local drug delivery system
TRANSCRIPT
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Good Morning..
LOCAL DRUG DELIVERY SYSTEMS
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CONTENTS• Introduction• Historical perspective• Terminology• Objectives• Indications• Contraindications• Advantages• Disadvantages• Systemic Versus Local Drug Delivery• Requirements For Local Antimicrobial Agents• Factors Affecting the Bio-availability of an antimicrobial agent• Classification of local antimicrobial therapy in periodontics• Drug delivery systems• Local Drug Delivery’s Impact on Deep Probing Depths (7 mm)• Inhibition of Periodontal Disease Progression• Impact of Local Drug Delivery on Furcations • Repair of Osseous Defects• Future trends• Conclusion
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INTRODUCTION:
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addition of antimicrobials (systemic and local) adjuncts to mechanical therapy.
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Systemic antimicrobia
l agents Adverse effects
Local drug deliveries
HISTORICAL PERSPECTIVE:
W.D. Miller in the 1880’s suggested the use of an antimicrobial mouthrinse (Listerine) to aid in fighting what was then known as ‘Pyorrhea alveolaris’.
The concept of targeted drug delivery had its origin in the 1970’s based on the theory that if one could substantially improve the cellular specificity of a drug there would be an accompanying significant improvement in the therapeutic index; i.e, efficacy to side effects.
Dr. Max GoodSon (1979) first proposed the concept of controlled release local delivery of therapeutic agents for the treatment of periodontitis.
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TERMINOLOGY:• Antimicrobial agents are chemotherapeutic agents that reduce
the amount of bacteria present either by superficially targeting certain organisms or by nonspecifically reducing all bacteria.
• Targeted drug delivery: refers to delivery of medication to a patient in a manner that increases the concentration of the medication in some parts of the body relative to others.
• Local delivery of antimicrobial agents in periodontics Implies antimicrobial therapy placed directly in the subgingival region. The term local delivery is usually used to suggest more specific or targeted delivery of an agent.
• Non-sustained subgingival drug delivery Provides high pocket concentrations of the antimicrobial agent for only short time periods.
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• Sustained subgingival drug delivery/ Controlled release delivery (CRD)
Synonyms: Sustained release, Prolonged release, timed release, slow release, sustained action, prolonged action or extended action.
CRD’s are designed to release a drug slowly and to retain therapeutic level for a prolonged period of time.
Controlled release local delivery: Implies release of chemotherapeutic agents into the periodontal pockets over an extended period of time, provides prolonged drug availability, and sustained drug action.
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OBJECTIVES:
• The use of a local antimicrobial is to prevent or control microbial induced inflammation in an effective concentration and be maintained there long enough for the desired effect to be accomplished without causing any side effects.
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ADVANTAGES:
• Local drug delivery can attain 100 folds higher concentrations of the agent in subgingival sites compared with a systemic drug regimen.
• Local delivery may employ antimicrobial agents not suitable for systemic administration such as various broad spectrum antiseptic solutions e.g. chlorhexidine.
• Personally applied antimicrobial regimens offer the potential of daily placement into pockets, for compliant patients.
• Professionally applied antimicrobial regimens reduce potential problems with patient compliance.
• Local antimicrobial delivery reduces the dangers associated with systemic administration such as toxicity, adverse reactions, resistant strains and superimposed infections.
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INDICATIONS:
• Isolated periodontal pockets (>5mm), with successful phase I therapy.
• Periodontal patients who are medically compromised where surgical therapy is contraindicated.
• In combination with mechanical debridement or alone.
• In patients who are suffering from recurrent or refractory periodontitis.
• During periodontal regenerative procedures.
• Where periodontal surgery is to be avoided or the patient is on supportive periodontal treatment.
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DISADVANTAGES:• Difficulty in placing antimicrobial agents into deeper
parts of pockets and furcation lesions.
• Patient compliance and manual dexterity.
• Time consuming in patients with numerous advanced lesions.
• Do not markedly affect pathogens residing on other oral surfaces.
• Non-sustained drug delivery provides only a brief exposure of the target microorganism to the applied antimicrobial agent.
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Systemic Local 1. Route of administration2. Pain/Discomfort3. Drug dosage
4. Peak levels5. Pharmacokinetics
6. Frequency
7. Super infection
8. Microbial resistance
Oral or ParentalNot painfulHigher drug dosage(in mg)Few hours in plasmaDistribution in variouscompartments whereantimicrobial effect may not be required.Once in 6-12 hours
Present
Present
Site SpecificNilLower dosage(in micrograms)Within few minutes in GCFMinimal body distributionto different compartmentswith maximum concentration at delivered sites.Usually once a week
Limited
Limited
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Systemic Local 9.Patients compliance
10.Time required
11. Side effects12. Effects on connective
tissue associated plaque
Required for better efficacy
Less time
More
Effective
Patient delivered -compliance requiredProfessional Delivered - not requiredLonger time if many sites are involvedLimited
Limited
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REQUIREMENTS FOR LOCAL ANTIMICROBIAL AGENTS
• Safety• Stability• Substantivity• Efficacy• Adequate subgingival delivery• Achievement of effective concentrations• Biodegradable• Retention after placement• No emergence of bacterial resistance• Should be effective only against periodontal
pathogens and not on commensal microflora.• Cost-effectiveness and patient compliance.
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CLASSIFICATION OF LOCAL ANTIMICROBIAL THERAPY IN PERIODONTICS
LANGER AND PEPPAS (1988) - based on their mechanism of action. I. Diffusion controlled systems A. Reservoirs (membrane devices) B. Matrices (monolithic device) II. Chemically controlled systems A. Bio-erodible systems B. Pendant chain systems III. Swelling controlled systems IV. Magnetically controlled systems
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2. RAMS AND SLOTS (1996) - depending on usage I. PERSONALLY APPLIED by patient at home (self-care) A. NON-SUSTAINED SUBGINGIVAL DRUG DELIVERY
Home oral irrigationHome oral irrigation devices:
Devices with traditional jet tips Oral irrigator Soft cone-rubber tips Blunt tipped metal cannula connected to
syringe or oral irrigator B.SUSTAINED SUBGINGIVAL DRUG DELIVERY (none developed to date)
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II. PROFESSIONALLY APPLIED (In dental office) A. NON-SUSTAINED SUBGINGIVAL DRUG
DELIVERYProfessional pocket irrigation devices :
Syringe with blunt end needle Blunt-tipped cannula attached to oral irrigator Thin ultrasonic scaling inserts
B. SUSTAINED SUBGINGIVAL DRUG DELIVERYControlled release devices:
Reservoirs without a rate-controlling systemHollow fibers, gels, dialysis tubing
Reservoirs with a rate-controlling systemCoated drug particles, microporous polymer membranes, monolithic matrices, erodible polymeric matrices 21
Fibers• Fibers, or thread-like devices, are reservoir-type systems,
placed circumferentially into the pockets with an applicator and secured with cyanoacrylate adhesive for the sustained release of the trapped drug into the periodontal pocket.
• Several polymers such as – poly(ecaprolactone) (PCL), – polyurethane, – polypropylene, – cellulose acetate propionate and – ethyl vinyl acetate (EVA)
have been investigated as matrices for the delivery of drugto the periodontal pocket.
• Examples are Chlorhexidine fibers and tetracycline fibers.22
Films
• Films are matrix delivery systems in which drugs are distributed throughout the polymer and release occurs by drug diffusion and/or matrix dissolution or erosion.
• Film is prepared either by solvent casting or direct milling.
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• Bigger films either could be applied within the cavity onto the cheek mucosa or gingival surface or could be cut or punched into appropriate sizes so as to be inserted into the site of action.
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• Sustained release devices composed of cross-linked fish gelatin (bycoprotein) containing chlorhexidine diacetate or chlorhexidine hydrochloride have been developed by Steinberg.
• Films based on synthetic biodegradable polymers such as poly (lactide-co-glycolide) (PLGA) containing tetracycline have been developed for modulated-release of drug in the periodontal pocket as slab like device.
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Injectable System• The application can be easily
and rapidly carried out, without pain, by using a syringe.
• Thus, the cost of the therapy is considerably reduced compared to devices that need time to be placed and secured.
• Moreover, an injectable delivery system should be able to fill the pocket, thus reaching a large proportion of pathogens.
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Gels• Mucoadhesive, metronidazole (MTZ) containing gel
systems based on hydroxyethyl cellulose, corbopol 974, and polycarbophil have been made.
• Gel is applied sublingually with the help of blunt cannula and syringe.
• Locally applied controlled release DOX gel may partly counteract the negative effect of smoking on periodontal healing following no surgical therapy.
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• Tetracycline containing copolymer gels represents a safe and effective bioerodible therapy for periodontitis due to Safety profile, Longer-term retention, Antimicrobial activity.
• Comparative analysis of tetracycline containing dental gels: poloxamer and monoglyceride based formulations have been done which shows that poloxamer and monoglyceride gels, when applied subgingivally, produce a significant improved outcome in moderate to deep periodontal pockets.
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Injectable Gels
• Gels can be more easily prepared and administered.
• Moreover, they possess A higher biocompatibility and bioadhesivity, allowing adhesion
to the mucosa in the dental pocket and, finally, They can be rapidly eliminated through normal catabolic
pathways, decreasing the risk of irritative or allergic host reactions at the application site.
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• Various oleogels and hydrogels for the delivery of tetracycline (2.5%), metronidazole (25%), metronidazole benzoate (40%), as well as a combination of tetracycline (2.5%) and metronidazole benzoate (40%), have been tested and satisfactory results have been achieved.
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Strips and Compacts
• Acrylic strips have been fabricated using a mixture of polymers, monomers and different concentrations of antimicrobial agents.
• Strips were fabricated either by solvent casting or pressure melt method.
• Strips containing tetracycline, metronidazole or chlorhexidine demonstrated a decrease in number of motile rods, notably spirochetes.
• In a later development, the evaluation of amoxycillin-clavulanic acid loaded acrylic strips is reported.
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• 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.
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Vesicular Systems• Vesicular liposomal systems are designed to mimic the
bio-membranes in terms of structure and biobehaviour, and hence are investigated intensively for targeting periodontal biofilms.
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• 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.
• 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.
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Microparticle System• Microparticles based system of biodegradable poly
alpha hydroxy acids such as poly lactide (PLA) or poly (lactide – co-glycolide) PLGA containing tetracycline has been designed for periodontal disease therapy.
• PLGA microspheres containing minocycline have been formulated and have been used for the elimination of Porphyromonas gingivalis from the periodontal pocket .
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• Microparticles of poly (dl-lactic-coglycolic acid) (PLGA) containing chlorhexidine free base, chlorhexidine di gluconate and their association or inclusion complex with methylated-beta-cyclodextrin (HPBCD) were prepared with single emulsion, solvent evaporation technique.
• Non-biodegradable as well as biodegradable materials for the preparation of microspheres include the polymers of natural origin, modified natural substances and synthetic polymers.
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• They could preferably be formulated as a chip or could be part of a dental paste formulation, or otherwise be directly injected into the periodontal cavity.
• Tetracycline-containing microcapsules in Pluronic F127 were reported to form gel at body temperature and hold the microcapsules in the periodontal pocket for the duration of treatment.
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• PLGA microcapsules and microspheres have been proposed for the delivery of tetracycline and histatins.
• These microparticulate systems provide stability to the encapsulated drug.
• The in vitro drug release from such systems depends upon the polymer (lactide:glycolide) ratio, molecular weight, crystallinity and pH of the medium.
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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.
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• These systems Reduce the frequency of administration and 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.
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• Three preliminary studies have been conducted to assess the efficacy of nanoparticles in periodontal drug delivery.
a) Dung et al used Antisense oligonucleotide- loaded chitosan tripolyphosphate (TPP) nanoparticles and showed the sustained release of oligonucleotides which is suitable for the local therapeutic application in periodontal diseases.
b) Pinon et al conducted a preliminary in vivo study in dogs with induced periodontal defects using Triclosan-loaded polymeric (PLGA, PLA and cellulose acetate phthalate) nanoparticles and suggested that triclosan-loaded nanoparticles penetrate through the junctional epithelium.
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c) Moulari et. al, investigated the in vitro bactericidal activity of the Harungana madagascariensis leaf extract (HLE) on the oral bacterial strains largely implicated in dental caries and gingivitis infections.
HLE-loaded PLGA nanoparticles were prepared using interfacial polymer deposition following the solvent diffusion method.
Incorporation of the HLE into a colloidal carrier improved its antibacterial performance and diminution of the bactericidal concentration was observed.
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Some of the recently developed drug delivery vehicles are briefed here :
• Nanomaterials• Nanoparticles• Lipid core micelles and polymeric micelles• Liposomes• Nanowires• Nanoshells• Nanotubes• Nanobots• Nanoneedles• Nanorods• Nanocantilevers
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• Nanopores• Bucky balls (Fullerene)• Gold Nanoparticles• Quantum Dots• Nanorobots• Dendrimers• Hydrogels• Colloidosomes• Thin film drug delivery vehicles• Fast dissolving tablet• Implantable drug delivery vehicles• Controlled release formulations• Drug loaded erythrocytes• Self-emulsifying drug delivery systems
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TETRACYCLINE
• The tetracyclines were introduced into clinical practice in the late 1940s.
• They are primarily bacteriostatic agents that are effective against many Gram negative species including putative pathogens such as Aggregatibacter actinomycetemcomitans.
• They interfere with bacterial protein synthesis and also inhibit tissue collagenase activity.
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• Tetracyclines are used extensively in the management of periodontal diseases and the agents used commonly are
• Tetracycline HCl, • Doxycycline HCl, • Minocycline HCl.
• Tetracycline solutions also exhibited high substantivity in the periodontal environment. This property could be related to the formation of less soluble
calcium-tetracycline complexes as a result of partial dissolution of the hydroxyapatite of cementum or dentin at lower pH levels.
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•Exhibit greater oral absorption, •Have more prolonged half-lives, and •Show enhanced lipid solubility, Which is important for their antibacterial action.
• Most of the subgingival microorganisms are susceptible to tetracycline at a minimum inhibitory concentration (MIC) of ≤ 1-2 µg/ml.
• However, species such as Eikenella corrodens, Prevotella oralis, Selenomonas sputigena and some strains of Campylobacter and Veillonella exhibited intrinsic tetracycline resistance (MIC ≥ 16 µg/ml)
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Actisite (US ; Switzerland )• The first delivery devices involved hollow fibers of
cellulose acetate filled with tetracycline.
• These are non-resorbable biologically inert, generally considered as safe, plastic copolymer (ethylene and vinyl-acetate) loaded with 25% w/w tetracycline HCl powder packaged as a thread of 0.5 mm in diameter and 23 cm in length.
• Fiber is packed into pocket and secured with a thin layer of cyanoacrylate adhesive, left in place for 7-12 days.
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• 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 second appointment for removal as it biodegrades within 7 days.
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Tetracycline fiber
Systemic adm
GCF Conc
1590 µg/ml 4-8 µg/ml
Serum conc
0.4 µg/ml 2-4 µg/ml
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Gel
• Tetracycline-Serratiopeptidase-Containing Periodontal Gel Formulation has shown statistically significant results along with scaling and root planing.
• 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.
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• In a 60-day multicenter study - 107 periodontitis patients after supragingival scaling, (Goodson et al 1991)
Four non-adjacent teeth with pockets in the range of 6-10mm was selected
Randomly assigned to- Tetracycline fiber Placebo fiber Scaling Untreated
Analysis: fiber therapy significantly had Probing depth, BOP Attachment levels
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• Newman et al (1994)
• Conducted a study in periodontal maintenance patients needing treatment of localized recurrent periodontitis.
• Effect of fiber therapy was evaluated as an adjunct to SRP.
• Results – sites treated with fiber and SRP showed significantly higher attachment level, pocket depth reduction and less BOP.
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MINOCYCLINE
• Semisynthetic tetracycline - was first introduced in 1967
• Minocycline hydrochloride has in vitro antibacterial activity against a wide range of gram-ve and gram+ve microorganisms thought to be related to periodontal disease.
• Local delivery of minocycline has been tried clinically via three different modes i.e. film, microspheres, and ointment.
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Film
• Ethyl cellulose film containing 30% of Minocycline were tested as sustained release devices.
• The results indicated that the use of this device may cause complete eradication of pathogenic flora from the pocket after 14 days.
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Microsphere
• The FDA recently approved a new, locally delivered, sustained release form of minocycline microspheres (ARESTIN) for subgingival placement.
• The 2% minocycline is encapsulated into bioresorbable microspheres (20-60μm in diameter) in a gel carrier and has resorption time of 21 days.
• Gingival crevicular fluid hydrolyses the polymer and releases minocycline for a period of 14 days or longer before resorbing completely.
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The microspheres is dispensed subgingivally to the base of the periodontal pocket by means of a disposable plastic cartridge affixed to a stainless-steel handle
An electron photomicrograph of the minocycline microspheres, and a photomicrograph of the microspheres in cross-section. 59
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• Williams et al 2001 – multicenter trial -748 pts with moderate to advanced periodontitis
• Locally administered microencapsulated spheres of minocycline.
• Results – test sites showed significantly more PD reduction than either SRP alone.
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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 (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.
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• 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.
• It has shown that the combination of ointment with scaling and root planing was significantly better than scaling and root planing alone in pockets > 7mm.
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The Dentomycin gel has been reported to be effective in periodontal disease because of
Its power to eliminate key periodontal pathogens. Minimal risk of bacterial resistance.
Inhibits harmful bacterial collagenase without effecting normal collagen turnover and regeneration of gingival tissues.
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• Van Steenberghe et al.1993 – randomized double-blind study - 103
adults with moderate to severe periodontitis
• SRP done at baseline• Patients received either the test or a
control minocycline ointment in four sessions at an interval of 4 weeks
• Assessment – a significantly greater reduction of PD in test group.
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DOXYCYCLINE • Doxycycline is a broad-spectrum semi synthetic
tetracycline.
• Doxycycline is bacteriostatic, inhibiting bacterial protein synthesis due to disruption of transfer RNA and messenger RNA at ribosomal sites.
• In vitro testing has shown that Porphyromonas gingivalis, Prevotella intermedia, Campylobacter rectus, and Fusobacterium nucleatum, which are associated with periodontal disease, are susceptible to doxycycline at concentrations of 6.0 µg/ml.
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• Doxycycline has the ability to downregulate MMP’s a family of zinc dependent enzymes that are capable of degrading a variety extracellular matrix molecules including collagens.
• Such activity relates to the drug's ability to bind with calcium and zinc ions.
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Biodegradable formulation contains:
• 10% by weight Doxycycline• 33% by weight poly (DL- lactide)• 57% by weight NMP (N-methyl-2-
pyrrolidone)
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The ATRIDOX® product(US) is a subgingival controlled-release product composed of a 2 syringe mixing system.
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Syringe A contains 450 mg of the
ATRIGEL® Delivery System, which is a
bioabsorbable, flowable polymeric
formulation composed of 36.7% poly (DL-
lactide) dissolved in 63.3% N-methyl-2-
pyrrolidone
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Syringe B contains doxycycline
hyclate which is equivalent to 42.5
mg doxycycline.
The constituted product is a pale yellow to yellow viscous liquid with a concentration of 10% of doxycycline hyclate
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Upon contact with the crevicular fluid, the liquid product solidifies and quickly hardens to a wax-like substance, then allows for
controlled release of drug for a period of 7 days
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Doxycycline levels in GCF
Time
1,500 - 2000 μg/mL 2 hours
> 1000 μg/mL 18 hours
Well above the minimum inhibitory concentration for
periodontal pathogens (6.0 μg/mL)
Day 7
95% of the polymer is bio absorbed or expelled from the
pocketnaturally
Day 28
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• Garrett et al 1999, 2000 – 411 pts with moderate to severe adult periodontitis.
• Atridox was compared to placebo control and oral hygiene and SRP.
• Result : Treatment to be statistically superior to placebo control and oral hygiene and equally effective as SRP.
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CHLORHEXIDINE• Chlorhexidine gluconate is an antimicrobial agent
active against a wide spectrum of gram-positive and gram-negative organisms, yeast, fungi, facultative anaerobes and aerobes.
• In 1970, Loe and Schiott reported a total inhibition of new plaque formation and prevention of the development of gingivitis by an aqueous solution of 0.2% chlorhexidine digluconate in the form of a mouthrinse.
In order to affect the subgingival microbiota, sustained release devices (SRD) were developed. Such devices used ethylcellulose and polyethylene glycol as polymers and chlorhexidine as solvent.
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• Its mechanism of action relates to Reduction in pellicle formation, Alteration of bacterial adherence to teeth, and An alteration of bacterial cell walls, causing lysis.
• Its antibacterial action is due to an increase of the cellular membrane permeability, followed by the coagulation of intracellular cytoplasmic macromolecules.
• Because chlorhexidine is highly cationic, it exhibits high substantivity.
• Its chemical structure allows it to remain in the oral cavity for a prolonged period after a single rinse and thereby function in a slow release type manner.
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PERIO-CHIP Unique patented “targeted
controlled release” bio degradable polymer containing chlorhexidine (Israel).
Small, bullet-shaped or baby’s finger nail like thin film, weighing 7.4mg.
Measures 5x4 mm in size
and 0.35 mm thickness.
The chip contains 2.5 mg chlorhexidine gluconate incorporated in a biodegradable matrix of cross-linked hydrolyzed gelatin. 77
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Advantages of the Perio-chip• Very easy and convenient to use. Takes seconds to
place in any pocket.• Highly effective, safe and well tolerated. Painless to
the patient. In some instances there may be minor discomfort in the first 24 hrs.
• No restrictions on eating or oral hygiene after chip insertion.
• All quadrants can be treated at the same visit.• Does not affect taste or stain teeth.• Maintains effective concentration of chlorhexidine in
the pocket up to 10 days - 125µg/ml ( Soskolne 1997).• Delivers effective dosage even to the base of the
pocket.• Reduces amount of pathogenic bacteria up to 100
days – 99% of subgingival microflora( Soskolne 1990).79
• Soskolne et al 1997, Jeffcoat et al 1998 – split mouth design to compare the treatment outcomes of SRP alone with the combined use of SRP & PerioChip in pocket depth of 5-8mm.
• Results – average PD reduction in treated sites with chip was significantly greater than in the sites receiving mechanical treatment only.
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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.
• It has been shown to resorb after 30 days; however their coronal edge degrades within 10 days.
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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 l0-30 days of injection and effective concentration of chlorhexidine against microorganisms is established for at least 15 days in the region.
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• 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.
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METRONIDAZOLE
• Metronidazole is particularly attractive as an antimicrobial because of its selective efficacy against obligate anaerobes.
• Both systemic and local applications are effective against periodontal pathogens.
• Therefore, local application would be preferred.
• In the recent past, Metronidazole has been incorporated as collagen sponges, dialysis tubing, acrylic strips, films and gel forms for sustained subgingival delivery in the treatment of periodontal disease.
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METROGENE (SEPTODENT, FRANCE)
• It is a new combination of two known substances; bovine collagen (Type I) sponges into which Metronidazole is incorporated at a concentration of 5 percent in the finished product.
• In contact with human gingival fluid, this collagen rapidly forms a resorbable gel which is non-irritant as it is virtually devoid of any immunogenicity (Hugly 1983, Stein 1985).
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Elyzol (Copenhagen, Denmark)• Metronidazole benzoate 25% in a mixture of
glyceryl mono-oleate and sesame oil.
• The gel disintegrates in the pocket and releases Metronidazole.
• Estimated dose of Metronidazole per treated tooth was 3mg and drug concentration in GCF after one day was 1g/ml.
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• Ainamo et al 1992 – two randomly selected quadrants were treated with the gel twice a week; other two – 2 episodes of subgingival scaling.
• Differences were considered insignificant by the authors.
• Using similar design, the microbiological outcome of 2 gel applications Vs scaling was compared by Pedrazolli et al 1992 (6-month period).
• Total bacterial cultivable count and proportions of
anaerobic bacteria were affected in a similar way in both groups, and no difference was seen in PD reduction & BOP.
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• Grossi et al 1995 – 164 pts no significant difference between metronidazol
gel application and SRP
Opened the question of equivalence between the two treatment modalities.
From a practical standpoint, one form of treatment may be preferred to another of equal efficacy if it offers better tolerability for the patient or lower costs.
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Sanguinarine• Sanguinarine, a benzophenanthridine alkaloid with a
wide-spectrum antiseptic activity in vitro, was obtained from the bloodroot plant (Sanguinaria canadensis).
• Short-term studies have shown some plaque and gingivitis reduction.
• However, the results of long-term studies are conflicting: some showed no reduction in plaque or gingivitis, whereas others demonstrated a significant reduction when patients used both mouth-rinse and dentifrice forms.
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• The proposed mechanism of action is an alteration of the bacterial wall, so that aggregation and attachment are reduced.
• The product may be cationic and the degree of substantivity is unclear.
• Adverse effects include a burning sensation of the mouth.
• Its MIC against periodontal pathogens has been reported to range from 1 to 32 µg/ml compared to 0.06±32 µg/ml for tetracyclines.
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• Local application of sanguinarine via a controlled release system showed low clinical efficacy.
• The reason for this may be due to its conversion to the pseudobase form. This conversion has been shown to occur above pH 6.0 leading to increased insolubility and resulting in reduced bioavailability.
• With the pH of gingival crevicular fluid (GCF) in a periodontal pocket being in the range of 7.5±7.9, it is the likely cause of the sanguinarine conversion to its less bioavailable form.
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Histatins
• The histatins are a group of small, cationic histidine-rich peptides secreted by human parotid and submandibular salivary glands.
• These endogenous peptides have been shown to bind to hydroxyapatite, suggesting a role in the formation of the acquired enamel pellicle.
• The histatins play a major role in protecting the host oral cavity from etiologic pathogens.
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• In particular, the histatins are antifungal and also demonstrate bactericidal and bacteriostatic effects against periodontal pathogens such as Porphyromonas gingivalis, Prevotella intermedia and Bacteroides forsythus.
• However, one common problem encountered with most peptides is their relatively low stability.
• The physicochemical properties of many peptides make it difficult to obtain satisfactory formulations, in particular, since inactivation is possible during their incorporation into the controlled release system.
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Ofloxacin• Ofloxacin is a newly developed synthetic pyridone
carboxylic acid (PCA) derivative.
• Although the earlier PCA derivatives were not active against Gram positive bacteria and anaerobes, ofloxacin can kill Gram positive bacteria and anaerobic bacteria.
• This action is absent or very weak in the earlier antibiotic, i.e. erythromycin, tetracycline and clindamycin.
• Ofloxacin showed marked antibacterial activity against Bacteroides species, Fusobacterium species and
Aa.comitans. 94
• Furthermore, ofloxacin has high chemical stability and adverse effects have rarely been reported.
• Okade and co-workers developed a new sub gingival release delivery system
(PT-01) containing Ofloxacin for sub gingival therapy.
• The PT-01 was found to be effective in the reduction of supra gingival plaque, reduction in the plaque index, reduction in bleeding on probing.
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Clindamycin
• Systemic clindamycin therapy, as an adjunct to scaling, decreased the incidence of active disease from an annual rate of 8.0 to 0.5% of sites per patient.
• However, clindamycin did not permanently suppress subgingival Porphyromonas gingivalis, which may explain the recurrence of disease activity in some patients.
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• Following gel insertion of clindamycin in conjunction with subgingival scaling, motile rods and spirochetes were not detected after 1 month.
• Prevotella intermedia and Porphyromonas gingivalis were eliminated or below detectable levels after 1 week post-therapy but were again detected at 12 weeks.
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SPIRULINA• A study was done to assess the clinical effects of Spirulina in-situ gel as an
adjunct to Scaling And Root Planning (SRP) in the treatment of chronic periodontitis subjects.
• 64 sites were selected with probing pocket depth of ≥5mm and they were divided into 2 groups; 33 sites were treated with SRP along with spirulina gel (Group A) and 31 sites were treated with SRP alone (Group B).
• Results: Group A (SRP along with spirulina) showed statistically significant decrease in mean probing pocket depth and gain in the clinical attachment level after 120 days as compared to Group B SRP alone.
• It exerts strong anti-inflammatory effects which are closely connected with its antioxidative activity.
– Jaideep Mahendra et al. Clinical Effects of Subgingivally Delivered Spirulina Gel in Chronic Periodontitis Cases: A Placebo Controlled Clinical Trial. Journal of clinical and diagnostic research Year : 2013 | Month : 10 | Volume : 7 | Issue : 10 | Page : 2330 - 2333
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ALENDRONATE• Alendronate (ALN), an aminobisphosphonate, is known to inhibit
osteoclastic bone resorption and was proposed to have osteostimulative properties in vivo and in vitro as shown by an increase in matrix formation.
• A study was done to explore the efficacy of a 1% ALN gel compared to a placebo gel as a local drug delivery system in adjunct to scaling and root planing (SRP) for the treatment of intrabony defects in patients with chronic periodontitis.
• A total of 66 intrabony defects were treated with a 1%ALN or placebo gel.
• Results: The mean PD reduction and CAL gain were greater in the ALN group than in the placebo group at 2 and 6 months. Furthermore, a significantly greater mean percentage of bone fill was found in the ALN group (40.4% – 11.71%) than in the placebo group (2.5% – 1.02%).
– Anuj Sharma and A.R. Pradeep. Clinical Efficacy of 1% Alendronate Gel as a Local Drug Delivery System in the Treatment of Chronic Periodontitis: A Randomized, Controlled Clinical Trial. 2012 Volume 83.
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STATINS
• Simvastatin is derived from the product of the fermentation of Aspergillus terreus, which belongs to the Statin family.
• Statins such as SMV, are specific competitive inhibitors of 3-hydroxy-2-methyl-glutaryl coenzyme A (HMG- CoA) reductase.
• These agents are widely used to lower cholesterol, and treat hyperlipidemia and arteriosclerosis.
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• Statins also seem to modulate bone formation by increasing the expression of bone morphogenetic protein, inflammation, and angiogenesis, thus providing a new direction in the field of periodontal therapy.
• Various studies showed that SMV assists in bone regeneration as well as the anti-inflammatory effect when delivered or applied locally
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AZITHROMYCIN• Aim : to investigate the adjunctive effects of subgingivally
delivered Azithromycin (AZM) (0.5% concentration) as an adjunct to scaling and root planing (SRP) for treating chronic periodontitis in patients with type 2 diabetes.
• Methods : 63 patients were categorized into two treatment groups: Group 1: SRP plus placebo gel and Group 2: SRP plus 0.5% AZM.
• Results : patients in Group 2 treated with SRP + 0.5 %AZM showed enhanced reductions in PI, GI, PD and gains in CAL (p <0.05) over a period of 9 months as compared to Group 1.
– Esha Agarwal et al. Locally Delivered 0.5% Azithromycin, as an Adjunct to Non Surgical Treatment in Chronic Periodontitis With Type 2 Diabetes: A Randomized Controlled Clinical Trial. Journal of Periodontology, 06/2012.
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• Aim : to evaluate the adjunctive effects of subgingivally delivered 0.5% azithromycin (AZM) as an adjunct to scaling and root planing (SRP) in the treatment of chronic periodontitis in smokers.
• METHODS: Fifty-four patients were randomized and categorized into two treatment groups: Group 1 - 26 subjects who received (SRP) plus placebo gel and Group 2 - 28 subjects who received (SRP) plus 0.5% azithromycin.
• RESULTS: A single application of AZM resulted in attachment gain at 9 months of 2.44 ± 0.64 mm as compared to 0.18 ± 0.68 mm for the placebo. Similarly, pocket depth and PI were significantly reduced but no change in the mSBI was noted.
– Pradeep AR et al. Local drug delivery of 0.5% azithromycin in the treatment of chronic periodontitis among smokers. Aust Dent J. 2013 Mar;58(1):34-40.
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Local Drug Delivery’s Impact on Deep Probing Depths (7 mm)
• As probing depths increase, SRP becomes less efficient; therefore investigators evaluated the potential benefit of employing local drug delivery at deep sites (7 mm).
• Timmerman et al.(1996) reported that there was no benefit of employing 2% minocycline gel as an adjunct to SRP to reduce probing depths at deep sites, whereas Van Steenberghe et al.(1999) noted that combined therapy provided a better result than SRP alone at sites 7 mm deep.
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• In summary, sites with deep probing depths provide an opportunity to attain greater probing depth reductions than shallow pockets.
• However, there are limited data related to the ability of individual drug delivery systems to enhance probing depth reductions at pockets 7 mm.
• Therefore, this facet of therapy requires further study.
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Inhibition of Periodontal Disease Progression
• Garrett et al 1999 compared doxycycline gel versus SRP, and found that there was no statistically significant benefit regarding inhibition of disease progression associated with drug therapy.
• Jeffcoat et al 2000, after employing chlorhexidine chips plus SRP, noted that these sites achieved a mean 0.1 mm gain of bone, whereas 15% of the sites administered SRP alone lost bone (0.04mm) during a 9-month clinical trial.
• Overall, it is difficult to project outcomes regarding the ability of local drug delivery to inhibit disease progression because a limited number of studies, diverse study protocols, and different thresholds for disease progression were used.
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Impact of Local Drug Delivery on Furcations
• Tonetti et al. (1998) reported that tetracycline fibers in conjunction with SRP initially provided a better result than SRP alone at molar furcations; however, after 6 months, there were no statistically significant differences with respect to mean probing depth reduction or gain of clinical attachment.
• In contrast, Williams et al. and Meimberg et al.(2002) noted a statistically significant greater probing depth reduction in molar furcation when SRP plus minocycline microspheres were compared to SRP alone.
• Additional studies are needed to assess the effect of local delivery in a variety of defects to include furcations and intrabony lesions.
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Repair of Osseous Defects• Bone deposition in infrabony defects is a
desirable treatment outcome; however, the amount of bone fill that occurred after local drug delivery is limited.
• Aimetti et al.(2004) reported that tetracycline
fibers plus SRP resulted in 0.94 mm bone deposition in osseous defects versus 0.09 mm after SRP alone.
• In general, results regarding bone fill need to
be interpreted in light of the fact that other clinical procedures provide better bone repair in osseous defects.
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Future trends in local drug delivery
1. Clarithromycin gel • A study has been conducted to investigate the
adjunctive effects of subgingivally delivered 0.5 % clarithromycin as an adjunct to scaling and root planing for treating chronic periodontitis smoker subjects.
• It was observed that the adjunctive use of 0.5%
clarithromycin as a controlled drug delivery system enhanced the clinical outcome.
• This product is still under investigation and yet to be patented.
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2. Herbal products • Various herbal formulations like aloe vera, neem, tulsi,
propolis, cocoa husk, pomegranate, cranberry etc. are being used widely these days.
• These products have shown promising results with no side effects and are economical as well.
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Aloe vera
• The medicinal value of the plant lies in a gel‑like pulp obtained on peeling the leaves.
• These substances include Lignins : Cellulose‑based substances which have the capacity
to penetrate the tissue and carry elements with it. Saponins : Glycosides that promote cleansing and provide an
antiseptic quality. Vitamins : Vit A which is necessary for integrity of epithelial
cells, Vit C which helps in connective tissue regeneration (collagen synthesis), and Vit E which is an antioxidant and neutralises free radicals by donating one of their electrons, ending the electron stealing reaction.
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Minerals : increase tensile strength of wound, so helpful in early wound healing.
Amino acids : building blocks for repair and regeneration of traumatized tissue.
Anthroquinones : similar to alkaloids & produce analgesia and have healing, antibacterial, antiviral, and antifungal properties.
Sugars : such as polymannose, glucose, and fructose which have immune modulating and anti‑inflammatory actions.
Enzymes.
• Aloe vera gel improves wound healing by Increasing blood supply, which increased oxygenation as a result. Has a positive influence on the collagen content and stability.
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• Yagi et al. in 2002 in a study found that three aloesin derivatives from aloe (namely isorabaichromione, feruloylaloesin, and p‑coumaroylaloesin) have potent free radical and superoxide anion scavenging properties.
• It was found that aloesin compounds inhibited cyclooxygenase‑2 (COX‑2) and thromboxane (TX) A2 synthase, which explains the healing effects of aloe vera.
• Due to some chemical structural similarity between aloins and tetracyclines, aloe derivatives could inhibit the MMP’s through a mechanism similar to that of inhibitory tetracyclines such as doxycycline.
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• Aim : To evaluate the effect of aloe vera gel as an adjunct to scaling and root planing (SRP) in the management of chronic periodontitis.
• SRP‑ALOE group showed significantly better results than SRP alone.
– Harjit Kaur Virdi et al. Effect of locally delivered aloe vera gel as an adjunct to scaling and root planing in the treatment of chronic periodontitis: A clinical study. Indian Journal of Oral Sciences Vol. 3 Issue 2 May-Aug 2012
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• Geetha Bhat et al. concluded that subgingival administration of Aloe vera gel results in improvement of periodontal condition.
– Geetha Bhat et al. Aloe vera: Nature's soothing healer to periodontal disease. J Indian Soc Periodontol. 2011 Jul-Sep; 15(3): 205–209.
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Neem • Neem extract contains
(i) Azadiractin - the active principle, (ii) Glycosides -antimicrobial, (iii) Sterols (iv) Luminols-anti-inflammatory and (v) Flavenoids.
• Neem has showed better efficacy in the treatment of oral infections and plaque growth inhibition in treating periodontal disorders.
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• Neem has multivarious actions like Antibacterial, Astringent, Antiseptic, Anti-inflammatory, Antiviral and Antimicrobial properties.
• It removes toxins from the body, purifies the blood and neutralizes damaging free radicals. So, locally it may also have an effect in enhancing healing.
• It is easily available and has no known adverse reactions.
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• Neem extract gel produced more improvements in clinical as well as microbiological parameters than the control. The approach of local delivery of a natural extract with no known side effects has proved promising results.
– Dr. Verdine Virginia Antony et al. “Evaluation of the Efficacy of Azadirachta Indica (Neem) Extract Gel as a Local Drug Delivery in the Treatment of Patients with Chronic Periodontitis. ” A Double Blind Randomised Clinical Trial. IOSR Journal Of Pharmacy Volume 3, Issue 4 (May 2013), Pp 15-21
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Turmeric
• It has proven properties like Anti-inflammatory, Antioxidant, Antimicrobial, Hepatoprotective, Immunostimulant, Antiseptic, Antimutagenic, and It also accelerates wound healing.
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• A study was done to evaluate the adjunctive efficacy of turmeric, curcumin, and traditional nonsurgical methods for treating periodontal pockets.
• Plaque index and gingival index scores showed significant improvement from baseline through the end of the study.
– Kudva P et al. Comparative evaluation of the efficacy of turmeric and curcumin as a local drug delivery system: a clinicomicrobiological study. Gen Dent. 2012 Sep-Oct;60(5):e283-7
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• The experimental local drug-delivery system containing 2% whole turmeric gel can be effectively used as an adjunct to scaling and root planing and is more effective than scaling and root planing alone in the treatment of periodontal pockets.
– Roobal Behal et al. Evaluation of local drug-delivery system containing 2% whole turmeric gel used as an adjunct to scaling and root planing in chronic periodontitis: A clinical and microbiological study. J Indian Soc Periodontol. 2011 Jan-Mar; 15(1): 35–38.
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Propolis
• Propolis is a resinous mixture that honey bees collect from tree buds, sap flows, or other botanical sources.
• It is used as a sealant for unwanted open spaces in the hive.
• Its actions are : Antimicrobial : due to active constituents
including flavonoids like galangin and hydroxycinnamic acids like caffeic acid.
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Immunomodulator : Propolis exhibit both immunosuppressive and immunostimulant effects.
As an oral hygiene product : protect against dental caries and periodontal diseases, due to its antimicrobial properties. Propolis is also being investigated for its efficacy in the
treatment of canker sores and in reducing the inflammation associated with canal debridement and endodontic procedures.
Antioxidant.
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• The study indicated a potentially useful role of Semisolid systems containing propolis in the treatment of periodontitis and suggest they are worthy of clinical evaluation.
– Marcos L. Bruschi et al. Semisolid systems containing propolis for the treatment of periodontal disease: In Vitro release kinetics, syringeability, rheological, textural, and mucoadhesive properties. Journal of Pharmaceutical Sciences Volume 96, Issue 8, pages 2074-2089, August 2007
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Pomegranate
• A clinical study conducted by Sastracaha et al (2003) concluded that extracts of Punica granatum plus scaling and root planning significantly reduced the clinical signs of chronic periodontitis.
• Vasconcelos et al (2006) investigated the antimicrobial effect of Punica granatum Linn (pomegranate) phytotherapeutic gel and concluded that Punica granatum L. gel had greater efficiency in inhibiting microbial adherence in oral cavity.
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3. Fibroblast growth factor • would be a very efficacious introduction in local drug
delivery.
• To regenerate periodontal tissues, a sandwich membrane composed of a collagen sponge scaffold and gelatin microspheres containing basic fibroblast growth factor (bFGF) in a controlled-release system was developed.
• This sandwich membrane induced successful regeneration of the periodontal tissues in a short period of time (4weeks ).
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The strategic approaches with associated challenges and achievements towards the
formation of periodontal drug delivery system :
Strategy 1: systemic delivery devices • Low benefit to risk ratio, ingestion of large drug doses • Inadequate drug concentration at periodontal site • Rapid/non-sustained drug release • Poor patient compliance: frequent administration • No penetration of delivery system • No adhesion/retention into periodontal pocket • High incidence of bacterial resistance
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Strategy 2: local mouth rinses and dental irrigation
• Inadequate drug concentration at periodontal site • Drug dose is reduced • Rapid/non-sustained drug release • Systemic toxicity is decreased • Poor patient compliance: frequent administration • No penetration of delivery system • No adhesion/retention into periodontal pocket • High incidence of bacterial resistance
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Strategy 3: non-biodegradable, intrapocket fibres, strips, films and microparticles
• Poor patient compliance: discomfort during the placement of device, at least two visits to therapist is required and development of foreign body response, if left in situ
• Adequate drug concentration at periodontal site • Poor penetration of system/drug • Prolonged/sustain drug release • Poor retention of system into periodontal pocket • Less frequent administration • Low incidence of bacterial resistance
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Strategy 4: biodegradable, intra-pocket fibres, strips, films and microparticles
• Poor patient compliance: discomfort during placement • Visit to therapist is reduced • Poor penetration of system/drug • No foreign body response • Poor retention of system into periodontal pocket • Low incidence of bacterial resistance
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Strategy 5: biodegradable nanoparticles • Poor retention of system into periodontal pocket • Placement is easier • Low incidence of bacterial resistance • Good penetration due to nano-sized particles
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Strategy 6: Mucoadhesive, biodegradable nanoparticles
• Low incidence of bacterial resistance • Good retention of system
Strategy 7: antibiotic-free, mucoadhesive, biodegradable nanoparticles
• Bacterial resistance does not develop
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• Evidence suggests that compared with SRP alone, when SRP is combined with certain anti-infective agents in sustained-release vehicles, statistically significant adjunctive effects on PD reduction and a decreased percentage of sites with BOP can be anticipated. Statistically significant effects of PD reduction were seen with CHX chip.
• Compared with SRP alone, no evidence was found for the adjunctive effects on reduction of PI with ATRIDOX and MINO microspheres. BOP reductions were not significant with ATRIDOX and TET fibres.
• Meta-analysis has revealed a large effect of adjunctive therapy in pocket depth reduction, with a moderate effect on reduction of bleeding scores and mild effect on reduction of plaque scores.
• Use of anti-infective sustained-release systems as adjuncts to SRP does not result in significant patient-centered adverse events or morbidity.
– Rupali Kalsi et al. Effect of local drug delivery in chronic periodontitis patients: A meta-analysis. J Indian Soc Periodontol. 2011 Oct-Dec; 15(4): 304–309.
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CONCLUSION
• Local drug delivery often appears to be as effective as scaling and root planing with regards to reducing signs of periodontal inflammatory disease.
• Local drug delivery systems usually do not provide a benefit beyond what is achievable with conventional scaling and root planing in the treatment of adult periodontitis and in isolated pockets also. Therefore, their routine utilization is unnecessary.
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• Local delivery may be an adjunct to the conventional therapy. The sites most likely to be responsive to this adjunctive treatment method may have refractory or recurrent periodontitis, or specific locations where it is difficult to instrument root surfaces.
• At present, there are insufficient data to indicate that one local drug delivery device is clearly superior to all the other systems. However, desired characteristics include ease of placement, controlled release of drugs and resorbability.
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REFERENCES• Carranza’s Clinical Periodontology 10th Ed.
• Pramod Vishwanath Prasad et al. Bird’s Eye View on the Recent Advances in Drug Delivery Systems. Journal of Biomaterials and Nanobiotechnology, 2011, 2, 544-556
• Vidya Dodwad et al. Magic Bullet to treat Periodontitis: A targeted approach. JPBMS, 2012, 20 (19)
• Amit Bhardwaj et al. Advances in periodontal drug delivery systems. International Journal of Novel Drug Delivery Technology. Jan-Mar 2012, Vol-2, Issue-1
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• Vidya Dodwad et al. Local Drug Delivery In Periodontics: A Strategic Intervention. International Journal of Pharmacy and Pharmaceutical Sciences. Vol 4, Issue 4, 2012
• Pragati S et al. Recent advances in periodontal drug delivery systems. International Journal of Drug Delivery 1(2009) 1-14
• K. Schwach-Abdellaoui et al. Local delivery of antimicrobial agents for the treatment of periodontal diseases. European Journal of Pharmaceutics and Biopharmaceutics 50 (2000) 83-99
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• RAMS & SLOTS. Local delivery of antimicrobial agents in the periodontal pocket. Perio 2000, Vol. 10, 1996, 139-159
• Internet sources.
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Thank You