LOCAL DRUG DELIVERY IN PERIODONTAL THERAPY

Inroduction It is a well established fact today that the many variants of periodontal disease are essentially infections of the periodontal structures with differing micro-organisms predominating in the different presentations of the disease. The establishment of the fact that all forms of periodontal disease are infections, had led to the resurgence of the usage of antibiotics in the treatment and management of periodontal disease. Systemic antibiotics has their role to play, but are limited by the duration of treatment and also the availability of the antibiotic at the site of action in sufficient quantity. It is not possible to administer broad spectrum anti-biotics at its optimum dosage levels multiple times over large periods. This has led to a lot of research and development on the ways and means of applying the same antibiotic, albeit locally at total body weight constituents which is literally a tiny fraction but at the local level is present in extremely high concentrations. If the drug can be sustained and constantly released at these concentrations over a period of 6 to 10 days, the results promise to be excellent. As regards the active ingredient, there are a number of them to choose from, all with proven efficacies. The focus on development is the vehicle to carry the antibiotic to the site of action and to have a sustained release of the active ingredient. The predominant research is now focusing on the vehicles systems which will carry the antibiotic to the base of the pocket, keep it there in a stable form and release it slowly over 7 to 10 days and then resorbs. Let us have a look through at the various systems available and the principles on which the products have been formulated and put to use. Principles The most salient and critical criteria to be understood, in no uncertain terms, is the expectation out of a local drug delivery system. A local delivery system can be considered as an adjunct in periodontal therapy, it can be considered to be an extension of scaling and root planning, it can be considered to be an add-on supportive therapy in conjunction with systemic antibiotic therapy or it can be considered to be a key element of the complex form of therapy for the management of periodontal disease. If the local drug delivery is to be used as an extension of scaling and root planning the most important component of the system should be ease of usage and economics. The rationale for the use of the local drug under such situations is to totally eliminate any residual infective/inflammatory component still harbouring in the periodontal apparatus. Since scaling and root planning is a general purpose

task carried out in minimal timing with sophisticated instruments, the application of local drugs should also be as simple and fast. In such situations the most ideal form of local drug is the gel form which will allow for very fast generalized application in all afflicted areas. If local drugs are used as an add-on to systemic drug therapy for severe infective lesions of the periodontium, the most important criteria is the prolonged availability of the drug in sufficient minimum inhibitory concentrations over a number of days. Such lesions even though generalized, will not be present in all the teeth. Such lesions will be isolated and flare up over sporadic intervals of time in different locations. Such lesions will also have pathogens which have invaded the soft tissue which shields them from routine mechanical cleaning and irrigating procedures. Hence in such situations, the paramount importance of high concentrations of the antibiotic drug becomes inevitable. Active Agent The active agent for a local drug delivery system is one of the time tested anti-biotic or antibacterial agent, which has a broad spectrum action against most periodontal pathogens. The drugs of choice for such sustained local delivery systems is one of Tetracycline, Doxycycline Hyclate, Minocycline, Metronidazole or Chlorhexidine digluconate. Each of these five drugs has its own pros and cons for its utility as an active ingredient for a local drug delivery system. The tetracycline Family is represented by the first three drugs that are closely related antibiotics which are derivatives of the same family. All of them have a broad spectrum range of activity and are particularly effective against the predominant pathogens which tend to colonize in periodontal lesions. This wide spectrum bacteriocidal activity is efficacious in controlling the destructive process of the pathogens. Chlorhexidine has been shown to be a very effective anti plaque agent. Chlorhexidine has a dual mode of action when used intra orally. It binds to receptor sides on plaque and the acquired pellicle thereby preventing further consolidation of plaque and at the same time has a bacteriostatic effect on the pathogens. Its ability to bind also generates substantivity for an extended duration. However, the important property of substantivity is not so critical in its role as a local drug since it would be placed with a reservoir which would keep on providing the chemical continuously over a period of days. Since it is not such a powerful bacteriocidal agent, its may not be as effective as the other agents in local therapy to combat periodontal pathogens. Metronidazole is a powerfull antibiotic which is very effective, particularly against the primary anaerobic pathogens involved in severe periodontitis. The spectrum of activity of the antibiotic is sufficiently wide spectrum to be efficacious against the variants in the different presentations of periodontal disease. The difficult aspect of using this antibiotic is to keep in stable within the carrier agent and achieve a sustained depot action over 6 to 7 days. Delivery Systems

One of the least discussed but sill, the most critical aspect of a local drug delivery system is the method by which the active ingredient is made available at the site of action. The delivery system will dictate the ease with which the drug can be dispensed, the ability to be able to deliver right at the base of the pocket and the time period for which the active ingredient is sustained at the site of action. Cupraphane Cellulose Hollow Fiber Systems: The credit for pioneering the science of local drug delivery systems undoubtedly goes to Dr. Max Goodson. In the early 80s he carried out a number of studies using hollow cupraphane cellulose fibers or acetate cellulose fibers. He loaded these fibers with systemic tetracycline and placed them in deep lesions. The hollow fibers slowly leached out the tetracycline over a period of days and provided an extremely large concentration of the antibiotic at the site of action. The downside was the necessity to remove the hollow fibers once all the tetracycline had leached out. The other major downside was the drug slipping out of the fibers much before the tetracycline had played its role. Currently products have been developed wherein the hollow fibers have been preloaded with either tetracycline/doxycycline/minocycline in the liquid form. The desired length of the fiber has to be snipped and placed into the periodontal pocket. Once the period over which the drug is leached out of the fiber has elapsed the fiber has to be removed from the pocket as it is nonresorbable and will interfere with the healing process. Mucous Adhesive Gels: Further research led to the formulation of specific mucous adhesive gels which had a high concentration of the active ingredient to start with. Over a period of days the antibiotic concentration in the gel decreases and then reaches zero levels. The other components of the gel also will biodegrade over a period of time and usually within 3 weeks there are no traces of the material noticed in the pocket. Most of these gels are usually supplied in thin syringes with blunt ended needles. The major drawback of the delivery systems is that the needles are of very thick guage and it is at times not possible to be able to place the needle deep into a periodontal pocket. Another cause for concern is the amount of pressure required to force the gel out of the needle which makes the entire placement of the syringe/needle very unstable. Gel Delivery Syringe: Most of the mucous adhesive gels which have been suggested for use in periodontal lesions are very viscous. This high viscosity precludes their usage in conventional syringes with thin bores for eg.. it is very difficult to administer a gel even through a 22 guage needle. The suggested technique of effectively delivering local drugs right to the base of he pocket with a syringe is to use a special Multi Mode Syringe which has been primarily designed to deliver very hard mixed Zoe right upto the apical third of a root canal. The system consists of a cartridge which has to be loaded with the gel and then controlled amounts of the gel can then be expressed out through a blunt ended endodontic 26/28 guage needle tip. The material is forced out either via a spring loaded side plunger system or via a micr0meter type screw knob. Either of the plunger systems work efficiently. More information on this syringe system can be found at a website called www.betterendo.com

Synthetic Polymer Chips: One system is available in which the active ingredient is delivered via a non-resorbable polymer basesd semi flexible chip. This chip is presoaked with the active ingredient and it has to be placed in periodontal lesions. The chip will release the active ingredient over a period or 10 days by which time it gets inactivated. The polymer, by itself is inert and will lie in the pocket for a certain period of time and then chemically disintegrate. Collagen Fiber Vehicle (Biodegradable): This is a unique patented delivery system in which biodegradable collagen is used as a vehicle. The collagen is impregnated with the active agent which is released over a period of 7 to 10 days. The collagen itself also has a positive enzymatic action, which enhances wound healing. The effect of the collagen is a bonus. There will be no trace of the active agent by the end of two weeks and the collagen itself will be complete biodegraded in another couple of weeks. Products There are a number of products which have now become available on the market as local drugs for periodontal disease. The following is a short review on each of them. Actisite: This system has tetracycline preloaded in hollow ethylene/vinyl acetate fibers loaded with tetracycline HCL. It is manufactured by Proctor & Gamble, USA and dispensed in 23 cm long fibres, 0.5 mm in diameter containing 12.7 mg of tetracycline. The entire length is usually inserted in a single lesion all around the tooth. In case the lesion is isolated to specific areas, the fiber can be cut to size and then placed into the lesion. The tetracycline is released from the fiber over a period of 7 to 10 days. The concentrations of tetracycline achieved in the gingival crevicular fluid are more than enough to be able to disinfect the lesion totally. The crucial issue is to remove the fiber after the specified period as it will not dissolve or resorb. Another important consideration is the relative chance of the fiber slipping out of the pocket during the 7 to 10 day period. One can optionally seal the pocket with a cynoacrylate dressing to safeguard against this eventuality. The biggest disadvantage of this product is its non-resorbable nature of the drug delivery matrix. A large number of studies have proved the highest antibacterial ability of Tetracycline when compared to any other potential drug having a wide spectrum actions on both anaerobic and aeroabic bacterial species. Atridox: This is a gel based system manufactured by Atrix Laboratories and marketed by Collagenex. The active ingredient is Doxycycline Hyclate (10%) which is carried in a mucous adhesive gel system called the Atrigel delivery system. It is to be placed into the pocket with a blunt ended needle on a syringe. The gel solidifies to a wax like consistency when placed into the pocket within a matter of minutes. The gel delivers sustained MIC levels of doxycycline for upto a 7 day period. Subsequently the gel biodegrades. A cause of concern is the release of acidic and necrotic monomers which are formed as a byproduct of the degradation of the gel. The gel will get completely resorbed by 8 to 10 weeks. The potential problem with this product is the delivery vehicle that is used. The polylactide or

glycolide polymer when degraded releases the monomers that are lactic acid and glycolic acids. These acidic environment during the degradation of the product may have an adverse effect on the regenerative process of the new tissue. It is a well known fact the acidic environment is necrogenic compared to the slight basic pH conditions needed for the tisse growth and remodeling of a tissue. Periochip: PerioChip is a biodegradable chip made of hydrolyzed gelatin impregnated with 2.5 mg of the antibiotic chlorhexidine gluconate. Chlorhexidine is released from the PerioChip in a biphasic manner with 40% being released in the first 24 hours following placement and the remaining 60% released over the following seven to 10 days. The PerioChip, a 4 mm x 5 mm x 350 m chip about the size of a baby's fingernail, with a weight of 7.5 mg is inserted directly into the infected periodontal pocket. The GCF concentrations achieved is 1000 mcg/ml over a period of about 7 days. One chip can be placed in a single lesion on a tooth for eg. If a tooth has a lesion on the buccal side as well as the lingual or a the palatal side, two chips would be required to be placed on either side of the tooth. The chip itself will biodegrade and dissolve in about 8 to 10 days time. The negative point in this product is the nonbiocompatibility of the matrix probably due to the additives and the crosslinking chemicals used. Arestin: This is an antibiotic delivered in a unique delivery system manufactured by OraPharma Inc.USA.. These are microspheres of Minocycline HCL (each micosphere containing 1 mg of the antibiotic) which are to be injected into the pocket. These mircosphere adhere to the soft tissue and then start dissolving slowly thereby releasing the Minocycline in a sustained manner. The spheres are bioadhesive, bioresorbable polymer in powder form produced by a microencapsulation process. Once in the pocket the micospheres react with the crevicular fluid which hydrolyzes the polymer causing water-filled channels to form inside the microspheres. These holes become the pathway for the antibiotic for sustained release. The minocycline then diffuses through these portals and permeates the surrounding tissues. Over a period of time, the microspheres themselves get fragmented through polymer hydrolysis and degrade and are ultimately bioresorbed. It is reported that the microspheres are completely biodegraded in about 21 days. Studies have shown more the MIC levels, approximately 1000mcg/ml of minocycline in the crevicular fluid for upto 14 days from placement. Similar to Atridox, the potential problem with this product is the delivery vehicle that is used. The polylactide or glycolide polymer when degraded releases the monomers that are lactic acid and glycolic acids which may interfere in the reparative and regenerative process. Elyzol: This is a metronidazole based gel/strip which can be placed in the periodontal pockety. The vehicle biodegrades after the active drug has been released over a period of short time. The gel is a 25% metronidazole gel which has been suggested for topical application. The substantiviy of any topical gel in the oral cavity is very doubtfull to start with. The second issue is the ability of the gel to penetrate to any substantial depth in the pocket. This is basically not a product that could be compared to a longer term sustained local drug delivery product. There is

also a strip which is pre-impregnated with Metronidazole for placement in pockets. This form of the drug is appropriate in its comparison to the other local delivery agents. Periodontal Plus AB (PPAB): This is a unique system based on the collagen fibril delivery system manufactured by Advanced Biotech Products Pvt Ltd. The product utilizes fibrillar collagen which it not cross linked and has been impregnated with tetracycline HCL which is leached out as the fibrils themselves degrade. The fibrils itself release anti collagenase enzymes as they degrade. The system is dispensed in vials containing 25 mg of fibrillar collagen which contains 2 mg of tetracycline HCL. This system seems to present a win-win situation in all aspects. The vehicle is an effective tool in carrying tetracycline to the site of action. In fact, studies have shown that greater peaks of tetracycline in the gingival crevicular fluid are observed in lesions with higher pathogenic activity. There seems to be a direct co-relation in the ability of the tetracycline to be released from the collagen fibrils and need of the drug in differing situations. Studies have shown that most of the tetracycline is completely released by 10 days with variation dependant on the clinical situations. PPAB generates a concentration of at least 1500mcg/ml of GCF. This concentration is more than lethal as regards the periodontal pathogens. The other key benefit is that once most of the tetracycline is consumed , the vehicle starts coming into action. There is no need to remove the fibrils. Since the collagen fibrils are extremely soft and are basically an organic product, they do not interfere as the reparative process starts in a periodontal lesion. In fact, they play a very positive enzymatic role in repairing the periodontium. By 6 to 12 weeks the collagen fibril itself dissolves and there is no trace of it left as the healing process completes. A critical aspect to be noted is that there is no burden on the reparative process at all due to the vehicle in terms of clearing away undesirable by products created due to the disintegration process nor is there any physical impediment created due to the vehicle. The material has to be moistioned preferably in sterile water just prior to placement. Once moist it becomes easy to handle as it tends to stick to any surface it is placed on, due to osmotic pressure. The wet fibrils should be placed near the gingival margin and then gently inserted deep into the pocket with the help of any thin composite plastic handling instrument. Another added advantage of the collagen matrix comes from its natural hemaostatic ability. Accordingly an healthy clot is initiated which invites proper growth factors and cytokines for the enhancement of tissue regenerative process. The product also has a claim of high purity patented type-I collagen that does not exhibit any adverse immunogenic response in patients. Several clinical studies, including our independent studies have proven this added feature of the product. Conclusion The current market offers a wide variety of products for the dentist to use a therapeutic material for local drug delivery in combating periodontal disease. The

aspects to consider in selecting a particular product would be to get the product with the maximum potential in curtailing and eliminating the infective process while at the same time not creating any impediment in any form whatsoever for the reparative process to take place. The next issue to be considered would be the ease of use of the delivery system and the time levels as well as placement efficiency levels of the system so as to be able to accurately place the drug right at the base of the pocket in multiple lesions in a patient, in as short a time as possible. Some formats of the drug may be easier to apply, however the reach of the product to all branches of the tunnels of infection is not so easy. Some of the delivery modes are definitely not the method of choice to reach the deeper areas of infection. PPAB has a reasonable chance of getting applied to the deeper places and the brached tunnels when adequately experienced with the handling of the material. However, the healing advantages of the product seem to over throw any of the slight difficulties or handling practice needs in using the fibrillar collagen product. It is recommended that one should try out the available drugs of choice as well as check out the pros and cons of each modality and make the best of the available choices.