(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`25 November 2010 (25.11.2010) (10) International Publication Number
`
`(43) International Publication Date
`
`WO 2010/134074 A1
`
`
`(51)
`
`International Patent Classification:
`A61K 9/08 (2006.01)
`A61K 31/198 (2006.01)
`A61K 9/10 (2006.01)
`A61P 25/16 (2006.01)
`
`(81)
`
`(21)
`
`International Application Number:
`
`PCT/1L20 10/000400
`
`(22)
`
`1nternational Filing Date:
`
`(25)
`
`(26)
`
`(30)
`
`(71)
`
`(72)
`(75)
`
`Filing Language:
`
`Publication Language:
`
`17 May 2010 (17.05.2010)
`
`English
`
`English
`
`Priority Data:
`61/179,511
`
`19 May 2009 (19.05.2009)
`
`US
`
`Applicant (fljr all designated States except US): NEU-
`RODERM LTD [IL/IL]; 3 Golda Meir Street, Weizmann
`Science Park, 74036 Ness Ziona (IL)
`Inventors; and
`Inventors/Applicants for US only): YACOBY-ZEEVI,
`Oron [IL/IL]; 204 Hanarkissim Street, 60946 Bitsaron
`(IL). NEMAS, Mara [IL/IL]; 17/4 Ha'atsmaut Street,
`70700 Gedera (IL).
`
`(74)
`
`Agent: BEN-AMI & ASSOCIATES; P.O.Box 94,
`76100 Rehovot (IL).
`
`Designated States (unless otherwise indicated, for evety
`kind ofnational protection available): AE, AG, AL, AM,
`A0, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ,
`CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO,
`DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT,
`HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP,
`KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD,
`ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI,
`NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD,
`SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR,
`TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
`
`(84)
`
`Designated States (unless otherwise indicated, for every
`kind ofregional protection available): ARIPO (BW, GH,
`GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG,
`ZM, ZVV), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ,
`TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK,
`EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, tr, LT, LU,
`LV, MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK,
`SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ,
`GW, ML, MR, NE, SN, TD, TG).
`Published:
`
`with international search report (Art. 21(3))
`
`(54) Title: COMPOSITIONS FOR CONTINUOUS ADMINISTRATION OF DOPA DECARBOXYLASE INHIBITORS
`
`(57) Abstract: Disclosed herein are arginine salts of carbidopa and leVOdopa and compositions that include for example the argi-
`nine salt of carbidopa suitable for continuous administration for treating neurological or movement diseases or disorders such as
`restless leg syndrome, Parkinson's disease, secondary parkinsonism, Huntington's disease, Parkinson's—like syndrome, PSP, MSA,
`ALS, Shy-Drager syndrome and conditions resulting from brain injury including carbon monoxide or manganese intoxication, to-
`gether with administration of levodopa
`
`
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`W02010/134074A11||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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`WO 2010/134074
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`PCT/IL2010/000400
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`COMPOSITIONS FOR CONTINUOUS ADMINISTRATION OF DOPA
`
`DECARBOXYLASE INHIBITORS
`
`RELATED APPLICATION
`
`This application claims priority to U.S.S.N. 61/179,511, filed May 19, 2009, which
`
`is hereby incorporated by reference in its entirety.
`
`10
`
`FIELD OF THE INVENTION
`
`The present invention relates to compounds and formulations useful in methods for
`
`treating diseases and disorders in which the dopamine level in the brain is reduced, e.g.,
`
`Parkinson's disease. In particular, the invention relates to arginine salts of carbidopa and
`
`levodopa and compositions comprising them.
`
`15
`
`20
`
`25
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`30
`
`BACKGROUND OF THE INVENTION
`
`Parkinson‘s disease
`
`is
`
`a degenerative
`
`condition characterized by reduced
`
`concentration of the neurotransmitter dopamine in the brain. Levodopa (L—dopa or L—3,4—
`
`dihydroxyphenylalanine) is an immediate metabolic precursor of dopamine that, unlike
`
`dopamine, is able to cross the blood—brain barrier, and is most commonly used for restoring
`
`the dopamine concentration in the brain. For the past 40 years, levodopa has remained the
`
`most effective therapy for the treatment of Parkinson’s disease.
`
`However, levodopa has a short half life in plasma that, even under best common
`
`cuireiit standard of care, results in pulsatile dopaminergic stimulation. Long—term therapy
`
`is therefore complicated by motor fluctuations and dyskinesia that can represent a source of
`
`significant disability for some patients. A therapeutic strategy that could ultimately deliver
`levodopa/dopamine to the brain in a more continuous and physiologic manner would
`
`provide the benefits of standard levodopa with reduced motor complications and is much
`
`needed by patients suffering from Parkinson’s disease and other neurological or movement
`
`disorders (Olanow CW; Mov. Dis. 2008, 23(Suppl. 3):S613—S622). Sustained—release oral
`
`levodopa formulations have been developed, but, at best, such preparations have been
`
`found to be no more efficacious than standard tablets. Continuous administration of
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`WO 2010/134074
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`PCT/IL2010/000400
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`levodopa by intraduodenal administration or infusion has also been attempted by using
`
`ambulatory pumps or patches. Such treatments, especially intraduodenal, are extremely
`
`invasive and inconvenient. Further, such treatments may be associated with dopaminergic
`
`adverse events; continuous administration of levodopa or dopa agonists is still associated
`
`with off periods that are self-limiting despite continued delivery of the drug. Nutt JG;
`
`Mov. Dis. 2008, 23(Suppl. 3):SS80—4.
`
`The metabolic transformation of levodopa to dopamine is catalyzed by the aromatic
`
`acid decarboxylase enzyme,
`L—amino
`concentrations in the intestinal mucosa,
`
`a ubiquitous enzyme with particularly high
`liver, brain and brain capillaries. Due to the
`
`10
`
`possibility of extracerebral metabolism of levodopa, it is necessary to administer large
`
`doses of levodopa leading to high extracerebral concentrations of dOpamine that cause
`
`nausea in some patients. Therefore, levodopa is usually administered concurrently with
`
`oral administration of a dopa decarboxylase inhibitor, such as carbidopa or benserazide,
`
`which reduces by 60-80% the levodopa dose required for a clinical response, and thus
`
`15
`
`prevents certain of its side effects by inhibiting the conversion of levodopa to dopamine
`outside the brain. Exactly how this dose reduction is accomplished is uncertain. Various
`
`formulations comprising levodopa alone or together with inhibitors of enzymes associated
`
`with the metabolic degradation of levodopa are well known, for example, decarboxylase
`
`inhibitors such as carbidopa and benserazide, catechol—O—methyl
`
`transferase (COMT)
`
`20
`
`inhibitors such as entacapone and tolcapone, and monoarnone oxidase (MAO)—A or MAO—
`
`B inhibitors such as moclobemide,
`
`rasagiline or selegiline or safinamide. Currently
`
`available oral drugs include SINEMET® and SINEMET®CR sustained—release tablets that
`
`include carbidopa or levodopa; STALEVO® tablets containing carbidopa, entacapone and
`
`25
`
`levodopa; and MADOPAR® tablets containing levodopa and benserazide. There is an on—
`going and urgent need for methods and compositions that can effect continuous stimulation
`of L—dopa to more effectively treat movement disorders such as Parkinson’s disease.
`
`Carbidopa [(—)-L—oz-hydrazino—oz—methyl—B—(3,4—dihydroxybenzene) propanoic acid
`
`monohydrate], a white, crystalline compound, only slightly soluble in water,
`
`is a dopa
`
`decarboxylase inhibitor commonly administered with levodopa. Only 40—70% of an oral
`
`30
`
`dose of carbidopa is absorbed in man, monkey and dog. Although carbidopa has been
`
`orally administered with levodopa for over 30 years, no stable liquid formulation having
`
`e. g., an effective concentration in a volume suitable for use for subcutaneous or
`
`transdermal delivery has ever been achieved. There is an urgent, long standing need for
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`such carpidopa formulations that can be administered more easily to patients, especially as
`
`compared to current invasive modes such as duodenal administration.
`
`SUMMARY OF THE INVENTION
`
`It has now been found in accordance with the present invention that an arginine salt
`
`of carbidopa can form a stable,
`
`liquid formulation,
`
`suitable for e.g., continuous
`
`subcutaneous, transdennal, intradermal, intravenous and/or intraduodenal administration,
`
`at a physiologically acceptable pH.
`
`Such disclosed compositions are capable of
`
`substantially continuously administering carbidopa to a patient.
`
`10
`
`It has been further found that substantially continuously administering a dopa
`
`decarboxylase inhibitor
`
`such as carbidopa,
`
`together with discrete (e.g. oral)
`
`co-
`
`administration of levodopa, may stimulate L—dopa substantially continuously and thus e.g.,
`
`extend the effectiveness of a levodopa oral dosing regimen and/or reduce the daily dosage
`
`of levodopa, While effectively treating a movement and/or neurological disorder such as
`
`15
`
`Parkinson’s disease.
`
`The present invention relates, in one aspect, to an arginine salt of an active agent
`
`selected from carbidopa and levodopa that are suitable for e. g., continuous subcutaneous,
`
`trandermal, intradermal, intravenous, oral, or intraduodenal administration.
`
`Also contemplated herein are pharmaceutically acceptable liquid (e.g.,
`
`liquid at
`
`20
`
`room temperature) or gel formulations or compositions that include an arginine salt of
`
`carbidopa, e. g.,
`
`include carbidopa and arginine, that may be suitable for substantially
`
`continuous administration to a patient e. g. with or without use of,
`
`for example, a
`
`transdermal patch or subcutaneous pump (e.g. an insulin—like pump). Such contemplated
`
`liquid compositions may include at least 1%, at least 4%, at least 6% or more by weight
`
`25
`
`carbidopa, (e. g. about 2% to about 6% by weight carbidopa) and therefore may facilitate
`
`administration of smaller amounts of a pharmacologically acceptable formulation to
`
`achieve efficacy as compared to a carbidopa formulation that is only capable of having less
`
`than 1% by weight carbidopa.
`
`In another embodiment, contemplated herein is a liquid or
`
`gel composition that includes a molar ratio of about 1.0205 to about 1: to about 2.5, e.g., l:
`
`30
`
`1.0—1.2 molar ratio of carbidopazbasic amino acid, e.g. carbidopa2arginine. A liquid
`
`composition that includes carbidopa and arginine, as contemplated herein, may have a
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`WO 2010/134074
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`PCT/IL2010/000400
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`physiologically acceptable pH, e.g. a pH of about 6.5 to 9.5, e.g., about 7 to about 9, or
`
`about 8 to about 9, at 25 °C.
`
`In yet another embodiment, contemplated herein is a phannaceutically acceptable
`
`liquid or gel composition that includes a molar ratio of about l.0:0.5 to about 1:2, e.g.,
`
`about 1:18 molar ratio of levodopazarginine. For example, provided herein is a liquid
`
`composition that may include at least about 4% by weight, or at least 5%, at least about 6%
`
`(eg. about 3% to about 7%) or more by weight levodopa. A liquid composition having
`
`levodOpa and a basic amino acid, as contemplated herein, may have a pH of about 8 to 10,
`
`e.g., about 8.5 to about 9.5, at 25°C.
`
`10
`
`Exemplary liquid compositions contemplated herein may be liquid solutions, e. g.
`
`may be a substantially homo genous mixture that includes carbidopa and arginine, and may
`
`include water, or alternatively may be substantially non-aqueous.
`
`In other embodiments,
`
`contemplated compositions may also include one or more phannaceutically acceptable
`
`excipients such as N—methylpyrrolidone (NMP), polyvinylpyrrolidone (PVP), propylene
`
`15
`
`glycol, antioxidants, or combinations thereof.
`
`In some embodiments, the pharmaceutically acceptable liquid composition of the
`
`invention may comprise additional active agents such as entacapone or tolcapone.
`
`Also provided herein is a kit comprising: a) a first composition suitable for
`
`continuous administration comprising the liquid or gel formulation of the invention
`
`20
`
`comprising an arginine salt of carbidopa; b) a second composition suitable for oral
`
`administration comprising levodopa or a pharmaceutically acceptable salt or ester thereof;
`
`and c) optionally instructions administration of the first formulation in conjunction with the
`
`second formulation.
`
`The first composition in the kit for continuous administration of the arginine salt of
`
`25
`
`carbidopa may be formulated for transdermal, intradermal, subcutaneous, intravenous, or
`
`intraduodenal administration such as by using an infusion pump.
`
`The second composition in the kit, i.e., the levodopa composition may comprise
`
`levodopa, a pharmaceutically acceptable salt of levodopa., preferably an arginine salt
`
`thereof as disclosed herein, or may be a composition that includes levodopa and further
`
`30
`
`comprises one or more decarboxylase inhibitors such as carbidopa and/or benserazide, or
`
`one or more catechol-O—methyl transferase (COMT) inhibitors such as entacapone and/or
`
`tolcapone, or one or more MAO—A or MOA—B inhibitors such as selegiline and/or
`
`rasagiline, or combination thereof.
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`PCT/IL2010/000400
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`Also provided herein is a method for
`
`treatment of a disease or disorder
`
`characterized by reduced levels of dopamine in a patient's brain (6. g. Parkinson’s disease),
`
`comprising substantially continuously administering to a patient
`
`in need thereof a
`
`therapeutically effective amount of a decarboxylase inhibitor, a salt
`
`thereof, e.g., an
`
`arginine salt of carbidopa, or an ester thereof, and administering a therapeutically effective
`
`amount of levodopa or phannaceutically acceptable salt thereof (e. g, arginine levodopa),
`
`or composition comprising levodopa (for example, administering a composition e.g. a
`
`tablet, having levodopa as its sole active agent, or a composition that includes levodopa
`
`and one or more other active agents such as carbidopa, benserazide, entacapone, tolcapone,
`
`10
`
`selegiline and/or rasagiline
`
`In one embodiment, a method of treating or ameliorating a neurological or
`
`movement disorder in a patient in need thereof is provided comprising: administering a
`
`therapeutically effective amount of a composition comprising a carbidopa basic amino acid
`
`salt (e.g., carbidopa arginine) and administering a therapeutically effective amount of a
`
`15
`
`composition comprising levodopa. For example, a composition comprising carbidopa and
`
`arginine may be administered substantially continuously and/or
`
`the composition
`
`comprising levodopa may be administered at discrete intervals (for example by oral
`
`administration one, two, three or more times a day), during the substantially continuous
`
`administration of composition comprising a carbidopa arginine salt.
`
`20
`
`Also provided herein is
`
`a method of substantially continuously inhibiting
`
`decarbcxylase activity and/or a method of increasing the half—life of levodopa in a patient
`
`receiving levodopa, comprising administering (e. g. substantially continuously) to the
`
`patient a liquid or gel composition comprising a carbidopa salt such as carbidopa arginine.
`
`For example, the disclosed methods may result in a half—life of levodopa in the plasma of a
`
`25
`
`patient that is at least 1.5, or at least two times, longer after continuous administration of
`
`carbidopa as compared to the half life of levodopa in a patient’s serum after administering
`
`levodopa with discrete, oral administration of carbidopa.
`
`BRIEF DESCRIPTION OF THE FIGURES
`
`30
`
`FigslA—lC depict the mass spectra of carbidopa (CD) arginine salt.
`
`Figs. 2A—2C depict the mass spectra of levodopa (LD) arginine salt.
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`WO 2010/134074
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`PCT/IL2010/000400
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`Figs. 3A—3C show the mean levels of carbidopa determined in plasma of female
`
`Landrace ><
`
`large white swine (30—35kg) following oral administration of (3A) Stalevo
`
`(100/25/200 mg, LD/CD/E), (3B) Dopicar+Lodosyn (125/25 mg LD/CD), (3C) Sinemet
`
`CR (100/25 mg, LD/CD) C18 and 12h, with (squares) or without (diamonds) continuous
`
`subcutaneous administration of 3% carbidopa solution.
`
`Figs. 4A—4B show brain levels of L—Dopa and dopamine (4A, left and right panels,
`
`respectively), and plasma levels of carbidopa and L-Dopa (4B,
`
`left and right panels,
`
`respectively),
`
`determined
`
`in
`
`CD—1 mice
`
`following
`
`oral
`
`administration
`
`of
`
`levodopa/carbidopa with or without continuous subcutaneous administration of carbidopa.
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`10
`
`Figs. 5A—5B depict mean levels of L—Dopa (5A) and carbidopa (5B) determined in
`
`plasma of female Landrace ><
`
`large white swine (30—35kg)
`
`following continuous
`
`subcutaneous administration of O, 2 and 4% carbidopa with oral administration of
`
`Sinemet® (100/25 mg) q8h.
`
`Figs. 6A—6B depict mean levels of L—Dopa determined in plasma of two female
`
`15
`
`Landrace ><
`
`large white swine (30—35kg) (6A,Pig #3; 6B, Pig #4) following continuous
`
`subcutaneous administration of 2 and 4% carbidopa with oral administration of Dopicar®
`
`(125/125 mg LD/CD) + Lodosyn® (12.5 mg CD) q12h..
`
`Fig. 7 shows the mean (i-SD) LD (levodopa) concentrations (ng/ml) as determined
`
`in plasma of female Landrace >< large white swine (30—35kg) following oral administration
`
`20
`
`of Stalevo (LD/CD/E 100/25/200), q8h, with or without continuous subcutaneous
`
`benserazide or carbidopa administration (60 mg /day).
`
`Figs. 8A—8B depict plasma levels of (8A) L—dopa and (8B) 3—O—methyldopa (3—
`
`OMD) as determined in plasma of female Landrace ><
`
`large white swine (30—35kg)
`
`following continuous subcutaneous administration of 2% carbidopa, with or Without 2.5%
`
`25
`
`entacapone, and oral administration of L—dop a/Carbidopa (LD/CD).
`
`Fig. 9 shows the results of transdermal delivery of carbidopa propyl ester (CDPE).
`
`Figs. 10A—1OB depict plasma levels of (10A) levodopa and (10B) carbidopa as
`
`determined in plasma of female Landrace ><
`
`large White swine (30—35kg) following oral
`
`administration of enteric coated or uncoated LD and CD as arginine salts (designated LDs
`
`30
`
`and CDs, respectively, 100/25 mg LD/CD) as compared to Sinemet (100/25 mg LD/CD).
`
`Fig.
`
`11 depicts the inhibition of L—Dopa decarboxylation by carbidopa and
`
`carbidopa propyl ester (CDPE).
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`Figs. 12A—12B depict the inhibition of L-dopa decarboxylation (12A) and the
`
`metabolism of L-dopa to dopamine (12B) by carbidopa and carbidopa propyl ester in liver
`
`extract.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`Disclosed herein is a liquid composition having a physiologically acceptable pH
`
`that includes an arginine salt of carbidopa (e.g., arginine and carbidopa) that is stable at
`
`room temperature, which can facilitate continuous delivery of an effective amount
`
`carbidopa to a patient in a minimally invasive fashion (e. g. a disclosed liquid formulation
`
`10
`
`comprises a significantly high concentration of carbidopa so that administration of large
`
`amounts of liquid are not required)
`
`Such formulations may facilitate continuous
`
`decarboxylase inhibition which prolongs the half life of levodopa. For example, results
`
`from in vivo studies, as described below, in which L—dopa was administered continuously
`
`in parallel with oral administration of carbidopa every 6—8 hours demonstrate a pulsatile
`
`15
`
`pattern of L—dopa plasma levels that coincide with carbidopa oral dosing regimen, but
`
`concomitant and/or frequently repeated, e.g., simultaneous dosing of dopa decarboxylase
`
`inhibitor (e.g. of carbidopa or a salt thereof, or benserazide) with or without COMT
`
`inhibitors with discrete or continuous administration of levodopa is more effective in the
`
`treatment of e.g., Parkinson's disease.
`
`Further,
`
`it has been discovered that
`
`the
`
`20
`
`pharmacokinetic profile of, for example, carbidopa (with or without entacapone) supports
`
`such new therapies
`
`that
`
`include substantially continuous administration of dopa
`
`decarboxylase inhibitors (6. g. benserazide or carbidopa or a salt thereof) with or without
`
`COMT inhibitors together with administration (continuous or at discrete intervals) of e. g.
`
`levodopa or a salt thereof.
`
`25
`
`Provided herein are formulations of carbidopa that unexpectedly allow for stable
`
`dissolution of higher concentrations (e.g., greater than 1% by weight) of carbidopa and/or
`
`levodopa at
`
`e. g. physiologically acceptable pH,
`
`for e.g.,
`
`substantially continuous
`
`subcutaneous or transdermal administration. Such formulations may also be suitable for
`
`intravenous,
`
`intradermal, oral or intraduodenal administration. For example, provided
`
`30
`
`herein are formulations and methods capable of obtaining substantially constant inhibition
`
`of dopa decarboxylase activity upon administration, thereby increasing the half life of
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`WO 2010/134074
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`administered levodopa and substantially reducing the pulsatility of levodopa plasma levels
`
`to avoid low trough levels of plasma levodopa.
`
`A treatment strategy of continuous carbidopa administration in accordance with the
`
`present invention may simulate L—dopa substantially continuously. For example, therapies
`
`and/or methods of the present invention may extend a levodopa oral dosing regimen to
`
`about 2 to about 3 times/day, and/or reduce daily dose of levodopa, and/0r reduce or even
`
`eliminate the risk of motor complications associated with standard oral
`
`levodopa
`
`formulations in Parkinson's patients.
`
`Provided herein, in an embodiment, is a phannaceutically acceptable formulation
`
`that
`
`includes
`
`a carbidopa arginine salt
`
`that allows
`
`for
`
`substantially continuous
`
`administration of carbidopa.
`
`For example, while carbidopa free base is practically
`
`insoluble in alcohol, chloroform or ether and only slightly soluble in water, provided
`
`herein, for example,
`
`is a stable liquid formulation that includes carbidopa and may be
`
`suitable for substantially continuous administration to a patient. Further, such formulations
`
`may have a physiologically acceptable pH.
`
`In one aspect, the present invention relates to a carbidopa arginine salt.
`
`The disclosure also provides, in an embodiment, a liquid formulation comprising a
`
`carbidopa salt of the invention. For example, a disclosed carbidopa arginine salt may be
`
`dissolved in an aqueous solution, e. g., having a pH of about 6 to 9.5, preferably from about
`
`7 to about 9, more preferably from about 8 to 9 at 25°C or at 30°C. Alternatively,
`
`carbidopa (free base) and arginine are dissolved together in a liquid (eg. an aqueous
`liquid) to form a disclosed liquid formulation. Disclosed liquid formulations may include
`
`about 1.0% by weight or more carbidopa or carbidopa arginine salt, for example, may
`
`include about 1% to about 20% by weight or more carbidopa, e. g., about 2% to about 10%
`
`by weight carbidopa. For example, a liquid formulation may include carbidopa and
`
`arginine in molar ratio of about 1: 0.5 to about 122.5, or about 1:1 to about a 1:12, e.g.,
`
`about 1:1 or 1:1.1.
`
`Disclosed liquid formulations (e. g. a liquid composition comprising carbidopa and
`
`arginine or an arginine salt of carbidopa) may be stable for 24 hours, for 48 hours, for 7
`
`days, or more at 25°C. For example, an exemplary liquid formulation may include a 121.1
`
`molar ratio of carbidopazarginine, with about 2% to about 15%, or about 2% to about 10%,
`
`or 2% to about 6% by weight carbidopa. Such a carbidopa:arginine liquid formulation may
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`be more stable at 7 days as compared to a liquid composition that includes a lysine or
`
`histidine salt of carbidopa.
`
`In some embodiments, disclosed liquid fonnulations 0r compositions are liquid
`
`solutions, i.e. are substantially homo genous liquid mixtures. Such liquid mixtures may
`
`comprise water and/or other excipients.
`
`In another embodiment, disclosed liquid
`
`compositions may be substantially non—aqueous.
`
`For example, as disclosed in Example 6, below, a stable liquid solution can be
`
`unexpectedly formed from carbidopa and arginine. Such a solution is stable at room
`
`temperature, e. g, is a substantially clear solution, even at high carbidopa concentrations of
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`2, 3, 4, 6, and/or 8 weight percent carbidopa. Such solutions, e.g. up to about 6 weight
`
`percent carbidopa, are stable (e.g., no precipitation) at least for 48 hours. Further, because
`
`such disclosed solutions, even at high concentrations of carbidopa, have a physiologically
`
`acceptable pH, such solutions can be adjusted to an appropriate pH, but still have a
`
`significant amount of carbidopa in a smaller volume so that
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`it
`
`facilitates patient
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`administration, without e. g. administering large volumes of solution.
`
`Further, solutions having carbidopa and arginine (e. g,
`
`the arginine salt of
`
`carbidopa) are unexpectedly more stable even as compared to solutions of carbidopa with
`
`other basic amino acids such as histidine or lysine, as shown below in e. g. Example 6.
`
`Contemplated liquid formulations may, in some embodiments, further comprise
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`levodopa or levodopa and arginine, and/or optionally a catechol—O—methyl transferase
`
`(COMT) inhibitor, such as entacapone or tolcapone; and/or a monoamine oxidase (MAO)—
`
`A or MAO-B inhibitor, such as moclobemide, rasagiline, selegiline or safinamide.
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`Also provided herein is a liquid formulation comprising an arginine salt of
`
`levodopa, or a liquid formulation comprising arginine and levodopa.
`
`In an embodiment,
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`provided herein is a liquid formulation that includes levodopa and arginine in a molar ratio
`
`of about 1:15 to about 1:25, or about 1: 1.8 to about 1.20. Such levodopa and arginine
`
`formulations or solutions may have a pH of about 8 to about 10, for example, about 8.5 to
`
`about 9.5. A disclosed formulation having levodopa and arginine may include about 2%,
`
`3%, 4%, 5%, 6% or more by weight levodopa, e.g., may include about 4% or more by
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`weight levodopa.
`
`In some embodiments, a disclosed liquid formulation will be stable for a period of 1
`
`day, 2 days, 3 days,
`
`1 week, or 1 month or more at room temperature.
`
`In preferred
`
`embodiments of the invention, a disclosed liquid formulation further comprise a
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`pharmaceutically acceptable excipient
`
`such as
`
`e. g.,
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`N—methylpyrrolidone (NMP),
`
`polyvinylpyrrolidone (PVP), propyleneglycol, or a combination of one or more thereof,
`
`and may further comprise one or more antioxidants such as, but not limited to, N—acetyl
`
`cysteine,
`
`sodium bisulfite, gluthatione, and ascorbic acid.
`
`For example,
`
`in one
`
`embodiment, provided herein is a stable liquid formulation that comprises about 0.5 to
`
`about 20% of carbidopa (e.g. about 2% to about 6%), about 0.25 to about 20% arginine,
`
`about 0 to about 30% NMP, about 0 to about 5% PVP, and/or about 0 to about 5% of one
`
`or more water soluble antioxidants, by weight.
`
`The invention further provides a stable lyophilized powder comprising a carbidopa
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`arginine salt. In one embodiment, such stable lyophilized powder may comprise about 20—
`
`99% of the carbidopa salt, about 0—60% NMP, about 0—15% PVP, and about 0—5% of one
`
`or more water soluble anti oxidants. The lyophilized powder can be reconstituted into a
`
`liquid formulation by addition of water alone or water with NMP, and may include or not
`
`include antioxidants.
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`Liquid formulations of
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`the
`
`invention may be designed for
`
`continuous
`
`administration of a carbidopa or levodopa salt to a patient in need thereof. For example, a
`
`subcutaneously,
`(e. g.
`administered
`continuously
`substantially
`be
`patient may
`transdemially, intraduodenally, intradermally, or intravenously) a fonnulation that includes
`
`the disclosed carbidopa arginine salt, while levodopa, a levodopa salt, or a composition
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`comprising levodopa is orally administered at discrete intervals, e.g., 2, 3, 4, or 5 times a
`
`day.
`
`As used herein in the specification, the term "a composition comprising levodopa"
`
`contemplates formulations that comprise levodopa, optionally together with one or more
`
`decarboxylase inhibitors, one or more catechol—O—methyl transferase (COMT) inhibitors,
`and/or one or more MAO—A or MAO-B inhibitors.
`For example, a composition
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`comprising levodopa may include a dosage formulation that comprises levodopa (or a salt
`thereof) and optionally one or more other drugs, where the dosage formulation may be an
`
`immediate release, controlled release, dual release or multiple release formulation suitable
`
`for oral administration.
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`The term "decarboxylase inhibitor" refers to a dOpa decarboxylase (DDC) inhibitor,
`
`e.g., a drug that inhibits the peripheral metabolism of levodopa to dopamine by aromatic L—
`
`amino acid decarboxylase such as carbidopa and benserazide.
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`The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable
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`excipient” as used herein refers to any and all solvents, dispersion media, preservatives,
`
`antioxidants, coatings,
`
`isotonic and absorption delaying agents, and the like,
`
`that are
`
`compatible with pharmaceutical administration. The use of such media and agents for
`
`, pharmaceutically active substances is well known in the art. The compositions may also
`
`contain other active compounds providing supplemental, additional, or enhanced
`
`therapeutic functions.
`
`The term “physiologically acceptable pH” is understood to mean a pH of e. g., a
`
`composition that
`
`facilitates administration of the composition to a patient without
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`significant adverse effects, e.g. a pH of about 4 to about 9.
`
`The term "COMT inhibitors" refers to inhibitors that inhibit the degradation of
`
`levodopa to 3—methyldopa by catechol—O—methyl transferase and prolong the action of
`
`levodopa, such as such as entacapone or tolcapone. For example, compositions comprising
`
`levodopa contemplated herein may also include a decarboxylase inhibitor (carbidopa or
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`benserazide) and entacapone, e. g. "triple therapy".
`
`The terms "MAO—A or MAO—B inhibitors" refer to inhibitors that prevent the
`
`breakdown of dopamine by monoamine oxidases A or B, e.g., moclobemide, rasagiline,
`
`selegiline or safinamide, more preferably, rasagiline.
`
`Also contemplated herein is a kit comprising: a) a first formulation comprising a
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`2O
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`carbidopa arginine salt and/or carbidopa and arginine, wherein said first formulation is
`
`suitable for continuous administration; b) a second formulation comprising levodopa or an
`
`arginine salt of levodopa, wherein said second fonnulation is
`
`suitable for oral
`
`administration; and c) instructions for administration of formulation a) in conjunction with
`
`fonnulation b). The formulation a) comprising the carbidopa salt may be suitable for
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`continuous administration by any suitable route such as transdennally,
`
`intravenously,
`
`subcutaneously, intradennally, intramuscularly or intraduodenally.
`
`The first formulation of a contemplated kit comprising the carbidopa salt may be
`
`liquid or a lyophilized powder that can be reconstituted into a liquid formulation, or, for
`
`example, may form part of a transdeimal patch, and may be designed for continuous
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`administration by any suitable route such as, but not
`
`limited to,
`
`transdermally,
`
`intravenously, subcutaneously, intradermally, intramuscularly or intraduodenally. In an
`
`embodiment, the first formulation comprises the disclosed carbidopa arginine salt and is
`
`suitable for administration subcutaneously. The second formulation of a contemplated kit
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`may include the levodopa, a levodopa ester, a levodopa salt, or a composition comprising
`
`levodopa, and may be presented as any suitable oral dosage such as, but not limited to,
`
`pills, tablets, dispersible tablets, capsules,
`
`liquid, and the like.
`
`In an embodiment,
`
`the
`
`second formulation may be in the form of an immediate release, controlled release or dual
`
`release oral formulation that comprises both levodopa and benserazide, or both levodopa
`
`and carbidopa.
`
`Such oral formulation in the form of pills,
`
`tablets, or the like, may
`
`comprise a ratio of carbidopa or benserazide to levodopa of about 1:10 to 1:4, preferably
`
`from about 1:4 to 1:1. Other contemplated second formulations include formulations, e.g.,
`
`tablets that include levodopa, carbidopa, and entacapone, or e.g. a tablet that includes
`
`levodopa arginine salt and/or carbidopa arginine salt.
`
`In another embodiment, the kit comprises a first liquid formulation comprising
`
`carbidopa and arginine suitable for, but not
`
`limited to,
`
`transdennal,
`
`intravenous,
`
`subcutaneous, intradermal, intramuscular, intraduodenal continuous administration, and a
`
`second formulation in the form of an immediate release, controlled release or dual release
`
`oral formulation comprising levodopa and carbidopa. The oral fonnulation in the form of
`
`pills, tablets, or the like, may comprise a ratio of carbidopa to levodopa from about 1:10 to
`
`about 1:4, preferably from about 1:4 to about 1:1.
`
`In another aspect,
`
`the present invention relates to a fomiulation comprising a
`
`car