local drug delivery

Overview

Introduction
Rationale
Advantage
Limitation
Local Delivery Devices

Fibers
Strips and compacts
Films
Injectable systems
Gels

Clinical consideration
Conclusion
References
2

Introduction
Periodontal disease is associated with
bacteria and treatment by
chemotherapeutic agents appears to be
appropriate
Chemotherapeutic agents may be
administered
systemically or
delivered locally
3

 Pocket irrigation
Reduce microbial levels and provide some
improvement in clinical parameters
Response to therapy - mixed
Requires daily professional or patient
administration for best results - (Greenstein - 1991)

lack of drug retention in the periodontal pocket

chief reason for these mixed results
4

 Controlled release local delivery

systems
Antimicrobial is available at therapeutic
levels for several days
Evaluated in several forms and using
different antimicrobials
5

Rationale
Early 1970s - concern emerged with
respect to systemic antibiotic therapy for
chronic infections such as periodontal
disease
Side effects including
hypersensitivity,
gastrointestinal intolerance and the
development of bacterial resistance
6

 severe or aggressive forms of

periodontitis in young subjects often
cannot be arrested by mechanical
treatment alone
Some patients or sites where even
repeated treatment fails to stop the
disease
referred as refractory subjects or nonresponding sites

 Related to the persistence of pathogens in the pocket

after treatment or to the production by the bacteria
of specific virulence factors interfering with the host
defense (e.g. leukotoxin production, encapsulation,
etc.)
Could be due to the recolonization of treated sites
from bacterial reservoirs such as dentinal tubules
and soft tissues
In this context - antimicrobial agents are of great interest
and may be valuable as adjuncts to mechanical therapy
8

Advantage
Show improve patient acceptance and compliance
More possible for direct access to target
diseases/various periodontal diseases
Reduce oral healthcare treatment cost
Offers avoidance of GI tract with problems of oral
drug administration
9

 Serve as a reliable route for drug administration

in very ill patient who are not able to swallow
Bypasses the first pass metabolism by the liver
Can offer increase therapeutic efficacy of the
drug
10

 Route is safe and convenient route

Can produce longer duration of action
Offers noninvasive, painless, and simple
application
11

Limitation
Not feasible for local irritants
Drug and other excipients used in the formulation
processing either erythema, itching, or local arrhythmia
cannot be delivered by this route

Dose is limited because of relatively small area

Presystemic metabolism may occur by the enzymes
like peptidase and esterase
12

 Should be devoid of irritancy or a

sensitization
Manufacturing cost of the patches or
devices should be taken in
consideration
13

Local Delivery Devices

1.
2.
3.
4.
5.

Fibers
Strips and compacts
Films
Injectable systems
Gels
14

Fibers
Hollow fibers
Ethylene vinyl acetate fibers

15

Hollow fibers
Released tetracycline at a first order
rate with 95% of the drug released in
the first 2 h
GCF - remained in the therapeutic range
for 24 h and some effects on spirochetes

Study should be viewed primarily as an

evaluation of drug delivery
16

Ethylene vinyl acetate fibers

Tetracycline
incorporated
into
polymers
Polyethylene,
Polypropylene,
Polycaprolactone,
Polyurethane,
Cellulose acetate propionate and
Ethylene vinyl acetate (EVA)

different

17

 EVA fibers Tetracycline

maintained constant drug levels in GCF of
periodontal pockets above 600 mg/ml throughout
day 10

M. Tonetti et al. - 1990

GCF - equilibrium with the same binding sites

occupied by tetracycline following 1% irrigation
18

 Tetracycline fibers
with the exception of
Porphyromonas
gingivalis
R.A. Lowenguth et.al. Evaluation of periodontal treatments using
controlled release tetracycline fibers. Microbiological response, J.
Periodontol. 66 (1995) 700 -707.
19

Strips and compacts

Larsen
studied in vitro release of doxycycline from
different bioabsorbable materials and acrylic
strips

Acrylic strip and Colla Cote decreased to

low levels of both concentration and
residual antibacterial activity in a few days
20

 25% tetracycline hydrochloride or

metronidazole in poly(hydroxybutyric
acid) (PHBA) as a biodegradable
polymer matrix showed sustained
release over 4-5 days with a
significant burst effect at day 1
21

 may involve the risk of leaving injurious

acrylic material in the periodontal
pocket upon removal of the strip
Removal of the strip - may cause
damage to regenerating tissue
Showed sustained release over 4 - days
with a significant burst effect at day 1
22

Compacts
Compacts based on PHBA containing
tetracycline hydrochloride
50% (w/w) of tetracycline, the mean
drug concentration obtained was in the
therapeutic range over the 10 days
23

 controlled release strip coded PT-01 and

made of poly (methacrylic acid) and
hydroxypropyl-cellulose containing 10%
ofloxacin - Kimura et al. (1991)
found in higher concentrations than the MIC of
most periodontopathic bacteria in GCF over 7
days by a single application in the human
periodontal pocket
24

Films
Made of
Eudragit L and Eudragit S, two water soluble
poly(methacrylic acid-co-methyl methacrylate),
and
Eudragit RL - non-water soluble polymer poly(ethyl
methacrylate-co-chlorotrimethyl ammonium
methyl methacrylate),

developed by Higashi et al. (1991) for the

delivery of clindamycin
25

 Total drug release varies from 1 to 100

h
concentration in the GCF
maintained at a constant level for 24-72 h

Time of drug release - too low for

further clinical studies
26

 Sustained release devices composed of a

cross-linked fish gelatin containing
chlorhexidine diacetate or chlorhexidine
hydrochloride
developed by Steinberg et al. (1990)

In vitro release profile of chlorhexidine from

such degradable films is dependent on the amount of CHX incorporated
into the film (cross-link density of the polymer
and chlorhexidine salt used)

Time of total drug release is short & varies

from 4 - 80 h

27

 Films based on synthetic biodegradable polymers

poly(lactide-co-glycolide) (PLGA) containing
tetracycline

Incomplete release of tetracycline;

only 30-60% of total tetracycline - released

- R.K. Agarwal et al. 1993

28

 Atelocollagen
preparations
with
immobilized tetracycline
Collagen film treated by cross-linking and
containing tetracycline
showed an amount of tetracycline exceeding
the effective dose ( 8 mg/ml) in the GCF, even
on day 10 after insertion of the preparation

- M. Minabe et al.1989
29

 Ethyl cellulose films - 20% metronidazole or

20% chlorhexidine
compared to short-term use of systemic antibiotic
therapy in patients with advanced forms of
periodontal disease in order to prevent the
normally necessary access surgery

All teeth - scaled just before the insertion of the

films
93% reduction in the need for periodontal
surgery for individual teeth and an 81%
reduction in the need for tooth extractions
W.J. Loesche et al. Oral Surg. Oral Med. Oral Pathol.
Endod. 81 (1996) 533-543.
30

 New film composed of cross-linked

hydrolyzed gelatin and glycerin for local
delivery of chlorhexidine digluconate
has
been
developed
and
commercialized under the trademark
Periochip
- G. Goffin (1998)
31

 biodegradable film
showed an initial burst effect in the first
24 h, whereby 40% of chlorhexidine was
released, probably due to diffusion,
Constant slower release over about 7
days, occurring partially in parallel with
enzymatic degradation of the film
32

Insertion of a chlorhexidine chip into a residual

pocket mesial to an upper molar with a furcation
involvement
33

 in vivo study on 12 patients reported chlorhexidine concentrations of 800-1000 mg/ml in

the GCF in the first 48 h after the Periochip placement
Followed by lower concentrations of 100 - 500 mg/ml
over the next 6 days

Concentrations above the MIC for most

pathogens (150 mg/ml) were seen for at least 7
days
34

 Compared to scaling and root planing alone

Periochip treatment adjunctive to scaling and
root planing showed significant reduction in the
probing pocket depth, a gain in attachment
level for pockets > 7 mm at 6 months
decrease in the GI & in BOP at 3 months

Advantage
Remains inside the pocket with no additional
aids for retention because of the adhesive
nature of the Periochip components
35

36

Injectable systems
Attractive for the delivery of antibiotic
agents into the periodontal pocket
Easily and rapidly carried out, without
pain, by using a syringe
Cost of the therapy is considerably
reduced compared to devices that need
time to be placed and secured
Biodegradable micro particles and gels
37

Microparticles
Based on biodegradable poly(ahydroxyacids)
poly(lactide) (PLA) or
poly(lactide-co-glycolide) (PLGA)

containing tetracycline - designed for

periodontal disease therapy
P. Esposito et al. (1997)
38

 Tetracycline release rate is influenced by the

polymer choice (lactide/glycolide ratio)
polymer molecular weight and crystallinity)
pH of the medium

Tetracycline release rate is increased as the pH

increases
PLGA microspheres - proposed for delivery of
histatins
39

 PLGA microspheres containing minocycline

were evaluated alone or as an adjunct to
scaling and root planing, in comparison to
scaling and root planing alone or to no
subgingival treatment in adult periodontitis
A.A. Jones et al-1994

Data - probing depth reduction with

treatment plus scaling and root planing was
significantly greater than all other groups at
1 month
40

 No differences in probing depth

reduction - at 6 months
Significant reduction in
Porphyromonas gingivalis 1 month
after therapy
41

Electron photomicrograph of
minocycline microsphere
Right cross-sectional
photomicrograph of microsphere
showing minocyclin HCL particles

Minocycline microsphere:
unit dose cartridge and
handle
42

43

Gels
1. Metronidazole- containing gel
2. Tetracycline containing gel
3. Gel containing 1% clindamycin
hydrochloride
4. gel formulation based on 2.5%
hydroxy propylmethyl cellulose
containing 0.125% histatin
44

Metronidazole-containing gel
based on hydroxyethylcellulose, Carbopol 974P
and Polycarbophil

In vitro drug
decreased

release

was

significantly

as the concentration of each polymeric component

was increased, due to both the concomitant
increased viscosity of the formulation and
additionally, the swelling kinetics of polycarbophil
following contact with dissolution fluid
D.S. Jones et al. 1997
45

 Increasing the concentrations of each

polymeric component
significantly
increased
formulation
hardness,
compressibility,
adhesiveness and syringeability due to
polymeric effects on formulation viscosity.
46

Elyzol
Injectable lipid-like vehicle based on glycerol
monooleate and sesame oil containing 25%
metronidazole
Initially thixotropic carrier thickens into a gel
According to the manufacturer,
formation of highly viscous liquid crystals when
the formulation is in contact with water is
responsible for this effect
47

 Therapeutic levels of metronidazole are reported

for a period of 2-3 days and the agent should be
used twice in 3 weeks

Data indicate that local metronidazole gel in combination with SRP

seems to be more effective in terms of
producing both clinical and microbiological
improvements
compared to pure mechanical and pure
metronidazole treatments
48

 Controversial results reported in another study

do not support the routine use of adjunctive
Elyzol in the non-surgical treatment of
periodontitis because of the poor clinical and
microbiological efficacy compared to scaling and
root planing alone
R.M. Palmer - 1998

Probably due to the rapid elimination of Elyzol gel

from the periodontal pocket
K. Stoltze, Elimination of Elyzol 25% Dentalgel
matrix from periodontal pockets, J. Clin. Periodontol.
22 (1995) 185-187.
49

Probing depth reduction with

metronidazole gel

50

Tetracycline gel
Bioadhesive semi-solid systems based on
Hydroxyethyl cellulose (HEC)
Polyvinyl pyrrolidone (PVP)

Increased concentrations of HEC decreased the rate of

release of tetracycline, due to the concomitant increase
in product viscosity and the subsequent decreased rate
of penetration of dissolution fluid into the formulation
Conversely, an increased PVP concentration increased
tetracycline release rates, due to an increased
formulation porosity
51

 Increased concentrations of HEC and

PVP
increased the hardness,
compressibility
work of syringeability of semi-solid
formulations and
Adhesiveness
52

 Two other semi-solid lipid-like formulations based on

poly(oxyethylene-co-oxypropylene) (poloxamer) and
glycerol monooleate developed for tetracycline released
- Esposito et al. (1996)

Characterized by a solid-gel transition and become

semi-solid once in the periodontal pocket
After 7 h, in vitro tetracycline release - 18% and
65% of the entrapped drug for monoglyceride and
poloxamer gels, respectively
53

 persistence of monoglyceride gel is

more prolonged than that of
poloxamer gel
Poloxamer disappeared after 1 h while
monoglyceride gel - still retained after 8
h
54

 A short-term split mouth clinical trial subgingival application of both gels in conjunction
with scaling and root planing produced
clinically and statistically significant improvement
outcome in moderate to deep periodontal pockets

Surprisingly, in spite of the rapid drug release

and the poor retention of such gels,
positive clinical results were obtained
55

 2% minocycline have been commercialized

under several trademarks
Periocline
T. Nakagawa et al- 1991
K. Hayashi et al -1998

Dentomycin
M.A. Graca et al (1997)
56

 Gel is composed of
Hydroxyethylcellulose,
Aminoalkyl-methacrylate copolymer,
triacetine,
Magnesium chloride and
Glycerynum concentratum
57

 Administration of periocline - once a week for 4

consecutive weeks
At week 4, proportions of P. gingivalis & A.
actinomycetemcomitans - significantly
decreased in treated sites
Prevotella intermedia was detected
from 7 of 22 sites at week 4 and
16 sites at week 12 in treated sites

Minocycline treated sites

associated with a significant decrease in probing
depth and bleeding on probing compared with
those of control sites at week 4
58

Dentomycin gel
Adjunctive formulation provided a more
advantageous outcome for non-surgical
periodontal treatment in terms of attachment
level and bleeding on probing
M.A. Graca, T.L.P. Watts, R.F. Wilson, R.M. Palmer, A
randomized controlled trial of a 2%minocycline gel as
an adjunct to non-surgical periodontal treatment,
using a design with multiple matching criteria, J. Clin.
Periodontol. 24 (1997) 249-253.
59

 study - 54 patients with four pockets 5

mm and bleeding on probing, the efficacy of
three commercialized available periodontal
systems for local delivery of antibiotics as
adjuncts to scaling and root planing was
evaluated
M. Radvar, N. Pourtaghi, D.F. Kinane, Comparison
of 3 periodontal local antibiotic therapies in
persistent periodontal pockets, J. Periodontol. 67
(1996) 860-865.
60

 Four treatment groups included

1. scaling and root planing alone,
2. scaling and root planing plus application of
25% tetracycline fiber (Actisite),
3. scaling and root planing plus application of
2% minocycline gel (Dentomycin) and
4. scaling and root planing plus application of
25% metronidazole gel (Elyzol)
61

 Clinical measurements - baseline and 6

weeks after the end of treatment periods
improvements in clinical parameters
scaling and root planing alone in all
three adjunctive treatment groups
probing depth reduction - significantly
greater in the scaling plus tetracycline
fiber group (1.35 mm) than the scaling
and root planing alone group (0.6 mm)
62

 improvement of the attachment level

or bleeding on probing - not significant
Scaling plus tetracycline fiber
treatment - greatest reduction in the
gingival index scores
63

 Considering the time and cost involved in using

different
locally
delivered
antimicrobial
systems, using these agents does not seem
justified as part of initial periodontal therapy
suggested - following initial phase therapy,
tetracycline fibers could be used in place of
surgery for sites with remaining severe
disease, whereas the other systems might be
applicable in less severe cases
64

Atridos injection

Injectable biodegradable delivery system

containing 10% doxycycline hyclate (Atrigel
based on a biodegradable polyester
poly(DL-lactide) dissolved in a
biocompatible solvent N-methyl-2pyrrolidone (NMP)
65

 can pass through a cannula into a

periodontal pocket where it solidifies in situ
to deliver the therapeutic agent over 7 days
Analyses of the bioactive doxycycline levels
into the GCF showed a level of 250 mg/ml
during a period of 7 days
levels of 10-20 mg/ml were still present for 35 days after the polymer had been removed
G.L. Yewey et al (1997)
66

 A comparative study using the same

Atrigel delivery system containing either
10%
doxycycline
hyclate
or
5%
sanguinarine hydrochloride
clinical
and
statistical
superiority
were
observed in the doxycycline group for all
parameters when compared to the formulation
containing sanguinarine and the vehicle alone
A.M. Polson et al.(1997)
67

Gel containing 1% clindamycin

hydrochloride
mucoadhesive gel formulation based on
4% Carbopol
evaluated in vivo on microbial flora of
periodontal pockets deeper than 5 mm - E.
Sauvetre et al. 1993
Active and placebo gels were inserted once
a week for 2 weeks in sites that received
subgingival scaling and root planing
68

 Changes in the microbial content of the

periodontal pockets treated by subgingival
scaling and 1% clindamycin gel were significant,
compared with negative controls, particularly
with respect to anaerobic blackpigmented
bacteria and the motile gram-negative flora
after 3 months, most of the treated cases were
recolonized by the same initial species
69

Gel containing 0.125% histatin

based on 2.5% hydroxy propyl methylcellulose
Studied in vivo in beagle dogs - Paquette et al. (1997)
Active and placebo formulations were tested for 10 weeks
and applied twice daily around premolar teeth
Reported that beagles treated with active gel demonstrated
significantly lower plaque index scores at day 42,
significantly lower gingival index scores from day 21 through 42
significantly lower percentage of bleeding on probing scores at
days 14 and 28 compared to beagles treated with placebo gel

70

Clinical consideration
The following medications are the
most often prescribed
Actisite
Atridox FDA approved
Arestin
PerioChip
Periostat
71

Susceptibility of suspected pathogens

to various antimicrobials agents

72

 Atrigel delivery system

Maintained in the pocket by the addition of
periodontal adhesive (Octyldente) or periodontal
dressing (Coe-Pack or Periocare)

Poor retention of oil-based delivery systems

within the aqueous environment of the
periodontal pocket as in the case of Elyzol
Deleterious effects of plasticizers leached
from solid polymeric drug delivery systems
on the periodontal tissues
73

Tetracycline fiber

doxycycline hyclate in Biodegradable

polymer

25% metronidazole dental gel

74

Local drug delivery at deep pocket

depth
Greater than 7 mm pocket
SRP become less efficient

75

76

When to administer ?
Patient may respond to conventional
therapy so routine local drug therapy is
not advocated
Not indicated in aggressive form of
periodontitis
Indicated in non responding to SRP alone
Localised recurrent disease
77

Conclusion
Effectiveness of SRP may be enhanced with
antiseptics and antibiotics
Medication - released over 1 to 3 weeks and
helps eliminate the disease causing bacteria
with a high concentration of a drug or
antiseptic
Gives the gum tissue more time and a better chance
to heal without the disease causing bacteria present
78

 Useful adjunct to conventional

surgical or non-surgical treatments,
but are no substitute for these measures

Controlled delivery systems are of

interest as an adjunct for recurrent
and refractory periodontitis

79

References
1. K. Schwach-Abdellaouia, N. Vivien-Castionib, R. Gurny. Local
delivery of antimicrobial agents for the treatment of
periodontal diseases. European Journal of Pharmaceutics
and Biopharmaceutics 50 (2000) 83-99.
2. Mahesh R. Dabhi et.al. Formulation development of smart
gel periodontal drug delivery system for local delivery of
chemotherapeutic agents with application of experimental
design. Drug Delivery, 2010; 17(7): 520531.
3. Arthur J. Bonito et al. Impact of local adjuncts to scaling and
root planing in periodontal disease therapy: A systematic
review. J Periodontol 2005;76:1227-1236.
4. R.J, Oringer et.al.effect of locally delivered Minocyclin
microsphere on marker of bone resorption. J Periodontol
2002;73:835-842.
80

5. Maria Pavia,Carmelo G.A. Nobile, and Italo F. Angelillo.

Meta-analysis of local tetracycllin in treating chronic
periodontitis. J Periodontol 2003;74:916-932.
6. Maria Emanuel Ryan. Nonsurgical Approaches for the
Treatment of Periodontal Diseases. Dent Clin N Am 49
(2005) 611636
7. Pragati S, Ashok S., Kuldeep S. Recent advances in
periodontal drug delivery systems . International Journal
of Drug Delivery 1(2009) 1-14
8. Gary Greenstein. Local drug delivery in the treatment of
periodontal disease: assessing the clinical significance of
the results. . J Periodontol 2006;77:565-578.
9. Killoy WJ: The clinical significance of local chemotherapies.
J Clin Periodontol 2002; 29 (Suppl 2): 2229.
81

Thank you !

82