US 2009024.7537A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/024.7537 A1 Overfield (43) Pub. Date: Oct. 1, 2009

(54) METHODS FOR PREVENTING OR Publication Classification TREATING BRUXISMUSING (51) Int. Cl. DOPAMINERGICAGENTS A63L/506 (2006.01) A6II 3/428 (2006.01) (76) Inventor: William Dale Overfield, A63L/38 (2006.01) Edgewood, WA (US) A63L/36 (2006.01) Correspondence Address: A63L/4045 (2006.01) BLACKLOWE & GRAHAM, PLLC A63L/437 (2006.01) 701 FIFTHAVENUE, SUITE 4800 (52) U.S. Cl...... 514/252.14: 514/367: 514/438: SEATTLE, WA 98104 (US) 514/415: 514/292: 514/657 (21) Appl. No.: 12/264,806 (57) ABSTRACT Methods for preventing or treating bruxism, including alle (22) Filed: Nov. 4, 2008 viating or eliminating one or more symptoms, diseases or conditions associated with or resulting from bruxism, using Related U.S. Application Data dopaminergic agents such as monoamine oxidase inhibitors (63) Continuation-in-part of application No. 12/054,816, that increase dopaminergic activity and dopamine agonists, filed on Mar. 25, 2008, now abandoned. are disclosed. US 2009/024.7537 A1 Oct. 1, 2009

METHODS FOR PREVENTING OR patient in need of Such prevention or treatment a therapeuti TREATING BRUXISMUSING cally effective amount of a dopaminergic agent. DOPAMINERGICAGENTS 0008. In certain embodiments, the present invention pro vides methods for preventing or treating bruxism, comprising REFERENCE TO RELATED APPLICATIONS administering to a patient in need of such prevention or treat 0001. This application is a continuation-in-part of U.S. ment a therapeutically effective amount of a dopamine ago patent application Ser. No. 12/054,816 filed on Mar. 25, 2008, nist or a pharmaceutically acceptable salt, enantiomer, Sol which is incorporated herein by reference in its entirety. Vate, hydrate, polymorph or prodrug thereof 0009. In other embodiments, the present invention pro FIELD OF THE INVENTION vides methods for preventing or treating bruxism, comprising administering to a patient in need of such prevention or treat 0002 The present invention relates to novel methods for mentatherapeutically effective amount of a monoamine oxi preventing or treating bruxism, including alleviating or elimi dase inhibitor that increases dopaminergic activity or a phar nating one or more symptoms, diseases or conditions associ maceutically acceptable salt, enantiomer, Solvate, hydrate, ated with or resulting from bruxism, using dopaminergic polymorph or prodrug thereof. agents such as monoamine oxidase inhibitors that increase 0010. In additional embodiments, the present invention dopaminergic activity and dopamine agonists. provides methods for preventing or treating bruxism wherein Such prevention or treatment alleviates or eliminates one or BACKGROUND OF THE INVENTION more symptoms, diseases or conditions associated with or 0003 Bruxism, otherwise known as teeth clenching or resulting from bruxism. teeth grinding, is a commonly occurring condition involving 0011. The foregoing objects and additional objects, fea forceful contact between the biting surfaces of the upper and tures, aspects and advantages of the present invention are lower teeth. Bruxism is typically accompanied by clenching further exemplified and described in the following detailed of the jaw. Bruxism often occurs during sleep, although it can description. also occur while an individual is awake. While the causes of bruxism are unknown, factors that have been related to the DETAILED DESCRIPTION OF EXEMPLARY condition include disturbed sleep patterns, high levels of EMBODIMENTS OF THE INVENTION anxiety and stress, use of serotonin selective reuptake inhibi 0012. It has been found that compounds that act as dopam tors, use of the drug Provigil R, consumption of amphet inergic agents can be effectively used in the prevention and amines and related drugs, and disorders such as Huntington's treatment of bruxism and thereby alleviate or eliminate one or disease and Parkinson's disease. Bruxism can result in dam more symptoms, diseases or conditions associated with or age to the teeth, including abfractions, abnormal wear of resulting from bruxism. This is a Surprising result, since some occlusal Surfaces, fractures, occlusal trauma and tooth loss. compounds that act as dopaminergic agents, such as amphet Other symptoms, diseases and conditions resulting from or amines and L-dopa, have been causally related to bruxism, associated with bruxism include myofacial muscle pain, while another, the ergot derivative bromocriptine, has been chronic headaches, migraine headaches, periodontal disease, shown to be ineffective in reducing the frequency and severity upper neck pain and temporomandibular disorder. of bruxism during sleep in a double blind, crossover, placebo 0004. A number of different methods have been tried for controlled clinical trial, thereby disproving earlier prelimi the treatment of bruxism, including psychotherapy, biofeed nary results to the contrary. back, negative feedback techniques, exercise of the mandible, 0013 The present invention therefore provides methods drugs and equilibration adjustment. These methods have been for preventing or treating bruxism, comprising administering largely ineffective. The most common approach for treating to a patient in need of Such prevention or treatment a thera bruxism is splint therapy, which involves the use of splints peutically effective amount of a compound that acts as a Such as mouthguards, removable appliances and the like. dopaminergic agent. While the use of splints can prevent damage to teeth caused by 0014. As used herein, the term "dopaminergic agent' grinding, this approach does not actually prevent or cure means a compound or composition that stimulates neural bruxism. Additionally, the use of splints in some cases can signaling via the dopaminergic system. cause damage to the teeth, including caries, gum inflamma 0015 Various compounds that act as dopaminergic agents tion and splint-induced open bite. can be used in practicing the methods of the present invention 0005. In view of the foregoing, there remains a need for for preventing or treating bruxism. Suitable compounds new methods for the prevention and treatment of bruxism, include, for example, monoamine oxidase inhibitors that including the reduction or elimination of one or more symp increase dopaminergic activity and dopamine agonists. As toms, diseases or conditions associated with or resulting from used herein, the term "dopamine agonist’ means a compound bruxism. that binds to one or more of the different types and subtypes of dopamine receptors and stimulates neural signaling via the SUMMARY OF THE INVENTION dopaminergic system. In certain embodiments, the dopamine 0006. It is therefore an object of the present invention to agonist preferentially binds particular members of the provide new methods for the prevention and treatment of dopamine receptor family. In additional embodiments, the bruxism, including the alleviation or elimination of one or dopamine agonist preferentially binds one or more members more symptoms, diseases or conditions associated with or of the D-like family of dopamine receptors. In other embodi resulting from bruxism. ments, the dopamine agonist preferentially binds one or more 0007. The invention achieves these objects and satisfies members of the D-like family of dopamine receptors. In additional objects and advantages by providing methods for further embodiments, the dopamine agonist preferentially preventing or treating bruxism, comprising administering to a binds the dopamine D receptor subtype. In additional US 2009/024.7537 A1 Oct. 1, 2009 embodiments, the dopamine agonist preferentially binds the napthalenol. Rotigotine has been shown to bind the D. D. dopamine D receptor Subtype. In other embodiments, the and Ds dopamine receptor Subtypes. It is available in a trans dopamine agonist preferentially binds the dopamine D. dermal delivery system containing 4.5 mg, 9.0 mg or 13.5 mg receptor Subtype. In further embodiments, the dopamine ago of the active compound and capable of delivering 2.0 mg. 4.0 nist preferentially binds the dopamine D receptor Subtype. In mg or 6.0 mg, respectively, of the active compound over a 24 additional embodiments, the dopamine agonist preferentially hour period. The transdermal delivery system also contains binds the dopamine Ds receptor subtype. In other embodi various inactive ingredients including ascorbyl palmitate, ments, the dopamine agonist binds multiple dopamine recep poVidone, silicon adhesive, sodium metabisulfite and dl-al tortypes and Subtypes. In further embodiments, the dopamine pha-tocopherol. Methods for the preparation of rotigotine and receptor agonist binds the D., D and D4 dopamine receptor related compounds and compositions are known in the art and Subtypes. In additional embodiments, the dopamine receptor described, for example, in U.S. Pat. No. 6,884,434. agonist binds the D and D dopamine receptor Subtypes. In 0019. The dopamine agonist pardoprunox is currently in other embodiments, the dopamine receptor agonist binds the clinical trials as the hydrochloride salt. The chemical name of D., D and Ds dopamine receptor Subtypes. Dopamine ago this compound is 7-(4-methylpiperazin-1-yl)-1,3-benzox nists are sometime classified as ergot derivatives (e.g., per azol-(3H)-one hydrochloride. Pardoprunox has been shown golide, lysuride, cabergoline) and nonergot derivatives Such to bind the D and D dopamine receptor subtypes as well as as ropinirole, pramipexole, rotigotine, pardoprunoX, piribedil well as the 5-HT serotonin receptor subtype. It is supplied and Sumanirole. Suitable dopamine agonists that can be used for clinical trial purposes as tablets for oral administration in practicing the methods of the present invention for prevent containing 6 mg and 12 mg of the active compound along with ing or treating bruxism include, for example, pramipexole, various inactive ingredients. Methods for the preparation of ropinirole, rotigotine, pardoprunoX, piribediland Sumanirole. pardoprunoX and related compounds and compositions are Other Suitable dopamine agonists include, for example, apo known in the art and described, for example, in U.S. Pat. No. morphine, amantadine, fenoldopam, talipexale and quin 4,782,061. pirole. Suitable monoamine oxidase inhibitors that increase 0020. The dopamine agonist Sumanirole is currently in dopaminergic activity that can be used in practicing the meth clinical trials as the maleate salt. The chemical name of this ods of the present invention include, for example, rasagiline compound is (R)-5,6-dihydro-5-(methylamino)-4H-imida and selegiline. Zol4,5,1-ijquinolin-2(1H)-one(Z)-2-butenedioate. 0016. The dopamine agonist pramipexZole is commer Sumanirole has been shown to selectively bind the D dopam cially available and sold under the trademark Mirapex(R) as the ine receptor subtype. It is available for clinical trial purposes dihydrochloride monohydrate. The chemical name of this as tablets for oral administration containing 0.5 mg, 1 mg, 2 compound is (S)-2-amino-4,5,6,7-tetrahydro-6-(propy mg, 4 mg., 8 mg and 24 mg of the active compound. The lamino)benzothiazole dihydrochloride monohydrate. Prami tablets also contain various inactive ingredients including a peXZole has been shown to bind the D., D and D dopamine matrix comprising hydroxypropylmethylcellulose (HPMC) receptor subtypes. It is available as tablets for oral adminis and starch. Methods for the preparation of Sumanirole and tration containing 0.125 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1.0 related compounds and compositions are known in the art and mg and 1.5 mg of the active compound. The tablets also described, for example, in U.S. Pat. Nos. 5.273,975 and contain various inactive ingredients including mannitol, corn 5,436,240. starch, collodial silicon dioxide, povidone and magnesium 0021. The dopamine agonist piribedil is commercially stearate. Methods for the preparation of pramipexZole and available and sold under the trademark Trivastal(R) as the related compounds and compositions are known in the art and maleate salt. The chemical name of this compound is 2-4- described, for example, in US Pat. Nos. 4,886,812, 6,001,861 (benzo. 1.3dioxol-5-ylmethyl)piperazin-1-ylpyrimidine. and 6,194,445. Piribedil has been shown to bind the D and D dopamine 0017. The dopamine agonist ropinirole is commercially receptor subtypes as well as the C and Cadrenergic recep available and sold under the trademark Requip(R) as the mono tor subtypes. It is available as tablets for oral administration hydrochloride salt. The chemical name of this compound is containing 50 mg of the active compound. The tablets also 4-2-(dipropylamino)ethyl-1,3-dihydro-2H-indole-2-one contain various inactive ingredients including starch, collo monohydrochloride. Ropinirole has been shown to bind the dial silicon dioxide, Stearic acid and talc. Methods for the D and D dopamine receptor subtypes. It is available as preparation of piribedil and related compounds and compo tablets for oral administration containing 0.25 mg, 0.5 mg. sitions are known in the art and described, for example, in 0.75 mg, 1.0 mg, 2.0 mg, 3.0 mg, 4.0 mg and 5.0 mg of the U.S. Pat. No. 3,299,067. active compound. The tablets also contain various inactive 0022. The monoamine oxidase inhibitor rasigiline is com ingredients including croScarmellose sodium, hydrous lac mercially available and sold under the trademark Azilect(R) as tose, microcrystalline cellulose, magnesium Stearate and one the mesylate salt. The chemical name of this compound is or more of the following substances: carmine, FD&C Blue (1R)-N-prop-2-ynyl-2,3-dihydro-1H-inden-1-amine meth No. 2 aluminum lake, FD&C Yellow No. 6 aluminum lake, anesulfonate. It acts as a selective inhibitor of MAO-B. It is hypromellose, iron oxides, polyethylene glycol, polysorbate available as tablets for oral administration containing an 80 and titanium dioxide. Methods for the preparation of rop amount of rasigiline mesylate equivalent to 0.5 mg or 1.0 of inirole and related compounds and compositions are known rasigiline base. The tablets also contain various inactive in the art and described, for example, in U.S. Pat. Nos. 4,452, ingredients including mannitol, starch, collodial silicon diox 808 and 4,824,860. ide, stearic acid and talc. Methods for the preparation of 0018. The dopamine agonist rotigotine is commercially rasigiline and related compounds and compositions are available and sold under the trademark NeuproR) as the (6S) known in the art and described, for example, in U.S. Pat. Nos. enantiomer. The chemical name of this compound is (6S)-6- 5,387,612, 5,454,446, 5,457,133, 5,532,415, 5,786,390 and {propyl 2-(2-thienyl)ethylamino-5,6,7,8-tetrahydro-1- 6,126,968. US 2009/024.7537 A1 Oct. 1, 2009

0023 The monoamine oxidase inhibitor selegiline is com cesium salt and the like: alkaline earth metals such as calcium mercially available and sold under the trademark Emsam R. salt, magnesium salt and the like; organic amine salts such as The chemical name of this compound is (-)-(N)-methyl-N- triethylamine salt, pyridine salt, picoline salt, ethanolamine (1R)-1-methyl-2-phenylethylprop-2-yn-1-amine. It acts as salt, triethanolamine salt, dicyclohexylamine salt, N,N'- an inhibitor of both MAO-A and MAO-B. It is available in a dibenzylethylenediamine salt and the like; organic acid salts transdermal delivery system containing 1.0 mg/cm of the active compound in sizes of 20 mg/cm, 30 mg/cm and 40 Such as acetate, citrate, lactate. Succinate, tartrate, maleate, mg/cm and capable of delivering 6.0 mg, 9.0 mg or 12 mg, fumarate, mandelate, acetate, dichloroacetate, trifluoroac respectively, of the active compound over a 24 hour period. etate, oxalate, formate and the like; Sulfonates such as mesy The transdermal delivery system also contains various inac late, benzenesulfonate, p-toluenesulfonate and the like; and tive ingredients including acrylic adhesive, ethylene vinyl amino acid salts such as arginate, asparginate, glutamate, acetate/polyethylene polyester, polyurethane and silicon tartrate, gluconate and the like. Suitable base salts are formed coated polyester. Methods for the preparation of selegiline from bases, which form non-toxic salts and include, for and related compounds and compositions are well-known in example, aluminum, calcium, lithium, magnesium, potas the art and described, for example, in U.S. Pat. Nos. 5,423, sium, Sodium, Zinc and diethanolamine salts. 342, 6,423,342, 7,070,808, 7,150,881 and RE34,579. 0032. In accordance with the present invention, the com 0024. In general, the compounds that can be used in prac pounds that can be used in practicing the methods of the ticing the methods of the present invention can be provided in present invention, optionally formulated with additional a variety of forms, including pharmaceutically acceptable, ingredients in a pharmaceutically acceptable composition, active salts, Solvates, hydrates, polymorphs, and/or prodrugs are administered to mammalian Subjects, for example a of the compounds disclosed herein, or any combination human patient, to prevent and treat bruxism and thereby alle thereof. The compounds that can be used in practicing the viate or eliminate one or more symptoms, diseases or condi methods of the present invention can also be provided as tions associated with or resulting from bruxism. Symptoms, enantiomers, diastereomers, and other Stereoisomeric forms, diseases or conditions that can be alleviated or eliminated including racemic and resolved forms and mixtures thereof. include, for example, chronic headache Such as chronic daily The individual enantiomers may be separated according to headache, tooth damage, migraine headache, upper neck methods that are well known to those of ordinary skill in the pain, periodontal disease and temporomandibular disorder, art. Also contemplated are derivatives and modifications of the compounds disclosed hereunder. jaw pain, atypical face pain and myofacial pain. In certain 0025. As used herein, the term “prodrug” refers to any embodiments, “treatment” or “treating refers to ameliora covalently bonded carriers which release the active parent tion of bruxism or one or more symptoms of bruxism, drug in vivo. Examples of prodrugs include esters or amides whereby the symptom(s) is/are alleviated by increasing of a compound that can be used in practicing the methods of dopaminergic activity. In other embodiments, “treatment” or the present invention with hydroxyalkyl or aminoalkyl as a “treating refers to an amelioration of at least one measurable Substituent. These may be prepared by reacting Such com physical parameter associated with bruxism. In yet another pounds with anhydrides Such as Succinic anhydride. embodiment, “treatment” or “treating refers to inhibiting or 0026. As used herein, the term “stereoisomers' is a gen reducing the progression or severity of bruxism (or one or eral term for all isomers of individual molecules that differ more symptoms thereof), e.g., as discerned based on physical, only in the orientation of their atoms in space. It includes physiological, and/or psychological parameters. In additional enantiomers and isomers of compounds with more than one embodiments, “treatment' or “treating refers to delaying the chiral center that are not mirror images of one another (dias onset of bruxism (or one or more symptoms thereof). tereomers). 0033. In certain embodiments, the compounds that can be 0027. The term "chiral center” refers to a carbon atom to used in practicing the methods of the present invention are which four different groups are attached. administered to a mammalian Subject, for example a human 0028. The term “enantiomer or “enantiomeric' refers to a patient, as a preventative or prophylactic treatment against molecule that is nonsuperimposeable on its mirror image and bruxism (or one or more symptom(s) thereof). As used herein, hence optically active wherein the enantiomer rotates the “prevention”, “preventing, and prophylaxis refers to a plane of polarized light in one direction and its mirror image reduction in the risk or likelihood that the subject will acquire rotates the plane of polarized light in the opposite direction. bruxism or one or more symptoms thereof. Alternatively, 0029. The term “racemic' refers to a mixture of equal parts prevention and prophylaxis may correlate with a reduced risk of enantiomers and which is optically inactive. of recurrence of bruxism in the subject once the subject has 0030. The term “resolution” refers to the separation or been cured, restored to a normal state, or placed in remission concentration or depletion of one of the two enantiomeric from bruxism. forms of a molecule. 0034 Administration of an effective amount of a com 0031. The compounds that can be used in practicing the pound that can be used in practicing the methods of the methods of the present invention can be can be prepared as present invention to a mammalian Subject presenting with both acid addition salts formed from an acid and base salts. bruxism or one or more symptoms, diseases or conditions Suitable acid addition salts include, for example, hydrochlo associated with or resulting from bruxism will detectably ride, hydrobromide, hydroiodide, Sulphate, hydrogen Sul alleviate, eliminate, or prevent bruxism and/or one or more of phate, nitrate, phosphate, and hydrogen phosphate salts. the associated or resultant symptoms, diseases or conditions. Other examples of pharmaceutically acceptable acid addition In exemplary embodiments, administration a compound that salts include inorganic and organic acid addition salts. Addi can be used in practicing the methods of the present invention tional pharmaceutically acceptable salts include, but are not to a mammalian Subject will detectably alleviate, eliminate, limited to, metal salts such as Sodium salt, potassium salt, or prevent bruxism or one or more symptoms, diseases or US 2009/024.7537 A1 Oct. 1, 2009

conditions associated with or resulting from bruxism by at mg are administered one, two, three, or four times per day. In least 10%, 20%, 30%, 50% or greater, up to a 75-90%, or 95% other embodiments, dosages of about 0.125 mg to about 12 or greater. mg, about 12 mg to about 25 mg, about 25 mg to about 50 mg 0035. An “effective amount,” “therapeutic amount.” and about 50 mg to about 100 mg are administered one, two “therapeutically effective amount,” or “effective dose' is an or three times per day. In additional embodiments, pramipex effective amount or dose of a compound that can be used in Zole is administered in dosages from about 0.125 mg to about practicing the methods of the present invention Sufficient to 1.5 mg three times per day, ropinirole is administered in elicit a desired pharmacological or therapeutic effect in a dosages from about 0.25 mg to about 5.0 mg three times per mammalian Subject—typically resulting in a measurable day, rotigotine is administered in dosages of about 0.5 mg to reduction in the occurrence, frequency, or severity of brux about 6.0 mg once per day, rasigiline is administered in dos ism, including any combination of symptoms, diseases, or ages of about 0.5 mg to about 1.0 mg once per day, selegiline conditions, associated with or caused by bruxism, in the Sub is administered in dosages of about 6.0 mg to about 12 mg ject. In certain embodiments, when a compound that can be once per day, pardoprunoX is administered in dosages of used in practicing the methods of the present invention is about 6 mg to about 42 mg per day, Sumanirole is adminis administered to treat bruxism, an effective amount of the tered in dosages of about 0.5 mg to about 8 mg per day and compound will be an amount sufficient in vivo to delay or piribedil is administered in dosages of about 50 mg to about eliminate onset of the symptoms of bruxism. Therapeutic 300 mg per day. In alternate embodiments, dosages are cal efficacy can alternatively be demonstrated by a decrease in culated according to body weight, based on the dosage crite the frequency or severity of symptoms associated bruxism, or ria set forth above. by altering the nature, recurrence, or duration of symptoms 0038. The amount, timing and mode of delivery of com associated with bruxism. Therapeutically effective amounts, pounds that can be used in practicing the methods of the and dosage regimens, of a compound that can be used in present invention will be routinely adjusted on an individual practicing the methods of the present invention, including basis, depending on Such factors as weight, age, gender, and pharmaceutically effective salts, Solvates, hydrates, polymor condition of the individual, the acuteness of the condition to phs or prodrugs thereof, will be readily determinable by those be treated and/or related symptoms, whether the administra of ordinary skill in the art, often based on routine clinical or tion is prophylactic or therapeutic, and on the basis of other patient-specific factors. factors known to effect drug delivery, absorption, pharmaco 0036 Suitable routes of administration and delivery meth kinetics, including half-life, and efficacy. An effective dose or ods for a compound that can be used in practicing the methods multi-dose treatment regimen for the compounds that can be of the present invention include, but are not limited to, oral, used in practicing the methods of the present invention will buccal, nasal, aerosol, topical, transdermal, mucosal, rectal, ordinarily be selected to approximate a minimal dosing regi parental, slow release, controlled release, iontophoresis, men that is necessary and Sufficient to Substantially treat or Sonophoresis, and other conventional delivery routes, devices prevent bruxism or alleviate or eliminate one or more symp and methods. Injectable delivery methods are also contem toms, diseases or conditions associated with or resulting from plated, including but not limited to, intravenous, intramuscu bruxism in the subject, as described herein. lar, intraperitoneal, intraspinal, intrathecal, intracerebroven 0039. It should be understood that the compounds that can tricular, intraarterial, and Subcutaneous injection and infusion be used in practicing the methods of the present invention can technology. be used in combination with other drugs (e.g., by co-admin 0037 Suitable effective unit dosage amounts of a com istration, concurrent administration or sequential administra pound that can be used in practicing the methods of the tion) that provide additional therapeutic benefits. For present invention for mammalian Subjects may range from example, the compounds that can be used in practicing the about 0.01 mg to about 100 mg, about 0.125 mg to about 100 methods of the present invention can be used in combination mg, about 0.25 mg to about 50 mg, about 0.5 mg to about 25 with other drugs that treat symptoms, diseases, or conditions mg or about 1.0 mg to about 12 mg. In other embodiments, the associated with or caused by bruxism, including chronic effective dosage will be selected within narrower ranges of headache, tooth damage, migraine headache, upper neck for example, about 0.125 mg to about 12 mg, about 12 mg to pain, periodontal disease and temporomandibular disorder. about 25 mg, about 25 mg to about 50 mg and about 50 mg to Examples of drugs providing symptomatic relief for chronic about 100 mg. In additional embodiments, unit dosage headache, migraine headache, upper neck pain and temporo amounts of a compound that can be used in practicing the mandibular disorder include: non-sterodial anti-inflamma methods of the present invention for mammalian Subjects tory drugs (NSAID’s) Such as ketoprofen, aminopyrine, amo may range from about 0.125 mg to about 1.5 mg for prami diacquine, ampyrone, antipyrine, apaZone, aspirin, peXZole, about 0.25 mg to about 5.0 mg for ropinirole, about benzydamine, bromelains, bufeXamac, clofazimine, clonixin, 0.5 mg to about 6.0 mg for rotigotine, about 0.5 mg to about curcumin, dapsone, diclofenac, diflunisal, dipyrone, epiri 1.0 mg for rasigiline, about 6.0 mg to about 12 mg for sel Zole, etodolac, fenoprofen, flufenamic acid, flurbiprofen, gly egiline, about 6 mg to about 42 mg for pardoprunoX, about 0.5 cyrrhizic acid, ibuprofen, indomethacin, ketorolac, ketorolac mg to about 8 mg for Sumanirole and about 50 mg to about tromethamine, meclofenamic acid, mefenamic acid, 300 mg for piribedil. These and other effective unit dosage mesalamine, naproxen, niflumic acid, oxyphenbutaZone, amounts may be administered in a single dose, or in the form pentosan Sulfuric polyester, phenylbutaZone, piroxicam, of multiple daily, weekly or monthly doses, for example in a prenaZone, salicylates, Sodium salicylate, Sulfasalazine, dosing regimen comprising from 1 to 5, or 2 to 3, doses Sulindac. Suprofen, and tolmetin; and analgesics/antipyretics administered per day, per week, or per month. In certain Such as ketoprofen, flurbiprofen, aspirin, acetaminophen, embodiments, dosages of about 0.01 mg to about 100 mg. ibuprofen, naproxen Sodium, buprenorphine hydrochloride, about 0.125 mg to about 100 mg, about 0.25 mg to about 50 propoxyphene hydrochloride, propoxyphene napsylate, mep mg, about 0.5 mg to about 25 mg or about 1.0 mg to about 12 eridine hydrochloride, hydromorphone hydrochloride, mor US 2009/024.7537 A1 Oct. 1, 2009

phine Sulfate, oxycodone hydrochloride, codeine phosphate, oxide, talc, Sweeteners and colorants. The aforementioned dihydrocodeine bitartrate, pentazocine hydrochloride, hydro effervescent agents and disintegrants are useful in the formu codone bitartrate, levorphanol tartrate, diflunisal, trolamine lation of rapidly disintegrating tablets known to those skilled salicylate, nalbuphine hydrochloride, mefenamic acid, butor in the art. These typically disintegrate in the mouth in less phanol tartrate, choline salicylate, butalbital, phenyltoloxam than one minute, and preferably inless than thirty seconds. By ine citrate, diphenhydramine citrate, methotrimeprazine, cin effervescentagentis meant a couple, typically an organic acid namedrine hydrochloride and meprobamate. Other examples and a carbonate orbicarbonate. of drugs providing symptomatic relief from migraine head 0043. If desired, the compounds that can be used in prac ache include triptans, ergotamine tartrate, propanolol hydro ticing the methods of the present invention can be adminis chloride, isometheptene mucate and dichloralphenaZone. tered in a controlled release form, for example by use of a 0040. In general, compounds that can be used in practicing slow release carrier Such as a hydrophilic, slow release poly the methods of the present invention can be formulated into mer. Exemplary controlled release agents in this context pharmaceutical compositions for administration to an indi include, but are not limited to, hydroxypropyl methyl cellu vidual according to standard pharmaceutical texts and proto lose, having a viscosity in the range of about 100 cps to about cols (e.g., Remington's Pharmaceutical, 18" ed., Alfonso R. 100,000 cps. Gennaro, ed. (Mack Publishing Co., Easton, Pa. 1990)). Such 0044. Yet additional compositions and methods of the pharmaceutical compositions may optionally include excipi invention are provided for topical administration of com ents recognized in the art of pharmaceutical compounding as pounds that can be used in practicing the methods of the being Suitable for the preparation of dosage units as described present invention. Topical compositions may comprise a herein. Such excipients include, without limitation, binders, compound that can be used in practicing the methods of the fillers, lubricants, emulsifiers, Suspending agents, Sweeten present invention and any other active or inactive component ers, flavorings, preservatives, buffers, wetting agents, disin (s) incorporated in a dermatological or mucosally acceptable tegrants, effervescent agents and other conventional excipi carrier, including in the form of aerosol sprays, powders, ents and additives. dermal patches, Sticks, granules, creams, pastes, gels, lotions, 0041. The compositions containing compounds that can syrups, ointments, impregnated Sponges, cotton applicators, be used in practicing the methods of the present invention can or as a solution or Suspension in an aqueous liquid, non thus include any one or combination of the following: one or aqueous liquid, oil-in-water emulsion, or water-in-oil liquid more pharmaceutically acceptable carriers or excipients; emulsion. These topical compositions may comprise a com other medicinal agent(s), pharmaceutical agent(s): adjuvants: pound that can be used in practicing the methods of the and various other pharmaceutical additives and agents known present invention dissolved or dispersed in a portion of a to those skilled in the art. These additional formulation addi water or other solvent or liquid to be incorporated in the tives and agents will often be biologically inactive and can be topical composition or delivery device. Transdermal admin administered to patients without causing unacceptable del istration may be enhanced by the use of dermal penetration eterious side effects or serious adverse interactions with the enhancers known to those skilled in the art. active agent. 0045. Yet additional formulations are provided for 0.042 Compositions containing compounds that can be parenteral administration of compounds that can be used in used in practicing the methods of the present invention will practicing the methods of the present invention, including most often be formulated and administered in an oral dosage aqueous and non-aqueous sterile injection solutions which form, optionally in combination with a carrier or other addi may optionally contain anti-oxidants, buffers, bacteriostats tive(s). Suitable carriers common to pharmaceutical formu and/or solutes which render the formulation isotonic with the lation technology include, but are not limited to, microcrys blood of the mammalian Subject; aqueous and non-aqueous talline cellulose, lactose. Sucrose, fructose, glucose, dextrose, sterile Suspensions which may include Suspending agents or other Sugars, di-basic calcium phosphate, calcium Sulfate, and/or thickening agents; and aqueous and non-aqueous dis cellulose, methylcellulose, cellulose derivatives, kaolin, persions and emulsions. The formulations may be presented mannitol, lactitol, maltitol. Xylitol, Sorbitol, or other Sugar in unit-dose or multi-dose containers. alcohols, dry starch, dextrin, maltodextrin or other polysac 0046 Compositions comprising compounds that can be charides, inositol, or mixtures thereof. Exemplary unit oral used in practicing the methods of the present invention may dosage forms for use in this invention include tablets, cap also include polymers for extended release following Sules, caplets, pills, lozenges, powders, granuels, Solutions, parenteral administration. Such polymeric materials are well Suspensions, syrups or elixirs which may be prepared by any known to those of ordinary skill in the pharmaceutical com conventional method of preparing pharmaceutical oral unit pounding arts. Pharmaceutically acceptable formulations and dosage form. Oral unit dosage forms, such as tablets, may ingredients will typically be sterile or readily sterilizable, contain one or more conventional additional formulation biologically inert, and easily administered. Parenteral prepa ingredients, including, but not limited to, release modifying rations typically contain buffering agents and preservatives, agents, glidants, compression aides, effervescent agents, dis and may be lyophilized to be re-constituted at the time of integrants, lubricants, binders, flavors, flavor enhancers, administration. Injection solutions, dispersions, emulsions sweeteners and/or preservatives. Suitable lubricants include and Suspensions may be prepared from sterile powders, gran Stearic acid, magnesium Stearate, talc, calcium Stearate, ules and tablets of the kind previously described. Preferred hydrogenated vegetable oils, Sodium benzoate, leucine car unit dosage formulations are those containing a daily dose or bowax, magnesium lauryl Sulfate, colloidal silicon dioxide unit, daily Sub-dose, as described herein above, or an appro and glyceryl monostearate. Suitable glidants include colloi priate fraction thereof, of the active ingredient(s). dal silica, fumed silicon dioxide, silica, talc, fumed silica, 0047. In more detailed embodiments, compositions com gypsum and glyceryl monostearate. Substances which may prising compounds that can be used in practicing the methods be used for coating includehydroxypropyl cellulose, titanium of the present invention may be encapsulated for delivery in US 2009/024.7537 A1 Oct. 1, 2009

microcapsules, microparticles, or microspheres, prepared, or evidence of bruxism, including the reduction or elimina for example, by coacervation techniques or by interfacial tion of headache, jaw pain and migraine. polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly(methylmethacylate) micro Example 3 capsules, respectively, in colloidal drug delivery systems (for 0053 Seven patients with symptoms and evidence of example, liposomes, albumin microspheres, microemul bruxism were treated with rotigotine (NeuproR) in accor sions, nano-particles and nanocapsules) or in macro emul dance with the present invention. Evidence and symptoms of S1O.S. bruxism varied from patient to patient and included Soreness 0.048 Pharmaceutical compositions comprising com of the masseter, temporalis, medial pterygoid and lateral pounds that can be used in practicing the methods of the pterygoid muscles, temporomandibular joint tenderness, present invention may be packaged in a variety of containers headache and migraine. The patients were treated with 2.0 mg appropriate to the dosage form and mode of administration. to 4.0 mg of rotigotine per day for a total of 30 to 60 days. These include but are not limited to vials, bottles, cans, pack Results were obtained for six of the seven patients treated. Of ets, ampoules, cartons and flexible containers. these six patients, five exhibited a reduction or elimination of 0049. The invention also provides pharmaceutical packs one or more symptoms or evidence of bruxism, including the or kits comprising one or more containers holding a compo reduction or elimination of headache, jaw pain and migraine. sition comprising a compound that can be used in practicing Example 4 the methods of the present invention as described herein, including pharmaceutically acceptable salts and other forms 0054. Two patients with symptoms and evidence of brux of Such compounds, in a pharmaceutically acceptable, stable ism were treated with rasigiline (AZilect R) in accordance form. Optionally packaged with these packs and kits can be a with the present invention. Evidence and symptoms of brux ism varied from patient to patient and included Soreness of the notice, e.g., in a form prescribed by a governmental agency masseter, temporalis, medial pterygoid and lateral pterygoid regulating pharmaceuticals or biological products, reflecting muscles, temporomandibular joint tenderness, headache and approval by the agency of the manufacture, use and/or sale of migraine. The patients were treated with 0.5 mg to 1.0 mg of the product contained in the pack or kit for human adminis rasigiline one time per day for a total of 30 days. Of the two tration (optionally specifying one or more approved treat patients treated, both exhibited a reduction or elimination of ment indications as described herein). one or more symptoms or evidence of bruxism, including the 0050. The following examples illustrate certain embodi reduction or elimination of headache, jaw pain and migraine. ments of the present invention, and are not to be construed as 0055. It is to be understood that this invention is not lim limiting the present disclosure. ited to the particular methods, formulations and materials disclosed hereinas such methods, formulations and materials EXAMPLES may vary somewhat. It is also to be understood that the terminology employed herein is used for the purpose of Example 1 describing particular embodiments only and is not intended to be limiting since the scope of the present invention will be 0051 Nine patients with symptoms and evidence of brux limited only by the appended claims and equivalents thereof. ism were treated with pramipexzole (Mirapex(R) in accor 0056 All publications and patents mentioned herein are dance with the present invention. Evidence and symptoms of incorporated herein by reference in their entirety for the pur bruxism varied from patient to patient and included Soreness pose of describing and disclosing, for example, the materials of the masseter, temporalis, medial pterygoid and lateral and methodologies that are described in the publications, pterygoid muscles, temporomandibular joint tenderness, which might be used in connection with the presently headache and migraine. The patients were treated with 0.125 described invention. The publications discussed above and to 1.0 mg of pramipexZole one to three times per day for a throughout the text are provided solely for their disclosure total of 30 to 90 days. Results were obtained for seven of the prior to the filing date of the present application. Nothing nine patients treated. Of these seven patients, six exhibited a herein is to be construed as an admission that the inventor is reduction or elimination of one or more symptoms or evi not entitled to antedate such disclosure by virtue of prior dence of bruxism, including the reduction or elimination of invention. headache, jaw pain and migraine. The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows: Example 2 1. A method for preventing or treating bruxism, comprising administering to a patient in need of such prevention or treat 0052 Sixteen patients with symptoms and evidence of ment a therapeutically effective amount of a dopamine ago bruxism were treated with ropinirole (Requip(R) in accor nist or a pharmaceutically acceptable salt, enantiomer, Sol dance with the present invention. Evidence and symptoms of Vate, hydrate, polymorph or prodrug thereof. bruxism varied from patient to patient and included Soreness 2. The method according to claim 1, wherein the dopamine of the masseter, temporalis, medial pterygoid and lateral agonist is a nonergot dopamine agonist. pterygoid muscles, temporomandibular joint tenderness, 3. The method according to claim 2 wherein the nonergot headache and migraine. The patients were treated with 0.25 dopamine agonist is pramipexole. mg to 3.0mg of ropinirole one to three times per day for a total 4. The method according to claim 2, wherein the nonergot of 30 to 90 days. Results were obtained for thirteen of the dopamine agonist is ropinirole. sixteen patients treated. Of these thirteen patients, eleven 5. The method according to claim 2, wherein the nonergot exhibited a reduction or elimination of one or more symptoms dopamine agonist is rotigotine. US 2009/024.7537 A1 Oct. 1, 2009

6. The method according to claim 2, wherein the nonergot pharmaceutically acceptable salt, enantiomer, Solvate, dopamine agonist is pardoprunoX. hydrate, polymorph or prodrug thereof. 7. The method according to claim 2, wherein the nonergot 17. The method according to claim 16 wherein the dopamine agonist is Sumanirole. monoamine oxidase inhibitor is rasagiline. 8. The method according to claim 2, wherein the nonergot 18. The method according to claim 16 wherein such pre dopamine agonist is piribedil. vention or treatment reduces or eliminates one or more symp toms, diseases or conditions associated with or resulting from 9. The method according to claim 1 wherein such preven bruxism. tion or treatment reduces or eliminates one or more symp 19. The method according to claim 18, wherein the symp toms, diseases or conditions associated with or resulting from tom, disease or condition associated with or resulting from bruxism. bruxism is chronic headache. 10. The method according to claim 9, wherein the symp 20. The method according to claim 18, wherein the symp tom, disease or condition associated with or resulting from tom, disease or condition associated with or resulting from bruxism is chronic headache. bruxism is tooth damage. 11. The method according to claim 9, wherein the symp 21. The method according to claim 18, wherein the symp tom, disease or condition associated with or resulting from tom, disease or condition associated with or resulting from bruxism is tooth damage. bruxism is temporomandibular disorder. 22. The method according to claim 18, wherein the symp 12. The method according to claim 9, wherein the symp tom, disease or condition associated with or resulting from tom, disease or condition associated with or resulting from bruxism is migraine headache. bruxism is temporomandibular disorder. 23. The method according to claim 18, wherein the symp 13. The method according to claim 9, wherein the symp tom, disease or condition associated with or resulting from tom, disease or condition associated with or resulting from bruxism is upper neck pain. bruxism is migraine headache. 24. The method according to claim 18, wherein the symp 14. The method according to claim 9, wherein the symp tom, disease or condition associated with or resulting from tom, disease or condition associated with or resulting from bruxism is jaw pain. bruxism is upper neck pain. 25. A method for preventing or treating bruxism, compris 15. The method according to claim 9, wherein the symp ing administering to a patient in need of Such prevention or tom, disease or condition associated with or resulting from treatment a therapeutically effective amount of a compound bruxism is jaw pain. that acts as a dopaminergic agent or a pharmaceutically 16. A method for preventing or treating bruxism, compris acceptable salt, enantiomer, Solvate, hydrate, polymorph or ing administering to a patient in need of Such prevention or prodrug thereof. treatmentatherapeutically effective amount of a momoamine oxidase inhibitor that increases dopaminergic activity or a