US 201000987.46A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/009874.6 A1 King (43) Pub. Date: Apr. 22, 2010 (54) COMPOSITIONS AND METHODS FOR Related U.S. Application Data TREATING PERIODONTAL DISEASE COMPRISING CLONDINE, SULINDAC (60) Provisional application No. 61/106,815, filed on Oct. AND/OR FLUOCNOLONE 20, 2008. Publication Classification (75) Inventor: Vanja Margareta King, Memphis, TN (US) (51) Int. Cl. A6F I3/00 (2006.01) Correspondence Address: A6II 3/56 (2006.01) MEDTRONIC (52) U.S. Cl. ......................................... 424/435: 514/171 Attn: Noreen Johnson - IP Legal Department (57) ABSTRACT 2600 Sofamor Danek Drive MEMPHIS, TN38132 (US) Effective treatments of periodontal disease for extended peri ods of time are provided. Through the administration of an (73) Assignee: Warsaw Orthopedic, Inc., Warsaw, effective amount of clonidine, Sulindac, and/or fluocinolone IN (US) at or near a target site, one can reduce, prevent, and/or treat periodontal disease. In some embodiments, when appropriate (21) Appl. No.: 12/572,387 formulations are provided within biodegradable polymers, treatment can be continued for at least two weeks to two (22) Filed: Oct. 2, 2009 months. Patent Application Publication Apr. 22, 2010 Sheet 1 of 3 US 2010/009874.6 A1 FIG. 1 Clonidine 15 o 9. 10 wd O O 2 SS 5 O RANK Control 100 M 10 M M 0.1 LM Concentration Patent Application Publication Apr. 22, 2010 Sheet 2 of 3 US 2010/009874.6 A1 FIG. 2 Sulindac 5 1 O RANK Control 70 M 35M 7.5 M ConCentration Patent Application Publication Apr. 22, 2010 Sheet 3 of 3 US 2010/009874.6 A1 FIG. 3 Inflammation Assessment Following Treatment 4.5 Pre-Surgery 1 Days post Surgery p-0.05 vs. 4 - Vehicle 3Days Post Surgery 4Days Post Surgery 3.5 3 - 25 . 15 - - 0.5 Vehicle Clinidine tow Clinidine High Bupivacaine Bupivacaine Morphine low High US 2010/009874.6 A1 Apr. 22, 2010 COMPOSITIONS AND METHODS FOR predictable compositions and methods to regenerate, aug TREATING PERIODONTAL DISEASE ment, or restore alveolar bone loss and cementum loss COMPRISING CLONDINE, SULINDAC inflicted by periodontitis. AND/OR FLUOCNOLONE 0004 Another initial treatment for periodontitis is admin istration of antibiotics, which may be optionally performed in BACKGROUND conjunction with Scaling and root planing procedures. Tetra 0001 Periodontitis is a chronic inflammatory response cycline, minocycline, amoxicillin or metronidazole may be caused by bacterial plaque that has spread below the gum line. used to remove the highly diverse populations of bacteria Starting in the early stages as gingivitis, the later stages of from the periodontal pockets. Despite the effectiveness of periodontitis involves inflammation of the gums, connective antibiotics in reducing inflammation and bacterial infection, tissues, and bones Surrounding the teeth i.e. alveolar bones. antibiotic administration, like Scaling and root planing, is also Prolonged inflammation causes degenerative loss of tissues deficient in Stimulating re-growth or replacement of the Supporting the teeth and alveolar bone loss, eventually lead destroyed bone and cementum caused by severe periodontal ing to loss of teeth. Tooth loss, caused by the loss of alveolar disease. bone, is one of the major problems in clinical dentistry. In 0005. When patients are not responsive to scaling and root fact, periodontitis is the primary cause of tooth loss. planing procedures and/or antibiotic treatment, periodontal 0002 The periodontitis-associated inflammation occur Surgery, such as for example, gingivectomy or periodontal ring in the Surrounding tissues that Support the teeth is char flap Surgery is often required. In gingivectomy, the dentist acterized by formation of infected “pockets” or spaces reshapes the unhealthy gum tissue in order to reduce the size between the teeth and gums. These infected pockets contain of the infected pocket. Reduction of the pocket size allows the debris, predominantly composed of microorganisms and patient to hygienically maintain the pocket by routine brush their products (enzymes, endotoxins and other metabolic ing and flossing, thereby eliminating a favorable environment products), dental plaque, gingival fluid, food remnants, Sali for bacterial growth. Periodontal flap surgery is performed vary mucin, descquamated epithelial cells, and leukocytes. also when scaling and root planing procedures are unsuccess Periodontal pockets are chronic inflammatory lesions, and as ful, especially when there is loss of bone or tissue detachment. Such are constantly undergoing repair. The condition of the In this procedure, incisions are made in the gums and the soft tissue walls of the periodontal pocket results from a Surrounding alveolar bone is re-contoured to assist in healing balance between destructive and constructive tissue changes. of the infected area. Often times, Surgical treatments are The destructive changes include the fluid and cellular inflam insufficient in stimulating re-growth or replacement of the matory exudates and the associated degenerative changes destroyed bone and cementum caused by severe periodontal stimulated by local bacterial infiltrate. The constructive disease. changes include the formation of connective tissue cells, col 0006. One pharmaceutical that is known to the medical lagen fibers, and blood vessels in an effort to repair tissue profession is clonidine, which is widely recognized as an damage caused by the inflammatory process. Healing does antihypertensive agent that acts as an agonist on the alpha-2- not go to completion because of the persistence of local adrenergic receptor and as a neural receptor agonist. In gen irritants e.g., bacteria and the enzymes that they produce. eral, clonidine, also referred to as 2,6-dichloro-N-2-imidazo These irritants stimulate fluid and cellular exudates, which in lidinyldenebenzenamine (CHCl2N) may be represented turn causes degeneration of the new tissue elements formed in by the following chemical structure: the repair process. If purulent exudates are present in the infected pockets, it can contain living, degenerated and necrotic leukocytes (predominantly polymorphonuclear), C living cells and deadbacterial cells, serum and a small amount of fibrin. 0003 Conventional treatments for periodontal disease N include Scaling and root planing procedures. These proce X dures involve manually removing calculus, plaque and other C deposits, Smoothing the root Surface to rid it of necrotic tooth Substances, and curetting the inner Surface of the gingival 0007 Another pharmaceutical that is known to the medi wall of the periodontal pockets to separate away any diseased cal profession is Sulindac, (commercially available as Clino soft tissue. The procedures aim to eliminate the infected ril.R from Sigma as a free acid) which is widely recognized as pockets by reattaching connective tissue and epithelium to the a non-steroidal anti-inflammatory of the arylalkanoic acid tooth surface. By eliminating the environment for the micro class. It may be represented by the following chemical for organisms to grow, Scaling and root planing procedures can mula C20H17FO3S. Sulindac is a prodrug, derived from successfully obliterate the infected pockets. These proce sulfinylindene that is converted in the body to an active dures may result in the replacement of diseased soft tissue NSAID (non-steroidal anti-inflammatory agent). More spe with new soft tissue from growth and differentiation of new cifically, the agent is converted by liver enzymes to a sulfide cells and intercellular Substances. However, Scaling and root that is excreted in the bile and then reabsorbed from the planing procedures are ineffective in reducing the inflamma intestine. This is thought to help maintain constant blood tory process and stimulating the re-growth or replacement of levels with reduced gastrointestinal side effects. destroyed bone and cementum caused by severe periodonti 0008. Yet another pharmaceutical that is known to reduce tis. Often severe inflammation occurs in periodontitis leading inflammation is fluocinolone, which in its acetonide form to macrophage-like cells that enter the affected site that are (CHFOs) has been administered topically as a cream to eventually replaced with osteoclasts that breakdown bone treat skin inflammation. It may also be referred to as 4b, 12 leading to bone loss. Hence, there is a need for reliable or Difluoro-6b-glycoloyl-5-hydroxy-4a,6a,8,8-tetramethyl-4a, US 2010/009874.6 A1 Apr. 22, 2010 4b,5,6,6a,6b.9a, 10.10a, 10b,11,12-dodecahydro-2H-naphtho least one biodegradable polymer. The pharmaceutical com 2", 1":4.5indeno1,2-d1.3dioxol-2-one or 6C-9C.- position may for example, be part of a drug depot. The drug Difluoro-16 C-hydroxyprednisolone 16,17-acetonide. depot may: (i) consist of only the drug(s) (or one or more of its 0009. However, to date clonidine, Sulindac, and/or fluoci pharmaceutically acceptable salts) and the biodegradable nolone have not been appreciated as an effective treatment for polymer(s); or (ii) consist essentially of the drug(s) (or one or periodontal disease in Sustained release formulations that more of its pharmaceutically acceptable salts) and the biode provide treatment over at least 2 weeks. Thus, there is a need gradable polymer(s); or (iii) comprise the drug(s) (or one or to develop effective formulations of clonidine, sulindac, and/ more of its pharmaceutically acceptable salts), the biodegrad or fluocinolone for reducing, preventing or treating periodon able polymer(s)