US 2015O126612A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0126612 A1 Went et al. (43) Pub. Date: May 7, 2015

54) COMPOSITION AND METHOD FOR Jan.an. 31, 2013 , now abandoned,bandoned, whichwhichi 1s a continuation TREATING NEUROLOGICAL DISEASE of application No. 1 1/286,448, filed on Nov. 23, 2005, now Pat. No. 8,389,578. (71) Applicant: Adamas Pharmaceuticals, Inc., E meryville,ille, CA (US(US) (60) 24,Provisional 2004. application No. 60/631,095, filed on Nov. (72) Inventors: Gregory T. Went, Mill Valley, CA (US); O O Timothy J. Fultz, Jasper, GA (US) Publication Classification (51) Int. Cl. A619/00 (2006.01) (22) Filed: Jan. 7, 2015 (52) U.S. C. O O CPC ...... A61K 31/13 (2013.01); A61 K9/0004 Related U.S. Application Data (2013.01) (63) Continuation of application No. 14/451,262, filed on (57) ABSTRACT Aug. 4, 2014, now Pat. No. 8,987,333, which is a continuation of application No. 14/328,440, filed on Disclosed are compositions comprising , or a Jul. 10, 2014, now Pat. No. 8,895,614, which is a pharmaceutically acceptable salt thereof, and one or more continuation of application No. 13/958,153, filed on excipients, wherein at least one of the excipients modifies Aug. 2, 2013, now Pat. No. 8,796,337, which is a release of amantadine. Methods of administering the same are continuation of application No. 13/756.275, filed on also provided. Patent Application Publication May 7, 2015 Sheet 1 of 7 US 2015/O126612 A1

Figure 1: Simulated Dissolution for TD Amantadine R & SR 120

80

SO

40 ------Amantadine-in (SR) Patent Application Publication May 7, 2015 Sheet 2 of 7 US 2015/O126612 A1

Figure 2: Simulated Plasma Concentration for TIDAmantadine IR & SR over 120hrs.

Amantadine 70mg TID (IR)

- - - - - Amantadine 75mg TID (SR)

O 20 40 60 80 100 20 Time (hr) Patent Application Publication May 7, 2015 Sheet 3 of 7 US 2015/O126612 A1

Figure 3: Simulated Plasma Concentration for TID Levodopa/Carbidopa/Amantadine (IR, IR, IR) over 24hrs

- - - Levodopa 100mg TD (R) a'a's Cartbidopa 25mg TID (IR) - Amantadine 70mg TID (IR)

Time (hr) Patent Application Publication May 7, 2015 Sheet 4 of 7 US 2015/O1266.12 A1

Figure 4: Simulated Plasma Concentration for TD Levodopa/Carbidopa/Amantadine (IR, IR, SR) over 24hrs

r Levodopa 100mg TID (IR) * Carbidopa 25mg TID (IR) Amantadine 75mg TD (SR)

Time (hr) Patent Application Publication May 7, 2015 Sheet 5 of 7 US 2015/O1266.12 A1

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Time (hr) Patent Application Publication May 7, 2015 Sheet 6 of 7 US 2015/O1266.12 A1

Figure 6: , Levodopa and Carbidopa Human Pharmacokinetics

10 mg Memantine 1150 mg Levodopal 37.5 mg Carbidopa Oral

Modified Release Pharmacokinetics

-O-levodopa --- Cartidopa -O-Memantine ------

Patent Application Publication May 7, 2015 Sheet 7 of 7 US 2015/O1266.12 A1

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COMPOSITION AND METHOD FOR below. Because levodopa is metabolized before crossing the TREATING NEUROLOGICAL DISEASE blood-brain barrier and has a short half-life in the circulatory system, it is typically administered in conjunction with a RELATED APPLICATION dopa-decarboxylase inhibitor. Examples of dopa-decarboxy 0001. This application is a continuation of U.S. patent lase inhibitors include carbidopa, 3-hydroxy-benzylhydra application Ser. No. 14/451,262, filed Aug. 4, 2014, which is Zinedihydrochloride (NSD-1015), and benseraxide hydro a continuation of U.S. patent application Ser. No. 14/328,440, chloride. The combination may further include a catechol-O- filed Jul. 10, 2014, now U.S. Pat. No. 8,895,614, which is a methyltransferase (COMT) inhibitor including, for example, continuation of U.S. patent application Ser. No. 13/958,153, talcapone and entacapone. As used herein, levodopa/carbi filed Aug. 2, 2013, now U.S. Pat. No. 8,796,337, which is a dopa shall mean levodopa alone or in combination with a continuation of U.S. patent application Ser. No. 13/756.275, dopa-decarboxylase inhibitor such as carbidopa. Desirably, filed Jan. 31, 2013, now abandoned, which is a continuation the levodopa/carbidopa is in an immediate release formula application of U.S. patent application Ser. No. 1 1/286,448, tion and the NMDA antagonist is in an extended filed on Nov. 23, 2005, now U.S. Pat. No. 8,389,578, which release formulation. One preferred embodiment of the inven claims priority to U.S. Provisional Application No. 60/631, tion involves the combination of amantadine and levodopa/ 095 filed on Nov. 24, 2004, all of which applications are carbidopa. Desirably, amantadine is provided in an extended incorporated herein by reference in their entirety. release formulation and levodopa/carbidopa is provided as an immediate release formulation. By combining an NMDAr FIELD OF THE INVENTION antagonist (e.g., amantadine) with the second agents described herein (e.g., levodopa/carbidopa), this invention 0002 This invention relates to compositions and methods provides an effective pharmaceutical composition for treating for treating neurological diseases, such as Parkinson's dis neurological diseases such as Parkinson's disease or other CaSC. Parkinson's-like diseases or conditions. The administration of this combination is postulated to maintain or enhance the BACKGROUND OF THE INVENTION efficacy of levodopa while significantly reducing its dyskine 0003 Parkinson's disease (PD) is a progressive, degenera sia side effects. tive neurologic disorder which usually occurs in late mid-life. 0007. The combinations described herein provide PD is clinically characterized by bradykinesia, tremor, and complementary benefits associated with the NMDArantago rigidity. Bradykinesia is characterized by a slowness in move nist or levodopa/carbidopa individually, while minimizing ment, slowing the pace of Such routine activities as walking difficulties previously presented when each component is and eating. Tremor is a shakiness that generally affects limbs used separately in a patient. For example, amantadine dosing that are not otherwise in motion. For those PD-patients diag is limited by neurotoxicity that is likely associated with its nosed at a relatively young age, tremoris reported as the most short Tmax. By extending the release of amantadine, a higher disabling symptom. Older patients face their greatest chal effective dose can be maintained providing both dyskinesia lenge in walking or keeping their balance. Rigidity is caused relief and a reduction in the amount of levodopa required for by the inability of muscles to relax as opposing muscle groups treatment of the disease symptoms. Given the inherent toxic contract, causing tension which can produce aches and pains ity of levodopa, such a levodopa sparing combination will in the back, neck, shoulders, temples, or chest. 0004 PD predominantly affects the substantia nigra (SNc) result in a decline in both the dyskinesia and overall disease. dopamine (DA) neurons and is therefore associated with a 0008 Accordingly, the pharmaceutical compositions decrease in striatal DA content. Because dopamine does not described herein are administered so as to deliver to a subject, cross the blood-brain barrier, PD patients may be adminis an amount of an NMDArantagonist, levodopa/carbidopa or tered a precursor, levodopa, that does cross the blood-brain both agents that is high enough to treat symptoms or damag barrier where it is metabolized to dopamine. Levodopa ing effects of an underlying disease while avoiding undesir therapy is intended to compensate for reduced dopamine able side effects. These compositions may be employed to levels and is a widely prescribed therapeutic agent for patients administer the NMDArantagonist, the levodopa/carbidopa, with Parkinson's disease. Chronic treatment with levodopa or both agents at a lower frequency than presently employed, however, is associated with various debilitating side-effects improving patient compliance, adherence, and caregiver con Such as dyskinesia. Venience. These compositions are particularly useful as they 0005 Since currently available drugs containing levodopa provide the NMDArantagonist, levodopa/carbidopa, or both are associated with debilitating side effects, better therapies agents, at a therapeutically effective amount from the onset of are needed for the management of PD. therapy further improving patient compliance and adherence and enable the achievement of a therapeutically effective SUMMARY OF THE INVENTION steady-state concentration of either or both agents of the 0006. In general, the present invention provides methods combination in a shorter period of time resulting in an earlier and compositions for treating and preventing CNS-related indication of effectiveness and increasing the utility of these conditions, such as Parkinson's disease or other Parkinson’s- therapeutic agents for diseases and conditions where time is like diseases or conditions, by administering to a subject in of the essence. Also provided are methods for making and need thereof a combination that includes an N-Methyl-D- using such compositions. Aspartate receptor (NMDAr) antagonist and levodopa. 0009. The NMDArantagonist, the levodopa/carbidopa, or Exemplary NMDAr antagonists include the aminoadaman both agents may be provided in a controlled or extended tanes, such as memantine (1-amino-3,5-dimethyladaman release form with or without an immediate release component tane), (1-(1-aminoethyl)adamantane), or aman in order to maximize the therapeutic benefit of Such agents, tadine (1-amino-adamantane) as well as others described while reducing unwanted side effects. In preferred embodi US 2015/O 1266 12 A1 May 7, 2015

ments for oral administration, levodopa/carbidopa is pro similar in height to the immediate release formulation even vided as an immediate-release formulation. with a higher administered dose and the diurnal variation is 0010. The NMDArantagonist, the levodopa/carbidopa, or substantially reduced. both agents may be administered in an amount similar to that 0016 FIG. 3 is a graph showing the plasma profiles simu typically administered to subjects. Preferably, the amount of lated using Gastro-Plus for t.i.d. administration of amanta the NMDAr antagonist may be administered in an amount dine (70 mg), levodopa (100 mg), and carbidopa (25 mg), all greater than or less than the amount that is typically admin in an immediate release form. istered to subjects while the levodopa/carbidopa is provided 0017 FIG. 4 is a graph showing the plasma profiles simu at a lower dose than normally used. For example, the amount lated using Gastro-Plus for t.i.d. administration of amanta of amantadine required to positively affect the patient dine (75 mg), levodopa (100 mg), and carbidopa (25 mg), response (inclusive of adverse effects) may be 300, 400, 500, where the amantadine is in a Sustained release form and the 600 mg per day rather than the typical 200-300 mg per day levodopa and carbidopa are in an immediate release form. administered for presently approved indications i.e. without 0018 FIG. 5 is a graph representing dissolution profiles the improved formulation described herein, while the for various aminoadamantane formulations including an levodopa, and optionally the carbidopa, can be reduced inde immediate release form of the NMDArantagonist memantine pendently by 10%, 20%, 30%, 40%, 50%, 60%, 70% or up to (Namenda). 80% of what is currently required in the absence of the 0019 FIG. 6 is a graphical representation of plasma NMDArantagonist. release profiles in a human of memantine, levodopa, and 0011 Optionally, lower or reduced amounts of both the carbidopa when memantine is administered separately from NMDArantagonist and the levodopa/carbidopa are used in a levodopa and carbidopa. unit dose relative to the amount of each agent when admin 0020 FIG. 7 is a graphical representation of plasma istered independently. The present invention therefore fea release profiles in a human of memantine, levodopa, and tures formulations of combinations directed to dose optimi carbidopa when memantine, levodopa, and carbidopa are zation or release modification to reduce adverse effects administered as part of a single controlled-release pharma associated with separate administration of each agent. The ceutical composition. combination of the NMDAr antagonist and the levodopa/ 0021 FIG. 8 is a bar graph showing the effects on a pri carbidopa may result in an additive or synergistic response, mate (squirrel monkey) treated with a combination of and using the unique formulations described herein, the goal levodopa/carbidopa and amantadine. of minimizing the levodopa burden is achieved. Preferably, the NMDArantagonist and the levodopa/carbidopa are pro DETAILED DESCRIPTION OF THE INVENTION vided in a unit dosage form. 0022. In general, the present invention features pharma 0012. The compositions and methods of the invention are ceutical compositions that contain therapeutically effective particularly useful for the treatment of Parkinson's disease or levels of an NMDArantagonist and levodopa/carbidopa and, conditions associated with Parkinson's disease. These condi optionally, a pharmaceutical carrier. Preferably the composi tions include dementia, dyskinesia, dystonia, depression, tions are formulated for modified or extended release to pro fatigue and other neuropsychiatric complications of Parkin vide a serum or plasma concentration of the NMDArantago son's disease. nist over a desired time period that is high enough to be 0013. Unless otherwise defined, all technical and scien therapeutically effective but at a rate low enough so as to tific terms used herein have the same meaning as commonly avoid adverse events associated with the NMDArantagonist. understood by one of ordinary skill in the art to which this Control of drug release is particularly desirable for reducing invention belongs. Although methods and materials similar or and delaying the peak plasma level while maintaining the equivalent to those described herein can be used in the prac extent of drug bioavailability. Therapeutic levels are therefore tice or testing of the invention, Suitable methods and materials achieved while minimizing debilitating side-effects that are are described below. All publications, patent applications, usually associated with immediate release formulations. Fur patents, and other references mentioned herein are incorpo thermore, as a result of the delay in the time to obtain peak rated by reference in their entirety. In the case of conflict, the serum or plasma level and the extended period of time at the present Specification, including definitions, will control. In therapeutically effective serum or plasma level, the dosage addition, the materials, methods, and examples are illustra frequency is reduced to, for example, once or twice daily tive only and not intended to be limiting. All parts and per dosage, thereby improving patient compliance and adher centages are by weight unless otherwise specified. ence. For example, side effects including psychosis and cog nitive deficits associated with the administration of NMDAr BRIEF DESCRIPTION OF THE FIGURES antagonists may be lessened in severity and frequency through the use of controlled-release methods that shift the 0014 FIG. 1 is a graph showing the dissolution profiles for Tmax to longer times, thereby reducing the dC/dT of the drug. an immediate and Sustained release formulation of amanta Reducing the dC/dT of the drug not only increases Tmax, but dine. The sustained release formulation exhibits a dC/dT also reduces the drug concentration at Tmax and reduces the during the initial phase that is about 10% of that for the Cmax/Cmean ratio providing a more constant amount of drug immediate release formulation. to the Subject being treated over a given period of time, 0015 FIG. 2 is a graph showing the amantadine plasma enabling increased dosages for appropriate indications. concentration over a period of 5 days, as predicted by Gastro 0023. In addition, the present invention encompasses opti Plus Software package V.4.0.2, following the administration mal ratios of NMDAr and levodopa/carbidopa, designed to of either 70 mg amantadine in an immediate release formu not only treat the dyskinesia associated with levodopa, but lation t.i.d. or 75 mg amantadine in a Sustained release for also take advantage of the additivity and Synergy between mulation t.i.d. The Sustained release formulation peaks are these drug classes. For example, the level of levodopa US 2015/O 1266 12 A1 May 7, 2015 required to treat the disease symptoms can unexpectedly be combination preferably also includes a dopa-decarboxylase reduced by up to 50% by the addition of 400 mg/day of inhibitor. An example of a suitable dopa-decarboxylase amantadine. inhibitor is carbidopa. Other dopa-decarboxylase inhibitors include, for example, 3-hydroxy-benzylhydrazinedihydro Making NMDAr Antagonist Controlled Release chloride (NSD-1015) and benseraxide hydrochloride. The Formulations combination may further include a catechol-O-methyltrans 0024. A pharmaceutical composition according to the ferase (COMT) inhibitor including, for example, talcapone invention is prepared by combining a desired NMDAr and entacapone. antagonist or antagonists with one or more additional ingre dients that, when administered to a subject, causes the Dosing, PK, & Toxicity NMDAr antagonist to be released at a targeted rate for a 0030 The NMDA receptor antagonist used in combina specified period of time. A release profile, i.e., the extent of tion therapies are administered at a dosage of generally release of the NMDArantagonist over a desired time, can be between about 1 and 5000 mg/day, between 1 and about 800 conveniently determined for a given time by measuring the mg/day, or between 1 and 500 mg/day. For example, NMDA release using a USP dissolution apparatus under controlled receptor antagonist agents may be administered at a dosage conditions. Preferred release profiles are those which slow the ranging between about 1 and about 500 mg/day, more pref rate of uptake of the NMDArantagonist in the neural fluids erably from about 10 to about 40, 50, 60, 70 or 80 mg/day, while providing therapeutically effective levels of the advantageously from about 10 to about 20 mg per day. Aman NMDArantagonist. One of ordinary skill in the art can pre tadine may be administered at a dose ranging from about 90, pare combinations with a desired release profile using the 100 mg/day to about 400, 500, 600, 700 or 800 mg/day, NMDAr antagonists and formulation methods described advantageously from about 100 to about 500, 600 mg per day. below. For example, the pharmaceutical composition may beformu lated to provide memantine in an amount ranging between NMDAr Antagonists 1-200 mg/day, 1 and 80 mg/day, 2-80 mg/day, 10-80 mg/day, 0025. Any NMDArantagonist can be used in the methods 10 and 80 mg/day, 10 and 70 mg/day, 10 and 60 mg/day, 10 and compositions of the invention, particularly those that are and 50 mg/day, 10 and 40 mg/day, 5 and 65 mg/day, 5 and 40 non-toxic when used in the compositions of the invention. mg/day, 15 and 45 mg/day, or 10 and 20 mg/day; dex The term "nontoxic' is used in a relative sense and is intended tromethorphan in an amount ranging between 1-5000 to designate any Substance that has been approved by the mg/day, 1-1000 mg/day, and 100-800 mg/day, or 200-500 United States Food and Drug Administration (“FDA) for mg/day. Pediatric doses will typically be lower than those administration to humans or, in keeping with established determined for adults. regulatory criteria and practice, is Susceptible to approval by 0031 Table 1 shows exemplary pharmacokinetic proper the FDA or similar regulatory agency for any country for ties (e.g., Tmax and T/2) of memantine, amantadine, and administration to humans or animals. rimantadine. 0026. The term “NMDAr antagonist', as used herein, includes any amino-adamantane compound including, for TABLE 1 example, memantine (1-amino-3,5-dimethyladamantane), rimantadine (1-(1-aminoethyl)adamantane), amantadine Pharmacokinetics and Toxicity in humans for selected NIVIDAr (1-amino-adamantane), as well as pharmaceutically accept antagonists able salts thereof. Memantine is described, for example, in Dose U.S. Pat. Nos. 3,391,142, 5,891,885, 5,919,826, and 6,187, Human PK Tmax Normal Dependent 338. Amantadine is described, for example, in U.S. Pat. Nos. Compound (t/2) (hours) (hours) Dose Toxicity 3,152,180, 5,891,885, 5,919,826, and 6,187,338. Additional Memantine 60 3 10-20 mg/day, Dose escalation aminoadamantane compounds are described, for example, in starting at 5 mg required, U.S. Pat. Nos. 4,346,112, 5,061,703, 5,334,618, 6,444,702, hallucination Amantadine 15 3 100-300 mg/day, Hallucination 6,620,845, and 6,662,845. All of these patents are hereby starting at incorporated by reference. 100 mg/day 0027. Further NMDArantagonists that may be employed Rimantadine 25 6 100-200 mg/day Insomnia include, for example, aminocylohexanes such as neramex ane, , , ifenprodil, , , iamotrigine, , , , , 0032. When levodopa and carbidopa are both included in celfotel, , , , levemopamil, dex the composition, the levodopa dose ranges between 100 to tromethorphan ((+)-3-hydroxy-N-methylmorphinan) and its 3000 mg per day, 75 mg and 2500 mg/day, 100-2000 mg/day, metabolite, ((+)-3-hydroxy-N-methylmorphi or 250 and 1000 mg/day divided for administration t.i.d. or nan), a pharmaceutically acceptable salt, derivative, or ester more frequently. Carbidopa doses may range between the thereof, or a metabolic precursor of any of the foregoing. amounts of 1 to 1000 mg/day, 10 to 500 mg/day, and 25 to 100 0028 Optionally, the NMDAr antagonist in the instant mg/day. Optionally, the carbidopa is present in the combina invention is memantine and not amantadine or dextrometho tion at about 75%, 70%. 65%, 60%, 50%, 40%, 30%, 25%, rphan. 20%, and 10% of the mass of the levodopa. Alternatively, the amount of levodopa is less than 300% than the amount of carbidopa. For example, 75 mg of carbidopa (amount that is Second Agents sufficient to extend the half-life of levodopa in the circulatory 0029. In all foregoing aspects of the invention, the second system) may be used in combination with 300 to 3000 mg of agent is levodopa. When levodopa is in the combination, the levodopa per day. The combination may contain a single US 2015/O 1266 12 A1 May 7, 2015 dosage form comprising 30 to 200 mg amantadine, 30 to 250 matrix forming materials include, for example, waxes (e.g., mg levodopa, and 10 to 100 mg of carbidopa fort.i.d. or more carnauba, beeswax, paraffin wax, ceresine, shellac wax, fatty frequent administration, including multiple dosage forms per acids, and fatty alcohols), oils, hardened oils or fats (e.g., administration. hardened rapeseed oil, castor oil, beef tallow, palm oil, and 0033. As a result, the preferred dosage forms for opti Soya bean oil), and polymers (e.g., hydroxypropyl cellulose, mized use are shown in Table 2 below, with their correspond polyvinylpyrrolidone, hydroxypropyl methyl cellulose, and ing commercial equivalent. polyethylene glycol). Other suitable matrix tabletting mate rials are microcrystalline cellulose, powdered cellulose, TABLE 2 hydroxypropyl cellulose, ethyl cellulose, with other carriers, and fillers. Tablets may also contain granulates, coated pow Dosage forms with and without NMDAr antagonist (amount per unit dose ders, or pellets. Tablets may also be multi-layered. Multi Compositions of layered tablets are especially preferred when the active ingre Sinemet Compositions Present Invention dients have markedly different pharmacokinetic profiles. Levodopa Carbidopa Levodopa Carbidopa Amantadine Optionally, the finished tablet may be coated or uncoated. 100 mg 25 mg IR 50-100 mg 25 mg IR 100-200 mg IR 0037. The coating composition typically contains an IR: IR insoluble matrix polymer (approximately 15-85% by weight 100 mg 10 mg IR 50-100 mg 10 mg IR 50-100 mg IR of the coating composition) and a water Soluble material (e.g., IR IR approximately 15-85% by weight of the coating composi 100 mg 25 mg IR 50-100 mg 25 mg IR 100-200 mg CR** IR IR tion). Optionally an enteric polymer (approximately 1 to 99% 100 mg 10 mg IR 50-100 mg 10 mg IR 50-100 mg CR by weight of the coating composition) may be used or IR IR included. Suitable water soluble materials include polymers IR: immediate release Such as polyethylene glycol, hydroxypropyl cellulose, **CR: modified release hydroxypropyl methyl cellulose, polyvinylpyrrolidone, poly vinyl , and monomeric materials such as Sugars (e.g., lactose, Sucrose, fructose, mannitol and the like), salts (e.g., Excipients Sodium chloride, potassium chloride and the like), organic acids (e.g., fumaric acid, Succinic acid, lactic acid, and tartaric 0034) “Pharmaceutically or Pharmacologically Accept acid), and mixtures thereof. Suitable enteric polymers include able' includes molecular entities and compositions that do hydroxypropyl methyl cellulose, acetate Succinate, hydrox not produce an adverse, allergic or other untoward reaction ypropyl methyl cellulose, phthalate, polyvinyl acetate phtha when administered to an animal, or a human, as appropriate. late, cellulose acetate phthalate, cellulose acetate trimellitate, "Pharmaceutically Acceptable Carrier includes any and all shellac, Zein, and polymethacrylates containing carboxyl Solvents, dispersion media, coatings, antibacterial and anti fungal agents, isotonic and absorption delaying agents and groups. the like. The use of such media and agents for pharmaceutical 0038. The coating composition may be plasticised accord active Substances is well known in the art. Except insofar as ing to the properties of the coating blend Such as the glass any conventional media or agent is incompatible with the transition temperature of the main component or mixture of active ingredient, its use in the therapeutic compositions is components or the Solvent used for applying the coating contemplated. Supplementary active ingredients can also be compositions. Suitable plasticisers may be added from 0 to incorporated into the compositions. "Pharmaceutically 50% by weight of the coating composition and include, for Acceptable Salts' include acid addition salts and which are example, diethyl phthalate, citrate esters, polyethylene gly formed with inorganic acids such as, for example, hydrochlo col, glycerol, acetylated glycerides, acetylated citrate esters, ric orphosphoric acids, or Such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free dibutylsebacate, and castor oil. If desired, the coating com carboxyl groups can also be derived from inorganic bases position may include a filler. The amount of the filler may be Such as, for example, Sodium, potassium, ammonium, cal I% to approximately 99% by weight based on the total weight cium, or ferric hydroxides, and Such organic bases as isopro of the coating composition and may be an insoluble material pylamine, trimethylamine, histidine, procaine and the like. Such as silicon dioxide, titanium dioxide, talc, kaolin, alu mina, starch, powdered cellulose, MCC, or polacrilin potas 0035. The preparation of pharmaceutical or pharmaco S1. logical compositions is known to those of skill in the art in light of the present disclosure. General techniques for formu 0039. The coating composition may be applied as a solu lation and administration are found in “Remington: The Sci tion or latex in organic solvents or aqueous solvents or mix ence and Practice of Pharmacy, Twentieth Edition.” Lippin tures thereof. If solutions are applied, the solvent may be cott Williams & Wilkins, Philadelphia, Pa. Tablets, capsules, present in amounts from approximate by 25-99% by weight pills, powders, granules, dragees, gels, slurries, ointments, based on the total weight of dissolved solids. Suitable sol Solutions Suppositories, injections, inhalants and aerosols are vents are water, lower alcohol, lower chlorinated hydrocar examples of Such formulations. bons, ketones, or mixtures thereof. If latexes are applied, the 0036 By way of example, modified or extended release solvent is present in amounts from approximately 25-97% by oral formulation can be prepared using additional methods weight based on the quantity of polymeric material in the known in the art. For example, a suitable extended release latex. The solvent may be predominantly water. form of the either active pharmaceutical ingredient or both 0040. The NMDAr antagonist may be formulated using may be a matrix tablet or capsule composition. Suitable any of the following excipients or combinations thereof US 2015/O 1266 12 A1 May 7, 2015

Excipient name Chemical name Function Avicel PH102 Microcrystalline Cellulose Filler, binder, wicking, disintegrant Avicel PH101 Microcrystalline Cellulose Filler, binder, disintegrant Eudragit RS- Polymethacrylate Poly(ethyl acrylate, Film former, tablet binder, tablet diluent; 3OD nethyl methacrylate, Rate controlling polymer for controlled timethylammonioethyl methacrylate release chloride) 1:2:0.1 Methocel Hydroxypropyl methylcellulose Rate controlling polymer for controlled K10OM release; binder; Viscosity-increasing Premium CR agent Methocel Hydroxypropyl methylcellulose Rate controlling polymer for controlled K10OM release; binder; Viscosity-increasing agent Magnesium Stearate Lubricant Stearate Talc Talc Dissolution control; anti-adherent, glidant Triethyl Citrate Triethyl Citrate Plasticizer Methocel E5 Hydroxypropyl methylcellulose Film-former Opadry (R) Hydroxypropyl methylcellulose One-step customized coating system which combines polymer, plasticizer and, if desired, pigment in a dry concentrate. Surelease (R) Aqueous Ethylcellulose Dispersion Film-forming polymer; plasticizer and stabilizers. Rate controlling polymer coating.

0041. The pharmaceutical composition described herein carbidopa may also be formulated as a Sustained release for may also include a carrier Such as a solvent, dispersion media, mulation; in most cases, however, this will not be optimal. coatings, antibacterial and antifungal agents, isotonic and 0043 Suitable methods for preparing the compositions absorption delaying agents. The use of such media and agents described herein in which the NMDArantagonist is provided for pharmaceutically active Substances is well known in the in modified or extended release-formulations include those art. Pharmaceutically acceptable salts can also be used in the described in U.S. Pat. No. 4,606,909 (hereby incorporated by composition, for example, mineral salts such as hydrochlo reference). This reference describes a controlled release mul rides, hydrobromides, phosphates, or Sulfates, as well as the tiple unit formulation in which a multiplicity of individually salts of organic acids such as acetates, proprionates, mal coated or microencapsulated units are made available upon onates, or benzoates. The composition may also contain liq disintegration of the formulation (e.g., pill or tablet) in the uids, Such as water, Saline, glycerol, and ethanol, as well as stomach of the Subject (see, for example, column 3, line 26 Substances Such as wetting agents, emulsifying agents, or pH through column 5, line 10 and column 6, line 29 through buffering agents. Liposomes, such as those described in U.S. column 9, line 16). Each of these individually coated or Pat. No. 5,422,120, WO95/13796, WO 91/14445, or EP microencapsulated units contains cross-sectionally Substan 524.968 B1, may also be used as a carrier. tially homogenous cores containing particles of a sparingly soluble active Substance, the cores being coated with a coat Methods for Preparing Modified or Extended Release ing that is substantially resistant to gastric conditions but Formulations which is erodable under the conditions prevailing in the gas trointestinal tract. 0042. The NMDArantagonist, the levodopa/carbidopa, or 0044) The composition of the invention may alternatively both agents may be provided in a controlled or extended be formulated using the methods disclosed in U.S. Pat. No. release form with or without an immediate release component 4.769,027, for example. Accordingly, extended release for in order to maximize the therapeutic benefit of Such agents, mulations involve prills of pharmaceutically acceptable while reducing unwanted side effects. In the absence of modi material (e.g., Sugar/starch, salts, and waxes) may be coated fied release components (referred to herein as controlled, with a water permeable polymeric matrix containing an extended, or delayed release components), the NMDAr NMDArantagonist and next overcoated with a water-perme antagonist, levodopa/carbidopa, or both is released and trans able film containing dispersed within it a water soluble par ported into the body fluids over a period of minutes to several ticulate pore forming material. hours. The combination described herein however, may con 0045. The NMDArantagonist composition may addition tain an NMDAr antagonist and a Sustained release compo ally be prepared as described in U.S. Pat. No. 4,897.268, nent, such as a coated Sustained release matrix, a Sustained involving a biocompatible, biodegradable microcapsule release matrix, or a Sustained release bead matrix. In one delivery system. Thus, the NMDArantagonist may beformu example, in addition to levodopa/carbidopa, amantadine lated as a composition containing a blend of free-flowing (e.g., 50- 400 mg) is formulated without an immediate spherical particles obtained by individually microencapsulat release component using a polymer matrix (e.g., Eudragit), ing quantities of memantine, for example, in different copoly Hydroxypropyl methyl cellulose (HPMC) and a polymer mer excipients which biodegrade at different rates, therefore coating (e.g., Eudragit). Such formulations are compressed releasing memantine into the circulation at a predetermined into solid tablets or granules and coated with a controlled rates. A quantity of these particles may be of Such a copoly release material such as Opadry(R) or Surelease(R). Levodopa/ mer excipient that the core active ingredient is released US 2015/O 1266 12 A1 May 7, 2015

quickly after administration, and thereby delivers the active time in hours and t is greater than Zero and equal or less than ingredient for an initial period. A second quantity of the 17. Thus, the fraction of NMDAr antagonist or levodopa/ particles is of Such type excipient that delivery of the encap carbidopa that is released may range between 0.1%-62% in Sulated ingredient begins as the first quantity's delivery one hour, 0.2%-86% in two hours, 0.6%-100% in six hours, begins to decline. A third quantity of ingredient may be 2.9%-100% in 10 hours, and 7.7%-100% in 12 hours using a encapsulated with a still different excipient which results in USP type 2 (paddle) dissolution system at 50 rpm, at a tem delivery beginning as the delivery of the second quantity perature of 37+0.5°C. in a neutral pH (e.g. water or buffered beings to decline. The rate of delivery may be altered, for example, by varying the lactide/glycolide ratio in a poly(D. aqueous solution) or acidic (e.g. 0.1 NHCl) dissolution L-lactide-co-glycolide) encapsulation. Other polymers that medium. Optionally, the NMDA receptor antagonist has a may be used include polyacetal polymers, polyorthoesters, release profile ranging between 0.1%-20% in one hour, polyesteramides, polycaprolactone and copolymers thereof, 5%-30% in two hours, 40%-80% in six hours, 70% or greater polycarbonates, polyhydroxybuterate and copolymers (e.g., 70%-90%) in 10 hours, and 90% or greater (e.g., thereof, polymaleamides, copolyaxalates and polysaccha 90-95%) in 12 hours as measured in a dissolution media rides. having a neutral pH (e.g. water or buffered aqueous solution) 0046 Alternatively, the composition may be prepared as or in an acidic (e.g. 0.1 NHCl) dissolution medium. For described in U.S. Pat. No. 5,395,626, which features a mul example, a formulation containing amantadine may have a tilayered controlled release pharmaceutical dosage form. The release profile ranging between 0-60% or 0.1-20% in one dosage form contains a plurality of coated particles wherein hour, 0-86% or 5-30% at two hours, 0.6-100% or 40-80% at each has multiple layers about a core containing an NMDAr six hours, 3-100% or 50% or more (e.g., 50-90%) atten hours, antagonist whereby the drug containing core and at least one and 7.7-100% at twelve hours in a dissolution media having a other layer of drug active is overcoated with a controlled neutral pH (e.g. water or buffered aqueous solution) or in an release barrier layer therefore providing at least two con acidic (e.g. 0.1 NHCl) dissolution medium. In one embodi trolled releasing layers of a water soluble drug from the ment, the NMDAr antagonist, the levodopa/carbidopa, or multilayered coated particle both agents have an in vitro dissolution profile of less than 25%, 15%, 10%, or 5% in fifteen minutes; 50%, 30%, 25%, Release Profile 20%, 15%, or 10% in 30 minutes and more than 60%. 65% 70%, 75%, 80%, 85%, 90%, 95% at 16 hours as obtained 0047. The compositions described herein are formulated using a USP type II (paddle) dissolution system at 50 rpm, at such that the NMDAr antagonist, levodopa/carbidopa, or a temperature of 37+0.5° C. in water. Desirably, the NMDAr both agents have an in vitro dissolution profile that is equal to antagonist, the levodopa/carbidopa, or both agents has a dis or slower than that for an immediate release formulation. As solution of at least 65%, 70%, 75%, 80%, 85%, 90%, or 95% used herein, the immediate release (IR) formulation for in a dissolution media having a pH of 1.2 at 10 hours. It is memantine means the present commercially available 5 mg important to note that the dissolution profile for the NMDAr and 10 mg tablets (i.e., Namenda from Forest Laboratories, antagonist may be different than the release profile for Inc. or formulations having Substantially the same release levodopa/carbidopa. In a preferred embodiment, the profiles as Namenda); and the immediate release (IR) formu levodopa/carbidopa release profile is equal to or similar to lation of amantadine means the present commercially avail that for an immediate release formulation and the release able 100 mg tablets (i.e., Symmetrel from Endo Pharmaceu profile for the NMDArantagonist is controlled to provide a ticals, Inc. or formulations having Substantially the same dissolution profile of less than 30% in one hour, less than 50% release profiles as Symmetrel); and the immediate release in two hours, and greater than 95% in twelve hours using a (IR) formulation of levodopa/carbidopa means the present USP type II (paddle) dissolution system at 50 rpm, at a tem commercially available 25 mg/100 mg, 10 mg/100 mg, 25 perature of 37+0.5° C. in water. mg/250 mg tablets of carbidopa/levodopa (i.e., Sinemet from Merck & Co. Inc. or formulations having substantially the 0048. Desirably, the compositions described herein have same release profiles as Sinemet). These compositions may an in vitro profile that is substantially identical to the disso comprise immediate release, Sustained or extended release, or lution profile shown in FIG. 5 and, upon administration to a delayed release components, or may include combinations of Subject at a Substantially constant daily dose, achieves a same to produce release profiles such that the fraction of serum concentration profile that is Substantially identical to NMDArantagonist or levodopa/carbidopa released is greater that shown in FIGS. 2 and 4. or equal to 0.01 (0.297+0.0153*e''') and less than or 0049. As described above, the NMDAr antagonist, the equal to 1-e' as measured using a USP type 2 (paddle) levodopa/carbidopa, or both agents may be provided in a dissolution system at 50 rpm, at a temperature of 37+0.5°C., modified or extended release form. Modified or extended in water, where t is the time in hours and t is greater than Zero drug release is generally controlled either by diffusion and equal or less than 17. Thus, the fraction of NMDAr through a coating or matrix or by erosion of a coating or antagonist or levodopa/carbidopa released is less than 93% in matrix by a process dependent on, for example, enzymes or 15 minutes and 7.7%-100% in 12 hours using a USP type 2 pH. The NMDArantagonist or the levodopa/carbidopa may (paddle) dissolution system at 50 rpm, at a temperature of be formulated for modified or extended release as described 37+0.5° C. in a neutral pH (e.g. water or buffered aqueous herein or using standard techniques in the art. In one example, solution) or acidic (e.g. 0.1N HCl) dissolution medium. at least 50%, 75%, 90%, 95%, 96%, 97%, 98%, 99%, or even Optionally, the fraction of released NMDAr antagonist or in excess of 99% of the NMDArantagonist or the levodopa/ levodopa/carbidopa is greater than or equal to 0.01 (0.297+0. carbidopa is provided in an extended release dosage form. In 0153*e'''), and less than or equal to 1-e''''' as a preferred embodiment, the levodopa/carbidopa is provided measured using a USP type 2 (paddle) dissolution system at in an immediate release formulation and the NMDArantago 50 rpm, at a temperature of 37+0.5°C., in water, where t is the nist is in either an immediate or modified release form. US 2015/O 1266 12 A1 May 7, 2015

0050. The composition described herein is formulated change in the biological sample measured as the dC/dT over such the NMDArantagonist or levodopa/carbidopa has an in a defined period within the period of 0 to Tmax for the IR vitro dissolution profile ranging between 0.1%-20% in one formulation (e.g., Namenda, a commercially available IR hour, 5%-30% in two hours, 40%-80% in six hours, 50%- formulation of memantine). In some embodiments, the dC/dT 90% in 10 hours, and 90%-95% in 12 hours using a USP type rate is less than about 80%, 70%, 60%, 50%, 40%, 30%, 20%, 2 (paddle) dissolution system at 50 rpm, at a temperature of or 10% of the rate for the IR formulation. In some embodi 37+0.5°C. using 0.1N HCl as a dissolution medium. Alter ments, the dC/dT rate is less than about 60%, 50%, 40%, natively, the NMDAr antagonist has an in vitro dissolution 30%, 20%, or 10% of the rate for the IR formulation. Simi profile in a solution with a neutral pH (e.g., water) that is larly, the rate of release of the NMDAr antagonist or the Substantially the same as its dissolution profile in an acidic levodopa/carbidopa from the present invention as measured dissolution medium. Thus, the NMDAr antagonist may be in dissolution studies is less than 80%, 70%, 60% 50%, 40%, released in both dissolution media at the following rate: 30%, 20%, or 10% of the rate for an IR formulation of the between 0.1-20% in one hour, 5-30% in two hours, 40-80% in same NMDArantagonist or levodopa/carbidopa over the first six hours, 70-90% in 10 hours, and 90%-95% in 12 hours as 1, 2, 4, 6, 8, 10, or 12 hours. obtained using a USP type 2 (paddle) dissolution system at 50 0054. In a preferred embodiment, the dosage form is pro rpm, at a temperature of 37+0.5°C. In one embodiment, the vided in a non-dose escalating, three times per day (t.i.d.) NMDArantagonist has an in vitro dissolution profile of less form. In preferred embodiments, the concentration ramp (or than 15%, 10%, or 5% in fifteen minutes, 25%, 20%, 15%, or Tmax effect) may be reduced so that the change in concen 10% in 30 minutes, and more than 60% at 16 hours as tration as a function of time (dC/dT) is altered to reduce or obtained using a USP type II (paddle) dissolution system at 50 eliminate the need to dose escalate the NMDArantagonist. A rpm, at a temperature of 37+0.5°C. in water. Desirably, the reduction in dC/dT may be accomplished, for example, by NMDAr antagonist has a dissolution of at least 65%, 70%, increasing the Tmax in a relatively proportional manner. 75%, 80%, 85%, 90%, or 95% at 10 hours in a dissolution Accordingly, a two-fold increase in the Tmax value may medium having a pH of 1.2. reduce dC/dT by approximately a factor of 2. Thus, the NMDArantagonist may be provided so that it is released at a Initial Rate In Vivo, Delayed Tmax rate that is significantly reduced over an immediate release 0051. As used herein, “C” refers to the concentration of an (IR) dosage form, with an associated delay in the Tmax. The active pharmaceutical ingredient in a biological sample. Such pharmaceutical composition may be formulated to provide a as a patient Sample (e.g. blood, Serum, and cerebrospinal shift in Tmax by 24 hours, 16 hours, 8 hours, 4 hours, 2 hours, fluid). The time required to reach the maximal concentration or at least 1 hour. The associated reduction in dC/dT may be ("Cmax”) in a particular patient sample type is referred to as by a factor of approximately 0.05, 0.10, 0.25, 0.5 or at least the “Tmax'. The change in concentration is termed “dC and 0.8. In certain embodiments, this is accomplished by releas the change over a prescribed time is “dC/dT. ing less than 30%, 50%, 75%, 90%, or 95% of the NMDAr 0052. The NMDAr antagonist or levodopa/carbidopa is antagonist into the circulatory or neural system within one provided as a Sustained release formulation that may or may hour of such administration. not contain an immediate release formulation. If desired, the 0055. The concentration ramp for levodopa/carbidopa NMDArantagonist may be formulated so that it is released at may also be reduced, however Such changes will not be pre a rate that is significantly reduced over an immediate release ferred in most oral formulations due to the marked reduction (IR) dosage form, with an associated delay in the Tmax. The in absorption of levodopa/carbidopa after it passes the duode pharmaceutical composition may be formulated to provide a nal region of the gastrointestinal tract. shift in Tmax by 24 hours, 16 hours, 8 hours, 4 hours, 2 hours, or at least 1 hour. The associated reduction in dC/dT may be 0056. Optionally, the modified release formulations by a factor of approximately 0.05, 0.10, 0.25, 0.5 or at least exhibit plasma concentration curves having initial (e.g., 0.8. In addition, the NMDArantagonist levodopa/carbidopa from 2 hours after administration to 4 hours after adminis may be provided Such that it is released at a rate resulting in a tration) slopes less-than 75%, 50%, 40%, 30%, 20% or 10% Cmax/Cmean of approximately 2 or less for approximately 2 of those for an IR formulation of the same dosage of the same hours to at least 8 hours after the NMDArantagonist is intro NMDArantagonist or levodopa/carbidopa. The precise slope duced into a subject. Optionally, the Sustained release formu for a given individual will vary according to the NMDAr lations exhibit plasma concentration curves having initial antagonist or levodopa/carbidopa being used, the quantity (e.g., from 0, 1, 2 hours after administration to 4, 6, 8 hours delivered, or other factors, including, for Some active phar after administration) slopes less than 75%, 50%, 40%, 30%, maceutical agents, whether the patient has eaten or not. For 20% or 10% of those for an IR formulation of the same dosage other doses, e.g., those mentioned above, the slopes vary of the same NMDArantagonist. The precise slope for a given directly in relationship to dose. individual will vary according to the NMDAr antagonist 0057. Using the sustained release formulations or admin being used or other factors, including whether the patient has istration methods described herein, the NMDAr antagonist eaten or not. For other doses, e.g., those mentioned above, the reaches a therapeutically effective steady state plasma con slopes vary directly in relationship to dose. The determination centration in a subject within the course of the first two, three, of initial slopes of plasma concentration is described, for five, seven, nine, ten, twelve, fifteen, or twenty days of admin example, by U.S. Pat. No. 6,913,768, hereby incorporated by istration. For example, the formulations described herein, reference. when administered at a Substantially constant daily dose (e.g., 0053. Desirably, the NMDArantagonist or the levodopa/ at a dose ranging between 200 mg and 800 mg, preferably carbidopa is released into a Subject sample at a slower rate between 200 mg and 600 mg, and more preferably between than observed for an immediate release (IR) formulation of 200 mg and 400 mg per day) may reach a steady state plasma the same quantity of the antagonist, Such that the rate of concentration in approximately 70%, 60%, 50%, 40%, 30%, US 2015/O 1266 12 A1 May 7, 2015

or less of the time required to reach Such plasma concentra improved (i.e., frequency or severity of symptoms or damag tion when using a dose escalating regimen. ing effects will have decreased, or the time to Sustained pro gression will have increased). In the model described in the Dosing Frequency and Dose Escalation previous paragraph, the steady state (and effective) concen tration of the NMDAr antagonist is reached in 25%, 40%, 0058 According to the present invention, a subject (e.g., 50%, 60%, 70%, 75%, or 80% less time than in the dose human) having or at risk of having Such conditions is admin escalated approach. istered any of the compositions described herein (e.g., three times per day (t.i.d.), twice per day (b.i.d.), or once per day 0061. In another embodiment, a composition is prepared (q.d.). While immediate release formulations of NMDAr using the methods described herein, wherein such composi antagonists are typically administered in a dose-escalating tion comprises memantine oramantadine and a release modi fashion, the compositions described herein may be essen fying excipient, wherein the excipient is present in an amount tially administered at a constant, therapeutically-effective sufficient to ameliorate or reduce the dose-dependent toxicity dose from the onset of therapy. For example, a composition associated with the memantine or amantadine relative to an containing a Sustained release formulation of amantadine immediate release (IR) formulation of memantine, Such as may be administered three times per day, twice per day, or Namenda, or amantadine, Such as Symmetrel. The use of once per day in a unit dose comprising a total daily amanta these compositions enables safer administration of these dine dose of 100 mg, 200 mg, 300 mg. 400 mg, 500 mg, 600 agents, and even permits the safe use of higher levels for mg, 700 mg. or 800 mg. In embodiments comprising a single appropriate indications, beyond the useful range for the pres dosage form containing an NMDArantagonist and levodopa/ ently available versions of memantine (5 mg and 10 mg per carbidopa wherein the levodopa/carbidopa is in an immediate dose to 20 mg per day) and amantadine (100 mg to 300 mg per release form, the dosing frequency will be chosen according day with escalation). to the levodopa/carbidopa requirements, (e.g. three times per day). Indications Suitable for Treatment 0062. The compositions and methods of the present inven Reduced Time to Therapeutic Concentration and Efficacy tion are particularly suitable for the treatment of Parkinson's 0059. Immediate release (IR) formulations of memantine disease or conditions associated with Parkinson's disease. (e.g., Namenda) are typically administered at low doses (e.g., These conditions include dementia, dyskinesia, dystonia, 5 mg/day) and are progressively administered at increasing depression, fatigue and other neuropsychiatric complications frequency and dose over time to reach a steady state serum of Parkinson's disease. concentration that is therapeutically effective. According to the manufacturer's FDA approved label, Namenda, an imme Formulations for Alternate Specific Routes of Administration diate release (IR) formulation of memantine, is first admin istered to Subjects at a dose of 5 mg per day. After an accli 0063. The pharmaceutical compositions may be opti mation period of typically one week, Subjects are mized for particular types of delivery. For example, pharma administered with this dose twice per day. Subjects are next ceutical compositions for oral delivery are formulated using administered with a 5 mg and 10 mg dosing per day and pharmaceutically acceptable carriers that are well known in finally administered with 10 mg Namenda twice daily. Using the art. The carriers enable the agents in the composition to be this dosing regimen, a therapeutically effective steady state formulated, for example, as a tablet, pill, capsule, solution, serum concentration may be achieved within 30 days of the Suspension, Sustained release formulation; powder, liquid or onset of therapy. Using a modified release formulation com gel for oral ingestion by the Subject. prising (22.5 mg memantine,) however, a therapeutically 0064. The NMDArantagonist may also be delivered in an effective steady State concentration may be achieved Substan aerosol spray preparation from a pressurized pack, a nebu tially sooner (within about 13 days), without using a dose lizer or from a dry powder inhaler. Suitable propellants that escalating regimen. Furthermore, the slope during each can be used in a nebulizer include, for example, dichlorodif absorption period for the Sustained release formulation is less luoro-methane, trichlorofluoromethane, dichlorotetrafluoro (i.e. not as steep) as the slope for Namenda. Accordingly, the ethane and carbon dioxide. The dosage can be determined by dC/dT of the sustained release formulation is reduced relative providing a valve to deliver a regulated amount of the com to the immediate release formulation even though the dose pound in the case of a pressurized aerosol. administered is larger than for the immediate release formu 0065 Compositions for inhalation or insufflation include lation. Based on this model, a Sustained release formulation Solutions and Suspensions in pharmaceutically acceptable, of an NMDArantagonist may be administered to a subject in aqueous or organic solvents, or mixtures thereof, and pow an amount that is approximately the full strength dose (or that ders. The liquid or Solid compositions may contain Suitable effectively reaches a therapeutically effective dose) from the pharmaceutically acceptable excipients as set out above. onset of therapy and throughout the duration of treatment. Preferably the compositions are administered by the oral, Accordingly, a dose escalation would not be required. intranasal or respiratory route for local or systemic effect. 0060 Treatment of a subject with the subject of the present Compositions in preferably sterile pharmaceutically accept invention may be monitored using methods known in the art. able solvents may be nebulized by use of inert gases. Nebu The efficacy of treatment using the composition is preferably lized solutions may be breathed directly from the nebulizing evaluated by examining the Subject's symptoms in a quanti device or the nebulizing device may be attached to a face tative way, e.g., by noting a decrease in the frequency or mask, tent or intermittent positive pressure breathing severity of symptoms or damaging effects of the condition, or machine. Solution, Suspension or powder compositions may an increase in the time for Sustained worsening of symptoms. be administered, preferably orally or nasally, from devices In a successful treatment, the subject’s status will have that deliver the formulation in an appropriate manner. US 2015/O 1266 12 A1 May 7, 2015

0066. In some embodiments, for example, the composi formed using methods known in the art, Such as those tion may be delivered intranasally to the cribriform plate described in, e.g., U.S. Pat. Nos. 3,992,518; 5.660,848; and rather than by inhalation to enable transfer of the active agents 5,756,115. through the olfactory passages into the CNS and reducing the (0075. The invention will be illustrated in the following systemic administration. Devices commonly used for this non-limiting examples. route of administration are included in U.S. Pat. No. 6,715, 485. Compositions delivered via this route may enable increased CNS dosing or reduced total body burden reducing EXAMPLES systemic toxicity risks associated with certain drugs. 0067. Additional formulations suitable for other modes of Example 1 administration include rectal capsules or Suppositories. For Suppositories, traditional binders and carriers may include, Measuring Release Profiles In Vitro for example, polyalkylene glycols or triglycerides; such Sup positories may beformed from mixtures containing the active 0076 Compositions containing an aminoadamantane and ingredient in the range of 0.5% to 10%, preferably 1%-2%. levodopa/carbidopa are analyzed for release of the aminoada 0068. The composition may optionally be formulated for mantane and levodopa/carbidopa, according to the USP type delivery in a vessel that provides for continuous long-term 2 apparatus at a speed of 50 rpm. The dissolution media used delivery, e.g., for delivery up to 30 days, 60 days, 90 days, 180 include water, 0.1N HCl, or 0.1N HCl adjusted to pH 6.8 at 2 days, or one year. For example the vessel can be provided in hours with phosphate buffer. The dissolution medium is a biocompatible material Such as titanium. Long-term deliv equilibrated to 37+0.5° C. ery formulations are particularly useful in subjects with (0077. The USP reference assay method foramantadine is chronic conditions, for assuring improved patient compli used to measure the fraction of memantine released from the ance, and for enhancing the stability of the compositions. compositions prepared herein. Briefly, 0.6 mL sample (from 0069 Optionally, the NMDA receptor antagonist, the dissolution apparatus at a given time point) is placed into levodopa/carbidopa, or both is prepared using the OROS(R) a 15 mL culture tube. 1.6 mL 0.1% Bromocresol Purple (in technology, described for example, in U.S. Pat. Nos. 6,919, acetic acid) is added and vortexed for five seconds. The mix 373, 6,923,800, 6,929,803, 6,939,556, and 6,930,128, all of ture is allowed to stand for approximately five minutes. 3 mL which are hereby incorporated by reference. This technology is added and Vortexed for five seconds. The solu employs osmosis to provide precise, controlled drug delivery tion is next centrifuged (speed 50 rpm) for five minutes. The for up to 24 hours and can be used with a range of compounds, top layer is removed with a disposable pipette. A sample is including poorly soluble or highly soluble drugs. OROS(R) drawn into 1 cm flow cell and the absorbance is measured at technology can be used to deliver high drug doses meeting 408 nm at 37° C. and compared against a standard curve high drug loading requirements. By targeting specific areas of prepared with known quantities of the same aminoadaman the gastrointestinal tract, OROS(R) technology may provide tane. The quantity of determined is plotted against the disso more efficient drug absorption and enhanced bioavailability. lution time for the sample. The osmotic driving force of OROS(R) and protection of the (0078. The USP reference assay method for levodopa is drug until the time of release eliminate the variability of drug used to measure the fraction of levodopa released from the absorption and metabolism often caused by gastric pH and compositions prepared herein. Briefly, 0.5 ml samples from motility. the dissolution apparatus removed at various times are 0070 Formulations for continuous long-term delivery are assayed by liquid chromatography. The chromatograph is provided in, e.g., U.S. Pat. Nos. 6,797.283: 6,764, 697; 6,635, equipped with a 280 nm detector and a 3.9 mmx30 cm column 268, and 6,648,083. containing packing Ll. The mobile phase is 0.09 N sodium 0071. If desired, the components may be provided in a kit. phosphate, 1 mM sodium 1-decanesulfonate, pH 2.8. With The kit can additionally include instructions for using the kit. the flow rate adjusted to about 2 mL per minute, the levodopa elutes in about 4 minutes and carbidopa elutes in about 11 Additional Methods for Making Modified Release minutes. From the saved dissolution samples, a 0.02 ml ali Formulations quot is injected into the chromatograph and the absorbance is measure and compared to standard to determine concentra 0072 Additional methods for making modified release tion & quantity. The quantity dissolved is then plotted against formulations are described in, e.g., U.S. Pat. Nos. 5,422,123, the dissolution time for the sample. 5,601,845, 5,912,013, and 6,194,000, all of which are hereby incorporated by reference. Example 2 0073. In some embodiments, for example, the composi tion may be delivered via intranasal, buccal, or Sublingual routes to the brain rather than by inhalation to enable transfer Preparation of Amantadine Extended Release of the active agents through the olfactory passages into the Capsules CNS and reducing the systemic administration. Devices com monly used for this route of administration are included in 0079 Amantadine extended release capsules may be for U.S. Pat. No. 6,715.485. Compositions delivered via this mulated as follows or as described, for example, in U.S. Pat. route may enable increased CNS dosing or reduced total body No. 5,395,626. burden reducing systemic toxicity risks associated with cer 0080 A. Composition: Unit Dose tain drugs. I0081. The theoretical quantitative composition (per unit 0074 Preparation of a pharmaceutical composition for dose) for amantadine extended release capsules is provided delivery in a subdermally implantable device can be per below. US 2015/O 1266 12 A1 May 7, 2015 10

-continued Component % weightweight mg Capsule Component Weight (kg) Amantadine 68.34 2OOOO OPADRY (R) Clear YS-3-7011 1.14 S.O1 Total Weight Amantadine 12.392 kg (Colorcon, Westpoint, PA) Beads Purified Water, USP2 Sugar Spheres, NF 12.SO 54.87 OPADRY (R) Clear YS-1- 4.48 1966 7006 (Colorcon, Westpoint, PA) I0088. The amantadine beads obtained from step 3 are for SURELEASE (R) E-7-7050 13.54 59.44 mulated as follows. (Colorcon, Westpoint, PA) Capsules Step 4: Clear & Sustained Release Bead Coating #2 TOTAL 100.00% 338.98 mg 0089 A mixture of hydroxypropyl methylcellulose, polyethylene glycol, propylene glycol, 'Purified Water, USP is evaporated during processing, A mixture of hydroxypropyl methylcellulose and polyethylene glycol Component Weight (kg) 'Solid content only of a 25% aqueous dispersion of a mixture of ethyl cellulose, dibutyl sebacate, oleic acid, ammoniated water and fumed silica. The water in the dispersion is Amantadine Beads 1.O.OOO evaporated during processing, White, opaque, hard gelatin capsule, size 00, OPADRY (R) Clear YS-1-7006 O.2SO Each batch is assayed prior to filling and the capsule weight is adjusted as required to attain Purified Water, USP 6.450 200 mg amantadine per capsule, Surelease (R) E-7-7050 1.OSO Total Weight Amantadine 11.300 kg 0082. The quantitative batch composition for amantadine Extended Release Beads extended release capsule is shown below. (Theoretical batch quantity 25,741 capsules). Step 5: Capsule Filling Gelatin Capsules, Size 00, are Filled Step 1: Prep of Amantadine HCl Beads (Bead Build-Up #1) with 339 mg of the Amantadine Beads Prepared in Step 4. 0083 Example 3

Extended Release Amantadine Formulation with Component Weight (kg) Immediate Release Carbidopa and Levodopa Amantadine 12.000 OPADRY (R) Clear YS-3-7011 O.200 0090 Levodopa and Carbidopa are formulated into pellets Purified Water, USP 5.454 Suitable for filling, yet having an immediate release profile. Sugar Sphere, NF 4.OOO (see, for example, U.S. Pat. No. 5,912,013). Total Weight Amantadine 16.200 kg Beads Levodopa plus Carbidopa Core Pellets 0084. The amantadine beads obtained from step 1 are used as follows. Weight Percent Kilograms MCC 2S.O O.25 Step 2: Clear & Sustained Release Bead Coating #1 Hydroxypropylmethylcellulose 1O.O O.10 Phthalate (HPMCP) 0085 Tartaric Acid 1O.O O.10 Sodium Monoglycerate 7.5 0.075 DSS O.S O.OOS Component Weight (kg) Levodopa 35.8 O.358 Carbidopa 11.2 O112 Amantadine Beads 8.OOO OPADRY (R) Clear YS-1-7006 O.360 TOTAL 100.0% 1.00 kg Purified Water, USP S.928 Coating Surelease (R) E-7-7050 O.672 Total Weight Clear Coated 9.032 kg Cellulose Acetate Phthalate 6O.O O.60 Sustained Release Beads (CAP) Ethylcellulose 2S.O O.25 PEG-400 1S.O O.15 I0086. The sustained release beads obtained from step 2 are used as follows. TOTAL 100.0% 1.00 kg Step 3: Amantadine HCl Beads (Build-Up #2) 0091. The pellets are assayed for levodopa and carbidopa content. It is determined that approximately 223 mg of the 0087 pellets contain 80 mg levodopa and 25 mg carbidopa. Disso lution greater than 90% in 30 minutes is also confirmed. Component Weight (kg) 0092. A total of 669 grams of the pellets are blended with 510 grams of the amantadine pellets from Example 2 in a Sustained Release Beads 8.OOO Amantadine 4.32O V-blender for 30 minutes at 30 rpm. Gelatin capsules are filled OPADRY (R) Clear YS-3-7011 O.O72 with 393 mg of the mixture and the assays for content are Purified Water, USP 1964 repeated verifying a composition of 100 mg amantadine, 80 mg levodopa, and 25 mg carbidopa. US 2015/O 1266 12 A1 May 7, 2015

Example 4 UPDRS and dyskinesia measurement was established. Amantadine was added to the regimen simultaneously with Predicted Dissolution and Plasma Profiles of the levodopa, and the amount raised from 1 mg/kg to 45 Amantadine Controlled Release mg/kg for four of the Squirrel monkeys, corresponding to an 0093. Using the formulations described above, the disso estimated 3 um concentration. As shown in FIG. 8, the com lution profiles for amantadine were simulated and used to bination led to a 60% reduction in dyskinesia. We hypothesize calculate plasma profiles resulting from single or multiple that this translates into a potential 40% reduction in levodopa administrations using the pharmacokinetic Software, Gas required to maintain UPDRS. troPlus V.4.0.2, from Simulations Plus (see FIG.2). The initial slope of the dissolution for the sustained release formulation Example 8 is less than the slope determined for the immediate release Levodopa Sparing Therapy formulation (see FIG. 1) and the corresponding serum profile also shows a slower dC/dT (see FIG. 4). 0097. The following protocol is employed to determine the optimal reduction of levodopa achieved with the addition Example 5 of Amantadine to a fixed dose combination product. 0.098 Parkinson's DISEASE PROTOCOL SUMMARY Release Profile of Amantadine and L-DOPA NPI (Levodopa/Carbidopa) 0099 MEMANTINE CRMONOTHERAPY 0094 Release proportions are shown in the tables below 0100 Protocol Number: NPI-Amantadine CR for a combination of amantadine and levodopa/carbidopa. 0101 Study Phase: 24 The cumulative fraction is the amount of drug Substance 0102 Name of Drug: NPI-Amantadine/C/L released from the formulation matrix to the serum or gut (0103 Dosage: 25/100/100 c/1/a given ti.d. environment (e.g., U.S. Pat. No. 4,839,177 or 5,326,570) or as 0104 25/80/100 c/1/a given ti.d. measured with a USP II Paddle system using 0.1N HCl as the 0105 25/60/100 c/1/a given ti.d. dissolution medium. 0106 Concurrent Control: 25/100 c/l given ti.d. 01.07 Route: Oral 0.108 Subject Population: Male and female patients diag AMANTADINE LEVODOPACARBIDOPAT/3 = T/2 = 15 hrs 1.5 hrs nosed with Parkinson's Disease Hoehn and Yahr score of Time cum. fraction A Cum. fraction B 2-4 0109 Structure: Parallel-group, three-arm study O O.OO O.OO O.S O.10 O.40 0110 Study Term Two weeks 0111 Study Sites: Multi-center 10 centers 2.0 O.35 1.00 (O112 Blinding: Double blind 4.0 O.60 1.00 8.O O.90 1.00 0113 Method of Subject Randomized to one of three 12.O O.98 1.00 treatment groups (3:1) 0114 Assignment: 0115 Total Sample Size: 320 subjects (160 men, 160 Example 6 women) 0116 Primary Efficacy UPDRS Treating Dyskinesia in Patients with Parkinson's 0117 Endpoints: Abnormal involuntary movement scale Disease (AIMS) 0-4 0095 A Parkinson's patient experiencing dyskinesia is 0118 Secondary Endpoints: Modified Obeso dyskinesia administered the composition of Example 3 three times each rating scale 0-4 day to receive 300 mg amantadine, 240 mg levodopa, and 75 0119 Mini-mental state examination (MMSE); Neu mg carbidopa daily. The Parkinsonism is reduced as mea ropsychiatric Inventory Score (NPI) sured by the UPDRS (Goetz et al., Mov. Disord. 19:1020-8, I0120 Adverse Events: Monitored and elicited by clinic 2004, incorporated by reference) as is the dyskinesia (Vitale personnel throughout the study, Volunteered by patients et al., Neurol. Sci. 22:105-6, 2001, incorporated by reference) Example 9 Example 7 Pharmaceutical Composition Including Memantine, Animal Models Showing Reduced Dyskinesia, Levodopa, and Carbidopa Reduced Levodopa Potential I0121 A co-formulation of memantine, levodopa and car 0096. The following protocol was employed to demon bidopa is prepared. This co-formulation matches the absorp strate the beneficial effects of the compositions of this inven tion properties of levodopa and carbidopa more closely than tion. Briefly, squirrel monkeys (N=4) were lesioned with those of Memantine, thereby extending the effectiveness per MPTP according to the protocol of Di Monte et al. (Mov. dose of levodopa and carbidopa. The co-formulation provides Disord. 15: 459-66 (2000)). After 3 months, the monkeys Tmax values to about 4 hours and allows b.i.d. dosing of the showed full symptoms of Parkinson's disease as measured by combination. a modified UPDRS (Goetz et al., Mov. Disord. 19:1020-8, 0.122 FIG. 6 provides the current single oral dose phar 2004). Levodopa treatment at approximately 15 mg/kg (with macokinetic (PK) profiles for levodopa, carbidopa and 1.5 mg/kg carbidopa) mg/kg b.i.d. commenced a baseline memantine. FIG. 7 provides idealized pharmacokinetic pro US 2015/O 1266 12 A1 May 7, 2015

files for the target co-formulation, in which the Tmax values spray-coating or the like. As will be appreciated by those for levodopa and carbidopa more closely match that of skilled in the art, the specific components listed in the above Memantine. tables may be replaced with other functionally equivalent components, e.g., diluents, binders, lubricants, fillers, coat Dosage Form: Tablet ings, and the like. I0128 Oral administration of the capsule to a patient will Formulation Content: Levodopa 150 mg result in a release profile having three pulses, with initial release of the memantine and levodopa from the first tablet (0123 Carbidopa 37.5 mg being Substantially immediate, release of the memantine and 0.124 Memantine 10 mg levodopa from the second tablet occurring 3-5 hours follow 0.125 Excipients: FDA approved excipients and drug ing administration, and release of the memantine and release modifiers. Additional embodiments are within levodopa from the third tablet occurring 7-9 hours following the claims. administration. Example 10 Example 11 Pharmaceutical Composition Including Extended Pharmaceutical Composition Including Extended Release Formulations of Memantine and Levodopa Release Formulations of Memantine, Levodopa, and 0126. A pulsatile release dosage form for administration Carbidopa of memantine and levodopa may be prepared as three indi I0129. The method of Example 9 is repeated, except that vidual compartments. Three individual tablets are com drug-containing beads are used in place of tablets. Carbidopa pressed, each having a different release profile, followed by is also added in each of the fractions at 25% of the mass of the encapsulation into a gelatin capsule, which are then closed levodopa. A first fraction of beads is prepared by coating an and sealed. The components of the three tablets areas follows. inert Support material Such as lactose with the drug which provides the first (immediate release) pulse. A second fraction of beads is prepared by coating immediate release beads with Component Function Amount per tablet an amount of enteric coating material Sufficient to provide a TABLET 1 (IMMEDIATE RELEASE): drug release-free period of 3-5 hours. A third fraction of beads is prepared by coating immediate release beads having half Memantine Active agent 8 mg Levodopa Active agent 70 mg the dose of the first fraction of beads with a Dicalcium phosphate dihydrate Diluent 26.6 mg greater amount of enteric coating material, Sufficient to pro Microcrystalline cellulose Diluent 26.6 mg vide a drug release-free period of 7-9 hours. The three groups Sodium starch glycolate Disintegrant 1.2 mg of beads may be encapsulated or compressed, in the presence Magnesium Stearate Lubricant 0.6 mg of a cushioning agent, into a single pulsatile release tablet. TABLET 2 (RELEASE DELAYED 3-5 HOURS FOLLOWING 0.130. Alternatively, three groups of drug particles may be ADMINISTRATION): provided and coated as above, in lieu of the drug-coated Memantine Active agent 8 mg lactose beads. Levodopa Active agent 70 mg Dicalcium phosphate dihydrate Diluent 26.6 mg Microcrystalline cellulose Diluent 26.6 mg Other Embodiments Sodium starch glycolate Disintegrant 1.2 mg Magnesium Stearate Lubricant 0.6 mg I0131 While the invention has been described in conjunc Eudragit RS3OD Delayed release 4.76 mg tion with the detailed description thereof, the foregoing coating material description is intended to illustrate and not limit the scope of Talc Coating component 3.3 mg Triethylcitrate Coating component 0.95 mg the invention, which is defined by the scope of the appended TABLET 3 (RELEASE DELAYED 7-9 HOURS FOLLOWING claims. Other aspects, advantages, and modifications are ADMINISTRATION): within the scope of the following claims. What is claimed is: Memantine Active agent 2.5 mg Levodopa Active agent 70 mg 1. A pharmaceutical composition Suitable for once daily Dicalcium phosphate dihydrate Diluent 26.6 mg oral administration to a human Subject consisting of Microcrystalline cellulose Diluent 26.6 mg (i) 50 to 500 mg of a drug selected from the group consist Sodium starch glycolate Disintegrant 1.2 mg ing of amantadine and pharmaceutically acceptable salts Magnesium Stearate Lubricant 0.6 mg Eudragit RS3OD Delayed release 6.34 mg thereof, and (ii) at least one excipient, coating material wherein at least 50% of the drug in the composition is in an Talc Coating component 4.4 mg extended release form, and Triethylcitrate Coating component 1.27 mg wherein the composition has an in vitro dissolution profile ranging between 35% and 55% in 2 hours, 60% and 80% in 4 0127. The tablets are prepared by wet granulation of the hours, and greater than 90% in 8 hours using a USP type 2 individual drug particles and other core components as may (paddle) dissolution system at 50 rpm at a temperature of be done using a fluid-bed granulator, or are prepared by direct 37-0.5° C. in water. compression of the admixture of components. Tablet 1 is an 2. A pharmaceutical composition Suitable for once daily immediate release dosage form, releasing the active agents oral administration to a human Subject consisting of within 1-2 hours following administration. Tablets 2 and 3 are (i) 50 to 500 mg of a drug selected from the group consist coated with the delayed release coating material as may be ing of amantadine and pharmaceutically acceptable salts carried out using conventional coating techniques such as thereof, and (ii) at least one excipient, US 2015/O 1266 12 A1 May 7, 2015

wherein at least 50% of the drug in the composition is in an 5. The composition of any one of claims 1 to 3, wherein the extended release form and the extended release form of the amount of drug is 100 to 500 mg. composition has an in vitro dissolution profile ranging 6. The composition of any one of claims 1 to 3, wherein the between 35% and 55% in 2 hours, 60% and 80% in 4 hours, and greater than 90% in 8 hours using a USP type 2 (paddle) amount of drug is 200 to 500 mg. dissolution system at 50 rpm at a temperature of 37+0.5°C. in 7. The composition of any one of claims 1 to 3, wherein at Water. least 75% of the drug in the composition is in an extended 3. A pharmaceutical composition Suitable for once daily release form. oral administration to a human Subject consisting of 8. The composition of any one of claims 1 to 3, wherein at (i) 50 to 500 mg of a drug selected from the group consist least 90% of the drug in the composition is in an extended ing of amantadine and pharmaceutically acceptable salts release form. thereof, and (ii) at least one excipient, 9. The composition of any one of claims 1 to 3, wherein the wherein at least 50% of the drug in the composition is in an composition provides a shift in amantadine Tmax of 2 hours extended release form and the extended release form of the to 16 hours relative to an immediate release form of amanta composition has an in vitro dissolution profile ranging dine, wherein the Tmax is measured in a single dose human between 60% and 80% in 4 hours, and greater than 90% in 8 pharmacokinetic study. hours using a USP type 2 (paddle) dissolution system at 50 10. The composition of any one of claims 1 to 3, wherein rpm at a temperature of 37+0.5°C. in water. the extent of drug bioavailability is maintained. 4. The composition of any one of claims 1 to 3, wherein the extended release form comprises an osmotic device, which 11. The composition of any one of claims 1 to 3, wherein at utilizes an osmotic driving force to provide extended release least Some of the drug is in an immediate release form. of amantadine. k k k k k