Advance Local Drug Drug Delivery Approaches for Periodentitis.

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Research & Reviews: A Journal of Pharmaceutical Science
ISSN: 2229-7006 (Online)
Volume 9, Issue 1
www.stmjournals.com
Advanced Local Drug Delivery Approaches for
Periodontitis: A Strategic Intervention
Shivani Patel, Jaimini Gandhi*, Harita Naik, Lakshmi Pillai, Pranav Shah
Department of Pharmaceutics, Maliba Pharmacy College, UKA Tarsadia University, Maliba Campus,
Bardoli, Surat, Gujarat, India
Abstract
Periodontal disease, one of the most prevalent oral diseases is caused by the gram negative
bacterial infection of periodontal pocket identified by inflammation of subgingival plaque and
degeneration of alveolar bones, teeth, dental cementum and periodontal ligaments. 80% of
American adult and more than 50% of Indian community suffers from this chronic
inflammatory disease depicting the severity of the disease. The objectives of the available
therapies are to minimize the bacterial infection and to regenerate the damage done by
infection and inflammation. The therapies involve systemic therapy, conventional therapy, as
well as local therapy. Conventional therapy is further divided into two subtypes: surgical
therapy and non-surgical therapy. Surgical therapy involves scale up and root planning but it
leaves microorganisms behind due to the use of metallic instruments. Non-surgical therapy
and systemic therapy involves the use of antibiotics but both the therapies fail as a result of
the insufficient drug concentration attained at the target site. Local therapy which involves the
use of novel dosage forms like gels, films, strips, fibers, nanoparticles and microparticles
maintains the drug concentration at a level greater than the Minimum Inhibitory
Concentration (MIC) in the gingival crevicular fluid for a prolonged period of time (10–
12 days). This ultimately reduces the dosing frequency, thereby increasing patient
compliance.
Keywords: Inflammation, infection, therapy, plaque, drug
*Author for Correspondence E-mail: jaimini.gandhi@utu.ac.in
INTRODUCTION
Periodontal disease, an infection of
periodontal pocket is caused by gram negative
bacteria and is identified by symptoms like
subgingival plaque, inflammation and
degeneration of alveolar bones, teeth, dental
cementum and periodontal ligaments [1, 2].
Gingivitis at an early stage is identified by
gingival swelling of gums, bleeding, bad
breath and at severe stage, it shows symptoms
like degeneration and inflammation of gums,
alveolar bone, and dental cementum which is
commonly known as periodontitis. At the
severe phase of disease, there occurs
degeneration of supporting collagen and
periodontal ligament and resorption of alveolar
bone and gingival epithelium that finally leads
to the formation of periodontal pocket.
The source of periodontal diseases are usually
gram negative, facultative anaerobic bacterial
species like B. intermedius and B. gingivalis;
fusiform organisms: Actinobacillus,
actinomycetemcomitans, Wolinella recta and
Eikenella spp.; and various bacilli and cocci;
spirochetes; amoebas and trichomonas.
The condition even gets worsened to a greater
degree when the bacterial species releases
their harmful byproducts, mainly enzymes
leucotoxins, collagenases, fibrinolysins and
other proteases and chemicals that cause an
immune reaction by activating the immune
system into the periodontal pocket. All these
events occur simultaneously and eventually it
leads to the loss of teeth [2].
Periodontal diseases are one of the most
widespread oral diseases, where 80% of
American adults and more than 50% of Indian
community suffers from this chronic
inflammatory disease which demonstrates the
severity of the disease [3].
TREATMENT STRATEGIES
Ideal treatment strategies should focus mainly
on the following:

Advanced Local Drug Delivery Approaches for Periodontitis Gandhi et al.
RRJoPS (2018) 4-11 © STM Journals 2018. All Rights Reserved Page 5
1. It should give more or equivalent drug
concentration than MIC in periodontal
pocket to destroy bacterial culture.
2. It should reach deep enough in the
periodontal pocket to treat periodontal
disease.
3. It should give prominent effect at normal
dose.
4. It should give sustained effect with
constant release rate to maintain MIC.
Due to the pathological conditions existing at
the periodontal pocket, it serves as a
cultivating space for bacterial species.
Therefore, the target of any proposed therapy
should be to regenerate the damage caused by
bacterial infection and to maintain the normal
condition.
Conventional Drug Delivery
The objective of conventional therapy is to
reduce the bacterial flora, reduce inflammation
and to stop bone resorption. Conventional drug
therapy is further split into:
1. Surgical therapy, and
2. Non-surgical therapy.
1. Surgical therapy involves mechanical
scaling, root planning and curettage.
Surgical therapy aims at the removal of
plaque and cleansing of the area damaged
by periodontal infection that would result
in non-favorable conditions for the growth
of bacteria. In spite of the merits, such
therapies can be painful and can have
bacteria left at the site due to the
instruments used in the therapy.
2. Non-surgical therapy involves
antimicrobial/chemotherapeutic drug
treatment that directly attacks the
microbes giving a more pronounced effect
but such therapies are unable to assess the
much deeper regions of periodontal pocket
[1].
Systemic Therapy [4, 5]
Systemic therapy involves antimicrobial
agents like minocycline, azithromycin,
moxifloxacin, doxycycline, clindamycin,
metronidazole or their combinations. Such
agents, when given systemically, reach the
gingival area as it has good blood supply,
providing effect at the periodontal pocket.
Demerits involve:
1. Low benefit/risk ratio,
2. Requirement of large dose,
3. Inability to give sustained drug release,
4. Frequent dosing,
5. Frequent chances of bacterial resistance,
and
6. Inability to assess deeper areas of
periodontal pocket.
Local Drug Delivery System [6, 7]
Local drug delivery involves different
mechanisms and approaches to release drug in
the periodontal pocket. Such systems release
the drug directly into the periodontal pocket
and are able to give sustained release up to
11 days. Benefits of local drug delivery into
periodontal pocket are as follows:
• Directly reaches the target site.
• Improvement of patient compliance.
• Avoidance of GIT-related issues due to
oral drug delivery.
• Avoidance of first pass metabolism.
• Enhanced therapeutic efficacy of the drug.
• Reduced treatment cost.
• Suitable for those patients having
presystemic metabolism.
• Safer and convenient route of drug
administration.
• Enhanced duration of action.
• Simple, painless and non-invasive therapy.
• Drug concentration maintained at the
target site.
• Reduced side effects.
• Reduction of dosing frequency.
Limitations of local drug delivery into
periodontal pocket are as follows:
• Local irritants cannot be administered.
• Dose is limited because of relatively small
area.
• Presystemic metabolism occurs for drugs
that degrade through peptidase and
esterase.
• Administration of peptides not feasible
due to the degradation by the enzyme
peptidase.
• This route understood the needs for high-
potency drugs.
• Manufacturing cost of the patches and
devices.

Research & Reviews: A Journal of Pharmaceutical Science
Volume 9, Issue 1
ISSN: 2229-7006 (Online)
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Classification of Local Drug Delivery [1]
1. Based on Type of Therapy:
• Personally applied (patient home
care):
a. Non Sustained (Oral irrigation), and
b. Sustained (not developed till now).
• Professionally applied (in dental
office):
a. Non Sustained (Supra and subgingival
irrigation), and
b. Sustained (Controlled release device).
2. Based on Degradability of the Device:
• Biodegradable, and
• Non- Biodegradable.
3. Based on Duration of Action:
• Sustained Released Devices: These are
the delivery systems whose actions
last for less than 24 h; thereby require
multiple applications. It follows the
first order kinetics.
• Controlled Delivery Devices: These
are the delivery systems whose actions
last longer than 24 h; thereby reducing
the number of applications. It follows
zero order kinetics.
VARIOUS APPROACHES FOR THE
TREATMENT OF PERIODONTITIS
Gels [6]
Gels are semisolid dosage forms used to target
antibiotics. Gels can be easily prepared, have
good biocompatibility, mucoadhesiveness and
patient compliance. It is widely used dosage
form for local drug delivery. Gel can also be
eliminated easily, so there are least chances of
sensitivity reaction or irritation to the patient.
Different compositions of gels containing
tetracycline (2.5%), metronidazole (25%),
metronidazole benzoate (40%), combination of
tetracycline (2.5%) and metronidazolebenzoate
(40%) made with HPMC (hydroxyl propyl
methyl cellulose) had demonstrated positive
clinical result but were unable to show
sustained release [8–10].
Merits
• Provides controlled drug delivery,
• Enhanced bioadhesive property,
• Greater biocompatibility,
• Elimination of immune reaction, and
• Prolonged release at the target site.
Demerits
• Reduced retention, and
• Rapid drug release.
Figure 1 shows the insertion of gel.
Fig. 1: Insertion of Gel.
Fibers
Fibers are thread like, reservoir type of drug
delivery devices, placed into the periodontal
pocket using an applicator and sealed by
means of a cyanoacrylate adhesive. Fibers
made up of polymers like ethyl cellulose or
polyethylene can give sustained release for up
to 7 days. Patients have experienced
discomfort and gingival redness to various
degrees but such redness can be reduced by
removing the fiber after 7–10 days [2]. Hollow
fibers of cellulose acetate with tetracycline
HCl kept in periodontal pocket resulted in the
prominent reduction of microorganisms in
comparison to scaling and root planning
whereas it was observed that fibers have
released their 95% of drug content within 2 h
[11, 12]. A number of polymers such as
poly(e-caprolactone) (PCL), polyurethane,
polypropylene, cellulose acetate propionate,
ethyl vinyl acetate (EVA) have been tested for
controlling drug release. Among the tested
polymers, EVA controlled the drug release
exceptionally well. Monolithic EVA fibers
were also found to control the rate of the drug
release and similar results were observed in-
vivo and in-vitro [13–15]. EVA fibers
containing 25% tetracycline hydrochloride
maintained constant drug concentration in the
GCF above 600 mg/ml for 10 days,
representing zero-order release characteristics
of fibers [8].
Merits
• Sufficient drug concentration,
• sustained release,
• Reduced dosing frequency, and
• Reduced frequency of bacterial resistance.

Advanced Local Drug Delivery Approaches for Periodontitis Gandhi et al.
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Demerits
• Reduced patient compliance,
• Reduced retention of the system, and
• Reduced penetration of system.
Figure 2 sows the insertion of fiber into the
periodontal pocket.
Fig. 2: Insertion of Fiber into the Periodontal
Pocket.
Films
Films are prepared either by solvent casting
method or direct milling method. Films are
applied to the cavity, gingival surface, cheek
mucosa or can be modified to a specific size
for application in the pocket by cutting. Films
are basically matrix systems in which the drug
is dispersed into the matrix and gets released
by diffusion or matrix erosion or dissolution.
Dimensions of the film can be designed
according to the pocket size. Patient feels
uneasy when the size of the film is more than
400 µm. Films which release drug by diffusion
have good adherence property [2]. Non-
biodegradable ethyl cellulose film of
chlorhexidine diacetate [16], metronidazole
[17], tetracycline [18] and minocycline [19]
using chloroform insolvent evaporation
method have been prepared and tested
clinically. These films established sustained
release but rate of drug release was dependent
on drug loading and the type of solvent used.
For instance, chloroform comparison to
ethanol as a solvent reduced the drug release
rate to a greater extent [20], whereas the use of
polyethylene glycol increases the drug release
rate [17]. But clinical results state that using
the ethyl cellulose films increases the chances
of bleeding as compared to conventional
therapy. There is no requirement of removing
the biodegradable films after application that
adds to the benefits of the film [2].
Advancements in polymer studies suggest that
biopolymers like atelocollagen, (preparation of
pepsin digested insoluble bovine skin
collagen) can be used as a promising carrier
for the transport of antibiotics. Tetracycline
when incorporated with glutaraldehyde cross
linked atelocollagen showed prominent level
of tetracycline in GCF (gingival cervical
fluid).
Gelatin obtained from fish was crosslinked to
sustain the release of chlorhexidine diacetate
or chlorhexidine HCl which showed 4 to 80 h
of release, dependent on the type of the
polymer and on the degree of cross-linking
[21, 22].
Figure 3 shows the insertion of film and chip
into the periodontal pocket.
Fig. 3: Insertion of Film and Chip into the
Periodontal Pocket.
Strips
Strips are thin elongated matrix system
containing drugs that are distributed uniformly
in the polymer. It is mainly made up of elastic
polymers possessing a wide range of
interproximal space [23, 24]. Metronidazole
strips were found to be effective in the
treatment of the subgingival flora [23]. Acrylic
strips when in contact with the serum,
effectively eradicate the microbials from the
pocket but such strips were found to alter its

Research & Reviews: A Journal of Pharmaceutical Science
Volume 9, Issue 1
ISSN: 2229-7006 (Online)
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physical properties when in contact with the
serum which limits the use of such strips.
There are even chances of disruption of such
material during its preparation which may
cause the risk of leaving behind the traces into
the periodontal pocket and thereby provoking
the inflammatory response [25]. In order to
overcome the above said complications,
bioabsorbable strips were prepared that are
biocompatible and biodegradable in nature
incorporating the moieties like tetracycline,
chlorhexidine and doxycycline [26, 27]. Other
natural and synthetic polymers include PCL,
ethyl cellulose, polyhydroxybutyric acid,
hydroxypropyl cellulose,
polymethylmethacrylate, poly (D, L-
lactide/glycolide) and Hydroxypropyl
methylcellulose [6]. Green catechin containing
hydroxy cellulose strips when administered in
the pockets of the patients once a week
continued to give release for 8 weeks; showed
a decrease in the pocket depth and were
effective against P. gingivalis and Prevotella
spp. with an MIC of 1.0 mg/ml [28].
Microparticles
Microparticles are free flowing, solid spherical
polymeric structures of particle size ranging
between 1 and 1000 µm. The drug is
homogenously dispersed in the polymeric
matrix for controlled and sustained release at
the target site. They show good retention
property in the pocket and thereby maintain
the therapeutic level of drug in the pocket and
improve efficacy of the treatment [29]. It also
provides sustained release and enhanced
bioavailability and thereby provides improved
patient compliance by reducing the frequency
of administration [30]; e.g. Chitosan
containing metronidazole loaded
microparticles provides sustained drug release
[31], chitosan microspheres containing
minocycline hydrochloride reduces
periodontal depths and causes a significant
reduction in bleeding on probing at 6 months
[32]. Doxycycline microspheres prepared in
PLGA and PCL provide controlled release in
vitro as well as in vivo. It provides burst effect
initially and followed by controlled release up
to 11 days with good clinical results such as
probing pocket depth. Plaque index [33].
Naproxen and succinyl sulphathiazolein poly
phosphazenes microspheres provide
satisfactory therapeutic levels in periodontal
pocket for eradication of periodontal microbes
[34]. Combination of PLGA and Zein
containing tetracycline forms monolithic
biodegradable microparticulate system in
which there occurs hydrodrophobic interaction
between Zein and drug that was confirmed by
C(NMR) and X-ray diffraction studies [35].
Microparticulate system can be prepared from
non-biodegradable and degradable polymers.
Biodegradable polymers are generally
preferred as they are biodegradable and
biocompatible in nature [36]. The
chlorhexidine loaded PLGA microspheres
modulates the release profile and
encapsulation due to complexation. It shows
good release profile for at least 2 week period
and suitable for targeting antimicrobial agents
[37].
Figure 4 shows the insertion of microparticles
into the periodontal pocket.
Fig. 4: Insertion of Microparticles into the
Periodontal Pocket.
Nanoparticulate System
Nanoparticulates are the dispersed solid
particles of size range about 10–1000 nm. The
drug is either dissolved, entrapped,
encapsulated or attached to a nanoparticle
matrix [30]. Nanoparticles provide control
release rate, enhanced stability, sustained
release of drug, reduced frequency of
administration and can access to unreachable
sites like the periodontal pocket regions [37].
Calcium sulphate bone cement beads
incorporating tetracycline nanoparticles by
ionic gelation method were developed [36].

Advanced Local Drug Delivery Approaches for Periodontitis Gandhi et al.
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The NPs were prepared using Poly (D,L-
lactide-co-glycolide) (PLGA), poly(D,L-
lactide) (PLA) and cellulose acetate phthalate
(CAP) by emulsification-diffusion process. A
preliminary in-vivo study with induced
periodontitis in dogs demonstrated that
tetracycline loaded NPs penetrate through the
junctional epithelium [38]. Harungana
madagascariensis leaf extract (HLE) loaded in
PLGA NPs showed optimized antibacterial
activity [39, 40].
CONCLUSION
Periodontal disease is not easy to treat by one
or many therapies, because every therapy
comes with certain advantages and certain
drawbacks. For improvement of patient
treatment, it is advisable to use combination of
therapies like using gels in periodontal pocket
and scale up and root planning. It is necessary
to choose patient relevant therapy according to
the growth of disease and condition of patient.
Local drug delivery has shown most promising
results with high level of patient compliance.
Care should be taken that proper therapy is
being chosen with proper combination and use
of drugs. Antibiotics like chlorhexidine HCl,
tetracycline, minocycline, moxifloxacin,
ofloxacin and doxycycline are used in
combination. Newer approach for the future
therapies should aim at regenerating the
damage done to teeth, alveolar bone and cavity
as well as periodontal pocket. The difficulty is
in achieving adequate drug concentration
greater than the MIC at the periodontal pocket
without creating drug resistance.
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Cite this Article
Shivani Patel, Jaimini Gandhi, Harita Naik
et al. Advanced Local Drug Delivery
Approaches for Periodontitis: A Strategic
Intervention. Research & Reviews: A
Journal of Pharmaceutical Science. 2018;
9(1): 4–11p.