 mm fiber and they provide a controlled release
system (Goodson et al 1985)
 Resorbable fibres:
Minabe (1989) described a device in which tetracycline is
incorporated into cross-linked collagen matrix, capable
of delivering tetracycline in the crevicular fluid at therapeutic levels
for upto 10 days after insertion and drug levels ranged from 17 to
180µg/ml.

29. TECHNIQUE
 An individual or several teeth can be treated at a time
 Short lengths of fibre, 2-3 inches are taken in a cotton
forceps and placed at the opening of the pocket to be
treated
 The fibre folded on itself
 The folding procedure might be repeated until all the
pockets are nearly filled

30.  Interproximal pockets should be packed from both the
buccal and the lingual sides
 After placement, the area is isolated with cotton rolls or
gauze, tooth dried with the air syringe and a drop of tissue
adhesive applied at each interdental area as well as facially
and lingually
 Alternatively, periodontal pack can be placed
(Goodson et al 1985)
 Fibres should be in place for 7-14 days
 Fibre removal (in case of non-resorbable fibres) is fairly
simple. They can be teased out of the pockets with a
curette

32. INSTRUCTIONS TO BE GIVEN TO THE
PATIENT
 Not to brush or floss the treated areas until fibres are
removed
 To rinse with chlorhexidine mouth rinse while the
fibres are in place and for 1 week after their removal
 Advised to return back to normal original oral hygiene
procedure after 1 week or after fibre removal (in case
of non-resorbable fibres)
 To come for recall visit at 4-6 weeks

34. Can be concluded that local delivery of tetracycline
improves the clinical outcomes of traditional treatment
and should be considered particularly as an adjunct to
scaling root planing. Considerations regarding the
adverse effects of widespread use of tetracycline should
be taken into account when choosing a therapeutic
strategy of chronic periodontitis
Pavia et al (2003)

35. DOXYCYCLINE POLYMER (ATRIDOX)
 A biodegradable formulation containing
10% by weight doxycycline,
33% by weight poly (DL-Lactide) and
57% by weight N-methyl 2-pyrrolidone
was developed
 Mechanism of action :
Activity against putative periodontal pathogens and
effective in the management of human diseases
(Golub et al 1984, McCulloch et al 1990)
 It is a liquid biodegradable system that hardens when
placed in periodontal pocket

36. TECHNIQUE
 Liquid delivery system containing 10% doxycycline
hyclate is contained within a syringe that has a blunt
ended 23 gauge cannula attached. The cannula has a
diameter of a periodontal probe
 The tip of the cannula is introduced to the depth of the
pocket and the drug is expressed out

37.  As it begins to harden on contact with the moisture
and during the 1-2 minutes of hardening, it is packed
into the pocket using the underside of the moistened
curette or other blunt-ended instrument
 Immediately after administration, the polymer
slightly protrudes from the pocket orifice
 Periodontal dressing or adhesive is used as an aid in
retention of the system
 Instructions given to the patient is in lieu with
tetracycline fibres

39. MINOCYCLINE
(DENTOMYCINE AND PERIOCLINE)
 3 modes of local application are available:
film
microspheres
ointment
 It is a bacteriostatic

40. Film
 Ethylcellulose containing 30% of minocycline cast
from ethanol, chloroform or chloroform with
polyethylene glycol were tested as sustained release
devices (Elkayam et al)
 The results of this study indicated that the use of this
device may cause complete eradication of pathogenic
flora from the pocket

41. Microspheres:
 Minocycline micro-encapsulated in a resorbable poly
glycolide-lactide slow release polymer
(Braswell et al) can be administered by means of
disposable plastic syringe. The volume of
microspheres in each syringe is 4 mg which is
equivalent to 1 mg of minocycline base

42. Microspheres :
Injected into the pocket
Adhered to the soft tissue
Dissolves
Releases minocycline in sustained manner

43.  Once in the pocket the micospheres react with the
crevicular fluid which hydrolyzes the polymer causing
water-filled channels to form inside the microspheres
 These holes become the pathway for the antibiotic for
sustained release
 The minocycline then diffuses through these portals and
permeates the surrounding tissues
 Over a period of time, the microspheres themselves get
fragmented through polymer hydrolysis and degrade and
are ultimately bioresorbed.
 It is reported that the microspheres are completely
biodegraded in about 21 days

44. Ointment:
 It is a light yellow colored ointment base of
20 mg hydroxyethyl cellulose,
10 mg eudragit RS,
60 mg triacetine and
glycerine 0.5 g
supplied in a disposable
polypropylene applicator and each applicator contains the
equivalent of 10 mg minocycline in 0.5 g ointment
 Repeated applications of 2% minocycline, 1 application
per week for 4 weeks, 2 applications at intervals of 1 or 2
weeks, 3 applications at 2 weekly intervals were effective

46.  Thus, minocycline can be used as a adjunct to
mechanical debridement with improved
effectiveness for treatment of chronic periodontitis
Vanderkerckhove et al

47. METRONIDAZOLE
 A 5-nitroimidazole compound specifically targets anaerobic
microbes but has essentially no activity against aerobic or
microaerophilic bacteria but its hydroxyl metabolite enhances
its effect even against other group of bacteria (Pavicic et al)
 Upon entry into an organism, metronidazole is reduced at 5-
nitro position by electron transport proteins. The reduction of
parent molecule produces free radicals. These react with
bacterial DNA causing cell death. Hence it is primarily a
bactericidal agent (Drisko et al).
 Serum concentration of Metronidazole has shown to attain MIC
levels for most periodontal pathogens (Brit and Prohlod 1986)
and it is found to eliminate spirochetes from ANUG lesions.

48. METRONIDAZOLE DENTAL GEL
(ELYZOL)
 Resorbable
 Consists of 25 % of Metronidazole benzoate in a
matrix consisting of
Glyceryl mono-oleate
Sesame oil
 The gel is subgingivally placed with a syringe and a
blunt cannula. The drug concentration in crevicular
fluid follows an exponential pattern which is
compatible with sustained drug delivery

51.  Thus the effectiveness of metronidazole as an
adjunct to SRP in the treatment of chronic adult
periodontitis, but clinical significance and
dissemination of antibiotics should be taken into
account in the evaluation of metronidazole as an
alternative to SRP
(Pavia et al 2004)

52. CHLORHEXIDINE
 It is a topical antiseptic belonging to the family of
bisguanides. It is mainly active against gram positive
group of organisms
 It is bacteriostatic at lower and bactericidal at higher
concentrations
 It has been detected in excess of 125 µg/ml in
crevicular fluid for 1 week following a single
application (Soskolne et al 1998)

53. CHLORHEXIDINE CHIP (PERIOCHIP)
 It is a bio absorbable device
 Comprises of 34% Chlorhexidine in a cross linked
gelatin matrix
 Chip is 5 mm long, 4 mm wide with 2.5 mg of
chlorhexidine gluconate

54. TECHNIQUE
 After scaling and root planing, the chip is grasped in a
cotton forceps and gently inserted into the pocket
 It is advisable to dry the area before placing the chip
 As burning sensation is reported after the chip placement,
placement of multiple chips around a single tooth may
result in discomfort
 The chip degrades in a period of 7-10 days and requires no
retentive system
 Instructions given to the patient is in lieu with tetracycline
fibres

57. OFLOXACIN
 Ofloxacin belongs to quinolone family which
constitute a group of 1,8 naphthyridine derivatives and
are synthetically produced drugs
 They are considered to be bactericidal as they inhibit
the enzyme DNA replication by acting on the enzyme
DNA gyrase. The bactericidal effect can only occur
in the presence of competent RNA and protein
synthesis. The imbalance of inhibited DNA replication
and continued protein synthesis results in inhibition of
cell division

58. OFLOXACIN INSERTS (PT-01)
 PT-01 is a soluble insert, with both fast and sustained
release parts containing 10% ofloxacin and showed a
constant drug level of above 2 mg/ml, (minimum MIC
for most pathogenic organisms) which could be
sustained for up to 7 days
 The controlled release system exhibited a biphasic
pattern with a rapid early release phase peaking at
approximately 12µg/ml and stabilizing at
approximately 2µg/ml from day 3 to 7 following
insertion (Higashi et al 1990)

59.  Initial investigations failed to any additional
microbiological effect in a split mouth design
(Kimura et al 1991)
 Further investigations by Yamagami et al (1992)
showed four weekly applications of the insert resulted
in significant resolution of periodontal inflammation
and improvement in other clinical parameters
compared to controls.

62. COMPARISON OF DRUGS USED FOR LOCAL
DELIVERY

63.  Tetracycline, minocycline and metronidazole as an
adjunct to scaling and planing compared with scaling
and planing alone
(Radvar et al 1996; Kinane et al 1999)
 Both the studies showed all the 3 drug delivery
systems provided some benefit beyond scaling and
planing. However, only tetracycline fibers
demonstrated a significant advantage over scaling and
planing in the treatment of persistent periodontal
lesions

64. ANTIBIOTIC RESISTANCE ASSOCIATED WITH
LOCAL DRUG DELIVERY SYSTEMS
 Local drug delivery provides a high drug
concentration at a specific site
 Sublethal amounts of administered drugs leak out of
pockets during therapy. Therefore, the potential exists
that local drug delivery may contribute to development
of drug resistant organisms in areas other than the
treated sites

65.  Exposure to sub inhibitory concentrations of
metronidazole or minocycline resulted in
development of resistance among
P.gingivalis,
P.intermedia,
F.nucleatum and
P.anaerobius
Walker et al, Larsen et al
 This suggests that repeated use of these agents can
result in increased levels of drug resistant bacteria

66.  Thus, it can be concluded local delivery systems are
logical adjuncts for the treatment of a few, localized
non-responding sites, and systemic delivery reserved
to control infections at multiple sites in patients with
persistent disease and for treating atypical and
aggressive forms of periodontitis
(Tonetti 2000)

67. DISEASES THAT CAN BE TREATED WITH
LOCAL DRUG DELIVERY SYSTEMS
 All drugs were used to treat patients with chronic periodontitis
 Only tetracycline fibres and metronidazole were used to treat
aggressive periodontitis
 Mandell 1986 - Tetracycline fibers were not efficient
in suppressing Aa – in J P
 Mombelli et al (1997) - Tetracycline fibers were able to
suppress, but not eliminate Aa
 Riep et al (1996) - ocal delivery of metronidazole too is not effective
at suppressing Aa levels
These findings need to be considered when treating patients with these
aggressive forms of disease, as they might harbor increased levels of
these above said organisms.

68. Thus, at present there is no concrete evidence to use
local delivery agents in the treatment of aggressive
periodontal diseases

69. REMEMBER……..
 There is no single universal drug that would be
effective in all situations
 Local drug delivery often appears to be as effective as
scaling and root planing with regards to reducing
signs of periodontal inflammatory diseases
 Local delivery may be an adjunct to conventional
therapy. The sites most likely to be responsive to this
adjunctive treatment method may be refractory or
recurrent periodontitis

70. REMEMBER……..
 At present, there are insufficient data to indicate that one
local drug delivery service is clearly superior to all the
other systems
 There is a lack of data to support the impression that local
drug delivery in conjunction with root planing reduces the
need for periodontal surgery more than scaling and root
planing alone.
 Should not be substituted for oral hygiene procedures.
 Cigarette smoking has a negative influence on outcome of
local drug therapy (Kinane et al 1999)

71. CONCLUSION
 The number of problems encountered in delivering the drugs
to the intended target site with the right dosage is a challenge to the
clinician since drugs often have limited solubility, suffer breakdown
before they reach their target tissues and might cause unintentional
damage to the healthy tissues
 Therefore, the nanoparticle based drugs may be ideal to meet up
these challenges
 It has been claimed that benefits of nanoparticle based drug delivery
systems have high stability than conventional delivery mechanisms
 Therefore, the introduction of nanoparticle delivery system
has been tried and, has gained popularity

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