USOO7074426B2 (12) United States Patent (10) Patent No.: US 7,074,426 B2 Kochinke (45) Date of Patent: Jul. 11, 2006

(54) METHODS AND DRUG DELIVERY (56) References Cited SYSTEMIS FOR THE TREATMENT OF OROFACAL DISEASES U.S. PATENT DOCUMENTS (76) Inventor: Frank Kochinke, 3413 Antonacci Ct. 6,386,869 B1 5/2002 Zegarelli San Jose, CA (US) 95148 (*) Notice: Subject to any disclaimer, the term of this Primary Examiner Carlos A. Azpuru patent is extended or adjusted under 35 (74) Attorney, Agent, or Firm Reed Intellectual Property U.S.C. 154(b) by 640 days. Law Group (21) Appl. No.: 10/113,730 (57) ABSTRACT (22)22) FileFiled: Mara. 27,Af 2002 This invention relates to methods of treating various orofa (65) Prior Publication Data cial diseases involving inflammation, infection and/or pain, US 2003/0185872 A1 Oct. 2, 2003 using intratissue controlled release drug delivery systems. More particularly, the invention relates to methods for (51) 'E', ;3/02 (2006.01) localized or targeted administration of a Sustained release formulation of an agent such as an anti-inflammatory agent (52) U.S. Cl 424/435 to a specified tissue location within the orofacial environ (58) Field of Classification Search ...... 424/435, ment. 424/423 See application file for complete search history. 136 Claims, No Drawings US 7,074,426 B2 1. 2 METHODS AND DRUG DELVERY (AtridoxTM, 8.5% doxycycline in the ATRIGEL(R) Delivery SYSTEMIS FOR THE TREATMENT OF System, Atrix Laboratories, Inc.). OROFACAL DISEASES However, conventional and even the so-called advanced administration, including those involving the periodontal pocket have several limitations, ranging from low drug FIELD OF THE INVENTION levels at the disease site and drug level fluctuation between This invention relates to methods of treating various applications to inconsistent patient compliance. And in the diseases in or originating in the orofacial environment, using case of non-predetermined dosage forms, like for example intratissue controlled release drug delivery systems. More the gel system, there is no assurance that any of the product particularly, the invention relates to methods for localized or 10 has been placed properly into the pocket or spilled before or targeted administration of a Sustained release formulation to during application. Even when an attempt was made to place a specified tissue location within the orofacial environment, part of the product into the pocket, the dosage was not which includes the oral cavity, head and neck. known. For these types of dosage forms there is no control over the accurate dosage amount and consequently over the BACKGROUND OF THE INVENTION 15 delivery rate, negatively compounded by the fact that the There are several different drug delivery technologies that final system can have variable shapes and Surface areas, are utilized to treat disease. Conventional drug delivery factors that critically influence drug delivery rates. In methods typically result in the patient experiencing severe addition, besides being very clumsy to apply some products "peaks and valleys' in the plasma level of the therapeutic have to be manipulated before application (not ready-for-use agent being administered, as well as often requiring multiple right out of the storage system, e.g., multi-component sys dosings per day. tems that have to be mixed by the administrator before use) making the system prone to inappropriate handling, spilling These problems were addressed somewhat by the devel and therefore having the potential for being non-therapeutic opment of Sustained release drug delivery products, where or not working as originally designed. But even when the patient experienced less severe plasma level “peaks and 25 therapeutic agents are placed as directed within the oral alleys' and there were reduced dosings per day. Subsequent cavity, the agent is Subjected to wash-out or dilution due to development of controlled release drug delivery technolo the constant flow of saliva, crevicular fluid outflow from the gies provided for no "peaks and Valleys' in the daily plasma periodontal pocket, as well as the patients intake of food level, as well as providing for a daily, weekly or monthly and beverages, all of which affect/minimize/reduce the dosing regimen. Controlled release drug delivery systems 30 can be designed to target a local area or the systemic amount of agent that is able to effectively treat the oral circulation and can be administered in a variety of ways, disease. including orally, transdermally, as an implant, by injections, Another limitation with conventional administration is and so forth. that the selection of therapeutic agents is somewhat limited to those that are less potent, to prevent toxicity. Based on Many methods of treating diseases in and originating in 35 thermodynamic reasons, very high systemic concentration the orofacial environment, have involved oral administration levels (So high that they may cause systemic toxicity), are of drugs such as anti-inflammatory or anti-infective agents, often required to drive the drug into the localized diseased for example. However, Such systemic therapies are often area in an attempt to establish the therapeutic concentration unable to reach the targeted diseased local area. In addition, level in the targeted tissue. Therefore, only therapeutic patients can experience sub-therapeutic levels and/or fluc 40 agents that have a large therapeutic index and are not too tuating concentrations of agent with systemic therapies. expensive, find utilization in conventional therapy. Active Further, in order for such systemic administration to provide agents that may be more effective but are associated with adequate drug levels to treat the orofacial tissue, the actual toxicity or are very costly to administer in high doses, can dosage administered often needs to be extremely high. As not be used in the state of the art methodologies. the systemic concentration is elevated, there is a greater 45 likelihood of the patient experiencing systemic side-effects Accordingly, there is a continuing need to find improved and even toxicity. Another problem with high-dosing methods for treating orofacial diseases that will overcome therapies, particularly when administering anti-infective Some or all of the shortcomings of the art, as well as present agents such as antibiotics, is the increase likelihood of new methodologies for administering a wider range of bacterial resistance. 50 therapeutic agents. The present invention addresses those Other methods of treating orofacial diseases have needs by means of an implantable or insertable controlled involved topical applications and intra-oral products that are release drug delivery system that is positioned within the applied in the mouth or dental area on the Surface of diseased orofacial tissue and provides a uniform concentra structures. Some formulations are placed within the peri tion of therapeutic agent at the target tissue site. odontal pocket, others are on the mucous membrane or other 55 SUMMARY OF THE INVENTION surfaces, etc. Such formulations often include anti-infectives as it is often desirable to minimize or eliminate the bacteria One aspect of the invention relates to a method of treating present in the mouth while treating orofacial diseases Such disease in or originating in the orofacial environment in a as periodontal disease. Examples of products that are posi patient comprising the step of administering a drug delivery tioned within the periodontal pocket include a tetracycline 60 system within orofacial tissue, wherein the system com containing ethylene/vinyl acetate copolymer that is posi prises a semi-solid or solid depot and a therapeutically tioned within the periodontal pocket (Actisite(R), Proctor & effective amount of at least one therapeutic agent contained Gamble); a chorhexidine gluconate-containing biodegrad therein, and is within the range of about 0.03–17 mm in able hydrolyzed gelatin matrix (PerioChip(R), Astra S17C. Pharmaceuticals); and a doxycycline-containing biodegrad 65 Another aspect of the invention pertains to a method of able polymer that is administered as a liquid and Solidifies in treating disease in or originating in the orofacial environ situ to conform to the shape of the periodontal pocket ment in a patient comprising the step of administering a drug US 7,074,426 B2 3 4 delivery system within orofacial tissue, wherein the system agent includes a single therapeutic agent as well as a comprises a semi-solid or Solid depot and a therapeutically combination of two or more therapeutic agents, reference to effective amount of an anti-inflammatory agent contained “a pharmaceutically acceptable carrier includes a single therein. pharmaceutically acceptable carrier as well as combinations Yet another aspect of the invention relates to a drug of two or more pharmaceutically acceptable carriers, and the delivery system configured to be positioned within orofacial like. tissue comprising a semi-solid or solid depot and at least one I. Definitions therapeutic agent contained therein, and having a size within As used herein, the terms “therapeutic agent' and “drug’ the range of about 0.03–17 mm. are used interchangeably and are intended to include agents Still another aspect of the invention is a drug delivery 10 that are useful in treating orofacial diseases states and agents system configured to be positioned within orofacial tissue that are useful in treating pain and other conditions associ comprising a semi-solid or solid depot and about 35–4500 ated with orofacial disease states. The terms also encom ug of a therapeutic agent contained therein, and having a size passes pharmaceutically acceptable, pharmacologically within the range of about 0.03–17 mm. active derivatives of those agents specifically mentioned 15 herein, including, but not limited to, salts, esters, amides, DETAILED DESCRIPTION OF THE prodrugs, active metabolites, analogs, and the like. Such INVENTION therapeutic agents include by way of illustration and not The present invention comprises methods treating dis limitation, anti-inflammatory agents, anti-infective agents, eases in the orofacial environment orofacial diseases or tissue and bone growth factors, pain management diseases that originate in the orofacial environment and medication, antineoplastic agents, bone alteration agents, complications therefrom, by the intratissue administration of and combinations thereof. When the term “therapeutic a controlled release drug delivery system to an orofacial site. agent' is used, it is also to be understood that the active The controlled release drug delivery systems used in the agent per se as well as pharmaceutically acceptable, phar methods of the invention are suitable for use in administer macologically active salts, esters, amides, prodrugs, ing one or more therapeutic agents at a predefined rate for 25 metabolites, analogs, etc. are included. periods of up to one month or longer. The agent(s) can be The term “pharmaceutically acceptable carrier' is delivered directly to the target tissue or can be delivered to intended to mean a material or materials that are suitable for the nearby local vasculature or gland that in turn provides drug administration and not biologically or otherwise the means of carrying the agent to the desired target tissue undesirable, i.e., that may be administered to an individual 30 along with a therapeutic agent without causing any unde location. sirable biological effects or interacting in a deleterious The controlled release drug delivery systems used in the manner with any of the other components of the pharma methods are implantable or insertable systems comprised of ceutical formulation in which it is contained. a pre-manufactured Small depot, having a therapeutic agent The terms “tissue within the orofacial environment” and incorporated therein. Typically, the depot will be a biode 35 'orofacial tissue are used interchangeably to mean tissue gradable semi-solid or Solid, but non-biodegradable appli sites located within the orofacial environment, which cations are also contemplated. Exemplary materials and includes the oral cavity, head and neck, including the brain. systems will be described in detail below as well as being Such tissue includes by way of illustration and not described in the patents cited below. limitation, periodontal tissue Such as the periodontium; The controlled release drug delivery systems used in the 40 periodontal ligaments; bone tissue at the end of an infected methods are Small in size compared to existing products, tooth, inside the tooth or within the bone cavity such as may which provides versatility in how and where they can be be present after an apicoectomy or tooth extraction; endo placed. Since these metered dosage systems provide for dontic tissue; bone tissue Surrounding an implant fixture; ear precise targeting of diseased tissue, Smaller amounts of drug tissue such as that affected by a stapedectomy procedure; are needed than in conventional therapies. This provides 45 jaw tissue such as the temporomandibular joint, the tempo several advantages in that a minute amount of drug can be ralis muscle, the temporal bone the masseter muscle and the delivered with maximum therapeutic benefit and minimum mandible, lymph nodes, glands, like for example thyroid or toxic side effects. This opens up an opportunity to deliver pituitary, tissue affected by Surgery, e.g. tonsillectomy; and agents that are too costly or too toxic to deliver by traditional so forth. routes and methodologies. 50 The terms “intratissue’ and “intraorofacial tissue' are Before describing detailed embodiments of the invention, used interchangeably and are intended to mean that the it will be useful to set forth definitions that are used in controlled release drug delivery system of the invention is describing the invention. The definitions set forth apply only positioned inside the orofacial tissue in contrast to topically. to the terms as they are used in this patent and may not be The drug delivery system of the invention can be implanted applicable to the same terms as used elsewhere, for example 55 within the tissue by a punch biopsy procedure, inserted into in Scientific literature or other patents or applications includ the tissue with a trocar, inserted into the tissue after a ing other applications by these inventors or assigned to Surgical incision, left in the open wound after a Surgical common owners. Additionally, when examples are given, procedure, and so forth. The term intratissue is intended to they are intended to be exemplary only and not to be include intraosseous. The term specifically excludes Suprat restrictive. For example, when an example is said to 60 issue placement Such as on top of the gum tissue or inter “include a specific feature, that is intended to imply that it tissue (interSulcular) placement Such as within the periodon may have that feature but not that such examples are limited tal pocket. to those that include that feature. The term “placement site' is intended to mean the intrat It must also be noted that, as used in this specification and issue location of the drug delivery system of the invention. the appended claims, the singular forms “a,” “an,” and “the 65 The “target site' is the location of the tissue to be treated. include plural referents unless the context clearly dictates Typically the placement site will be the same as the target otherwise. Thus, for example, reference to “a therapeutic site to provide for optimal targeted drug delivery. However, US 7,074,426 B2 5 6 the invention also contemplates positioning the drug deliv caused by periodontal disease; cranomandibular disease ery system at a placement site nearby the target site Such that which produces facial, head, ear and jaw pain, examples of the therapeutic agent can be delivered to the Surrounding which include temporomandibular joint syndrome; ear Sur vasculature, which carries the agent to the desired nearby gery: eye surgery (including Strabismus Surgery); drug deliv target site. As used herein, the term “nearby implies that the ery to the eye (in contrast to intraocular); othoptics; vision placement site and target site are within close proximity. therapy; cosmetic and plastic Surgery to reconstruct and Preferably, both sites are within the orofacial environment. rebuild facial features after accidents or other deformations; This drug delivery strategy is of benefit in the case the target wrinkle removal and anti-wrinkle therapy (e.g. long-lasting Botulinum Toxin Type A delivery); cranial nerve and ocu site is a larger tissue area or orofacial structure or if it is lomotor pals; Surgical correction of drooping lid; Surgery to desired to distribute the agent over a larger tissue segment 10 repair palsies and to prevent amblyopia; meningitis; Parkin not only by passive diffusion through the adjacent tissue, but son's disease; Alzheimer's disease; brain cancer, viral infec also utilize convective transport via the nearby vasculature. tions; cold Sores; otologic Surgery; treatment of Menier's Convective transport is often much faster than passive syndrome; ear tumors; otitis and otitis media; otosclerosis: diffusion and allows for a more effective and far-reaching tinnitus; meringotomy; structures of balance; prevention of drug administration. For those skilled in the art the appro 15 complications from ear drum perforation; cholesteatomas; priate placement sites can be easily determined by assessing sinusitis; mastoditis; tonsillitis; pharyngitis; adenitis; hair the course of the principal arteries Supplying the head and transplantation; skin transplants; nose Surgery; tonsillec neck that convey oxygenated blood and nutrition to the tomy; and so forth. The term “orofacial disease' is intended orofacial tissues. It is known that the two common carotids to encompass diseases within the orofacial environment, as that ascend in the neck, each divide into two branches, the well as diseases that originate in the orofacial environment. external carotid, Supplying the exterior of the head, the face, The term “treatment as used herein covers any treatment and the greater part of the neck and the internal carotid, of any orofacial disease in a mammal, particularly a human, Supplying to a great extent the parts within the cranial and and includes: (i) preventing the disease from occurring in a orbital cavities, where they further divide into other subject which may be predisposed to the disease but has not branches Supplying specific orofacial areas and structures. 25 yet been diagnosed as having it; (ii) inhibiting the disease, To those skilled in the art, the specific locations of these i.e. arresting its development; or (iii) relieving the disease, artery branches and their anatomical relations to the targeted i.e. causing regression of the disease. For example, treatment diseased orofacial tissues are very well known. Distribution can include reducing acute or chronic inflammation; allevi of an agent via a blood vessel to a nearby orofacial tissue site ating pain and mitigating and inducing re-growth of new (muscle, gland, cavity, nerve, lymph node, teeth, gingiva, 30 periodontal ligament, bone and other tissues; as an adjunct eye, ear, joint, brain, etc.) can be selected according to the in orthognathic Surgery; any elective cosmetic Surgical or prevailing nearby blood vessel anatomy and the ability to repair procedure; and so forth. place the drug delivery system at the desired site. Desired The term “therapeutically effective amount” refers to that placement sites are easy accessible or locations before the amount which is sufficient to effect treatment, as defined vessel(s) of interest enter(s) a bony cavity or arise(s) from it. 35 above, when administered to a mammal in need of Such Exemplary placement sites that may not also be the target treatment. The therapeutically effective amount will vary site include the three bilateral sublingual and submandibular depending on the Subject and disease state being treated, the glands (open into the floor of mouth, one on each side of the severity of the affliction and the manner of administration, frenulum of the tongue) and the parotid. Their secretions and may be determined routinely by one of ordinary skill in (transferred via long ducts) lubricate the mouth and thus 40 the art. Typically, the drug delivery system of the invention could act to deliver drug from a drug delivery system administers the therapeutic agent at a predefined and con positioned therein. The advantage with Such a placement is trolled release rate that creates local concentration levels that it is quite practical to position a drug delivery system within the desired therapeutic range or therapeutic index of within one of these glands or the parotid, and provide the drug. The upper limit of this therapeutic range prevents delivery to treat a variety of orofacial diseases. Other glands 45 toxicity and other unwanted effects, while the lower limit of present in the orofacial environment may also be suitable the range prevents sub-therapeutic levels from being admin placement sites. Such as the lingual, labial, tonsillar or istered. buccal glands. The strategic placement sites of the drug The invention pertains to methods and drug delivery delivery system may include lymph nodes or the corre systems for the treatment of a variety of diseases within or sponding drainage system. The intercellular spaces contain 50 originating in the orofacial environment. These methods small endothelial-lined tubes, resembling blood vessels, but generally involve the step of administering a controlled are blind ending. The network of these vessels drain the release drug delivery system inside the diseased tissue. The lymph from a particular area into the lymph node serving controlled release drug delivery systems useful in these that area. Primary diseases of the lymphatics that could be methods generally comprise a depot and at least one thera treated in this manner includes Hodgkin’s disease and 55 peutic agent encapsulated, dissolved or dispersed therein, lymphatic neoplasms. and are described in detail below. In general, the therapeutic The term “orofacial disease' is intended to include, by agent can be any therapeutic that is useful in treating way of illustration and not limitation, acute and chronic diseases within or originating in the orofacial environment. inflammation, including chronic inflammation of the tissue Specific non-limiting examples are set forth below. (including host response reactions) to stop the process of the 60 One embodiment of the invention is a drug delivery on-going tissue decay; infection; pain and related inflam system configured to be positioned within orofacial tissue matory and other complications of mechanical teeth clean comprising a semi-solid or solid depot and at least one ing (including root planning and Scaling), all periodontal therapeutic agent contained therein, and having a size within Surgical procedures, and other Surgical procedures such as the range of about 0.03–17 cubic millimeters (mm). The an apicoectomy or root canal, procedures done to facilitate 65 actual size selected will be based upon considerations such tooth movement such as orthodontia; repair damage to as the average daily dosage, the drug loading capacity and periodontal ligament, bone and other tissues that has been duration of delivery, drug delivery density, and so forth. US 7,074,426 B2 7 8 The following table exemplifies numerous variables (all A monolith can be of solution or dispersion-type, both of stated as approximations) that affect the size selected for the which are homogeneous mixtures of the depot material and drug delivery system. the therapeutic agent, i.e., the therapeutic agent is dispersed uniformly throughout a rate-controlling material that forms the depot. In general, monoliths systems may have addi tional layers such as a drug-permeable membrane, adhesive desired average daily dosage drug loading density size layer and so forth, and may therefore constitute a mixed (g/day) (wt %) (g/cm) duration (mm) reservoir/monolithic system. Monolithic dispersions include simple monoliths, com S-10 30-90 O.9–1.3 7–14 days O.O3 O.S 10 S-10 30-90 O.9–1.3 up to 1 month 0.13–1.1 plex monoliths and matrix monoliths, all of which are all S-10 30-90 O.9–1.3 2 months O.26-22 Suitable for use as drug delivery systems of the invention. A S-10 30-90 O.9–1.3 3 months O.38-33 simple monolith is a drug depot formed of a Suitable material 25 50 30-90 O.9–1.3 up to 2 weeks 0.15-2.6 having the drug dispersed within the material, where 25 50 30-90 O.9–1.3 up to 1 month 0.64–5.6 25 50 30-90 O.9–1.3 2 months 1.3–11 Cs-Coz.5%. For a complex monolith, 5%.alclofenac; biodegradable particle former, e.g. compounds that are used 65 alclometasone dipropionate; algestone acetonide; alendr already in the dental arena which include gutta perch, or the onate Sodium; alpha amylase; amcinafal; amcinafide; amci typical scaffolding materials, and so forth. nonide; amfenac sodium; amiprilose hydrochloride; anak US 7,074,426 B2 13 14 inra, anirolac, anitraZafen; apaZone; balsalazide disodium; Dexamethasone is of particular interest for use as an beclomethasone diproprionate; bendaZac; benoxaprofen; anti-inflammatory to treat orofacial diseases. Besides its benzydamine hydrochloride; betamethasone; bromelains: anti-inflammatory property, dexamethasone can be deliv broperamole; budesonide; carprofen; cicloprofen; cinta ered to up-regulate certain enzyme activities. Specifically Zone; cliprofen; clobetasol propionate; clobetaSone butyrate; dexamethasone can be used to increase or up-regulate alka clopirac, cloticaSone propionate; cormethasone acetate; cor line phosphotase activity in regenerating human periodontal tisone acetate; cortodoxone; deflazacort; desonide; des oximetaSone; dexamethasone dipropionate; diclofenac cells, as described by Kuru et al., J. Periodont Res. potassium; diclofenac sodium; diflorasone diacetate; diflu 34:123-127 (1999). midone sodium; diflunisal; difluprednate; diftalone; dim b. Anti-infective Agents ethyl Sulfoxide; drocinonide; endry Sone; enlimomab; enoli 10 Exemplary anti-infective agents to treat infection include cam Sodium; epirizole; etodolac, etofenamate; felbinac; by way of example and not limitation, antibacterial agents; fenamole; fenbufen; fenclofenac; fenclorac; fendosal; fen quinolones and in particular fluoroquinolones (e.g. pipalone; fentiazac, flazalone; fluazacort; fludrocortisone; norfloxacin, ciprofloxacin, lomefloxacin, ofloxacin, etc.); flufenamic acid; flumizole; flunisolide acetate; flunixin; and other broad spectrum antibiotics having a low minimum flunixin meglumine; fluocinonide; fluocinolone acetonide; 15 inhibitory concentrations (MIC) or low bactericidal con fluocortin butyl; fluorometholone acetate; flucuaZone; flu centrations ('MBC') including aminoglycosides (e.g. randrenolide; flurbiprofen; fluretofen; fluticasone propi gentamycin, tobramycin, etc.), glycopeptides (e.g. onate; furaprofen; furobufen; halcinonide; halobetasol pro Vancomycin, etc.), lincosamides (e.g. clindamycin), cepha pionate; halopredone acetate; hydrocortisone; ibufenac; losporins and related beta-lactams (preferably third ibuprofen; ibuprofen aluminum; ibuprofen piconol; generation), macrollides (e.g. azithromycin, erythromycin, ilonidap; indomethacin; indomethacin Sodium; indoprofen; etc.), nitroimidazoles (e.g. metronidazole), penicillins, indoxole; intrazole; isoflupredone acetate; isoxepac; isoxi polymyxins, tetracyclines, and combinations thereof. cam; ketoprofen; lofemizole hydrochloride; lomoxicam, Other exemplary antibacterial agents include, by way of loteprednol etabonate; meclofenamate sodium; meclofe illustration and not limitation, acedapsone; acetosulfone namic acid; meclorisone dibutyrate; medry Sone; mefenamic 25 Sodium; alamecin, alexidine; amdinocillin; amdinocillin acid; mesalamine; meseclaZone; methylprednisolone Sulep pivoxil, amicycline; amifloxacin; amifloxacin meSylate; tanate; momiflumate; nabumetone; naproxen; naproxen amikacin; amikacin Sulfate; aminosalicylic acid; aminosali Sodium; naproxol; nimaZone; nilutamide; olsalazine Sodium; cylate Sodium; amoxicillin; amphomycin; amplicillin; ampi orgotein; orpanoxin, oxaprozin, oxyphenbutaZone; pamidr cillin Sodium; apalcillin Sodium: apramycin; aspartocin, onate disodium; paramethasone; paranyline hydrochloride; 30 astromicin Sulfate; avilamycin; avoparcin; azithromycin; pentosan polysulfate Sodium; phenbutaZone sodium glycer azlocillin; azlocillin sodium; bacampicillin hydrochloride: ate; pirfenidone: piroxicam, piroxicam cinnamate: piroxi bacitracin; bacitracin methylene disalicylate; bacitracin cam olamine; pirprofen; prednazate; prednisolone; prife Zinc, bambermycins; benzoylpas calcium; berythromycin; lone; prodolic acid; produaZone; proxazole; proxazole betamicin Sulfate; biapenem; biniramycin; biphenamine citrate; rimexolone; romazarit; Salcolex; salnacedin; Sal 35 hydrochloride; bispyrithione magsulfex; butikacin; butirosin salate; sanguinarium chloride; seclaZone; sermetacin; Sulfate; capreomycin Sulfate; carbadox; carbenicillin diso Sudoxicam, Sulindac; Suprofen; talmetacin; talniflumate; dium; carbenicillin indanyl Sodium; carbenicillin phenyl talosalate; tebufelone; tenidap; tenidap Sodium; tenoxicam, Sodium; carbenicillin potassium; carumonam Sodium, cefa tesicam, tesimide; tetrydamine; tiopinac; tixocortol pivalate; clor, cefadroxil, cefamandole, cefamandole nafate; cefa tolimetin; tolmetin sodium; triamcinelone; triclonide; triflu 40 mandole sodium, cefaparole; cefatrizine, cefazaflur Sodium; midate; Zidometacin: Zomepirac sodium; and combinations cefazolin, cefazolin Sodium, cefbuperaZone; cefdinir, thereof. cefepime; cefepime hydrochloride; cefetecol; cefixime; cef A preferred class of anti-inflammatory agents are the menoxime hydrochloride; cefmetazole; cefmetazole steroidal agents or glucocorticosteroids. Phospholipase A2 Sodium, cefonicid monosodium, cefonicid sodium, cefop (“PLA2) is a lipolytic enzyme that has been implicated as 45 eraZone sodium, ceforanide; cefotaxime sodium, cefotetan: a possible mediator of inflammation. Specifically, PLA2 cefotetan disodium; cefotiam hydrochloride; cefoxitin; hydrolyses the 2-acyl position of glycerophospholipids, lib cefoxitin Sodium, cefpimizole; ce?pimizole Sodium, cefpi erating free-fatty acids, mainly arachidonic acid. ramide; ce?piramide sodium; ce?pirome Sulfate; ce?po Subsequently, it is believed that arachidonic acid is con doXime proxetil, cefprozil; cefroxadine, cefsulodin Sodium; verted into a variety of proinflammatory eicosanoids. Glu 50 ceftazidime; ceftibuten; ceftizoxime sodium; ceftriaxone cocorticosteroids are known to stop or reduce the Suggested Sodium, cefuroxime; cefuroxime axetil, cefuroxime pivox mechanisms of inflammation that involves the activation of etil, cefuroxime Sodium; cephacetrile sodium; cephalexin; the arachidonic acid cascade which results in the liberation cephalexin hydrochloride; cephaloglycin; cephaloridine; of a variety of proinflammatory eicosanoids by inducing cephalothin Sodium; cephapirin sodium; cephradine; ceto lipocortin that inhibits PLA2. This provides a significant 55 cycline hydrochloride; cetophenicol; chloramphenicol; advantage over non-steroidal anti-inflammatory agents that chloramphenicol palmitate; chloramphenicol pantothenate enter the cascade much later. complex; chloramphenicol sodium Succinate; chlorhexidine Suitable glucocorticosteroids include agents such as phosphanilate; chloroxylenol; chlortetracycline bisulfate; alclometasone diproprionate, alendronate Sodium, amcino chlortetracycline hydrochloride; cinoxacin; ciprofloxacin; nide , beclomethasone diproprionate, betamethasone, 60 ciprofloxacin hydrochloride; cirolemycin; clarithromycin; bude Sonide, clobeta Sol propio nate, cortisone, clinafloxacin hydrochloride; clindamycin; clindamycin dexamethasone, diflorasone diacetate, hydrocortisone, hydrochloride; clindamycin palmitate hydrochloride; clin fludrocortisone; flunisolide acetate, fluocinolone acetonide, damycin phosphate; clofazimine; cloxacillin benzathine; fluocinonide, fluorometholone acetate, flurandrenolide, cloxacillin Sodium; cloxyquin; colistimethate sodium; colis halcinonide, medrysone; methylprednisone Suleptanate, 65 tin Sulfate; coumermycin; coumermycin Sodium; cyclacillin; pamidronate, paramethasone, prednisolone, nilutamide, cycloserine; dalfopristin; dapsone; daptomycin; demeclocy triamcinelone, and combinations thereof. cline; demeclocycline hydrochloride; demecycline; deno US 7,074,426 B2 15 16 fungin; diaveridine; dicloxacillin; dicloxacillin sodium; oprim; thiamphenicol; thiphencillin potassium; ticarcillin dihydrostreptomycin Sulfate; dipyrithione; dirithromycin; cresyl Sodium, ticarcillin disodium, ticarcillin monosodium; doxycycline: doxycycline calcium; doxycycline fosfatex; ticlatone; tiodonium chloride; tobramycin; tobramycin Sul doxycycline hyclate; droxacin sodium; enoxacing epicillin; fate; to Sufloxacin; trimethoprim; trimethoprim Sulfate; epitetracycline hydrochloride; erythromycin; erythromycin 5 trisulfapyrimidines; troleandomycin; trospectomycin Sul acistrate; erythromycin estolate; erythromycin ethylsucci fate; tyrothricin; Vancomycin; Vancomycin hydrochloride; nate, erythromycin gluceptate; erythromycin lactobionate; Virginiamycin; Zorbamycin; and combinations thereof. erythromycin propionate; erythromycin Stearate; ethambutol Of particular interest are those anti-infective agents that have low minimum inhibitory or bactericidal concentrations hydrochloride; ethionamide; fleroxacin; floxacillin; fludala (“MIC or “MBC') such as quinolones in particular nine; flumequine; fosfomycin; fosfomycin tromethamine; 10 fluoroquinolones, and so forth, as noted above. Typically fumoxicillin; furazolium chloride; furazolium tartrate; fusi such MIC or MBC values will be less than about 5 ug/ml. date sodium; fusidic acid; ganciclovir and ganciclovir There are several methods to evaluate an organisms (e.g., Sodium; gentamicin Sulfate; gloXimonam, gramicidin; halo bacteria) level of resistance to an anti-infective agent. progin; hetacillin; hetacillin potassium; hexedine; ibafloxa Typically, serial dilutions of the agent are made in a liquid cin, imipenem; isoconazole; isepamicin; isoniazid; josamy 15 medium which is inoculated with a standardized number of cin; kanamycin Sulfate; kitasamycin; levofuraltadone; organisms and incubated for a prescribed time. The lowest levopropylcillin potassium, lexithromycin; lincomycin; lin concentration (highest dilution) of agent preventing appear comycin hydrochloride; lomefloxacin, lomefloxacin hydro ance of turbidity is considered to be the “minimum inhibi chloride; lomefloxacin mesylate; loracarbef mafenide; tory concentration’. At this dilution the agent is considered meclocycline; meclocycline Sulfosalicylate; megalomicin to be bacteriostatic. potassium phosphate; medulidox; meropenem; methacy The systems of this invention are particularly well suited cline; methacycline hydrochloride; methenamine; meth for the administration of low “MIC anti-infective agents enamine hippurate; methenamine mandelate; methicillin due to the small size of the system. For example a high MIC Sodium; metioprim; metronidazole hydrochloride; metron drug requires a similarly high dosage to be effective, and idazole phosphate; meZlocillin; meZlocillin sodium; 25 thus would require a large drug delivery system to accom minocycline; minocycline hydrochloride; mirincamycin modate the needed dosage amount. A low MIC drug that is hydrochloride; monensin; monensin Sodiumr, nafcillin 1000 times more potent than the high MIC drug, would Sodium; nalidixate Sodium; nalidixic acid; natainycin; require 1000 time less drug, and therefore a suitable drug nebramycin; neomycin palmitate; neomycin Sulfate; neomy delivery system could similarly be 1000 times smaller. cin undecylenate; netilmicin Sulfate; neutramycin; 30 Typically, orofacial infections are polymirobial and domi nifuiradene; nifuraldezone; nifuratel; nifuratrone; nifurdazil; nant organisms can vary greatly. The most common organ nifurimide: nifiupirinol; nifurcquinazol; nifurthiazole; nitro isms found in periodontal disease include Spirochete, Strep cycline; nitrofurantoin: nitromide; norfloxacin; novobiocin tococcus mutans, Streptococcus oralis, Streptococcus Sodium; ofloxacin; onnetoprim; oxacillin and oxacillin sanguis, Actinomyces naeslundi, Porphyromonas gingivalis, Sodium; oximonam; oximonam sodium; oxolinic acid; 35 PrevOtella intermedia, Fusobacterium nucleatum, Pep oxytetracycline; oxytetracycline calcium; oxytetracycline to streptococcus micros, Actinmyces naeslundi, Leptotrichia hydrochloride; paldimycin; parachlorophenol; paulomycin; buccalis, Eikenella corro dens, Microaerophillic pefloxacin; pefloxacin mesylate; penamecillin: penicillins streptococci, and so forth. Exemplary anti-infective agents Such as penicillin g benzathine, penicilling potassium, with low MICs that can be used in the methods of the penicilling procaine, penicilling sodium, penicillin V, 40 invention include aminoglycosides such as gentamycin and penicillin V benzathine, penicillin V hydrabamine, and peni tobramycin; dicloxacillin, fluoroquinolones such as ciprof cillin V potassium; pentizidone sodium; phenyl aminosali loxacin, glycopeptides such as Vancomycin; lincosamides cylate; piperacillin Sodium; pirbenicillin Sodium; piridicillin Such as clindamycin; macrollides such as azithromycin and Sodium; pirlimycin hydrochloride; pivampicillin hydrochlo erythromycin; nitroimidazoles such as metronidazole; ride; pivampicillin pamoate; pivampicillin probenate; poly 45 oxacillin; penicillins; tetracyclines; and so forth. myxin b sulfate; porfiromycin; propikacin; pyrazinamide; c. Tissue and Bone Growth Factors pyrithione Zinc, quindecamine acetate; quinupristin; raceph Exemplary tissue and bone growth factors to facilitate enicol; ramoplanin; ranimycin; relomycin; repromicin; tissue and/or bone growth include by way of example and rifabutin: rifametane; rifamexil; rifamide: rifampin: rifapen not limitation, growth hormones Such as transforming tine; rifaximin; rollitetracycline; rollitetracycline nitrate; rosa 50 growth factor-B. There are also other factors or enzymes ramicin; rosaramicin butyrate; rosaramicin propionate; rosa Such as alkaline phosphatase that are involved in the facili ramicin Sodium phosphate; rosaramicin Stearate; roSoxacin; tation of tissue and/or bone regeneration. Alkaline phos roXarsone; roXithromycin; Sancycline; Sanfetrinem Sodium; phatase has been shown to be a biochemical indicator of Sarmoxicillin; Sarpicillin; scopafungin; Sisomicin; sisomicin bone turnover. Osteoblasts, generally regarded as bone Sulfate; sparfloxacin; spectinomycin hydrochloride; spira 55 forming cells, arise from marrow stroma cells. They are mycin; stallimycin hydrochloride; Steflimycin; Streptomycin found on the surfaces where bone is being formed. Their Sulfate; streptonicoZid; Sulfabenz, Sulfabenzamide: Sulfac most obvious function is to synthesize osteoid and collagen etamide; Sulfacetamide Sodium; Sulfacytine; Sulfadiazine; and control its Subsequent mineralization. Both cytoplasm Sulfadiazine sodium; Sulfadoxine, Sulfalene; Sulfamerazine; and nucleus of osteoblasts contain the enzyme alkaline sulfameter, sulfamethazine; sulfamethizole; sulfamethox 60 phosphatase, which can be used as a marker for osteoblast azole; sulfamonomethoxine; Sulfamoxole; Sulfanilate zinc: activity. Alkaline phosphatase is a calcium- and phosphate Sulfanitran; Sulfasalazine; Sulfasomizole; Sulfathiazole; Sul binding protein that is distributed for example in periodontal faZamet; Sulfisoxazole; Sulfisoxazole acetyl; Sulfisboxazole ligament and more prominent in regions close to the alveolar diolamine; Sulfomyxin; Sulopenem; Sultamricillin; Suncillin bone and markedly lower in gingival connective tissue. Sodium; talampicillin hydrochloride; teicoplanin; tema 65 Drugs, like dexamethasone, promote the differentiation of floxacin hydrochloride; temocillin; tetracycline; tetracycline osteoprogenitor cells into osteoblasts and therefore can be hydrochloride; tetracycline phosphate complex; tetroX used in lieu of growth factors. US 7,074,426 B2 17 18 Tissue and bone growth factors can also be administered face where the branches of the nerve are distributed, such as to reduce tissue destruction and/or bone loss, such as to the lips, eyes, nose, Scalp, forehead, upper jaw, and lower reduce alveolar bone loss. Such tissue and bone growth jaw. Simples and routine acts such as brushing the teeth, factors are referred to herein as anti-degenerative agents and putting on makeup or even a slight breeze can trigger an include by way of example and not limitation, cyclooxyge attack, resulting in sheer agony for the individual. Trigemi nase inhibitors such as 2',4,4'-tricholoro-2-hydroxy nal neuralgia (“TN') is not fatal, but it is universally diphenylether, non-antimicrobial tetracyclines such as 12C considered to be the most painful affliction known to medi deoxytetracyclines; matrix metalloendoproteinase inhibitors cal practice. Initial conventional treatment of TN is usually by means of anti-convulsant or antiepileptic drugs, such as Such as inhibitors of collagenase, stormelysin and gelati carbamazepine or gabapentin. Some anti-depressant drugs nase; 5-lipoxygenase inhibitors such as quinolones; nonste 10 also have significant pain relieving effects roidal anti-inflammatory drugs such as etodolac, bisphos Exemplary analgesics include by way of example and not phonates such as alendronate and etidronate; and limitation, acetaminophen; alfentanil hydrochloride; ami combinations thereof. nobenzoate potassium; aminobenzoate Sodium; anidoxime; Of particular interest are NSAIDs such as etodolac, which anileridine; anileridine hydrochloride; anilopam hydrochlo exhibits anti-inflammatory, analgesic, and antipyretic activi 15 ride; anirolac, antipyrine; aspirin; benoxaprofen; benzy ties. The mechanism of action of etodolac, like that of other damine hydrochloride; bici fadine hydrochloride; brifentanil NSAIDs, is not known, but is believed to be associated with hydrochloride; bromadoline maleate; bromfenac sodium; the inhibition of prostaglandin biosynthesis. Bisphospho buprenorphine hydrochloride; butacetin; butixirate; butor nates are also of particular interest, for example, alendronate phanol; butorphanol tartrate; carbamazepine; carbaspirin Sodium, which is an aminobisphosphonate that acts as a calcium; carbiphene hydrochloride; carfentanil citrate; specific inhibitor of osteoclast-mediated bone resorption. ciprefadol Succinate; ciramadol; ciramadol hydrochloride; Bisphosphonates are synthetic analogs of pyrophosphate clonixeril; clonixin; codeine; codeine phosphate; codeine that bind to the hydroxyapatite found in bone. At the cellular Sulfate; conorphone hydrochloride; cyclazocine; dexoxadrol level, alendronate shows preferential localization to sites of hydrochloride; dexpemedolac, dezocine; diflunisal; dihy bone resorption, specifically under osteoclasts. Alendronate 25 drocodeine bitartrate; dimefadane; dipyrone; doXpicomine does not interfere with osteoclast recruitment or attachment, hydrochloride; drinidene; enadoline hydrochloride: epiri but it does inhibit osteoclast activity. Studies in mice on the Zole; ergotamine tartrate; ethoxazene hydrochloride; etofe localization of radioactive Halendronate in bone showed namate; eugenol; fenoprofen; fenoprofen calcium; fentanyl about 10-fold higher uptake on osteoclast Surfaces than on citrate; floctafenine; flufenisal; flunixin; flunixin meglu osteoblast Surfaces. After alendronate administration normal 30 mine; flupirtine maleate; fluproduaZone; fluradoline hydro bone is formed on top of the alendronate, which is incor chloride; flurbiprofen; hydromorphone hydrochloride: porated inside the matrix. While incorporated in bone ibufenac; indoprofen; ketazocine; ketorfanol; ketorolac and matrix, alendronate is not pharmacologically active. Thus, ketorolac tromethamine; letimide hydrochloride; alendronate is preferably continuously administered to Sup levomethadyl acetate; levomethadyl acetate hydrochloride: press osteoclasts on newly formed resorption Surfaces. In 35 levonantradol hydrochloride; levorphanol tartrate; lofemi alendronate treatment bone formation exceeds bone resorp Zole hydrochloride; lofentanil oxalate; lorcinadol; lomoxi tion at these remodeling sites, leading to progressive gains cam; magnesium salicylate; mefenamic acid; menabitan in bone mass. hydrochloride; meperidine hydrochloride; meptazinol Drugs like phenytoin (dilantin) can also be delivered to hydrochloride; methadone hydrochloride; methadyl acetate; facilitate gum tissue re-growth. Phenytoin is an antiepileptic 40 methopholine; methotrimeprazine; metkephamid acetate; drug and is related to the barbiturates in chemical structure. mimbane hydrochloride; mirfentanil hydrochloride; molina Typically, it is administered to treat seizures and epilepsy. Zone; morphine Sulfate; moxazocine; nabitan hydrochloride; One of its pharmaceutical side-effects (gingival hyperplasia) malbuphine hydrochloride; malmexone hydrochloride: can be used to enhance the gingival tissue regeneration. namoxyrate; nantradol hydrochloride; naproxen; naproxen d. Pain Management Medication 45 Sodium; naproXol; nefopam hydrochloride; nexeridine The term "pain management medication' covers an hydrochloride; noracymethadol hydrochloride; ocfentanil assortment of therapeutic agents that are administered to hydrochloride; octaZamide; olvanil; OXetorone fumarate; prevent, alleviate or remove pain entirely. These include oxycodone; oxycodone hydrochloride; oxycodone tereph anti-inflammatory agents, muscle relaxants, analgesics, thalate; oxymorphone hydrochloride; pemedolac, pentam anesthetics, narcotics, and so forth, and combinations 50 orphone; pentazocine; pentazocine hydrochloride; pentaZo thereof. cine lactate; phenazopyridine hydrochloride; phenyramidol Exemplary muscle relaxants include by way of example hydrochloride: picenadol hydrochloride; pinadoline: pirfeni and not limitation, alcuronium chloride, atracurium done; piroxicam olamine; pravadoline maleate; prodilidine bescylate, baclofen, carbolonium, carisoprodol, chlorphen hydrochloride; profadol hydrochloride; propirarn fumarate; es in carbamate, chlorZoXaZone, cycloben Zaprine, 55 propoxyphene hydrochloride; propoxyphene napsylate: dantrolene, decamethonium bromide, faZadinium, gallamine proxazole; proxazole citrate; proXorphan tartrate; pyrro triethiodide, hexafluorenium, meladrazine, mephensin, liphene hydrochloride; remifentanil hydrochloride; salcolex: metaxalone, methocarbamol, metocurine iodide, Salethamide maleate; salicylamide; Salicylate meglumine; pancuronium, pridinol mesy late, Styramate, Salsalate; sodium salicylate; spiradoline mesylate; Sufenta suxamethonium, SuXethonium, thiocolchicoside, tizanidine, 60 nil; Sufentanil citrate; talmetacin; talniflumate; talosalate; tolperisone, tubocuarine, vecuronium, and combinations taZadolene Succinate; tebufelone; tetrydamine; tifurac thereof. Sodium; tilidine hydrochloride, tiopinac; tonazocine mesy Of particular interest is chlorphenesin carbamate, a drug late; tramadol hydrochloride; trefentanil hydrochloride; tro which also has antifungal activity. Chlorphenesin carbamate lamine: Veradoline hydrochloride; verilopam hydrochloride: is used in the treatment of trigeminal neuralgia, a disorder of 65 volazocine; Xorphanol mesylate; Xylazine hydrochloride; the fifth cranial (trigeminal) nerve that causes episodes of Zenazocine mesylate; Zomepirac sodium; Zucapsaicin; and intense, stabbing, electric shock-like pain in the areas of the combinations thereof. US 7,074,426 B2 19 20 Exemplary anesthetics include by way of example and not prine; rogletimide; safmgol, Safingol hydrochloride; Semus limitation, alliflurane; benoximate hydrochloride; ben tine; simtraZene; sparfosate Sodium; sparsomycin; Spiroger Zocaine; biphenamine hydrochloride; bupivacaine hydro manium hydrochloride; Spiromustine; Spiroplatin: chloride; butamben; butamben picrate; chloroprocaine streptonigrin: streptozocin; strontium chloride Sr 89: hydrochloride; cocaine; cocaine hydrochloride; cyclopro Sulofenur; talisomycin; taxane; taxoid; tecogalan Sodium; pane; desflurane; dexivacaine; diamocaine cyclamate; tegafur, teloxantrone hydrochloride; temoporfin, teniposide; dibucaine: dibucaine hydrochloride: dyclonine hydrochlo teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; ride; enflurane; ether; ethyl chloride; etidocaine; etoxadrol tiaZoflurin; tirapa Zamine; topotecan hydrochloride; hydrochloride: euprocin hydrochloride; fluroxene; hal toremifene citrate; trestolone acetate; triciribine phosphate: othane; isobutamben; isoflurane; ketamine hydrochloride; 10 trimetrexate; trimetrexate glucuronate, triptorelin; tubulo levoxadrol hydrochloride; lidocaine; lidocaine hydrochlo Zole hydrochloride; uracil mustard; uredepa; vapreotide; ride; mepivacaine hydrochloride; methohexital Sodium; verteporfin; vinblastine sulfate; Vincristine sulfate; Vin methoxyflurane; midazolam hydrochloride; midazolam desine; Vindesine Sulfate; Vinepidine Sulfate; Vinglycinate maleate; minaxolone; nitrous oxide; norflurane; octodrine; sulfate; Vinleurosine sulfate; Vinorelbine tartrate; Vinrosidine oxethazaine; phencyclidine hydrochloride; pramoxine 15 Sulfate; Vinzolidine Sulfate; Vorozole; Zeniplatin: Zinostatin: hydrochloride; prilocaine hydrochloride; procaine hydro Zorubicin hydrochloride; and combinations thereof. chloride; propanidid; proparacaine hydrochloride; propofol; For the treatment of cancers of the head and neck, propoxycaine hydrochloride; pyrrocaine; ris ocaine; including cancers of the oral cavity, oropharyngeal cancer, rodocaine; roflurane; salicyl alcohol; sevoflurane; teflurane; cancer of the nose, cancer in the bones of the face, cancer of tetracaine; tetracaine hydrochloride; thiamylal; thiamylal the ear, cancer of the eye, skin of the eyelids, cancer of the Sodium; thiopental sodium; tiletamine hydrochloride; Zola lymph nodes, cancer of the thyroid gland, larynx and Sali mine hydrochloride; and combinations thereof. vary glands, paranasal sinuses, the nasopharynx and ocular e. Antineoplastic Agents melanoma, preferred antineoplastic agents include, by way Exemplary antineoplastic agents include by way of of illustration and not limitation, carboplatin, cisplatin, example and not limitation, acivicin, aclarubicin; acodazole 25 cyclophosphamide, fluorouracil, leucovorin in combination hydrochloride; acronine; adoZelesin; aldesleukin; altre with fluorouracil, leucovorin in combination with tamine; ambomycin; ametantrone acetate; aminoglutethim methotrexate, methotrexate, and combinations thereof. ide; amsacrine; anastrozole; anthramycin; asparaginase; f. Bone Alteration Agents asperlin; azacitidine; azetepa; azotomycin; batimastat; ben Exemplary bone alteration agents to facilitate bone move Zodepa; bicalutamide; bisantrene hydrochloride; bisnafide 30 ment include by way of example and not limitation, dimesylate; bizelesin; bleomycin Sulfate; brequinar Sodium; eicosanoids. This class of compounds includes the bropirimine; busulfan; cactinomycin; calusterone; carace prostaglandin, thromboxane and leukotriene families. The mide; carbetimer, carboplatin: carmustine; carubicin hydro eicosanoid class of compounds also includes the common chloride; carZelesin; cedefingol; chlorambucil; cirolemycin; precursor, arachidonic acid and compounds such as cisplatin: cladribine; crisinatol mesylate; cyclophosphamide; 35 alfaprostol, alprostadil, arbaprostil, methyl, carboprost, cytarabine; dacarbazine; dactinomycin; daunorubicin hydro ciprostene, cloprostenol Sodium, dinoprost, dinoprostone, chloride; decitabine; dexormaplatin; deZaguanine; deZagua enaprostil, epoprostenol, fenprostalene, flu prostenol nine mesylate; diaziquone; docetaxel, doxorubicin, doxoru Sodium, iloprost, gemeprost, luprostiol, meteneprost, bicin hydrochloride; droloxifene; droloxifene citrate; misoprotol, prostalene, rosaprostol, Sulprostone, dromostanolone propionate; duaZomycin, edatrexate; eflo 40 trimoprostil, Viprostol; and combinations thereof. mithine hydrochloride; elsamitrucin; enloplatin; enpromate; 3. Optional Ingredients epipropidine; epirubicin hydrochloride; erbulozole; esoru The depot may optionally contain inactive materials such bicin hydrochloride; estramustine; estramustine phosphate as buffering agents and pH adjusting agents such as potas sodium; etanidazole; ethiodized oil I 131: etoposide: etopo sium bicarbonate, potassium carbonate and potassium side phosphate: etoprine; fadrozole hydrochloride; faZara 45 hydroxide, sodium acetate, sodium borate, sodium bine; fenretinide; floxuridine; fludarabine phosphate; fluo bicarbonate, Sodium carbonate and Sodium hydroxide and rouracil; flurocitabine; fosquidone; fostriecin sodium; Sodium phosphate; degradation/release modifiers; drug gemcitabine; gemcitabine hydrochloride; gold Au 198; release adjusting agents; emulsifiers; preservatives such as hydroxyurea; idarubicin hydrochloride; ifosfamide: ilmo benzalkonium chloride, chlorobutanol, phenylmercuric fosine; interferon C-2a: interferono.-2b; interferon C-n1; 50 acetate and phenylmercuric nitrate, sodium bisulfite, sodium interferon C.-n3; interferon B-Ia; interferon Y-Ib, iproplatin: bisulfate, sodium thiosulfate, thimerosal, methylparaben, irinotecan hydrochloride; lanreotide acetate; letrozole; leu polyvinyl alcohol and phenylethyl alcohol; solubility adjust covorin in combination with fluorouracil or methotrexate; ing agents; stabilizers; cohesion modifiers, typically high leuprolide acetate; liarozole hydrochloride; lometrexol molecular weight compounds as described above, that may Sodium, lomustine; losoxantrone hydrochloride; masopro 55 be branched and where the short side-chains could in col; maytansine; mechlorethamine hydrochloride; megestrol addition potentially provide or facilitate adherence of the acetate; melengestrol acetate; melphalan; menogaril; mer drug delivery system to the orofacial tissue; and so forth. captopurine; methotrexate; methotrexate sodium; meto Typically, any such inactive materials will be present within prine; meturedepa; mitindomide; mitocarcin, mitocromin: the range of 0.75 wt %, and more typically within the range mitogillin, mitomalcin, mitomycin, mitosper, mitotane; 60 of 0 30 wt %. mitoxantrone hydrochloride; mycophenolic acid; nocoda B. Configuration Zole: nogalamycin; ormaplatin: oxiSuran, paclitaxel; pegas There are several factors that can be taken into consider pargase; peliomycin; pentamustine; peplomycin Sulfate; per ation in determining the size, shape and configuration of the fosfamide; pipobroman; piposulfan, piroXantrone drug delivery system. For example, both the size and shape hydrochloride; plicamycin; plomestane; porfimer Sodium; 65 preferably allow for ease in positioning the system inside the porfiromycin; prednimustine; procarbazine hydrochloride; region of the diseased oral tissue that is selected as the puromycin; puromycin hydrochloride; pyrazofurin: ribo implantation or injection site. In addition, the shape and size US 7,074,426 B2 21 22 of the system should be selected so as to minimize or prevent delivery device, then several or all surfaces of the depot will the system from moving after implantation or injection. ideally be therapeutic agent delivery Surfaces. Typically, The system can be shaped like a sphere, a cylinder Such such a drug delivery device will be completely biodegrad as a rod or fiber, a flat surface Such as a disc, film or sheet, able. However, on occasion, the targeted tissue may be and so forth. Flexibility may be a consideration so as to adjacent to only one side of the depot. In that instance, the facilitate placement of the system in the diseased oral tissue. face of the device that contacts the targeted tissue is The size of the drug delivery system is critical for the designed to be the therapeutic agent delivery surface, while treatment efficacy and the general patient's acceptance. the opposing face of the depot can be covered with a Often local dimensions associated with the specific treat ment or therapies restrict the drug delivery system size. therapeutic agent-impermeable layer to minimize diffusion Therefore, the drug delivery system of the invention pref 10 of the therapeutic agent away from the targeted oral tissue. erably has very small dimensions. Typically the higher the Such barrier layers would be positioned on the depot surface amount of loaded therapeutic agent(s) per total delivery distal from the targeted tissue. The barrier layer would system amount, the Smaller is the drug delivery system at a preferably be biodegradable, and would ideally degrade at a given dose or at a given drug delivery system weight the rate slower than that of the other system components. higher the loaded total dose. Consequently, by maximizing 15 C. Membrane the loaded therapeutic agent(s) amount(s), either the drug Additional structural features can be added to the system delivery interval can be extended or the local drug concen to control the rate of diffusion of the therapeutic agent from tration can elevated at a given drug delivery system size. the system. For example, diffusion of the agent from the Therefore, one of the unique features of this invention is the depot may be controlled by means of a drug-permeable potential for designing a very Small drug delivery system. membrane adjacent to the depot and positioned between the This results in the ability to position the system within the depot and the targeted tissue. The system could have a depot target tissue so as to optimize drug delivery to the targeted layer/membrane layer configuration or the system could region that cannot be achieved with current products. In have a central depot encased within the membrane layer, doing so, minute amounts of otherwise toxic drugs can be with these configurations being merely exemplary of the administered at maximum effect. In this manner, depending 25 configurations that are Suited to use in the invention. on the average daily dosage, drug loading capacity and The membrane may be composed of any of the materials duration of delivery and drug delivery density, the volume of described above, and will desirably have the same biode the drug delivery system will typically be within the range gradable or non-biodegradable characteristics as the depot of about 0.03–17 cubic millimeters (mm) in size. The material. In some systems, the depot will be saturated with following table exemplifies several variables (all stated as 30 therapeutic agent which results in a high release rate. One approximations) that affect the size selected for the drug means of slowing the release of agent is be selecting a delivery system. membrane material that is less permeable to the agent than the depot material is. In this instance, the lower agent permeability characteristic of the membrane results in the 35 agent remaining concentrated in the polymer. Thus, the desired average overall rate of diffusion will be determined by the mem daily dosage drug loading density size brane's agent-permeability characteristics, which can allow (g/day) (wt %) (g/cm) duration (mm) for more controlled and/or extended delivery of the agent to 10-2S 50- 70 1 up to 2 weeks 0.28–0.7 the diseased tissue. 10-2S 50- 70 1 up to 1 month 0.6–1.5 40 Exemplary non-biodegradable membrane materials 10-2S 50- 70 1 2 month 1.2–3 include ethylene vinyl acetate, ethylene/vinyl alcohol, 10-2S 50- 70 1 3 months 1.8-4.5 polyurethane, as well as polypropylene, polyethylene, nylon, polycarbonate, which are Suited for use as Approximate dimensions of exemplary drug delivery sys microporous membranes; as well as blends of any of the tems of the invention are as follows: 45 foregoing. Exemplary preferred biodegradable materials are described above. D. Backing Layer Exemplary Exemplary When the controlled release drug delivery system com Configuration Dimension Range 1 week system" 4 week system prises a depot as well as a membrane layer, it may be 50 desirable for the system to include a backing layer. The Spherical backing layer is positioned on the Surface(s) of the system Diameter about 50 m about 400 m about 1–1.5 mm that are not in contact with or adjacent to the targeted tissue. to 3 mm For example, when the system is configured as a sheet, the Cylindrical backing layer would typically be positioned on the side of 55 Length about 0.5–10 mm about 1 mm about 1.5 mm the system most distal from the target tissue. The backing Diameter about 0.05–3 mm about 600 m about 0.74 mm layer is preferably of a material which is impermeable to the Flat therapeutic agent that is contained within the depot. The backing layer can be biodegradable or not, but will desirably Length about 0.5–10 mm about 1 mm about 2 mm have the same erodible or non-erodible characteristics as the Width about 0.5–10 mm about 1 mm about 1 mm 60 depot material. Thickness about 0.1–1.0 mm about 280 m about 0.3 mm By including a backing layer in the system, the diffusion "desired average daily dosage of 10 Ig day; drug loading of about 50 wt of agent from the depot will be limited to passage through % desired average daily dosage of 15 Lig/day drug loading of about 70 wt % the depot and/or the membrane layer. The backing payer can be made of any of the aforementioned biodegradable or The configuration of the drug delivery system is deter 65 non-biodegradable materials. Particularly suitable materials mined by the location of the targeted oral tissue. For include, by way of illustration and not limitation, polyesters example, if the targeted tissue completely surrounds the drug (e.g., Mylar R), polyethylene, polypropylene, halogenated US 7,074,426 B2 23 24 polymers such as polytetrafluorethylene (e.g., Teflon(R) and treated, as a reduction in inflammation may bring about an polychlorotrifluoroethylene (e.g., Aclar(R) and other film alleviation of the accompanying pain symptoms. materials as are well known in the art. The invention also relates to the treatment of diseases that E. Adhesive Layer originate in the orofacial environment. For example, the In some embodiments of the invention, an adhesive layer methods and systems of the invention can be used to prevent can be included in the system to aid in securing the system myocarditis in general, and in particular, to prevent infective at the desired site. Since the system in an intratissue system, and viral myocarditis. Infective myocarditis is often linked the adhesive layer would facilitate initial placement of the with periodontal surgery. It is therefore desirable to mini system within the desired tissue. Preferably, the adhesive mize or eliminate the number of pathogenic organisms in the layer will be on the portion of the system that contacts with 10 periodontal tissue before the area is operated on and the target tissue. pathogens have the opportunity to spread into the body, The adhesive layer may be composed of a bioadhesive, particularly to the heart. In this instance, an anti-infective mucoadhesive and for biocompatible pressure sensitive agent can be delivered to the orofacial tissue, while prevent material. Exemplary adhesive materials include polyure ing a systemic complication. thanes; acrylic or methacrylic resins, and their copolymers 15 Typically the drug delivery system will be positioned at a with other compounds; polyoxyethylenes; polyanhydrides; placement site that is the same as the target site so as to natural or synthetic rubbers; polyvinylacetate; poly provide targeted localized drug delivery. However, there are (vinylpyrrolidone); cellulose derivatives: hyaluronic acid; instances where it may be desirable to treat diseased tissue chitosan; natural gums, and so forth. The adhesive may also at a location that is distal from the placement site, in addition include tackifiers, stabilizers or plasticizers (e.g., triethyl to or instead of treating the tissue at the placement site. For citrate, dibutylphthalate, diethylphthalate, acetyltriethyl example, when treating the disease state of periodontitis, citrate, tributyl citrate, acetyltetrabutyl citrate, triacetin, more than one tooth might be affected by the disease. One polyethylene glycol, castor oil), as are well known in the art. method might involve placement of a drug delivery system F. Release Liner at each diseased tissue site. However, in a preferred method, The system (e.g., depot, membrane or adhesive layer) 25 a single drug delivery system would be positioned in the may be affixed to a release liner. The release liner, which proximity of microvasculatory structures so that the released may be of any suitable material which is impermeable to the drug would be absorbed by the microvasculature in the therapeutic agent, serves to prevent or minimize diffusion of vicinity of the system, which would then carry the drug to the agent out of the system during storage. In those embodi the diseased tissue. In another example, if drug delivery to ments where the system includes an adhesive layer, the 30 the gingival tissue proximal to more than one tooth is release liner also serves to prevent the adhesive layer from desired, the placement of the drug delivery system can be adhering to materials during storage. Exemplary materials selected nearby the target site in the vicinity of vessels Suited for use as the release liner include a silicone-coated or responsible forgingival blood Supply. Gingival blood Supply fluorocarbon-coated polyester film. originates from blood vessels in the periodontal ligament, III. Methods of Treatment 35 the marrow spaces of the alveolar process and Supraperi The compositions and controlled release drug delivery osteal blood vessels. These vessels in turn Supply major system of the invention are useful for localized or targeted capillary plexuses that are located in the connective tissue drug application into the desired intratissue placement site or adjacent to the oral epithelium and the junctional epithelium. target site by means of a trocar, punch biopsy or Surgical Other anatomical structures include glands, for example, incision. The invention also contemplates methods of treat 40 lymph nodes and the corresponding drainage system. ment wherein forceps, for example are used to place the The concept of agent diffusion or transport to different system in open wounds, Surgically created cavities or can orofacial tissue sites is well understood. For example, in cerous tissue, or during any routine Surgical manipulation. dental practice, anesthesia of teeth and gingival tissue is The drug delivery system geometry and the application achieved either by infiltration or regional nerve block. In means are factors to consider based upon the particular 45 infiltration anesthesia, the anesthetic solution is injected into disease being treated since the appropriate placement of the the area concerned, and the anesthetic agent diffuses through system and the final location helps to insure effective treat the tissues to anesthetize local nerve fibers. In regional nerve ment of certain diseases. For example, when taking advan block the injection is given to affect the nerve?s) supplying tage of dexamethasone’s effect on alkaline phosphotase the area, which may be at Some distance from the operative activity, placement of the system should take into consid 50 site. eration whether the enzyme activity may vary among the The bone of the alveolar part of the maxilla, especially specific tissue layers being considered for placement of the that of the buccal (outer) surface, is relatively porous. system. Therefore, agents that can penetrate to the region of the apex Of particular interest is the treatment of diseases within of a tooth (where the root canal opens and the nerve enters the orofacial environment such as inflammation (both acute 55 the pulp) will effectively be administered to the tooth and and chronic), infection and/or pain that is associated with Surrounding gingiva. Similarly, treatment of the buccal periodontal disease, periodontal Surgeries, root canal aspect of the jaw is usually effective for all the upper teeth. therapy, root canal Surgery, extractions, oral Surgeries, dental For the teeth of the lower jaw, drug diffusion will likely only implants, cosmetic and facial Surgery and temporomandibu be effective for the incisors. The other mandibular teeth are lar joint syndrome or any Surgery related to the ear, nose, eye 60 embedded in bone that is denser and does not allow suffi and the brain. Such therapies are described in detail below. cient penetration of therapeutic agent; for these teeth, tar It is important to understand that several conditions may geting the inferior alveolar nerve may be required. co-exist in that the patient may be experiencing inflamma Accordingly, drug delivery systems can be placed strategi tion and pain. The invention encompasses administering a cally to take advantage of the Surrounding microvasculature therapeutic agent to reduce inflammation and a separate 65 to carry the released therapeutic agents to the desired site. agent to alleviate pain. However, the invention also encom The advantage to common injections is that the drug deliv passes those methods where only the inflammation is ery system delivery is extended and avoids the high spike US 7,074,426 B2 25 26 (potential for local toxicity) and fast wash-out (non thyroid hormone production. In the case of lack of iodine, therapeutic) typically experienced with common injections. drug delivery can be geared towards preventing or the The drug delivery systems of the invention can carry anes treatment of goiter. thetic or pain medication, for example, and can be placed at Drug delivery to the Sublingual gland and its related and the usual injection sites to provide long-term pain relief. Surrounding tissues can be achieved by the Sublingual Furthermore drug delivery can be directed to the periph Artery, which branches off the lingual artery at the anterior eral nervous system in particular to the 12 pairs of cranial margin of the Hyoglossus, running forward between the nerves in an attempt to alter or modify their principal Genioglossus and Mylohyoideus to the Sublingual gland. Its function. These nerves are related to smell (olfactory), branches reach also the Mylohyoideus and neighboring vision (optic), movement of the eye and constriction of the 10 muscles, as well as the mucous membrane of the mouth and pupil and altering the curvature of the lens (oculomotor, gums. One of its branches continues behind the alveolar trochlear, abducent), main sensor of the head and motor to process of the mandible in the gum to anastomose with its the muscles of mastication and moving the lower jaw opposing artery. (trigeminal), motor to muscles of face, taste, parasympa In another embodiment of the invention, the drug delivery thetic for lacrimal, salivary and nasal glands (facial), taste 15 system is placed in the vicinity of the Inferior Labial or and other sensory functions related to throat, control of Superior Labial Artery to provide drug to the lips and the blood pressure (glossopharyngeal), speech and Swallowing Surrounding mucous membrane, for example for the treat (vagus), motor to the larynx, pharynx and Soft palate ment of cold sores, to inhibit oral herpes (HSV1), or to (accessory) and moving the tongue (hypoglossal). In relieve inflammation and pain that may occur with post trigeminal neuralgia, pain occurs in numerous areas of the herpetic neuralgia. The labial glands, the mucous face where the branches of the nerve are distributed. Thus, membrane, and the muscles of the lower lip are supplied by the trigeminal nerve can be the target of local drug delivery the Inferior Labial Artery supplies, which arises near the of antiepileptic drugs or even muscle relaxants like angle of the mouth. From there it runs upward and forward chlorphenesin, which serve to mitigate the pain associated under the Triangularis and penetrates the Orbicularis oris. with trigeminal neuralgia. 25 Between this muscle and the mucous membrane, it follows Another structure that can be targeted for positioning of a tortuous path along the edge of the lower lip to anasto the drug delivery system of the invention, is the thyroid, moses with its opposing artery and with the mental branch where localized drug therapy may act to treat thyroid of the inferior alveolar artery. The larger and more tortuous diseases Such as hypo- and hyperthyroidism, Grave's and Superior Labial Artery Supplies the upper lip. Along its Hashimoto's disease, autoimmune thyroiditis, etc. Targeted 30 course it branches off smaller vessels, which ascend to the delivery to the thyroid can be achieved by utilizing the nose; a septal branch ramifies on the nasal septum as far as superior thyroid artery, which branches from the external the point of the nose, and an alar branch supplies the ala of carotid artery right below the level of the greater cornu of the the nose. hyoid bone and ends in the thyroid gland. More specifically, In another embodiment, the Deep Auricular Artery or the the Superior thyroid artery originates right under the anterior 35 Anterior Tympanic Artery is utilized to Supply the tympanic border of the ternocleidomastoideus. Covered by the skin it cavity or the temporomandibular joint. Both of these arteries runs upward and forward, in the carotid triangle, arching branch off the first part (mandibular portion) of the internal downward beneath the Omohyoideus, Sternohyoideus, and maxillary artery. The Deep Auricular Artery passes through Sternothyreoideus, distributing twigs to the adjacent the parotid gland, behind the temporomandibular muscles and to the external branch of the Superior laryngeal 40 articulation, entering through the cartilaginous or bony wall nerve, which lie medial to it. Numerous branches reach the of the external acoustic meatus and Supplying the cuticular thyroid gland, anastomosing with its fellow of the opposite lining and the outer Surface of the tympanic membrane, with side, and with the inferior thyroid arteries. By utilizing the branches to the temporomandibular joint. After piercing the artery to carry the agent into the thyroid, one would elimi petrotympanic fissure the Anterior Tympanic Artery circles nate the need for placing a drug delivery system inside the 45 around the membrane. gland. On the other hand placing a triiodothyronine (“T3') For the treatment of vertigo or prevention of motion or thyroxine (“T4) delivery system close to thyroid veins sickness, drugs may be delivered to the postauricular region would allow the agents to be carried into the circulation. One via the posterior auricular artery, which is a small branch example of targeting the thyroid is the treatment of Hash from the external carotid that arises above the Digastricus imoto's disease by delivering a glucocorticoid. Glucocorti 50 and Stylohyoideus, opposite the apex of the styloid process. coid therapy during the acute onset of the disease, in Under the parotid gland, it ascends on the styloid process of association with pain, alleviates the symptoms and improves the temporal bone to the groove between the cartilage of the the associated biochemical abnormalities, and has been ear and the mastoid process, dividing into the auricular and shown to increase plasma T3 and thyroxine T4 levels by occipital branches. The Auricular Branch runs behind the Suppression of the autoimmune process. Long-term delivery 55 ear, beneath the Auricularis posterior, and is distributed to of steroids in children may be administered via a local drug the back of the auricula, curving around the margin of the delivery system in an attempt to Suppress antibody produc cartilage to Supply the anterior Surface. tion and possibly to achieve a permanent remission. In In yet another embodiment, drug can be delivered to the general treatment of hypothyroidism, therapeutic delivery of root of the teeth, lips or structures of the mandible and T3 and T4 can be achieved with a local drug delivery 60 mucous membrane of the mouth, by placing the drug deliv system. In hyperthyroidism or Grave's disease the localized ery system along the Inferior Alveolar Artery and its sub drug delivery is geared towards an overactive thyroid that is sequent divisions. The Inferior Alveolar Artery branches off producing an excess of thyroid hormones. Glucocortocoids, the first part (mandibular portion) of the internal maxillary like dexamethasone may be delivered via the local drug artery. Parallel to the inferior alveolar nerve it descends to delivery system of the invention, to reduce thyroiditis. 65 the mandibular foremen on the medial surface of the ramus Localized antithroid drugs, like propylthiouracil or methi of the mandible. Running along side the nerve in the mazole are also effective to block pathways leading to mandibular canal in the bone, it divides into two branches US 7,074,426 B2 27 28 (incisor and mental) right opposite the first premolar tooth. tissue for arresting the deterioration due to host response Beneath the incisor teeth the incisor branch continues to run complications caused by periodontal disease and to further forward as far as the middle line, where it anastomoses with promote the regeneration of the destroyed and/or lost tissue. the opposing artery. At the mental foremen, the nerve and Such systems can be formulated to provide delivery of an mental branch rise, the latter Supplying the chin and anas 5 anti-inflammatory agent within the range of about 5–50 tomosing with the submental and inferior labial arteries. The ug/day, for a time period of 7–90 days. lingual branch of the inferior alveolar artery descends with In addition to the delivery of anti-inflammatory agents, the lingual nerve and Supplies the mucous membrane of the Such as dexamethasone, the systems of the invention can be mouth. The several twigs of the inferior alveolar artery and formulated to provide delivery of a tissue and bone growth the incisor branch enter the minute apertures at the extremi 10 factor within the range of about 5–50 ug/day, for a time ties of the roots, and supply the pulp of the teeth. period of 7–90 days and would typically be positioned Other drug delivery target structures can be, for example within gingival vestibular mucosal tissue for targeted drug and not limited to, the brain (1-dopa in Parkinson's disease); delivery to the regenerating bone tissue location. inflamed nasal mucous membranes that are lining the pas It has also been found that specific anaerobic bacteria in sages of the nose due to, for example, seasonal allergic, 15 the periodontal pockets are initiators of periodontal disease. perennial allergic, or perennial nonallergic rhinitis (anti Therefore, it may be desirable to utilize the systems of the histamines and/or steroids); eye muscles in exophthalmos, invention to provide intragingival tissue delivery of an which is the condition in which one or both of the eyes bulge anti-infective agent, particularly those having MIC or MBC out of their sockets as a consequence of Grave disease, and values on the average less than about 5 g/ml for the which can cause loss of eye muscle control, double vision, bacterial species of interest, within the range of about 5–25 and may require specialized treatment with steroids; and so ug/day, for a time period of 3-14 days. For the common forth. Susceptible organisms found in periodontal disease anti One embodiment of the invention is a method of treating infective agents can be administered for effective treatment. orofacial disease in a patient comprising the step of admin These include, for example, aminoglycosides Such as gen istering a drug delivery system within orofacial tissue, 25 tamycin and tobramycin; dicloxacillin; fluoroquinolones wherein the system comprises a semi-solid or Solid depot Such as ciprofloxacin, glycopeptides such as Vancomycin; and a therapeutically effective amount of at least one thera lincosamides such as clindamycin; macrollides Such as peutic agent and is within the range of about 0.03–17 mm azithromycin and erythromycin; nitroimidazoles such as in size. metronidazole; oxacillin; penicillins; tetracyclines; and so Another embodiment of the invention is a method of 30 forth. treating orofacial disease in a patient comprising the step of The indirect effects mediated by the hosts reaction to the administering a drug delivery system within orofacial tissue, bacteria primarily cause the actual destruction of the peri wherein the system comprises a semi-solid or Solid depot odontal tissue. Bacterial metabolites induce leucocyte and a therapeutically effective amount of an anti chemotaxis, which results in the inflammatory cells accu inflammatory agent. 35 mulating at the site of the bacterial challenge. Furthermore, One skilled in the art and having a fundamental under bacterial metabolites induce the production of inflammatory standing of the cardiovascular system, in particular the mediators by leucocytic cells, in particular monocytes. arteries of head and neck (external carotid), can readily Amongst these are local disease mediators such as metabo ascertain how to position a drug delivery system of the lites of arachidonic acid, e.g. leukotrienes, prostaglandins invention, in Such a manner so as to deliver therapeutic agent 40 and thromboxanes. Additionally, the loss of alveolar bone to the desired target tissue in the orofacial environments. may be directly induced by pathogenic metabolites of Specific applications of these methods are set forth below. bacteria, in particular proteolyte enzymes. Prostaglandins A. Treatment of Periodontal Disease have been found to be particularly important in the metabo The methods and drug delivery systems described herein lism and destruction of tissue and alveolar bone. Prostag find utility in treating periodontal disease in its various 45 landins and thromboxanes are formed from arachidonic acid stages. Early periodontal disease occurs when bacterial by an enzyme cascade, the first step of which is the cyclo plaque accumulates along the gum line, the periodontal oxygenation by an enzyme called cyclo-oxygenase. Inhib tissue, and periodontium in particular, becomes inflamed, iting the cyclo-oxygenase would inhibit the formation of resulting in a condition known as gingivitis. If left untreated, prostaglandins and thus reduce alveolar bone loss. For that the inflammation associated with early periodontal disease 50 reason, delivery of glucocorticosteroids such as dexametha can result in the gingival tissue pulling away from the teeth, Sone are particularly useful in the treatment of periodontal which then allows for the formation of periodontal pockets disease. In addition, dexamethasone not only provides anti that become a depository for bacteria, tartar, food debris, and inflammatory and pain reducing benefits, but also So forth. In its advanced stage, periodontal disease can result up-regulates alkaline phosphatase activity in regenerating in the formation of painful gum abscesses. However, most 55 human periodontal cells and thereby promotes the tissue detrimentally, continued inflammation of the periodontium regenerating process, which is essential in the treatment of leads to a visibly receding gum line and eventually to a periodontal disease. Re-attaching gingival tissue to the critical bone loss. As a result the teeth can become loose and regenerated bone eliminates the periodontal pocket, the ultimately may be lost. preferred location for bacteria re-colonization that would For the treatment of periodontal disease and the resulting 60 continue or restart the periodontal disease process. tissue and bone loss, the systems of the invention would B. Treatment of Acute and Chronic Inflammation typically be positioned within gingival vestibular mucosal The methods and drug delivery systems described herein tissue for targeted drug delivery to the diseased supporting find utility in treating both acute and chronic inflammation periodontal tissue (periodontal ligament, bone tissue and of orofacial tissue. Acute inflammation can be due to factor gingival tissue). In another embodiment, the drug delivery 65 Such as mechanical teeth cleaning (including root planning system can be positioned inside the attached gingival and an and scaling), oral Surgery, periodontal Surgery to cut down anti-inflammatory agent can be delivered to the periodontal the periodontal pocket flap, apicoectomy, root canal US 7,074,426 B2 29 30 procedure, a 3" molar extraction procedure, any surgery to also other benefits. For example, a drug delivery system repair nose, ear or eye problems, and so forth, resulting in placed to deliver dexamethasone to the cochlea Suppresses inflammation of manipulated tissues. For the treatment of the autoimmune response that is thought to be associated acute inflammation, the systems of the invention would with Meniere's disease. Additional therapeutic agents such typically be positioned within the inflamed tissue or the 5 as anti-emetic, anti-nausea and anti-vertigo drugs may be location of the Surgical operation for targeted drug delivery delivered to treat the symptoms of Meniere's disease. Local to inflamed tissue Surrounding the Surgical or manipulated administration of anti-inflammatory agents also affects aller site. Such systems can be formulated to provide delivery of gic rhinitis symptoms. For example corticosteroids have an anti-inflammatory agent within the range of about 5–50 been shown to have a wide range of effects on multiple cell ug/day, for a time period of 3-14 days. The administration 10 types (e.g., mast cells, eosinophils, neutrophils, of an anti-inflammatory agent post-Surgically in this manner, macrophages, and lymphocytes) and mediators (e.g., will also serve to reduce pain, edema, Scarring, and other histamine, eicosanoids, leukotrienes, and cytokines) complications resulting from the oral, nose, eye or ear involved in inflammation. Surgery, as well as reduce inflammation. In addition, to C. Prevention or Treatment of Infection prevent infection due to pre-existing or bacteria introduced 15 The methods and drug delivery systems described herein during the Surgery an anti-infective agent can be find utility in preventing or treating infection in orofacial co-delivered, as well as an additional pain medication for the tissue. Infections are often associated with Surgical proce treatment or prevention of excessive pain. dures such as an apicoectomy, a root canal procedure, or a More specifically, if the treatment of acute inflammation 3" molar extraction, either as an existing condition or a and pain, associated with a teeth cleaning procedure, Scaling condition that can arise after the patient has undergone the and root planing, or any other periodontal Surgery, is desired specific procedure, as well as being associated with peri the systems of the invention would typically be positioned odontal disease, resulting in infection of manipulated tissue. withingingival vestibular mucosal tissue (preferably distally Anti-infective agents such as aminoglycosides such as gen and buccally) not more than 10–15 mm away from the tamycin and tobramycin; dicloxacillin; fluoroquinolones manipulated tissue or within the Surgical opening before 25 Such as ciprofloxacin, glycopeptides such as Vancomycin; closure. Such systems can be formulated to provide delivery lincosamides such as clindamycin; macrollides Such as of an anti-inflammatory agent within the range of about azithromycin and erythromycin; nitroimidazoles such as 5-50 ug/day, for a time period of 3–7 days. metronidazole; oxacillin; penicillins; and tetracyclines; are Chronic inflammation can be due to factors, including preferably administered. on-going tissue decay due to periodontal disease, temporo 30 For both prophylactic treatment of such infections as well mandibular joint syndrome, placement of devices for facili as the treatment of existing infections, the systems of the tating tooth movement or providing orthodontic support, invention would typically be positioned within the tissue seasonal allergic, perennial allergic, or perennial nonallergic that is susceptible to becoming infected or which is already rhinitis, resulting in inflammation of the nasal mucosa. infected, for targeted drug delivery to the susceptible or Chronic inflammation can also be the result of an underlying 35 infected tissue. Such systems can be formulated to provide systemic disease Such as Hashimoto's disease. For the delivery of an anti-infective agent within the range of about treatment of chronic inflammation, the systems of the inven 5-50 ug/day, for a time period of 3–30 days. tion would typically be positioned within the inflamed tissue D. Treatment of Pain for targeted drug delivery to inflamed tissue. Such systems The methods and drug delivery systems described herein can be formulated to provide delivery of an anti 40 find utility in treating pain in orofacial tissue. Pain can be inflammatory agent within the range of about 5–50 Lig/day, due to numerous factors, such as an underlying disease (e.g., for a time period of 1490 days. periodontal disease, cranomandibular disease Such as tem The methods and systems of the invention can also be poromandibular joint syndrome, etc.) or a Surgical or other designed to treat both acute and chronic inflammation with procedure (e.g., placement of devices for facilitating tooth a single system. The system would typically be positioned 45 movement or providing orthodontic Support, root Scaling within the inflamed tissue for targeted drug delivery to and planning, stapedectomy, tonsillectomy, elective Surgery inflamed tissue. Such systems can be formulated to first or reconstructive Surgery to repair tissues damaged in provide delivery of an anti-inflammatory agent within the accidents, etc.). For the treatment of pain, the systems of the range of about 5–50 g/day, for a time period of 5–10 days, invention would typically be positioned within the affected followed by delivery of an anti-inflammatory agent within 50 tissues or within the open wound before closure for targeted the range of about 2–25 ug/day, for a time period of at least drug delivery to the particular pain receptors. Such systems one month, and up to 3 months. The higher 5–50 ug/day can be formulated to provide delivery of a pain management dose for the initial short time period of 5–10 days is directed medication within the range of about 5–50 Lig/day, for a time at treatment of acute inflammation, while the lower 2–25 period of 3–30 days. Since alleviation of inflammation often ug/day dose for the Subsequent longer time period of up to 55 results in a reduction in pain, such systems can also be 3 months is directed at treatment of chronic inflammation. formulated to provide delivery of an anti-inflammatory Such a dosing regimen is particularly Suited for administra agent within the range of about 5–50 Lig/day, for a time tion of a anti-inflammatory agent such as dexamethasone for period of 3–30 days. treatment of acute and chronic inflammation in the context E. Treatment of Tissue or Bone Loss of periodontal disease, since dexamethasone serves as a pain 60 Tissue and/or bone loss can be due to numerous factors, and anti-inflammatory medicine in the initial state of the including periodontal disease, the wearing of a prosthesis, delivery (acute inflammation after periodontal cleaning removal of cancerous tissue and structures, an accident, etc. procedure) and also treats the underlying chronic inflamma The treatment of tissue or bone loss can involve reducing the tion (host response reaction) as well as facilitates tissue amount of Such destruction and/or facilitating tissue or bone regeneration by Stimulating ALP activity. 65 growth. Accordingly, the methods and drug delivery systems In addition, the local administration of an anti described herein find utility in treating tissue or bone loss in inflammatory agent to a diseased tissue structure can have restoration Surgery, aesthetic Surgery practices, US 7,074,426 B2 31 32 apicoectomies, 3" molar extraction, tooth extraction in The system of the invention can be positioned within the general to rebuild bone material for implant placement orofacial tissue near the vasculature, i.e., near the arterial (facilitate osseointegration process), extraction, periodontal Supply. In this manner, localized delivery of anti tissue regeneration, Surgery that causes tissue or bone loss inflammatory agents would treat the inflammation and ulcer Such as the Surgical removal of cancerous lesions, anti ation of the mouth lining and throat. The systems of the wrinkle treatment (Botox, vitamin C, etc), and so forth. For invention can be formulated to deliver within the range of the treatment of tissue and/or bone loss, the systems of the about 5–50 Lig/day of an anti-inflammatory agent Such as a invention would typically be positioned within the Surgical glucocorticoid, for a time period of about 7–30 days. The lesion or open wound right before closure or place within or systems of the invention are preferably formulated to deliver close to the to be treated tissue. Such systems can be 10 dexamethasone within the aforementioned range and time formulated to provide delivery of a tissue or bone growth frame. factor or agents that promote bone or tissue regeneration G. Treatment of Glandular Disorders within the range of about 2–50 g/day, for a time period of The methods and drug delivery systems described herein 7–90 days. find utility in treating orofacial diseases related to malfunc In another embodiment of the invention, the methods and 15 tioning glands or disease of the glands including tumors, drug delivery systems described herein find utility in treating pleomorphic adenoma, dry mouth, drooling; any gland orofacial diseases, in combination with a device for facili destruction by for example an autoimmune disease Such as tating tooth movement or providing orthodontic Support. Sjogrens syndrome, etc.; pain, infection, and/or inflamma Instead of regenerating bone tissue, the systems of the tion due to Surgery to repair glands (diversion of ducts, stone invention would be positioned in front of a tooth or teeth that removal, etc.). are desired to be moved to, for example, align and adjust the In addition, the three major glands: the bilateral sublin bit of a patient. Such systems can be formulated to provide gual and Submandibular glands (both open into the floor of delivery of an agent that alters bone constitution (e.g. bone mouth, one on each side of the frenulum of the tongue) and alteration agents such as prostaglandin) within the range of parotid can be used to carry therapeutics agents delivered to about 2–50 ug/day, for a time period of about 7–60 days. 25 them into areas the typically serve. Therapeutic agent deliv F. Treatment of Cancer and Cancer-Related Disorders ery includes fluoride (prevention of cavities); anti The methods and drug delivery systems described herein inflammatory agents (mucositis, etc.), anti-infectives find utility in treating cancer and cancer-related disorders of (halitosis), compounds that aid the ingestion process by orofacial tissue. Orofacial tissue cancers or cancers of the therapeutic agent spiked saliva that moistens and lubricates head and neck can be grouped together in relation to their 30 the food and agents influence the peristalsis to the stomach position in the body. Cancers of the oral cavity are those (esophagitis, problems with Swallowing, etc.). which develop on the lips or in the mouth itself. More These drug delivery access areas can also be used to specifically, cancers of the oral cavity can occur inside the deliver therapeutic agents slowly and for extended periods to mouth in the tongue, the hard palate, the gums, the floor of the upper regions of the esophagus. For example, Barrett's the mouth and the inner lining of the lips and cheeks 35 esophagus is a condition that develops in some people who (sometimes referred to as the buccal mucosa). Oropharyn have chronic gastroesophageal reflux disease (GERD) or geal cancer develops in the oropharynx, the part of the throat inflammation of the esophagus (esophagitis). In Barrett's that sits directly behind the mouth and includes the soft esophagus, the normal cells that line the esophagus palate, the base of the tongue, the side walls of the throat, (squamous cells) are damaged by acid reflux from GERD where the tonsils are located and the back wall of the throat 40 resulting in abnormal changes. Other minor glands Such as (also called the posterior pharyngeal wall). Cancer of the lingual, labial, tonsillar and buccal maybe be used for more nose can develop in the skin of the nostril and the lining of area targeted delivery. the nose, the nasopharynx (nasopharyngeal carcinoma), and in the air spaces in the bones of the face alongside the nose EXAMPLES (paranasal sinuses). Cancers can also develop in the linings 45 The practice of the present invention will employ, unless of these areas. Cancer of the ear typically develop in the skin otherwise indicated, conventional techniques of pharmaceu of the ear, and more rarely occur in the structures deep inside tical formulation, medicinal chemistry, and the like, which the ear. Cancer is the eye itself is unusual, but can develop are within the skill of the art. Such techniques are explained in the skin of the eyelids (ocular melanoma). Occasionally, fully in the literature. The following examples are put forth cancer of the lymph nodes, lymphoma, can develop behind 50 so as to provide those of ordinary skill in the art with a the eye. Other cancers of the head and neck area include complete disclosure and description of how to make and use cancers of the thyroid gland, larynx (voicebox), Salivary the systems of the invention, and are not intended to limit the glands and brain. scope of what the inventor regard as the invention. Efforts For the treatment of cancer, the systems of the invention have been made to ensure accuracy with respect to numbers would typically be positioned within the cancerous tissue or 55 (e.g., amounts, temperature, etc.) but some errors and devia close to vasculature that would convectively carry the drug tions should be accounted for. Unless indicated otherwise, into the cancerous tissue for targeted drug delivery to the parts are parts by weight, temperature is in C. and pressure cancerous tissue. Alternately, the drug can be targeted to the is at or near atmospheric. All components are obtainable vasculature Supporting the cancerous tissue so as to focus on commercially unless otherwise indicated. primarily killing the vasculature. Such systems can be 60 formulated to provide delivery of an antineoplastic agent Example 1 within the range of about 5–50 g/day, for a time period of 7–30 days. Large microparticles are prepared using the solvent In addition, the methods and systems described herein evaporation process. Briefly, in the solvent-evaporation find utility in treating chemotherapy or radiotherapy induced 65 process, a polymer Solution containing the drug is emulsified oral mucositis, which is inflammation and ulceration of the in a second phase to create Small droplets. A variety of lining of mouth, the throat and/or the gastrointestinal tract. different agitation techniques can be used. The second or US 7,074,426 B2 33 34 continuous phase consists of an emulsifier in a low volatile typical drug release characteristic is shown in the following and preferably poor solvent for the components of the first table: phase. During the evaporation of the highly volatile solvent of the first phase, the polymer and drug-containing droplets solidify. These formed microparticles are then separated by filtration from the continuous phase solvent and washed to Time of measurement Cumulative Drug released (mg) remove remaining emulsifier. If water is the continuous Day 1 29 phase solvent, agents with high water Solubility can be lost Day 2 42 in significant amounts during this procedure. Aqueous phase Day 4 53 Volume, vessel and stirrer geometry, stir rate, concentration 10 Day 7 59 of emulsifier, Volume and viscosity of oil phase, etc. are all important factors that influence the final particle size distribution, while the polymer depot material to drug ratio The drug delivery system can provide a high initial release and the polymer depot chemistry define the biodegradation which would, in the clinical environment, generate locally and agent release rate. high anti-infective concentrating levels. This is desirable, for A predetermined amount of the drug dexamethasone (3.3 15 example after Surgery, to prevent microorganisms that may g) is added to the oil phase (polymer in solvent 5 g/8 g). The be introduced during the Surgical procedure from replicating polymer is 50/50 polylactic acid/glycolic acid with a and causing an infection of the wound area. The Subsequent molecular weight of about 20,000 g/mol, and the solvent is drug release would be lower, which is sufficient to generate methylene chloride. The aqueous phase (23.5 g) contains the an in Vivo maintenance level that can prevent the microbial emulsifier polyvinyl alcohol (2.5 g) to adjust the Viscosity. re-colonization of the Surgical area. At day 7 the cumulative Approximately 3 drops of octanol are added to the aqueous drug release would equal the theoretical drug-loading phase to prevent or minimize foaming. Furthermore, to amount. prevent drug loss into the aqueous phase, the aqueous phase is Saturated with the drug. Example 3 An I-inch impeller mixer is used to agitate the continuous phase at about 700 rpm. Then the oil phase is slowly added * For the preparation of disc-shaped drug delivery systems, to the aqueous phase. This mixture is stirred for about an 2 grams of Pharma coat (R) 606 hour, and air is passed over it to remove the evaporating (hydroxypropylmethylcellulose commercially available solvent. At about 30 minutes most of the methylene chloride from Shin-Etsu) is wetted with 2 grams of water. To that will have evaporated and the emulsion droplets solidified. 30 paste is added 3 grams of microparticles from Example 1, Agitation is continued at about 60 rpm for another 45 from the size fraction range of 250 to 500 microns. After minutes to prevent agglomeration. The solidified micropar thorough mixing the resulting paste is then molded into a flat ticles then are separated from the aqueous Solution using a film of 1 mm thickness using a carver press. The pressed film vacuum funnel and filter paper. After continued washing to is then cut into 1, 2 and 5 mm discs using thin walled Teflon remove any emulsifier the microparticles are dried, sieved Straws. The discs are then dried overnight in a vacuum oven. and only particles larger than 500 microns are kept. 35 Measuring in vitro Drug Release Example 4 Large microparticles of about 330 micron radius from For the preparation of disc-shaped drug delivery systems, Example 1 are placed into Screw cap glass vials filled with 2 grams of Metolose SR (90SH, 100000SR, methylcellulose 10 ml of aqueous saline solution (0.9% NaCl) and placed 40 commercially available from Shin-Etsu) is wetted with 2 into a shaking water bath kept at a temperature of 37° C. grams of water. To that paste is added 2 grams USP Samples of 8 ml are periodically removed and replaced with dexamethasone. After thorough mixing the resulting paste is same amount of fresh saline. The samples are then analyzed then molded into a flat film of 1 mm thickness using a carver by HPLC (USP method) for their drug concentration. A press. The pressed film is then cut into 1, 2 and 5 mm discs typical drug release characteristic is shown in the following 45 using thin walled Teflon straws. The discs are then dried table: overnight in a vacuum oven. Example 5 Time of measurement Cumulative Drug released (mg) For the preparation of disc-shaped drug delivery systems, 50 Day 1 25 2 grams of Metolose SR is wetted with 2 grams of water. To Day 2 35 that paste is added 3.6 grams USP Vancomycin. After Day 4 50 thorough mixing the resulting paste is then molded into a flat Day 7 61 film of 1 mm thickness using a carver press. The pressed film is then cut into 1, 2 and 5 mm discs using thin walled Teflon The drug delivery system can provide a high initial drug 55 Straws. The discs are then dried overnight in a vacuum oven. release. This is desirable, for example, to prevent inflam mation flare-up and the associated edema, etc. after a Sur Example 6 gical procedure. Prevention of inflammation will also pre vent or minimize post-Surgical pain. Subsequent drug For the preparation of disc-shaped drug delivery systems, release would be lower, but remains fairly steady until about 60 2 grams of L-HPC (LH-20, low-substituted hydroxypropy 7 days when the theoretical drug load is reached. During this lcellulose commercially available from Shin-Etsu) is wetted phase, lower drug delivery would be sufficient to maintain a with 2 grams of water. To that paste is added 3.6 grams USP therapeutically effective anti-inflammatory drug level. Vancomycin. After thorough mixing the resulting paste is then molded into a flat film of 1 mm thickness using a carver Example 2 65 press. The pressed film is then cut into 1, 2 and 5 mm discs As described in Example 1 microparticles of 500 microns using thin walled Teflon straws. The discs are then dried and larger are made using the anti-infective ciprofloxacin. A overnight in a vacuum oven. US 7,074,426 B2 35 36 Example 7 Example 13 For the preparation of disc-shaped drug delivery systems, A Saturated solution of hyaluronic acid in water is pre 2 grams of L-HPC is wetted with 2 grams of water. To that pared. Micronized R(-)methadone is added to achieve a paste is added 2 grams USP dexamethasone. After thorough 5 mixture having a polymer to drug ratio of 40:60. The mixing the resulting paste is then molded into a flat film of resulting mixture is poured on a glass plate covered with a 1 mm thickness using a carver press. The pressed film is then standard silicone coated polyester release liner. A gardener cut into 1, 2 and 5 mm discs using thin walled Teflon knife is used to create a 300 mm thick film. The glass plate Straws. The discs are then dried overnight in a vacuum oven. with the resulting film is placed into a vacuum oven and dried overnight at 80°C. The resulting film is cut into strips Example 8 10 of 1.5 mm by 3 mm. For the preparation of disc-shaped drug delivery systems, 2 grams of AQOAT Enteric Coating Agent (AS/HF, hydrox Example 14 ypropylmethyl cellulose acetate Succinate commercially The drug delivery systems can also be manufactured by available from Shin-Etsu) is wetted with 2 grams of water. 15 the extrusion method. This is preferred in those instances To that paste is added 1.5 grams USP dexamethasone and 1.5 where the therapeutic agent is heat-stable at temperatures g of Vancomycin. After thorough mixing the resulting paste below 100° C., but contact with solvents is not desired. is then molded into a flat film of 1 mm thickness using a Preferred depot polymers include polymers with low glass carver press. The pressed film is then cut into 1, 2 and 5 mm transition temperature or low melting point, preferably in the discs using thin walled Teflon straws. The discs are then range below 70° C. or thereabout or temperature lower then dried overnight in a vacuum oven. the temperature that would cause harm to the agent. Example 9 In general, the polymers to form the depot are thoroughly pre-mixed with the agent(s) and extruded through an orifice For the preparation of disc-shaped drug delivery systems, of desired geometry. Depending upon the design of the 2 grams of gelatin (Norland High Molecular Weight Fish 25 extrusion apparatus, the mixing process can also be part of Gelatin, Food/Pharmaceutical Grade) is wetted with 2 grams the extrusion process where appropriate screw geometry of water. To that paste is added 1.5 grams USP dexametha assures optimum mixing. The extruder orifice can have Sone and 1.5 g of USP Vancomycin. After thorough mixing different shapes, including a round opening allowing the the resulting paste is then molded into a flat film of 1 mm formation of a cylinder-like extrusion product, a flat orifice thickness using a carver press. The pressed film is then cut 30 to form sheet-like extrusion product, etc. To minimize or into 1, 2 and 5 mm discs using thin walled Teflon straws. prevent the fine powder explosion potential during the The discs are then dried overnight in a vacuum oven. mixing and handling while preparing the embodiments of this invention, flame Suppressant materials, like ethyl cel Example 10 lulose (Island Pyrochemical Industries) can be incorporated For the preparation of disc-shaped drug delivery systems, 35 into the mix. Other inactive depot materials may be intro 2 grams of gelatin (Norland High Molecular Weight Fish duced to improve adhesion to the placement tissue (gelatin, Gelatin, Food/Pharmaceutical Grade) is wetted with 2 grams hyaluronic acid, cellulosics, etc.) or to improve the flowabil of water. To that paste is added 1.5 grams USP dexametha ity of the melt through the extrusion orifice. sone and 1.5 g of USP ciprofloxacin. After thorough mixing Two grams of well-mixed powder of active and inactive the resulting paste is then molded into a flat film of 1 mm 40 materials at a ratio of 50:50 are prepared. The active agent thickness using a carver press. The pressed film is then cut is dexamethasone and the biodegradable polymer is a 50:50 into 1, 2 and 5 mm discs using thin walled Teflon straws. polylactic acid/polyglycolic acid copolymer with an average The discs are then dried overnight in a vacuum oven. molecular weight of 17,000 g/mol. The well-mixed powder is filled into a batch extruder and heated for 1 hour at 95°C. Example 11 45 The melt is then extruded through a circular orifice to create A Saturated solution of hyaluronic acid in water is pre a filament of 0.46 mm diameter. From the filament various pared. Micronized S(-)ketorolac is added to achieve a length sub-units are cut and tested in in vitro drug release mixture having a polymer to drug ratio of 40:60. The tests as described in Example 1. A typical drug release resulting mixture is poured on a glass plate covered with a 50 characteristic of a 1.2 mm long drug delivery system is standard silicone coated polyester release liner. A gardener shown in the following table: knife is used to create a 300 mm thick film. The glass plate with the resulting film is placed into a vacuum oven and dried overnight at 80°C. The resulting film is cut into strips Time of measurement Cumulative Drug released (mg) of 1.5 mm by 3 mm. 55 Day 1 35 Example 12 Day 2 52 Day 4 77 A saturated solution of gelatin (Norland High Molecular Day 7 98 Weight Fish Gelatin, Food/Pharmaceutical Grade) in water is prepared. Micronized clindamycin is added to achieve a 60 mixture having a polymer to drug ratio of 50:50. The Example 15 resulting mixture is poured on a glass plate covered with a standard silicone coated polyester release liner. A gardener Two grams of well-mixed powder of active and inactive knife is used to create a 300 mm thick film. The glass plate materials at a ratio of 70:30 is prepared. The active agent is with the resulting film is placed into a vacuum oven and 65 dexamethasone and the biodegradable polymer is a 50:50 dried overnight at 80°C. The resulting film is cut into strips polylactic acid/polyglycolic acid copolymer with an average of 1.5 mm by 3 mm. molecular weight of 50,000 g/mol. The well-mixed powder US 7,074,426 B2 37 38 is filled into a batch extruder and heated for 1 hour at 115° polylactic acid/polyglycolic acid copolymer with an average C. The melt is then extruded through a circular orifice to molecular weight of 20,000 g/mol. The well-mixed powder create a filament of 1.1 mm diameter. From the filament is filled into a batch extruder and heated for 1 hour at 115° various length sub-units are cut and tested in in vitro drug C. The melt is then extruded through a circular orifice to release tests as described in Example 1. A typical drug create a filament of 0.46 mm diameter. Sub-units of various release characteristic of a 3 mm long drug delivery system length are cut from the filament. is shown in the following table: Example 19

10 Two grams of well-mixed powder of active and inactive Time of measurement Cumulative Drug released (mg) materials at a ratio of 60:40 is prepared. The active agent is R(-)methadone and the biodegradable polymer is a 50:50 Day 1 290 polylactic acid/polyglycolic acid copolymer with an average Day 2 420 Day 4 589 molecular weight of 45,000 g/mol. The well-mixed powder Day 7 821 15 is filled into a batch extruder and heated for 1 hour at 115° Day 14 1160 C. The melt is then extruded through a circular orifice to Day 21 1478 create a filament of 0.9 mm diameter. Sub-units of various Day 28 1666 Day 35 1824 length are cut from the filament. Day 42 1934 Example 20 2O Two grams of well-mixed powder of active and inactive Example 16 materials at a ratio of 50:50 is prepared. The active agent is Extruded filament sections from Example 15 (10-cm clindamycin and the biodegradable polymer is a 50:50 length) are overcoated with a thin film of an additional polylactic acid/polyglycolic acid copolymer with an average polymer. This is achieved by dipping the selected filament molecular weight of 20,000 g/mol. The well-mixed powder sections into a 3-wt % aqueous solution of Pharmacoat(R615 is filled into a batch extruder and heated for 1 hour at 1 15° (Shin-Etsu). The coated filament sections are then dried C. The melt is then extruded through a circular orifice to overnight in a vacuum oven at room temperature. From the create a filament of 0.46 mm diameter. Sub-units of various overcoated filaments various length sub-units are cut and length are cut from the filament. 30 tested in in vitro drug release tests as described in Example Example 21 1. A typical drug release characteristic of a 3 mm long drug delivery system is shown in the following table: Two grams of well-mixed powder of active and inactive materials at a ratio of 80:20 is prepared. The active agent is ganciclovir and the biodegradable polymer is a 50:50 poly 35 lactic acid/polyglycolic acid copolymer with an average Time of measurement Cumulative Drug released (mg) molecular weight of 50,000 g/mol. The well-mixed powder Day 1 98 is filled into a batch extruder and heated for 1 hour at 110° Day 2 159 C. The melt is then extruded through a circular orifice to Day 4 286 create a filament of 1.1 mm diameter. The extruded filament Day 7 467 40 Day 14 807 sections are dipped into a 3-wt % aqueous solution of Day 21 1112 Pharmacoat(R615. The coated filament sections are then Day 28 1389 dried overnight in a vacuum oven at room temperature. Day 35 1597 Sub-units of various length are cut from the overcoated Day 49 1956 filament. 45 The overcoated drug delivery systems can provide a reduced Example 22 initial drug release (burst effect) and a closer to zero-order average drug release with a slightly extended drug delivery Two grams of well-mixed powder of active and inactive interval. materials at a ratio of 80:20 is prepared. The active agent is 50 thyroxine (T4) and the biodegradable polymer is a 50:50 Example 17 polylactic acid/polyglycolic acid copolymer with an average molecular weight of 40,000 g/mol. The well-mixed powder To establish a lower permeability coating for the extruded is filled into a batch extruder and heated for 1 hour at 95°C. filament sections of Example 15 (10-cm length), EAST The melt is then extruded through a circular orifice to create MAN Cellulose Acetate (CA-398-10NF) is used. The per 55 a filament of 1.1 mm diameter. The extruded filament meability of cellulose acetate films can be chemically sections are dipped into a 3-wt % aqueous solution of adjusted by varying the acetyl content. As the amount of Pharmacoat(R615. The coated filament sections are then acetyl increases, the permeability decreases and solvent dried overnight in a vacuum oven at room temperature. resistance and glass transition temperature increases. The Sub-units of various length are cut from the overcoated filaments are dipped in a 0.5 wt % CA-398-1ONF solution in 60 filament. acetone and dried overnight under vacuum. Drug release from Such systems can be extended to 3 months. Example 23 For the preparation of disc-shaped drug delivery systems, Example 18 2 grams of Metolose SR are wetted with 2 grams of water. Two grams of well-mixed powder of active and inactive 65 To that paste is added 2 grams USP lidocaine. After thorough materials at a ratio of 50:50 is prepared. The active agent is mixing the resulting paste is then molded into a flat film of S(-)ketorolac and the biodegradable polymer is a 50:50 1 mm thickness using a carver press. The pressed film is then US 7,074,426 B2 39 40 sprayed on one side with a solution of 0.5 wt % CA-398 drug delivery systems, each comprising a semi-solid or Solid 1ONF solution in acetone. Strips of 3 mm by 5 mm are cut depot and a therapeutically effective amount of the thera and dried overnight in a vacuum oven. peutic agent contained therein, and having a size within the range of about 0.03–17 mm. Example 24 12. The method of claim 9 wherein the additional thera peutic agents are selected from the group consisting of The vitamin E ester d-C.-tocopheryl acetate is mixed with anti-inflammatory agents, anti-infective agents, tissue and dexamethasone powder in a ratio of 50:50 and then extruded bone growth factors, pain management medication, antine through a round orifice (0.5 mm) at a temperature of 50° C. oplastic agents, bone alteration agents, thyroid drugs, and The melt is then sub-divided into dosage units of various combinations thereof. lengths and cooled overnight. 10 13. The method of claim 1 wherein the drug delivery system delivers therapeutic agent at a rate of about 5–50 jug Example 25 per day. The vitamin E ester d-O-tocopheryl succinate is mixed 14. The method of claim 13 wherein the drug delivery with dexamethasone powder in a ratio of 50:50 and then system delivers therapeutic agent at a rate of about 5–35 ug extruded through a round orifice (0.5 mm) at a temperature 15 per day. 15. The method of claim 14 wherein the drug delivery of 90° C. The melt is then sub-divided into dosage units of system delivers therapeutic agent at a rate of about 7-15 ug various lengths and cooled overnight. per day. Each of the patents, publications, and other published 16. The method of claim 1 wherein the drug delivery documents mentioned or referred to in this specification is system delivers therapeutic agent for at least about 3 days. herein incorporated by reference in its entirety. 17. The method of claim 16 wherein the drug delivery While the present invention has been described with system delivers therapeutic agent for about 3–7 days. reference to the specific embodiments thereof, it should be 18. The method of claim 16 wherein the drug delivery understood by those skilled in the art that various changes system delivers therapeutic agent for at least about 7 days. may be made and equivalents may be substituted without 25 19. The method of claim 18 wherein the drug delivery departing from the scope of the invention. In addition, many system delivers therapeutic agent for about 14–30 days. modifications may be made to adapt a particular situation, 20. The method of claim 18 wherein the drug delivery material, composition of matter, process, process step or system delivers therapeutic agent for about 30–90 days. steps, while remaining within the scope of the present 21. The method of claim 1 wherein the disease is peri invention. 30 odontal disease. Accordingly, the scope of the invention should therefore 22. The method of claim 21 wherein the therapeutic agent be determined with reference to the appended claims, along is an anti-inflammatory agent administered within the range with the full range of equivalents to which those claims are of about 5–50 ug/day, for a time period of 7–90 days. entitled. 23. The method of claim 21 wherein the therapeutic agent We claim: 35 is a bone and tissue growth factor administered within the 1. A method of treating disease in or originating in the range of about 5–50 ug/day, for a time period of 7–90 days. orofacial environment in a patient comprising the step of 24. The method of claim 21 wherein the therapeutic agent administering a drug delivery system within orofacial tissue, is an anti-infective agent having an MIC or MBC value of wherein the system comprises a semi-solid or Solid depot less than about 5 g/ml for the bacterial species of interest and a therapeutically effective amount of at least one thera 40 and is administered within the range of about 5–25 ug/day, peutic agent contained therein, and is within the range of for a time period of 3-14 days. about 0.03–17 mm in size, and wherein the therapeutic 25. The method of claim 1 wherein the disease is acute agent comprises about 30–95 wt % of the depot. inflammation and the therapeutic agent is an anti 2. The method of claim 1 wherein the depot is biodegrad inflammatory agent. able. 45 26. The method of claim 25 wherein the anti 3. The method of claim 2 wherein the system is implanted inflammatory agent is administered within the range of by a punch biopsy procedure. about 5–50 ug/day, for a time period of 3-14 days. 4. The method of claim 2 wherein the system is inserted 27. The method of claim 25 wherein the disease further with a trocar. comprises chronic inflammation and the anti-inflammatory 5. The method of claim 2 wherein the system is inserted 50 agent is administered within the range of about 5–50 jug per after a Surgical incision. day for about 5–10 days and about 2–25 ug thereafter for at 6. The method of claim 1 wherein the depot is non least one month. biodegradable. 28. The method of claim 1 wherein the disease is chronic 7. The method of claim 6 wherein the system is implanted inflammation. by a Surgical incision. 55 29. The method of claim 28 wherein the therapeutic agent 8. The method of claim 1 wherein the therapeutic agent is is an anti-inflammatory agent administered within the range selected from the group consisting of anti-inflammatory of about 5–50 ug/day, for a time period of 14-90 days. agents, anti-infective agents, tissue and bone growth factors, 30. The method of claim 1 wherein the disease is infection pain management medication, antineoplastic agents, bone or susceptibility to infection. alteration agents, thyroid drugs, and combinations thereof. 60 31. The method of claim 30 wherein the therapeutic agent 9. The method of claim 1 which further comprises admin is an anti-infective agent for treating or preventing the istering one or more additional therapeutic agents. infection and is administered within the range of about 5–50 10. The method of claim 9 wherein the one or more ug/day, for a time period of 3–30 days. additional therapeutic agents are contained within the drug 32. The method of claim 1 wherein the disease is asso delivery system. 65 ciated with pain and the therapeutic agent is a pain man 11. The method of claim 9 wherein the one or more agement medication and is administered within the range of additional therapeutic agents are contained within additional about 5–50 ug/day, for a time period of 3–30 days. US 7,074,426 B2 41 42 33. The method of claim 1 wherein the disease is asso selected from the group consisting of anti-infective agents, ciated with pain and the therapeutic agent is an anti tissue and bone growth factors, pain management inflammatory agent and is administered within the range of medication, antineoplastic agents, bone alteration agents, about 5–50 ug/day, for a time period of 3–30 days. thyroid drugs, and combinations thereof. 34. The method of claim 1 wherein the disease is tissue or 50. The method of claim 49 wherein the one or more bone loss and the therapeutic agent is a tissue or bone growth additional therapeutic agents are contained within the drug factor or agent that promotes bone or tissue regeneration delivery system. administered within the range of about 2–50 ug/day, for a 51. The method of claim 49 wherein the one or more time period of 7–90 days. additional therapeutic agents are contained within additional 35. The method of claim 1 which further comprises 10 drug delivery systems, each comprising a semi-solid or Solid treating the patient with a device for facilitating tooth depot and a therapeutically effective amount of the thera movement or providing orthodontic Support by placing the peutic agent contained therein, and having a size within the device within the orofacial environment, and the therapeutic range of about 0.03–17 mm. agent is a bone alteration agent and is administered within 52. The method of claim 47 wherein the anti the range of about 2–50 ug/day, for a time period of about 15 inflammatory agent is administered within the range of 7–60 days. about 5–50 ug/day. 36. The method of claim 1 wherein the disease is cancer 53. The method of claim 47 wherein the drug delivery and the therapeutic agent is an antineoplastic agent admin system delivers the anti-inflammatory agent for at least istered within the range of about 5–50 lug/day, for a time about 3 days. period of 7–30 days. 54. The method of claim 47 wherein the disease is 37. The method of claim 1 wherein the disease is che periodontal disease. motherapy or radiotherapy induced oral mucositis and the 55. The method of claim 47 wherein the disease is acute therapeutic agent is an anti-inflammatory agent administered inflammation. within the range of about 5–50 g/day, for a time period of 56. The method of claim 55 wherein the disease further 7–30 days. 25 comprises chronic inflammation and the anti-inflammatory 38. The method of claim 13 wherein the therapeutic agent agent is administered within the range of about 5–50 jug per is an anti-inflammatory agent and is administered within the day for about 5–10 days and about 2–25 ug thereafter for at range of about 5-50 ug/day. least one month. 39. The method of claim 13 wherein the therapeutic agent 57. The method of claim 47 wherein the disease is chronic is a bone alteration agent and is administered within the 30 inflammation. range of about 5-50 ug/day. 58. The method of claim 47 wherein the disease is 40. The method of claim 13 wherein the therapeutic agent associated with pain. is an anti-infective agent and is administered within the 59. The method of claim 47 wherein the anti range of about 5-50 ug/day. inflammatory agent is dexamethasone. 41. The method of claim 40 wherein the therapeutic agent 35 60. The method of claim 47 wherein the disease is thyroid has a minimum inhibitory concentration or minimum bac disease. tericidal concentration of less than about 5 L/ml and is 61. A drug delivery system configured to be positioned administered within the range of about 5–25 ug/day. within orofacial tissue comprising a semi-solid or Solid 42. The method of claim 13 wherein the therapeutic agent depot and at least one therapeutic agent contained therein, is a pain management medication and is administered within 40 and having a size within the range of about 0.03–17 mm, the range of about 5–50 Lig/day. and wherein the therapeutic agent comprises about 30–95 43. The method of claim 13 wherein the therapeutic agent wt'/6 of the depot. is a tissue or bone growth factor and is administered within 62. The drug delivery system of claim 61 wherein the the range of about 2–50 Lig/day. depot is biodegradable. 44. The method of claim 13 wherein the therapeutic agent 45 63. The drug delivery system of claim 61 wherein the is an antineoplastic agent and is administered within the depot is non-biodegradable. range of about 5-50 ug/day. 64. The drug delivery system of claim 61 wherein the 45. The method of claim 13 wherein the therapeutic agent depot is a monolith. is a bone alteration agent and is administered within the 65. The drug delivery system of claim 61 wherein the range of about 2–50 ug/day. 50 depot is a reservoir. 46. The method of claim 13 wherein the therapeutic agent 66. The drug delivery system of claim 61 wherein the is a thyroid drug and is administered within the range of depot is a sponge. about 5–50 ug per day. 67. The drug delivery system of claim 61 wherein the 47. A method of treating disease in or originating in the therapeutic agent comprises about 50–95 wt % of the depot. orofacial environment in a patient comprising the step of 55 68. The drug delivery system of claim 61 which com administering a drug delivery system within orofacial tissue, prises about 450–4500 ug of the therapeutic agent. wherein the system comprises a semi-solid or Solid depot 69. The drug delivery system of claim 68 which com and a therapeutically effective amount of an anti prises about 35–1500 g of the therapeutic agent. inflammatory agent contained therein, and wherein the anti 70. The drug delivery system of claim 61 wherein the inflammatory agent comprises about 30–95 wt.% of the 60 therapeutic agent is selected from the group consisting of depot. anti-inflammatory agents, anti-infective agents, tissue and 48. The method of claim 47 wherein the system is bone growth factors, pain management medication, antine implanted by a punch biopsy procedure, inserted with a oplastic agents, bone alteration agents, thyroid drugs, and trocar, inserted after a Surgical incision or implanted by a combinations thereof. Surgical incision. 65 71. The drug delivery system of claim 70 wherein the 49. The method of claim 47 which further comprises anti-inflammatory agent is a steroidal anti-inflammatory administering one or more additional therapeutic agents agent selected from the group consisting of alclometaSone US 7,074,426 B2 43 44 diproprionate, alendronate Sodium, amcinonide, beclom 93. The drug delivery system of claim 86 which has a ethasone diproprionate, betamethasone, budesonide, clobe therapeutic agent delivery duration of up to 3 months. tasol propionate, cortisone, dexamethasone, diflorasone 94. The drug delivery system of claim 93 which is about diacetate, hydrocortisone, fludrocortisone; flunisolide 0.38–3.3 mm in size. acetate, fluocinolone acetonide, fluocinonide, fluo 95. The drug delivery system of claim 61 which provides rometholone acetate, flurand renolide, halcinonide, a dosage of about 10–25 ug of therapeutic agent per day. medrysone; methylprednisone Suleptanate, pamidronate, 96. The drug delivery system of claim 95 which has a paramethasone, prednisolone, nilutamide, triamcinelone, therapeutic agent loading of about 50–70 wt'/6. and combinations thereof. 97. The drug delivery system of claim 96 which has a 72. The drug delivery system of claim 71 wherein the 10 density of about 1 g/cm. anti-inflammatory agent is dexamethasone. 98. The drug delivery system of claim 97 which has a 73. The drug delivery system of claim 70 wherein the therapeutic agent delivery duration of up to 2 weeks. anti-infective agent has a minimum inhibitory concentration 99. The drug delivery system of claim 98 which is about or minimum bactericidal concentration of less than about 5 0.28–0.7 mm in size. g/ml. 15 100. The drug delivery system of claim 97 which has a 74. The drug delivery system of claim 70 wherein the therapeutic agent delivery duration of up to 1 month. tissue and bone growth factors are selected from the group 101. The drug delivery system of claim 100 which is consisting of growth hormones, alkaline phosphatase, about 0.6–1.5 mm in size. dexamethasone, anti-degenerative agents, non-antimicrobial 102. The drug delivery system of claim 97 which has a tetracyclines, matrix metalloendoproteinase inhibitors, therapeutic agent delivery duration of up to 2 months. 5-lipoxygenase inhibitors, nonsteroidal anti-inflammatory 103. The drug delivery system of claim 102 which is drugs, bisphosphonates, and combinations thereof. about 1.2–3 mm in size. 75. The drug delivery system of claim 70 wherein the pain 104. The drug delivery system of claim 97 which has a management medication is selected from the group consist therapeutic agent delivery duration of up to 3 months. ing of anti-inflammatory agents, muscle relaxants, 25 105. The drug delivery system of claim 104 which is analgesics, anesthetics, and combinations thereof. about 1.8-4.5 mm in size. 76. The drug delivery system of claim 70 wherein the 106. The drug delivery system of claim 61 which provides antineoplastic agent is selected from the group consisting of a dosage of about 25–50 jug of therapeutic agent per day. carboplatin, cisplatin, cyclophosphamide, fluorouracil, leu 107. The drug delivery system of claim 106 which has a covorin in combination with fluorouracil, leucovorin in 30 therapeutic agent loading of about 30–90 wt'/6. combination with methotrexate, methotrexate, and combi 108. The drug delivery system of claim 107 which has a nations thereof. density of about 0.9–1.3 g/cm. 77. The drug delivery system of claim 70 wherein the 109. The drug delivery system of claim 108 which has a bone alteration agent is selected from the group consisting of therapeutic agent delivery duration of up to 2 weeks. prostaglandins. 35 110. The drug delivery system of claim 109 which is about 78. The drug delivery system of claim 70 wherein the 0.15-2.6 mm in size. thyroid drug is selected from the group consisting of 111. The drug delivery system of claim 108 which has a thyroxine, triiodothyronine, propylthiouracil, methimazole, therapeutic agent delivery duration of up to 1 month. and combinations thereof. 112. The drug delivery system of claim 111 which is about 79. The drug delivery system of claim 61 which further 40 0.64–5.6 mm in size. comprises a membrane positioned adjacent the depot. 113. The drug delivery system of claim 108 which has a 80. The drug delivery system of claim 61 which further therapeutic agent delivery duration of up to 2 months. comprises a backing layer. 114. The drug delivery system of claim 113 which is about 81. The drug delivery system of claim 61 which further 1.3–11 mm in size. comprises an adhesive layer. 45 115. The drug delivery system of claim 108 which has a 82. The drug delivery system of claim 61 which further therapeutic agent delivery duration of up to 3 months. comprises a release liner. 116. The drug delivery system of claim 115 which is about 83. The drug delivery system of claim 61 which is 1.9–17 mm in size. spherical, cylindrical or flat. 117. A drug delivery system configured to be positioned 84. The drug delivery system of claim 61 which provides 50 within orofacial tissue comprising a semi-solid or Solid a dosage of about 5-10 ug of therapeutic agent per day. depot and about 35–4500 ug of a therapeutic agent contained 85. The drug delivery system of claim 84 which has a therein, and having a size within the range of about 0.03–17 therapeutic agent loading of about 30–90 wit%. mm, and wherein the therapeutic agent comprises about 86. The drug delivery system of claim 85 which has a 30–95 wt.% of the depot. density of about 0.9–1.3 g/cm. 55 118. The drug delivery system of claim 117 wherein the 87. The drug delivery system of claim 86 which has a depot is a monolith, a reservoir or a sponge. therapeutic agent delivery duration of about 7–14 days. 119. The drug delivery system of claim 117 wherein the 88. The drug delivery system of claim 87 which is about therapeutic agent comprises about 50–95 wt % of the depot. 0.03–0.5 mm in size. 120. The drug delivery system of claim 117 wherein the 89. The drug delivery system of claim 86 which has a 60 therapeutic agent is selected from the group consisting of therapeutic agent delivery duration of up to 1 month. anti-inflammatory agents, anti-infective agents, tissue and 90. The drug delivery system of claim 89 which is about bone growth factors, pain management medication, antine 0.13–1.1 mm in size. oplastic agents, bone alteration agents, thyroid drugs, and 91. The drug delivery system of claim 86 which has a combinations thereof. therapeutic agent delivery duration of up to 2 months. 65 121. The drug delivery system of claim 120 wherein the 92. The drug delivery system of claim 91 which is about anti-inflammatory agent is a steroidal anti-inflammatory 0.26–2.2 mm in size. agent selected from the group consisting of alclometaSone US 7,074,426 B2 45 46 diproprionate, alendronate Sodium, amcinonide, beclom 132. A method of treating disease in or originating in the ethasone diproprionate, betamethasone, budesonide, clobe orofacial environment in a patient comprising the step of (1) tasol propionate, cortisone, dexamethasone, diflorasone administering a first drug delivery system within orofacial diacetate, hydrocortisone, fludrocortisone; flunisolide tissue, wherein the system comprises a semi-solid or Solid acetate, fluocinolone acetonide, fluocinonide, fluo depot and a therapeutically effective amount of at least one rometholone acetate, flurand renolide, halcinonide, therapeutic agent contained therein, and is within the range medrysone; methylprednisone Suleptanate, pamidronate, of about 0.03–17 mm in size, wherein the therapeutic agent paramethasone, prednisolone, nilutamide, triamcinelone, comprises about 30–95 wt.% of the depot; and (2) adminis and combinations thereof. tering one or more additional therapeutic agents; wherein the 122. The drug delivery system of claim 121 wherein the 10 one or more additional therapeutic agents are contained anti-inflammatory agent is dexamethasone. within the first drug delivery system or are contained within 123. The drug delivery system of claim 120 wherein the additional drug delivery systems, each comprising a semi anti-infective agent has a minimum inhibitory concentration solid or solid depot and a therapeutically effective amount of or minimum bactericidal concentration of less than about 5 the therapeutic agent contained therein, and having a size g/ml. 15 within the range of about 0.03–17 mm. wherein the thera 124. The drug delivery system of claim 120 wherein the peutic agent comprises about 30–95 wt % of the depot. tissue and bone growth factors are selected from the group 133. The method of claim 132 wherein the additional consisting of growth hormones, alkaline phosphatase, therapeutic agents are selected from the group consisting of dexamethasone, anti-degenerative agents, non-antimicrobial anti-inflammatory agents, anti-infective agents, tissue and tetracyclines, matrix metalloendoproteinase inhibitors, bone growth factors, pain management medication, antine 5-lipoxygenase inhibitors, nonsteroidal anti-inflammatory oplastic agents, bone alteration agents, thyroid drugs, and drugs, bisphosphonates, and combinations thereof. combinations thereof. 125. The drug delivery system of claim 120 wherein the 134. A method of treating disease in or originating in the pain management medication is selected from the group orofacial environment in a patient comprising the step of 1) consisting of anti-inflammatory agents, muscle relaxants, 25 administering a drug delivery system within orofacial tissue, analgesics, anesthetics, and combinations thereof. wherein the system comprises a semi-solid or Solid depot 126. The drug delivery system of claim 120 wherein the and a therapeutically effective amount of an anti antineoplastic agent is selected from the group consisting of inflammatory agent contained therein, wherein the therapeu carboplatin, cisplatin, cyclophosphamide, fluorouracil, leu tic agent comprises about 30–95 wt.% of the depot: and (2) covorin in combination with fluorouracil, leucovorin in 30 administering one or more additional therapeutic agents combination with methotrexate, methotrexate, and combi selected from the group consisting of anti-infective agents, nations thereof. tissue and bone growth factors, pain management 127. The drug delivery system of claim 120 wherein the medication, antineoplastic agents, bone alteration agents, bone alteration agent is selected from the group consisting of thyroid drugs, and combinations thereof. prostaglandins. 35 135. The method of claim 134 wherein the one or more 128. The drug delivery system of claim 120 wherein the additional therapeutic agents are contained within the drug thyroid drug is selected from the group consisting of delivery system. thyroxine, triiodothyronine, propylthiouracil, methimazole, 136. The method of claim 134 wherein the one or more and combinations thereof. additional therapeutic agents are contained within additional 129. The drug delivery system of claim 117 having a size 40 drug delivery systems, each comprising a semi-solid or Solid within the range of 0.1–3 mm. depot and a therapeutically effective amount of the thera 130. The drug delivery system of claim 129 which has a peutic agent contained therein, and having a size within the therapeutic agent delivery duration of about 1 week to 3 range of about 0.03–17 mm and wherein the therapeutic months. agent comprises about 30–95 wt % of the depot. 131. The drug delivery system of claim 130 which has a 45 therapeutic agent loading of about 50 wt.%. k k k k k