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(12) Patent Application Publication (10) Pub. No.: US 2015/0126612 A1 Went Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2015/0126612 A1 Went Et Al 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., Emeryville, 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 amantadine, 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 FIGURE 5 27/1 || V | T - -0 - Namenda -HNP-6990 (AAAF |A || IAI -A-NP-6804 5 O I / f -b - NP8990-1 Y AT A/ -X - NP-6804-1 Y | | | | | | - 12hrstraight 7 //al A. A-4, 41. O 2 4 6 8 10 12 14 16 18 20 Time (hr) Patent Application Publication May 7, 2015 Sheet 6 of 7 US 2015/O1266.12 A1 Figure 6: Memantine, 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 is s an 2,D Š O S C r r o i. cy co N o w O cro a seen OO 2 No Data to its co CD - - N is s Cen E a st RNo. as 2 O F wg NE sis c w NE scoas C 2s :HN PC se5 CD 5 N E--N log cyce e. : E Na Totalled HAMS Score US 2015/O 1266 12 A1 May 7, 2015 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 receptor 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), rimantadine (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.
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