(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`(19) World Intellectual Property
`Organization
`International Bureau
`
`(43) International Publication Date
`28 July 2016 (28.07.2016)
`
`WIPOI PCT
`
`\é
`
`(51) International Patent Classification:
`A61K 9/00 (2006.01)
`A61K 31/195 (2006.01)
`A61K 9/10 (2006.01)
`A61K 31/198 (2006.01)
`A61K 47/38 (2006.01)
`
`(21)
`
`International Application Number:
`
`PCT/[18201 6/0 14005
`
`(74)
`
`(81)
`
`20 January 2016 (20.01.2016)
`
`(22) International Filing Date:
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`US
`US
`
`(30) Priority Data:
`62/105,565
`62/272,922
`
`20 January 2015 (20.01.2015)
`30 December 2015 (30.12.2015)
`
`1 North Waukegan
`(71) Applicant: ABBVIE INC. [US/US];
`Road, North Chicago, Illinois 60064 (US).
`
`(84)
`
`(72)
`
`Inventors: CONJEEVARAM, Rajkumar; 914 Safford
`Avenue, Lake Bluff, Illinois 60044 (US). DEAC, Alexan-
`dru; 9133 Crawford Avenue, Skokie, lllinois 60076 (US).
`HUANG, Ye; 33873 N. Summerfields Dr, Gurnee, Illinois
`60031 (US). MACKEY, Sean E.; 744 Walton Lane,
`Grayslake, Illinois 60030 (US). MENGES, Randy A.;
`36621 North Yew Tree Drive, Lake Villa, Illinois 60046
`
`(10) International Publication Number
`
`WO 2016/118556 A1
`
`(US). ZIMMERMAN, Jayne B.; 637 Elder Lane, Deer-
`field, Illinois 60606 (US).
`
`Agent: RAKERS, Leanne, M.; Harness, Dickey & Piece,
`P.L.C., 7700 Bonhomme, Suite 400, St. Louis, Missouri
`63105 (US).
`
`Designated States (unless otherwise indicated, for every
`kind ofnational protection available): AE, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG, BH, BN, 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, IR, IS, JP, KE, KG, KN, KP, KR,
`KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG,
`MK, MN, MW, MX, MY, MZ, NA, NG, N1, NO, NZ, OM,
`PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, 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.
`
`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, ST, SZ,
`TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, 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, KM, ML, MR, NE, SN, TD, TG).
`
`[Continued on nextpage]
`
`(54) Title: LEVODOPA AND CARBIDOPA INTESTINAL GEL AND METHODS OF USE
`
`Figure 4
`
`....\\\..
`LC gel (N=12)
`As» HC gel (N:12)
`
`2000
`1800
`1600
`1400
`1200 -
`1000 -
`800 -
`600 -
`400 -
`
`
`
`
`
`
`
`
` 200 - LevodopaPlasmaConcentration(ng/mL)
`
`
`
`(57) Abstract: The present disclosure relates to (a) an improved pharmaceutical composition comprising a levodopa active agent and
`a carbidopa active agent (b) methods of producing the pharmaceutical composition and (0) methods of treating Parkinson's disease
`and associated conditions comprising administering the pharmaceutical composition to a subject With Parkinson's disease.
`
`
`
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`WO 2016/118556 A1 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
`
`Declarations under Rule 4.17:
`
`Published:
`
`— as to applicant’s entitlement to applyfor and be granted — with international search report (Art. 21(3))
`apatent (Rule 4.17(ii))
`
`

`

`WO 2016/118556
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`PCT/US2016/014005
`
`LEVODOPA AND CARBIDOPA INTESTINAL GEL AND METHODS OF USE
`
`FIELD OF THE INVENTION
`
`[0001] The present disclosure relates to (a) an improved pharmaceutical
`
`composition comprising levodopa and carbidopa and (b) methods of
`
`treating
`
`Parkinson's disease and associated conditions comprising administering the
`
`pharmaceutical composition to a subject with Parkinson’s disease.
`
`10
`
`BACKGROUND OF THE INVENTION
`
`[0002]
`
`Parkinson's disease is a chronic and progressive neurodegenerative
`
`condition characterized by reduced levels in the brain of the neurotransmitter
`
`dopamine (i.e., 3,4-dihydroxyphenethylamine). Administration of L-dopa currently
`
`15
`
`is the most effective therapy for treating a patient with Parkinson’s disease. L-
`
`dopa, which unlike dopamine can cross the blood-brain barrier,
`
`is enzymatically
`
`converted in the brain to dopamine resulting in an increase in dopamine levels:
`
`HO
`
`HO
`
`0
`
`NH2
`
`Aromatic L-Amlno ACId
`Decarboxylase
`O H —>
`
`HO
`
`HO
`
`NH2
`
`L-Dopa
`
`Dopamine
`
`Formula (I)
`
`20
`
`25
`
`[0003]
`
`The conversion of L-dopa to dopamine is catalyzed by aromatic L-
`
`amino acid decarboxylase, a ubiquitous enzyme that promotes central as well as
`
`peripheral metabolism of L-dopa to dopamine. A relatively large dose of L-dopa is
`
`required to achieve therapeutically effective dopamine levels
`
`in
`
`the brain.
`
`Administration of such large L-dopa doses results in elevated peripheral dopamine
`
`levels that can cause nausea in some patients. To overcome these problems, L-
`
`dopa generally is co-administered with a peripheral aromatic L-amino acid
`
`-1-
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`

`

`WO 2016/118556
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`PCT/US2016/014005
`
`decarboxylase inhibitor such as carbidopa (i.e., (2S)-3-(3,4-dihydroxy-phenyl)-2-
`
`hydrazino—2—methylpropanoic acid):
`
`
`
`Carbidopa
`
`Formula (II)
`
`Co-administration of carbidopa with L-dopa inhibits the peripheral metabolism of
`
`L—dopa to dopamine, which significantly reduces the L—dopa dose required for a
`
`therapeutically effective response and reduces the associated side effects.
`
`10
`
`15
`
`20
`
`25
`
`[0004]
`
`Even when L-dopa and carbidopa are co-administered, however,
`
`it
`
`is difficult to consistently maintain the desired dopamine levels in the brain due to
`
`the relatively short half-life of L-dopa in plasma. In addition, the tolerance of many
`
`patients to variability in dopamine levels in the brain decreases as the disease
`
`progresses. One approach that has been effective in reducing variability of
`
`dopamine levels is the continuous intestinal delivery of an adjustable dose of an L-
`
`dopa/carbidopa gel known by its commercial name, DuoDopa®. DuoDopa® is a
`
`suspension of L—dopa/carbidopa monohydrate (4:1 ratio of L—dopa to carbidopa
`
`monohydrate) in an aqueous gel. The gel
`
`is delivered to the proximal small
`
`intestine through a jejunal
`
`tube inserted through a percutaneous endoscopic
`
`gastrostomy port. DuoDopa® is packaged in disposable drug reservoirs (“DDRs”)
`
`and continuously administered via a software-controlled ambulatory infusion
`
`pump. Although L-dopa and carbidopa have been co-administered to treat
`
`Parkinson’s disease for several decades, a pharmaceutical composition suitable
`
`for use in a newer generation of lighter, smaller infusion pumps that deliver gel
`
`compositions to the intestine is not currently commercially available.
`
`[0005]
`
`The
`
`current composition of
`
`the DuoDopa® L—dopa/carbidopa
`
`intestinal gel
`
`is a gel
`
`for continuous intestinal administration. For
`
`long—term
`
`administration,
`
`the gel
`
`is administered with a portable pump directly into the
`
`duodenum or upper jejunum via a percutaneous endoscopic gastrostomy tube
`
`-2-
`
`

`

`WO 2016/118556
`
`PCT/US2016/014005
`
`with an inner intestinal/jejunal tube. Each 1 ml of Duodopa® contains 20 mg
`
`levodopa and 5 mg carbidopa monohydrate. Despite the current commercial
`
`success of DuoDopa®, the product is subject to limitations in product preparation,
`
`including (1)
`
`risk of
`
`sedimentation of drug particles during storage and
`
`administration,
`
`(2) chemical
`
`instability of carbidopa, which leads to hydrazine
`
`formation.
`
`[0006] Accordingly, there is a continuing need for improved formulations
`
`and methods that can provide continuous and consistent dopamine levels in the
`
`brain to effectively treat movement disorders such as Parkinson's disease. The
`
`present disclosure provides such improved formulations and methods.
`
`SUMMARY OF THE INVENTION
`
`[0007]
`
`In one aspect, the present disclosure relates to a pharmaceutical
`
`composition comprising a levodopa active agent and a carbidopa active agent for
`
`intraduodenal administration wherein the levodopa active agent is provided in an
`
`amount of about 4 weight/weight percent
`
`(w/w%) of
`
`the composition and
`
`carbidopa (e.g., carbidopa monohydrate) is provided in an amount of about
`
`1
`
`weight/weight percent of the composition wherein the levodopa and carbidopa are
`
`suspended in an aqueous carrier. The pharmaceutical composition has a desired
`
`viscosity suitable for storage under refrigerated conditions and/or delivery (e.g.,
`
`delivered via a pump) at room temperature (e.g., ~20 °C to ~25 °C).
`
`[0008]
`
`In another aspect,
`
`the present disclosure relates to a method of
`
`treating Parkinson’s disease in a patient in need thereof, wherein the method
`
`comprises administering to the patient a pharmaceutical composition comprising a
`
`levodopa
`
`active
`
`agent
`
`and a carbidopa active
`
`agent
`
`for
`
`intraduodenal
`
`administration wherein the levodopa active agent and carbidopa active agent
`
`(e.g., carbidopa monohydrate) are provided in an amount of
`
`from about 4
`
`weight/weight percent
`
`and 1 weight/weight percent
`
`of
`
`the
`
`composition,
`
`respectively, suspended in an aqueous carrier. The pharmaceutical composition
`
`10
`
`15
`
`20
`
`25
`
`30
`
`

`

`WO 2016/118556
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`PCT/US2016/014005
`
`has a desired viscosity suitable for storage under refrigerated conditions and/or
`
`delivery (e.g., delivered via a pump) at room temperature (e.g., ~20°C to ~25 °C).
`
`[0009]
`
`In another aspect,
`
`the present disclosure relates to methods of
`
`manufacturing a pharmaceutical composition of the invention, in particular a high
`
`concentration pharmaceutical composition as disclosed, for example, in Example
`
`1 and Figure 1 below.
`
`[0010] These and additional embodiments of
`
`the invention are further
`
`described herein.
`
`[0011]
`
`Further benefits of the present disclosure will be apparent to one
`
`skilled in the art from reading this patent application. The embodiments of the
`
`disclosure described in the following paragraphs are intended to illustrate the
`
`invention and should not be deemed to narrow the scope of the invention.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`[0012]
`
`Figure 1
`
`is a manufacturing process flowchart for producing an
`
`exemplary pharmaceutical formulation of the invention.
`
`[0013]
`
`Figure 2 shows the L—Dopa blood level time—concentration profile in
`
`mini—pigs of an exemplary pharmaceutical composition of the invention as against
`
`two comparators, all given in a six-hour continuous infusion.
`
`[0014]
`
`Figure 3 shows the carbidopa blood level time-concentration profile
`
`in mini-pigs of an exemplary pharmaceutical composition of the invention as
`
`against two comparators, all given in a six-hour continuous infusion.
`
`[0015]
`
`Figure 4 shows average Ievodopa plasma concentrations in 12
`
`human subjects at various time points post administration.
`
`[0016]
`
`Figure 5 shows average carbidopa plasma concentrations in 12
`
`human subjects at various time points post administration.
`
`10
`
`15
`
`20
`
`

`

`WO 2016/118556
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`PCT/US2016/014005
`
`[0017]
`
`Figure 6 shows the dissolution rate at which levodopa and carbidopa
`
`dissolve in a pH 4.5 media.
`
`[0018]
`
`Figure 7 shows the dissolution rate at which levodopa and carbidopa
`
`dissolve in a pH 6.8 media.
`
`U]
`
`[0019]
`
`Figure 8 charts the decomposition of low and high concentration gel
`
`formulations into 3,4-dihydroxyphenylacetone (DHPA) over the course of 15
`
`weeks storage at 2—8°C.
`
`[0020]
`
`Figure 9 charts the decomposition of low and high concentration gel
`
`formulations into 2-methyl-3-(3,4-dihydroxyphenyl) propanoic acid (DHPPA) over
`
`10
`
`the course of 15 weeks storage at 2—8 °C.
`
`[0021]
`
`Figure 10 charts the decomposition of low and high concentration
`
`gel formulations into hydrazine over the course of 15 weeks storage at 2—8 °C.
`
`[0022]
`
`Figure 11
`
`shows the effects of oxygen scavengers in different
`
`packages on the accumulation of DHPA (panel A) and DHPPA (panel B)
`
`15
`
`degradation products. The abbreviations in
`
`the legend have the following
`
`significations: 1X = 2 w/w% levodopa, 0.5 w/w% carbidopa; 2X = 4 w/w%
`
`levodopa, 1.0 w/w% carbidopa; EVA = container closure bag made from
`
`EVA/EVOH/EVA material; Smiths = PVC bag used in Smiths Medical cassette
`
`reservoir; OW + Scav = with oxygen scavenger inside overwrapped aluminum foil
`
`20
`
`pouch.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`[0023]
`
`This written description uses examples to disclose the invention,
`
`25
`
`including the best mode, and also to enable any person skilled in the art
`
`to
`
`practice the invention,
`
`including making and using any of
`
`the disclosed
`
`pharmaceutical compositions, kits, pharmaceutical dosage forms, and performing
`
`any of the disclosed methods or processes. The patentable scope of the invention
`
`is defined by the claims, and may include other examples that occur to those
`
`-5-
`
`

`

`WO 2016/118556
`
`PCT/US2016/014005
`
`skilled in the art. Such other examples are intended to be within the scope of the
`
`claims if they have elements that do not differ from the literal language of the
`
`claims, or if they include equivalent elements.
`
`|.
`
`Definitions
`
`[0024]
`
`Section headings as used in this section and the entire disclosure
`
`are not intended to be limiting.
`
`[0025] Where a numeric range is recited, each intervening number within
`
`the range is explicitly contemplated with the same degree of precision. For
`
`example, for the range 6 to 9, the numbers 7 and 8 are contemplated in addition
`
`to 6 and 9, and for the range 6.0 to 7.0, the numbers 6.0, 6.1, 6.2, 6.3, 6.4, 6.5,
`
`10
`
`6.6, 6.7, 6.8, 6.9 and 7.0 are explicitly contemplated.
`
`In the same manner, all
`
`recited ratios also include all sub-ratios falling within the broader ratio.
`
`[0026]
`
`The singular forms “a,
`
`an,” and “the” include plural referents unless
`
`5! n
`
`the context clearly dictates otherwise.
`
`[0027]
`
`The term “and/or” as used in a phrase such as “A and/or B” herein is
`
`15
`
`intended to include “A and B”, “A or B”, “”A, and “”.B
`
`[0028]
`
`The term “about” generally refers to a range of numbers that one of
`
`skill in the art would consider equivalent to the recited value (i.e., having the same
`
`function or result).
`
`In many instances, the term "about" may include numbers that
`
`are rounded to the nearest significant figure.
`
`[0029] Unless
`
`the context
`
`requires otherwise,
`
`the terms
`
`"comprise,"
`
`"comprises," and “comprising" are used on the basis and clear understanding that
`
`they are to be interpreted inclusively, rather than exclusively, and that Applicant
`
`intends each of
`
`those words to be so interpreted in construing this patent,
`
`including the claims below.
`
`[0030]
`
`The terms "improve" and “improving” have their plain and ordinary
`
`meaning to one skilled in the art of pharmaceutical or medical sciences and
`
`20
`
`25
`
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`WO 2016/118556
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`PCT/US2016/014005
`
`specifically include ameliorating the effects of Parkinson’s disease, or decreasing
`
`or lessening a symptom or side effect of Parkinson’s disease.
`
`[0031]
`
`The term "patient" includes mammals and humans, particularly
`
`humans.
`
`U]
`
`[0032]
`
`The term "pharmaceutically acceptable carrier" or "pharmaceutically
`
`acceptable
`
`excipient"
`
`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 term
`
`“aqueous carrier” refers to a pharmaceutically acceptable carrier in which the
`
`10
`
`solvent is water.
`
`15
`
`20
`
`25
`
`[0033]
`
`The term "pharmaceutically acceptable salt" refers to a salt of a
`
`compound that is pharmaceutically acceptable and that possesses the desired
`
`pharmacological activity of the parent compound. Such salts include:
`
`(1) acid
`
`addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic
`
`acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic
`
`acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic
`
`acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid,
`
`maleic
`
`acid,
`
`fumaric
`
`acid,
`
`tartaric
`
`acid,
`
`citric
`
`acid, benzoic acid,
`
`3-(4-
`
`hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,
`
`ethanesulfonic acid, 1,2—ethane—disulfonic acid, 2—hydroxyethanesulfonic acid,
`
`benzenesulfonic acid, 4—chlorobenzenesulfonic acid, 2—naphthalenesulfonic acid,
`
`4-toluenesulfonic acid, camphorsulfonic acid, 4-methyl-bicyclo[2.2.2]-oct-2—ene-1-
`
`carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid,
`
`tertiary butylacetic acid,
`
`lauryl
`
`sulfuric acid, gluconic acid, glutamic acid,
`
`hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; and
`
`(2) salts formed when an acidic proton present in the parent compound either is
`
`replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an
`
`aluminum ion; or coordinates with an organic base such as ethanolamine,
`
`diethanolamine, triethanolamine, N—methylglucamine, dicyclohexylamine, and the
`
`30
`
`like.
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`

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`WO 2016/118556
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`
`[0034]
`
`The terms "reduce" and "reducing" have their plain and ordinary
`
`meanings to one skilled in the art of pharmaceutical or medical sciences and
`
`specifically include diminishing or decreasing the number of occurrences,
`
`the
`
`duration, or the intensity, of a Parkinson’s disease symptom or side effect, such as
`
`dyskinesias or hallucinations.
`
`[0035]
`
`The term "therapeutically effective amount" means an amount of a
`
`compound that, when administered to a patient suffering from or susceptible to
`
`Parkinson’s disease or an associated condition is sufficient, either alone or in
`
`combination with additional therapies, to effect treatment for Parkinson’s disease
`
`or the associated condition. The "therapeutically effective amount" will vary
`
`depending,
`
`for example, on the compound, pharmaceutical composition or
`
`pharmaceutical dosage form, the condition treated and its severity, and the age
`
`and weight of the patient to be treated.
`
`[0036]
`
`The terms "treat" and "treating" have their plain and ordinary
`
`meaning to one skilled in the art of pharmaceutical or medical sciences and
`
`specifically include improving the quality of life or reducing the symptoms or side
`
`effects of Parkinson’s disease.
`
`ll.
`
`Pharmaceutical Compositions
`
`[0037]
`
`The present disclosure relates to a pharmaceutical composition
`
`comprising a
`
`levodopa
`
`active
`
`agent and a carbidopa active agent
`
`for
`
`intraduodenal administration wherein the levodopa active agent and carbidopa
`
`active agent are present in a therapeutically effective amount suspended in an
`
`aqueous carrier, characterized in
`
`that
`
`the levodopa active agent and the
`
`carbidopa active agent in the carrier has a high shear viscosity of no more than
`
`about 4500 cps at room temperature (e.g., ~20 °C to ~25 °C, such as ~22 °C) and a
`
`low shear viscosity of no less than about 45000 cps under refrigerated storage
`
`conditions (for example, at about 2°C to about 8°C, such as 5°C). Additionally or
`
`alternatively, the pharmaceutical composition—i.e., the aqueous carrier with the
`
`levodopa active agent and carbidopa active agent suspended therein—can have a
`
`ratio of low shear viscosity to high shear viscosity of not less than about 10.
`
`In
`
`particular,
`
`the aqueous carrier with the levodopa active agent and carbidopa
`
`-8-
`
`10
`
`15
`
`20
`
`25
`
`30
`
`

`

`WO 2016/118556
`
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`
`active agent suspended therein can have a high shear viscosity of no more than
`
`about 4500 cps at room temperature (e.g., ~20 °C to ~25 °C, such as ~22 °C) and a
`
`low shear viscosity of no less than about 45000 cps under refrigerated storage
`
`conditions (for example, at about 2°C to about 8°C, such as 5°C) and a ratio of
`
`low shear viscosity to high shear viscosity of not
`
`less than about 10. The
`
`pharmaceutical compositions may have the aforementioned low shear viscosity
`
`and high shear viscosity throughout shelf life. As used herein, “shelf life” includes
`
`at least about 2 weeks, for example, at least about 5 weeks, at least about 10
`
`weeks, at least about 15 weeks, or at least about 20 weeks. For example, the
`
`pharmaceutical composition can have a high shear viscosity of about 4300—4400
`
`cps (at ~22 °C) and a low shear viscosity of about 49600 cps (at ~5°C) throughout
`
`its shelf life.
`
`[0038]
`
`Both low shear and high shear viscosity can be measured by routine
`
`methods known in
`
`the art. For purposes of measuring viscosity of
`
`the
`
`compositions and formulations disclosed herein,
`
`low shear viscosity should be
`
`measured in a sample of ~9 mL at a temperature of ~5°C and a shear rate of ~0.1
`
`sec—1.
`
`If the viscosity is measured in, e.g., a BROOKFIELD Model LV viscometer
`
`(for example in sample chamber SC4-13R with temperature probe and water
`
`jacket assembly SC4—45Y), then the test should be conducted with an SC4—31
`
`model spindle. Where other equipment
`
`is used, a spindle of corresponding
`
`dimensions and specifications can be substituted accordingly.
`
`[0039] High sheer viscosity should be measured in a sample of ~16 mL at a
`
`temperature of ~22 °C and a shear rate of ~24.1 sec—1.
`
`If the viscosity is measured
`
`in, e-g., a BOHLIN model 88 BV rotational viscometer, then the test should be
`
`conducted with a C25 cylinder/spindle system. Where other equipment is used, a
`
`spindle of corresponding dimensions and specifications can be substituted
`
`accordingly.
`
`[0040]
`
`In various aspects,
`
`the therapeutically effective amount of a
`
`levodopa
`
`active
`
`agent
`
`and a
`
`carbidopa
`
`active
`
`agent
`
`(e.g.,
`
`carbidopa
`
`monohydrate) present in the pharmaceutical composition may be about 4.0 and
`
`1.0 weight/weight percent of the composition, respectively.
`
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`[0041] As previously noted, the inherently low aqueous solubility of L-dopa
`
`and carbidopa at physiologically acceptable pH for infusion presents a significant
`
`technical challenge to the development of improved pharmaceutical compositions
`
`and methods of treatment. Such challenges include, for example, difficulties in
`
`achieving formulation stability within the required pH limitations. These challenges
`
`are further complicated by the requirement that the pharmaceutical compositions
`
`and methods
`
`of
`
`treatment
`
`provide
`
`pharmacokinetically-appropriate
`
`and
`
`pharmacokinetically-consistent control of dopamine levels in the patient’s brain.
`
`[0042]
`
`In one embodiment,
`
`the pharmaceutical composition comprises a
`
`levodopa active agent in an amount of about 4.0 weight/weight percent of the total
`
`composition; a carbidopa active agent
`
`(e.g., carbidopa monohydrate)
`
`in an
`
`amount of about 1.0 weight/weight percent of the total composition; at least one
`
`suspending agent; and a liquid vehicle
`
`(for example, water).
`
`In various
`
`embodiments,
`
`the liquid vehicle can make up from about zero weight/weight
`
`percent to about 95 weight/weight percent of the total composition, for example
`
`from about 10 weight/weight percent to about 70 weight/weight percent, or from
`
`about 40 weight/weight percent to about 60 weight/weight percent of the total
`
`composition.
`
`[0043]
`
`In one embodiment,
`
`the levodopa active agent
`
`is levodopa and
`
`pharmaceutically acceptable salts or hydrates
`
`thereof,
`
`such as
`
`levodopa
`
`monohydrate. Levodopa is preferably present in the composition in an amount of
`
`from about 1.0 to 5.0 weight/weight percent in the total composition. In a preferred
`
`embodiment the pharmaceutical composition comprises about 4.0 weight/weight
`
`percent of a levodopa active agent. In one embodiment, the levodopa active agent
`
`can be processed into microparticles or microspheres or the like, for example as
`
`described in Example 1 below,
`
`for
`
`inclusion in the present pharmaceutical
`
`compositions.
`
`[0044]
`
`In one embodiment,
`
`the carbidopa active agent is carbidopa and
`
`pharmaceutically acceptable salts or hydrates thereof,
`
`such as carbidopa
`
`monohydrate. The carbidopa active agent is preferably present in the composition
`
`in an amount of from about 0.25 to 1.25 weight/weight percent
`
`in the total
`
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`composition.
`
`In
`
`a preferred embodiment
`
`the pharmaceutical
`
`composition
`
`comprises about 1.0 weight/weight percent of a carbidopa active agent. The
`
`preferred form of carbidopa active agent
`
`to be administered is carbidopa
`
`monohydrate.
`
`In one embodiment, the carbidopa active agent can be processed
`
`into microparticles or microspheres or the like,
`
`for example as described in
`
`Example 1 below, for inclusion in the present pharmaceutical compositions.
`
`10
`
`15
`
`[0045]
`
`The levodopa active agent and carbidopa active agent may be
`
`present in the pharmaceutical composition in any suitable ratio, for example, the
`
`ratio of
`
`levodopa active agent
`
`to carbidopa active agent
`
`(e.g., carbidopa
`
`monohydrate) in the present pharmaceutical compositions may be about 4:1. For
`
`example,
`
`the pharmaceutical composition can comprise about 4 weight/weight
`
`percent of levodopa active agent and 1 weight/weight percent carbidopa active
`
`agent (e.g., carbidopa monohydrate).
`
`In one embodiment,
`
`the pharmaceutical
`
`composition comprises a liquid or viscous liquid comprising about 200 mg
`
`levodopa and about 50 mg carbidopa (e.g., carbidopa monohydrate) per each 5.0
`
`mL volume.
`
`In one embodiment, the levodopa active agent and the carbidopa
`
`active agent are processed into microparticles or microspheres or the like, for
`
`example as described in Example 1
`
`below,
`
`for
`
`inclusion in
`
`the present
`
`20
`
`pharmaceutical compositions.
`
`25
`
`30
`
`[0046] The ratio of levodopa active agent, or of the combination of levodopa
`
`active agent to carbidopa active agent, to a suspending agent is from about 3 to
`
`about 1 w/w% to about 1
`
`to about 30 w/w%, with a generally preferred range from
`
`about 2 to about 1 w/w% to about 1
`
`to about 10 w/w%. Such readily available
`
`suspending agents are well known in the art and can include polymer-based
`
`suspending agents, such as, but not limited to, carbohydrate-based suspending
`
`agents and acrylic acid—based polymers (e.g., Carbomer, Carbopol®). Exemplary
`
`carbohydrate—based
`
`suspending agents
`
`include,
`
`but
`
`are
`
`not
`
`limited
`
`to
`
`hydroxypropylcellulose,
`
`hydroxymethylcellulose,
`
`and sodium carboxymethyl
`
`cellulose (NaCMC). Acrylic acid-based polymers may be cross-linked,
`
`for
`
`example, cross-linked with polyalkenyl ethers or divinyl glycol.
`
`In particular, the
`
`suspending agent may be sodium carboxymethyl cellulose (NaCMC) or Carbopol.
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`[0047]
`
`For the present compositions, one or more suspending agents can
`
`be used to obtain the ratios of levodopa active agent, or of the combination of
`
`levodopa active agent to carbidopa active agent, to suspending agent as set forth
`
`above.
`
`U]
`
`[0048] However, when a surfactant
`
`is used,
`
`it may be best to add the
`
`surfactant or surfactants following addition of levodopa active agent and carbidopa
`
`active agent and suspending agent as taught herein.
`
`[0049]
`
`It should be understood that each component comprising the
`
`compositions of the present invention must be pharmaceutically acceptable and
`
`10
`
`utilized in a non-toxic concentration.
`
`[0050]
`
`In one embodiment,
`
`the pharmaceutical composition is a
`
`viscous liquid composition.
`
`In one aspect,
`
`the pharmaceutical composition
`
`comprises water and is suitable for infusion.
`
`[0051]
`
`In another embodiment,
`
`the pharmaceutical composition is an
`
`aqueous
`
`pharmaceutical
`
`composition
`
`having
`
`a
`
`levodopa
`
`active
`
`agent
`
`concentration of at least about 5 mg/mL. In one aspect, the levodopa active agent
`
`concentration is at least about 10 mg/mL.
`
`In another aspect, the levodopa active
`
`agent concentration is at least about 20 mg/mL.
`
`In another aspect, the levodopa
`
`active agent concentration is at least about 30 mg/mL.
`
`In another aspect, the
`
`levodopa active agent concentration is at
`
`least about 35 mg/mL.
`
`In another
`
`aspect, the levodopa active agent concentration is at least about 40 mg/mL.
`
`In
`
`another aspect,
`
`the levodopa active agent concentration is at
`
`least about 45
`
`mg/mL.
`
`In another aspect,
`
`the levodopa active agent concentration is at least
`
`about 50 mg/mL. In another aspect, the levodopa active agent concentration is at
`
`least about
`
`100 mg/mL.
`
`In
`
`another aspect,
`
`the
`
`levodopa active agent
`
`concentration is at least about 150 mg/ mL. In another aspect, the levodopa active
`
`agent concentration is at least about 200 mg/mL.
`
`[0052]
`
`In another embodiment,
`
`the pharmaceutical composition is an
`
`aqueous pharmaceutical composition having a carbidopa active agent
`
`(e.g.,
`
`carbidopa monohydrate) concentration of at least about 5 mg/mL.
`
`In one aspect,
`
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`the carbidopa active agent concentration is at least about 10 mg/mL.
`
`In another
`
`aspect, the carbidopa active agent concentration is at least about 20 mg/mL.
`
`In
`
`another aspect,
`
`the carbidopa active agent concentration is at least about 30
`
`mg/mL.
`
`In another aspect, the carbidopa active agent concentration is at least
`
`about 50 mg/mL. In another aspect, the carbidopa active agent concentration is at
`
`least about 100 mg/mL.
`
`In another aspect,
`
`the carbidopa active agent
`
`concentration is at least about 150 mg/ mL.
`
`In another aspect, the active agent
`
`carbidopa concentration is at least about 200 mg/mL.
`
`[0053]
`
`The
`
`pharmaceutical
`
`compositions
`
`of
`
`the present disclosure
`
`optionally comprise one
`
`or more
`
`additional pharmaceutically acceptable
`
`excipients. The term "excipient" refers to any substance, not itself a therapeutic
`
`agent, used as a carrier or vehicle for delivery of a therapeutic agent to a subject
`
`or added to a pharmaceutical composition to improve its handling or storage
`
`properties or to permit or facilitate formation of a unit dose of the composition.
`
`[0054]
`
`Excipients include, for example, antioxidants, agents to adjust the
`
`pH and osmolarity, preservatives, thickening agents, colorants, buffering agents,
`
`bacteriostats, and stabilizers. A given excipient,
`
`if present, generally will be
`
`present in an amount of about 0.001% to about 95%, about 0.01% to about 80%,
`
`about 0.02% to about 25%, or about 0.3% to about 10%, by weight.
`
`[0055]
`
`In one embodiment,
`
`the pharmaceutical compositions optionally
`
`comprise an antioxidant. Suitable antioxidants for use in the pharmaceutical
`
`compositions
`
`include,
`
`for
`
`example,
`
`butylated
`
`hydroxytoluene,
`
`butylated
`
`hydroxyanisole, potassium metabisulfite, cysteine, and the like.
`
`[0056]
`
`In one embodiment,
`
`the pharmaceutical compositions optionally
`
`comprise a buffering agent. Buffering agents include agents that reduce pH
`
`changes. Suitable classes of buffering agents for use in various embodiments of
`
`the present invention comprise a salt of a Group IA metal including, for example, a
`
`bicarbonate salt of a Group IA metal, a carbonate salt of a Group IA metal, an
`
`alkaline or alkali earth metal buffering agent, an aluminum buffering agent, a
`
`calcium buffering agent, a sodium buffering agent, or a magnesium buffering
`
`agent. Suitable buffering agents
`
`further
`
`include
`
`carbonates, phosphates,
`
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`bicarbonates, citrates, borates, acetates, phthalates, tartrates, succinates of any
`
`of the foregoing, for example, sodium or potassium phosphate, citrate, borate,
`
`acetate, bicarbonate and carbonate.
`
`[0057]
`
`In one embodiment, the composition has a pH from about 3.5 to
`
`about 8.
`
`In one aspect, the pH is from about 3.5 to about 7.5.
`
`In another aspect,
`
`the pH is from about 4.0 to about 7.5.
`
`In another aspect, the pH is from about 5.0
`
`to about 7.5.
`
`In another aspect, the pH is from about 5.5 to about 7.5.
`
`In another
`
`aspect, the pH is from about 6.0 to about 7.5.
`
`[0058]
`
`In various embodiments,
`
`the pharmaceutical composition may be
`
`present in a container. Suitable containers include containers (e.g., a bag) with
`
`lower
`
`oxygen
`
`permeability
`
`(e.g.,
`
`oxygen
`
`transmission
`
`rate
`
`of
`
`~0.95
`
`cc/(100in2*day))
`
`or which
`
`are oxygen
`
`impermeable. These
`
`low oxygen
`
`permeability barriers may be incorporated into the primary container of a
`
`secondary outer container. Non-limiting examples of suitable containers include
`
`DDR (Disposable Drug Reservoirs) bags, such as an EVA/EVOH/EVA bag.
`
`[0059]
`
`In still other embodiments, the present disclosure relates to a ready-
`
`to-use vial or cartridge or container or enclosure suitable for liquid pharmaceutical
`
`dosage formulation containment. Such container may serve the function of holding
`
`a liquid formulation containing one or more active ingredients. The vials can also
`
`serve as storage for powder forms of the active ingredients such that the vial can
`
`be in a ready to use format wherei