(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`(19) World Intellectual Property
`Organization
`International Bureau
`
`(43) International Publication Date
`14 June 2012 (14.06.2012)
`
`WIPOI PCT
`
`\9
`
`(10) International Publication Number
`
`WO 2012/079072 A2
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`(51)
`
`International Patent Classification:
`A61K 31/198 (2006.01)
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`(21)
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`International Application Number:
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`PCT/US201 1/064398
`
`(22)
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`International Filing Date:
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`12 December 2011 (12.12.2011)
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`(25)
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`(26)
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`(30)
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`(71)
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`(72)
`(75)
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`(74)
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`(81)
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`Filing Language:
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`Publication Language:
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`Priority Data:
`61/421,902
`61/431,256
`61/492,227
`61/538,449
`
`10 December 2010 (10.12.2010)
`10 January 2011 (10.01.2011)
`1 June 2011 (01.06.2011)
`23 September 2011 (23.09.2011)
`
`English
`
`English
`
`US
`US
`US
`US
`
`Applicant for all designated States except US): SYN-
`AGILE CORPORATION [US/US]; 70 Sotele Avenue,
`Piedmont, CA 94611 (US).
`
`Inventors; and
`Inventors/Applicants (for US only: HELLER, Adam
`[US/US]; 5217 Old Spicewood Springs Road, Apt. 1505,
`Austin, TX 78731 (US). HELLER, Ephraim [US/US];
`61 14 Lasalle Avenue, #427, Oakland, CA 94611 (US).
`
`Agents: BEIKER-BRADY, Kristina el al.; Clark & E1-
`bing LLP, 101 Federal Street, Boston, MA 021 10 (US).
`
`Designated States (unless otherwise indicated, for every
`kind ofnational protection available): AE, AG, AL, AM,
`
`A0, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ,
`CA, CII, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO,
`DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN,
`11R, IIU, 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.
`
`(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).
`Declarations under Rule 4.17:
`
`as to applicant’s entitlement to applyfor and be granted a
`patent (Rule 4.1 7(ii))
`
`as to the applicant’s entitlement to claim the priority ofthe
`earlier application (Rule 4.1 7(iii))
`Published:
`
`without international search report and to be republished
`upon receipt ofthat report (Rule 48.2(g))
`
`(54) Title: SUBCUTANEOUSLY INFUSIBLE LEVODOPA PRODRUG COMPOSITIONS AND METHODS OF INFUSION
`
`(57) Abstract: The invention features methods compositions and infusion pumps for infusing levodopa prodrugs (e.g., levodopa es—
`ters, levodopa amides, levodopa carboxamides, and levodopa sulfonamides) for the treatment of Parkinson's disease.
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`
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`Subcutaneously Infusible Levodopa Prodrug Compositions and Methods of Infusion
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`Background of the Invention
`
`The invention relates to compositions, including levodopa esters, for the treatment of Parkinson’s
`
`disease.
`
`Parkinson” s disease (PD) is characterized by the inability of the dopaminergic neurons in the
`
`substantia nigra to produce the neurotransmitter dopamine. PD impairs motor skills, cognitive processes,
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`autonomic functions and sleep. Motor symptoms include tremor, rigidity, slow movement
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`(bradykinesia), and loss of the ability to initiate movement (akinesia) (collectively, the “off ” state). Non-
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`motor symptoms of PD include dementia, dysphagia (difficulty swallowing), slurred speech, orthostatic
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`hypotension, seborrheic dermatitis, urinary incontinence, constipation, mood alterations, sexual
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`dysfunction, and sleep issues (e.g., daytime somnolence, insomnia).
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`After more than 40 years of clinical use levodopa therapy remains the most effective method for
`
`managing PD and provides the greatest improvement in motor function. Consequently, levodopa (LD)
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`administration is the primary treatment for PD. Levodopa is usually orally administered. The orally
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`administered levodopa enters the blood and part of the levodopa in the blood crosses the blood brain
`
`barrier. It is metabolized, in part, in the brain to dopamine which temporarily diminishes the motor
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`symptoms of PD. As the neurodegeration underlying PD progresses, the patients require increasing doses
`
`of levodopa and the fluctuations of brain dopamine levels increase. When too much levodopa is
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`transported to the brain, dyskinesia sets in, (uncontrolled movements such as writhing, twitching and
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`shaking); when too little is transported, the patient re-enters the off state. As PD progresses, the
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`therapeutic window for oral formulations of levodopa narrows, and it becomes increasingly difficult to
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`control PD motor symptoms without inducing motor complications. In addition, most PD patients
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`develop response fluctuations to oral levodopa therapy, such as end of dose wearng off, sudden on/off’s,
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`delayed time to on, and response failures.
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`Besides levodopa, other drugs commonly used for treatment of PD include DDC inhibitors, such
`
`as carbidopa and bcnserazide; dopamine receptor agonists, such as pramipexole, ropinirolc,
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`bromocriptine, pergolide, piribedil, cabergoline, lisuride, and apomorphine; MAO-B inhibitors, such as
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`rasagiline and selegiline; COMT inhibitors, such as entacapone and tolcapone; anticholinergics, such as
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`tIihexiphenidyl, benztropine, biperiden, and ethopropazine; and amantadine.
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`Most of the oral levodopa is metabolized before reaching the brain. Peripheral levodopa
`
`metabolization to dopamine causes nausea, tremors, and stiffness. Nausea is reduced and bioavailability
`
`in the brain is increased by co-administration of DDC-inhibitors, primarily CD or benserazide. CD
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`extends the plasma half—life of levodopa to approximately 90 minutes. These DDC—inhi bitors do not
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`substantially cross the blood-brain barrier and thus inhibit only peripheral DDC. The results are
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`reduction in side effects caused by dopamine on the periphery and increase of the concentration of
`
`levodopa and dopamine in the brain.
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`Standard levodopa treatment with oral delivery typically leads to intermittent plasma levodopa
`
`levels, which are thought to contribute to motor complications. By contrast, more continuous delivery of
`
`levodopa that provides smooth, predictable plasma levels leads to a good therapeutic response with
`
`reduced motor complications.
`
`The development of an effective controlled release oral dosage form of levodopa that provides
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`substantially reduced variability in plasma levodopa concentrations and more stable, continuous levodopa
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`delivery to the brain is difficult. Some of the underlying causes of this difficulty, and of the response
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`fluctuations themselves, are believed to be: (a) the short biological half-life of levodopa; (b) erratic
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`gastric emptying, due to effects of PD on the autonomic nervous system; (c) poor absorption of levodopa
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`in the gut in the presence of food, due to competition between levodopa and other amino acids for
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`transport across the intestines; (d) absorption of levodopa taking place only in the duodenum, a short
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`segment of the intestines; and (e) competition between levodopa and other amino acids for active
`
`transport from the blood into the brain.
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`Numerous studies demonstrate that IV infusion of levodopa stabilizes its concentration in plasma
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`and dramatically reduces motor complications and fluctuations (see, for example, Shoulson et al.,
`
`Neurology 25:1144 (1975); Rosin et al., Arch Neurol. 36:32 (1979); Quinn et al., Lancet. 2:412 (1982);
`
`Quinn et al., Neurology. 34:1131 (1984); Nutt et al., N Engl J Med. 310:483 (1984); Hardie et al., Br J
`
`Clin Pharmac. 22:429 (1986); and Hardie et al., Brain. 107:487 (1984)).
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`Likewise, many studies show similarly favorable results upon continuous levodopa infusion
`
`directly into the duodenum, using an ambulatory infusion pump (Duodopa therapy). Studies of Duodopa
`
`therapy confirm >50% reductions in time spent in the “off ” state and time spent with severe dyskinesias.
`
`These studies also demonstrate significant improvement in quality of life of the patients (see, for
`
`example, Bredberg et al., Eur J Clin Pharmacol. 45: 117 (1993); Kurth et al., Neurology 43: 1698 (1993);
`
`Nilsson et al., Acta Neurol Scand. 97:175 (1998); Syed et al., Mov Disord. 13:336 (1998); Nilsson et al.,
`
`Acta Neurol Scand. 104:343 (2001); Nyholm et al., Clin Neuropharmacol. 26:156 (2003); Nyholm et al.,
`
`Neurology. 65: 1506 (2005); and Nyholm et al., Clin Neuropharmacol. 31:63 (2008); Antonini et al., Mov
`
`Disord. 22:1145 (2007)).
`
`Chronic subcutaneous infusion of drugs such as insulin and pain medications is widely practiced.
`
`Such systems are safe for chronic use by patients outside the hospital, convenient, and relatively low cost.
`
`It would be desirable to be able to also deliver levodopa or a levodopa prodrug subcutaneously.
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`The practicality of subcutaneous levodopa infusion depends on the liquid volume that must be
`
`infused for the typical daily dose of 0.3-2 g of levodopa. The subcutaneous infusion of large volumes can
`
`cause persistent swelling and edema.
`
`Levodopa is poorly soluble in aqueous solutions near neutral pH. For example, at 25 0C and at
`
`pH 5 the solubility of levodopa is only about 2.8 g per liter, and at neutral pH it is even less soluble, only
`
`about 1.65 g per liter. A patient requiring l g levodopa per day would correspondingly require the daily
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`infusion of 0.36 liters of the pH 5 solution and of 0.6 liters of the neutral pH solution. In early studies of
`
`IV levodopa infusion, volumes of over 2 L of solution (saline or dextrose and water) per day with less
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`than 1 mg/mL of levodopa were often administered making this administration very cumbersome. The
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`acidity of the infusion substance can create an increased risk of thrombophlebitis, and to reduce this risk,
`central venous access was often utilized.
`
`The two most widely tested levodopa prodrugs are its methyl ester, known as Melevodopa or
`
`LDME, and its ethyl ester, known as Etilevodopa or LDEE (see, for example, Stocchi et al., Mov Disord
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`25 :1881 (2010); Stocchi et al., Clin Neuropharmacol 33: 198 (2010); Djaldetti et al., Clin Neuropharmacol
`
`26:322 (2003); and Blindaucr ct al., Arch Ncurol 63:210 (2006)). LDME and LDEE can be unstable in
`
`solution, making them difficult to store.
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`The invention features stable compositions that can permit subcutaneous administration of
`
`levodopa, or a levodopa prodru g, for the treatment of Parkinson’s disease.
`
`Abbreviations and Definitions
`
`The term “CD” refers to Carbidopa.
`
`The term “carbidopa prodrug” refers to carbidopa esters, carbidopa amides, and salts thereof,
`
`such as the hydrochloride salt of carbidopa ethyl ester, carbidopa methyl ester, or carbidopa amide.
`
`The term “COMT” refers to catechol-O-methyl transferase.
`
`The term “DDC” refers to DOPA decarboxylase.
`
`The term “hyaluronic acid” refers to hyaluronic acid and salts thereof.
`The term “IV” refers to intravenous.
`
`The term “ID” refers to levodopa, also known as L-DOPA, or a salt thereof.
`
`The term “LD50” refers to the median lethal oral dose of an LD prodrug in rats at 48 hours (e. g.,
`
`the dose of LD prodrug required to kill half the rats within 48 hours after ingestion of the LD prodrug).
`
`The term “LDA” refers to an LD prodrug that is a levodopa amide of formula (III):
`0
`
`HO
`
`Ho
`
`,R
`N 5
`I
`NH R
`2
`
`6
`
`(III),
`
`or a pharmaceutically acceptable salt thereof. In formula (III), each of R5 and R6 is, independently,
`
`selected from 11, C14 alkyl, C24 alkenyl, C24 alkynyl, C24 heterocyclyl, CM; aryl, C744 alkaryl, C340
`
`alkheterocyclyl, and C 1,7 heteroalkyl. In particular preferred embodiments, R5 is H or CH3, and R6 is
`
`CH3, CH2CH3, CH2CH2CH3, benzyl, 2-deoxy-2-glucosyl, or CHZCHZNHZ. LDAs are hydrolyzed in vivo
`
`to form LD and an amine or ammonium salt. The LDAs of the invention and their hydrolysis products
`
`have an LD50 in rats of greater than 3 millimoles/kg. The LDA can be administered, for example, in its
`
`free base form, or as an acid addition salt.
`
`The term “LDC” refers to an LD prodrug that is a levodopa carboxamide of formula (II):
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`0
`
`(11),
`
`OH
`
`0
`
`Y R
`
`2
`
`HN
`
`HO
`
`110
`
`or a pharmaceutically acceptable salt thereof. In formula (II), R2 is selected from C14 alkyl, C24 alkenyl,
`
`C24 alkynyl, C642 aryl, CH4 alkaryl, C340 alkheteroeyelyl, and CH heteroalkyl. In particular preferred
`
`embodiments, R2 is CHZCH3, CH(OH)CH3, CHZCHZCOOH, CH2CH2CH3, benzenepropenyl, phenyl, or
`
`(CHOH)4CHZOH. LDCs are hydrolyzed in vivo to form LD and a carboxylale or carboxylic acid. The
`
`LDCs of the invention and their hydrolysis products have an LDSO in rats of greater than 3 millimoles/kg.
`
`The LDC can be administered, for example, in its neutral form, or as an alkali metal or alkaline earth salt.
`
`The term “LDE” refers to an LD prodrug that is a levodopa ester of formula (I):
`O
`
`HO
`
`HO
`
`, R10
`
`NH2
`
`(1),
`
`or a pharmaceutically acceptable salt thereof. In formula (1), R1 is selected from C H, alkyl, C24, alkenyl,
`
`C2,6 alkynyl, C2,6 heterocyclyl, C(Hz aryl, C744 alkaryl, C340 alkhelerocyclyl, and C14 heleroalkyl. In
`
`particular preferred embodiments, 0R1 is OCH3, OCHZCH3, OCHZCHZCHg, OCH(CH3)2,
`
`OCHZCHZCHZCHg, OCH(CH3)CH2CH3,O-benzyl, O-cyclohexyl, OCHZCHZOH, OCHZCH(CH3)OH, an
`
`LD ester of sorbitol, an LD ester of mannitol, an LD ester of xylitol, or an LD ester of glycerol. LDEs are
`
`hydrolyzed in vivo to form LD and an alcohol. The LDEs of the invention and their hydrolysis products
`
`have an LD50 in rats of greater than 3 millimoles/kg. The LDE can be administered, for example, in its
`
`free base form, or as an acid addition salt.
`
`The term “LDS” refers to an LD prodrug that is a levodopa sulfonamide of formula (IV):
`0
`
`no
`
`110
`
`OH
`
`HN‘S‘O
`0” I
`R3
`
`(IV),
`
`or a pharmaceutically acceptable salt thereof. In formula (IV), R3 is selected from C 14 alkyl, (32,6
`
`alkenyl, ng alkynyl, C24 heterocyclyl, sz aryl, CH4 alkaryl, C340 alkheterocyelyl, and CH
`
`heteroalkyl. In particular preferred embodiments, R3 is CH3, or 4-methylbenzyl. LDSs are hydrolyzed in
`
`Vivo to form LD and a sulfonate. The LDSs of the invention and their hydrolysis products have an LD50
`
`in rats of greater than 3 millimoles/kg. The LDS can be administered, for example, in its neutral form, or
`as an alkali metal or alkaline earth salt.
`
`The term “LDEE” refers to levodopa ethyl ester, or a salt thereof.
`
`The term “LDME” refers to levodopa methyl ester, or a salt thereof.
`
`U1
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`The term “LD prodrug” refers to a pharmaceutical composition suitable for infusion, preferably
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`for subcutaneous or intramuscular infusion, forming LD upon its hydrolysis. Examples include LDA,
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`LDE, LDC, LDS, LDEE, and LDME, and their salts. The salts are usually formed, in the cases of LDEs
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`and LDCs, by neutralizing their basic amines with an acid; and, in the cases of LDAs and LDSs, by
`
`neutralizing their carboxylic acids or sulfonic acids with a base.
`
`The term “MAO-B” refers to monoamine oxidase-B.
`
`As used herein, “neutral amino acid” refers to an amino acid having only one carboxylic acid and
`
`only one amine function. Although phenolic amino acids like LD and OMD are partly ionized to anions
`
`and hydrated protons at neutral pH, they are classified as neutral.
`The term “PD” refers to Parkinson’ s disease.
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`The term “PEG” refers to polyethylene glycol.
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`As used herein, the term “pH” refers to the pH measured using a pH motor having a glass
`electrode connected to an electronic meter.
`
`The term “polybasic acid” means an acid having two or more ionizable functions and acid salts of
`
`these acids. Examples of polybasic acids include citric acid, succinic acid and phosphoric acid and
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`examples of their acid salts include monosodium citrate, monosodium succinate and monosodium
`
`phosphate.
`The term “s.c.” refers to subcutaneous.
`
`The term “administration” or “administering” refers to a parenteral method (e. g., infusion,
`
`injection, transdermal delivery, or buccal delivery) of giving a dosage of Ll) or LD prodrug (e.g., LDA,
`
`LDE, LDC, or LDS) to a subject. The dosage form of the invention is preferably administered
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`intramuscularly or subcutaneously, optionally using an infusion pump.
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`As used herein, “aqueous” refers to formulations of the invention including greater than 10% or
`
`20 % (w/w) water and, optionally, a cosolvent (e. g., glycerol or ethanol).
`
`As used herein, “coinfused” refers to two or more pharmaceutically active agents, formulated
`
`together, or separately, and infused simultaneously, either to the same site (e. g., infused via the same
`
`infusion cannula or needle), or adjacent sites (e. g., infused via separate infusion cannulae or needles
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`within 1 cm of each other).
`
`As used herein “continuous administration” or “continuous infusion” refers to both uninterrupted
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`administration/infusion and frequent administration/infusion. In the case of frequent
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`administration/infusion, the frequency is typically at least once per hour, preferably at least twice per
`
`hour, more preferably at least four times per hour, and most preferably at least six times per hour.
`
`Typical daily durations of continuous administration or infusion typically exceed 12 hours, and are
`
`usually 16 hours or 24 hours. The rate of administration or infusion may be reduced during intended
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`sleep periods, optionally to nil.
`
`As used herein, the terms “effective particle size” and “particle size” are used interchangeably
`
`and refer to a mixture of particles having a distribution in which 50% of the particles are below and 50%
`
`of the particles are above a defined measurement. The “effective particle size” refers to the volume-
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`weighted median diameter as measured by a laser/light scattering method or equivalent, wherein 50% of
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`the particles, by volume, have a smaller diameter, while 50% by volume have a larger diameter. The
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`effective particle size can be measured by conventional particle size measuring techniques well known to
`
`those skilled in the art. Such techniques include, for example, sedimentation field flow fractionation,
`
`photon correlation spectroscopy, light scattering (e.g., with a Microtrac UPA 150), laser diffraction, and
`
`disc centrifugation.
`
`By “fatty acid salt” is meant a fatty acid addition salt of LD or LD prodrug (e.g., LDE, or LDC)
`
`in which the anion is a carboxylate, R-C(O)O-, in which R is a saturated or partially-saturated straight
`
`chain or branched hydrocarbon group having between 8 and 26 carbon atoms. Fatty acid salts are derived
`
`from fatty acids including, without limitation, those occurring naturally in the brain, or found in blood
`
`lipids like triglycerides or cholesterol esters. For example, fatty acids having 16 carbon atoms and 0, 1 or
`
`2 double bonds (C16:0; C16:1 and C16:2), those with 18 carbon atoms and 1, 2 or 3 double bonds
`
`(C18: 1; C182; and C183), those with 20 carbon atoms and 1, 2 or 4 double bonds (C20:1; C202; and
`
`C20:4) and those with 22 carbon atoms and 4, 5 or 6 double bonds (C22:4; C22:5 and C22:6). The fatty
`
`acids can be substituted or unsubstituted. Exemplary substituents include hydroxyl, halide, methyl, ethyl,
`
`propyl, isopropyl, butyl, and pentyl groups. Desirably, the fatty acid salt is 4, 7, 10, 13, 16, 19
`
`docosahexanoate, oleate, ricinoleate, octanoate, alpha-linoleate, eicosapentaenoate, docosahexaenoate,
`
`linoleate, gamma linoleate, palmitoleate, dihomogamma linoleate, arachidonate, myristate, palmitate, and
`stearate.
`
`As used herein, “infused” or “infusion” includes infusion into any part of the body, including the
`
`stomach, intestines, abdominal cavity, muscles, fat, dermis, or subcutaneous tissue.
`
`As used herein, “fluid liquid crystal” refers to a liquid dosage form of the invention that includes
`
`an ordered phase. The presence of a liquid crystal phase can be identified optically (e. g., via optical
`
`properties, such as birefringence).
`
`As used herein, “liquid salt form” refers to a salt of an Ll) prodrug that is a liquid at 25°C. The
`
`liquid salt can be a thermodynamically stable liquid, or it can be a liquid that is thermodynamically
`
`metastable and, for example, because of its high viscosity, it does not readily crystallize. When
`
`metastable, it is preferred that the liquid salt be stored at about 4°C or less, where its viscosity is usually
`
`higher than it is at 25 OC. The liquid is typically clear, although it may contain particles with a particle
`
`size smaller than about 1 pm.
`
`As used herein, “liquidus” refers to the temperature of a mixture not having a sharp melting
`
`point. The liquidus is the temperature where practically the entire mixture is liquid. While above the
`
`liquidus temperature the mixture is usually clear, below the liquidus temperature it usually includes light-
`
`scattering crystallites.
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`As used herein, “Newtonian fluid” refers to a liquid dosage form of the invention that flows
`
`regardless of the forces acting on it (e. g., continues to exhibit fluid properties no matter how fast it is
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`stirred or mixed).
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`As used herein, “non-aqueous” refers to formulations of the invention including less than 10%
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`(w/w) water (e.g., less than 5%, 3%, 2%, 1.5%, 1%, 0.5%, or less than 0.1% (w/w) of the formulation is
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`water).
`
`As used herein, the term “shelf life” means the shelf life of the inventive LD prodrug product sold
`
`for use by consumers, during which period the product is suitable for use by a subject. The shelf life of
`
`the LD prodrugs of the invention can be greater than 3, 6, 12, 18, or preferably 24 months. The shelf life
`
`may be achieved when the product is stored frozen (e.g., at about -18 oC), stored refrigerated (at about 5 i
`
`3 0C, for example at about 4 i 2 0C), or stored at room temperature (e.g., at about 25°C). The LD
`
`prodrug product sold to consumers may be the solution ready for infusion, or it may be its components.
`
`For example, the LD prodrug product for use by consumers may be the dry solid LD prodrug and,
`
`optionally, the solution used for its reconstitution; or the LD prodrug stored in an acidic solution and,
`
`optionally, a neutralizing basic solution; etc.
`
`As used herein, the term “operational life” means the time period during which the infusion
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`solution containing the LD prodrug is suitable for infusion into a subject, under actual infusion
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`conditions. The operational life of the LD prodrugs of the invention can be greater than 12 hours, 24
`
`hours, 48 hours, 72 hours, 96 hours (4 days), or 7 days. It typically requires that the product is not frozen
`
`or refrigerated. The product is often infused at room temperature (e.g., about 25 0C), at body temperature
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`(about 37°C), or in-between (e.g., 30 OC).
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`As used herein, “stable” refers to formulations of the invention which are “oxidatively stable”
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`and “hydrolytieally stable.” Stable formulations exhibit a reduced susceptibility to chemical
`
`transformation (e. g., oxidation and/or hydrolysis) prior to infusion into a subject. Stable dry or liquid
`
`formulations are those having a shelf life during which less than 10%, 5%, 4%, 3%, 2% or less than 1%
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`of the LD prodrug (e.g., LDA, LDE, LDC, or LDS) is oxidized or hydrolyzed when stored for a period of
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`3, 6, 12, 18, or 24 months. In general, the solutions of the stable formulations remain clear, meaning that
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`they have no substantial visible precipitate, after their storage. Stable liquid formulations have an
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`operational life during which less than 10%, 5%, 4%, 3%, 2% or less than 1% of the LD prodrug (e.g.,
`
`LDA, LDE, LDC, or LDS) is oxidized or hydrolyzed over a period of 8 hours, 12 hours, 16 hours, 24
`
`hours, 48 hours, 72 hours, 96 hours, or 7 days. An “oxidatively stable” formulation exhibits a reduced
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`susceptibility to oxidation during its shelf life and/or its operational life, during which less than 10%, 5%,
`
`4%, 3%, or less than 2% of the LD prodrug (e.g., LDA, LDE, LDC, or LDS) is oxidized. A
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`“hydrolytieally stable” formulation exhibits a reduced susceptibility to hydrolysis during its shelf life
`
`and/or operational life in which less than 20%, 10%, 5%, 4%, 3%, 2% or less than 1% of the LD prodrug
`
`(e.g., LDA, LDE, LDC, or LDS) is hydrolyzed.
`
`As used herein, “substantially free LD precipitate” refers to formulations of the invention that are
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`clear and without visible precipitates of LD.
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`As used herein, “substantially free of oxygen” refers to compositions of the invention packaged
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`in a container for storage or for use wherein the packaged compositions are largely free of oxygen gas
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`(e.g., less than 10%, or less than 5%, of the gas that is in contact with the composition is oxygen gas) or
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`wherein the partial pressure of the oxygen is less than 15 torr, 10 torr, or 5 torr. This can be
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`accomplished by, for example, replacing a part or all of the ambient air in the container with an inert
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`atmosphere, such as nitrogen, carbon dioxide, argon, or neon, or by packaging the composition in a
`container under a vacuum.
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`As used herein, “substantially free of water” refers to compositions of the invention packaged in
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`a container (e. g., a cartridge) for storage or for use wherein the packaged compositions are largely free of
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`water (e.g., less than 2%, 1%, 0.5%, 0.1%, 0.05%, or less than 0.01% (w/w) of the composition is water).
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`This can be accomplished by, for example, drying the constituents of the formulation prior to sealing the
`container.
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`As used herein, the term “treating” refers to administering a pharmaceutical composition for
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`prophylactic and/or therapeutic purposes. To “prevent disease” refers to prophylactic treatment of a
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`subjcct who is not yet ill, but who is susceptible to, or otherwise at risk of, a particular disease. To “treat
`
`disease” or use for “therapeutic treatment” refers to administering treatment to a subject already suffering
`
`from a disease to ameliorate the disease and improve the subject’s condition. The term “treating” also
`
`comprises treating a subject to delay progression of a disease or its symptoms. Thus, in the claims and
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`embodiments, treating is the administration to a subject either for therapeutic or prophylactic purposes.
`
`As used herein, the terms “alkyl” and the prefix “alk-” are inclusive of both straight chain and
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`branched chain groups and of cyclic groups, i.e., cycloalkyl. Cyclic groups can be monocyclic or
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`polycyclic and preferably have from 3 to 6 ring carbon atoms, inclusive. Exemplary cyclic groups
`
`include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.
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`By “C 14 alkyl” is meant a branched or unbranched hydrocarbon group having from 1 to 6 carbon
`
`atoms. A C14 alkyl may be substituted or unsubstituted, may optionally include monocyclic or
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`polycyclic rings. Exemplary substituents include alkoxy, aryloxy, sulfliydryl, alkylthio, arylthio, halide,
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`hydroxyl, fluoroalkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, quaternary amino,
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`hydroxyalkyl, carboxyalkyl, and carboxyl groups.
`
`C 1,6 alkyls include, without limitation, methyl, ethyl, n-propyl, isopropyl, cyclopropyl,
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`cyclopropylmethyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, and cyclobutyl.
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`By “C255 alkenyl" is meant a branched or unbranched hydrocarbon group containing one or more
`
`double bonds and having from 2 to 6 carbon atoms. A CH, alkenyl may be substituted or unsubstituted,
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`may optionally include monocyclic or polycyclic rings. Exemplary substituents include alkoxy, aryloxy,
`
`sulfliydryl, alkylthio, arylthio, halide, hydroxyl, fluoroalkyl, perfluoralkyl, amino, aminoalkyl,
`
`disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups. CH; alkenyls
`
`include, without limitation, vinyl, allyl, 2-cyclopropyl-1-ethenyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-
`
`butenyl, 2-methyl-l-propenyl, and 2-methyl-2—propenyl.
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`
`By “ng alkynyl” is meant a branched or unbranched hydrocarbon group containing one or more
`
`triple bonds and having from 2 to 12 carbon atoms. A C24 alkynyl may be substituted or unsubstituted,
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`may optionally include monocyclic or polycyclic rings. Exemplary substituents include alkoxy, aryloxy,
`
`sulfliydryl, alkylthio, arylthio, halide, hydroxy, fluoroalkyl, perfluoralkyl, amino, aminoalkyl,
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`disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups. C245 alkynyls
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`include, without limitation, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and 3-butynyl.
`
`By “C642 aryl” is meant an aromatic group having a ring system comprised of carbon atoms with
`
`conjugated 7r electrons (e. g., phenyl). The aryl group has from 6 to 12 carbon atoms. Aryl groups may
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`optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has five or six
`
`members. The aryl group may be substituted or unsubstituted. Exemplary substituents include alkyl,
`
`hydroxy, alkoxy, aryloxy, sulfllydryl, alkylthio, arylthio, halide, fluoroalkyl, carboxyl, hydroxyalkyl,
`
`carboxyalkyl, amino, aminoalkyl, monosubstituted amino, disubstituted amino, and quaternary amino
`
`groups.
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`By “C744 alkaryl” is meant an alkyl or heteroalkyl substituted by an aryl group (e. g., benzyl,
`
`phenethyl, phenoxyethyl, or 3,4-dichlorophenethyl) having from 7 to 14 carbon atoms.
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`By “C 1,7 hctcroalkyl” is meant a branched or unbranchcd alkyl, alkcnyl, or alkynyl group having
`
`from 1 to 7 carbon atoms in addition tol, 2, 3 or 4 heteroatoms independently selected from the group
`
`consisting of N, O, S, and P. Heteroalkyls include, without limitation, saccharide radicals, tertiary
`
`amines, secondary amines, ethers, thioethers, amides, thioamides, carbamates, thiocarbamates,
`
`hydrazones, imines, phosphodiesters, phosphoramidates, sulfonamides, and disulfides. A heteroalkyl
`
`may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has three to
`
`six members. The heteroalkyl group may be substituted or unsubstituted. Exemplary substituents include
`
`alkoxy, aryloxy, sulfliydryl, alkylthio, arylthio, halide, hydroxyl, fluoroalkyl, perfluoralkyl, amino,
`
`aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, hydroxyalkyl, carboxyalkyl, and
`
`carboxyl groups. Examples of C 1,7 heteroalkyls include, without limitation, methoxymethyl and
`
`ethoxyethyl.
`
`By “C245 heterocyclyl” is meant a stable 5- to 7-membered monocyclic or 7- to 14-membered
`
`bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which
`
`consists of 2 to 6 carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from N, O, and S and
`
`including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene
`
`ring. The heterocyclyl group may be substituted or unsubstituted. Exemplary substituents include
`
`alkoxy, aryloxy, sulfliydryl, alkylthio, arylthio, halide, hydroxy, fluoroalkyl, perfluoralkyl, amino,
`
`aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups.
`
`The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be
`
`covalently attached Via any heteroatom or carbon atom which results in a stable structure, e.g., an
`
`imidazolinyl ring may be linked at either of the ring-carbon atom positions or at the nitrogen atom. A
`
`nitrogen atom in the heterocycle may optionally be quaternized. Preferably when the total number of S
`
`and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another.
`
`35
`
`Heterocycles include, without limitation, saccharide radicals.
`
`By “C340 alkheterocyclyl” is meant an alkyl or heteroalkyl substituted heterocyclic group having
`
`from 3 to 10 carbon atoms in addition to one or more heteroatoms (e. g., 3-furanylmethyl, 2-
`
`furanylmethyl, 3-tetrahydrofuranylmethyl, or 2-tetrahydrofuranylmethyl).
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`Summary of the Invention
`
`The invention features pharmaceutical compositions, devices and methods for the [management of
`
`PD. Specifically, it features compositions, devices and methods for maintaining plasma LD
`
`concentrations in a desired therapeutic range, thereby reducing the motor symptoms, non-motor
`
`symptoms, and