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(12) Patent Application Publication (10) Pub. No.: US 2013/0253056A1 Nemas Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2013/0253056A1 Nemas Et Al US 20130253 056A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0253056A1 Nemas et al. (43) Pub. Date: Sep. 26, 2013 (54) CONTINUOUS ADMINISTRATION OF (60) Provisional application No. 61/179,511, filed on May LEVODOPA AND/OR DOPA 19, 2009. DECARBOXYLASE INHIBITORS AND COMPOSITIONS FOR SAME Publication Classification (71) Applicant: NEURODERM, LTD., Ness-Ziona (IL) (51) Int. Cl. A63L/216 (2006.01) (72) Inventors: Mara Nemas, Gedera (IL); Oron (52) U.S. Cl. Yacoby-Zeevi, Moshav Bitsaron (IL) CPC .................................... A6 IK3I/216 (2013.01) USPC .......................................................... 514/538 (73) Assignee: Neuroderm, Ltd., Ness-Ziona (IL) (57) ABSTRACT (21) Appl. No.: 13/796,232 Disclosed herein are for example, liquid aqueous composi (22) Filed: Mar 12, 2013 tions that include for example an ester or salt of levodopa, or an ester or salt of carbidopa, and methods for treating neuro Related U.S. Application Data logical or movement diseases or disorders such as restless leg (63) Continuation-in-part of application No. 12/961,534, syndrome, Parkinson's disease, secondary parkinsonism, filed on Dec. 7, 2010, which is a continuation of appli Huntington's disease, Parkinson's like syndrome, PSP. MSA, cation No. 12/836,130, filed on Jul. 14, 2010, now Pat. ALS, Shy-Drager syndrome, dystonia, and conditions result No. 7,863.336, which is a continuation of application ing from brain injury including carbon monoxide or manga No. 12/781,357, filed on May 17, 2010, now Pat. No. nese intoxication, using Substantially continuous administra 8,193,243. tion of levodopa and/or carbidopa or ester and/or salt thereof. Patent Application Publication Sep. 26, 2013 Sheet 1 of 27 US 2013/025.305.6 A1 FIGURE A : s . wakkakawaxes:: -..."-...-kx.a.s...akewow... & •rs". ; : 3: 3:3: Patent Application Publication Sep. 26, 2013 Sheet 2 of 27 US 2013/025.305.6 A1 FIGURE B s s s Ex 8 : :: ------ : ; : ; 3. 2: 3: ;3:2 Patent Application Publication Sep. 26, 2013 Sheet 3 of 27 US 2013/025.305.6 A1 FIGURE IC ***************…---.-.-.-.-.-.-.-.-.-.-.-.-.-.-.- 3:2 Patent Application Publication Sep. 26, 2013 Sheet 4 of 27 US 2013/025.305.6 A1 FIGURE 2A 04 s x: ---. a------------------ r ass-raa &------ : 8-8 ser-k-k-cro ------- : *:::: S: 3. ai: i: Patent Application Publication Sep. 26, 2013 Sheet 5 of 27 US 2013/025.305.6 A1 Fig. 2B _-_-_-_--_-_>_~~~~~~~~~~~~~)****&&&&&&&\************************ ress'. ass-------axx-xx-----------as-a-Swiss... as YYYYYYY 50" sa-- 1 OO 200 250 rifz Patent Application Publication Sep. 26, 2013 Sheet 6 of 27 US 2013/025.305.6 A1 FIGURE 2C s (8. 83 s s sessesses:*8.Tis" M-8-8 is -----------8 ''''''''''''''''''''''''--------------ee8, 2. Patent Application Publication Sep. 26, 2013 Sheet 7 of 27 US 2013/025.305.6 A1 FIGURE 3 Patent Application Publication Sep. 26, 2013 Sheet 8 of 27 US 2013/025.305.6 A1 FIGURE 4A xx'eice ww. Tire Post Ora Dosing (h) : s S. 8: 125 Time Pest Oral Dosingh Patent Application Publication Sep. 26, 2013 Sheet 9 of 27 US 2013/025.305.6 A1 Figure 4B xyacie xx : : Tire Post Oral Dosing xx, eities xxx 3 : S. 8 8 Tire Post Ora Dosingh Patent Application Publication Sep. 26, 2013 Sheet 10 of 27 US 2013/0253056A1 FIGURES 3: r x &isie Patent Application Publication Sep. 26, 2013 Sheet 11 of 27 US 2013/0253056A1 FIGURE 6 s 3 & 8 3: Tirreh :::::: 3. 3: a 2500 2000 getS(0. i: Patent Application Publication Sep. 26, 2013 Sheet 12 of 27 US 2013/025.305.6 A1 L(HRHÍAÐI,H. (uifsud eissed Patent Application Publication Sep. 26, 2013 Sheet 13 of 27 US 2013/0253056A1 FIGURE 8 A. 3CO 3: i ROCO 3CO : Oasissing of RCD xxx x2%, 2.88:it:30388he 3: 3: s 383 { 3:33 38: Patent Application Publication Sep. 26, 2013 Sheet 14 of 27 US 2013/025.305.6 A1 FIGURE 9 - - 8.33 :::::::::::::::::: Patent Application Publication Sep. 26, 2013 Sheet 15 of 27 US 2013/0253056A1 FIGURE 10 A. Sh: s: x 33 C3 C3ted E 4000 WXx: Sigiri: As 35i. s 3 E3 *x-SCs incs cated CE 2000130 3 ICC 5:30 O 3. & s S. Tire x is CES Coatec A. x Site::get ~x.33 CES for Coated C Patent Application Publication Sep. 26, 2013 Sheet 16 of 27 US 2013/0253056A1 FIGURE x *iegative consist -x-CI 20{ppris « COE 2.00pm Time min} Patent Application Publication Sep. 26, 2013 Sheet 17 of 27 US 2013/0253056A1 FIGURE 2 x::::: x CE) ().56try x8e:Sera:::.68: Evi {} 33 33 : 33 Eirik of iculation in 8. x-gi's g w&x , ssfy * * ** *:xi : E 3.88 ful * ... } a^ & * * * : S.: x .. * 8. -------:-----------------8& ----------------------------: : 3: 3; at 5: 88) 20: fire of incubation in Patent Application Publication Sep. 26, 2013 Sheet 18 of 27 US 2013/0253056A1 FIGURE 13 --Dopa in Plasma Following Spiking of D Compounds in to Blood O DipE LOpE OgE Patent Application Publication Sep. 26, 2013 Sheet 19 of 27 US 2013/0253056A1 FIGURE 14 Blood and Plasma levels of i-Dopa Following intradermal infusion of D Benzyl Ester 60 mgfh ..} :- Blood and Pasna levels of -opa Following tradermai infusion of D isopropyi Ester 60 figfh) 15,000 2,000 : ^ 888 x is 9,000 *x. 6,630 Patent Application Publication Sep. 26, 2013 Sheet 20 of 27 US 2013/0253056A1 FIGURE 14 (cont.) : 0 1 2 3 4 5 6 8 9 xx E is as a "8-PE is Bird Tine (): - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - Patent Application Publication Sep. 26, 2013 Sheet 21 of 27 US 2013/0253056A1 FIGURE 15 it piastia eweis citating atti faiigwig Waitainistration of it is propy Esteriipt 80 gif 3438 : 3.288 3. -- Steg ::fisia: 1888 808 68 {{: fire si: it piasia ieweis Eigg a ficitywig Wadinistration of it propyi esteriipf 60 gif 3:38 : 3.338 : Stop it:3sixt: 388 1. 88 800 388: fire trix} Patent Application Publication Sep. 26, 2013 Sheet 22 of 27 US 2013/025.305.6 A1 | gaexxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxºg 100000Z Patent Application Publication Sep. 26, 2013 Sheet 23 of 27 US 2013/0253056A1 FIGURE 7 Piasa D. Following Continuous Subcutaneous Administration of LD Benzyl Ester - HC 88: 388 28; SE : Patent Application Publication Sep. 26, 2013 Sheet 24 of 27 US 2013/0253056A1 FIGURE 8 LD in Plasma Following Continuous Subcutaneous Administration of 300 mg LDE With or W/O 60mg CDE 88: 83 a 38 3. 883 88: 388: 88: E. x&8E (3 x: EiES x8:f3 Pump Removal Patent Application Publication Sep. 26, 2013 Sheet 25 of 27 US 2013/025.305.6 A1 FIGURE 9 Effect of pH and storage temperature or the Statiity of itipi. sexes . 3. 3.3 8: Effect of pH and Temperature on hydrolys is of ige Eg is aga Mx...tops. T ············································································---······2^················································································· 8.83 3.3 2. 83 3. 383 .83 8.8 Patent Application Publication Sep. 26, 2013 Sheet 26 of 27 US 2013/0253056A1 S. S. S. n. t (s (5 sersgy. X SE S. CR S. C. St. {N: * - toS C3 C2 (NE C. SC c. .5 &S Kf st < s { (S N CD N. ill SC CC S. (5. c a. w na. c s cy s &S Oc Patent Application Publication Sep. 26, 2013 Sheet 27 of 27 US 2013/025.305.6 A1 US 2013/025.305.6 A1 Sep. 26, 2013 CONTINUOUS ADMINISTRATION OF of enzymes associated with the metabolic degradation of LEVODOPA AND/OR DOPA levodopa are well known, for example, decarboxylase inhibi DECARBOXYLASE INHIBITORS AND tors such as carbidopa and benserazide, catechol-O-methyl COMPOSITIONS FOR SAME transferase (COMT) inhibitors such as entacapone and tolca pone, and monoamine oxidase (MAO)-A or MAO-B inhibi RELATED APPLICATIONS tors such as moclobemide, rasagiline or selegiline or Safina mide. Currently available oral drugs include SINEMETR) and 0001. This application is a continuation-in-part of U.S. SINEMETR) CR Sustained-release tablets that include carbi Ser. No. 12/961534, filed Dec. 7, 2010, which is continuation dopa or levodopa; STALEVOR tablets containing carbidopa, of U.S. Ser. No. 12/836,130 filed Jul. 14, 2010, which is a entacapone and levodopa; and MADOPAR(R) tablets contain continuation of 12/781,357, filed May 17, 2010, which in turn ing levodopa and benserazide. There is an on-going and claims priority to U.S. Ser. No. 61/179,511, filed May 19, urgent need for methods and compositions that can effect 2009, each of which is hereby incorporated by reference in its continuous stimulation of L-dopa to more effectively treat entirety. movement disorders such as Parkinson's disease. 0005 Carbidopa (-)-L-O-hydrazino-C.-methyl-3-(3,4- BACKGROUND dihydroxybenzene)propanoic acid monohydrate, a white, 0002 Parkinson's disease is a degenerative condition crystalline compound, only slightly soluble in water, is a dopa characterized by reduced concentration of the neurotransmit decarboxylase inhibitor commonly administered with ter dopamine in the brain. Levodopa (L-dopa or L-3,4-dihy levodopa. Only 40-70% of an oral dose of carbidopa is droxyphenylalanine) is an immediate metabolic precursor of absorbed in man, monkey and dog. Although carbidopa has dopamine that, unlike dopamine, is able to cross the blood been orally administered with levodopa for over 30 years, no brain barrier, and is most commonly used for restoring the stable liquid formulation having e.g., an effective concentra dopamine concentration in the brain. For the past 40 years, tion in a volume Suitable for use for Subcutaneous or trans levodopa has remained the most effective therapy for the dermal delivery has ever been achieved.
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