Levodopa and carbidopa intestinal gel and methods of use

Abstract

To provide improved formulations and methods that can maintain continuous and consistent dopamine levels in the brain to effectively treat movement disorders such as Parkinson's disease.SOLUTION: 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.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present disclosure provides (a) a pharmaceutical composition comprising a levodopa active agent and a carbidopa active agent, and (b) a method of treating Parkinson's disease and associated conditions comprising administering the pharmaceutical composition to a subject having Parkinson's disease. [Background technology]

[0002] Parkinson's disease is a chronic and progressive neurodegenerative condition characterized by low brain levels of the neurotransmitter dopamine (i.e., 3,4-dihydroxyphenethylamine). Administration of levodopa (or L-dopa) is currently the most effective treatment for treating patients with Parkinson's disease. Unlike dopamine, L-dopa can cross the blood-brain barrier and is enzymatically converted to dopamine in the brain, increasing dopamine levels.

[0003] [ka]

[0004] The conversion of L-dopa to dopamine is catalyzed by aromatic L-amino acid decarboxylase, a ubiquitous enzyme that facilitates the central as well as peripheral metabolism of L-dopa to dopamine. Relatively large doses of L-dopa are required to achieve therapeutically effective dopamine levels in the brain. Administration of such large doses of L-dopa can increase peripheral dopamine levels and induce vomiting in some patients. To overcome these problems, L-dopa is generally administered in combination with a peripheral aromatic L-amino acid decarboxylase inhibitor, such as carbidopa (i.e., (2S)-3-(3,4-dihydroxy-phenyl)-2-hydrazino-2-methylpropanoic acid).

[0005] [ka] Coadministration of carbidopa with L-dopa inhibits the peripheral metabolism of L-dopa to dopamine, thereby significantly lowering the L-dopa dose required for a therapeutically effective response and reducing associated side effects.

[0006] However, even when L-dopa and carbidopa are administered together, it is difficult to consistently maintain desirable dopamine levels in the brain due to the relatively short half-life of L-dopa in plasma. Furthermore, as the disease progresses, many patients become less tolerant of variability in dopamine levels in the brain. One approach that has been shown to be effective in reducing variability in dopamine levels is the continuous intestinal delivery of an adjustable dose of L-dopa / carbidopa gel, known by the trade 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 a disposable drug reservoir ("DDR") and is administered continuously via a software-controlled portable infusion pump. L-dopa and carbidopa have been administered in combination for decades to treat Parkinson's disease, but pharmaceutical gel compositions suitable for storage at room temperature are not currently commercially available.

[0007] The current composition of DuoDopa® L-dopa / carbidopa intestinal gel is a gel for continuous intestinal administration. For long-term administration, the gel is administered directly to the duodenum or upper jejunum using an intestinal / jejunal tube, via a percutaneous endoscopic gastrostomy tube, or using a portable pump. Each ml of Duodopa® contains 20 mg of levodopa and 5 mg of carbidopa monohydrate. Despite the current commercial success of DuoDopa®, the product has limitations in its preparation, including (1) the risk of drug particle settling during storage and administration, and (2) the chemical instability of carbidopa, which can lead to the formation of hydrazine. Summary of the Invention [Problem to be solved by the invention]

[0008] Thus, there continues to be a 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. [Means for solving the problem]

[0009] Summary of the Invention In one aspect, the 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, such as carbomer, and the pharmaceutical composition has a yield value of at least about 0.3 Pascal (Pa) and an acceptance value of ≦15. The levodopa active agent can 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) can be provided in an amount of about 1 weight / weight percent of the composition. The pharmaceutical compositions of the present disclosure have a yield value that provides physical stability under one or more storage conditions, for example at 5° C., room temperature (e.g., about 20° C. to about 25° C.) and about 60% relative humidity (RH), or at about 40° C. and about 75% RH, for at least about 8 weeks, at least about 15 weeks, at least about 26 weeks, or at least about 60 weeks.

[0010] 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 Pascals (Pa). The levodopa active agent can 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) can be provided in an amount of about 1 weight / weight percent of the composition. The pharmaceutical composition has a desirable yield value suitable for having physical stability at room temperature (e.g., about 20°C to about 25°C) for at least about 15 weeks.

[0011] 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 4 weight / weight percent (w / w%) of the composition, and the carbidopa (e.g., carbidopa monohydrate) is provided in an amount of about 1 weight / weight percent of the composition, and the levodopa and carbidopa are suspended in an aqueous carrier and stored in individual disposable drug reservoirs ("DDRs"). The DDRs containing the pharmaceutical compositions are 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 at room temperature (e.g., about 20°C to about 25°C) for at least about 15 weeks.

[0012] In another aspect, the disclosure provides a method of treating Parkinson's disease in a patient in need thereof, comprising 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 can 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) can be provided in an amount of about 1 weight / weight percent of the composition. The pharmaceutical composition has a desirable yield value suitable for having physical stability at room temperature (e.g., about 20° C. to about 25° C.) for at least about 15 weeks.

[0013] In another aspect, the present disclosure relates to methods of making pharmaceutical compositions of the present disclosure, particularly highly concentrated pharmaceutical compositions, as disclosed, for example, in Example 1 and FIG. 1 below.

[0014] These and additional embodiments of the present disclosure are further described herein.

[0015] Further benefits of the present disclosure will be apparent to those skilled in the art upon reading the present application. The embodiments of the present disclosure described in the following paragraphs are intended to illustrate the present invention and should not be considered as narrowing the scope of the present invention. [Brief description of the drawings]

[0016] [Figure 1] 1 is a flow diagram of a manufacturing process for producing an exemplary pharmaceutical formulation of the present disclosure. [Diagram 2] FIG. 1 is a line graph showing the time-concentration profile of L-dopa blood levels in minipigs of an exemplary pharmaceutical composition of the disclosure versus two comparators, all given as a bolus and as a 6-hour continuous infusion. [Diagram 3]1 is a line graph showing the time-concentration profile of carbidopa blood levels in minipigs of an exemplary pharmaceutical composition of the disclosure versus two comparators, all given as a bolus and as a 6-hour continuous infusion. [Figure 4A] 1 is a line graph showing the dissolution rate of levodopa in pH 4.5 media at initial time points and at 15 weeks for levodopa-carbidopa intestinal gel made with Carbopol® 974P and packaged in a foil pouch. [Figure 4B] 1 is a line graph showing the dissolution rate of carbidopa in pH 4.5 media at initial time points and at 15 weeks for levodopa-carbidopa intestinal gel made with Carbopol® 974P and packaged in a foil pouch. [Diagram 5] FIG. 1 shows three different vials filled with levodopa-carbidopa intestinal gel made with Carbopol® 971P. From left to right, the samples have the following 971P concentrations: 0.5% w / w, 0.2% w / w, 0.1% w / w (or w / w%). [Figure 6] 1 is a line graph showing the low shear (LS) viscosity of pharmaceutical compositions containing levodopa and carbidopa after storage under various conditions. [Figure 7] 1 is a line graph showing the high shear (HS) viscosity of pharmaceutical compositions containing levodopa and carbidopa after storage under various conditions. [Figure 8] FIG. 1 illustrates a process for how to determine the call value of a pharmaceutical composition. [Figure 9] 1 is a line graph showing the pharmacokinetics of Formulation B (large levodopa particle size) and Formulation C (small levodopa particle size) in minipigs. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] This written description uses several examples to disclose the disclosure including the best mode and 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 contemplated to be within the scope of the claims if they have elements that are not inconsistent with the literal language of the claims or if they contain equivalent elements.

[0018] I. Definition The section headings used in this section and throughout the disclosure are not intended to be limiting.

[0019] When numerical ranges are recited, each intervening number within the range is expressly contemplated to have 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 expressly contemplated. In a similar manner, all ratios recited include all sub-ratios included within the broader ratio.

[0020] The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0021] The term "and / or," as used herein in phrases such as "A and / or B," is intended to include "A and B," "A or B," or "A" and "B."

[0022] The term "about" generally refers to a range of numbers that one of ordinary skill in the art would consider equivalent to the recited value (i.e., having the same function or result). In many cases, the term "about" can include numbers that are rounded to the nearest significant figure.

[0023] In some embodiments, the term "about" includes the recited number plus or minus 10%, so "about 10" means between 9 and 11.

[0024] Unless otherwise required by context, the terms "comprise", "comprises" and "including" are to be interpreted inclusively rather than exclusively and are used with the express understanding that applicant intends that each of those terms be so interpreted in interpreting this patent, including the claims which follow.

[0025] The terms "ameliorate" and "ameliorating" have their plain and ordinary meaning to one of ordinary skill in the art of pharmaceutical or medical sciences, and specifically include alleviating the effects of Parkinson's disease or reducing or alleviating the symptoms or side effects of Parkinson's disease.

[0026] The term "patient" includes mammals and humans, especially humans.

[0027] The term "pharmaceutically acceptable excipient" refers to any and all solvents, dispersion media, preservatives, antioxidants, isotonic and absorption delaying agents, etc., that are compatible with pharmaceutical administration. Dispersion media can include water-insoluble excipients such as microcrystalline cellulose.

[0028] The term "pharmaceutically acceptable salt" refers to a salt of a compound that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. Such salts include (1) salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or salts formed with 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. and (2) acid addition salts formed with organic acids such as 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 any of the parent compounds 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.

[0029] The terms "reduce" and "reducing" have their plain and ordinary meaning to one of ordinary skill in the art of pharmaceutical or medical sciences, and specifically include reducing or alleviating the occurrence, duration, or intensity of a symptom or side effect of Parkinson's disease, such as dyskinesia or hallucinations.

[0030] The term "therapeutically effective amount" means an amount of a compound sufficient to effect treatment for Parkinson's disease or an associated condition when administered alone or in combination with additional therapy to a patient suffering from or susceptible to Parkinson's disease or an associated condition. A "therapeutically effective amount" will vary depending, for example, on the compound, pharmaceutical composition or pharmaceutical dosage form, the condition being treated and its severity, and the age and weight of the patient being treated.

[0031] The terms "treat" and "treating" have their plain and ordinary meaning to one of ordinary skill 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.

[0032] The terms "a" and "an" can refer to one or to a plurality of two or more.

[0033] The term "levodopa active agent" as used herein refers to levodopa and pharma- ceutically acceptable salts or hydrates thereof. In one embodiment, the levodopa active agent is a hydrate 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 known as L-dopa.

[0034] The term "carbidopa active agent" as used herein refers to carbidopa and pharma- ceutically acceptable salts or hydrates thereof. In one embodiment, the carbidopa active agent is a hydrate form of carbidopa. In another embodiment, the carbidopa active agent is carbidopa monohydrate. In another embodiment, the carbidopa active agent is carbidopa.

[0035] The term "room temperature" generally refers to ambient conditions at a temperature of about 20 to about 25 degrees Celsius.

[0036] II. Pharmaceutical Compositions As discussed above, pharmaceutical compositions including levodopa and carbidopa suspensions for intraduodenal administration face various challenges, including settling of drug particles during storage and administration, and lack of chemical stability during storage. To address these challenges, it has been unexpectedly discovered that such challenges can be overcome if the pharmaceutical composition has an appropriate yield value and is packaged in a foil pouch or any other packaging that acts as an oxygen barrier. The yield value relates to the initial resistance to flow under fluid stress, and therefore the yield value can also be referred to as the yield stress. The 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 effects of gravity or buoyancy on the particles. The yield value is independent of viscosity.

[0037] 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 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.

[0038] As understood herein, the yield value is measured using a Discovery HR-2 rheometer from TA instruments. The rheometer can be fitted with concentric cylinders or other suitable geometry (e.g., cone and plate). The sample is first soaked at 25° C. for 600 seconds or until the sample reaches equilibrium. The sample can be pre-sheared at 200 l / s for 120 seconds if desired. An upward flow-ramp is performed by first soaking the pre-sheared sample for 360 seconds, then increasing the shear rate from 0.001 l / s to 250 l / s, or to other suitable range that allows the yield value to be well resolved, over 300 seconds. The sample can then be held at 250 l / s for another 300 seconds if desired. Finally, a downward flow-ramp is performed from 250 l / s to 0.001 l / s, or to other suitable range that allows the yield value to be well resolved, over 300 seconds. The resulting downward or upward flow slopes are fitted with the Herschel-Bulkley model to obtain the yield values.

[0039] Pharmaceutical compositions described herein having the aforementioned yield values ​​resist settling 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.

[0040] In another embodiment, the pharmaceutical compositions described herein having a yield value of at least about 0.3 Pa are physically stable and resistant to settling when stored at room temperature 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.

[0041] In another embodiment, the pharmaceutical composition is chemically stable for at least about 15 weeks at room temperature (e.g., about 20° C. to about 25° C., such as about 22° C.) when packaged in a foil pouch or other suitable packaging that acts as an oxygen barrier. Additionally, the pharmaceutical compositions described herein are stable for at least about 15 weeks at room temperature (e.g., about 20° C. to about 25° C., such as about 22° C.) when packaged in a foil pouch or other suitable packaging that acts as an oxygen barrier, alternatively 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.

[0042] In another embodiment, the pharmaceutical composition, when packaged in a foil pouch or other suitable packaging that acts as an oxygen barrier, is 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, optionally when either the pharmaceutical composition or the foil pouch contains an oxygen scavenger. In another embodiment, the pharmaceutical composition is 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 charcoal, and ascorbic acid.

[0043] In various aspects, the therapeutically effective amounts of the levodopa and carbidopa active agents (e.g., carbidopa monohydrate) present in the pharmaceutical composition can be about 4.0 percent weight / weight and about 1.0 percent weight / weight of the composition, respectively.

[0044] In one embodiment, the pharmaceutical composition comprises a levodopa active agent in an amount of about 4.0 weight percent of the total composition, a carbidopa active agent (e.g., carbidopa monohydrate) in an amount of about 1.0 weight percent of the total composition, at least one suspending agent (e.g., a polymer base), and a liquid vehicle (e.g., water, polyethylene glycol). In various embodiments, the liquid vehicle can comprise from about 0 weight percent to about 95 weight percent of the total composition, for example, from about 10 weight percent to about 70 weight percent or from about 40 weight percent to about 60 weight percent of the total composition.

[0045] In one embodiment, the levodopa active agent is levodopa and its pharma- ceutically acceptable salts or hydrates such as levodopa monohydrate. In one embodiment, levodopa is present in the composition in an amount of about 1.0 to 5.0 weight percent of the total composition. In one embodiment, the pharmaceutical composition comprises about 4.0 weight percent of the levodopa active agent. In one embodiment, the levodopa active agent can be processed into microparticles or microspheres, for inclusion in the pharmaceutical compositions of the invention, for example, as described in Example 1 below.

[0046] In one embodiment, the carbidopa active agent is carbidopa and its pharma- ceutically acceptable salts or hydrates such as carbidopa monohydrate. In one embodiment, the carbidopa active agent is present in the composition in an amount of about 0.25 to 1.25 weight percent of the total composition. In one embodiment, the pharmaceutical composition comprises about 1.0 weight percent of the carbidopa active agent. In one embodiment, the form of the carbidopa active agent administered is a hydrate form of carbidopa. In one embodiment, the form of the carbidopa active agent administered is carbidopa monohydrate. In one embodiment, the carbidopa active agent can be processed, such as into microparticles or microspheres, for inclusion in the pharmaceutical compositions of the invention, for example, as described in Example 1 below.

[0047] The levodopa active agent and the carbidopa active agent can be present in the pharmaceutical composition in any suitable ratio, for example, the ratio of the levodopa active agent to the carbidopa active agent (e.g., carbidopa monohydrate) in the pharmaceutical composition of the present invention can be about 4:1. For example, the pharmaceutical composition can include about 4 weight / weight percent of the levodopa active agent and 1 weight / weight percent of the carbidopa active agent (e.g., carbidopa monohydrate). In one embodiment, the pharmaceutical composition comprises a liquid or viscous liquid containing about 200 mg of levodopa and about 50 mg of carbidopa (e.g., carbidopa monohydrate) per 5.0 mL volume. In one embodiment, the levodopa active agent and the carbidopa active agent are processed into microparticles or microspheres, for inclusion in the pharmaceutical composition of the present invention, for example, as described in Example 1 below.

[0048] In another embodiment, a suitable suspending agent may be any polymer-based suspending agent that provides a pharmaceutical composition with a yield value of at least about 0.3 Pa. The pharmaceutical composition of the present disclosure may include one or more suspending agents. Examples of suitable polymer-based suspending agents include, but are not limited to, acrylic acid-based polymers, such as polymers made primarily from acrylic acid, known as carbomers or acrylic acid-based polymers, such as those sold under the trademark Carbopol®, and hydrocolloid polymers, such as locust bean gum, guar gum, methylcellulose, sodium carboxymethylcellulose with microcrystalline cellulose, such as Avicel® CL-611 or Avicel® RC591, xanthan gum, such as Vanzan, and tragacanth gum. Carbomers may be high molecular weight polymers of acrylic acid crosslinked with ally ethers of polyhydric alcohols. The acrylic acid-based polymers may be crosslinked, such as with polyalkenyl ethers or divinyl glycol. In particular, the one or more suspending agents may be Carbopol® 934P, Carbopol® 971P, or Carbopol® 974P. Carbopol® 934P can be described by its USP / NF Pharmacopeia Monograph Compendial Name Carbomer 934P. Carbopol® 971P can be described by its USP / NF Pharmacopeia Monograph Compendial Name Carbomer Homopolymer Type A. Carbopol® 974P can be described by its USP / NF Pharmacopeia Monograph Compendial Name Carbomer Homopolymer Type B. Polymer-based suspending agents such as Carbopol® 971P and Carbopol® 974P are synthetic, unlike cellulose-based agents, thereby reducing lot-to-lot variability.Additionally, polymer-based suspending agents such as Carbopol® 971P and Carbopol® 974P are substantially insoluble, thereby reducing any negative interactions with the levodopa and carbidopa active agents. Also, polymer-based suspending agents such as Carbopol® 971P and Carbopol® 974P are not cellulose-based, thereby reducing the environmental impact of producing such cellulose-based agents. The one or more suspending agents are incorporated into the composition in an amount of 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 within the range, including, for example, about 0.1 to about 1 w / w%, about 0.1 to about 0.5 w / w%, or about 0.1 to about 0.2 w / w%.

[0049] In another embodiment, the suitable suspending agent may be any polymer-based suspending agent that provides the pharmaceutical composition with a yield value of at least about 4 Pa. Examples of suitable polymer-based suspending agents include, but are not limited to, acrylic acid-based polymers, such as those made primarily from acrylic acid, known as carbomers or acrylic acid-based polymers sold under the trademark Carbopol®, and hydrocolloid polymers, such as locust bean gum, guar gum, methylcellulose, sodium carboxymethylcellulose with microcrystalline cellulose, and tragacanth gum. The acrylic acid-based polymers may be crosslinked, such as with polyalkenyl ethers or divinyl glycol. In particular, one or more suspending agents may be Carbopol® 971P and Carbopol® 974P. Unlike cellulose-based agents, polymer-based suspending agents such as Carbopol® 971P and Carbopol® 974P are synthetic, thereby reducing lot-to-lot variability. Additionally, polymer-based suspending agents such as Carbopol® 971P and Carbopol® 974P are substantially insoluble, thereby reducing any negative interactions with the levodopa and carbidopa active agents. Also, polymer-based suspending agents such as Carbopol® 971P and Carbopol® 974P are not cellulose-based, thereby reducing the environmental impact of producing such cellulose-based agents. The suspending agent is incorporated into the composition in an amount of about 0.1 to about 5 w / w% of the total weight of the pharmaceutical composition. The suspending agent can be used in any amount within the range, including, for example, about 0.1 to about 1 w / w% or about 0.1 to 0.5 w / w%.

[0050] In another embodiment, the suspending agent is an acrylic acid based polymer, such as a carbomer, such as Carbopol® 971P or Carbopol® 974P, and the composition comprises the acrylic acid based polymer in an amount of about 0.1 w / w% to about 0.5 w / w% of the total composition, such as about 0.1 w / w% to about 0.3 w / w% of the total composition, such as about 0.1 w / w% to about 0.2 w / w% of the total composition. In another embodiment, the composition comprises the acrylic acid based polymer in an amount of about 0.10 w / w% of the total composition. In another embodiment, the composition comprises an acrylic acid-based polymer in an amount of about 0.11 w / w%, about 0.12 w / w%, about 0.13 w / w%, about 0.14 w / w%, about 0.15 w / w%, about 0.16 w / w%, about 0.17 w / w%, about 0.18 w / w%, about 0.19 w / w%, about 0.20 w / w% or about 0.20 w / w% of the total composition.

[0051] In another embodiment, the suspending agent is a hydrocolloid polymer, such as locust bean gum, guar gum, methylcellulose, sodium carboxymethylcellulose with microcrystalline cellulose, or tragacanth gum, and the composition comprises the hydrocolloid polymer in an amount of about 1 w / w% to about 6 w / w% of the total composition. In another embodiment, the composition comprises the hydrocolloid polymer in an amount of about 1 w / w% of the total composition. In another embodiment, the composition comprises the hydrocolloid polymer in an amount of about 2 w / w%, about 3 w / w%, about 4 w / w%, or about 5 w / w% of the total composition.

[0052] In the present compositions, one or more suspending agents may be used to obtain a suspension for intraduodenal administration having a desirable yield value, as discussed above.

[0053] However, if a surfactant is used, it may be best to add the one or more surfactants after adding the levodopa and carbidopa active agents and suspending agents, as taught herein.

[0054] It should be understood that each component that makes up the compositions of the present disclosure must be pharma- ceutically acceptable and safe for administration in formulations intended to be administered to human subjects.

[0055] Antibacterial agents can be added to preserve the composition by inhibiting the growth of microorganisms.Any pharma- ceutically acceptable antibacterial agent can be used, such as, for example, sodium benzoate, sodium propionate, and sorbate.One or more surfactants can be incorporated after adding the levodopa and carbidopa active agents and suspending agents as taught herein.

[0056] When carbomers, i.e. Carbopol® 971P or Carbopol® 974P, are used as suspending agents, neutralizing agents must be added, examples of which are inorganic bases such as sodium hydroxide and potassium hydroxide, or amines such as triethanolamine and tromethamine, but are not limited thereto.

[0057] In one embodiment, the pharmaceutical composition is a viscous liquid composition. In one aspect, the pharmaceutical composition comprises water and is suitable for injection.

[0058] In another embodiment, the pharmaceutical composition has a concentration of levodopa active agent of at least about 5 mg / mL. In one aspect, the concentration of levodopa active agent is at least about 10 mg / mL. In another aspect, the concentration of levodopa active agent is at least about 20 mg / mL. In another aspect, the concentration of levodopa active agent is at least about 30 mg / mL. In another aspect, the concentration of levodopa active agent is at least about 35 mg / mL. In another aspect, the concentration of levodopa active agent is at least about 40 mg / mL. In another aspect, the concentration of levodopa active agent is at least about 45 mg / mL. In another aspect, the concentration of levodopa active agent is at least about 50 mg / mL. In another aspect, the concentration of levodopa active agent is at least about 100 mg / mL. In another aspect, the concentration of levodopa active agent is at least about 150 mg / mL. In another embodiment, the concentration of the levodopa active agent is at least about 200 mg / mL.

[0059] In another embodiment, the pharmaceutical composition has a concentration of carbidopa active agent (e.g., carbidopa monohydrate) of at least about 5 mg / mL. In one aspect, the concentration of the carbidopa active agent is at least about 10 mg / mL. In another aspect, the concentration of the carbidopa active agent is at least about 20 mg / mL. In another aspect, the concentration of the carbidopa active agent is at least about 30 mg / mL. In another aspect, the concentration of the carbidopa active agent is at least about 50 mg / mL. In another aspect, the concentration of the carbidopa active agent is at least about 100 mg / mL. In another aspect, the concentration of the carbidopa active agent is at least about 150 mg / mL. In another aspect, the concentration of the carbidopa active agent is at least about 200 mg / mL.

[0060] The pharmaceutical compositions of the present disclosure optionally include one or more additional pharma- ceutically acceptable excipients. The term "excipient" refers to any substance, not itself a therapeutic agent, that is used as a carrier or vehicle for delivery of a therapeutic agent to a subject, or that is added to a pharmaceutical composition to improve the handling or storage properties of the pharmaceutical composition, or to enable or facilitate the formation of a unit dose of the composition.

[0061] Excipients include, for example, antioxidants, agents for adjusting pH and osmolality, preservatives, thickening agents, colorants, buffers, bacteriostats, and stabilizers. A given excipient, when present, is generally 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%, w / w%.

[0062] In one embodiment, the pharmaceutical composition optionally comprises an antioxidant. Suitable antioxidants for use in the pharmaceutical composition include, for example, butylated hydroxytoluene, butylated hydroxyanisole, potassium metabisulfite, cysteine, and the like.

[0063] In one embodiment, the pharmaceutical composition optionally includes a buffering agent. Buffering agents include agents that reduce pH changes. Classes of buffering agents suitable for use in various embodiments of the present disclosure include, for example, Group IA metal bicarbonates, Group IA metal carbonates, alkali or alkaline earth metal buffers, aluminum buffers, calcium buffers, sodium buffers, or magnesium buffers. Suitable buffering agents further include any of the carbonates, phosphates, bicarbonates, citrates, borates, acetates, phthalates, tartrates, and succinates of the foregoing, such as sodium or potassium phosphate, sodium or potassium citrate, sodium or potassium borate, sodium or potassium acetate, sodium or potassium bicarbonate, and sodium or potassium carbonate.

[0064] In one embodiment, the composition has a pH of about 3.5 to about 8. In one aspect, the pH is about 3.5 to about 7.5. In another aspect, the pH is about 4.0 to about 7.5. In another aspect, the pH is about 5.0 to about 7.5. In another aspect, the pH is about 5.5 to about 7.5. In another aspect, the pH is about 6.0 to about 7.5.

[0065] In various embodiments, the pharmaceutical composition can be present in a container. Suitable containers include oxygen-impermeable containers (e.g., bags). These oxygen-permeable barriers can be incorporated into the first container or the second outer container. Non-limiting examples of suitable containers include foil pouches.

[0066] In another embodiment, a pharmaceutical dosage form is provided. The pharmaceutical dosage form can include a pharmaceutical composition described herein in a DDR in which an oxygen-impermeable enclosure is disposed, the oxygen-impermeable enclosure being filled with an inert gas (e.g., N 2 ). An oxygen scavenger (e.g., ferrous or non-ferrous based canister or sachet) may also be added. The pharmaceutical dosage form may be suitable for use in a continuous infusion pump that can deliver the composition in a therapeutically effective manner. Suitable oxygen impermeable enclosures may include, for example, foil bags.

[0067] III. Methods of Preparing Pharmaceutical Compositions The present disclosure further provides a method of preparing the pharmaceutical compositions described herein. In various aspects, the method of preparing the pharmaceutical compositions described herein may include providing a levodopa active agent and a carbidopa active agent in an appropriate amount such that the levodopa active agent and the carbidopa active agent are present in the pharmaceutical composition in a therapeutically effective amount. The levodopa active agent and the carbidopa active agent may be added to water to produce a slurry. The slurry may be added to a mixture of one or more suspending agents (e.g., Carbopol® 971P or Carbopol® 974P), a neutralizing agent, and water as described herein to form a suspension. A neutralizing agent (e.g., sodium hydroxide) may be added to bring the pH to within the aforementioned range. The suspension may be added to a mixture of N 2 O 3 to reduce oxygen levels. 2 It may or may not be sparged. In particular, the suspension is 2The suspension may be subjected to sparging. Optionally, the suspension may be degassed to remove any trapped nitrogen or air from the suspension. The suspension may then be loaded into an oxygen-impermeable container as described herein. Optionally, an oxygen scavenger may be added to the suspension as well. The N 2 The combination of sparging and the use of a container with lower oxygen permeability advantageously reduces the amount of initially solubilized O 2 present in the composition. 2 and to the composition during storage 2 Reducing both the amount of protein and the amount of protein loaded can result in a pharmaceutical composition with increased chemical stability.

[0068] In various aspects, the levodopa active agent can have any particle size suitable for preparing a pharmaceutical composition having an appropriate pharmacokinetic profile and maintaining the desired physical and chemical stability of the composition. Although a wide range of particle sizes can be used, the levodopa active agent (e.g., prior to forming the suspension) can have the following particle size distribution: (i) D50 may be about 5 μm or less, about 3 μm or less, or about 1 μm or less; (ii) D90 may be about 11 μm or less, about 9 μm or less, about 7 μm or less, about 5 μm or less, or about 3 μm or less; (iii) D100 may be about 22 μm or less, about 21 μm or less, about 19 μm or less, about 17 μm or less, about 15 μm or less, about 13 μm or less, or about 11 μm or less.

[0069] In one embodiment, the levodopa active agent has a particle size distribution of (i) a D50 of about 5 μm or less, (ii) a D90 of 11 μm or less, and (iii) a D100 of 22 μm or less.

[0070] In another embodiment, the levodopa active agent (eg, prior to forming the suspension) has the following particle size distribution: (i) D10 is about 50 μm or less, about 20 μm or less, or about 10 μm or less; (ii) D50 is about 100 μm or less, about 50 μm or less, or about 37 μm or less; (iii) D90 may be about 200 μm or less, about 150 μm or less, or about 120 μm or less.

[0071] In another embodiment, the levodopa active agent has a particle size distribution of (i) a D50 of about 37.2 μm or less, (ii) a D90 of 121.4 μm or less, and (iii) a D10 of 9.8 μm or less.

[0072] The carbidopa active agent can also have any particle size suitable for preparing a pharmaceutical composition of the present disclosure having an appropriate pharmacokinetic profile and maintaining the desired physical and chemical stability of the composition. The carbidopa active agent (e.g., prior to forming the suspension) can have the following particle size distribution: (i) D50 may be 3 μm or less; (ii) D90 may be 7 μm or less, or 5 μm or less; (iii) D100 may be 21 μm or less, 19 μm or less, 17 μm or less, 15 μm or less, 13 μm or less, 11 μm or less, 9 μm or less.

[0073] In one embodiment, the carbidopa active agent, such as carbidopa monohydrate, can have a particle size distribution of (i) a D50 of about 3 μm or less, (ii) a D90 of 7 μm or less, and (iii) a D100 of 21 μm or less.

[0074] In another embodiment, the carbidopa active agent has a particle size distribution of (i) a D50 of about 9.4 μm or less, (ii) a D90 of 34.5 μm or less, and (iii) a D10 of 3.1 μm or less.

[0075] The levodopa and / or carbidopa active agents can be milled or micronized to achieve such particle size distribution.

[0076] In another embodiment, the carbidopa active agent (eg, prior to forming the suspension) can have the following particle size distribution: (i) D10 is about 10 μm or less, about 5 μm or less, or about 3 μm or less; (ii) D50 is about 20 μm or less, about 15 μm or less, or about 10 μm or less; (iii) D90 may be about 50 μm or less, about 40 μm or less, or about 35 μm or less.

[0077] In one embodiment, a pharmaceutical composition of the present disclosure comprising about 4 percent weight / weight of a levodopa active agent and about 1 percent weight / weight of a carbidopa active agent, e.g., carbidopa monohydrate, having the particle size distribution described above maintains physical stability for at least about 8 weeks, at least about 10 weeks, at least about 15 weeks, at least about 26 weeks, or at least about 60 weeks, so long as the yield value of the composition is at least about 0.3 Pa when measured after exposing the pharmaceutical composition to a temperature of about 5° C.

[0078] In another embodiment, a pharmaceutical composition of the present disclosure comprising about 4 weight / weight percent levodopa active agent and about 1 weight / weight percent carbidopa active agent, e.g., carbidopa monohydrate, having the particle size distribution described above, has a yield value of at least about 0.34 Pa, at least about 0.4 Pa, at least about 0.5 Pa, at least about 0.6 Pa, at least about 0.7 Pa, at least about 0.8 Pa, at least about 0.9 Pa, at least about 1.0 Pa, at least about 1.1 Pa, at least about 1.2 Pa, at least about 1.3 Pa, at least about 1.4 Pa, when measured after exposing the pharmaceutical composition to a temperature of about 5° C. , at least about 1.5 Pa, at least about 1.6 Pa, at least about 1.7 Pa, at least about 1.8 Pa, at least about 1.9 Pa, at least about 2.0 Pa, at least about 2.1 Pa, at least about 2.2 Pa, at least about 2.3 Pa, at least about 2.4 Pa, at least about 2.5 Pa, at least about 2.6 Pa, at least about 2.7 Pa, at least about 2.8 Pa, at least about 2.9 Pa, or at least about 3.0 Pa, and / or for at least about 8 weeks, at least about 10 weeks, at least about 15 weeks, at least about 26 weeks, or at least about 60 weeks.

[0079] In another embodiment, a pharmaceutical composition comprising about 4 percent weight / weight of a levodopa active agent and about 1 percent weight / weight of a carbidopa active agent, e.g., carbidopa monohydrate, having the particle size distribution described above maintains physical stability for at least about 8 weeks, at least about 10 weeks, at least about 15 weeks, at least about 26 weeks, or at least about 60 weeks, so long as the yield value of the composition is at least about 0.3 Pa when measured after exposing the pharmaceutical composition to a temperature of about 25° C. and a relative humidity (RH) of about 60%.

[0080] In another embodiment, a pharmaceutical composition comprising about 4 weight / weight percent levodopa active agent and about 1 weight / weight percent carbidopa active agent, e.g., carbidopa monohydrate, having the aforementioned particle size distribution, has a yield value of at least about 0.34 Pa, at least about 0.4 Pa, at least about 0.5 Pa, at least about 0.6 Pa, at least about 0.7 Pa, at least about 0.8 Pa, at least about 0.9 Pa, at least about 1.0 Pa, at least about 1.1 Pa, at least about 1.2 Pa, at least about 1.3 Pa, at least about 1.4 Pa, at least about 1.6 Pa, at least about 1.8 Pa, at least about 1.9 Pa, at least about 2.0 Pa, at least about 2.2 Pa, at least about 2.4 Pa, at least about 2.6 Pa, at least about 2.8 Pa, at least about 2.9 Pa, at least about 3.0 Pa, at least about 3.1 Pa, at least about 3.2 Pa, at least about 3.3 Pa, at least about 3.4 Pa, at least about 3.5 Pa, at least about 3.6 Pa, at least about 3.7 Pa, at least about 3.8 Pa, at least about 3.9 Pa, at least about 3.1 Pa, at least about 3.2 ...3 Pa, 4 Pa, at least about 1.5 Pa, at least about 1.6 Pa, at least about 1.7 Pa, at least about 1.8 Pa, at least about 1.9 Pa, at least about 2.0 Pa, at least about 2.1 Pa, at least about 2.2 Pa, at least about 2.3 Pa, at least about 2.4 Pa, at least about 2.5 Pa, at least about 2.6 Pa, at least about 2.7 Pa, at least about 2.8 Pa, at least about 2.9 Pa, or at least about 3.0 Pa, and / or for at least about 8 weeks, at least about 10 weeks, at least about 15 weeks, at least about 26 weeks, or at least about 60 weeks.

[0081] In another embodiment, a pharmaceutical composition comprising about 4 percent weight / weight of a levodopa active agent and about 1 percent weight / weight of a carbidopa active agent, e.g., carbidopa monohydrate, having the particle size distribution described above maintains physical stability for at least about 8 weeks, at least about 10 weeks, at least about 15 weeks, at least about 26 weeks, or at least about 60 weeks, so long as the yield value of the composition is at least about 0.3 Pa when measured after exposing the pharmaceutical composition to a temperature of about 40° C. and a RH of about 75%.

[0082] In another embodiment, a pharmaceutical composition comprising about 4 weight / weight percent levodopa active agent and about 1 weight / weight percent carbidopa active agent, e.g., carbidopa monohydrate, having the aforementioned particle size distribution has a yield value of the composition of at least about 0.34 Pa, at least about 0.4 Pa, at least about 0.5 Pa, at least about 0.6 Pa, at least about 0.7 Pa, at least about 0.8 Pa, at least about 0.9 Pa, at least about 1.0 Pa, at least about 1.1 Pa, at least about 1.2 Pa, at least about 1.3 Pa, at least about 1.4 Pa, at least about 1.6 Pa, at least about 1.8 Pa, at least about 1.9 Pa, at least about 2.0 Pa, at least about 2.1 Pa, at least about 2.2 Pa, at least about 2.4 Pa, at least about 2.5 Pa, at least about 2.6 Pa, at least about 2.7 Pa, at least about 2.8 Pa, at least about 2.9 Pa, at least about 3.0 Pa, at least about 3.1 Pa, at least about 3.2 Pa, at least about 3.4 Pa, at least about 3.5 Pa, at least about 3.6 Pa, at least about 3.7 Pa, at least about 3.8 Pa, at least about 3.9 Pa, at least about 4.0 ... 4 Pa, at least about 1.5 Pa, at least about 1.6 Pa, at least about 1.7 Pa, at least about 1.8 Pa, at least about 1.9 Pa, at least about 2.0 Pa, at least about 2.1 Pa, at least about 2.2 Pa, at least about 2.3 Pa, at least about 2.4 Pa, at least about 2.5 Pa, at least about 2.6 Pa, at least about 2.7 Pa, at least about 2.8 Pa, at least about 2.9 Pa, or at least about 3.0 Pa, and / or for at least about 8 weeks, at least about 10 weeks, at least about 15 weeks, at least about 26 weeks, or at least about 60 weeks.

[0083] The physical stability of the pharmaceutical composition of the present disclosure can be determined by its assessment value (AV). A pharmaceutical composition is physically stable when its assessment value (AV) defined by Equation 2 is 15 or less for levodopa and 15 or less for carbidopa. Equation 2.

[0084]

number

[0085] [Table 1]

[0086] In some embodiments, the AV of the levodopa active agent in the pharmaceutical composition is about 15. In other embodiments, the AV of the levodopa active agent in the pharmaceutical composition is less than about 15, e.g., about 14, about 13, about 12, about 11, about 10, about 9, about 8, about 7, about 6, about 5, about 4, about 3, about 2, or about 1. In some embodiments, the AV of the levodopa active agent is measured after storing the pharmaceutical composition in a foil pouch for at least about 8 weeks, at least about 10 weeks, at least about 15 weeks, at least about 26 weeks, or at least about 60 weeks.

[0087] In some embodiments, the AV of the carbidopa active agent in the pharmaceutical composition is about 15. In other embodiments, the AV of the levodopa active agent in the pharmaceutical composition is less than about 15, e.g., about 14, about 13, about 12, about 11, about 10, about 9, about 8, about 7, about 6, about 5, about 4, about 3, about 2, or about 1. In some embodiments, the AV of the carbidopa active agent is measured after storing the pharmaceutical composition in a foil pouch for at least about 8 weeks, at least about 10 weeks, at least about 15 weeks, at least about 26 weeks, or at least about 60 weeks.

[0088] In another embodiment, the levodopa and carbidopa active agents having the particle size distribution described above can successfully form a suspension and maintain the physical stability of the suspension throughout the shelf life of the pharmaceutical composition, even when the levodopa and carbidopa active agents are present in higher concentrations in the composition, so long as the composition has a yield value of at least 1.1 Pa. For example, physical stability can be maintained even when the pharmaceutical composition includes about 4 weight percent levodopa active agent and 1 weight percent carbidopa active agent (e.g., carbidopa monohydrate). In another embodiment, the composition has a yield value of at least about 0.3 Pa.

[0089] In another embodiment, a pharmaceutical composition comprising about 4 percent weight / weight of levodopa active agent and 1 percent weight / weight of carbidopa active agent has a yield value of at least about 2.0 Pa. In another embodiment, the yield value is at least about 3.0 Pa. In another embodiment, the yield value is at least about 4.0 Pa. In another embodiment, the yield value is at least about 5.0 Pa. In another embodiment, the yield value is at least about 6.0 Pa. In another embodiment, the yield value is at least about 7.0 Pa. In another embodiment, the yield value is at least about 8.0 Pa. In another embodiment, the yield value is at least about 9.0 Pa. In another embodiment, the yield value is at least about 10.0 Pa.

[0090] In another embodiment, a pharmaceutical composition as described herein is provided, prepared by the method as described herein. In particular, the levodopa active agent and the carbidopa active agent can be provided in a suitable amount such that the levodopa active agent and the carbidopa active agent are present in the pharmaceutical composition in a therapeutically effective amount. The provided levodopa active agent and the carbidopa active agent have a particle size distribution as described above. The levodopa active agent and the carbidopa active agent are added to water to generate a slurry. The slurry is added to a mixture that may contain one or more suspending agents (e.g., Carbopol® 971P or Carbopol® 974P), a neutralizing agent, and water, as described herein. The suspension is added to a mixture of N 2 O 3 to reduce oxygen levels. 2 The suspension may be subjected to sparging. The suspension may be loaded into a less oxygen permeable or oxygen impermeable container as described herein. Optionally, an oxygen scavenger may be added to the suspension as well.

[0091] IV. Treatment Method The present disclosure further provides a method of treating Parkinson's disease and associated conditions comprising administering to a patient a therapeutically effective amount of a pharmaceutical composition comprising high concentrations of levodopa and carbidopa active agents. The pharmaceutical composition comprising high concentrations of levodopa and carbidopa active agents can comprise a liquid or viscous liquid, for example, containing about 200 mg of levodopa and about 50 mg of carbidopa monohydrate per 5.0 mL volume of each.

[0092] In one embodiment, the present disclosure provides a method of treating a condition in need of treatment, comprising administering to a patient a therapeutically effective amount of a pharmaceutical composition of the present disclosure.

[0093] In one embodiment, the condition treated by administering the pharmaceutical composition is Parkinson's disease.

[0094] In another embodiment, the condition treated by administering the pharmaceutical composition is impaired motor performance in patients with Parkinson's disease (i.e., a method of improving motor performance in patients with Parkinson's disease).

[0095] In another embodiment, the pharmaceutical composition is administered to treat motor fluctuations in a patient with Parkinson's disease.

[0096] In another embodiment, the pharmaceutical composition is administered to treat dyskinesias in a patient with Parkinson's disease.

[0097] In another embodiment, the pharmaceutical composition of the present invention is administered via enteral administration. The pharmaceutical composition of the present invention can be administered (or "injected") directly into the intestine, such as the small intestine (e.g., the duodenum or jejunum), by a permanent tube inserted via a percutaneous endoscopic gastrostomy, for example, using an external transperitoneal tube and an intraenteral tube. In one aspect, the first compound and the second compound are administered via a tube inserted by a radiological gastrojejunostomy. In another aspect, the pharmaceutical composition of the present invention is administered via a temporary nasoduodenal tube that is inserted into the patient, for example, to initially determine whether the patient will respond well to the treatment method before a permanent tube is inserted.

[0098] In embodiments in which one or more of the pharmaceutical compositions of the present invention are administered via enteral administration, administration can be performed using a portable pump, such as the pump sold under the trademark CADD-Legacy Duodopa® pump. Specifically, a cassette, pouch, vial, or cartridge containing a first compound and a second compound can be coupled to a pump to create a delivery system. The delivery system is then connected to a nasoduodenal tube, a transperitoneal port, a duodenal tube, or a jejunal tube for enteral administration.

[0099] In one embodiment, the method comprises administering one or more of the pharmaceutical compositions of the present invention to a patient substantially continuously for a period of at least about 12 hours. In further aspects, the pharmaceutical compositions of the present invention can be administered substantially continuously for a period of about 16 hours, about 24 hours, about 36 hours, about 48 hours, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, or longer.

[0100] In one embodiment, the dose of a pharmaceutical composition of the invention administered to a patient is adjusted to optimize the clinical response achieved by the patient, which means, for example, maximizing functional on-time during the day by minimizing the number and duration of off-time episodes (i.e., bradykinesia) and minimizing on-time associated with disabling dyskinesias.

[0101] In one embodiment, the daily dose of the levodopa active agent administered to a patient according to the methods of the present disclosure may be, for example, from about 20 to about 5000 mg, from about 20 mg to about 4000 mg, from about 20 mg to about 3000 mg, from about 20 mg to about 2000 mg, or from about 20 mg to about 1000 mg per day. In various embodiments, the patient may receive, for example, about 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, 1000, 1010, 102 30, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, 1000, 1010, 1020, 1030, 1040, 1050, 10 60, 1070, 1080, 1090, 1100, 1110, 1120, 1130, 1140, 1150, 1160, 1170, 1180, 1190, 1200, 1210, 1220, 1230, 1240, 1250, 1260, 1270, 1280, 1290, 1300, 1310, 1320, 1330, 1340, 1350, 1360, 1370, 1380, 1390, 1400, 1410, 1420, 1430, 1440, 1450, 1460, 1470, 1480, 1490, 1 500, 1510, 1520, 1530, 1540, 1550, 1560, 1570, 1580, 1590, 1600, 1610, 1620, 1630, 1640, 1650, 1660, 1670, 1680, 1690, 1700, 1710, 1720, 1730, 1740, 1750, 1760, 1770, 1780, 1790, 1800, 1810, 1820, 1830, 1840, 1850, 1860, 1870, 1880, 1890, 1900, 1910, 1920, 1930,1940, 1950, 1960, 1970, 1980, 1990, 2000, 2010, 2020, 2030, 2040, 2050, 2060, 2070, 2080, 2090, 2100, 2110, 2120, 2130, 2140, 2150, 2160, 2170, 2180, 2190, 2200, 2210, 2220, 2230, 2240, 2250, 2260, 2270, 2280, 2290, 2300, 2310, 2320, 2330, 2340, 2350, 2360, 2 The patient may receive 370, 2380, 2390, 2400, 2410, 2420, 2430, 2440, 2450, 2460, 2470, 2480, 2490, 2500, 2600, 2700, 2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600, 3700, 3800, 3900, 4000, 4100, 4200, 4300, 4400, 4500, 4600, 4700, 4800, 4900 or about 5000 mg of levodopa active agent.

[0102] In one embodiment, the daily dose of carbidopa active agent administered to a patient according to the methods of the present disclosure can be, for example, 0 to about 625 mg, 0 mg to about 500 mg, 0 mg to about 375 mg, 0 mg to about 250 mg, or 0 mg to about 125 mg per day. In various aspects, a patient can receive, for example, about 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 625, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 8 0, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 68 0, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, 1000, 1010, 1020 , 1030, 1040, 1050, 1060, 1070, 1080, 1090, 1100, 1110, 1120, 1130, 1140, 1150, 1160, 1170, 1180, 1190, 1200, 1210, 1220, 1230, 1240 or about 1250 mg of carbidopa active drug.

[0103] In some embodiments, the levodopa active agent and the carbidopa active agent are administered in an amount such that the levodopa active agent and the carbidopa active agent, in combination, are sufficient to achieve a plasma level of L-dopa of at least about 100 ng / mL in the patient. In one aspect, the plasma level of L-dopa is at least about 200 ng / mL. In another aspect, the plasma level of L-dopa is at least about 200 ng / mL. In another aspect, the plasma level of L-dopa is at least about 300 ng / mL. In another aspect, the plasma level of L-dopa is at least about 400 ng / mL. In another aspect, the plasma level of L-dopa is at least about 500 ng / mL. In another aspect, the plasma level of L-dopa is at least about 600 ng / mL. In another aspect, the plasma level of L-dopa is at least about 700 ng / mL. In another embodiment, the plasma level of L-dopa is at least about 800 ng / mL. In another embodiment, the plasma level of L-dopa is at least about 900 ng / mL. In another embodiment, the plasma level of L-dopa is at least about 1,000 ng / mL. In another embodiment, the plasma level of L-dopa is at least about 1,500 ng / mL. In another embodiment, the plasma level of L-dopa is at least about 2,000 ng / mL. In another embodiment, the plasma level of L-dopa is at least about 3,000 ng / mL. In another embodiment, the plasma level of L-dopa is at least about 4,000 ng / mL. In another embodiment, the plasma level of L-dopa is at least about 5,000 ng / mL.

[0104] In some embodiments, the levodopa active agent and the carbidopa active agent are administered in an amount sufficient to achieve, in combination, a plasma level of L-dopa of about 10 ng / mL to about 8,000 ng / mL. In one aspect, the plasma level of L-dopa is about 25 ng / mL to about 6,000 ng / mL. In another aspect, the plasma level of L-dopa is about 50 ng / mL to about 4,000 ng / mL. In another aspect, the plasma level of L-dopa is about 100 ng / mL to about 2,000 ng / mL. In another aspect, the plasma level of L-dopa is about 25 ng / mL to about 1,200 ng / mL. In another aspect, the plasma level of L-dopa is about 10 ng / mL to about 500 ng / mL. In another embodiment, the plasma level of L-dopa is from about 25 ng / mL to about 500 ng / mL.

[0105] In some embodiments, the aforementioned L-dopa concentration ranges are maintained over at least about a 1 hour interval, at least about a 2 hour interval, at least about a 3 hour interval, at least about a 4 hour interval, at least about a 5 hour interval, at least about a 6 hour interval, at least about a 7 hour interval, at least about a 8 hour interval, at least about a 9 hour interval, at least about a 10 hour interval, at least about a 11 hour interval, at least about a 12 hour interval, at least about a 18 hour interval, or at least about a 24 hour interval.

[0106] In some embodiments, the levodopa active agent and the carbidopa active agent are administered in an amount such that the levodopa active agent and the carbidopa active agent, in combination, are sufficient to maintain a plasma level of carbidopa of less than about 500 ng / mL. In one aspect, the plasma level of carbidopa is less than about 250 ng / mL. In another aspect, the plasma level of carbidopa is less than about 100 ng / mL. In another aspect, the plasma level of carbidopa is less than about 50 ng / mL. In another aspect, the plasma level of carbidopa is less than about 25 ng / mL.

[0107] In some embodiments, the levodopa active agent and the carbidopa active agent are administered in an amount such that the levodopa active agent and the carbidopa active agent, in combination, are sufficient to maintain a plasma level of carbidopa of about 1 to about 10 ng / mL. In one aspect, the plasma level of carbidopa is about 1 to about 25 ng / mL. In another aspect, the plasma level of carbidopa is about 1 to about 50 ng / mL. In another aspect, the plasma level of carbidopa is about 1 to about 100 ng / mL. In another aspect, the plasma level of carbidopa is about 1 to about 250 ng / mL. In another aspect, the plasma level of carbidopa is about 5 to about 250 ng / mL. In another aspect, the plasma level of carbidopa is about 5 to about 100 ng / mL. In another aspect, the plasma level of carbidopa is about 10 to about 250 ng / mL. In another embodiment, the plasma level of carbidopa is about 10 to about 100 ng / mL. In another embodiment, the plasma level of carbidopa is about 25 to about 250 ng / mL. In another embodiment, the plasma level of carbidopa is about 25 to about 100 ng / mL.

[0108] In some embodiments, the aforementioned carbidopa concentration ranges are maintained over at least about a 1 hour interval, at least about a 2 hour interval, at least about a 3 hour interval, at least about a 4 hour interval, at least about a 5 hour interval, at least about a 6 hour interval, at least about a 7 hour interval, at least about a 8 hour interval, at least about a 9 hour interval, at least about a 10 hour interval, at least about a 11 hour interval, at least about a 12 hour interval, at least about a 18 hour interval, or at least about a 24 hour interval.

[0109] In further embodiments, the administered levodopa and carbidopa active agents can have a particle size distribution as described above.

[0110] In various embodiments, the pharmaceutical composition may be in a container prior to administration to a patient, as described above, and the gel suspension may be in a container such as a container containing 2 The gel suspension may or may not be sparged. 2When sparged and the container has low oxygen permeability, the pharmaceutical composition cannot undergo degradation to produce DHPA at a rate faster than 0.04 w / w% per week of refrigerated storage. (Percentages are relative to the labeled amount of carbidopa.) Additionally or alternatively, the container may be refrigerated to produce DHPA at a rate faster than 0.04 w / w% per week of refrigerated storage. 2 When subjected to sparging, the pharmaceutical composition cannot undergo degradation to produce DHPPA at a rate faster than 0.04 w / w% per week of refrigerated storage. (Percentages are relative to the labeled amount of carbidopa.) Additionally or alternatively, the container may be sparged with N 2 When subjected to sparging, the pharmaceutical composition cannot undergo decomposition to produce hydrazine at a rate faster than 0.6 μg / g per week of refrigerated storage (μg / g indicates μg of hydrazine per gram of gel suspension).

[0111] V. Concomitant Administration of Additional Therapeutic Agents The treatment method of the present disclosure can optionally further include administration of one or more therapeutic agents for the treatment of Parkinson's disease in addition to administration of levodopa and carbidopa active agents. In one embodiment, the additional therapeutic agent(s) is selected from the group consisting of decarboxylase inhibitors other than carbidopa active agents (e.g., benserazide), catechol-O-methyltransferase ("COMT") inhibitors (e.g., entacapone and tolcapone), and monoamine oxidase A ("MAO-A") or monoamine oxidase B ("MAO-B") inhibitors (e.g., moclobemide, rasagiline, selegiline, and safinamide). In one aspect, the additional therapeutic agent(s) is selected from the group consisting of decarboxylase inhibitors other than carbidopa active agents. In another aspect, the additional therapeutic agent(s) is selected from the group consisting of COMT inhibitors. In another aspect, the additional therapeutic agent(s) is selected from the group consisting of MAO-A inhibitors. In another embodiment, the additional therapeutic agent(s) is selected from the group consisting of MAO-B inhibitors.

[0112] Similarly, the pharmaceutical compositions of the present disclosure can, optionally, further comprise one or more additional therapeutic agents for the treatment of Parkinson's disease, as described above.

[0113] VI. Kit The present disclosure also provides kits comprising one or more pharmaceutical dosage forms comprising a carbidopa active agent, kits comprising one or more pharmaceutical dosage forms comprising a levodopa active agent, and kits comprising one or more pharmaceutical dosage forms comprising both a levodopa active agent and a carbidopa active agent. 2 They can be present separately or together in a less permeable bag. The pharmaceutical dosage form can include high concentrations of levodopa and carbidopa active agents, for example, levodopa active agent in an amount of about 4.0 weight / weight percent of the total composition, and carbidopa monohydrate active agent in an amount of about 1.0 weight / weight percent of the total composition. The kit can optionally include one or more additional therapeutic agents and / or instructions, for example, instructions for using the kit to treat a patient with Parkinson's disease or a condition associated therewith.

[0114] VII. Examples The following non-limiting examples are provided to further illustrate the present disclosure. Abbreviations used in the following examples include the following: "Cmax" means maximum observed plasma concentration. "Tmax" means the time to reach maximum observed plasma concentration. "AUC" means area under the plasma concentration-time curve. "t 1 / 2 " means biological half-life, i.e., the time required for half of a drug or other substance administered to an organism to be metabolized or eliminated by normal biological processes.

[0115] VIII. Specific Embodiments The present disclosure provides embodiments I to XX1 as specific embodiments.

[0116] Embodiment I. 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 wherein the pharmaceutical composition has a yield value of at least about 1.1 Pa.

[0117] Embodiment II. A levodopa active agent in an amount of about 4.0 w / w percent of the total composition; carbidopa monohydrate active agent in an amount of about 1.0 w / w percent of the total composition; and Liquid Vehicle The pharmaceutical composition according to embodiment I, comprising:

[0118] Embodiment III. A pharmaceutical composition according to embodiment I or II, wherein the polymer-based suspending agent is an acrylic acid-based polymer.

[0119] Embodiment IV. A pharmaceutical composition according to embodiment I or II, wherein the polymer-based suspending agent is a hydrocolloid polymer.

[0120] Embodiment V. The pharmaceutical composition according to embodiment III, wherein the polymer-based suspending agent is a carbomer.

[0121] Embodiment VI. A pharmaceutical composition according to embodiment III, wherein the polymer-based suspending agent is a polymer of carboxypolymethylene and carbomer sold under the trademark Carbopol® 971P or Carbopol® 974P.

[0122] Embodiment VII. A pharmaceutical composition according to embodiment IV, wherein the polymer-based suspending agent is selected from the group consisting of locust bean gum, guar gum, methylcellulose, sodium carboxymethylcellulose with microcrystalline cellulose and gum tragacanth.

[0123] Embodiment VIII. A pharmaceutical composition according to embodiments I-VII, wherein the concentration of the liquid vehicle is in an amount from about 0 percent to about 95 percent weight / weight of the total composition.

[0124] Embodiment IX. The pharmaceutical composition according to embodiment VIII, wherein the liquid vehicle is selected from the group consisting of water or polyethylene glycol.

[0125] Embodiment X. A pharmaceutical composition according to embodiment VIII, wherein the liquid vehicle is only water.

[0126] Embodiment XI. A pharmaceutical composition according to any one of embodiments I-X, wherein the amount of an impurity in the pharmaceutical composition is less than about 5.8 w / w% of the total weight of the composition when maintained at a temperature of about 20-25° C. for a period of at least 15 weeks.

[0127] Embodiment XII. A pharmaceutical composition according to any one of embodiments I-XI, present within a first or second container that acts as an oxygen barrier.

[0128] Embodiment XIII. A pharmaceutical dosage form comprising the pharmaceutical composition of any one of embodiments I-XII in a disposable drug reservoir having an oxygen-impermeable enclosure disposed therein, wherein the oxygen-impermeable enclosure is purged with an inert gas and an oxygen scavenger is added.

[0129] Embodiment XIV. A pharmaceutical dosage form according to embodiment XIII, suitable for use in a continuous infusion pump capable of delivering the composition in a therapeutically effective manner.

[0130] Embodiment XI. A method of preparing a pharmaceutical composition comprising a levodopa active agent and a carbidopa active agent for intraduodenal administration, comprising: adding one or more suspending agents to the water to disperse the polymer; adding a neutralizing agent to produce a medium having a pH of about 6.5; adding levodopa and carbidopa active agents to water to form a slurry; adding the slurry to a medium to form a suspension; and Optionally, the suspension is subjected to N 2 Sparging A method comprising:

[0131] Embodiment XVI. The method according to embodiment XV, further comprising loading the suspension into a container having a lower oxygen permeability.

[0132] Embodiment XVII. The method according to embodiment XV, wherein the suspending agent is an acrylic acid-based polymer.

[0133] Embodiment XVIII. The method according to embodiment XV, wherein the polymer-based suspending agent is Carbopol® 971P or Carbopol® 974P.

[0134] Embodiment XX. The method according to embodiment XV, wherein the neutralizing agent is sodium hydroxide.

[0135] Embodiment XXI. A method of treating Parkinson's disease in a patient in need thereof comprising 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 provided in a manner that is therapeutically effective for the patient and are suspended in one or more polymer-based suspending agents, and wherein the pharmaceutical composition has a yield value of at least about 1.1 Pa.

[0136] The present disclosure also provides embodiments 1 to 50 as specific embodiments.

[0137] Embodiment 1. A pharmaceutical composition for intraduodenal administration, comprising: (a) a levodopa active agent in an amount of about 4.0 w / w% of the total composition; (b) a carbidopa active agent in an amount of about 1.0 w / w% of the total composition; (c) a polymer-based suspending agent in an amount of about 0.1 w / w% to about 5 w / w% of the total composition, and (d) Liquid vehicle Including, Where: (i) the liquid vehicle is water, polyethylene glycol, or a mixture of water and polyethylene glycol; (ii) the pharmaceutical composition has a determination value of 15 or less for the levodopa active agent and 15 or less for the carbidopa active agent; (iii) the pharmaceutical composition has a yield value of at least about 0.3 Pa; Where: A pharmaceutical composition, wherein the judgement value and yield value are measured after exposing the pharmaceutical composition to a temperature of about 25° C. and a relative humidity of about 60% for a period of at least about 8 weeks.

[0138] According to embodiment 1, "polymer-based suspending agent" can refer to one or more polymer-based suspending agents. When two polymer-based suspending agents are included in the pharmaceutical composition, they can both be acrylic acid-based polymers, such as Carbopol® 971P and Carbopol® 974P, they can both be hydrocolloid polymers, such as Avicel® CL-611 and Avicel® RC591, or one can be an acrylic acid-based polymer and the other can be a hydrocolloid polymer, such as Carbopol® 971P and Avicel® CL-61.

[0139] Embodiment 2. The pharmaceutical composition according to embodiment 1, wherein the decision value and yield value are measured after exposing the pharmaceutical composition to a temperature of about 25° C. and a relative humidity of about 60% for a period of at least about 15 weeks.

[0140] Embodiment 3. The pharmaceutical composition according to embodiment 1, wherein the decision value and yield value are measured after exposing the pharmaceutical composition to a temperature of about 25° C. and a relative humidity of about 60% for a period of at least about 26 weeks.

[0141] Embodiment 4. The pharmaceutical composition according to embodiment 1, wherein the decision value and yield value are measured after exposing the pharmaceutical composition to a temperature of about 25° C. and a relative humidity of about 60% for a period of at least about 60 weeks.

[0142] Embodiment 5. A pharmaceutical composition according to any one of embodiments 1 to 4, wherein the polymer-based suspending agent is an acrylic acid-based polymer.

[0143] Embodiment 6. A pharmaceutical composition according to any one of embodiments 1 to 5, wherein the polymer-based suspending agent is a carbomer, such as Carbopol® 934P, Carbopol® 971P, or Carbopol® 974P.

[0144] Embodiment 7. A pharmaceutical composition according to any one of embodiments 1 to 6, wherein the polymer-based suspending agent is Carbopol® 971P or Carbopol® 974P or a combination thereof.

[0145] Embodiment 8. About 0.1 w / w% to about 0.3 w / w% of the total composition, for example about 0.11 w / w%, about 0.12 w / w%, about 0.13 w / w%, about 0.13 w / w%, about 0.14 w / w%, about 0.15 w / w%, about 0.16 w / w%, about 0.17 w / w%, about 0.18 w / w%, about 0.19 w / w%, about 0 A pharmaceutical composition according to any one of embodiments 1 to 7 comprising a polymer-based suspending agent in an amount of about 0.20 w / w%, about 0.21 w / w%, about 0.22 w / w%, about 0.23 w / w%, about 0.24 w / w%, about 0.25 w / w%, about 0.26 w / w%, about 0.27 w / w%, about 0.28 w / w% or about 0.29 w / w%.

[0146] Embodiment 9. A pharmaceutical composition according to any one of embodiments 1 to 4, wherein the polymer-based suspending agent is a hydrocolloid polymer.

[0147] Embodiment 10. A pharmaceutical composition according to embodiment 1 or 9, wherein the polymer-based suspending agent is selected from the group consisting of locust bean gum, guar gum, methylcellulose, sodium carboxymethylcellulose with microcrystalline cellulose, xanthan gum and tragacanth gum or combinations thereof.

[0148] Embodiment 11. A pharmaceutical composition according to any one of embodiments 1, 9 or 10, wherein the polymer-based suspending agent is selected from the group consisting of locust bean gum, guar gum, xanthan gum and tragacanth gum or combinations thereof.

[0149] Embodiment 12. A pharmaceutical composition according to any one of embodiments 1, 9 or 10, wherein the polymer-based suspending agent is selected from the group consisting of sodium carboxymethylcellulose with methylcellulose and microcrystalline cellulose, or combinations thereof.

[0150] Embodiment 13. A pharmaceutical composition according to any one of embodiments 1, 9 or 10, wherein the polymer-based suspending agent is sodium carboxymethylcellulose with microcrystalline cellulose, such as Avicel® CL-611 or Avicel® RC591.

[0151] Embodiment 14. A pharmaceutical composition according to any one of embodiments 1 or 9-13, comprising a polymer-based suspending agent in an amount of about 1 w / w% to about 5 w / w% of the total composition.

[0152] Embodiment 15. A pharmaceutical composition according to any one of embodiments 1 to 14, wherein the liquid vehicle is a mixture of water and polyethylene glycol.

[0153] Embodiment 16. A pharmaceutical composition according to any one of embodiments 1 to 14, wherein the liquid vehicle is water.

[0154] EMBODIMENT 17. (a) levodopa in an amount of about 4.0 w / w% of the total composition; (b) carbidopa monohydrate in an amount of about 1.0 w / w% of the total composition; (c) Carbopol® 971P or Carbopol® 974P in an amount of about 0.1 w / w% to about 0.2 w / w% of the total composition, and (d) water 6. The pharmaceutical composition according to any one of embodiments 1 to 5, comprising:

[0155] EMBODIMENT 18. (a) levodopa in an amount of about 4.0 w / w% of the total composition; (b) carbidopa monohydrate in an amount of about 1.0 w / w% of the total composition; (c) Carbopol® 971P or Carbopol® 974P in an amount of about 0.1 w / w% to about 0.2 w / w% of the total composition; (d) a neutralizing agent, and (e) water 18. The pharmaceutical composition according to embodiment 17, consisting essentially of:

[0156] EMBODIMENT 19. (a) levodopa in an amount of about 4.0 w / w% of the total composition; (b) carbidopa monohydrate in an amount of about 1.0 w / w% of the total composition; (c) Carbopol® 971P or Carbopol® 974P in an amount of about 0.1 w / w% to about 0.2 w / w% of the total composition; (d) sodium hydroxide in an amount of about 0.01 w / w % to about 0.3 w / w %, and (e) water 19. The pharmaceutical composition according to embodiment 18, consisting of:

[0157] Embodiment 20. A pharmaceutical composition according to any one of embodiments 1 to 19, having a yield value of at least about 0.34 Pa.

[0158] Embodiment 21. A pharmaceutical composition according to embodiment 20, having a yield value of at least about 0.6 Pa.

[0159] Embodiment 22. A pharmaceutical composition according to embodiment 21, having a yield value of at least about 0.9 Pa.

[0160] Embodiment 23. A pharmaceutical composition according to embodiment 22, having a yield value of at least about 1.1 Pa.

[0161] Embodiment 24. A pharmaceutical composition according to any one of embodiments 1-18 or 20-23, further comprising a neutralizing agent in an amount of about 0.01 w / w% to about 0.5 w / w% of the total composition.

[0162] Embodiment 25. A pharmaceutical composition according to embodiment 24, wherein the neutralizing agent is sodium hydroxide.

[0163] Embodiment 26. A pharmaceutical composition according to any one of embodiments 1 to 25, wherein the levodopa active agent has a median particle size distribution (D50) of ≦100 μm.

[0164] Embodiment 27. A pharmaceutical composition according to embodiment 26, wherein the levodopa active agent has a median particle size distribution (D50) of ≦37 μm.

[0165] Embodiment 28. A pharmaceutical composition according to embodiment 27, wherein the levodopa active agent has a median particle size distribution (D50) of ≦5 μm.

[0166] Embodiment 29. A pharmaceutical composition according to any one of embodiments 1 to 28, wherein the carbidopa active agent has a median particle size distribution (D50) of ≦20 μm.

[0167] Embodiment 30. A pharmaceutical composition according to embodiment 29, wherein the carbidopa active agent has a median particle size distribution (D50) of about ≦10 μm.

[0168] Embodiment 31. A pharmaceutical composition according to embodiment 30, wherein the carbidopa active agent has a median particle size distribution (D50) of ≦3 μm.

[0169] Embodiment 32. A pharmaceutical composition according to any one of embodiments 1 to 31, wherein the amount of impurities in the pharmaceutical composition is less than about 5.8 w / w%, such as less than about 5 w / w%, less than about 4 w / w%, less than about 3 w / w%, less than about 2 w / w%, or less than about 1 w / w% of the total weight of the composition when maintained at a temperature of about 20-25°C and a relative humidity of about 60% for a period of at least 8 weeks.

[0170] Embodiment 33. A pharmaceutical composition according to any one of embodiments 1 to 31, wherein the amount of impurities in the pharmaceutical composition is less than about 5.8 w / w%, such as less than about 5 w / w%, less than about 4 w / w%, less than about 3 w / w%, less than about 2 w / w%, or less than about 1 w / w% of the total weight of the composition when maintained at a temperature of about 20-25°C and a relative humidity of about 60% for a period of at least 15 weeks.

[0171] Embodiment 34. A pharmaceutical composition according to any one of embodiments 1 to 31, wherein the amount of impurities in the pharmaceutical composition is less than about 5.8 w / w%, such as less than about 5 w / w%, less than about 4 w / w%, less than about 3 w / w%, less than about 2 w / w%, or less than about 1 w / w% of the total weight of the composition when maintained at a temperature of about 20-25°C and a relative humidity of about 60% for a period of at least 26 weeks.

[0172] Embodiment 35. A pharmaceutical composition according to any one of embodiments 1 to 31, wherein the amount of impurities in the pharmaceutical composition is less than about 5.8 w / w%, such as less than about 5 w / w%, less than about 4 w / w%, less than about 3 w / w%, less than about 2 w / w%, or less than about 1 w / w% of the total weight of the composition when maintained at a temperature of about 20-25°C and a relative humidity of about 60% for a period of at least 60 weeks.

[0173] Embodiment 36. A pharmaceutical composition according to any one of embodiments 1 to 35, present within a first or second container that acts as an oxygen barrier, such as a foil pouch.

[0174] Embodiment 37. A pharmaceutical dosage form comprising a pharmaceutical composition according to any one of embodiments 1 to 35 in a disposable drug reservoir having an oxygen-impermeable enclosure disposed therein, wherein the oxygen-impermeable enclosure is purged with an inert gas and an oxygen scavenger is added.

[0175] Embodiment 38. A pharmaceutical dosage form according to embodiment 37, suitable for use in a continuous infusion pump capable of delivering the composition in a therapeutically effective manner.

[0176] Embodiment 39. A method for preparing a pharmaceutical composition comprising a levodopa active agent and a carbidopa active agent for intraduodenal administration, comprising: (i) the pharmaceutical composition has a pharmaceutical composition determination value of 15 or less for the levodopa active agent and 15 or less for the carbidopa active agent; (ii) the pharmaceutical composition has a yield value of at least about 0.3 Pa; Where: The judgment value and the yield value are measured after exposing the pharmaceutical composition to a temperature of about 25° C. and a relative humidity of about 60% for a period of at least about 8 weeks; The method comprises: adding an acrylic acid based polymeric suspending agent to water to form a dispersion; adding a neutralizing agent to the dispersion to obtain a pH of about 6.5 to form a medium; adding levodopa and carbidopa active agents to water to form a slurry; and Adding the slurry to a vehicle to form a pharmaceutical composition. A method comprising:

[0177] Embodiment 40 The method according to embodiment 39, wherein the acrylic acid-based polymeric suspending agent is a carbomer.

[0178] Embodiment 41. The pharmaceutical composition according to embodiment 39, wherein the acrylic acid-based polymeric suspending agent is Carbopol® 971P or Carbopol® 974P.

[0179] Embodiment 42. The method according to any one of embodiments 38 to 40, wherein the neutralizing agent is sodium hydroxide.

[0180] Embodiment 43. A method of preparing a pharmaceutical composition comprising a levodopa active agent and a carbidopa active agent for intraduodenal administration, comprising: (i) the pharmaceutical composition has a pharmaceutical composition determination value of 15 or less for the levodopa active agent and 15 or less for the carbidopa active agent; (iii) the pharmaceutical composition has a yield value of at least about 0.3 Pa; Where: The judgment value and the yield value are measured after exposing the pharmaceutical composition to a temperature of about 25° C. and a relative humidity of about 60% for a period of at least about 8 weeks; The method comprises: adding a hydrocolloid polymeric suspending agent to water to form a dispersion; adding levodopa and carbidopa active agents to water to form a slurry; and Adding the slurry to a vehicle to form a pharmaceutical composition. A method comprising:

[0181] Embodiment 44. A pharmaceutical composition according to embodiment 43, wherein the polymer-based suspending agent is selected from the group consisting of locust bean gum, guar gum, sodium carboxymethylcellulose with microcrystalline cellulose, xanthan gum and tragacanth gum.

[0182] Embodiment 45. The pharmaceutical composition is 2 The method according to any one of embodiments 39 to 44, further comprising sparging.

[0183] Embodiment 46. The method according to any one of embodiments 39 to 45, further comprising loading the pharmaceutical composition into a container having a lower oxygen permeability.

[0184] Embodiment 47. A method of treating Parkinson's disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition according to any one of embodiments 1 to 36.

[0185] Embodiment 48. A pharmaceutical composition according to any one of embodiments 1 to 36, wherein the determined value of levodopa active drug is 15 or less, for example, about 14, about 13, about 12, about 11, about 10, about 9, about 8, about 7, about 6, about 5, about 4, about 3, about 2 or about 1.

[0186] Embodiment 49. A pharmaceutical composition according to any one of embodiments 1 to 36 or 48, wherein the determined value of the carbidopa active agent is 15 or less, e.g., about 14, about 13, about 12, about 11, about 10, about 9, about 8, about 7, about 6, about 5, about 4, about 3, about 2 or about 1.

[0187] Embodiment 50. A pharmaceutical dosage form according to embodiment 37 or 38, comprising about 40 mg / mL of levodopa active agent and about 10 mg / mL of carbidopa active agent. EXAMPLES

[0188] Example 1: Preparation of pharmaceutical composition A levodopa / carbidopa active agent pharmaceutical composition was prepared using Carbopol® 974P as shown in FIG. 1 and described below.

[0189] 1.1 Slurry preparation Levodopa and carbidopa were added to the water in a container and mixed using a high shear mixer. Alternatively, the overhead impeller can be replaced with a low shear mixer. The slurry was used to wet and de-lump the API (drug active agent).

[0190] 1.2 Preparation of gel suspension Carbopol® 974P was added to the water in a second container and mixed under vacuum using a low shear mixer. Sodium hydroxide was added to the mixture to neutralize the polymer. The slurry was added to the mixture and further mixed using a low shear mixer to complete the preparation of the gel suspension.

[0191] 1.3 Filling and Pouching The gel suspension was filled into a Disposable Drug Reservoir (DDR). The fill weight was checked at regular intervals by a balance. The filled DDR was covered with a foil pouch. The pouch was sparged with nitrogen and heat sealed.

[0192] 1.4 Packaging The foil pouches were packaged into kits holding seven DDRs. The kits were then stored at various conditions: 5° C., 25° C. and approximately 60% relative humidity (RH), and 40° C. and 75% RH.

[0193] [Table 2]

[0194] [Table 3]

[0195] [Example 2] Stability of high concentration pharmaceutical composition

[0196] 2.1 Preparation of the formulation Carbopol® 974P-based formulations were produced in a pilot-scale device. The overall manufacturing process was the same as in Example 1. The batches were filled into DDRs (disposable drug reservoirs). The DDR samples were then packaged in nitrogen-sparged foil pouches to prevent any oxygen transfer from the environment. Throughout the 15-week stability study at 25° C., the samples maintained their chemical and physical stability. This result cannot be achieved with other levodopa-carbidopa enteric gels (e.g., commercially available Duodopa).

[0197] [Table 4]

[0198] 2.2 Chemical Stability Data The Carbopol® formulation described in 2.1 was placed at 5° C. immediately after manufacture and then at 25° C. after a few weeks to initiate the stability study. The formulation was then thawed at 5° C. and then placed at 25° C. to initiate the stability study. After evaluating chemical stability, the formulation was placed at 25° C., which was defined as the initial time point, for 15 weeks. Testing of levodopa and carbidopa concentration percent from target (assay) and critical impurities (DHPA and DHPPA) was performed to evaluate chemical stability.

[0199] [Table 5]

[0200] 2.3 Physical stability of samples with regard to stability The uniformity of content distribution (UDC) method was used to evaluate the physical stability of the formulation. The UDC method provides the API concentration in the gel when administered. This simulates the API concentration that a patient would receive for every 5 g of gel delivered by the pump, ensuring that the patient receives a consistent amount of drug throughout the consumption of one DDR. Testing was performed at each time point throughout the 15-week stability study. The particle size distribution of the API used in this study was within the particle size limits mentioned herein. The results are summarized in Tables 5 (levodopa) and 6 (carbidopa) below.

[0201] [Table 6]

[0202] [Table 7]

[0203] [Example 3] Therapeutic effect of pharmaceutical composition in miniature pigs A high concentration (HC) L-dopa / carbidopa intestinal gel using sodium carboxymethylcellulose was compared to a low concentration (LC) L-dopa / carbidopa intestinal gel using sodium carboxymethylcellulose and a high concentration L-dopa / carbidopa intestinal gel using Carbopol® 974P in the following manner: Groups of four minipigs each were administered LC L-dopa / carbidopa intestinal gel, HC L-dopa / carbidopa intestinal gel, or L-dopa / carbidopa in Carbopol® 974P carrier in a crossover study design. Each of the four minipigs was administered one formulation on the first day of the week, followed by a one-week washout period, after which the second formulation was administered. After another one-week washout period, the third formulation was administered to the same minipigs. Total dose: 11.07 mg / kg levodopa dose over 6.5 hours; 20 mg / mL Group: LC; HC; Carbopol(R) 974P Bolus dose: 2.53 mg / kg bolus dose over 30 minutes Infusion dose: 8.54 mg / kg over 6 hours.

[0204] Bolus Infusion Rate: LC = 0.253 mL / kg / hr (e.g., 10 kg pig = 2.53 mL / hr pump rate) HC = 0.127 mL / kg / hr (e.g., 10 kg pig = 1.27 mL / hr pump rate) Carbopol® 974P = 0.127 mL / kg / hr (e.g., 10 kg pig = 1.27 mL / hr pump rate) Infusion rate over 6 hours: LC = 0.071 mL / kg / hr (e.g., 10 kg pig = 0.71 mL / hr pump rate) HC = 0.0355 mL / kg / hr (e.g., 10 kg pig = 0.355 mL / hr pump rate) Carbopol® 974P = 0.0355 mL / kg / hr (e.g., 10 kg pig = 0.355 mL / hr pump rate). Plasma sampling time points: 0.5 hours, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours, 9 hours, 10 hours, 12 hours The study results, as shown in Figures 2 and 3, demonstrated that the high concentration levodopa / carbidopa intestinal gel had comparable C values ​​to the LC formulation when administered under half-hour bolus and six-hour infusion conditions. max , T max and AUC values ​​are confirmed. Cassettes of 11.07 mg / kg levodopa and 2.77 mg / kg carbidopa monohydrate were administered at 80 μL / kg (LC gel) or 40 μL / kg (HC gel and Carbopol® 974P control). The bioavailability of levodopa is summarized in Tables 7 and 8 below. The half-life values ​​shown in Tables 7 and 8 are calculated as harmonic means.

[0205] [Table 8]

[0206] The bioavailability of carbidopa is further summarized below.

[0207] [Table 9]

[0208] LC and HC L-dopa / carbidopa intestinal gels using sodium carboxymethylcellulose (NaCMC) were manufactured on a commercial scale. NaCMC was first added to water and mixed at high shear using a homogenizer to prepare an aqueous gel. The gel was then sparged with nitrogen to remove most of the dissolved oxygen. Levodopa and carbidopa monohydrate were added to water in a separate container and mixed at high shear using a homogenizer (this step can also be performed using low shear) to produce a slurry. The slurry was then added to the gel and mixed at high shear using a homogenizer (the slurry step was repeated twice for the HC formulation). The entire composition was then degassed and filled into cassettes. The HC formulations were then packaged into kits of 7 and immediately placed at -20°C. The LC formulations were packaged into foil pouches filled with oxygen scavengers and sparged with nitrogen before sealing. HC L-dopa / carbidopa intestinal gel using Carbopol® 974P was prepared on a laboratory scale using a process similar to that described in Example 1.

[0209] Example 4: Minimum yield value of physical stability at room temperature over 12 weeks using Carbopol® 971P Three formulations of levodopa-carbidopa intestinal gel 40 mg / ml-10 mg / ml (LCIG40 / 10) were prepared similar to Example 1 using three different concentrations of Carbopol® 971P: 0.1 w / w%, 0.2 w / w% and 0.5 w / w%. These formulations were neutralized with NaOH to a final pH of about 6.5. The ratio of Carbopol® to NaOH required to achieve a pH of about 6.5 was first determined using the 0.2 w / w% Carbopol formulation.

[0210] The 0.1 w / w%, 0.2 w / w% and 0.5 w / w% formulations had yield values ​​of 0.2 Pa, 1.1 Pa and 4.5 Pa, respectively. The formulations were placed in long vials at room temperature (approximately 20° C.) and covered with cardboard to prevent photodegradation. All three formulations were uniformly white in color at the initial time point. After 8 weeks, the 0.1 w / w% formulation began to precipitate and form a clear layer. After 12 weeks, the 0.5 w / w% and 0.2 w / w% formulations were still visually acceptable, as shown in FIG. 5.

[0211] Based on these results, a yield value of at least 1.1 Pa is required to resist settling. The data is summarized in Table 9 below.

[0212] [Table 10]

[0213] Example 5: Physical stability of levodopa / carbidopa compositions Pharmaceutical compositions containing (a) levodopa in an amount of 3.88 w / w% of the total composition, (b) carbidopa monohydrate in an amount of 0.97 w / w% of the total composition, (c) a polymer-based suspending agent in the indicated amount, (d) sodium hydroxide in the indicated amount, and (e) water were prepared as outlined in Table 11. The UDC conditions for the levodopa determination, viscosity, and yield value at various time points of 1 week, 8 weeks, and 15 weeks for these formulations are provided. The particle size of levodopa (particle size of API) is also provided. The compositions were stored in foil pouches at a temperature of about 25° C. and a relative humidity of about 60%. Based on these results, a yield value of at least 0.3 Pa is required to resist settling. The data is summarized in Table 11.

[0214] In a similar study, a pharmaceutical composition comprising (a) levodopa (particle size: D50=3 μm, D90=7 μm, and D100=18 μm) in an amount of 3.77 w / w% of the total composition, (b) carbidopa monohydrate (particle size: D50=2 μm, D90=6 μm, and D100=16 μm) in an amount of 0.94 w / w% of the total composition, (c) Carbopol® 974P in an amount of 0.18 w / w% of the total composition, (d) sodium hydroxide in an amount of 0.306 w / w% of the total composition, and (e) water was prepared and stored in a foil bag under the conditions shown in Table 12. The physical and chemical stability of the pharmaceutical composition is provided. The low shear (LS) viscosities measured at about 0.13 1 / sec and the high shear (HS) viscosities measured at about 27 1 / sec of formulations stored under the conditions shown in Table 12 are shown in Figures 6 and 7, respectively.

[0215] The yield values ​​and viscosities in Table 11 and the yield values ​​in Table 12 were measured using a Discovery HR-2 rheometer from TA instruments. The rheometer was fitted with concentric cylinders. The samples were first soaked at 25° C. for 600 seconds or until the samples reached equilibrium. The samples were optionally pre-sheared at 200 l / s for 120 seconds. An upward flow ramp was performed by first soaking the pre-sheared samples for 360 seconds and then increasing the shear rate from 0.001 l / s to 250 l / s over 300 seconds. The samples were held at 250 l / s for a further 300 seconds as required. Finally, a downward flow ramp was performed from 250 l / s to 0.001 l / s over 300 seconds. The resulting downward flow ramps were fitted with a Herschel-Bulkley model to obtain the yield values ​​and viscosities.

[0216] To determine the callout value, the pharmaceutical composition was drawn from a disposable drug reservoir (DDR) through integrated tubing in ten approximately equal fractions. Each fraction was analyzed for drug concentration using high pressure liquid chromatography. See USP, Chapter 905 and Figure 8.

[0217] Example 6: Pharmacokinetic (PK) study in minipigs using formulations containing large and small particle size levodopa The minipigs underwent surgery to place a J-tube in the jejunum. Formulation B (large particle size levodopa) and Formulation C (small particle size levodopa) were delivered by a medical pump via the J-tube. See Table 13. A crossover design was used with 4 minipigs in each arm. Each minipigs was administered 0.6 ml at a constant infusion rate over 30 minutes. Blood samples were taken at 0, 0.1, 0.25, 0.5, 1, 2, 4, 6, and 7 hours and plasma levodopa concentrations were measured by LC-MS. PK data are shown in Table 14 and Figure 9. There is no significant difference in AUC, Tmax, Cmax between the two gel formulations.

[0218] [Table 11]

[0219] [Table 12]

[0220] [Table 13]

[0221] [Table 14]

Claims

1. (a) a levodopa active agent in an amount of about 4.0 w / w% of the total composition; (b) a carbidopa active agent in an amount of about 1.0 w / w% of the total composition; (c) a polymer-based suspending agent in an amount of about 0.1% to about 5% w / w of the total composition; and (d) Liquid Vehicle A pharmaceutical composition for intraduodenal administration comprising: (i) the liquid vehicle is water, polyethylene glycol, or a mixture of water and polyethylene glycol; (ii) the pharmaceutical composition has a determination value of 15 or less for the levodopa active agent and 15 or less for the carbidopa active agent; (iii) the pharmaceutical composition has a yield value of at least about 0.3 Pa; A pharmaceutical composition, wherein the judgement value and yield value are measured after exposing the pharmaceutical composition to a temperature of about 25° C. and a relative humidity of about 60% for a period of at least about 8 weeks.

2. 2. The pharmaceutical composition of claim 1, wherein the judgment value and yield value are measured after exposing the pharmaceutical composition to a temperature of about 25° C. and a relative humidity of about 60% for a period of at least about 15 weeks.

3. 3. The pharmaceutical composition according to claim 1 or 2, wherein the polymer-based suspending agent is an acrylic acid-based polymer.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the polymer-based suspending agent is a carbomer.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the polymer-based suspending agent is Carbopol® 971P or Carbopol® 974P.

6. 6. The pharmaceutical composition of any one of claims 1 to 5, comprising a polymer-based suspending agent in an amount of about 0.1% to about 0.3% w / w of the total composition.

7. 3. The pharmaceutical composition of claim 1, wherein the polymer-based suspending agent is a hydrocolloid polymer.

8. 8. The pharmaceutical composition of claim 1 or 7, wherein the polymer-based suspending agent is selected from the group consisting of locust bean gum, guar gum, methylcellulose, sodium carboxymethylcellulose with microcrystalline cellulose, xanthan gum and tragacanth gum.

9. 9. A pharmaceutical composition according to any one of claims 1, 7 or 8, wherein the polymer-based suspending agent is selected from the group consisting of locust bean gum, guar gum, xanthan gum and tragacanth gum.

10. 9. The pharmaceutical composition of claim 1, 7 or 8, wherein the polymer-based suspending agent is selected from the group consisting of methylcellulose and sodium carboxymethylcellulose with microcrystalline cellulose.

11. 11. The pharmaceutical composition of any one of claims 1 or 7-10, comprising a polymer-based suspending agent in an amount of about 1% w / w to about 5% w / w of the total composition.

12. The pharmaceutical composition according to any one of claims 1 to 11, wherein the liquid vehicle is a mixture of water and polyethylene glycol.

13. The pharmaceutical composition according to any one of claims 1 to 11, wherein the liquid vehicle is water.

14. (a) levodopa in an amount of about 4.0 w / w% of the total composition; (b) carbidopa monohydrate in an amount of about 1.0 w / w% of the total composition; (c) Carbopol® 971P or Carbopol® 974P in an amount of about 0.1% to about 0.2% w / w of the total composition, and (d) Water The pharmaceutical composition according to any one of claims 1 to 3, comprising:

15. (a) levodopa in an amount of about 4.0 w / w% of the total composition; (b) carbidopa monohydrate in an amount of about 1.0 w / w% of the total composition; (c) Carbopol® 971P or Carbopol® 974P in an amount of about 0.1% to about 0.2% w / w of the total composition; (d) a neutralizing agent, and (e) Water 15. The pharmaceutical composition of claim 14, consisting essentially of:

16. (a) levodopa in an amount of about 4.0 w / w% of the total composition; (b) carbidopa monohydrate in an amount of about 1.0 w / w% of the total composition; (c) Carbopol® 971P or Carbopol® 974P in an amount of about 0.1% to about 0.2% w / w of the total composition; (d) sodium hydroxide in an amount of about 0.01% to about 0.3% w / w, and (e) Water The pharmaceutical composition according to claim 15, comprising:

17. 17. The pharmaceutical composition of any one of claims 1 to 16, having a yield value of at least about 0.34 Pa.

18. 18. The pharmaceutical composition of claim 17 having a yield value of at least about 0.6 Pa.

19. 20. The pharmaceutical composition of claim 18 having a yield value of at least about 0.9 Pa.

20. 20. The pharmaceutical composition of claim 19 having a yield value of at least about 1.1 Pa.

21. 21. The pharmaceutical composition of any one of claims 1-15 or 17-20, further comprising a neutralizing agent in an amount of about 0.01% w / w to about 0.5% w / w of the total composition.

22. 22. The pharmaceutical composition of claim 21, wherein the neutralizing agent is sodium hydroxide.

23. 23. The pharmaceutical composition of any one of claims 1 to 22, wherein the levodopa active agent has a median particle size distribution (D50) of ≦100 μm.

24. 24. The pharmaceutical composition of claim 23, wherein the levodopa active agent has a median particle size distribution (D50) of ≦37 μm.

25. 25. The pharmaceutical composition of claim 24, wherein the levodopa active agent has a median particle size distribution (D50) of ≦5 μm.

26. 26. A pharmaceutical composition according to any one of claims 1 to 25, wherein the carbidopa active agent has a median particle size distribution (D50) of ≦20 μm.

27. 27. The pharmaceutical composition of claim 26, wherein the carbidopa active agent has a median particle size distribution (D50) of about ≦10 μm.

28. 28. The pharmaceutical composition of claim 27, wherein the carbidopa active agent has a median particle size distribution (D50) of ≦3 μm.

29. 29. The pharmaceutical composition of any one of claims 1 to 28, wherein the amount of impurities in the pharmaceutical composition is in an amount of less than about 5.8 w / w% of the total weight of the composition when maintained at a temperature of about 20-25°C and a relative humidity of about 60% for a period of at least 15 weeks.

30. 30. The pharmaceutical composition of any one of claims 1 to 29, present within a first or second container that acts as an oxygen barrier.

31. 30. A pharmaceutical dosage form comprising the pharmaceutical composition of any one of claims 1 to 29 in a disposable drug reservoir having an oxygen-impermeable enclosure disposed therein, the oxygen-impermeable enclosure being purged with an inert gas and having an oxygen scavenger added thereto.

32. 32. The pharmaceutical dosage form of claim 31, suitable for use in a continuous infusion pump capable of delivering the composition in a therapeutically effective manner.

33. 1. A method for preparing a pharmaceutical composition comprising a levodopa active agent and a carbidopa active agent for intraduodenal administration, comprising: (i) the pharmaceutical composition has a pharmaceutical composition determination value of 15 or less for the levodopa active agent and 15 or less for the carbidopa active agent; (ii) the pharmaceutical composition has a yield value of at least about 0.3 Pa; The judgment value and the yield value are measured after exposing the pharmaceutical composition to a temperature of about 25° C. and a relative humidity of about 60% for a period of at least about 8 weeks; adding an acrylic acid based polymeric suspending agent to water to form a dispersion; adding a neutralizing agent to the dispersion to obtain a pH of about 6.5 to form a medium; adding levodopa and carbidopa active agents to water to form a slurry; and Adding the slurry to a vehicle to form a pharmaceutical composition. A method comprising:

34. 34. The method of claim 33, wherein the acrylic acid-based polymeric suspending agent is a carbomer.

35. 34. The pharmaceutical composition of claim 33, wherein the acrylic acid-based polymeric suspending agent is Carbopol® 971P or Carbopol® 974P.

36. The method of any one of claims 33 to 35, wherein the neutralizing agent is sodium hydroxide.

37. 1. A method for preparing a pharmaceutical composition comprising a levodopa active agent and a carbidopa active agent for intraduodenal administration, comprising: (i) the pharmaceutical composition has a pharmaceutical composition determination value of 15 or less for the levodopa active agent and 15 or less for the carbidopa active agent; (ii) the pharmaceutical composition has a yield value of at least about 0.3 Pa; The judgment value and the yield value are measured after exposing the pharmaceutical composition to a temperature of about 25° C. and a relative humidity of about 60% for a period of at least about 8 weeks; adding a hydrocolloid polymeric suspending agent to water to form a dispersion; adding levodopa and carbidopa active agents to water to form a slurry; and Adding the slurry to a vehicle to form a pharmaceutical composition. A method comprising:

38. 38. The pharmaceutical composition of claim 37, wherein the polymer-based suspending agent is selected from the group consisting of locust bean gum, guar gum, sodium carboxymethylcellulose with microcrystalline cellulose, xanthan gum and gum tragacanth.

39. The pharmaceutical composition ２ The method of any one of claims 33 to 38, further comprising sparging.

40. 40. The method of any one of claims 33 to 39, further comprising packaging the pharmaceutical composition in a container with lower oxygen permeability.

41. A method for treating Parkinson's disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition according to any one of claims 1 to 30.

42. 33. The pharmaceutical dosage form of claim 31 or 32, comprising about 40 mg / mL of levodopa active agent and about 10 mg / mL of carbidopa active agent.

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