Levodopa and carbidopa intestinal gel and methods of use

Abstract

To provide 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.SOLUTION: The present disclosure provides (a) an improved pharmaceutical composition comprising a levodopa active agent and a carbidopa active agent, (b) methods of producing the pharmaceutical composition, and (c) methods of treating Parkinson's disease and associated conditions, the methods comprising administering the pharmaceutical composition to a subject with Parkinson's disease.SELECTED DRAWING: Figure 4

Description

[Technical field]

[0001] The present disclosure relates to (a) an improved pharmaceutical composition comprising levodopa and carbidopa and (b) a method for treating Parkinson's disease and related conditions comprising administering the pharmaceutical composition to a subject with Parkinson's disease. [Background technology]

[0002] Parkinson's disease is a chronic and progressive neurodegenerative condition characterized by decreased brain levels of the neurotransmitter dopamine (i.e., 3,4-dihydroxyphenethylamine). Currently, administration of L-dopa is the most effective therapy 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, resulting in increased 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. Administering such large L-dopa doses results in elevated peripheral dopamine levels that can cause nausea in some patients. To overcome these problems, L-dopa is coadministered 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]

[0006] 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. Summary of the Invention [Problem to be solved by the invention]

[0007] However, even when L-dopa and carbidopa are administered concomitantly, it is difficult to consistently maintain desired dopamine levels due to the relatively short half-life of L-dopa in plasma. Furthermore, many patients' tolerance to variability in dopamine in the brain decreases as the disease progresses. One approach that has been successful in reducing variability in dopamine levels is the continuous intestinal delivery of an adjustable dose of L-dopa / carbidopa gel, known under the trade name DuoDopa®. DuoDopa® is a suspension of L-dopa / carbidopa monohydrate (4:1 ratio of L-dopa: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 contained in a disposable drug reservoir ("DDR") and is administered continuously via a software-controlled ambulatory infusion pump. Although L-dopa and carbidopa have been administered in combination to treat Parkinson's disease for decades, there are currently no commercially available pharmaceutical compositions suitable for use in the newer generation of metered, smaller infusion pumps that deliver gel compositions to the intestinal tract.

[0008] The current composition of DuoDopa® L-dopa / carbidopa enteral gel is a gel for continuous enteral administration. For long-term administration, the gel is administered using a portable pump directly into the duodenum or upper jejunum via a percutaneous endoscopic gastrostomy tube with an internal enteral / jejunal tube. Each mL of DuoDopa® contains 20 mg levodopa and 5 mg carbidopa monohydrate. Although DuoDopa® is currently commercially successful, the product has limitations in product manufacturing, including (1) the risk of drug particle settling during storage and administration, and (2) hydrazine formation due to the chemical instability of carbidopa.

[0009] Thus, there remains a need for improved formulations and methods that can provide continuous and constant 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]

[0010] In one embodiment, the disclosure relates to a pharmaceutical composition comprising a levodopa active agent and a carbidopa active agent for intraduodenal administration, wherein the levodopa active agent is provided in an amount of about 4 weight percent (w / w%) of the composition, and carbidopa (e.g., carbidopa monohydrate) is provided in an amount of about 1% by weight of the composition, and the levodopa and carbidopa are suspended in an aqueous carrier. The pharmaceutical composition has a desired viscosity suitable for storage under refrigerated conditions and / or delivery (e.g., via a pump) at room temperature (e.g., about 20° C. to about 25° C.).

[0011] In another aspect, the disclosure relates to 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 (e.g., carbidopa monohydrate) for intraduodenal administration, the levodopa active agent and the carbidopa active agent being provided in an amount of about 4 weight percent and 1 weight percent of the composition, respectively, suspended in an aqueous carrier, the pharmaceutical composition having a desired viscosity suitable for storage under refrigerated conditions and / or delivery (e.g., via a pump) at room temperature (e.g., about 20° C. to about 25° C.).

[0012] In another aspect, the present disclosure relates to methods of making the pharmaceutical compositions of the present invention, particularly the highly concentrated pharmaceutical compositions disclosed, for example, in Example 1 and FIG. 1 below.

[0013] These and additional embodiments of the invention are further described herein.

[0014] Further advantages of the present disclosure will be apparent to those skilled in the art upon reading this patent application. The disclosed embodiments described in the following paragraphs are illustrative of the present invention, but should not be considered as limiting the scope of the present invention. [Brief description of the drawings]

[0015] [Figure 1] 1 is a manufacturing process flow chart for producing an exemplary pharmaceutical formulation of the present invention. [Diagram 2] FIG. 1 shows L-dopa blood level time-concentration profiles in minipigs of an exemplary pharmaceutical composition of the invention against two comparators, both provided as a 6-hour continuous infusion. [Diagram 3] FIG. 1 shows carbidopa blood level time-concentration profiles in minipigs of an exemplary pharmaceutical composition of the invention against two comparators, both provided as a 6-hour continuous infusion. [Figure 4]FIG. 1 shows the mean levodopa plasma concentrations in 12 human subjects at various time points after administration. [Diagram 5] FIG. 1 shows the mean carbidopa plasma concentrations in 12 human subjects at various time points after dosing. [Figure 6] FIG. 1 shows the dissolution rates of levodopa and carbidopa in pH 4.5 media. [Figure 7] FIG. 1 shows the dissolution rates of levodopa and carbidopa in pH 6.8 media. [Figure 8] FIG. 1 shows the degradation of low and high concentration gel formulations to 3,4-dihydroxyphenylacetone (DHPA) over a 15 week storage period at 2 to 8° C. [Figure 9] FIG. 1 shows the degradation of low and high concentration gel formulations to 2-methyl-3-(3,4-dihydroxyphenyl)propanoic acid (DHPPA) over a 15 week storage period at 2 to 8° C. [Figure 10] FIG. 1 shows the decomposition of low and high concentration gel formulations to hydrazine over a 15 week storage period at 2 to 8° C. [Figure 11] Figure 1 shows the effect of oxygen scavengers in different packages on the accumulation of DHPA (panel A) and DHPPA (panel B) degradation products. Abbreviations in the legend mean: 1X = 2 wt% levodopa, 0.5 wt% carbidopa; 2X = 4 wt% levodopa, 1.0 wt% carbidopa; EVA = container stopper bag made of EVA / EVOH / EVA material; Smiths = PVC bag used in Smiths Medical cassette reservoir; OW+Scav = oxygen scavengers in overwrap aluminum foil pouch. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] This description uses examples to disclose the invention, including the best mode, and also to enable one of ordinary skill in the art to practice the invention, including making and using the disclosed pharmaceutical compositions, kits, pharmaceutical formulations, and performing 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 of ordinary skill in the art. Such other examples are intended to be encompassed by the claims as if they had elements that are no different from the literal language of the claims, or as if they contained equivalent elements.

[0017] I. definition The section headings used in this section and throughout the disclosure are not intended to be limiting of the invention.

[0018] Where numerical ranges are recited, each intervening number within the range is expressly contemplated with the same degree of precision. For example, for the range 6 to 9, the numbers 7 and 8 are expressly 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. Similarly, all recited ratios include all sub-ratios included within the broader ratio.

[0019] The singular forms "a", "an" and "the" include plural referents unless the context clearly indicates otherwise.

[0020] The term "and / or" as used herein in expressions such as "A and / or B" is intended to include "A and B," "A or B," "A," and "B."

[0021] The term "about" 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" may include numbers that are rounded to the nearest significant figure.

[0022] Unless the context otherwise requires, the terms "comprise," "comprises," and "comprising" are used with the clear understanding that they are to be interpreted inclusively rather than exclusively and that applicant intends that each of these terms be so interpreted in interpreting this patent, including the appended claims.

[0023] The terms "ameliorate" and "amelioration" have their plain and ordinary meaning to one of ordinary skill in the art of pharmacy or medicine, and specifically include ameliorating the effects of Parkinson's disease or reducing or lessening the symptoms or side effects of Parkinson's disease.

[0024] The term "patient" includes mammals and humans, especially humans.

[0025] The term "pharmaceutical acceptable carrier" or "pharmaceutical acceptable excipient" refers to any and all solvents, dispersion media, preservatives, antioxidants, coatings, isotonic and absorption delaying agents, etc., that are compatible with pharmaceutical administration. The term "aqueous carrier" refers to a pharmaceutical carrier in which the solvent is water.

[0026] The term "pharmaceutical acceptable salt" refers to a salt of a compound that is pharmaceutical acceptable and possesses the desired pharmacological activity of the parent compound. Such salts include: (1) those formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with 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] ... 1.2]-Oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and other organic acids; and (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or when an organic base, e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, dicyclohexylamine, and other organic bases, are coordinated.

[0027] The terms "reduce" and "reduction" have their plain and ordinary meaning to one of ordinary skill in the art of pharmacy or medicine and specifically include lessening or decreasing the occurrence, duration or intensity of a symptom or side effect of Parkinson's disease, such as dyskinesia or hallucinations.

[0028] The term "therapeutically effective amount" means an amount of a compound that, when administered alone or in combination with another therapy to a patient suffering from or susceptible to Parkinson's disease or a related condition, effects treatment of Parkinson's disease or a related condition. A "therapeutically effective amount" will vary depending, for example, on the compound, pharmaceutical composition or formulation, the condition being treated and its severity, and the age and weight of the patient being treated.

[0029] The terms "treat" and "treatment" have their plain and ordinary meaning to one of ordinary skill in the art of pharmaceutical or medical sciences, and specifically include enhancing the quality of life or reducing the symptoms or side effects of Parkinson's disease.

[0030] II. Pharmaceutical Compositions The present disclosure relates to a pharmaceutical composition comprising a levodopa active agent and a carbidopa active agent for intraduodenal administration, wherein the levodopa active agent and the carbidopa active agent are present in a therapeutically effective amount suspended in an aqueous carrier, characterized in that the levodopa active agent and the carbidopa active agent in the carrier have a high shear viscosity of about 4500 cps or less at room temperature (e.g., about 20° C. to about 25° C., e.g., about 22° C.) and a low shear viscosity of less than about 45000 cps under refrigerated storage conditions (e.g., about 2° C. to about 8° C., e.g., 5° C.). Additionally or alternatively, the pharmaceutical composition (i.e., the levodopa active agent and the carbidopa active agent suspended in the aqueous carrier) can have a ratio of low shear viscosity:high shear viscosity of about 10 or greater. In particular, a suspension of levodopa and carbidopa active agents in an aqueous carrier can have a high shear viscosity of about 4500 cps or less at room temperature (e.g., about 20° C. to about 25° C., e.g., about 22° C.) and a low shear viscosity of about 45000 cps or more under refrigerated storage conditions (e.g., about 2° C. to about 8° C., e.g., 5° C.), and a low shear viscosity:high shear viscosity ratio of about 10 or more. The pharmaceutical composition can have the low shear viscosity and high shear viscosity described above throughout its shelf life. As used herein, "shelf life" includes at least about 2 weeks, e.g., at least about 5 weeks, at least about 10 weeks, at least about 15 weeks, or at least about 20 weeks. For example, the pharmaceutical composition can have a high shear viscosity of about 4300 to 4400 cps (at about 22° C.) and a low shear viscosity of about 49600 cps (at about 5° C.) throughout its shelf life.

[0031] Both low shear and high shear viscosities can be measured by conventional methods known in the art. For purposes of measuring the viscosity of the compositions and formulations disclosed herein, low shear viscosity is measured at a temperature of about 5° C. and a shear rate of about 0.1 sec. -1The viscosity should be measured on a sample of about 9 mL at a shear rate of 100 rpm. If the viscosity is measured, for example, in a BROOKFIELD LV type viscometer (e.g., in a sample chamber SC4-13R with a temperature probe and a water jacket assembly SC4-45Y), the test should be performed with a SC4-31 type spindle. If other equipment is used, a spindle of corresponding dimensions and specifications should be used accordingly.

[0032] The high shear viscosity is determined at a temperature of about 22° C. and a shear viscosity of about 24.1 sec -1 The viscosity should be measured on a sample of approximately 16 mL at a shear rate of 100 Hz. If the viscosity is measured, for example, with a BOHLIN Type 88 BV rotational viscometer, it should be carried out using a C25 cylinder / spindle system. If other equipment is used, a spindle of comparable dimensions and specifications should be substituted accordingly.

[0033] In various embodiments, the therapeutically effective amounts of levodopa and carbidopa active agents (eg, carbidopa monohydrate) present in the pharmaceutical composition can be about 4.0 and 1.0% by weight of the composition, respectively.

[0034] As mentioned above, the inherently low aqueous solubility of L-dopa and carbidopa at physiologically acceptable pH for infusion creates significant technical problems in developing improved pharmaceutical compositions and methods of treatment. Such problems include, for example, the difficulty in achieving formulation stability within the required pH range. These problems are further complicated by the requirement that the pharmaceutical compositions and methods of treatment provide pharmacokinetically acceptable and pharmacodynamically consistent dopamine level control in the brain of the patient.

[0035] In one embodiment, the pharmaceutical composition comprises a levodopa active agent in an amount of about 4.0% by weight of the total composition; a carbidopa active agent (e.g., carbidopa monohydrate) in an amount of about 1.0% by weight of the total composition; at least one suspending agent; and a liquid medium (e.g., water). In various embodiments, the liquid medium can comprise from about 0% to about 95% by weight of the total composition, such as from about 10% to about 70% by weight, or from about 40% to about 60% by weight of the total composition.

[0036] In one embodiment, the levodopa active agent is levodopa and its pharma- ceutically acceptable salts or hydrates, such as levodopa monohydrate. Levodopa is preferably present in the composition in an amount of about 1.0 to 5.0% by weight of the total composition. In a preferred embodiment, the pharmaceutical composition comprises about 4.0% by weight of levodopa active agent. In one embodiment, the levodopa active agent can be processed into microparticles or microspheres, for inclusion in the pharmaceutical composition of the invention, for example, as described in Example 1 below.

[0037] In one embodiment, the carbidopa active agent is carbidopa and its pharma- ceutically acceptable salts or hydrates, such as carbidopa monohydrate. The carbidopa active agent is preferably present in the composition in an amount of about 0.25 to 1.25% by weight of the total composition. In a preferred embodiment, the pharmaceutical composition contains about 1.0% by weight of the carbidopa active agent. The preferred form of the carbidopa active agent for administration is carbidopa monohydrate. In one embodiment, the carbidopa active agent can be processed into microparticles or microspheres, for example, as described in Example 1 below, for inclusion in the pharmaceutical composition of the present invention.

[0038] 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 levodopa active agent:carbidopa active agent (e.g., carbidopa monohydrate) in the pharmaceutical composition can be about 4:1. For example, the pharmaceutical composition can include about 4% by weight of levodopa active agent and 1% by weight of carbidopa active agent (e.g., carbidopa monohydrate). In one embodiment, the pharmaceutical composition includes a liquid or viscous liquid that includes 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 invention, for example, as described in Example 1 below.

[0039] The ratio of levodopa active agent, or the combination of levodopa active agent with carbidopa active agent, to the suspending agent is from about 3-about 1% to about 1-about 30% by weight, with a preferred range of from about 2-about 1% to about 1-about 10% by weight. Such readily available suspending agents are known in the art and can include, but are not limited to, polymer-based suspending agents, such as carbohydrate-based suspending agents and acrylic acid-based polymers (e.g., Carbomer, Carbopol®). Examples of carbohydrate-based suspending agents include, but are not limited to, hydroxypropylcellulose, hydroxymethylcellulose, and sodium carboxymethylcellulose (NaCMC). The acrylic acid-based polymers can be crosslinked, for example with polyalkenyl ethers or divinyl glycol. In particular, the suspending agent can be sodium carboxymethylcellulose (NaCMC) or Carbopol.

[0040] In the compositions of the present invention, one or more suspending agents may be used to obtain the ratio of levodopa active agent or combination of levodopa active agent with carbidopa active agent to suspending agent, as described above.

[0041] However, if a surfactant is used, it may be best to add the surfactant or surfactants after the levodopa active agent, the carbidopa active agent, and the suspending agent, as described herein.

[0042] It is to be understood that each component comprising the compositions of the present invention must be pharma- ceutical acceptable and used in a non-toxic concentration.

[0043] In one embodiment, the pharmaceutical composition is a viscous liquid composition, hi one aspect, the pharmaceutical composition comprises water and is suitable for infusion.

[0044] In another embodiment, the pharmaceutical composition is an aqueous pharmaceutical composition having a levodopa active agent concentration of at least about 5 mg / mL. In one embodiment, the levodopa active agent concentration is at least about 10 mg / mL. In another embodiment, the levodopa active agent concentration is at least about 20 mg / mL. In another embodiment, the levodopa active agent concentration is at least about 30 mg / mL. In another embodiment, the levodopa active agent concentration is at least about 35 mg / mL. In another embodiment, the levodopa active agent concentration is at least about 40 mg / mL. In another embodiment, the levodopa active agent concentration is at least about 45 mg / mL. In another embodiment, the levodopa active agent concentration is at least about 50 mg / mL. In another embodiment, the levodopa active agent concentration is at least about 100 mg / mL. In another embodiment, the levodopa active agent concentration is at least about 150 mg / mL. In another embodiment, the levodopa active agent concentration is at least about 200 mg / mL.

[0045] In another embodiment, the pharmaceutical composition is an aqueous pharmaceutical composition having a carbidopa active agent (e.g., carbidopa monohydrate) concentration of at least about 5 mg / mL. In one embodiment, the carbidopa active agent concentration is at least about 10 mg / mL. In another embodiment, the carbidopa active agent concentration is at least about 20 mg / mL. In another embodiment, the carbidopa active agent concentration is at least about 30 mg / mL. In another embodiment, the carbidopa active agent concentration is at least about 50 mg / mL. In another embodiment, the carbidopa active agent concentration is at least about 100 mg / mL. In another embodiment, the carbidopa active agent concentration is at least about 150 mg / mL. In another embodiment, the carbidopa active agent concentration is at least about 200 mg / mL.

[0046] The pharmaceutical compositions of the present disclosure may contain one or more additional pharma- ceutically acceptable excipients. The term "excipient" refers to a substance that is not itself a therapeutic agent, but is used as a carrier or vehicle for delivering a therapeutic agent to a subject, or is added to a pharmaceutical composition to enhance handling or storage, or to enable or facilitate the formation of a unit dose of the composition.

[0047] Excipients include, for example, antioxidants, agents that adjust pH and osmolality, preservatives, thickening agents, colorants, buffers, bactericides, stabilizers, etc. When an excipient is present, it is typically present in an amount of about 0.001% to about 95% by weight, about 0.01% to about 80% by weight, about 0.02% to about 25% by weight, or about 0.3% to about 10% by weight.

[0048] In one embodiment, the pharmaceutical composition may include an antioxidant. Suitable antioxidants for use in the pharmaceutical composition include, for example, butylated hydroxytoluene, butylated hydroxyanisole, potassium metabisulfite, cysteine, and the like.

[0049] In one embodiment, the pharmaceutical composition may include a buffering agent. Buffering agents include agents that reduce pH changes. Suitable types of buffering agents for use in various embodiments of the present invention include salts of Group IA metals, such as bicarbonates of Group IA metals, carbonates of Group IA metals, alkali or alkaline earth metal buffers, aluminum buffers, calcium buffers, sodium buffers, or magnesium buffers. Suitable buffering agents further include carbonates, phosphates, bicarbonates, citrates, borates, acetates, phthalates, tartrates, succinates of any of the above, such as sodium or potassium phosphate, citric acid, boric acid, acetate, bicarbonate, and carbonate.

[0050] In one embodiment, the composition has a pH of about 3.5 to about 8. In one embodiment, the pH is about 3.5 to about 7.5. In another embodiment, the pH is about 4.0 to about 7.5. In another embodiment, the pH is about 5.0 to about 7.5. In another embodiment, the pH is about 5.5 to about 7.5. In another embodiment, the pH is about 6.0 to about 7.5.

[0051] In various embodiments, the pharmaceutical composition may be present in a container. Suitable containers include containers having a relatively low oxygen transmission rate (e.g., about 0.95 cc / (100 in 2* These low oxygen permeability barriers can be incorporated into the primary container of the secondary outer container. Examples of suitable containers include, but are not limited to, Disposable Drug Reservoirs (DDR) bags, such as EVA / EVOH / EVA bags.

[0052] In yet another embodiment, the present disclosure relates to a ready-to-use vial or cartridge or container or enclosure suitable for containment of a liquid pharmaceutical formulation. Such container may serve to hold a liquid formulation containing one or more active ingredients. The vial may also serve as a reservoir for active ingredients in powder form, the vial may be ready-to-use and reconstituted with an aqueous medium for immediate withdrawal or immediate injection into a patient.

[0053] In another embodiment, a pharmaceutical formulation is provided. The pharmaceutical formulation can include the pharmaceutical composition described herein in a DDR with an oxygen-impermeable enclosure, which is purged with an inert gas (e.g., N2). An oxygen scavenger (e.g., ferrous or non-ferrous can or pouch) can also be added. The pharmaceutical formulation can be suitable for use in a continuous infusion pump that can deliver the composition in a therapeutically effective form. Suitable oxygen-impermeable enclosures can include, for example, foil bags or bags with EVA-EVOH film layers.

[0054] III. Method for producing pharmaceutical composition The present disclosure further relates to methods of making the pharmaceutical compositions described herein. In various embodiments, the methods of making the pharmaceutical compositions described herein can include providing the levodopa and carbidopa active agents in suitable amounts such that the levodopa and carbidopa active agents are present in the pharmaceutical composition in a therapeutically effective amount. The levodopa and carbidopa active agents can be added to water to make a slurry. The slurry can be added with one or more suspending agents (e.g., NaCMC) as described herein to form a suspension. The suspension can be sparged with or without N2 to reduce oxygen levels. In particular, the suspension can be sparged with N2. Optionally, the suspension can be degassed to remove trapped nitrogen and air from the suspension. The suspension can then be placed in a low oxygen permeable or oxygen impermeable container as described herein. Optionally, an oxygen scavenger can be added to the suspension as well. Advantageously, the combination of sparging the suspension with N and using a low oxygen permeable container can result in a pharmaceutical composition with increased chemical stability by reducing both the initial dissolved O present in the composition and the amount of O ingress into the composition during storage.

[0055] Furthermore, when the suspension is sparged with N2 and / or the container has low oxygen permeability, the pharmaceutical composition does not degrade to DHPA at a rate faster than 0.04% by weight per week under refrigerated storage conditions (percentage is relative to the label amount of carbidopa). Additionally or alternatively, when the suspension is sparged with N2 and / or the container has low oxygen permeability, the pharmaceutical composition does not degrade to DHPPA at a rate faster than 0.04% by weight per week under refrigerated storage conditions (percentage is relative to the label amount of carbidopa). Additionally or alternatively, when the suspension is sparged with N2 and / or the container has low oxygen permeability, the pharmaceutical composition does not degrade to hydrazine at a rate faster than 0.6 μg / g per week under refrigerated storage conditions, where μg / g indicates μg of hydrazine per gram of gel-suspension.

[0056] In various embodiments, the levodopa active agent (eg, prior to suspension formation) can have a particle size distribution as follows:

[0057] (i) D50 can be about 5 μm or less, about 3 μm or less, or about 1 μm or less. (ii) D90 can 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.

[0058] (iii) D100 can 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.

[0059] In particular, the levodopa active agent can have 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.

[0060] Additionally, the carbidopa active agent (eg, prior to suspension formation) can have a particle size distribution as follows:

[0061] (i) D50 can be 3 μm or less.

[0062] (ii) D90 can be 7 μm or less, or 5 μm or less.

[0063] (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, or 9 μm or less.

[0064] In particular, the carbidopa active agent can have a particle size distribution of (i) D50 of about 3 μm or less; (ii) D90 of 7 μm or less; and (iii) D100 of 21 μm or less. The levodopa active agent and / or the carbidopa active agent can be milled or micronized to provide such a particle size distribution.

[0065] Advantageously, the levodopa and carbidopa active agents having the above particle size distribution can form a good 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 the composition at relatively high concentrations.For example, physical stability can be maintained even when the composition contains about 4% by weight of levodopa active agent and 1% by weight of carbidopa active agent (e.g., carbidopa monohydrate).

[0066] In another embodiment, a pharmaceutical composition as described herein is provided, which is produced 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 levodopa active agent and the carbidopa active agent provided have the particle size distribution described above. The levodopa active agent and the carbidopa active agent are added to water to produce a slurry. A suspending agent (e.g., NaCMC) can be added to the slurry as described herein to form a suspension, and the suspension can be sparged with N2 to reduce oxygen levels. The suspension can be placed in a low oxygen permeable or oxygen impermeable container as described herein. Optionally, an oxygen scavenger can be added to the suspension as well.

[0067] IV. Treatment method The present disclosure further relates to a method of treating Parkinson's disease and related conditions comprising administering to a patient a therapeutically effective amount of a pharmaceutical composition comprising a high concentration levodopa active agent and a carbidopa active agent. The pharmaceutical composition comprising a high concentration levodopa active agent and a carbidopa active agent can comprise, for example, a liquid or viscous liquid containing about 200 mg of levodopa and about 50 mg of carbidopa monohydrate per 5.0 mL volume.

[0068] In one embodiment, the present disclosure relates to 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.

[0069] In one embodiment, the condition treated by administering the pharmaceutical composition is Parkinson's disease.

[0070] In another embodiment, the condition treated by administering the pharmaceutical composition is motor dysfunction in Parkinson's disease patients (ie, a method of improving motor function in Parkinson's disease patients).

[0071] In another embodiment, the pharmaceutical composition is administered to treat motor fluctuations in a patient with Parkinson's disease.

[0072] In another embodiment, the pharmaceutical composition is administered to treat movement disorders in patients with Parkinson's disease.

[0073] In another embodiment, the pharmaceutical compositions of the present invention are administered via intestinal administration. They can be administered (or "infused") directly into the intestinal tract, such as the small intestine (e.g., duodenum or jejunum), via a permanent tube inserted, for example, via an external transperitoneal tube and an internal intestinal tube, via percutaneous endoscopic gastrostomy. In one embodiment, the first compound and the second compound are administered via a tube inserted via a radiological gastrojejunostomy. In another embodiment, the pharmaceutical compositions of the present invention are administered via a temporary nasoduodenal tube inserted into the patient, for example, to determine whether the patient will respond favorably to the treatment method before inserting a permanent tube.

[0074] 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 trade name CADD-Legacy DuoDopa® pump. Specifically, a cassette, pouch, vial or cartridge containing a first compound and a second compound can be attached to the pump to create a delivery system. The delivery system is then connected to a nasoduodenal tube, a transperitoneal opening, a duodenal tube or a jejunal tube for enteral administration.

[0075] In one embodiment, the method comprises administering to a patient one or more of the pharmaceutical compositions of the present invention substantially continuously for a period of at least about 12 hours, hi further embodiments, 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 more.

[0076] 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 of the day by minimizing the number and duration of OFF-time episodes (i.e., bradykinesia) and minimizing disruptive dyskinetic ON-time.

[0077] In one embodiment, the daily dose of levodopa active agent administered to a patient according to the methods of the present disclosure can 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, a patient is administered, 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, 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, 00, 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, 1020, 10 30, 1040, 1050, 1060, 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, 146 0, 1470, 1480, 1490, 1500, 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, 234 0, 2350, 2360, 2370, 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 5000 mg may be administered.

[0078] In one embodiment, the daily dose of carbidopa active administered to a patient according to the disclosed methods 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 embodiments, a patient can be administered, 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, 850, 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, 6 60, 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, 1060, 1070, 1080, 1090, 1100, 1110, 1120, 1130, 1140, 1150, 1160, 1170, 1180, 1190, 1200, 1210, 1220, 1230, 1240, or 1250 mg may be administered.

[0079] In some embodiments, the levodopa active agent and the carbidopa active agent are administered in an amount sufficient to, in combination, obtain an L-dopa plasma level in the patient of at least about 100 ng / mL. In one embodiment, the L-dopa plasma level is at least about 200 ng / mL. In another embodiment, the L-dopa plasma level is at least about 200 ng / mL. In another embodiment, the L-dopa plasma level is at least about 300 ng / mL. In another embodiment, the L-dopa plasma level is at least about 400 ng / mL. In another embodiment, the L-dopa plasma level is at least about 500 ng / mL. In another embodiment, the L-dopa plasma level is at least about 600 ng / mL. In another embodiment, the L-dopa plasma level is at least about 700 ng / mL. In another embodiment, the L-dopa plasma level is at least about 800 ng / mL. In another embodiment, the L-dopa plasma level is at least about 900 ng / mL. In another embodiment, the L-dopa plasma level is at least about 1,000 ng / mL. In another embodiment, the L-dopa plasma level is at least about 1,500 ng / mL. In another embodiment, the L-dopa plasma level is at least about 2,000 ng / mL. In another embodiment, the L-dopa plasma level is at least about 3,000 ng / mL. In another embodiment, the L-dopa plasma level is at least about 4,000 ng / mL. In another embodiment, the L-dopa plasma level is at least about 5,000 ng / mL.

[0080] In some embodiments, the levodopa active agent and the carbidopa active agent are administered in an amount sufficient to achieve, in combination, an L-dopa plasma level of about 10 ng / mL to about 8,000 ng / mL. In one embodiment, the L-dopa plasma level is about 25 ng / mL to about 6,000 ng / mL. In another embodiment, the L-dopa plasma level is about 50 ng / mL to about 4,000 ng / mL. In another embodiment, the L-dopa plasma level is about 100 ng / mL to about 2,000 ng / mL. In another embodiment, the L-dopa plasma level is about 25 ng / mL to about 1,200 ng / mL. In another embodiment, the L-dopa plasma level is about 10 ng / mL to about 500 ng / mL. In another embodiment, the L-dopa plasma level is about 25 ng / mL to about 500 ng / mL.

[0081] In some embodiments, the L-dopa concentration range is maintained for at least about a 1 hour period, a 2 hour period, a 3 hour period, a 4 hour period, a 5 hour period, a 6 hour period, a 7 hour period, a 8 hour period, a 9 hour period, a 10 hour period, a 11 hour period, a 12 hour period, a 18 hour period, or a 24 hour period.

[0082] In some embodiments, the levodopa active agent and the carbidopa active agent are administered in an amount sufficient to maintain a combined carbidopa plasma level of less than about 500 ng / mL. In one embodiment, the carbidopa plasma level is less than about 250 ng / mL. In another embodiment, the carbidopa plasma level is less than about 100 ng / mL. In another embodiment, the carbidopa plasma level is less than about 50 ng / mL. In another embodiment, the carbidopa plasma level is less than about 25 ng / mL.

[0083] In some embodiments, the levodopa active agent and the carbidopa active agent are administered in an amount sufficient to, in combination, maintain a carbidopa plasma level of about 1 to about 10 ng / mL. In one embodiment, the carbidopa plasma level is about 1 to about 25 ng / mL. In another embodiment, the carbidopa plasma level is about 1 to about 50 ng / mL. In another embodiment, the carbidopa plasma level is about 1 to about 100 ng / mL. In another embodiment, the carbidopa plasma level is about 1 to about 250 ng / mL. In another embodiment, the carbidopa plasma level is about 5 to about 250 ng / mL. In another embodiment, the carbidopa plasma level is about 5 to about 100 ng / mL. In another embodiment, the carbidopa plasma level is about 10 to about 250 ng / mL. In another embodiment, the carbidopa plasma level is about 10 to about 100 ng / mL. In another embodiment, the carbidopa plasma level is about 25 to about 250 ng / mL. In another embodiment, the carbidopa plasma level is from about 25 to about 100 ng / mL.

[0084] In some embodiments, the carbidopa concentration range is maintained for at least about a 1 hour period, a 2 hour period, a 3 hour period, a 4 hour period, a 5 hour period, a 6 hour period, a 7 hour period, a 8 hour period, a 9 hour period, a 10 hour period, a 11 hour period, a 12 hour period, a 18 hour period, or a 24 hour period.

[0085] In further embodiments, the administered levodopa and carbidopa active agents can have a particle size distribution as described above.

[0086] In various embodiments, the pharmaceutical composition can be in a container as described above and prior to administration to a patient, and the gel-suspension may or may not be sparged with N2. If the gel-suspension is sparged with N2 and the container has low oxygen permeability, the pharmaceutical composition does not undergo degradation to produce DHPA at a rate faster than 0.04% by weight per week under refrigerated storage conditions (percentage is relative to the label amount of carbidopa). Additionally or alternatively, if the container is sparged with N2, the pharmaceutical composition does not undergo degradation to produce DHPPA at a rate faster than 0.04% by weight per week under refrigerated storage conditions (percentage is relative to the label amount of carbidopa). Additionally or alternatively, if the container is sparged with N2, the pharmaceutical composition does not undergo degradation to produce hydrazine at a rate faster than 0.6 μg / g per week under refrigerated storage conditions, where μg / g indicates μg of hydrazine per gram of gel-suspension.

[0087] V. Concomitant administration of additional therapeutic agents The therapeutic methods of the present disclosure may further comprise administering one or more therapeutic agents for the treatment of Parkinson's disease in addition to administering a levodopa active agent and a carbidopa active agent. In one embodiment, the additional therapeutic agent is selected from the group consisting of a decarboxylase inhibitor different from the carbidopa active agent (e.g., benserazide), a catechol-O-methyltransferase ("COMT") inhibitor (e.g., entacapone and tolcapone), and a monoamine oxidase A ("MAO-A") or monoamine oxidase B ("MAO-B") inhibitor (e.g., moclobemide, rasagiline, selegiline, and safinamide). In one embodiment, the additional therapeutic agent is selected from the group consisting of a decarboxylase inhibitor other than the carbidopa active agent. In another embodiment, the additional therapeutic agent is selected from the group consisting of a COMT inhibitor. In another embodiment, the additional therapeutic agent is selected from the group consisting of a MAO-A inhibitor. In another embodiment, the additional therapeutic agent is selected from the group consisting of a MAO-B inhibitor.

[0088] Likewise, the pharmaceutical compositions of the present disclosure may further comprise one or more additional therapeutic agents for the treatment of Parkinson's disease as described above.

[0089] VI. kit The present disclosure also relates to kits including one or more pharmaceutical formulations including a carbidopa active agent; kits including one or more pharmaceutical formulations including a levodopa active agent; and kits including one or more formulations including both a levodopa active agent and a carbidopa active agent. In the kits, the pharmaceutical formulations can be present separately or together in a low O2 permeable bag. The pharmaceutical formulations can include high concentrations of levodopa active agent and carbidopa active agent, such as levodopa active agent, in an amount of about 4.0 weight percent of the total composition; and carbidopa monohydrate active agent in an amount of about 1.0 weight percent of the total composition. The kits may include one or more additional therapeutic agents and / or instructions, such as instructions for using the kit, for treating a patient with Parkinson's disease or a related condition.

[0090] VII. Working Example The following non-limiting examples are provided to further illustrate the present disclosure. Abbreviations used in the examples below include the following:

[0091] "Cmax" means the maximum observed plasma concentration.

[0092] "Tmax" means the time to maximum observed plasma concentration.

[0093] "AUC" means area under the plasma concentration-time curve.

[0094] "t 1 / 2 " means biological half-life, i.e., the time required for one-half of an administered drug or other substance to be metabolized or excreted by an organism through normal physiological processes. EXAMPLES

[0095] [Example 1] Preparation of pharmaceutical compositions A high concentration ("HC") levodopa active agent / carbidopa active agent pharmaceutical composition was prepared as shown in FIG. 1 and described below.

[0096] 1.1 Gel preparation Preliminary work was done in the lab to establish the ratio of NaCMC700:NaCMC2000 required to achieve a certain viscosity. Viscosity was measured using a rotational viscometer at two points: 22°C at 24.1 1 / s (also referred to as "high shear viscosity"); and 5°C at 0.1 1 / s (also referred to as "low shear viscosity"). The appropriate amounts of NaCMC2000 and NaCMC700 were then dispensed and added to a hopper, after which NaCMC was sent to a homogenizer tank and mixed at high shear. The gel was then degassed and examined visually to ensure that the NaCMC was dissolved. At this time, a sample of the gel was also taken for viscosity measurement.

[0097] 1.2 Blowing into the gel The gel was sparged with nitrogen to remove most of the oxygen before adding the APIs (levodopa and carbidopa), and oxygen concentration was monitored throughout the process via an in-line oxygen probe.

[0098] 1.3 First Slurry Preparation In a separate vessel, half of the levodopa and carbidopa were added to water and blended using one overhead impeller and one bottom driven impeller. This method is considered low shear. Alternatively, the overhead impeller can be replaced with a homogenizer for high shear blending. The slurry was used to wet the API and perform de-lumping. After the process was completed, the slurry was transferred to the homogenizer tank.

[0099] 1.4 Gel suspension preparation This involves mixing the API from the slurry and NaCMC gel under high shear to obtain a uniform suspension. The tank was sparged with nitrogen to reduce the oxygen level initially introduced during the slurry transfer.

[0100] 1.5 Second Slurry Preparation The other half of the levodopa and carbidopa was added to the water and mixed similarly to the process in step 1.3.

[0101] 1.6 Gel suspension preparation The API from the second slurry was mixed with the remainder of the gel suspension under the same conditions as in step 1.4. Nitrogen was sparged into the tank to reduce the oxygen level initially introduced by the slurry transfer.

[0102] 1.7 Degassing The gel suspension was degassed to remove trapped nitrogen or air from the gel.

[0103] 1.8 filling The fill line was initially flushed with nitrogen before pushing the gel suspension. 55 to 61 g of gel suspension was filled into a Disposable Drug Reservoir (DDR). Fill weight was checked at regular intervals using a balance. Oxygen readings were taken at the fill nozzle (for two case studies, readings were taken at the discharge end).

[0104] 1.9 packaging The DDRs were labeled and packaged into kits holding 7 DDRs, which protected the formulation from light, and then placed in a freezer.

[0105] [Table 1]

[0106] [Table 2]

[0107] [Example 2] Stability of high-concentration pharmaceutical compositions 2.1-High concentration (HC) formulation was made in a commercial scale equipment to improve the nitrogen sparging process time and mixing efficiency. The overall manufacturing process was similar to Example 1. For the HC formulation viscosity range, high viscosity was selected to ensure good physical stability. The batch was filled into a prototype DDR (Disposable Drug Reservoir) bag (without housing) and placed under stable conditions. The bag was made of EVA / EVOH / EVA multi-layer film with a thickness of 0.3 mm. The batch maintained its chemical and physical stability through 15 weeks of stability testing.

[0108] [Table 3]

[0109] 2.2-Analysis results Batch content uniformity - 100 mL of pharmaceutical composition was filled into cassettes at the beginning, middle and end of the filling operation, which represent the bottom, middle and top of the tank, respectively. These cassettes were then assayed and the results indicate that the batch content was uniform.

[0110] [Table 4]

[0111] 2.3- Formulation characteristics with respect to stability After manufacturing, the filled DDR bags were frozen and stored at -20°C. The test bags were then placed at 5°C for a 15 week stability study. Samples were evaluated at 0, 8 and 15 weeks. Additionally, after 8 or 15 weeks at 5°C, a portion of the samples were then placed at 30°C at 75% relative humidity (%RH) and tested at 24 and 48 hours. Assays, impurities, pH and viscosity were all examined. The results are summarized in Table 5 below.

[0112] [Table 5]

[0113] 2.4-Uniformity of sample distribution content with respect to stability The uniformity of dispensed content (UDC) method was used to obtain the API concentration in the administered gel. This simulates what a patient would receive per 5 g of gel delivered by the pump, ensuring that the patient receives a consistent dose of drug through the consumption of one DDR. Each time point was tested through 15 weeks of stability. The particle size distribution of the API used in the study was within the particle size ranges mentioned herein. The results are summarized below in Tables 6 (levodopa) and 7 (carbidopa).

[0114] [Table 6]

[0115] [Table 7]

[0116] [Example 3] Therapeutic Efficacy of Pharmaceutical Compositions in Minipigs A high-concentration L-dopa / carbidopa enteral gel was compared to a low-concentration L-dopa / carbidopa enteral gel in a study as follows: Groups of four minipigs were administered LCL-dopa / carbidopa enteral gel, HCL-dopa / carbidopa enteral gel, or L-dopa / carbidopa in a carbopol carrier in a crossover design. Each of the four minipigs was administered one formulation on the first day of the week, followed by a one-week washout period before being administered the second formulation. After a further one-week washout period, the same minipigs were administered the third formulation.

[0117] Total dose: 11.07 mg / kg levodopa dose over 6.5 hours; 20 mg / mL; Group: LC;HC;Carbopol; Bolus dose: 2.53 mg / kg bolus dose over 30 minutes; Infusion dose: 8.54 mg / kg over 6 hours.

[0118] Bolus infusion rate : LC = 0.253 mL / kg / hr (e.g.: 10 kg pig = 2.53 mL / hr pump rate); HC=0.127mL / kg / hr (e.g.: 10kg pig=1.27mL / hr pump rate); Carbopol = 0.127 mL / kg / hr (for example: 10 kg pig = 1.27 mL / hr pump rate).

[0119] 6 hour infusion rate : 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 = 0.0355 mL / kg / hr (for example: 10 kg pig = 0.355 mL / hr pump rate).

[0120] Plasma sampling time points: 0.5, 1, 1.5, 2, 4, 6, 8, 9, 10, 12 hours.

[0121] The study results, as shown in Figures 2 and 3, showed that the high-concentration levodopa / carbidopa enteral gel had a C value equivalent to that of the LC formulation when administered under 1 / 2-hour bolus and 6-hour infusion conditions. max , T max and AUC values ​​are shown. 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 control). The bioavailability of levodopa is summarized in Table 8 below. The half-lives in the table are calculated as harmonic means.

[0122] [Table 8]

[0123] The bioavailability of carbidopa is summarized in Table 9 below.

[0124] [Table 9]

[0125] [Example 4] Further bioavailability studies in human subjects To further explore the bioavailability of the LC and HC formulations discussed in Example 3 above, a total of 12 subjects were enrolled in an open-label, single-dose, randomized crossover study to study the bioavailability of the LC and HC formulations. Each subject received a single dose of levodopa (200 mg) and carbidopa monohydrate (50 mg) in the morning on days 1 and 4 under fasting conditions. Subjects were randomly assigned in equal numbers to duplicates of the commercial LC formulation and the commercial HC formulation. Each dose was administered over a 30-minute period via a nasojejunal tube connected to a portable infusion pump. Patients receiving the LC formulation were administered a 10.0 mL dose. Patients receiving the HC formulation were administered a 5.0 mL dose to deliver equal amounts of drug regardless of whether they received the LC or HC formulation. Subjects were confined for approximately 6 days (day 5 from the date of enrollment). Serial blood samples for levodopa, carbidopa and 3-O-methyldopa assays were collected after dosing on days 1 and 4. Blood collection times included 0 hours (pre-dose), 5, 10, 15, 30, 45 minutes after start of infusion, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours after start of infusion. Levodopa bioavailability is summarized in Table 10 below and Figure 4.

[0126] [Table 10]

[0127] The bioavailability of carbidopa is summarized in Table 11 below and in FIG.

[0128] [Table 11]

[0129] These studies demonstrated that the HC formulations weremax , AUC t and AUC ∞ Regarding and carbidopa AUC t and AUC ∞ The results show that the carbidopa C max The 90% confidence interval for is slightly over the range of 0.8 to 1.25. However, this is not a clinically relevant factor since dosing for efficacy is determined by the levodopa content, not carbidopa. Studies have shown that peripheral dopa decarboxylase is saturated with approximately 70 to 100 mg / day of carbidopa, and that patients with advanced Parkinson's disease receiving levodopa / carbidopagel gel therapy will exceed these daily carbidopa doses for saturation. The relative bioavailability of the LC and HC formulations for levodopa and carbidopa is summarized in Table 12 below.

[0130] [Table 12]

[0131] In summary, the amount of drug delivered was similar for both formulations. The dose delivered for both formulations was similar (approximately 6% difference). Levodopa and carbidopa exposure was very similar for both formulations. The variability of levodopa exposure was low to moderate (17 to 35% CV) for both the LC and HC formulations. Both the LC and HC formulations were equivalent for levodopa. The LC and HC formulations showed no clinically significant C max Except for carbidopa, they were equivalent.

[0132] Figures 6 and 7 show that the LC and HC formulations have similar dissolution rates at pH 4.5 and 6.8, which supports the bioavailability results summarized above. These solvent studies were performed by adding equal doses of drug formulation to a beaker containing 500 mL of 50 mM sodium acetate buffer at pH 4.5 (±0.05) or pH 6.8 (±0.05). During the procedure, each sample was maintained at 37°C with stirring at 50 RPM. Samples were taken at 5, 10, 15, 20, 30, 45, and 60 minutes after drug addition. The concentration of drug dissolved in the samples was measured by HPLC on a PHENOMENEX KINETEX C8 column (100 x 4.6 mm, 5 μm, with a SecurityGuard cartridge) at 30°C. The mobile phase was 88:12 10 mM sodium heptanesulfonate (HAS) / 0.2% H3PO4:acetonitrile. The sample was eluted through the column at a rate of approximately 3.0 mL / min and subjected to UV spectroscopy (OD 280 ) was measured.

[0133] [Example 5] Sedimentation and storage stability Stokes' law can be used to assess particle settling and therefore the physical stability of HC formulations. Stokes' law considers three forces acting on a particle in a continuous viscous liquid: buoyancy, drag and gravity. When the forces are balanced and there is no net acceleration, the particle will reach a terminal velocity or settling velocity given by the following equation:

[0134]

number

[0135] There are two factors that can be controlled in the HC formulation to adjust the physical stability: the particle size of levodopa and carbidopa monohydrate and the viscosity of the gel-suspension. The particle size of levodopa and carbidopa monohydrate is controlled within the particle size range mentioned herein by the micronization process. However, the viscosity can be adjusted by changing the ratio of sodium carmellose viscosity grades. The fluid viscosity at rest is approximated by the low shear viscosity method. As shown in Tables 13 and 14, the minimum low shear viscosity required to achieve the desired physical stability is 44,590 cps based on this example.

[0136] [Table 13]

[0137] [Table 14]

[0138] The criterion for "acceptable" physical stability was no significant precipitation for at least 15 weeks under refrigerated storage conditions (e.g., 5°C). The physical stability was evaluated by taking 5 mL samples from the DDR for a total of 10 samples and then analyzing them for levodopa and carbidopa content using a high performance liquid chromatography (HPLC) system with guard column: Agilent, Zorbax Eclipse XDB-C8, 4.6 x 12.5 mm, 5 μm (Agilent, part number: 820950-926) and Agilent Hardware kit High Press (Agilent, part number 820999-901) or equivalent; and analytical column: Zorbax Eclipse XDB-C8, 150 x 4.6 mm, 5 μm (Agilent part number 993967-906). The chromatographic conditions are shown in Table 15.

[0139] [Table 15]

[0140] Samples were defined as physically stable if the acceptance value (AV), defined by Equation 2, was less than or equal to 15 for both levodopa and carbidopa.

[0141]

number

[0142] [Table 16]

[0143] [Example 6] The effect of oxygen High concentration formulations can be oxygen purged during manufacture and stored in containers with low oxygen transmission. This significantly reduces the rate of degradation compared to formulations manufactured and stored in ambient oxygen conditions. Depending on the packaging, disposable drug reservoirs can have very low oxygen content at the time of filling. These DDRs consist of a hard shell outer container, inner packaging, and tubing / connectors. The inner bag helps maintain the O2 content of the final drug product gel. EVA / EVOH / EVA bags have very low O2 transmission rates (EVA / EVOH / EVA sheet film has an oxygen transmission rate of approximately 0.95 cc / (100 in 2* The incubation time was 15 days. Figure 11 shows the accumulation of DHPA degradation products when LC and HC gel formulations were left in 0.3 mm thick EVA / EVOH / EVA bags at 2 to 8 °C for 15 weeks. Additionally, N2 sparging can be used in the manufacturing process to purge oxygen. The combination of N2 sparging and low O2 permeability EVA / EVOH / EVA bags ensures very low overall O2 content.

[0144] To examine the effect of this low O2 packaging, samples of the LC gel formulation were not sparged with N2 and were packaged in polyvinyl chloride (PVC) bags. Samples of the HC gel formulation were sparged with N2 and packaged in EVA / EVOH / EVA bags. Both sets of bags were monitored for the evolution of DHPA, DHPPA and hydrazine degradation products over time. The results of these tests are shown below in Figures 8 through 10. DHPA and DHPPA were analyzed using an HPLC system with an analytical column: Waters, X-Bridge, C8, 3.5 μm particles, 4.6×150 mm column (catalog 186003055) or equivalent, with a stationary phase of octylsilane chemically bonded to fully porous silica particles (USP L7); and a guard column: Phenomenex safety cartridge PFP 4×3.0 mm (catalog AJ0-4290) or equivalent, safety cartridge holder, Phenomenox (catalog AJO-6071) or equivalent. The HPLC settings for DHPA and DHPPA testing are shown in Table 17 below.

[0145] [Table 17]

[0146] Hydrazine was analyzed using HPLC using a Grace Scientific column, Grom-Sil 120 ODS-5, 250×4.6 mm, 5 μm (part number GS0D50512S2505) or equivalent after elution of the samples from an SPE column: Chromabond® HR-X (15 mL / 1000 mg) by Macherey-Nagel, part number 730941. The HPLC settings for the hydrazine test are shown in Table 18 below.

[0147] [Table 18]

[0148] Degradation can also be delayed by adding an oxygen scavenger (e.g., ferrous or non-ferrous cans or sachets) and placing in a secondary container with low O2 permeability. The effect of oxygen scavengers in various packages on the accumulation of DHPA and DHPPA decomposition products is shown in Figure 11 below.

[0149] Although the present invention has been described with respect to specific embodiments and examples, it should be understood that other embodiments utilizing the concepts of the present invention are possible without departing from the scope of the present invention, which is defined by the elements claimed and any modifications, variations or equivalents that fall within the true spirit and scope of the underlying principles.

[0150] VIII. Further embodiments Embodiment 1: 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 an aqueous carrier, wherein the levodopa active agent and the carbidopa active agent in the carrier have a high shear viscosity of about 4500 cps or less at room temperature and a low shear viscosity of about 45000 cps or more under refrigerated conditions and a low shear viscosity / high shear viscosity ratio of 10 or more.

[0151] Embodiment 2: A pharmaceutical composition according to embodiment 1, wherein the pharmaceutical composition comprises: a levodopa active agent in an amount of about 4.0% by weight of the total composition; a carbidopa monohydrate active agent in an amount of about 1.0% by weight of the total composition; a liquid medium (e.g., in an amount of about 0% to about 95% by weight of the total composition, and / or selected from the group consisting of water), wherein the aqueous carrier comprises a suspending agent (e.g., one or more polymeric suspending agents, such as an acrylic acid-based polymer or a polymer selected from the group consisting of hydroxypropylcellulose, hydroxymethylcellulose, and sodium carboxymethylcellulose).

[0152] Embodiment 3: A pharmaceutical composition according to embodiment 1 or 2, wherein said pharmaceutical composition does not undergo degradation to DHPA at a rate greater than 0.04% by weight per week.

[0153] Embodiment 4: A pharmaceutical composition according to any one of the preceding embodiments, wherein the pharmaceutical composition does not undergo degradation to DHPPA at a rate greater than 0.04% by weight per week.

[0154] Embodiment 5: A pharmaceutical composition according to any one of the preceding embodiments, wherein the pharmaceutical composition does not undergo decomposition to produce hydrazine at a rate greater than 0.6 μg / g / week.

[0155] Embodiment 6: A pharmaceutical composition according to any one of the preceding embodiments, wherein the pharmaceutical composition is contained in a primary or secondary container that has low O2 permeability.

[0156] Embodiment 7: A pharmaceutical formulation comprising the pharmaceutical composition of any one of the preceding embodiments in a disposable drug reservoir containing an oxygen-impermeable enclosure, the oxygen-impermeable enclosure being purged with an inert gas and containing an oxygen scavenger, optionally such that the pharmaceutical formulation is suitable for use in a continuous infusion pump capable of delivering the composition in a therapeutically effective form.

[0157] Embodiment 8: A method for producing a pharmaceutical composition according to any one of embodiments 1 to 6, comprising: adding levodopa and carbidopa active agents to water to form a slurry; adding the slurry to one or more suspending agents (e.g., an acrylic acid based polymer or a polymer selected from the group consisting of hydroxypropylcellulose, hydroxymethylcellulose, and sodium carboxymethylcellulose) to form a suspension; sparging the suspension with N2; and optionally placing the suspension in a low oxygen permeable container.

[0158] Embodiment 9: The method according to embodiment 8, wherein prior to forming the suspension, the levodopa active agent has a particle size distribution of (i) D50 of about 5 μm or less; (ii) D90 of about 11 μm or less; and (iii) D100 of about 22 μm or less, and the carbidopa active agent has a particle size distribution of (i) D50 of about 3 μm or less; (ii) D90 of about 7 μm or less; and (iii) D100 of about 21 μm or less.

[0159] Embodiment 10: A pharmaceutical composition according to any one of embodiments 1 to 6, prepared by adding levodopa active agent and carbidopa active agent to water to form a slurry; adding the slurry to one or more suspending agents (e.g., an acrylic acid based polymer or a polymer selected from the group consisting of hydroxypropylcellulose, hydroxymethylcellulose and sodium carboxymethylcellulose) to form a suspension; sparging the suspension with N2; and optionally placing the suspension in a low oxygen permeable container.

[0160] Embodiment 11: A pharmaceutical composition according to embodiment 10, wherein prior to forming the suspension, the levodopa active agent has a particle size distribution of (i) D50 of about 5 μm or less; (ii) D90 of about 11 μm or less; and (iii) D100 of about 22 μm or less, and the carbidopa active agent has a particle size distribution of (i) D50 of about 3 μm or less; (ii) D90 of about 7 μm or less; and (iii) D100 of about 21 μm or less.

[0161] Embodiment 12: A method of treating Parkinson's disease in a patient in need of treatment 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 therapeutically effective form for the patient and are suspended in an aqueous carrier, wherein the levodopa active agent and the carbidopa active agent in the carrier have a high shear viscosity of about 4500 cps or less at room temperature and a low shear viscosity of about 45000 cps or more under refrigerated conditions and a low shear viscosity / high shear viscosity ratio of at least 10, and optionally wherein the pharmaceutical composition is administered in a pharmaceutical formulation according to embodiment 7.

[0162] Embodiment 13: The method according to embodiment 12, wherein the method comprises substantially continuous administration of the pharmaceutical composition for a period of at least about 16 hours, or for a period of at least about 24 hours.

[0163] Embodiment 14: The method according to embodiment 12 or 13, wherein the pharmaceutical composition comprises a levodopa active agent in an amount of about 4.0% by weight of the total composition; and a carbidopa monohydrate active agent in an amount of about 1.0% by weight of the total composition.

[0164] Embodiment 15: The method according to any one of embodiments 12 to 14, wherein the aqueous carrier comprises one or more polymeric suspending agents (e.g., acrylic acid-based polymers or polymers selected from the group consisting of hydroxypropyl cellulose, hydroxymethyl cellulose and sodium carboxymethyl cellulose).

[0165] Embodiment 16: A kit comprising the pharmaceutical composition of any one of embodiments 1 to 6 or the pharmaceutical formulation of embodiment 7.

Claims

1. A pharmaceutical composition for intraduodenal administration, comprising: levodopa active agent in an amount of 4.0% w / w of the total composition; Carbidopa monohydrate active agent in an amount of 1.0% w / w of the total composition; a suspending agent which is an acrylic acid-based polymer; and Water-based carriers Including, The pharmaceutical composition is －１ High shear viscosity of 4500 cps or less at 5° C. and 0.1 s －１ 45,000 cps or more at low shear viscosity and a low shear viscosity / high shear viscosity ratio of 10 or more.

2. 2. The pharmaceutical composition of claim 1, wherein the concentration of said aqueous carrier is greater than 0% and up to 95% w / w of the total composition.

3. 3. The pharmaceutical composition of claim 1 or 2, wherein the pharmaceutical composition does not undergo degradation to DHPA at a rate greater than 0.04% w / w / week.

4. 4. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition does not undergo degradation to DHPPA at a rate greater than 0.04% w / w / week.

5. 5. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition does not undergo decomposition to yield hydrazine at a rate greater than 0.6 μg / g / week.

6. 6. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is contained in a primary or secondary container that is low in oxygen permeability.

7. 7. A pharmaceutical formulation comprising the pharmaceutical composition of any one of claims 1 to 6 in a disposable drug reservoir containing an oxygen-impermeable enclosure, wherein the oxygen-impermeable enclosure is purged with an inert gas and an oxygen scavenger is added.

8. 8. The pharmaceutical formulation of claim 7, wherein the pharmaceutical formulation is suitable for use in a continuous infusion pump capable of delivering the composition in a therapeutically effective form.

9. adding levodopa active agent and carbidopa active agent to water to form a slurry; adding the slurry to a suspending agent that is an acrylic acid based polymer to form a suspension; and The suspension was added with N ２ To perform a blowing A method for producing the pharmaceutical composition according to any one of claims 1 to 6, comprising:

10. 10. The method of claim 9, further comprising placing the suspension in a low oxygen permeable container.

11. Prior to forming the suspension, the levodopa active agent is (i) D50 is 5 μm or less; (ii) D90 is 11 μm or less; and (iii) D100 is 22 μm or less and having a particle size distribution of The carbidopa active agent is (i) D50 is 3 μm or less; (ii) D90 is 7 μm or less; and (iii) D100 is 21 μm or less The method according to claim 9 or 10, wherein the particle size distribution is

12. adding levodopa active agent and carbidopa monohydrate active agent to water to form a slurry; adding the slurry to one or more suspending agents that are acrylic acid based polymers to form a suspension; and The suspension was added with N ２ To perform a blowing 7. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is produced by a process comprising:

13. 13. The pharmaceutical composition of claim 12, wherein the method further comprises placing the suspension in a low oxygen permeable container.

14. Prior to forming the suspension, the levodopa active agent is (i) D50 is 5 μm or less; (ii) D90 is 11 μm or less; and (iii) D100 is 22 μm or less and having a particle size distribution of The carbidopa monohydrate active agent is (i) D50 is 3 μm or less; (ii) D90 is 7 μm or less; and (iii) D100 is 21 μm or less 14. The pharmaceutical composition according to claim 12 or 13, having a particle size distribution of:

15. 7. A pharmaceutical composition according to any one of claims 1 to 6 for use in a method for treating Parkinson's disease in a patient in need of treatment, said method comprising administering a therapeutically effective amount of said pharmaceutical composition to said patient via intraduodenal administration.

16. 16. The pharmaceutical composition of claim 15, wherein the method comprises substantially continuous administration of the pharmaceutical composition for a period of at least 16 hours.

17. 17. The pharmaceutical composition of claim 16, wherein the method comprises substantially continuous administration of the pharmaceutical composition for a period of at least 24 hours.

18. 18. The pharmaceutical composition according to any one of claims 15 to 17, wherein the pharmaceutical composition is administered in a pharmaceutical formulation according to claim 7.

19. A kit comprising the pharmaceutical composition of any one of claims 1 to 6.

20. A kit comprising the pharmaceutical formulation of claim 7 or 8.

21. 15. A pharmaceutical composition for use in a method of treating a condition in a patient in need of treatment, said method comprising administering to said patient a pharmaceutical composition according to any one of claims 1 to 6 or 12 to 14.

22. 7. The pharmaceutical composition of any one of claims 1 to 6, further comprising one or more additional therapeutic agents, preferably therapeutic agents for the treatment of Parkinson's disease, such as decarboxylase inhibitors different from the carbidopa active agent (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).

23. 22. The pharmaceutical composition of claim 21, wherein the method comprises administering the pharmaceutical composition directly to the patient's intestinal tract, such as the small intestine (e.g., the duodenum or jejunum), via a permanent tube inserted, e.g., with an external transperitoneal tube and an internal intestinal tube, via a percutaneous endoscopic gastrostomy.

24. A steel sheet comprising the pharmaceutical composition according to any one of claims 1 to 6 or 12 to 14.

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