(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`(19) World Intellectual Property
`Organization
`International Bureau
`
`(43) International Publication Date
`24 May 2012 (24.05.2012)
`
`WIPOI PCT
`
`\9
`
`(10) International Publication Number
`
`WO 2012/066538 A1
`
`Designated States (unless otherwise indicated, for every
`kind ofnational protection available): AE, AG, AL, AM,
`AO, 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, QA, RO, RS, RU, RW, 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.
`
`(51)
`
`International Patent Classification:
`A61K 9/08 (2006.01)
`A61K 31/198 (2006.01)
`A61K 31/195 (2006.01)
`A61P 25/16 (2006.01)
`
`(81)
`
`(21)
`
`International Application Number:
`
`PCT/IL2011/000881
`
`(22)
`
`International Filing Date:
`
`15 November 2011 (15.11.2011)
`
`(25)
`
`(26)
`
`(30)
`
`(71)
`
`(72)
`(75)
`
`Filing Language:
`
`Publication Language:
`
`Priority Data:
`61/413,637
`15 November 2010 (15.11.2010)
`61/524,064
`16 August 2011 (16.08.2011)
`
`English
`
`English
`
`US
`US
`
`except US):
`designated States
`all
`for
`Applicant
`NEURODERM LTD [IL/IL]; 3 Golda Meir Street, Weiz-
`mann Science Park, 74036 Ness Ziona (IL).
`
`Inventors; and
`Inventors/Applicants flor US only): YACOBY-ZEEVI,
`Oron [IL/1L]; 204 Hanarkissim Street, 60946 Bitsaron
`(IL). NEMAS, Mara [IL/IL]; 17/4 Ha'atsmaut Street,
`70700 Gedera (IL).
`
`(74)
`
`Agent: BEN-AMI & ASSOCIATES; PO. Box 94, 76100
`Rehovot (IL).
`
`(84)
`
`Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ,
`UG, ZM, ZW), 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, IT, LT, LU,
`LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, 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))
`
`before the expiration of the time limit for amending the
`claims and to be republished in the event of receipt of
`amendments (Rule 48.2(h))
`
`Title:
`CONTINUOUS ADMINISTRATION OF L-DOPA, DOPA DECARBOXYLASE
`(54)
`ECHOL—O—METHYL TRANSFERASE INHIBITORS AND COMPOSITIONS FOR SAME
`
`INHIBITORS, CAT-
`
`(57) Abstract: Provided herein, in part, is a method of treating a neurological or movement disorder in a patient in need thereof,
`comprising subcutaneously administering to said patient a pharmaceutically acceptable composition comprising levodopa and op -
`tionally carbidopa and optionally entacapone or tolcapone, or pharmaceutically acceptable salts thereof, wherein said composition is
`administered substantially continuously, and compositions that can be used in the disclosed methods.
`
`
`
`W02012/066538A1|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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`

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`WO 2012/066538
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`PCT/lL2011/000881
`
`CONTINUOUS ADMINISTRATION OF L-DOPA, DOPA DECARBOXYLASE
`
`INHIBITORS, CATECHOL—O—METHYL TRANSFERASE INHIBITORS AND
`
`COMPOSITIONS FOR SAME
`
`TECHNICAL FIELD
`
`[0001] The present invention provides pharmaceutical compositions useful for treatment
`
`of neurological or movement disorders such as Parkinson's disease, and a method for
`
`treatment such disorders by substantially continuously subcutaneous administration of said
`
`compositions.
`
`BACKGROUND
`
`[0002]
`
`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.
`
`[0003] However, levodopa has a short half life in plasma that, even under best common
`
`current 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):Sol3—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 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.
`
`[0004]
`
`The metabolic transformation of levodopa to dopamine is catalyzed by the
`
`aromatic L—amino acid decarboxylase enzyme, a ubiquitous enzyme with particularly-high
`
`concentrations in the intestinal mucosa,
`
`liver, brain and brain capillaries. Due to the
`
`1
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`WO 2012/066538
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`
`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
`
`prevents, certain of its side effects by inhibiting the conversion of levodopa to dopamine
`
`outside the brain. Various oral formulations 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)
`
`inhibitors such as entacapone and tolcapone, and monoamone oxidase (MAO)—/\ or MAO—
`
`B inhibitors such as moclobemide,
`
`rasagiline or selegiline or safmamide. Currently
`
`available oral drugs include SINEMET® and SINEMET®CR sustained—release tablets that
`
`include carbidopa or levodopa; STALEVO® tablets containing carbidopa, entacapone and
`
`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.
`
`Nevertheless, no stable liquid formulation having e.g., an effective concentration in a
`
`volume suitable for use for subcutaneous or transdennal delivery has ever been achieved.
`
`SUMMARY OF INVENTION
`
`[0005]
`
`This disclosure generally relates,
`
`in part,
`
`to a pharmaceutically acceptable
`
`composition comprising 1) active components comprising carbidopa and at least about 4%
`
`by weight levodopa; and arginine and optionally meglumine. Such compositions may have
`a pH of about 9.1 to about 9.8 at 25°C.
`
`[0006]
`
`_ In some embodiments, a disclosed composition having arginine may have a molar
`
`ratio of active components to the arginine is about 121.8 to about 1:35, or about 122.3.
`In
`an exemplary embodiment, a disclosed composition may include about 4% to about 12%
`
`by weight or more of levodopa and/or may include 1% to about 6% by weight carbidopa,
`e.g. about 1% to about 2% by weight carbidopa.
`[0007]
`‘ When meglumine is present in a disclosed composition, the molar ratio of active
`
`components to the arginine may be, for example, about 121.1 to about 1:1.9, and the molar
`
`ratio of active components to the meglumine may about 120.3 to about 121.5, e.g., the
`
`molar ratio of active components to the meglumine may about 120.3 to about 121.2, or for
`
`2
`
`

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`WO 2012/066538
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`
`example, about 120.4, or about 121.1. Such contemplated compositions may include about
`
`2.0% to about 11% by weight meglumine. Contemplated compositions as above for
`
`example may include 10% to about 35% by weight arginine.
`
`[0008]
`
`' Disclosed compositions may further comprise an agent that inhibits the formation
`
`of oxidation products, for example, such an agent may selected from the group consisting
`
`of: ascorbic acid, Na—ascorbate, L—cysteine, N—acetylcysteine (NAC), gluthatione (GSH),
`Nag-EDTA, Nag—EDTA-Ca, and combinations thereof. For example, the pharmaceutically
`
`acceptable
`composition disclosed herein may further
`include,
`in an exemplary
`embodiment, ascorbic acid or a pharmaceutically acceptable salt thereof. In another or
`
`further embodiment, disclosed compositions may include sodium bisulfite.
`
`[0009] Contemplated herein, for example, is a pharmaceutically acceptable composition
`
`comprising levodopa, arginine and optionally meglumine; and ascorbic acid or a
`
`pharmaceutically acceptable salt thereof, e. g. the composition may have about 4% to about
`
`12% by weight levodopa The ascorbic acid salt may selected, for example, from the group
`
`consisting of: ascorbate, sodium ascorbate, calcium ascorbate, potassium ascorbate,
`
`ascorbyl palmitate, and ascorbyl stearate.
`
`For example, a disclosed pharmaceutically
`
`acceptable composition may include the ascorbic acid or a pharmaceutically acceptable salt
`
`thereof-is sodium ascorbate, e.g., about 0.25% by weight or more ascorbic acid or a
`
`pharmaceutically acceptable salt thereof, about 0.2% to about 3% by weight ascorbic acid
`
`or a pharmaceutically acceptable salt
`
`thereof, or about 0.5% to about 1% by weight
`
`ascorbic: acid or pharmaceutically acceptable salts thereof.
`
`In some embodiments, a
`
`contemplated pharmaceutically acceptable composition may have a molar
`
`ratio of
`
`levodopa to the arginine is about 111.8 to about 1:3.5, e.g., about 1:2.3.
`
`[0010]
`
`Such contemplated compositions may further comprise carbidopa in some
`
`embodiments, for example, 1% to about 2% by weight carbidopa.
`
`In such an embodiment,
`
`the molar ratio of the levodopa and the carbidopa together, to the arginine, may be about
`
`1:1.8 to about 123.5, e.g. about 1:23. Such a pharmaceutically acceptable composition
`
`may have a pH of about 9.1 to about 9.8 at 25°C.
`
`[0011] Contemplated compositions and formulations disclosed herein may be,
`
`for
`
`example, liquid at room temperature.
`
`In some embodiments, a disclosed pharmaceutically
`
`acceptable composition may further comprise entacapone or tolcapone.
`
`

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`WO 2012/066538
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`PCT/IL2011/000881
`
`[0012] Disclosed pharmaceutically acceptable formulations may be stable for at least
`
`two weeks at 25°Ci5°C, and/or for example, may be stable for at least two months at —
`
`20°Ci5°C.
`
`[0013]
`
`In an embodiment, a transdermal patch is contemplated herein suitable for
`
`administering a disclosed pharmaceutically acceptable composition.
`
`[0014] Also provided herein is a method oftreating a neurological or movement disorder
`
`in a patient in need thereof, e.g., Parkinson’s disease, comprising administering to said
`
`patient a composition disclosed herein, e.g. a liquid composition of levodopa and/or
`
`carbidopa.
`
`Also provided herein,
`
`in one embodiment,
`
`is a method for treatment of a
`
`disease or disorder such as a neurological disorder, or a disorder characterized by reduced
`
`levels of dopamine in a patient's brain, and/or for example a disorder such as Parkinson’s
`
`disease, wherein the method includes administration (e.g.
`
`substantially continuous
`
`administration) of a disclosed composition.
`
`In an embodiment, continuous administering
`
`may include transdermal,
`
`intradermal, subcutaneous,
`
`intravenous,
`
`intrathecal, epidural,
`
`intracranial, or intraduodenal administration, e. g. may include the use of an infusion pump.
`
`Such methods may further comprise orally administering levodopa and/or carbidopa and
`
`optionally entacapone or tolcapone.
`
`[0015] Disclosed compositions may be administered subcutaneously and/or
`
`e.g.
`
`substantially continuously. Such subcutaneous administration may comprise the use of one
`
`or more infusion pumps and/or transdermal and/or dermal patches.
`
`For example, a
`
`disclosed method may include a rate of administering a disclosed composition at
`
`least
`
`about 0.0l ml/hour to about 0.2 ml/h, or at least about 0.07 ml/hour, or for example, about
`
`0.15 ml/hour during the day or during patient activity, and about 0 to about 0.075 0.25
`
`ml/hour at rest or sleep. Alternatively, a disclosed composition may be administered
`
`intraduodenally or intravenously.
`
`[0016]
`
`' In some embodiments, a method that
`
`includes subcutaneously administering
`
`comprises the use of one or more infusion pumps, e.g., with a rate of administering the
`
`composition is about 0.20 ml/hour to about 2.0 ml/h, for example, about 1.0 i0.5 ml/hour.,
`
`or about 1.25 i0.5 ml/hour during the day or during patient activity, and about 0 to about
`
`0. 5 ml/hour at night or at rest.
`
`[0017] Also provided herein is a pharmaceutically acceptable composition comprising (i)
`
`carbidopa, at least 4% by weight levodopa, arginine and optionally meglumine; or (ii)
`
`levodopa, arginine, optionally meglumine, and ascorbic acid or a pharmaceutically
`
`4
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`WO 2012/066538
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`PCT/IL2011/000881
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`acceptable salt thereof, for use in treatment of a neurological or movement disorder. In one
`
`embodiment, the neurological or movement disorder is Parkinson's disease.
`
`[0018] A pharmaceutically acceptable
`
`formulation
`
`is
`
`disclosed
`
`herein,
`
`in
`
`an
`
`embodiment, comprising about 2.5 to about 7% by weight levodopa, about 0 to about 2%
`
`by weight carbidopa, about 5 to about 18% by weight arginine, and about 0.25% to about
`
`3% by weight ascorbic acid or a pharmaceutically acceptable salt thereof.
`
`[0019]
`
`In an embodiment, a pharmaceutically acceptable formulation comprising about 8
`
`to about 12% by weight levodopa, about 1
`
`to about 3% by weight carbidopa, about 15 to
`
`about 35% weight arginine is contemplated.
`
`In another embodiment, a pharmaceutically
`
`acceptable formulation comprising about 8 to about 12% by weight levodopa, about 1
`
`to
`
`about 3% by weight carbidopa, and about 12 to about 15% weight arginine, and about 3%
`
`to about 10% by weight meglumine is provided. Such compositions may further include
`
`about 0.25-3% by weight ascorbic acid.
`
`[0020] Also provided herein is a pharmaceutically acceptable liquid composition
`
`comprising arginine and at least about 7% by weight entaeapone or tolcapone, e.g. at least
`
`about 8%, or at
`
`least about 10%, or about 7% to about 12% by weight entaeapone or
`
`tolcapone. For example, a disclosed composition may have entaeapone or tolcapone and
`
`the arginine with a molar ratio of about 1:05 to about 1:2.5, for example about 1:1 to about
`
`1:1.5. Such liquid compositions may have a pH of about 6 to about 9 at 25°C, and/or may
`
`be substantially stable at 25°C for 48 hours or more.
`
`[0021]
`
`Provided herein,
`
`in an embodiment,
`
`is a process for preparing a stable liquid
`
`solution comprising levodopa and/or carbidopa, and arginine, comprising:
`
`- providing levodopa and/or carbidopa, and arginine to form a powder mixture;
`
`adding water to said powder mixture to form a suspension;
`
`heating said suspension at a temperature of about 40°C to about 90°C to form a
`
`solution; and
`
`cooling said solution to provide the stable liquid composition.
`
`In some
`
`embodiments, wherein heating said suspension further comprises stirring the suspension.
`
`[0022]
`
`This disclosure relates at least in part to the discovery that arginine can form a
`
`salt of carbidopa, and/0r levodopa and/or entaeapone, or tolcapone, that can be used to
`
`form a stable,
`
`liquid formulation that
`
`is suitable for e. g., continuous subcutaneous,
`
`transdermal, intradermal, intravenous and/or intraduodenal administration. Such disclosed
`
`compositions
`
`are
`
`capable of
`
`substantially continuously administering carbidopa,
`
`5
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`WO 2012/066538
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`PCT/IL2011/000881
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`entacapone, tolcapone and/or levodopa to a patient in need thereof. For example, disclosed
`
`herein are compositions
`
`that
`
`relate to the disclosed discovery that
`
`substantially
`
`continuously administering a dopa decarboxylase inhibitor such as carbidopa,
`
`together
`
`with substantially continuously administering levodopa and optionally entacapone or
`
`tolcapone, 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 or eliminate the need for oral levodopa, while effectively treating a movement
`
`and/or neurological disorder such as Parkinson’s disease.
`
`BRIEF DESCRIPTION OF THE FIGURES
`
`[0023]
`
`Figure 1 depicts the effect of carbidopa on the stability of levodopa In Vitro and
`
`Ex Vivo: A. 6% weight levodopa and arginine solution with various concentrations (2,
`
`1.5, 1, 0.5%) of carbidopa or no carbidopa were tested for physical stability in vitro. The
`
`results show that carbidopa prevented dark yellow color formation in the presence of air, in
`
`a dose related manner (small vials at the right hand side), and in the absence of air (with
`
`N2 in the head space) 0.5% carbidopa was sufficient to inhibit this color formation (large
`
`vials in the left hand side of the figure). B. 7% weight percent levodopa and arginine
`
`solution, with or without 2% carbidopa by weight, continuously administered in to the
`
`subcutaneous tissue of a 5x50m fresh, full—thickness pig skin. The right hand side depicts
`
`the inhibition of oxidation with the use of a levodopa formulation that includes carbidopa.
`
`[0024]
`
`Figure 2 depicts that the presence of 1% carbidopa in a levodopa solution reduces
`
`the severity and extent of local levodopa dependent subcutaneous toxicity in the pig.
`
`[0025] 3Figure 3 depicts the effect of carbidopa on the pharmacokinetics of levodopa in
`
`the pig. A:
`
`the plasma concentration of levodopa following continuous subcutaneous
`
`administration of 6% levodopa with various amounts of carbidopa. B: The correlation
`
`between plasma steady state concentration of levodopa, obtained following continuous
`
`subcutaneous administration of levodopa/carbidopa formulations and the formulation
`
`concentration of carbidopa. C. The correlation between plasma steady state concentration
`
`of carbidopa following continuous subcutaneous administration of levodopa/carbidopa
`
`formulations and the formulation concentration of carbidopa.
`
`[0026]
`
`Figure 4 shows the effect of various agents on oxidation of levodopa in the
`
`subcutaneous tissue of pig skin samples, ex-vivo, following subcutaneous administration of
`
`levodopa/carbidopa formulations.
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`[0027]
`
`Figure 5A depicts the effect of continuous subcutaneous (SC) entacapone (200
`
`mg/24h)» and/or carbidopa (CD) (40mg/24h) on the plasma concentrations of levodopa
`
`(ng/ml) following oral Administration of Sinemet (100/25 levodopa/carbidopa) in pigs.
`
`[0028]
`
`Figure 5B depicts the effect of continuous SC CD (40 mg/24h) and/or levodopa
`
`(LD) (140 mg/24h) administration on the plasma concentrations oflevodopa following oral
`
`administration of Sinemet (100/25) in pigs.
`
`[0029]
`
`Figure 6 shows the effect of carbidopa on the local subcutaneous toxicity of
`
`levodopa following 24h—continuous subcutaneous administration, at 0.16 ml/h, in pigs.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`[0030] Disclosed herein,
`
`in an embodiment,
`
`is a liquid composition that
`
`includes an
`
`arginine salt of levodopa (e.g., arginine and levodopa), and optionally carbidopa, that is
`
`stable at
`
`room temperature.
`
`Such disclosed compositions may facilitate continuous
`
`delivery of an effective amount of levodopa, carbidopa, and/or other active agents such as
`
`entacapone or tolcapone to a patient in a minimally invasive fashion. Further, disclosed
`
`formulations have a pH that is suitable for e.g., transdermal, subcutaneous, intravenous,
`
`intrathecal, epidural, intracranial or intraduodenal administration.
`
`[0031]
`
`For example, provided herein are formulations and methods capable of obtaining
`
`substantially constant inhibition of COMT activity upon administration, thereby increasing
`
`the halflife of administered levodopa and substantially reducing the pulsatility of levodopa
`
`plasma levels to avoid low trough levels of plasma levodopa.
`
`[0032]
`
`Further, provided herein are formulations of levodopa and optionally carbidopa
`
`that unexpectedly allow for stable dissolution of higher concentrations (e.g., greater than
`
`2% by weight) of levodopa at e.g. an 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
`
`herein are formulations and methods capable of obtaining substantially constant plasma
`
`levodopa concentrations and substantially reducing the pulsatility of levodopa plasma
`
`levels to avoid low trough levels of plasma levodopa.
`
`[0033]
`
`. A treatment strategy of continuous levodopa and carbidopa (and/or entacapone or
`
`tolcapone) 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
`
`7
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`daily dose of levodopa, and/or reduce or even eliminate oral dosing of levodopa and
`
`carbidopa.
`
`Compositions
`
`[0034]
`
`Provided herein,
`
`in an embodiment,
`
`is a liquid formulation comprising an
`
`arginine salt of levodopa, or a liquid formulation comprising arginine and levodopa.
`
`In an
`
`embodiment, provided herein is a liquid formulation that includes levodopa and arginine in
`
`a molar ratio of about 1:15 to about 1:2.5, or about 1: 2 to about 1:23 levodopazarginine,
`
`or, for example, when such a liquid composition further comprises carbidopa in a molar
`
`ratio of about 1:2 to about 1.3.5, or about 1:1.8 to about 1:3.5 carbidopazarginine.
`
`[0035]
`
`Such levodopa and arginine formulations or solutions may have a pH that is
`
`pharmaceutically acceptable for subcutaneous administration, e.g. a pH of about 8 to about
`
`10, for example, about 9.1 to about 9.8, e.g., 9.2 to 9.6 at 25°C. A disclosed formulation
`
`having levodopa and arginine may include at least about 7%, 8%, 9%, or more by weight
`
`levodopa, e.g., may include about 10%, 20% or more by weight
`
`levodopa.
`
`In some
`
`embodiments, a disclosed formulation may include about 2.5 to about 10 weight percent
`
`levodopa, 4 to about 7 weight percent levodopa, or about 7.5 to about 12 weight percent
`
`levodopa, or about 5% to about 30%, or about 10 to about 20 weight percent levodopa, and
`
`may further include about 9 to about 20 weight percent arginine or about 9 to about 30
`
`weight percent arginine, e.g. about 10 to about 18 weight percent arginine, about 10 to
`
`about 20% or about 15 to about 30% or more by weight arginine or about 12, 13, 14, or 15
`
`weight percent arginine.
`
`For example, arginine may be present
`
`in contemplated
`
`formulations at a molar ratio of about 1.5:] to about 3:1, e.g. 1.8:1 to about 3.521,
`
`ratio of
`
`arginineztotal active ingredients (which may include e. g., levodopa, carbidopa, etc.).
`
`[0036]
`
`For example, disclosed herein is a pharrnaceutically acceptable composition,
`
`having a pH of about 9.1 to about 9.8 at 25°C,
`
`that includes the active components
`
`levodopa and carbidopa (e.g. about 4% by weight or more levodopa), and arginine and/or
`
`meglumine. For example, contemplated compositions having levodopa and arginine may
`
`further comprise carbidopa, for example, may fiarther include at least about 1%,
`
`at least
`
`about 2%, at least about 4% by weight carbidopa, for example about 2% to about 4% by
`
`weight carbidopa. For example, provided herein is a composition comprising arginine and
`
`about 2% to about 12% by weight levodopa or more (e.g. about 4% to about 10%, about
`
`4% to about 7%, about 5% to about 10%, or about 6% to about 11% by weight levodopa,
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`or about 5% to about 20% by weight levodopa) and about 1% to about 6%, about 1% to
`
`about 2% (e.g. about 1.25 or about 1.5%), or about 2% to about 5% or about 2% to about
`4% by weight carbidopa. When administered subcutaneously and/or dcrmally, such
`
`compositions having levodopa and carbidopa may result in minimal local tissue damage,
`e.g., as compared to subcutaneous or dermal administration of a composition that includes
`
`levodopa (e. g., a levodopa/arginine composition) alone.
`
`Further, such levodopa and
`
`arginine compositions, when further including carbidopa, may have more stability (e.g.
`
`may not form unwanted oxidation products over time as compared to a composition having
`levodopa and arginine alone).
`
`[0037]
`
`In another embodiment, disclosed formulations may include an amino sugar such
`
`as meglumine, which may, for example, replace some or all of the arginine present in the
`
`formulations. For example, disclosed here is a formulation comprising levodopa and/or
`
`carbidopa and meglumine. Also contemplated herein is a meglumine salt of levodopa and
`
`a meglumine salt of carbidopa.
`
`In an embodiment, a composition comprising arginine and
`
`having active agents such as levodopa and carbidopa, wherein the molar ratio of active
`
`agents to arginine is less than about 1:2; to improve the stability of such compositions, this
`
`exemplary composition may further comprise meglumine, e.g., with a ratio of active agents
`to meglumine of aboutl: 0.3 to about 1.1.5. For example, provided herein is a composition
`
`having levodopa or carbidopa (or a combination) as active components, arginine, and
`
`meglumine, wherein the molar ratio of active components to arginine is about 1:1.1 to
`
`about1:l .9 (e. g. 1:1.3) and the molar ratio of active components to meglumine of about 1:
`
`0.3 to about 121.2 (e.g. about 1: 0.4, 1: 0.5, 120.8, 1: 1.1). Contemplated compositions can
`
`include levodopa (e.g. about 4 to about 10% by weight or more), carbidopa (e.g. about 0.5
`
`to about 3% by weight, e.g. about 1 or 2% by weight), about 9% to about 16 by weight
`
`arginine, and about 2% to about 10% by weight meglumine.
`
`[0038] . Also provided herein, in an embodiment, is a formulation comprising levodopa,
`
`arginine. and/or carbidopa, and optionally for example an agent that inhibits the formation
`
`of oxidation products. Such a formulation may be liquid at room temperature, with a pH of
`
`about 9.1 to 9.8. For example, provided herein is a composition that includes ascorbic acid
`
`or salt thereof.
`
`[0039]
`
`In an embodiment, a disclosed composition may further comprise one or more
`
`agents that inhibit the formation of oxidation products. Such agent may be e.g., tyrosinase
`.
`.
`.
`.
`++
`.
`.
`inhibitors and/or o—quinone scavengers and/or Cu
`chelators and/or antiox1dants.
`
`In some
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`embodiments, carbidopa may act as an agent that inhibits the formation of oxidation
`
`products.
`
`For example, contemplated formulations may include o-quinone scavengers
`
`such as, but not limited to, N-acetyl cysteine, gluthatione, ascorbic acid, Na-ascorbate,
`
`and/or L-cysteine.
`
`In an embodiment, formulations may include an agent chosen from one
`
`or more of tyrosinase inhibitors such as captopril; methimazole, quercetin, arbutin, aloesin,
`
`N-acetyl'glucoseamine,
`
`retinoic
`
`acid,
`
`(x—tocopheryl
`
`ferulate, MAP (Mg ascorbyl
`
`phosphate), substrate analogues (e.g., sodium benzoate, L—phenylalanine), Cu++ chelators
`
`for example, Nag-EDTA, Nag-EDTA-Ca, DMSA (succimer), DPA (D-penicillamine),
`
`trientine—HCI, dimercaprol, clioquinol,sodium thiosulfate, TETA, TEPA, curcumin,
`
`neocuproine, tannin, and/or cuprizone. Other contemplated anti—oxidants that may form
`
`part of a disclosed formulation include sulfite salts (e.g., sodium hydrogen sulfite or
`
`sodium metabisulfite),
`
`di-tert—butyl methyl
`
`phenols,
`
`tert—butyl—methoxyphenols,
`
`polyphenols, tocophcrols and/or ubiquinones, including but not limited to caffeic acid.
`
`[0040]
`
`In a particular embodiment, provided herein are compositions that
`
`include
`
`levodopa,
`
`carbidopa,
`
`arginine, optionally meglumine,
`
`and an
`
`ascorbic
`
`acid or
`
`pharmaceutically acceptable salt thereof. For example, contemplated compositions may
`
`filrther
`
`include ascorbate, sodium ascorbate, potassium ascorbate, calcium ascorbate,
`
`ascorbyl stearate, and/0r ascorbyl palmitate. For example, a composition may include
`
`about 0.5 percent by weight or more (e.g., about 0.5 to about 3 percent by weight, or about
`
`0.2 to about 2 percent or about 0.5 to about
`
`1 percent by weight, e.g. about 0.75% by
`
`weight ascorbic acid or salt thereof.
`
`[0041]
`
`Provided herein, in an embodiment, is a pharmaceutically acceptable formulation
`
`that
`
`includes entacapone (or
`
`tolcapone), and arginine,
`
`that allows for substantially
`
`continuous administration of entacapone or tolcapone. For example, provided herein, for
`
`example, is a stable liquid formulation that includes entacapone or tolcapone and may be
`
`suitable for substantially continuous administration to a patient. Further, such formulations
`
`may have a physiologically acceptable pH, for example, about 6 to about 9.5, or about 6.5
`
`to about 8.5, or about 7 to about 8.
`
`[0042]
`
`For example, entacapone (or tolcapone) and arginine may be dissolved in an
`
`aqueous solution, (e.g., having a pH of about 6 to 9, e.g., from about 6.5 to about 8.5, e.g.,
`
`from about 7 to 8 at 25 DC or at 30°C. Alternatively, entacapone (free base) (or tolcapone
`
`(free base) and a basic amino acid salt (e.g. arginine and/or lysine) are dissolved together
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`in a liquid (e.g. an aqueous liquid) to form a disclosed liquid formulation. Disclosed liquid
`
`formulations may include about 2% by weight entacapone or tolcapone, about 4% by
`
`weight entacapone or tolcapone, or about 2% to about 12% by weight entacapone or
`
`tolcapone, for example, may include about 7% by weight or more, about 8% by weight or
`
`more, or about 10% by weight or more entacapone or tolcapone , for example, may include
`
`about 3% to about 20% by weight or more entacapone or tolcapone, e.g., about 5% to
`
`about 8% by weight, about 8% to about 12% by weight entacapone or tolcapone. For
`
`example, a liquid formulation may include entacapone, and a basic amino acid (such as
`
`arginine) in molar ratio of about 1: 0.5 to about 1:25, or about 1:1 to about a 1:2, e.g.,
`
`about 1:] or 1:15. Such liquid formulations may further comprise carbidopa, for example,
`
`at least about 2% by weight or at least about 4% by weight carbidopa, e.g. about 2% to
`
`about 6% or more by weight carbidopa.
`
`In another embodiment, such liquid formulations
`
`may further comprise levodopa, for example, at least about 2%, 3%, 4%, 5%, 6%, or 7%
`
`by weight levodopa, e.g. about 2.5% to about 12 % by weight levodopa.
`
`In an exemplary
`
`embodiment, a composition that includes tolcapone or entacapone may further include an
`
`excipient such as an on, B or y cyclodextrin or derivative.
`
`[0043] Disclosed liquid formulations (e.g. a liquid composition comprising levodopa,
`
`carbidopa, entacapone tolcapone, or combinations of two or more) and arginine (and/or
`
`meglumine), e.g., a disclosed formulation comprising levodopa and arginine) 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 about a
`
`1:1 molar ratio of entacapone:arginine (or
`
`tolcaponezarginine), with about 5% to about 15%, or about 6% to about 12%, or 6% to
`
`about 10% by weight entacapone. Such an entacapone, argininc liquid formulation may be
`
`more stable,
`
`in some embodiments, at 7 days as compared to a liquid composition that
`
`includes a lysine or histidine salt of entacapone. In an embodiment, a disclosed formulation
`
`comprising levodopa and arginine may be stable for at least one week, or at least two
`
`weeks or more at room temperature, e.g. at 20°C to 30°C, e.g. at 25°C.
`
`In an embodiment,
`
`a disclosed formulation comprising levodopa and arginine may be stable for at least one
`
`month, or at least two months at temperature below freezing e. g. at —10 “C and/or at -20 °C,
`
`at -18 0C, or e.g., at —20 to -80 CC. The term “stable” in this context means that a
`
`formulation does not significantly precipitate out of solution and/or one or more active
`
`agents does not degrade significantly for a substantial amount of time.
`
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`[0044]
`
`In some embodiments, disclosed liquid formulation