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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