This document provides an overview of local drug delivery (LDD) agents for the treatment of periodontal disease. It discusses the drawbacks of systemic therapies and advantages of LDD systems in achieving higher drug concentrations directly in the periodontal pockets. Various antimicrobial agents delivered locally via fibers, chips, gels and other vehicles are summarized, including tetracycline, doxycycline, minocycline, chlorhexidine, metronidazole and their efficacy. The importance of adequate drug-microbial contact time and biodegradability of different systems is also highlighted. In conclusion, LDD provides an effective adjunct to mechanical debridement, especially for refractory cases and sites difficult to access.

1. T.Hudson Jonathan
2nd yr MDS

2. Contents
Introduction
Systemic therapy drawbacks
Local drug delivery agents
Advantages and disadvantages
of LDD
Subgingival drug-microbial
contact time
Tetracycline
Doxycycline
 Minocycline
 Chlorhexidine
 Metronidazole
 Other available LDD
systems
 Conclusion
 References

3.  Periodontal disease encompasses several pathological conditions
affecting the tooth supporting structures such as chronic
periodontitis, aggressive periodontitis, systemic disease-associated
periodontitis and necrotizing periodontitis.(Highfield 2009)
 It has been well-established that periodontal disease is the result of a
local bacterial infection with a pathogenic microflora within the
periodontal pocket.

4.  Traditional therapies for periodontal disease have included
mechanical debridement to disrupt the subgingival flora and provide
clean, smooth and biologically compatible root surfaces.
 Unfortunately, in some instances, the complex anatomy of the root
and the contours of the lesion may hamper the treatment and
prevent sufficient reduction of the bacterial load to make the tooth
surface biologically acceptable.

5.  Also, there are some patients or sites where even repeated treatment
fails to stop the disease. These are known as refractory subjects or non-
responding sites.(Abdellaouia et al 2000)
 So it is evident that antimicrobial agents are of great interest and may
be valuable as adjuncts to mechanical therapy.

6.  Systemically applied antimicrobials have been advocated for the
treatment of severe forms of periodontitis.
 Early approaches to systemic antibiotics in periodontal therapy
included mainly single drug therapies with Tetracyclines, Penicillins,
Metronidazole or Clindamycin (Slots J 2002).

7.  Indeed, side effects including hypersensitivity, gastrointestinal
intolerance and the development of bacterial resistance have been
described.(Mombelli et al 1997).These drawbacks would be markedly
reduced if antimicrobial agents could be used locally.
 The local tissue concentration of a drug can be enhanced by
incorporating the active agent into controlled release delivery systems
to be placed directly in the periodontal pocket.

8.  Such systems may have applications where systemic drugs are
currently used, for instance localized juvenile periodontitis, refractory
periodontitis and periodontitis with secondary systemic involvement,
e.g. HIV periodontitis.
 Sustained local delivery systems might also be recommended for sites
which are considered as difficult to instrument because of depth or
anatomical complexity, for example in the case of furcation
defects.(Needleman 1991).

9.  The choice of antimicrobial agents in periodontal diseases must be
based on the bacterial etiology of the infection.
 Several antibiotics have been tested for their clinical and
microbiological efficacy in periodontal diseases and only limited
number of agents have been used so far in local delivery
formulations.

10. Indication:
 As an adjunct to scaling and root planing and maintenance therapy.
 Used in medically compromised patients for whom surgery is not an
option or those who refuse surgical treatment.
Contra-indication:
 In patients with known hypersensitivity to the antimicrobials used as
local drug.
 Delivery of the antimicrobial using ultrasonic devices is contraindicated
in asthmatics and infective conditions such as AIDS, Tuberculosis.
(Goodson 2000)

11.  Local antimicrobial agents may be personally applied as a part of home
oral hygiene regimens, and professionally applied as part of office-based
treatment procedures.
Rams et al 1996

12.  Sustained release is said to be (drug delivery for less than 24 hrs) and
controlled release (drug delivery for more than 24 hrs).
Ankur Singh Rajpoot et al ,Local drug delivery in periodontics:A review, Inter
Journal of Research in Health and Allied Sciences,Vol. 3 Issue 4 July –August 2017

13. Advantages and disadvantages of LDD:
Advantages:
 A local route of drug delivery can attain 100-fold higher
concentrations of an antimicrobial agent in subgingival sites
compared with a systemic drug regimen.
 Personally applied antimicrobial regimens offer, for compliant
patients, the potential of daily drug placement, whereas Professional
pocket application of local antimicrobial agents reduces potential
problems with compliance that plague the use of systemic antibiotic
drug regimens.

14.  Local antibiotic delivery provides an alternative for individuals
predisposed to ulcerative colitis or other adverse reactions, from
systemic antibiotic administration and reduces the risk of developing
drug-resistant microbial populations at the sites.

15. Disadvantages:
 It includes the difficulty in placing therapeutic concentrations of the
antimicrobial agent into deeper parts of periodontal pockets and
furcation lesions.
 Personal application of antimicrobial agents- patient’s lack of
adequate manual dexterity, limited understanding of periodontal
anatomy, and poor compliance and performance with
recommended procedures.

16.  The task of professionally applying local antimicrobial agents in
periodontitis patients with numerous advanced lesions distributed
throughout their mouth is time-consuming and labor-intensive.
 Antimicrobial agents locally applied into periodontal pockets do not
markedly affect periodontal pathogens residing within adjacent gingival
connective tissues and on extra-pocket oral surfaces (tongue, tonsils
and buccal mucosa), which increases the risk of later reinfection and
disease recurrence in treated areas.

17. Subgingival drug-microbial contact time
 An adequate drug-microbial contact time must be attained for an
antimicrobial agent to exert its bactericidal or bacteriostatic effects
against targeted microorganisms.
 Gingival crevicular fluid flow into periodontal pockets averages 20 ul
per hour and markedly increases with gingival tissue inflammation
(Cimasoni et al 1983).

18.  Oosterwaal et al 1990 found a nearly
2-log decrease in gingival crevicular
fluid levels of an injected sodium
fluorescent dye within 5 minutes of
subgingival placement.
 The rapid clearance of substances
from the periodontal pocket limits the
efficacy of locally applied, nonbinding
antimicrobial agents in periodontitis
treatment.

19. Tetracycline:
I. Fibers:
 A new local drug delivery method, tetracycline-impregnated fibers,
became commercially available.
 Each tetracycline-impregnated fiber is 0.5 mm in diameter and is a
copolymer of ethylene vinyl acetate and tetracycline hydrochloride. It
is extruded as a 23-cm flexible monofilament that contains 12.7 mg
of evenly dispersed tetracycline.

20.  During a 10-day placement interval,
tetracycline-impregnated fibers delivered
25% of available tetracycline and produced a
sustained, high level of tetracycline
(averaging 1590 μg/ml) in GCF (Tonetti M et
al 1990).

21.  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 further
appointment for removal as it
biodegrades within 7 days.

22. II. Gel:
 Tetracycline-Serratiopeptidase-Containing
Periodontal Gel Formulation has shown
statistically significant results along with scaling
and root planing.(Maheshwari et al 2006)
 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.(Schwach et al 2002)

23.  In general, tetracycline fibers used as a monotherapy without
adjunctive scaling and root planing were effective at reducing probing
depths, in gaining clinical attachment and reducing monitored
bacteria, though the results of monotherapy were not significantly
different when compared to scaling and root planing.(Drisko et al
1995)
 Tetracycline fibers have shown a better result when used as an adjunct
to scaling and root planing in patients with refractory periodontitis and
when used at non-responsive sites.

24. Doxycycline:
 Doxycycline is a bacteriostatic agent and has the ability to
downregulate MMP’s a family of zinc dependent enzymes that are
capable of degrading a variety of extracellular matrix molecules
including collagens.(Preshaw 2008)
 Approximately 95% of the polymer is bio absorbed or expelled from
the pocket naturally within 28 days.(Polson et al 1997) Several studies
have reported the efficacy of 10% doxycycline hyclate as a local
delivery antimicrobial agent for achieving probing depth reduction and
gaining clinical attachment

25.  Atridox is a FDA approved
10% doxycycline in a gel
system using a syringe. It is a
subgingival controlled
released product composed
of two syringe mixing
system.
 GCF levels reached its peak
to 1,500-2,000 in 2 hours
following treatment with
Atridox.

26. Minocycline :
 A bacteriostatic antibiotic has been tried clinically via in three
different modes i.e. film, microspheres, and ointment(Akula et al
2000).
I. Film:
 Ethyl cellulose film containing 30% of Minocycline were tested as
sustained release devices. The results of this study indicated that the
use of this device may cause complete eradication of pathogenic
flora from the pocket after 14 days. (Pragati et al 2009)

27. II. Microsphere:
 FDA approved a new, locally delivered,
sustained release form of minocycline
microspheres (ARESTIN) for subgingival
placement.
 The 2% minocycline is encapsulated into
bioresorbable microspheres of 20-60μm
diameter, in a gel carrier and has
resorption time of 21 days. GCF
hydrolyses the polymer and release
minocycline for 14 days or longer before
resorbing completely. (Pragati et al 2009)

28. III. 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, a 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.

29.  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.
 Results have shown that the combination of ointment with scaling
and root planing was significantly better than scaling and root
planing alone in pockets > 7mm.(Van Steenebergh et al 1993)

30. Subgingival Chlorhexidine:
 The long term efficacy of chlorhexidine on periodontal pocket flora is
dependent on exposure time. However, intracrevicular irrigation of the
periodontal pocket with chlorhexidine has only a short lived effect on
the pocket flora.(Abdellaouia 2000).
 Chlorhexidine is available in the form of mouthrinses, Gels, varnishes,
and chip to be used as a local drug delivery agent for the treatment of
periodontal diseases.

31.  2.5 mg Chlorhexidine Gluconate PerioChip, is
a controlled subgingival delivery agent.
 PerioChip 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.

32.  Several large clinical trials were completed which compared the
efficacy of scaling/root planing and combined therapy employing
Chlorhexidine chips.
 The differences between therapies were statistically significant, but
may not be clinically relevant. Furthermore, the number of sites with
probing depth reduction was greater with combined therapy.(Jeffcoat
et al 1998)

33. 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.

34.  Collagen is a natural protein, which is chemotactic for fibroblasts,
enhances fibroblast attachment and stimulates platelet
degranulation, thereby accelerating fibers and clot attachment.
 It has been shown to resorb after 30 days; however their coronal
edge degrades within 10 days.(Nanda kumar 2006)

35. 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
10-30 days of injection and effective
concentration of chlorhexidine against
microorganisms is established for at least 15
days in the region.

36.  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.

37. Subgingival Metronidazole:
 Among the antibiotics that have been considered for periodontal
treatment, Metronidazole has often been chosen because of its
selective efficacy against obligate anaerobes.
 It acts by inhibiting DNA synthesis and is known to convert into a
reactive reduced form and affects specifically anaerobic rods and
spirochetes in subgingival microflora.

38.  A topical medication ELYZOL contains an oil-
based metronidazole 25% dental gel (glyceryl
mono-oleate and sesame oil).
 It is applied in viscous consistency to the
pocket, where it is liquidized by the body heat
and then hardens again, forming crystals in
contact with water.

39.  When metronidazole gel plus scaling and root planing were
compared to root planing alone, the results have not been
consistent.
 One investigation suggested that there was a better result over a 9-
month observation period when combined therapy was employed
for probing depth reduction.

40. Other available LDD systems:
Strips and Compacts:
 Strips are thin and elongated matrix bands in which drugs are
distributed throughout the polymer. Acrylic strips have been fabricated
using a mixture of polymers, monomers and different concentrations of
ant microbial agents by solvent casting or pressure melt method.
 Strips containing tetracycline, MTZ or chlorhexidine demonstrated a
decrease in number of motile rods, notably spirochetes. In a later
development, the evaluation of amoxycillin-clavulainic acid loaded
acrylic strips is reported.

41.  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(Eskanderi et
al 2006).

42. Vesicular system:
 Vesicular liposomal systems are designed to mimic the bio-
membranes in terms of structure and bio-behaviour, and hence are
investigated intensively for targeting periodontal biofilms.
 Jones and Kaszuba reported interactions between liposomes made
up of phosphatidylinositol (PI) and bacterial 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.

43.  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.

44.  Robinson and co-workers reported further on the affinity and
specificity of immunoliposomes to reduce dental plaque. The anti-
oralis immunoliposomes showed the greatest affinity for S. oralis and
affinity was unaffected by net charge on the lipid bilayer or by the
number of antibodies conjugated to the liposomal surface.
Recent advances in periodontal drug delivery systems, Inter Journal of Drug
Delivery 1(2009) 1-14, Pragati et al

45. 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 (Goodson et al 1983).

46.  These systems reduce the frequency of administration and further
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.

47. Hyaluronic acid (Gengigel):
 Available in forms of Membrane, Gels,
Sponges . It is a mucopolysaccharide found in
all living organisms and is a main component
of extracellular matrix.
 Studies have shown hyaluronic acid to be
antiinflammatory, anti-edematous, anti-
oxidative and anti-bacterial leading to their
wide scope in the treatment of
periodontitis.(Cristiana et al 2013)

48.  (Bansal J et al in 2010) showed the role of hyaluronic acid in the
periodontitis as
1. As an adjunct to scaling and root planning.
2. Bone regeneration in periodontal bony defects.
3. Non- surgical treatment of peri-implant pockets.
4. As an autologous cell hyaluronic acid graft in mucogingival surgeries.
5. As a carrier for PDGF (platelet derived growth factor ) and BMP-2 (
bone morphogenic protein) in regenerative therapies.

49.  (Pirnazar P et al in 1999) showed bacteriostatic effect of hyaluronic
acid causing reduction in the bacterial burden at the wound site, and
improving the clinical outcome of regenerative therapy.
 It is found to be particularly effective against Aggregatibacter
actinomycetemcomitans, Provetella oris, and Staphylococcus aureus
stains found in the periodontal wounds.

50. COENZYME Q 10(Perio Q):
 It is a compound naturally found in mitochondria and plays an
important role in electron transport chain process. It is synthesized
intracellularly inside the human body using tyrosine as the
fundamental building block.
 Its role as an antioxidant is well established so it is essential for
health of all tissues and organs. Soni S et al in 2012 has shown that
cells and tissues that are metabolically active like heart, immune
system, gingiva require CoQ in highest amount.

51.  Topical administration to the gingiva as a sole treatment may
decrease GCF flow and probing depths and improve clinical gingival
attachment.
 CoQ supplementation has been beneficial to patients at risk of
periodontal diseases especially diabetics.(Hanioka et al 1994)

52. Simvastatin (SMV):
 It is a new locally delivered drug of class statins, a specific
competitive inhibitor of 3-hydroxy-2-methyl-glutaryl coenzyme A
reductase.
 Statins, besides having lipid-lowering abilities,Studies have shown its
pleiotropic effects in periodontal therapy like host modulation and
bone regeneration(Pradeep et al 2010).

53. Growth factors:
 Platelet-derived growth factor (PDGF), vascular endothelial growth
factor (VEGF), and pyridinoline cross-linked carboxyterminal
telopeptide of Type I collagen (ICTP) are mediators involved in
mitogenesis, angiogenesis, and bone turnover.
 Studies have been done on the effect of the local delivery of PDGF-
BB when combined with reconstructive periodontal surgery on local
wound fluid (WF) levels of PDGF-AB, vascular endothelial growth
factor (VEGF), and bone collagen telopeptide (ICTP) in humans with
advanced periodontitis.
Effect of rhPDGF-BB delivery on mediators of periodontal wound repair. Tissue Eng.
2006 Jun;12(6):1441-50.Cooke et al

54. Conclusion:
 On the basis of available evidence, We conclude that the use of local
drug delivery in periodontal pocket can improve the periodontal
health. However these drugs fail to completely replace the
conventional scaling and root planing.
 Thus use of these drugs as monotherapy is still controversial for
improvement of periodontal parameters. When compared to
systemic antimicrobials the risk of developing resistant bacterial
strains is less.

55.  Also the controlled release properties of local drug delivery are
beneficial in maintaining localized lesions.
 From the advancements in periodontal drug delivery systems
Nanodentistry will make possible the maintenance of
comprehensive oral health by employing nanomaterials,
biotechnology, including tissue engineering and dental
nanorobotics.

56. References:
 Ankur Singh Rajpoot et al ,Local drug delivery in periodontics:A review,
Inter Journal of Research in Health and Allied Sciences,Vol. 3 Issue 4 July –
August 2017
 THOMAES. RAMS& JBRGEN SLOTS, Local delivery of anti-microbial agents
in periodontal pocket, Periodontology 2000, Vol. 10, 1996, 139-159
 Cooke et al,Effect of rhPDGF-BB delivery on mediators of periodontal
wound repair. Tissue Eng. 2006 Jun;12(6):1441-50.
Carranza .Clinical periodontology- 12th edition.

57.  Vicky Kaplish et al Loccal Drug Delivery System in Treatement of
Periodontitis: A REVIEW, Pharmacophore 2013, Vol. 4 (2), 39-49
 Jagjit Singh et al,Local Drug Delivery System in Treatement of Periodontitis:
A Review Journal of periodontal medicine and clinical practice, Vol-III, Issue -
III, Sep-Dec 2016
 Pragati et al Recent advances in periodontal drug delivery systems
Inter Journal of Drug Delivery 1(2009) 1-14,
 Prakash Sapra et al, Recent advances in periodontal formulations,
International Journal of Pharmaceutical Chemistry and Analysis Vol.1,
No.1, October 2014

58. Thank you