(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(10) International Publication Number
`
`WO 2018/017850 A1
`
`h a
`
`WIPOI PCT
`
`(19) World Intellectual Property
`Organization
`International Bureau
`
`(43) International Publication Date
`
`25 January 2018 (25.01.2018)
`
`(51)
`
`International Patent Classification:
`
`A61K 9/00 (2006.01)
`A61K 47/10 (2017.01)
`A61K 47/32 (2006.01)
`A61K 47/38 (2006.01)
`
`A61K 31/195 (2006.01)
`A61K31/198 (2006.01)
`A61P 25/16 (2006.01)
`
`cle, Lake Forest, Illinois 60045 (US). TUN, Thin Yu; 591
`Sandwedge Place, Gurnee, Illinois 60031 (US).
`
`(74)
`
`Agent: MILLONIG, Robert, C. et a1.; Sterne, Kessler,
`Goldstein & Fox P.L.L.C., l 100 New York Avenue N.W.,
`Washington, District of Columbia 20005-3934 (US).
`
`(21)
`
`International Application Number:
`
`PCT/US2017/043103
`
`(81)
`
`(22)
`
`International Filing Date:
`
`(25)
`
`(26)
`
`(30)
`
`(71)
`
`(72)
`
`Filing Language:
`
`Publication Language:
`
`20 July 2017 (20.07.2017)
`
`English
`
`English
`
`Priority Data:
`62/364,770
`
`20 July 2016 (20.07.2016)
`
`US
`
`1 North Waukcgan
`Applicant: ABBVIE INC. [US/US];
`Road, North Chicago, Illinois 60064 (US).
`
`(84)
`
`Inventors: DEAC, Alexandru; 9133 Crawford Avenue,
`Skokie, Illinois 60076 (US). HUANG, Ye; 33873 Sum-
`merfields Drive, Gurnee, Illinois 60031 (US). LIPARI,
`John, M.; 6600 Apollo Drive, Mount Pleasant, Wisconsin
`53406 (US). RUGGLES, Alexander; 175 Washington Cir-
`
`Designated States (unless otherwise indicated, for every
`kind ofnational protection available): AE, AG, AL, AM,
`A0, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ,
`CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO,
`DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN,
`HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP,
`KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME,
`MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, 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, IIR, IIU, IE, IS, IT, LT, LU, LV,
`MC, MK, MT, NL, N0, PL, PT, RO, RS, SE, S1, SK, SM,
`
`(54) Title: LEVODOPA AND CARBIDOPA INTESTINAL GEL AND METHODS OF USE
`
`Figure 1
`
`Process
`
`High or Low Shear Mixing
`(Slurry Preparation)
`
`
`
`Materials
`Water
`
`
`Suspending Agent (eg Carbopol 974p)
`Low Shear Mixing Under Vacuum
`
`
`
`Neutralizing Agentleg. NaOH)
`(Gel Preparation)
`
`
`
`Nitrogen
`
`
`
`Levodopa
`
`
`Carbidopa Monohyd rate
`
`Water
`
`
`low Shear Mixmg Under Vacuum
`Nitrogen
`
`
`(Gel Suspension Preparation)
`
`
`
`Filling
`Disposable Drug Reservoir (DDR1
`
`
`
`Foil Pouch
`Foil Pouching
`
`
`
`Kits.
`
`IT—fi
`
`Packaging
`
`
`
`(57) Abstract: The present disclosure provides (a) a pharmaceutical composition comprising a levodopa active agent and a carbidopa
`actiVe agent and (b) methods of treating Parkinson's disease and associated conditions comprising administering the pharmaceutical
`composition to a subject with Parkinson's disease.
`
`[Continued on nextpage]
`
`
`
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`
`

`

`WO 2018/017850 A1 ||||||||||||||||||||||||||||||||||||| ||||||||||||||| ||||||||||||||| ||||||||||||||||||||||||||||
`
`TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW,
`KM, ML, MR, NE, SN, TD, TG).
`
`Published:
`
`— with international search report (Art. 21(3))
`
`

`

`WO 2018/017850
`
`PCT/US2017/043103
`
`LEVODOPA AND CARBIDOPA INTESTINAL GEL AND METHODS OF USE
`
`FIELD OF THE INVENTION
`
`[0001]
`
`The present disclosure provides (a) a pharmaceutical composition comprising a
`
`levodopa active agent and a carbidopa active agent; and (b) methods of treating
`
`Parkinson's
`
`disease
`
`and
`
`associated
`
`conditions
`
`comprising
`
`administering
`
`the
`
`pharmaceutical composition to a subject with Parkinson's disease.
`
`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 levodopa (or L—dopa) currently 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:
`0
`
`HO
`
`HO
`
`NH2
`
`L-Dopa
`
`Formula (I)
`
`Aromatic L-Amino Acid
`Decarboxylase
`OH —>
`
`HO
`
`HO
`
`NHg
`
`Dopamine
`
`[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 decarboxylase inhibitor such as carbidopa (i.e., (ZS)-3-
`
`(3,4-dihydroxy-phenyl)-2-hydrazino-2-methylpropanoic acid):
`
`

`

`WO 2018/017850
`
`PCT/US2017/043103
`
`
`
`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.
`
`[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 gel composition suitable for storage at room temperature 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 with an inner intestinal/j ejunal 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
`
`

`

`WO 2018/017850
`
`PCT/US2017/043103
`
`treat movement disorders such as Parkinson's disease. The present disclosure provides
`
`such improved formulations and methods.
`
`SUlVllVIARY OF THE INVENTION
`
`[0007]
`
`In one aspect,
`
`the present disclosure provides a pharmaceutical composition
`
`comprising a levodopa active agent and a carbidopa active agent for intraduodenal
`
`administration, wherein the levodopa active agent and the carbidopa active agent are
`
`suspended in one or more polymer—based suspending agents, e.g., a carbomer, and the
`
`pharmaceutical composition has a yield value of at least about 0.3 Pascal (Pa) and an
`
`acceptance value of S 15. The levodopa active agent may be provided in an amount of
`
`about 4 weight/weight percent (w/w %) of the composition and the carbidopa active agent
`
`(e.g., carbidopa monohydrate) may be provided in an amount of about 1 weight/weight
`
`percent of the composition. Pharmaceutical compositions of the disclosure have a yield
`
`value that provides physical stability for at least about 8 weeks, at least about 15 weeks, at
`
`least about 26 weeks, or at least about 60 weeks, under one or more storage conditions,
`
`e. g, at 5 °C, at room temperature (e. g., about 20°C to about 25°C) and a relative humidity
`
`(RH) of about 60%, or at about 40°C and a RH of about 75%.
`
`[0008]
`
`In another aspect, the present disclosure provides a pharmaceutical composition
`
`comprising a levodopa active agent and a carbidopa active agent for intraduodenal
`
`administration wherein the levodopa active agent and the carbidopa active agent are
`
`suspended in one or more polymer-based suspending agents and the pharmaceutical
`
`composition has a yield value of at least about 1.1 Pascal (Pa). The levodopa active agent
`
`may be provided in an amount of about 4 weight/weight percent (w/w %) of the
`
`composition and the carbidopa active agent (e.g., carbidopa monohydrate) may be
`
`provided in an amount of about
`
`1 weight/weight percent of the composition. The
`
`pharmaceutical composition has a desired yield value suitable for physical stability for at
`
`least about 15 weeks at room temperature (e.g., about 20°C to about 25°C).
`
`[0009]
`
`In another aspect, the present disclosure provides 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
`
`4weight/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 and
`
`

`

`WO 2018/017850
`
`PCT/US2017/043103
`
`is stored in individual disposable drug reservoirs ("DDR"). The DDR containing the
`
`pharmaceutical composition is covered by a material that acts as a complete oxygen
`
`barrier, such as a foil pouch. This packaging ensures that the pharmaceutical composition
`
`is suitable for chemical stability for at least about 15 weeks at room temperature (e.g.,
`
`about 20°C to about 25°C).
`
`[0010]
`
`In another aspect, the present disclosure provides 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 the
`
`carbidopa active agent are suspended in one or more polymer-based suspending agents
`
`and the pharmaceutical composition has a yield value of at least about 4 Pa. The
`
`levodopa agent may be provided in an amount of about 4 weight/weight percent (w/w %)
`
`of the composition and the carbidopa active agent (e. g., carbidopa monohydrate) may be
`
`provided in an amount of about
`
`1 weight/weight percent of the composition. The
`
`pharmaceutical composition has a desired yield value suitable for physical stability for at
`
`least about 15 weeks at room temperature (e.g., about 20°C to about 25°C).
`
`[0011]
`
`In another aspect, the present disclosure relates to methods of manufacturing a
`
`pharmaceutical composition of the disclosure,
`
`in particular a high concentration
`
`pharmaceutical composition as disclosed, for example, in Example 1 and Figure 1 below.
`
`[0012]
`
`[0013]
`
`These and additional embodiments of the disclosure are further described herein.
`
`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
`
`[0014]
`
`Figure 1
`
`is a manufacturing process flowchart for producing an exemplary
`
`pharmaceutical formulation of the disclosure.
`
`[0015]
`
`Figure 2 is a line graph showing the L-Dopa blood level
`
`time-concentration
`
`profile in mini-pigs of an exemplary pharmaceutical composition of the disclosure as
`
`against two comparators, all given as a bolus plus a six-hour continuous infusion.
`
`

`

`WO 2018/017850
`
`PCT/US2017/043103
`
`[0016]
`
`Figure 3 is a line graph showing the carbidopa blood level time-concentration
`
`profile in mini-pigs of an exemplary pharmaceutical composition of the disclosure as
`
`against two comparators, all given as a bolus plus in a six-hour continuous infusion.
`
`[0017]
`
`Figure 4A is a line graph showing the dissolution rate of levodopa in a pH 4.5
`
`media for a levodopa carbidopa intestinal gel made with Carbopol® 974P and packaged
`
`with a foil pouch at initial time point and 15 weeks.
`
`[0018]
`
`Figure 4B is a line graph showing the dissolution rate of carbidopa in a pH 4.5
`
`media for a levodopa carbidopa intestinal gel made with Carbopol® 974P and packaged
`
`with a foil pouch at initial time point and 15 weeks.
`
`[0019]
`
`Figure 5 is an illustration showing 3 different vials filled with levodopa-carbidopa
`
`intestinal gel made with Carbopol® 97lP. The samples, from left to right, have the
`
`following 971P concentrations: 0.5%w/w, 0.2%w/w, 0.1%w/w (or w/w %).
`
`[0020]
`
`Figure 6 is a line graph showing low shear (LS) viscosity of pharmaceutical
`
`compositions comprising levodopa and carbidopa after storage at various conditions.
`
`[0021]
`
`Figure 7 is a line graph showing high shear (HS) viscosity of pharmaceutical
`
`compositions comprising levodopa and carbidopa after storage at various conditions.
`
`[0022]
`
`Figure 8 is a diagram showing the process of how the acceptance value of a
`
`pharmaceutical composition is determined.
`
`[0023]
`
`Figure 9 is a line graph showing the pharmacokinetics of Formulation B (large
`
`levodopa particle size) and Formulation C (small levodopa particle size) in mini-pigs.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`[0024]
`
`This written description uses examples to disclose the invention, 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 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.
`
`

`

`WO 2018/017850
`
`PCT/US2017/043103
`
`I.
`
`Definitions
`
`[0025]
`
`Section headings as used in this section and the entire disclosure are not intended
`
`to be limiting.
`
`[0026]
`
`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, 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.
`
`[0027]
`
`The singular forms "a," "an," and "the" include plural referents unless the context
`
`clearly dictates otherwise.
`
`[0028]
`
`The term "and/or" as used in a phrase such as "A and/or B" herein is intended to
`
`include "A and B", "A or B", "A", and "B".
`
`[0029]
`
`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.
`
`[0030]
`
`In some embodiments,
`
`the term "about" includes the recited number i 10%.
`
`Thus, "about 10" means 9 to 11.
`
`[0031]
`
`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.
`
`[0032]
`
`The terms "improve" and "improving" have their plain and ordinary meaning to
`
`one skilled in the art of pharmaceutical or medical sciences and specifically include
`
`ameliorating the effects of Parkinson's disease, or decreasing or lessening a symptom or
`
`side effect of Parkinson's disease.
`
`[0033]
`
`[0034]
`
`The term "patient" includes mammals and humans, particularly humans.
`
`The term "pharmaceutically acceptable excipient" refers to any and all solvents,
`
`dispersion media, preservatives, antioxidants, isotonic and absorption delaying agents,
`
`and the like, that are compatible with pharmaceutical administration. Dispersion media
`
`may include water insoluble excipients such as microcrystalline cellulose.
`
`

`

`WO 2018/017850
`
`PCT/US2017/043103
`
`[0035]
`
`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-di sulfonic
`
`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 like.
`
`[0036]
`
`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.
`
`[0037]
`
`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.
`
`[0038]
`
`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.
`
`[0039]
`
`The terms a and "an" may refer to one or more than one.
`
`

`

`WO 2018/017850
`
`PCT/US2017/043103
`
`[0040]
`
`The term "levodopa active agent" as used herein refers to levodopa, and
`
`pharmaceutically acceptable salts or hydrates thereof.
`
`In one embodiment, the levodopa
`
`active agent is a hydrated form of levodopa.
`
`In another embodiment, the levodopa active
`
`agent is levodopa monohydrate.
`
`In another embodiment, the levodopa active agent is
`
`levodopa. Levodopa is also referred to as L—dopa.
`
`[0041]
`
`The term "carbidopa active agent" as used herein refers to carbidopa, and
`
`pharmaceutically acceptable salts or hydrates thereof.
`
`In one embodiment, the carbidopa
`
`active agent is a hydrated form of carbidopa.
`
`In another embodiment, the carbidopa
`
`active agent is carbidopa monohydrate.
`
`In another embodiment, the carbidopa active
`
`agent is carbidopa.
`
`[0042]
`
`The term "room temperature" generally refers to ambient conditions at a
`
`temperature of about 20 to about 25 degrees Celsius.
`
`II.
`
`
`Pharmaceutical Compositions
`
`[0043]
`
`As discussed above, pharmaceutical compositions comprising a levodopa and
`
`carbidopa suspension for intraduodenal administration face various challenges including
`
`sedimentation of drug particles during storage and administration and lack of chemical
`
`stability during storage.
`
`In order to address these challenges, it has been unexpectedly
`
`discovered that such challenges may be overcome When the pharmaceutical composition
`
`has a suitable yield value and is packaged in a foil pouch or any other packaging that acts
`
`as an oxygen barrier. Yield value relates to the initial resistance to flow under stress of a
`
`fluid; thus, yield value may also be referred to as yield stress. Yield value affects the
`
`suspending ability of a medium (e.g., vehicle and/or suspending agent.
`
`Specifically,
`
`particles dispersed in a medium can remain suspended if the yield value of the medium is
`
`sufficient to overcome the effect of gravity or buoyancy on those particles. Yield value is
`
`independent of viscosity.
`
`[0044]
`
`Thus, the present disclosure provides a pharmaceutical composition comprising
`
`a levodopa active agent and a carbidopa active agent for intraduodenal administration,
`
`wherein the levodopa active agent and the carbidopa active agent are present
`
`in a
`
`therapeutically effective amount suspended in one or more polymer—based suspending
`
`agents and wherein the pharmaceutical composition has a suitable yield value. Examples
`
`of suitable yield values include, but are not limited to, at least about 1.1 Pa.
`
`In another
`
`embodiment, examples of suitable yield values include, but are not limited to, at least
`
`about 0.3 Pa.
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`[0045]
`
`As understood herein, yield value is measured using a Discovery HR-2 rheometer
`
`from TA instruments. The rheometer can be fitted with a concentric cylinder, or other
`
`suitable geometry (eg. cone and plate). The sample is first soaked at 25°C for 600
`
`seconds, or until it reaches equilibrium. The sample may be presheared at 200 1/ s for 120
`
`seconds if needed. An ascending flow—ramp is performed by first soaking the presheared
`
`sample for 360 seconds, then increasing the shear rate from 0001 Us to 250 US over 300
`
`seconds, or other suitable range that can give a good resolution of the yield value. The
`
`sample can then held at 250 1/5 for an additional 300 seconds, if needed. Finally, a
`
`descending flow-ramp is performed from 250 US to 0.001 US over 300 seconds, or other
`
`suitable range that can give a good resolution of the yield value. The resulting descending
`
`or ascending flow-ramp are fitted with the Herschel-Bulkley model to obtain the yield
`
`value.
`
`[0046]
`
`The pharmaceutical compositions described herein having the above—described
`
`yield value resist sedimentation at room temperature (e.g., about 20°C to about 25°C,
`
`such as about 22°C) for at least about 1 week, at least about 2 weeks, at least about 3
`
`weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about
`
`7 weeks, at least about 8 weeks, at least about 9 weeks, at least about 10 weeks, at least
`
`about 11 weeks, at least about 12 weeks, at least about 13 weeks, at least about 14 weeks,
`
`or at least about 15 weeks.
`
`[0047]
`
`In another embodiment, the pharmaceutical compositions described herein having
`
`a yield value of at least about 0.3 Pa are physically stable and resist sedimentation at
`
`room temperature when stored for at least about 8 weeks, at least about 10 weeks, at least
`
`about 15 weeks, at least about 20 weeks, at least about 26 weeks, at least about 30 weeks,
`
`at least about 40 weeks, at least about 50 weeks, or at least about 60 weeks.
`
`[0048]
`
`In another embodiment, when packaged in a foil pouch or, other suitable
`
`packaging that acts as an oxygen barrier, the pharmaceutical compositions are chemically
`
`stable at room temperature (e.g., about 20°C to about 25°C, such as about 22°C) for at
`
`least about 15 weeks. Additionally, the pharmaceutical compositions described herein are
`
`packaged in a foil pouch, or other suitable packaging that acts as an oxygen barrier, are
`
`stable at room temperature (e. g., about 20°C to about 25°C, such as about 22°C) for at
`
`least about 15 weeks, or alternatively for at least about 1 week, at least about 2 weeks, at
`
`least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks,
`
`at least about 7 weeks, at least about 8 weeks, at least about 9 weeks, at least about 10
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`weeks, at least about 11 weeks, at least about 12 weeks, at least about 13 weeks, at least
`
`about 14 weeks, or at least about 15 weeks.
`
`[0049]
`
`In another embodiment, when packaged in a foil pouch or, other suitable
`
`packaging that acts as an oxygen barrier and, optionally, when either the pharmaceutical
`
`composition or
`
`foil pouch comprises
`
`an oxygen scavenger,
`
`the pharmaceutical
`
`compositions are chemically stable at room temperature (e.g., about 20°C to about 25°C,
`
`such as about 22°C)
`
`for at
`
`least about 8 weeks.
`
`In another embodiment,
`
`the
`
`pharmaceutical compositions are chemically stable at room temperature for at least about
`
`9 weeks, at least about 10 weeks, at least about 11 weeks, at least about 12 weeks, at least
`
`about 13 weeks, at least about 14 weeks, at least about 15 weeks, at least about 26 weeks,
`
`or at least about 60 weeks. Oxygen scavengers include, but are not limited to a mixture
`
`of iron powder and sodium chloride, activated carbon, and ascorbic acid.
`
`[0050]
`
`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.
`
`[0051]
`
`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 (e.g.,
`
`polymer-based), and a liquid vehicle (for example, water, polyethylene glycol). 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.
`
`[0052]
`
`In one embodiment, the levodopa active agent is levodopa and pharmaceutically
`
`acceptable salts or hydrates thereof, such as levodopa monohydrate. In one embodiment,
`
`levodopa is present
`
`in the composition in an amount of from about 1.0 to 5.0
`
`weight/weight percent in the total composition. In one 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.
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`[0053]
`
`In one embodiment, the carbidopa active agent is carbidopa and pharmaceutically
`
`acceptable salts or hydrates thereof, such as carbidopa monohydrate. In one embodiment,
`
`the carbidopa active agent is present in the composition in an amount of from about 0.25
`
`to 1.25 weight/weight percent
`
`in the total composition.
`
`In one embodiment
`
`the
`
`pharmaceutical composition comprises about 1.0 weight/weight percent of a carbidopa
`
`active agent. In one embodiment, the form of carbidopa active agent to be administered is
`
`a hydrated form of carbidopa.
`
`In one embodiment, the 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.
`
`[0054]
`
`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 l
`
`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
`
`pharmaceutical compositions.
`
`[0055]
`
`In another embodiment, a suitable suspending agent can be any polymer—based
`
`suspending agent that provides a pharmaceutical composition having a yield value of at
`
`least about 0.3 Pa. Pharmaceutical compositions of the disclosure may comprise one or
`
`more suspending agents. Examples of suitable polymer-based suspending agents include,
`
`but are not limited to, acrylic acid-based polymers, e. g., polymers primarily made from
`
`acrylic acid known as carbomer or acrylic acid-based polymers sold under the trade name
`
`Carbopol®,
`
`and
`
`hydrocolloid
`
`polymers,
`
`e. g.,
`
`locust
`
`beam gum,
`
`guar
`
`gum,
`
`methylcellulose, sodium carboxymethylcellulose with microcrystalline cellulose, e.g.,
`
`Avicel® CL—611 or Avicel® RC 591, xanthan gum, e.g., Vanzan, and gum tragacanth.
`
`Carbomer can be a high molecular weight polymer of acrylic acid crosslinked with ally
`
`ethers of polyalcohols. Acrylic acid-based polymers may be cross-linked, for example,
`
`cross-linked with polyalkenyl ethers or divinyl glycol.
`
`In particular, the one or more
`
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`suspending agents may be Carbopol® 934P, Carbopol® 97lP or Carbopol® 974P.
`
`Carbopol® 934P can be described by the USP/NF Pharmacopeia Monograph Compendial
`
`Name Carbomer 934P. Carbopol® 971P can be described by the USP/NF Pharrnacopeia
`
`Monograph Compendial Name Carbomer Homopolymer Type A. Carbopol® 974P can
`
`be described by the USP/NF Pharmacopeia Monograph Compendial Name Carbomer
`
`Homopolymer Type B. Polymer—based suspending agents, such as Carbopol® 971P and
`
`Carbopol® 974P, are synthetic, which reduces lot-to-lot variability, unlike the cellulose-
`
`based agents. Furthermore, polymer-based suspending agents, such as Carbopol® 971P
`
`and Carbopol® 974P, do not substantially dissolve thereby reducing any negative
`
`interaction with the levodopa active agent and carbidopa active agent. Also, polymer-
`
`based suspending agents, such as Carbopol® 97lP and Carbopol® 974P, are not cellulose-
`
`based, which reduces the environmental impact of producing such cellulose-based agents.
`
`The one or more suspending agents are incorporated into the composition in an amount of
`
`from about 0.1 to about 6 w/w % of the total weight of the pharmaceutical composition.
`
`The one or more suspending agents can be used in any amount wi