CA2012665A1 - Periodontal disease treatment system - Google Patents

Abstract

PERIODONTAL DISEASE TREATMENT SYSTEM

ABSTRACT
A controlled release drug delivery system for placement in the periodontal pocket, gingival sulcus, tooth socket, wound or other cavity within the mouth.
The system incorporates drug-containing microparticles in a fluid carrier medium, and is effective in the environment of use for up to 30 days.

Description

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FIELD OF THE INVENTION
This invention relates to a con~rolled release drug deli~ery system for use in the mouth, and particularly So systerns for placement in the periodontal pocket to treat periodontal disease.

BACKGROUND OF THE IIWENTION
Periodontal disease, with caries, is tho most important cause of loss of teeth. It is well established that bacteria are directly involved in both the onset and progression of periodontal disease. See for oxample J. Slots, ~Sub~in8ival Microflora and Periodontal Disease," J, ~inl P~riQdQntal,_~, 315 (1979~ and S. S.
Socransky, "Microbiology of Periodontal Disease--Present Status and Future 20 Considerations,~ .eriQdontol. 48, 497 (1977). This has led to the widespread use of antibiotics in the troatment of periodontal disease, and partisularly to the use of tetracycline, since signiî icantly hipher levels of tetracycline are found ingingi~al fluid than in blood ~fter ~drninistration oî ~in~le or multiple oral doses.
(J. M. Gordo~ et al., "Sensitive ~ssay for Measuring l~tracycline Levels in 25 Gingival Crevice Fluid,~ ~ntimicrob. ~ents Chemothe~l 17, 193 (1980), ~. M.
Gordon et al., UConcentrations of Tetracycliae in Human Gingival Fluid sfter ~, , i. .
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Single Doses,~ J. ~lln PÇriodontQL- ~, 117 (1981) and J. M. Gordon et al., "Tetracycline: Levels Achievable in Gin8ival Crevice lFluid and in vitro Effect on Subgingival Organisms. Par~ 1. Concentrations in Crevicular Fluid after Repeated~oses," J. PeriQdontol. ~2, 609 (1981).) However, ~he typieal effective tetracycline oral dose of one gram per day for 30 days can lead to serious side eîfects. It has been estimated that the dose should be of the order of one hundred times smaller to avoid ~hese effects. A more satisfactory approach then is to administer the antibiotic topically using a controlled release device to sustain an effective dose for the required length of time. Because the drug is delivered I0 locally, a much reduced dose will suffice for effective therapy, and harmful side effects can be reduced or eliminated.
Long lasting drug delivery systems presently used in the oral cavity fall broadly into two groups; either troches, pastilles or table$ which adhere to theoral mucosa in some way, or drug containing strips or dosage forms which are attached to the gums, teeth or other interior surface of the mouth. A good e~ample of the former category is U.S. Patent No. 4,039,653. This patent - discloses a sustained release tablet coated with a pharmaceutically acceptable oral adhesive, which is placed in an upper corner of the mouth and is capable ofdispensing an odor-masking agent, local anaesthetic or other medication in a sustained fashion for periods of up to twelve hours. U.S. Patent No. 4,250,163 discloses a method of administering a broad range of medications to the oral CAVity by means of a water-swellable and mucosa-adhesive polymeric matrix, whichcan be in the form of a tablet, powder or granules and which is effective for times of the order of a few hours. As can be seen from these and other examples,such as U.S. Patents No. 4,226,848, 4,369,172 and 4,059,686, such troches and tablets are normally effective for periods oî hours rather than days, and a course r ~ ;~3 of treatment lasting one month would require the use of numerous tablets.
Furthermore they are inappropriate to the treatment of periodontal disease because the drug is released into the saliva or oral mucosa, and does not penetrate the periodontal pocket to any significant extent. Buccal tapes, stripsand forms suffer from the same disadvantages. For e~cample, the buccal dosage form disclosed ifi U.S. Patent No. 3,972,995 was found to be effective witbout leaking, if not wrinkled or dislodged by the teeth, for about one hour only. This highlights another disadvantage of existing me~hods of dispensing drugs for oraltherapy; they may slip or be dislodged by the tongue or teeih, may be uncomfortable to a 8reater or lesser degree, and may interfere yvith the normal oral functions to some e~tent. Recent developments in the art are directed toward delivering the therapeutic agenl~ directly to the periodontal pocket, in some cases in a controlled release formulation. Gordon et al. have described theuse of a drug-filled polymer hollow fiber. ( J. M. Goodson et al., RPeriodontal Therapy by Local Delivery of Tetracycline,U ,L Clin. PeriodontQI. ~, 83 (1979), J.
Lindhe et al., "Local Tetracycline Delivery Usin8 Hollow Fiber Devices in Periodontal Therapy,~ 1. Clin~ dontol. fi, 141 (1979~ snd R. L. Dunn et al.,"
Monolithic Fibers for Controlled Delivery of Tetracycline," in PrQç~inth ~nt.
SvmDosium on Control!e-~--R- elease of Bio~çtive M~sr~l~, Ft. Lauderdale, Fl., July ~1982).) This device is tied sround a tooth and gently pressed below the margin of the gingiva so that it resides in the periodontal pocket, and is capable of delivering an effective dose of 2.5 micrograms of tetracycline per day per periodontal pocket for a prolonged period of a week or more. Similar results have been obtained by Coventry and Newman (J. Coventry and H. N. Newman, "Experimental Use of a Slow Release Device employin~ Chlorhe~cidine Oluconate inAreas of Acute Periodontal Inflammation," J Clin. PeriQdo~tol. 9, J29 (1982)~ and . ' , Addy et al. ( M. Addy et al., "The Deve~opment and in vitro Evaluation of Acrylic Strips and Dialysis Tubing for Local Drug Delivery,~ 3. Periodontol. S3, 693 (1982)~
using acrylic strips I mm or more long, impregnated with chlorhexidine, tetracycline or metronidazole, which were inserted into the periodontal pocket S with tweezers. Such a strip, formed from ethylcellulose impregnated ~rith metronidazole, is disclosed by Loesche in U.S. Pat. No. 4,568,~38. Another strip, employing a water soluble polymer of a particular elasticity and viscosity, is disclosed by Suzuki et al. in U.S. Pat. No. 4,569,837. Although these devices may - be able to dispeDse an appropriate drug for a time span of a week or more, they are inappropriate to widespread use because they are difficult and time consumin8 to 8pply and may be dislodged by the patient during normal oral functions.
U.S. Patent Application serial number 856,g61, copending with the present invention, provides a novel controlled release system that can deliver antibiotics or other drugs in the periodontal pocket for a prolonged period of time, withoutinterfering in any way with normal oral functions.
- The present invention provides for the controlled delivery of a range of agents that are efficacious in the treatment of periodontal disease and other Bingival or oral problems.

SUMMARY OF THE INVENTION
This invention is a controlled release drug delivery system that can be placed in the periodontal pocket. The system is particularly useful in control and treatment of periodontal disease, but can also be used for controlled delivery at the affected site for post-operative pain, inflammation or bleedin~, or for treatment of other local diseases of the oral cavity or systemic diseases with oral F,~ ,r,l'' J . h, ~ "Ç 3 manifestations. The system offers a majo~ advanta8e over systemic therapy, in that the useful therapeutiG dose of many drugs is found to be one or two orders of magnitude less than the co~esponding oral dose, thereby avoidin~ all or many of the s}de effects associated wi~h lon8-term oral delivery of an~ibiotics, anti-inflammatories, or other potent drugs. The system comprises microparticles or microcapsules, hereinafter referred to as microparticles, suspend0d in a pharmaceutically acceptable carrier medium. The microparticles are between 10 and S00 microns in size, and consist of an active a8ent dispersed within or encapsulated by a rate-controlling polymer matrix. This microparticle/carrier I0 system is a ma;or improvement over previously known controlled release systems for use in treating periodontal disease. Because of the fluid carrier medium, and the small micropartic1e size, the system can penPtrate throughout deep, narrow or complex periodontal pockets. In comparison, solid s~rips, fibers or other comparatively large dosage forms are limited to placement in the region adjacentto the gingival margin, where the therapeutic effect is less, and where they aremore susceptible to dislodgement.
Microparticles of this specification can be prepared by a ~ariety of well-established techniques, for example solvent evaporation, coacervation or spray-drying. The active agent may be chosen from antiseptics, antibiotics, anti-inflammatories, local anaesthetics, ~issue growth promoters, and tissue destruction inhibitors, for e~tample. The system may also be used ~o encapsulate simple prophylactic agents, such as calcium or fluoride. The polymer matrix may be chosen from a range of medically suitable materials and varied to provide the required release rate for the drug involved. The drug release mechanism may be by diffusion of the drug through ~he intact polymer, by gradual erosioll of the polymer matrix, or by leaching of the a8ent from pores. Embodiments employing .

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biodegradable polymers can lirnit the microparticle life and prevent prolonged microparticle entrapment in the periodontal pocket.
The carrier medium may be an aqueous solution, paste or gel. In general, the properties required are that it should be pharmaceutically acceptable (non-toxicand non-allergenic), promote good adhesion in the periodontal pocket, and have ahigh permeability for the sctive agent involved. A preferred embodiment of the invention employs a thermally gelling polymer such as Pluronic F127 from E3ASF
Wyandotte. In aqueous solution this polymer is a free-flowin8 fluid at room temperature, but gels rapidly above 30 C. Embodiments of the invention are typically placed in the periodontal pocket or other desired site by means of a syringe and needle. The system may be tailored to release the desired agent for periods ranging from a few hours to many days.
It is an object of the invention is to provide a controlled release system to deliver a drug or other active agent to the periodontal pocket or other site - I5 within the oral cavity for prolonged periods.
It is another object of the inven~ion to provide a eontrolled release drug delivery system that is self-retaining in the periodontal pocket.
It is another object of the invention to provide a controlled release drug delivery system that can penetrate throughout the periodontal pocket.
lt is another object of the invention to provide a controlled release drug delivery system for the periodonta1 pocket or the oral cavity that does not interfere with normal oral functions, and is not easily dislodged by the patient.
It is another object of the inventiosl to provido a controlled re1ease drug delivery system for use in the periodontal pocket, gingival sulcus or other localized oral site, where the drug delivery is controlled by diffusion throu8h the polymer matrix.

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It is another object of the inven~ion to provide a controlled release drug d01ivery system for use in the periodontal pocket, ~in~ival sulcus or other localized oral site, where the drug delivery is controlled by erosion of the polymer matrix.
lt is snother object of the invention to provide a controlled release drug delivery system for use in the periodon~al pocket, ~in~ival sulcus or other localized oral site, where the drug delivery is controlled by leaching from pores within the matrix.
It is another object of the invention to provide a controlled release drug delivery system for dispensing antiseptics in the periodontal pocket, gingival sulcus or o~her localized oral site.
It is another object of the invention to provide a cozltrolled release drug delivery system for dispensing antibiotics in the periodontal pocket, gingival sulcus or other localized oral site.
It is another object of the invention to provide a controlled release drug delivery system for dispensing anaesthetics~1e periodontal pocket, gingival sulcus or other localized oral site.
lt is another object of the invention to provide a conlrolled release drug delivery system for dispensing anti-inflamma~ory agents in the periodontal pocket, gingival sulcus or other localized oral site.
It is another object of the invention to provide a controlled release drug delivery system for dispensing tissue growth promoters in the periodontal pocket, : ~ 8in8ival sulcus or other localized oral site.
It is another object of the invention to provide a conirolled release drug delivery system for dispensin8 tissue destruction inhibitors in the periodontal pocket, gingival sulcus or other localized oral site.

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It is another objeet of the invention to provide a controlled release drug delivery system for dispensing minerals in the periodontal pocket, gin~iYal sulcus or other localized oral site.
Other objects and advantages of the present invention will be apparen~
from the fol!owing description.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure I is a graph of in vitro release of tetsacycline free base from polysulfone and polycarbonate microparticles.
Figure 2 is a graph oî in vitso release of flurbiprofen frorn ethylcellulose particles.
Figure 3 is a graph of in vitro release of tetracycline hydrochloride from 50:50poly(lactide-co-glycolide) microparticles.

DETAILED DESCRIPTION OF THE INYENTI()N
~Active agent~ as used herein broadly includes any composition or compound of matter which when dispensed in the chosen environment of use produces a predetermined, beneficial and useful result.
~Drug~ as used herein broadly includes physiologically or pharmacologically active substances for producing a localized effect at the administration site or a systemic effect at a site remote from the administration site.
Periodontal disease is a general term for a number of diseases that affect ~he periodontal tissue. These diseases are characterized by a ran8e of symptoms including inflammation, bleeding, exudation of pus from the gingival sulcus, deepening of the sulcus to form periodontal pockets, tissue 1esions, loss of connective tissue, slveolar bone loss, and ultimately tooth loosening and loss.

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The primary cause of pe}iodontal disease is now believed to be bacterial inîection of the plaque that forms on tooth surfaces below the giogival margin.
Current treatments for periodontal disease include professional cleanin~ to remove plaque and tartar, use of oral antiseptics, local or systemic antibiotic thera~y, and various surgical procedures.
The system of the present invention is usetul for prolon~ed, controlled dispensing of a ran8e of drugs and agents used in connection with these types oftreatment. Some examples are:
a) Prophylactic prolonged application of minerals and iolas, such as calcium or fluoride.
b) Prolonged controlled exposure to local antiseptics. Preferred antiseptics foruse in the present system include chlorhe~idine and tibezonium iodide, an agent witll activity similar to that of chlorhexidine, and effective in the presence of plaques, e~cudates, or variations in salivary pH.
` 15 c) Controlled antibiotic therapy. The system of the present invention oîfers a major advantage over systemic antibiotic therapy in that effect;ve dosages per tooth may be 100 times smaller or less than the corresponding oral dose. Thus the harmful side effects associated with long term antibiotic treatment are minimized or èliminated entirely. Preferred antibiotics for use in the system of the present invention include:
o Aminoglycosides such as neomycin, ~entamycin, kanamycin, tobramycin, netilmicin, sisomicin, amicamycin, their sulfates os other derivatives.
Macrolides such as erythromycin, its salts and other derivatives, spiramycin, josamicin or miocamicin.
Penicillins such as ampicillin, amo~icillin and the like.
Cephalosporins, for example, cefaclor, cefadroxil, cefazolin, cefopera~one, ;

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cefotaxime, cephalothin, cefale~in, c0foranide, cefonicide or ceftriaxone.
d) Anaesthetic/analgesic delivery pre- or post surgery or to treat other mouth pain. Preferred agents include amide-type local anaesthetics such as lidocaine, mepivacaine, pyrrocaine, bupivacaine, prilocaine, etidocaine, or other widely used anaesthetics such as procaine.
e) Local controlled delivery of non-steroidal anti-inflammatory drugs. 4s with antibiotics, relativety small doses, with correspondingly fewer side effects, are possible with the present invention. Partic~llarly preferred drugs are ketorolac, napro~cen, diclofenac sodium, and flurbiprofen.
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Collagen is a fibrous protein found in connective tissue and bone matrix.
Advanced periodontal disease is characteriæed by destruction of collagen, resultjng in loss of connective tissue and bone. The sctivity of collagenase and other collagen-destructive enzymes has been shown to be responsible for this effect.
There are, however, a number of a~ents available that possess activity against collagen-attackin~ proteases. For example, U.S. Patent 4,735,945, incorporated herein by reference, describes the efficacy of sanguinari~e and sanguinarine pseudoethanolate in inhibitin~ collagenase activity. Tetracyclines In general exhibit similar effects. European Patent Application 0195906, incorporated herein by reference, pages 20-22, disc1Oses dedimethylaminotetracycline and other tetracyclines without antibiotic activity, that are useful as anti-collagenase agents. The prese~t invention provides a novel controlled release systom for delivering such anti collagen-destructive-enzyme agents.
It has also recently been shown that regrowth and repair of periodontal connective tissue can be encouraged with the aid of polypeptide mitogenic growthfactors. See, for e~ample, V.P. Terranova et al., ~Biochemically Mediated ~ ~ .J

Periodontal Regeneration", J, PQrio~ont. Res!. ~2, pages 248-~51, incorporated herein by reference. The system of the presen~ invention can be designed to encapsulate and release appropriate growth factors, includin8, but not limited to, epidermal ~rowth factors (EGF), human platelet deriYed TGF-B, endothelial cell 5 growth factors (ECGF), thymocyte-activating factors, e.~. fibroblast-derived TAF, platelet derived ~r~wth factors (PDGF), fibrob1ast growth factor (FGF), fibronectin or laminin.
The system comprises a plurality of microparticles or microcapsules between 10 and 500 microns in size, suspended in a pharmaceutically acceptable lO carrier. Microcapsules in this context sre defined as reservoir sys~ems in which a simple reservoir of active agen~ is surrounded by a membrane shell; microparticles are small monolithic entities in which ~he active a8ent is randomly dispersed through the particle matrix. Many practical formulations fall between these two definitions; for example microcapsules often agglomerate during the 15 microencapsulation process, whi1e the size of the active a8ent particles contained in a microparticle system is often of the same order as the size of the microparticles themselYes. In the following discussion then, "microparticle" will be defined to mean microparticle, microcapsule or any intermediate form.
Various physical and chemical methods for preparing microparticles have been 20 developed over the past twenty years and the techDology is well established and well documented. See for example Patrick B. Deasy, Microencapsl~la~ion and Rela~ed Dn~g Processes, Marcel Dekker Inc., New York, 1984. The more important methods are described below, and depending on the chemical and physical properties of the desired embodiment, any of these could be used to 25 prepare the microparticles.
Coacervation was the first microencapsulation technique and remains one of .
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the most widely used. Coacervation usually il~volves four steps. First a dispersion or emulsion of the active a8ent is prepared in an aqueous polymer solution.
Secondly, the polymer is caused to precipitate slowly by some means: addition ofa non-solvent, cooling, change of pH or ionic strength, or addition of an incompatible polymer solution for example. Under these conditions, most polymersinitially presipitate as a highly swollen liquid po1ymer phase, this phenomenon being known as coacervation. Durin~ the precipita~ion, the liquid phase coa~s the dispersed active agent droplets. Finally the microparticles thus formed are separated from the solvent/non-solvent mixture, dried and sieved into different l O size fractions. Most industrial coacervation processes use aqueous solutions of ~elatin and other water soluble polymers and can only encapsulate hydrophobic, water insoluble agents disso1ved in an organic solvent. However the process can be inverted by using organic-solvent-soluble polymers with organic-solvent-insoluble active agents dissolved in an aqueous solution. Since many drugs .. 15 are at least moderately water soluble, this makes the process appropriate to the preparation of microencapsulated pharmaceuticals. For example ethylcellulose hasbeen used to prepare microparticles containing aspirin, indomethacin, paracetamol, theophylline and vitamins among others. The main disadvanta~e of the coacervation technique is that it requires considerable skill to produce particles with sonsistent properties, since the particle sizes and wall thickness may varywidely.
Interfacial polymerization occurs when two reactive monomers, each in different immiscible liquids, sre brought into con~act. The monomers are able toreact only at the interface of the two solutions, where a polymer film forms.
When one solution is dispersed in the other, the polymer film formed encapsulates the disper~e phase. This process is not widely used for the ~`

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csmmercial preparation of pharmaceuticals because of various prac~ical problems;toxicity of remaining unreacted monomer, drug degradation as a result of reaction with the monomer, high permeability of th~ encapsulating polymer to the active a8ent involved, fragility of the capsules produced and s non-biodegradability of the particles amongst others. However ex~ensive research work has been done on the coating of high-molecular-weight biological materials such as enzymes with polyamides, and recently McGin;ty et al. have successfully encapsulated caffeine, sodium salicylate, theophy11ine and other drugs in a nylon coated particle by this technique.~J. W. McGinity et al., ~Influences 9f matrices on nylon-encapsulated pharmaceuticals,~ J. Pharm, Sci. 70, 372-375 (1981).) Solvent evaporation is another technique which is appropriate for the eDcapsulation of a water-soluble drug. First the polymer matrix material is dissolved in an organic solvent. Adding the active agent, dissolved in water, and emulsifying, produces a water-in-oil emulsion. This emulsion is re-emulsified inan aqueous solution, forming a water-in-oil-in-water emulsion. This final aqueous solution usually contains a polymer such as gelatin, to prevent aggregation. Thesolvent is then removed under reduced pressure to form a hard outer wall to the particles. Hydrophobic agents may also be prepared by solvent evaporation, bu~ in this case ~he procedure is modified by first preparing an oil-in-water emulsion of the a8ent. This process has been used for example by Wakiyama et al. to prapare microparticles of butamben, tetracaine and dibucaine, where 2he polymer materialused was polylactic acid in a solution of methylene chloride, methyl acetate or ethyl acetate. (N. Wakiysma et al., ~Preparation and evaluatiorl in vitro ot`
polylactic acid microspheres containing local anaesthetics," Chem, Ph~rm, By_~29, 3363-68 (1981).) Recently Kojima et al. used the solvent evaporation technique to enclose various local anaesthetics in polycarbonate microspheres: sustained "

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drug-release times measured in hundreds of hours resulted. ~chem~ Pharm. Bull.
~, 2795-2802 (~982).) Finally a number of simple physical techniques can be used to prepare microparticles, and spray drying, for example, is widely used in the preparationof food or pharmaceutical flavors. Spray dried particles are less satisfactory for preparing drugs however, as the particles ~end to be non-uniform and the coating porous, causing the active agent to disperse too rapidly for a controlled-release application. Howe~er several penicillins have been microencapsulated in ethylcellulose in this way, See for instance U.S. Patent No.
4,016,2~4 (April 1977).
Th0 polymer matrix material chosen should be pharmaceutically acceptable, soluble in a variety of suitable solvents and available in different grades to enable the release rate of the actiYe agent to be tailored as necessary. In general, biodegradable polymers, while not necessary, are preferred, because they avoid any potential problems associated with long-term entrapment of particles in the periodontal pocket. There are several mechanisms whereby the drug or agent can be released from the polymer material. These may be grouped into three broad categories: diffusion, erosion, and leaching. The aspects and advantages of each will now be discussed separately, although it should be appreciated that inan sctual microparticle system, the drug release may frequently occur by a combination oî two, or all three, of these mechanisms.
Diffusion-controlled systems operste by pe}meation of the substance to be released through the intact polymer to the surrounding environment. The system geometry may be either monolithic, with the agent to be released dispersed uniformly through the polymer matrix, or reservoir, with the a8ent surrounded bya shell of polymer material. In either case, the drug permeation rate through the - `; ':

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polymer depends on the diffusion coefficient of the agent in the polymer, the solubility of the agent in the polymer, and the geometry of the system. A
detailed discussion of the factors sffecting diffusion coefficient and solubility, and their relationship to the molecular weight, molecular size, and drug melting point, is given in Conlrolled Release oJ Biolog~ally Active Agen~s, Chapter 2, pages 22-36, incorporated herein by Jeference. As a general rule, diffusion-controlled release will be the preferred drug release mechanism for many standard drugs andagents, such as the antibiotics, anaesthetics, or antiseptics mentioned above. As shown in the Examples below, it is possible to tailor the drug/polymer ilo combination and the device geometry to obtain tl~e necessary therapeutic dose for the required time. Particularly preferred polymers for use in biodegradable diffusion-controlled systems are lactic-glycolic acid copolymers. These have an extensive history of use in medical applications, such as sutures and implants.
T~ey have also been used in other contexts to encapsulate drugs. For example, Setterstrom et al., Polvm. Mater. Sci~_En8., 53, 620-626 (1985) describes the use of ampicillin microencapsulated in poly(DL-lactide-co-glycolide) for topical application to wounds; effective levels of antibiotic are detectable at the wound site for at least four~een days. Lactic-glycollc acid copolymers degrade into innocuous degradation products over periods of a few weeks. Copolymers with ` 20 about equal percentages of lactic and glycolic deBrade more rapidly than those that are primarily either lactic or glycolic acid. Other preferred biodegradablepolymers that could be used in the system of the invention include polycaprolactones, polyorthoesters or polyacetals, all oî which have been used as s biodegradable matrices for drug delivery systems, or copolymers of these various materials. Embodiments incorporating non-biodegradable polymers can be prepared from a large number of polymers known in the art, including, but rot limited to ~ `
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polycarbonate, polysulfone, polystyrene, polyu~ethane, polyamide, polyvinyl chloride, polyvinyl acetate, cellulose a~etates, ethylcellulose, ethylene vinyl acetate, and various derivatiYes and copolymers of these.
In general, useful diffusion rates through the polymers listed above which typically have a ma~imum water sorption of 0 to 10 wt% h generally limited to - drugs with molecular weights less than 200 ~o 300. For drugs abo-~e this molecular weight, for example some of the macrolides csphalosporins, penicillinsand protein and polypeptide drugs, the rate of diffusion may be too low to be useful. In this case, microparticles made from highly hydrated and hydrophilic polymers can be used. These polymers typically sorb from 20 ~o 80 wt% water, and as a result, the rate of diffusion of even large molecules is relatively high.
Hydro~cy ethyl methacrylate and related polymers, polyacrylic acid copolymers, gelatin, starch, crossli~ked polyvinyl alcohol, crosslinked polyamino acids a~d polyacrylicamide are all e~amples of ~his type of material.
The theory of drug release from solid microspheres was developed by Higuchi (T. Higuchi, ,~, Pha_m, S~ ~, 1145 (1963)). The release is controlled bythe equation 32 (1 _ [1 _ Mt ] M0) ro2C
Mt/Moo is the fraction of total dru~ released after time t from a particle of radius rO. The drug permeability in the matri~ is ~ and the drug loading is CO.
This equation can be used to tailor the size of the microparticles, a~d the drugloading, so that the desired dos~ge level and release rate for the chosen embodiment is obtained.
Where polypeptides, or other large or uns~able macromolecules or biological materials are to be dispensed, the molecule may be too lar~e or too unstable to .
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permeate by difîusion throu~h the intact polymer phase. For delivering materialswith hi8h molecular weights, therefore, it may be necessary or preferable to deploy systems that operate by erosion control. Erosion-controlled systems normally have a monolithic geometry; in other words ~he actiYe a8ent is uniformly dispersed within the polymer matri~. The agen~ does not diffuse through the polymer to any significant e%tent, and is ~hus essentially immobilized in the matri~ until released by degradation of the surrounding material. Controlled release erosion-controlled systems are more difficult to design than diffusion-controlled systems; nevertheless they are useful where proteins or other large molecules are to be dispensed. ~aDy biodegradable materials brealc down homogeneously by hydrolysis of labile bonds within the polymer, thus their release pattern is characterized by an initial time period where negligible amounts of drug are released, followed by a period where the druQ release increases very rapidlyas the matri~ dissolves. This type of pattern represents a delayed, rather than a controlled, release system. To design a controlled release microparticle, capable of steady, slow release of s~gent, i~ is desirable, therefore, that the degradadtion of the particle occur as a surface phenomenon, so that the a8ent is released as progressive ~sheLls" of the matri~ are eroded away. Preferred polymers suitable for use in the system of the present inYention will be those that break down by a surface degradation mechanism, for e~ample certain polyanhydrides and polyacids.The polyanhydrides erode by a two-s~ep pr~cess, thus:

o 05~ HO ~o W~ W~
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R ~ ~011 H~ f C1~o , Wu~r ~hbb .

, 3 ~ l3 rh~ polyacids dissolv~ according to the mechanism:
'-\~/ \~/ +
R COOH R Coo~

the rate sf dissolution being dependent on the pH of the surroundirl~
environment. Particularly preferred are acids or anhydrides based on maleic anhydride/methyl Yinyl ester copolymers. The anhydrides can be converted into half esters of varying hydrophilicity by ring openiJ~g wi~h an approprjate ~Icohol, as follows:
O--CH3 ~ Rl~H O--CH3 _ -CH2--CH--CH--CH--_ ~ _ -CH2--CH--CH - CH--_ O O O l O OH RO O ..

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where R represents -CH3, -C2H~, -C~H8, and so OQ.
Polymers of this type have been used as matrices for biodegradable drug dispersions, because their surface erosion characteristics lead ~o 800d constantrelease rates. (See, for e~ample, J. Heller et 8L, ~Controlled Drug Release by Polymer Dissolution. 1. Partial esters of Maleic Allhydride Copolymers: Proper~ies and Theory~ L~, 1991 (1978).) These polymers are easily soluble in etha~ol or other simple solvents, and thus càn be used to prepare matrices containing large unstable biological molecules that would be dama~ed bymore aggressive solvents. The erosion rate can be tailored by adjusting the sizeo~ the ester group; the smaller the ester group, the more rapid bein~ the erosion.
Other polymers that could be used to make erosion-controlled systems include ~-cyanoacrylates, such as methyl, ethyl, or hi~her alkyl cyanoacrylate~. These ~ ., ~ . -.
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polymers have been used as surgical adhesives, and microparticle formul~tions ofmethyl, ethyl and butyl cyanoacrylate are known.
;- The third mechanism whereby agents can bq controllably released from the microparticles is by simple leaching. In this case, the polymer matrix may be non-biodegradable, or biodegradable after the agent supply is exhausted. The micropartieles comprise a polymer in which the agen~ to be dispensed is insoluble, and dispersed within the polymer a sufficient luading of the ac~ive agent to create a network where the particles of a~5ent touch. As the agent at the surface of the particle is leached away by the gingival fluid, an interpenetrating network of pores is created, and further delivery of the agent proceeds by dissolution of and flow of the ~gent out through these pores. In prac~ice, even in nominally diffusion- or erosion-controlled monolithic dispersions, if the solid dru~ loading is 8reater than about 15 vol%, this pore-creation effect will occur, and at least aportion of the drug rslease will be in this fashion. This type of system is alsouseful for delivering growth factors or other large molecules that are insolublesnd will not diffuse through the polymer matrix. Many polymer/agent combinations are possible, but the polymer chosen should be soluble in a solventthat will not attack the agent to be dispensed. In general, subject to this criterion, any of the polymers already listed ab~ve may be used. For example, asdisclosed in U.S. Patent 4,391,797, ethylene vinyl acetate has been used as a matrix for a variety of enzymes.
The size of the microparticles should be limited to between 10 and 500 microns. Very small particles with consistent properties are difficult to prepare and they may wash out of the periodontal pocket easily. Particles larger than 500 microns are too large to deiiver with a standard syringe and needle and may be uncomfortable or irritating to the ~ingival membranes.

The carrier medium used to contaio the rnicroparticles must conform to several requirements. First it should be biocompatible, non-toxic and non-allergenie. Secondly it should have a low solllbility but a hi8h permeability for the drug in question. A low solubilsty is preferred to minimize leaching of ~he drug from the microparticle prior to use. Alternatively, the active agent contained in the microparticles may also be deliberately incorporated into the carrier medium. This wîll both pre~ent the loss of agent from the particles and provide an initial dose of the a~ent to the patient as soon as the system Is in place. High permeability is required in order that the drug be well conducted from the microparticle to the mucous membranes. Thirdly the carrier medium should promote 800d adhesion of the microparticles in the periodontal pocket, and last it should have an appropriate viscosity for the intended use. The choice of medically acceptable carriers is very wide and can include amongst others, water, aqueous solutions, syrups, alcohols, glycerine, mineral oil, vegetable oils, synthetic mucilage-like substances such as polyvinyl alcohol, carboxymethyl-cellulose and so on. Further examples which may be mentioned are the water soluble polymers listed by Suzuki et al. in U.S. Pat. No. 4,569,837, col. 4, lines 9 through 21. Simple saline solutions and similar aqueous solutions can be used, but may be washed out of the periodontal pocket too quickly. A preferred alternativeis one of the thicker, Yiscous media such as carboxymethylcellulose. In general,the more viscous the medium, the better it will adhere in the periodontal pocket;
however highly viscous carriers may be difficult to insert with a syringe and needle and consequently may not spread through the pocket to any useful extent.
:` An especially preferred form then is a thermally gelling polymer, such as those vehicles disclosed by Krezanowski in U. S. Patent No. 4,188,373. The Pluronic0 ~. series of polyoxypropylene-polyoxyethylene copolymers, marketed by BASF
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Wyandotte, Parsippany, New 3ersey, contains several suitable examples. These polymers are compatible with many commonly used pharmaceutical materials, and have been approved by the FDA for medical use. The Pluronic series can be obtained in a ranBe of molecular weights and compositions; thus the carrier formulation may be tailored for optimum performance in the environment of the invention. Aqueous solutions of Pluronic F1~7 in the concentration range 20-40 wt% are free-flowin~ liquids at refrigerator or soom temperature, but gel rapidly at 30C or above. These solutions are amenable to delivery by the syringe/neeâlemethod, but quickly take on the necessary viscosity for good adhesion and durability once resident within the periodontal pocket. Thus thes,e solutions are particularly preferred in the context of the present invention. Optionally, a self-gelling preparation such as those disclosed by Caslavsky et al. in U. S. Patent No. 4,~63,351 could be used for the carrier medium.
The system of the invention is especially valuable for insertion into the ` 15 periodontal pocket for treatrnent of a variety of symptoms associated with periodontal disease. However, the scope of the invention is also intended to embrace use of the invention to ~reat infection, pain, inflammation and so on associated with other oral problems. As i~on-limiting examples, the system couldbe used in the healthy sulcus to dispense prophylactic agents, in the socket to treat alveolitis following tooth extraction, and isl lesions or wounds arising from surgery or other causes.

EXAMPLE I
Polycarbonate was used to prepare microparticles by the solvent ~5 evaporation process. The drug used was tetracycline free base (TFB). The aqueous phase was saturated with TFB before starting a microparticle , S~ rr~' ~ 3 preparation run. In this way migration of the TFB into the aqueous phase during particle formation was minimized, and it was possible to encapsulate 7û
to 100% of the TFB used. Known amounts of TFB and polycarbonate dissolved in methylene chloride were added to an squeous phase containing polyvinyl alcohol (PVA) and 3ppm n-octanol. The PVA is an emulsifier and the n-octanol an anti-foaming agent. The solution was stirred continuously, and air was passed over it. As the methylene chloride evaporated, the emulsion droplets solidified. The microparticles thus formed were separated from the aqueous solution, dried and sieved to obtain three size fractions; 50-110 microns, 110-210 microns and 210-~00 microns. The in vitro drug release rate was measured by dispersing a known amount of microparticles in a volume of aqueous saline solution (0.9% NaCI). Thedispersion was stirred and kept at a temperature of 37 C. Samples were periodically removed and diluted and their antibio~ic concentration determined by UV spectrophotometry. The total tetracycline content of the microparticles was determined in a similar way by dissolving a known amount of microparticles and measuring the antibiotic concentration. The presence of the matrix polymer in the solution does not interfere with the UY measurements. A typical result is shown by the upper curve in Figure 1. The initial release rate was high, then remainedfairly steady until it tapered ~ff at times in excess of 25 hours. Drug loadings between 18 and 35wt% were used. Unexpectedly, the release curves for the three size fractions were closely bunched; thus it appears that, contrary to ~heoretical prediction, the microparticle size is relatively unimportant as far as the drug release kinetics are concerned.
These experiments showed that microparticles made of polycarbonate containing 18 tD 35wt% tetracycline and ranging in size from 50 to ~00 microns were capable of deliverin~ tetracycline in a sustained fashion for periods of 2 ~

- about 25 hours. Since the periodontal pocket is small and its fluid exchange rate slow, the flow of gingival fluid in a sin81e periodontal pocket being of the order of lO microliters per hour, this in Yitro release rate is estimated to correspond to an in vivo release period of the order of lO to 20 days.

The method as described in E~ample I was used to prepare microparticles.
Polysulfone was chosen as the matri~ material; the drug used was TFB. A
typical release curve is shown as ~he lower curve in Figure l. As can be seen the drug release rate W8S very slow, only a small fr3ction of the total drug loading having been released after 24 hours.

A ser}es of flurbiprofen microcapsules suitable for use in a periodontal `~15 formulation was prepared by the solvent evaporation method. Varying amounts of flurbiprofen were dissolved in ethylcellulose (medium ethoxy, viscosity lO0 (Dow Chemical Co., Midland, MI) in methylene chloride solution. Fifteen ml of ~` this solution were emulsified in 600 ml of aqueous 60 bloom ge1atin stirred at 500 rpm. Two drops of octanol were added to eliminate foam. The methylene chloride was evaporated at 30C. After 55 minutes the stirrer was shu~ off and the mixture was allowed to settle. The hollow capsules floatin~ on the surface were decanted and the remaining capsules were collected on fine filter paper using a buchner funnel. The capsules were then placed in a foil dish in a dehumidifying cabinet. The dru~ release rates of the ethylcellulose capsules with ~- 25 varying drug contents were measured. These results are shown in Figure 2. The flurbiprofen content of various batches of microcapsules is also shown on this : `:
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figure. As shown, the microcapsule deliveJy rate can be varied over a wide range by varying the dru~ ~o polymer ratio in the microcapsules.

Batches oî biodegradable microparticles were prepared from poly(lactide-co-glycolide) having lactic and glycolic moieties in equal proportions. The drug used was tetracycline hydrochloride (THC). The microparticles were sieved into size fractions ranging from ~5 to 210 microns. Particles with dru~ loadings of 5wt%
and 30wt% were prepared. Drug release into saline solution was measured as described in Example I above. Typical results obtained with particles of 25-210 micron diameter are shown by the two curves in Figure 3.

EXAMPLES 5 TO 10. PREPARATION OF DIFFUSION-CONTROLLED SYSTEMS.
EXAMPLE 5. Microparticles of poly(hydroxyethyl methacrylate) (HEMA) containing cephalosporin C.
Water-swellable microparticles are prepared by îree-radical polymerization of 2-hydroxyethyl methacrylate with a difunctional vinyl crosslinking agent such asN,N'-methylene bisacrylamide. The permeability of the resulting hydrogel particles can be sailored to some e~tent by the degree of crosslinking. Typical ~0 proportions of monomer:crosslinker are 75:25. To encapsulate the antibiotic, the microparticles in the size fraction 250-500 microns are mixed in~o 8 satura~ed solution of the sodium salt of cephalosporin C in an aqueous solvent in a l-liter flask. The contents of the flask sre allowed to come to equilibrium, then the particles are removed, filtered, rinsed ~nd vacuum or freeze dried. The d}ug is then trapped in the particles uniil they are placed in an aqueous carrier, wherethey will swell, thereby releasing the antibiotic by diffusion.

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, EXAMPLES 6 AND 7. Microparticles of poly(D,L-lactide) containing chlorhexidine or penicillins.
The dihydrochloride salt of chlorhe~idine is prepared by neutralizing the chlorhexidine base with hydrochloric acid. The polymer is prepared by melting a quantity of crystalline D,L-lactide in a 2-liter ~ask at a ternperature of 125~C, addinp a suitable catalyst, such as stannous octoate, and stirring the contents of the flask for several hours. The resultillg high molecular weigh~ polymer is used to make drug-loaded microparticles according to the solvent evaporation me~hod of E~ample I as follows. An organic phase is prepared by suspendin8 equal weights of the dru~ and polymer in methylene chloride. This organic phase is sdded to an aqueous phase containing about 5% of PVA as an ernulsifier, and a few ppm n-octanol as anti-foaming agent. Stirring is continued for 2-4 hours, then the resulting microparticles are separated from the solution, briefly rinsed in deionized water, dried and sieved into size fractions.
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The same procedure is used to prepare microparticles loaded with Penicillin ~G Benzathine or Penicillin V Potassium.

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EXAMPLE 8. Alginic acid microparticles containin~ tibezonium iodide.
The microparticle material is prepared by combining 18 alginic acid, Ig tibezonium iodide and lOOml of saline and heating and stirring for up to I day until a11 the antiseptic is in suspension. A solution of 1.5wt% calcium chlori~e in saline is placed in a l-liter beaker. The microparticle so1ution is pumped through ~; a nozzle with a diameter of 3ao microns, and falls as droplets into the stirred calcium chloride solution. The thus formed particles are decanted 3 times with saline solution, and transferred to a smaller beaker, to which is added lOOml of a 0.1% poly-L-lysine (MW 14,000) in saline solution. The poly-L-lysine acts as a crossliDking agent. The solution is stirred for 1-2 hours, then decanted. The microparticles are washed seYeral times in saline and dried.
Microparticles of this type will normally release the agent contained by diffusion in vitro over a period of up to I week, and degrade o~er a period of 3-6 weeks.

EXAMPLE 9. Alginate microparticles containing human growth factor TGF-B.
The gene}al procedure followed is ~he same as that in E~ample 8. The microparticle material is a suspension of 2% tissue growth factor TBF-B in saline added to a 1.5% solution of sodium alginate in satine. The droplets are deposited `` into calcium chloride as above. The croslinking step is carried out in a 0.02%
poly-L-lySine (MW 35,000) solution for 5 minutes. The microparticles are washed several times each in dilute solutions of calcium chloride, saline, and alginic acid, then freeze dried and stored in sealed vials until required.
EXAMPLE 10. ~Iydrogel particles containing fluoride.
A copolymer of rnethyl methacrylate (MMA) and hydroxyethyl methacrylate (HEMA) is prepared by addin8 equal molar ratios of the two monomers to a 1-liter flask containing a 60:40 ethanol:water solution. The solution is purged with `~20 nitrogen, and a catalyst of 2:1 Na2S20~:K2S206 is added. The flask is sealed and left for 10 days. The resulting polymer is washed several times in wate}, filtered, and dried under vacuum at 50~C. Drug-loaded films are then prepared as follows.
Three grams of the copolymer is dissolved in 2~ ml of 60:40 acetone:p-dixoane.
One gram of micronized sodium fluoride is added to the solution, and the solution is cast as 200-micron thick films onto a glass plate. The film is left to dry, then ground in a laboratory mill to produce particles with aD average diameter of 100-`:

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~00 microns. The fluoride release from these particles can be tailored by varying the drug loading and ~he HEMA:MMA ratio.
Microparticles with a 50:S0 monomer ratio will normally produce a useful fluoride release over a period of about 5 to 15 days.
EXAMPLES 11 TO 13. PREPARATION OF EROSION-CONTROLLED SYSTEMS.
EXAMPLE 11. Microparticles of an n hexyl half gster of a methyl vinyl ether/maleic anhydride copolymer containing ketorolac gromethamine.
A 2-liter flask is charged with l-hexanol and methyl vinyl ether/maleic anhydride copolymer in a molar ratio of 11:1. The flask is heated to 145C and maintained st tha~ temperature for 2-3 hours. The solution is then cooled ~o room temperature and precipitated in a large volume of 1:1 methanol:water. The precipitated polymer is dissolved in acetone snd Jeprecipitated into 1:2 methanol:water. This step is repeated several times more, and the pure half-ester product ls finally oven-dried for 2-3 days at 50C.
The polymer is then used to prepare microparticles containing the potent anti-inflammatory ahd analgesic ketorolac. The ketorolac is used in the form of the tromethamine salt. The polymer is dissolved in a solvent consisting of 70:30by weight 2-ethoxy ethyl acetate and isopropyl acetone. One part of microDized drug is added to every 10 parts of polymer. The dispersion is homogenized on a bottle roller for 2-4 hours. The solution is lhen poured into molds, left to airdry slowly for a week, then oven-dried at 3SC for 1-2 days. The resulting filmsare then ground in a labortory mill to produce microparticles having an average diameter in the range 100-150 microns.
Microparticles of this type will normally de8rade in vitro over a period of 4-5 days.

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,. ' EXAMPLE ~2. Microp~rticles of a polyanhydride containing lidocaine.
Microparticles are prepared using the polyanhydride, poly(bis~p-carbxoypheno~y)methane), which may be synthesized, for e~ample, by the process described by A. Coni~ in Macromolecwlar Synthesis, ~ol. 2, (J.R. Elliot, Ed.) pages S 95-99, Wiley N.Y. (1566). Once prepared, the polymer is æround in a laboratory mill to obtain particles haviDg an average diameter in the range lû0-150 microns.
The micsonized drug is sieYed to obtain a particle fracltion with the same average diameter as the polymer. The dru~ and polymcr particles ~re mi~ed together in the desired ratio, typically, for instance, ISwt% drug, then compression molded by melt pressing at 20-SOKpsi for about 10 minutes. The resulting film is then cooled to room temperature and reground to 100-1~0 micron particles. These are then melt prèssed as above. The process is rgpeated three times more to produce particles with an evenly distributed anaesthetic loading.
Particles OI this type are generally found to completely degrade in vitro over ` lS about a week or more.

EXAMPLE 13. Cyanoacrylate microparticles containing human epidermal growth factor EGF.
Cyanoacrylate microparticles may be prepared by the interfacial polymerization method, by emulsifying an aqueous phase containing human epidermal growth factor EGF in an organic solvent mixture such as 5 vol%
sorbitan trioleate in 1:4 chloroform:cyclohe~ane. A second equal YOlume of organic phase containing butyl 2-cyanoacrylate is added, and the interfacial polymerization reaction is allowed to proceed for 2-S minutes. The reaction is carried out in a l-liter flask maintained at 4C by an ice jacket, and stirred continuously. Another equal Yolume of organic solvent is then added to dilute the .

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reac~ant and prevent f~r~her reaction. The micropaYticles are left to settle andthe solvent is drawn off. The pariicles are washed in a solution of polysorbate,water and ethanol, then ceDtrifuged in a buffer solution.
Microparticles of this type normally degrade in vitro over a period of 1-2 days.
EXAMPLES 14 and 15. PREPARATION OF LEACHING-CONTROLLED SYSTEM.
Antibiotic-containing rnicroparticles are made by addin~ 1 8 of microni~ed Cefadro~il to 20 rnl of a 10% solutis)n of El~/ax 400 (ethylene-vinyl wetate copolymer with 40 wt% vinyl acetate) in methylene chloride. The solution is stirred and then poured into glass molds and then dried under vacuum for 1-2 days. The resultin~ films are removed frcm the molds and ground to produce particles with an average diameter of 200-250 microns.
In an aqueous environment, this type of microparticle releases the antibiotic byIeaching.
The same general procedure can be used to prepare microparticles loaded with human tissue growth factors.

EXAMPLE 16. A COMBINED DIFFUSION/~ROSION CONTROLLED SYSTEM.
Microparticles containing 2wt% epidermal growth factor EGF are prepared from poly(lactide-co-glycolide) having lactic and glycolic moieties in equal proportions. An aqueous solution containing the growth factor is added to a solution of the polymer in methylene chloride. The solution is stirred vigorously to form a water-in-oil emulsion. A non-solvent is added to precipitate the polymer onto the aqueous phase. ~he resulting droplet suspension is added to a large volume of non-solvent to harden the particles, which are then washed, sieved snd dried under vacuum.

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, The growth factor is released from these rnicroparticles by both diffusion and erosion. The initial release is by ~if~usion of ~rowth fac~or that is relatively close to the surface of the particle. Release then slows until the particles be8in to erode, and drug is released as the particles disintegrate. The release pattern is adjusted by varying th~ molecslar wei~3ht of the polymer; low molecular weight polymers de8rade faster than those wjth high molecular weights. The molecular weight can be conveniently characterized by the intrinsic viscosity of the polymer. For this e~ample, a 50:50 copolymer should have an intri&sic viscoity of 0.4 dL/~ to produce a uniform pattern of release by erosion and diffusion.

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Claims (47)

1. A controlled drug delivery system for placement in a periodontal pocket, comprising:
a) a plurality of discrete microparticles, between 10 and 500 microns in diameter, comprising a drug and a polymer containing said drug, wherein when said microparticles are placed in an environment of use, said drug is released at 2 controlled rate by diffusion of said drug through said polymer; and b) a fluid suspending medium for said microparticles; said drug delivery system remaining active in the periodontal pocket for a period of between one and thirty days.

2. The drug delivery system of claim 1, wherein said drug is a prophylactic agent chosen from the group consisting of calcium and fluoride.

3. The drug delivery system of claim 1, wherein said drug is an antiseptic chosen from the group consisting of chlorhexidine and tibezonium iodide.

4. The drug delivery system of claim 1, wherein said drug is an antibiotic.

5. The drug delivery system of claim 4, wherein said antibiotic is chosen from the group consisting of aminoglycosides, macrolides, penicillins and cephalosporins.

6. The drug delivery system of claim 4, wherein said antibiotic is chosen from the group consisting of tetracycline and tetracycline hydrochloride.

7. The drug delivery system of claim 1, wherein said drug is a local anaesthetic.

8. The drug delivery system of claim 7, wherein said local anaesthetic is lidocaine or procaine.

9. The drug delivery system of claim 1, wherein said drug is an anti-inflammatory.

10. The drug delivery system of claim 9, wherein said anti-inflammatory is chosen from the group consisting of ketorolac, naproxen, diclofenac sodium and flurbiprofen.

11. The drug delivery system of claim 1, wherein said drug possesses activity against collagen destructive enzymes.

12. The drug delivery system of claim 11, wherein said drug is chosen from the group consisting of tetracyclines and sanguinarine, its compounds and derivatives.

13. A controlled drug delivery system for placement in a periodontal pocket, comprising:
a) a plurality of discrete microparticles, between 10 and 500 microns in diameter, comprising a drug and a polymer containing said drug, said drug being essentially insoluble in said polymer, wherein when said microparticles are placed in an environment of use, said drug is released at a controlled rate by erosion of said polymer; and b) a fluid suspending medium for said microparticles; said drug delivery system remaining active in the periodontal pocket for a period of between one and thirty days.

14. The drug delivery system of claim 13, wherein said drug is a prophylactic agent chosen from the group consisting of calcium and fluoride.

15. The drug delivery system of claim 13, wherein said drug is an antiseptic chosen from the group consisting of chlorhexidine and tibezonium iodide.

16. The drug delivery system of claim 13, wherein said drug is an antibiotic.

17. The drug delivery system of claim 16, wherein said antibiotic is chosen from the group consisting of aminoglycosides, macrolides, penicillins and cephalosporins.

18. The drug delivery system of claim 16, wherein said antibiotic is chosen from the group consisting of tetracycline and tetracycline hydrochloride.

19. The drug delivery system of claim 13, wherein said drug is a local anaesthetic.

20. The drug delivery system of claim 19, wherein said local anaesthetic is lidocaine or procaine.

21. The drug delivery system of claim 13, wherein said drug is an anti-inflammatory.

22. The drug delivery system of claim 21, wherein said anti-inflammatory is chosen from the group consisting of ketorolac, naproxen, diclofenac sodium and flurbiprofen.

23. The drug delivery system of claim 13, wherein said drug possesses activity against collagen-destructive enzymes.

24. The drug delivery system of claim 23, wherein said drug is chosen from the group consisting of tetracyclines and sanguinarine, its compounds and derivatives.

25. The drug delivery system of claim 13, wherein said drug is a tissue growth factor.

26. The drug delivery system of claim 25, wherein said tissue growth factor is chosen from the group consisting of epidermal growth factors (EGF), human platelet derived TGF-B, endothelial cell growth factors (ECGF), thymocyte-activating factors (TAF), platelet derived growth factors (PDGF), fibroblast growth factor (FGF), fibronectin and laminin.

27. A controlled drug delivery system for placement in a periodontal pocket, comprising:
a) a plurality of discrete microparticles, between 10 and 500 microns in diameter, comprising at least 15 vol% drug dispersed in a polymer, said drug being essentially insoluble is said polymer, wherein when said microparticles are placed in an environment of use, said drug is released at a controlled rate by leaching of said drug from said polymer; and b) a fluid suspending medium for said microparticles; said drug delivery system remaining active in the periodontal pocket for a period of between one and thirty days.

28. The drug delivery system of claim 27, wherein said drug is a prophylactic agent chosen from the group consisting of calcium and fluoride.

29. The drug delivery system of claim 27, wherein said drug is an antiseptic chosen from the group consisting of chlorhexidine and tibezonium iodide.

30. The drug delivery system of claim 27, wherein said drug is an antibiotic.

31. The drug delivery system of claim 30, wherein said antibiotic is chosen from the group consisting of aminoglycosides, macrolides, penicillins and cephalosporins.

32. The drug delivery system of claim 30, wherein said antibiotic is chosen from the group consisting of tetracycline and tetracycline hydrochloride.

33. The drug delivery system of claim 27, wherein said drug is a local anaesthetic.

34. The drug delivery system of claim 27, wherein said local anaesthetic is lidocaine or procaine.

35. The drug delivery system of claim 27, wherein said drug is an anti-inflammatory.

36. The drug delivery system of claim 35, wherein said anti-inflammatory is chosen from the group consisting of ketosolac, naproxen, diclofenac sodium and flurbiprofen.

37. The drug delivery system of claim 27, wherein said drug possesses activity against collagen-destructive enzymes.

38. The drug delivery system of claim 37, wherein said drug is chosen from the group consisting of tetracyclines and sanguinarine, its compounds and derivatives.

39. The drug delivery system of claim 27, wherein said drug is a tissue growth factor.

40. The drug delivery system of claim 39, wherein said tissue growth factor is chosen from the group consisting of epidermal growth factors (EGF), human platelet derived TGF-B, endothelial cell growth factors (ECGF), thymocyte-activating factors (TAF), platelet derived growth factors (PDGF), fibroblast growth factor (FGF), fibronectin and laminin.

41. A method for controlled delivery of a drug to a cavity within the mouth, comprising inserting into said cavity the drug delivery system of claim 1.

42. A method for controlled delivery of a drug to a cavity within the mouth, comprising inserting into said cavity the drug delivery system of claim 13.

43. A method for controlled delivery of a drug to a cavity within the mouth, comprising inserting into said cavity the drug delivery system of claim 27.

44. The method of claim 41, wherein said cavity is a wound.

45. The method of claim 41, wherein said cavity is a socket created by tooth extraction.

46. The method of claim 41, wherein said cavity is a periodontal pocket.

47. The method of claim 41, wherein said cavity is a gingival sulcus.