LOCAL DRUG DELIVERY

Dr.Padmini Hari
CONTENTS
INTRODUCTION
HISTORY
CLASSIFICATION
INDICATIONS
CONTRAINDICATIONS
ADVANTAGES
PHARMACOKINETICS OF LOCAL DRUG DELIVERY
EVALUATION OF LOCAL DRUG DELIVERY
DOXYCYCLINE
CHLORHEXIDINE
METRONIDAZOLE
MINOCYCLINE
TETRACYCLINE
ADVERSE EFFECTS
LIMITATIONS OF LOCAL DRUG DELIVERY
CONCLUSION
BIBLIOGRAPHY
Learning Outcomes
1. Introduction to Local drug Delivery agents:
Sustained and controlled release drugs.
2. Classify LDD agents and mention the ideal
properties of LDD agent.
3. List the various Indications and Contraindications of
Local drug delivery agents
4. Discuss about the various Local drug delivery agents
approved in periodontics.
5. Outline the benefits of LDD and Scope of use in
periodontics.


INTRODUCTION
The availability of safe and intrinsically efficacious antimicrobial
and anti- inflammatory agents and an increased ability to
locally deliver them in the periodontal pocket have provided
the pharmacological and pharmaceutical tools necessary to
achieve the desired therapeutic effects.

Methods employed to convey antimicrobial agents into
periodontal pockets have included rinsing, irrigation,
systemic administration and local application using sustained
and controlled delivery devices.
HISTORY
Most of the cited initial attempt to utilize controlled
local drug delivery for management of periodontitis is
the work of Goodson et al (1975) who administered
tetracycline to periodontal pocket via hollow dialysis
tubes filled with tetracycline
Though Bethmann in 1973 had investigated.
Ethylene vinyl acetate polymer fiber saturated with
25% tetracycline (Goodson 1983)
Tetracycline fiber was introduced in the United states
in 1994.
CLASSIFICATION
In general local drug delivery devices can be
divided into two classes according to duration of
drug release from the device (Langer and
Peppas, 1981)

a) Sustained delivery devices.
b) Controlled delivery devices

Another classification based on the manner of
application as
1. Personally applied (in patient home
self-care)
A. Nonsustained subgingival drug
delivery (home oral irrigation).
B. Sustained subgingival drug delivery
(none developed to date)

2.Professionally applied (in dental office)
A. Nonsustained subgingival drug
delivery(professional pocket irrigation)
B. Sustained subgingival drug delivery
(controlled-release device).

INDICATIONS
They are logical adjuncts for the treatment of few, localized, non-
responding sites in an otherwise controlled patients (Personalized
aggressive treatment).
Routine use as adjunct with scaling and root planing needs to be
demonstrated.
The ailing or failing implant may be an appropriate situation for local
delivery of antimicrobials.
Periodontal abscess could be ideal for use of nondegradable
tetracycline fibres.
Speculative is possible use of local delivery in periodontal pockets
before regenerative surgery .
Periodontal maintenance therapy.
CONTRAINDICATION
In patients with known hypersensitivity to the
drug.
In pregnancy and lactation
In children under the age of 12 years
In patients with complete renal failure.
IDEAL PROPERTIES OF A LOCAL
DRUG DELIVERY SYSTEM
Goodson(1985) has suggested that for a local drug
delivery system to be effective and clinically useful for
periodontal therapy it must satisfy three needs:
1.The device must deliver drug to base of pocket .
2. The device must deliver the drug at microbiologically
efficacious concentrations.
3. The device must sustain the concentration of the
drug in pocket for sufficient length of time and at
sufficient concentration to be clinically effective.
According to Greenstein and Polson (1998) the
other desirable properties are;
Ease of placement of the device.
Retention after placement
Biodegradability
Other factor is cost of device.
COMPARISON OF VARIOUS DRUG
DELIVERY DEVICES
Mouth
rinse
Subgingival
Irrigation
Systemic
delivery
Controlled
delivery
Reaches site of
disease activity

Adequate drug
concentration

Adequate
duration of
therapy
Poor


Good


Poor
Good


Good


Poor
Good


Fair


Fair
Good


Good


Good
EVALUATION OF LOCAL DRUG
DELIVERY
Pharmacological evaluation-Kinetics of decay
Microbiological evaluation-Decrease in microflora.
Clinical evaluation
-Probing depth
-Clinical attachment level
-Bleeding on probing
Local drug delivery systems with approval or pending
approval by the U.S.Food and Drug Administration
(FDA) or the regulatory bodies of European Union.
Following 5 products have become commercially
available:
Tetracycline fibers (Actisite)
Metronidazole gel (Elyzol)
Minocycline ointment (Periocline)
Chlorhexidine chip (Periochip)
Doxycycline hyclate (Atridox)


Carriers for LDD
DOXYCYCLINE
Doxycycline is substantive to dentin and cementum (Demeril
et al 1991).
Stroller(1998) established that 10% doxycycline in
bioresorbable poly(DL-lactide sustained gel formulation
reaches a GCF concentration of over 1200g/ml.
Salivary levels of doxycycline are over 800g/ml and are
reduced to low levels by first 24 hours.
Atridox
Studies on Doxycycline
Mainly 3 large, 9 month multicenter randomized parallel-
design controlled clinical trials tested the safety and
efficacy of subgingival doxycycline.

The first study was conducted by Polson et al in 1997.Here
pockets 5mm and 7mm treated with three
formulations 5% Sanguinarine chloride ,10%Doxycycline
hyclate and a vehicle control.The study concluded that
10% Doxycycline hyclate in a biodegradable system is a
safe and effective treatment for reduction of clinical signs
of adult periodontitis.
Commercially available doxycycline
Two studies were conducted by Garrett et al in 1998
which compared results of doxycycline hyclate(DH),
vehicle control (VC), oral hygeine(OH) and scaling
and root planing (SRP). The test materials were
applied at baseline and at 4 months.The results of
the study showed that doxycycline hyclate in a
bioabsorbable delivery system is equally as effective
as SRP and superior to VC and OH in reducing clinical
signs of adult periodontitis
CHLORHEXIDINE
The quality of substantivity was described first for
chlorhexidine in the 1970`s(Rolla et al
1971,Bonesvoll et al 1974).
Chlorhexidine chip (Periochip) is an orange-brown
rectangular, rounded on one end. Measures
4mm by 5mm by 0.35mm.It weighs 7.4mg and
contains 2.5mg of chlorhexidine gluconate in a
gelatin matrix.
Size of Periochip
Technique of application
This biodegradable chip is mainly used for pockets 5mm
or more and rounded end is inserted into pocket by
means of a cotton forceps.
The area to be treated is thoroughly dried since wet chip
is difficult to handle.
The entire procedure takes less than 1 min and no
retention system is required.
The patient is instructed to refrain from flossing for 10
days after which it biodegrades thus avoiding further
appointment
Placement of Periochip
Studies on chlorhexidine
European multicenter random clinical trial: This was
the first study conducted at 3 centers with 118 subjects
(Soskolne et al 1997) which had single blind, split mouth
design.Periochip was placed in pockets 5-8mm deep which
bled on probing after scaling and root planing (SRP) and
tested against SRP alone .When results were analyzed it
was seen that SRP plus chip group there was greater
improvement in reduction of probing pocket depth and
clinical attachment gain.
US multicenter random clinical trial: Two muticenter
clinical trials in 10 US centers by Jeffcoat et al in
1998.Here too chip was used adjunctively and tested
against controls in deep pockets .The end of 9
months following inferences were drawn.
- There was significant reduction of probing pocket
depth and probing attachment levels from baseline to
9 months.


- Probing pocket depth reduction was 2mm
-The chip was most effective when placed
every 3 months in pockets that remain 5mm
in depth.
-No adverse events were noted.
Thus chlorhexidine is a safe and effective
adjunctive chemotherapy for treatment of
adult periodontitis.

METRONIDAZOLE
This antimicrobial was introduced in 1960`s for treatment
of vaginal trichomatosis
Shinn reported the beneficial effects of metronidazole on
ANUG.
The various devices that have been used are cold-cured
polymethacrylate resin strips(Addy et al 1982),cellulose
based dialysis tube (Coventry & Newmann 1982), in a
matrix of glyceryl mono-oleate and sesame oil and ethylene
vinyl acetate copolymer hollow fibers (Goodson et al 1983).
Studies on metronidazole
Addy & Langeroudi in 1984 carried out a
microbiological study comparing 40% chlorhexidine
acryllic strips,40% metronidazole and 40%
tetracycline in patients with advanced periodontitis.
Though all of the antimicrobials decreased the
subgingival microflora metronidazole was effective
among all.
Elyzol which is metronidazole in gel form was studied by
Klinge et al in 1992 for a number of sessions in a week.
Similar reduction in the clinical parameters was noted
without adverse reactions.

Ainamo in 1992 studied the clinical effects of adjunctive
use of Elyzol on a large sample of patients and it was
found to be effective. Similar study by Pedrazzoli found
reduction of black pigmented anaerobes in addition to
clinical benefits.
Elyzol application
Application of elyzol
MINOCYCLINE
For minocycline 3 modes of local application have been used
clinically.
A. Film: These films are of ethylcellulose with 30% minocycline
(Elkayam et al 1988).
B. Microspheres: Minocycline microencapsulated in a resorbable
poly(glycolide-lactide) slow release polymer (Brasswell et al
1992 and Jones et al 1994).It can be applied with a syringe.
C. Ointment: Minocycline hydrochloride 2% can be incorporated in
ointment. It is yellow coloured ointment base of 20 mg
hydroxyethyl cellulose,25 mg magnesium chloride supplied in
disposable polypropylene applicator
Application of minocycline
Concentration of minocycline in periodontal
pocket was 1300g/ml 1 hr after application
and decreased to 90g/ml after 7 hours
(Satomi et al 1987).
Serum levels after subgingival administration
was 0.1-0.2g/ml (Wantabe et al 1998).
Van steenberghe in 1993 studied minocycline
ointment effect on probing depth reduction at the
end of 12 weeks wherein it was found have a positive
effect.
Timmerman et al in 1996 found contradictory results
in a parallel double blind study on minocycline where
test and control groups did not have a major
difference in clinical parameters.
TETRACYCLINE
The concept of local drug delivery in the form
of tetracycline hydrochloride was shown by
Goodson using dialysis tube.
Tetracycline HCl has the ability to bind to
hard tissue wall of pocket following
subgingival irrigation (Baker et al 1983).
They are nonresorbable cylindrical drug
delivery devices made of plastic copolymer
(ethylene and vinyl acetate)
loaded with 25% tetracycline hydrochloride
powder (Goodson 1983)
It is found to be individually packaged form 0.5
mm in diameter and 3cm in diameter.
It is applied to completely fill the pocket and
maintained with an adhesive for 10 days.
Concentration of tetracycline HCL in
different compartments after application

Compartment Concentration Reference
Gingival fluid
Pocket wall
Root surface
Saliva
Serum
>1300g/ml
43g/ml
detectable
8-51g/ml
undetectable
(Tonetti et al 1990)
(Ciancio et al 1992)
(Morrison et al 1985)
(Goodson et al 1985)
(Rapley et al 1992)
Studies on tetracycline
Several randomised single blind studies have proven the
additional beneficial effects of tetracycline on probing
pocket depth, clinical attachment level and bleeding on
probing.

Newmann et al in 1994 studied the effect of tetracycline
when used adjunctively and found it to be superior.
Drisko et al in 1995 compared various modes of
tetracycline application .Over a 12 month period no
significant difference was found.
ADVANTAGES(Goodson et al 1989)
Better patient compliance
Enhanced pharmacokinetic response
Greater access and ability position the drug adjacent
to the disease.
The ability to deliver a lower total dosage of a drug
at a more controlled concentration.
Elimination of non-oral effects due to extremely low
or undetectable serum drug levels.
Reduced risk of developing drug-resistant microbial
populations at non-oral sites.
ADVERSE REACTIONS
Local drug delivery does not preclude the possible
selection of resistant bacterial strains in the pocket or
the overgrowth of intrinsically resistant organisms
Occurrence of oral candidiasis
Pain on insertion of delivery device.
Development of abscesses
Tooth sensitivity
Patient acceptability
Altered taste sensation.

LIMITATIONS OF LOCAL DRUG
DELIVERY
An incomplete understanding of the etiology
and pathogenesis of different forms of
periodontitis.
Limitations in the intrinsic effectiveness of the
available medicaments.
An insufficient understanding of local
pharmacokinetic parameters of periodontal
pockets.
The lack of suitable carriers for prolonged
local delivery of medicaments in the target
sites.
An inadequate appreciation of the
relationship between the microbial ecology of
periodontal pocket and oral cavity.
The effectiveness of mechanical debridement
in majority of patients and sites.

CONCLUSION
The short and medium term improvement derived from
local drug delivery has been well documented.
Few studies have actually focussed on how local drug
delivery can be incorporated into overall treatment
strategy.
Following the use of local antimicrobial therapy
supragingival plaque control is essential for achieving
clinical improvements ,therefore at no cost should it be
substituted for meticulous oral hygeine (Kornmann 1993).
Maintenance patients are best candidates for local drug
delivery.

Difficulties in access, extent of periodontal destruction,
unfavourable anatomy and difficulty in plaque control may
affect the effectiveness of local drug delivery
To date evidence for furcation treatment nonsurgically
using local drug delivery is limited.
Local delivery devices are logical adjuncts for a few,
localized non-responding sites in an otherwise controlled
patient
Systemic administration on the other hand may prove to be
most beneficial to control infections at multiple sites in
patients with persistent disease.

The benefits of using local delivery systems as
monotherapy may improve periodontal health.
There is no single universal drug that would be
effective in all situations. Therefore bacterial and
antibiotic sensitivity testing may be necessary to
identify putative periodontal pathogens.
Local drug delivery appears to be as effective as
scaling and root planing with regards to reducing the
signs of periodontal inflammatory disease: redness,
bleeding upon probing, probing depth, and loss of
clinical attachment
There are limited term data (5years) evaluating the
efficacy of local drug delivery.
Additional studies are needed to evaluate if local
delivery is effective against tissue invasive organisms.
There is 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.
At present there is insufficient data to indicate that
one local drug delivery device is superior to another
The clinical diagnosis and possibly microbiologial
diagnosis, the treatment objective and a good
understanding of the overall oral ecology are
important factors to be considered in the selection of
most appropriate delivery route to achieve the
desired treatment objective.

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