Compositions for treating Parkinson's disease and their qualitative evaluation

Abstract

This disclosure provides compositions comprising compound 1, uses thereof, and methods for producing the same.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Application No. 63 / 492,365, filed on 27 March 2023, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] background Parkinson's disease is a neurological disorder that causes involuntary movements of the body, including tremors, tonics, and difficulty or loss of balance and coordination. As of 2016, approximately 6.1 million people were affected by the disease. See Bloem et al., The Lancet, 397(10291):12-18 (2021). There is no cure for Parkinson's disease. People with Parkinson's disease face the continuous progression of the disease throughout their lives. [Overview of the project] [Problems that the invention aims to solve]

[0003] overview For patients with neurodegenerative disorders, such as Parkinson's disease, specific treatment options are available to help them manage symptoms such as dyskinesia, involuntary movements, tremors, or tonics. One such treatment is a combination of two or three of the following drugs: carbidopa, entacapone, and levodopa. In some embodiments, carbidopa is carbidopa monohydrate.

[0004] The administration of these drugs, however, presents certain challenges, including specific stability issues when carbidopa, entacapone, and levodopa are administered in a single composition. The applicant, however, has discovered that a specific compound, Compound 1, a byproduct of carbidopa and entacapone, forms during storage.

[0005] [ka]

[0006] Compound 1 is also known as (2s)-2-[(E)-2-[(3,4-dihydroxy-5-nitrophenyl)methylidene]hydrazine-1-yl]-3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid.

[0007] Through the discovery and characterization of Compound 1, the applicant has, among other things, discovered a novel composition that can be used for the treatment of Parkinson's disease, and similarly, discovered certain insights regarding the qualitative analysis of compositions containing carbidopa and entacapone, which are useful for understanding and improving the stability of such compositions. This application demonstrates the applicant's identification of the source of a problem related to the stability of certain compositions containing carbidopa, entacapone, and levodopa, and presents herein a certain solution to that problem. [Means for solving the problem]

[0008] In some embodiments, the present disclosure relates to compound 1 exceeding 0.15% by weight:

[0009] [ka]

[0010] The present invention provides a composition comprising a pharmaceutically acceptable salt thereof. In some embodiments, the disclosure relates to carbidopa, entacapone, and compound 1 in an amount greater than 0.15% by weight:

[0011] [ka]

[0012] The present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable salt thereof. In some embodiments, this disclosure relates to compound 1

[0013]

Chem.

[0014] A method for producing a composition containing a compound 2 (i.e., 3,4-dihydroxy-5-nitrobenzaldehyde)

[0015]

Chem.

[0016] is contacted with a compound 3 (i.e., S-carbidopa)

[0017]

Chem.

[0018] in the presence of methanol and a sulfate, and the method is provided. In some embodiments, the present disclosure is a method for characterizing the purity of a pharmaceutical composition comprising levodopa, carbidopa, and entacapone, by comparing a sample of the pharmaceutical composition with a reference standard to determine the amount of compound 1 in the pharmaceutical composition:

[0019]

Chem.

[0020] and the reference standard contains a known amount of compound 1, and the method is provided.

[0021] In some embodiments, the present disclosure is a known amount of compound 1:

[0022]

Chem.

[0023] The present invention provides a method for determining the purity level of a pharmaceutical composition using a reference standard containing a compound 1, the method comprising comparing the amount of compound 1 in the reference standard with the amount of compound 1 in the pharmaceutical composition. [Brief explanation of the drawing]

[0024] [Figure 1] Figure 1 is a plot showing the purity at 220 nm of a composition containing compound 1 measured under indicated conditions and at indicated times. [Figure 2] Figure 2 is a plot showing the purity at 280 nm of a composition containing compound 1, measured under the indicated conditions and at the indicated time. [Figure 3] Figure 3 is a plot showing the purity at 220 nm of a composition containing compound 1 measured under the indicated conditions and at the indicated time. [Figure 4] Figure 4 is a plot showing the purity at 220 nm of a composition containing compound 1 measured under the indicated conditions and at the indicated time. [Figure 5] Figure 5 is a plot showing the water content of a composition containing compound 1 measured under the indicated conditions and at the indicated time. [Modes for carrying out the invention]

[0025] Detailed description of a particular embodiment This disclosure relates, in particular, to compositions comprising carbidopa and entacapone, to certain by-products, for example, Compound 1:

[0026] [ka]

[0027] This includes the insight that such findings can be formed, and such findings are implemented herein, in particular, in novel compositions, novel methods for qualifying compositions comprising carbidopa and entacapone, and novel methods for treating patients with neurodegenerative disorders, such as Parkinson's disease.

[0028] definition Approximately or about: As used herein, the terms “approximately” or “about” applied to one or more values ​​of interest refer to values ​​that are similar to the reference values ​​mentioned. Generally, a person skilled in the art familiar with the context will understand the degree of variation that is encompassed by “approximately” or “about” in that context. For example, in some embodiments, the terms “approximately” or “about” may encompass a range of values ​​within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less than these values ​​(i.e., ± these values).

[0029] Administration: As used herein, the terms “administer” or “dosage” typically refer to the administration of a composition to a subject in order to achieve delivery of the drug, which is a composition, or a drug contained in a composition, to a target site or site to be treated. Those skilled in the art will recognize the various routes that can be used for administration to a subject, e.g., a human, in appropriate circumstances. For example, in some embodiments, administration may be intraocular, oral, parenteral, topical, etc. In some specific embodiments, administration may be bronchial (e.g., by bronchial infusion), intracheek, skin (e.g., one or more of the following, including, topical into the dermis, intradermal, interdermal, transdermal, etc.), intestinal, intraarterial, intradermal, gastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, intraspecific organ (e.g., intrahepatic), mucous membrane, nose, oral, rectal, subcutaneous, sublingual, topical, trachea (e.g., by intratracheal infusion), vaginal, intravitreal, etc. In some embodiments, administration may be parenteral. In some embodiments, administration may be oral. In some specific embodiments, administration may be intravenous. In some specific embodiments, administration may be subcutaneous. In some embodiments, administration may consist of only a single dose. In some embodiments, administration may consist of the application of a fixed number of doses. In some embodiments, administration may consist of dosing that is intermittent (e.g., multiple dosings spaced apart in time) and / or cyclical (e.g., individual dosings spaced apart in a common period). In some embodiments, administration may consist of continuous dosing (e.g., perfusion) over at least a selected period of time. In some embodiments, administration may consist of a prime-and-boost protocol. A prime-and-boost protocol may include the administration of a first dose of a pharmaceutical composition (e.g., an immunogenic composition, e.g., a vaccine), followed by the administration of a second or subsequent dose of a pharmaceutical composition (e.g., an immunogenic composition, e.g., a vaccine) after a certain interval. In the case of an immunogenic composition, a prime-and-boost protocol can result in an increased immune response in the patient.

[0030] Antagonist: As those skilled in the art will understand, the term “antagonist” generally refers to a drug whose presence or level correlates with a reduced target level or activity compared to that observed in the absence of the drug (or at different levels of the drug). In some embodiments, the antagonist is one whose presence or level correlates with a target level or activity that is comparable to or lower than a specific reference level or activity (e.g., that observed under appropriate reference conditions, e.g., a known antagonist, e.g., in the presence of a positive control). In some embodiments, the antagonist may be a direct antagonist in that it exerts its effect directly on the target (e.g., by directly interacting with the target), and in some embodiments, the antagonist may be an indirect antagonist in that it exerts its effect indirectly (e.g., by acting on a modifier of the target or some other component or entity, e.g., by interacting with it).

[0031] Biological Sample: As used herein, the term “biological sample” typically refers to a sample obtained from or derived from a biological source of interest (e.g., tissue or organism or cell culture), as described herein. In some embodiments, the source of interest includes an organism, e.g., an animal or a human. In some embodiments, the biological sample is or includes a biological tissue or fluid. In some embodiments, the biological sample may be or include bone marrow, blood, blood cells, ascites, tissue or microneedle biopsy samples, cell-containing bodily fluids, free floating nucleic acid, sputum, saliva, urine, cerebrospinal fluid, peritoneal fluid, pleural fluid, feces, lymph, gynecological fluid, skin swabs, vaginal swabs, oral swabs, nasal swabs, washings or lavages, such as mammary duct lavage or bronchoalveolar lavage, aspirates, scrapes, bone marrow specimens, tissue biopsy specimens, surgical specimens, feces, other bodily fluids, secretions, and / or excretions, and / or cells derived therefrom. In some embodiments, the biological sample is or includes cells obtained from an individual. In some embodiments, the obtained cells are or include cells derived from the individual from which the sample is obtained. In some embodiments, the sample is a “primary sample” obtained directly from the intended source by some appropriate means. For example, in some embodiments, the primary biological sample is obtained by a method selected from the group consisting of biopsy (e.g., microneedle aspiration or tissue biopsy), surgical procedure, and collection of bodily fluids (e.g., blood, lymph, feces, etc.). In some embodiments, as will be apparent from the context, the term “sample” refers to a preparation obtained by processing the primary sample (e.g., by removing one or more components therefrom and / or by adding one or more agents thereto), for example, by filtration using a semipermeable membrane.Such “processed samples” may include nucleic acids or proteins, for example, extracted from a sample or obtained by subjecting a primary sample to techniques such as mRNA amplification or reverse transcription, isolation and / or purification of certain components.

[0032] Carrier: As used herein, the term "carrier" refers to a diluent, adjuvant, excipient, or vehicle to which the composition is administered together. In some exemplary embodiments, the carrier may include sterile liquids, such as water and oils, which may be of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. In some embodiments, the carrier may be one or more solid components.

[0033] Combination Therapy: As used herein, the term “combination therapy” refers to a situation in which a subject is simultaneously exposed to two or more treatment regimens (e.g., two or more therapeutic agents or modalities). In some embodiments, the two or more regimens may be administered simultaneously; in some embodiments, such regimens may be administered sequentially (e.g., all “doses” of the first regimen are administered before any dose of the second regimen); and in some embodiments, such agents are administered in overlapping drug regimens. In some embodiments, “administration” of combination therapy may include administering one or more agents or modalities in combination to a subject receiving other agents or modalities. For clarity, combination therapy does not require that individual agents be administered together (or even simultaneously) in a single composition; however, in some embodiments, two or more agents or their active portions may be administered together in a combination composition or even a combination compound (e.g., as part of a single chemical complex or covalent entity).

[0034] Comparable: As used herein, “comparable” means two or more drugs, entities, situations, conditions, etc., that do not need to be identical to each other but are similar enough to allow comparison between them, such that a person skilled in the art would understand that reasonable conclusions can be drawn based on observed differences or similarities. In some embodiments, a comparable set of conditions, situations, individuals, or groups is characterized by several substantially identical characteristics and one or a few variable characteristics. A person skilled in the art will understand, in context, what degree of identity is required for two or more such drugs, entities, situations, conditions, etc., to be considered comparable under any given situation. For example, a person skilled in the art will understand that a set of situations, individuals, or groups is comparable if it is characterized by a sufficient number and variety of substantially identical characteristics to ensure a reasonable conclusion that differences in results or observed phenomena under or using different sets of situations, individuals, or groups are caused by or demonstrate variations in variable characteristics.

[0035] Composition: Those skilled in the art will understand that the term “composition” may be used to refer to a distinct physical entity comprising one or more specified components. Generally, unless otherwise specified, a composition may be in any form, such as a gas, spray, gel, cream, ointment, solution, suspension, liquid, or solid.

[0036] Dosage Form or Unit Dosage Form: Those skilled in the art will understand that the term “dosage form” may be used to refer to a physically distinct unit of an active agent (e.g., a therapeutic or diagnostic agent) for administration to a subject. Typically, each such unit contains a predetermined amount of the active agent. In some embodiments, such an amount is a unit dose (or its entire fraction) appropriate for administration according to a drug regimen (i.e., a therapeutic drug regimen) that has been determined to correlate with a desired or beneficial outcome when administered to the population in question.

[0037] Dosing regimen or treatment regimen: Those skilled in the art will understand that the terms “dosing regimen” and “treatment regimen” can be used to refer to a set of unit doses (typically two or more) administered individually to a subject, typically divided into multiple periods. In some embodiments, a given therapeutic agent has a recommended dosing regimen which may comprise one or more doses. In some embodiments, a dosing regimen comprises multiple dosings, each separated in time from the others. In some embodiments, the individual dosings are separated from each other by periods of equal length, and in some embodiments, a dosing regimen comprises multiple dosings and at least two distinct periods separating the individual dosings. In some embodiments, all dosings within a dosing regimen are of the same unit dose. In some embodiments, different dosings within a dosing regimen are of different amounts. In some embodiments, a dosing regimen comprises a first dosing at a first dose, followed by one or more additional dosings at a second dose different from the first dose. In some embodiments, the drug regimen comprises a first dose of a first dose, followed by one or more additional doses of a second dose identical to the first dose. In some embodiments, the drug regimen correlates with desired or beneficial outcomes when administered across a relevant population (i.e., it is a therapeutic drug regimen).

[0038] Excipients: As used herein, the term “excipient” refers to non-therapeutic agents that may be included in a pharmaceutical composition to provide or contribute to a desired consistency or stabilizing effect. Suitable pharmaceutically acceptable excipients include, for example, carboxymethylcellulose (CMC), sodium carboxymethylcellulose (NaCMC), hydroxyethylcellulose (HEC), hydroxypropylmethylcellulose (HPMC), carbomer, carbophyl, starch, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, and ethanol.

[0039] Modulator: The term "modulator," as used herein, refers to a compound (e.g., a small molecule) that can alter the activity of another molecule (e.g., a protein). For example, in some embodiments, a modulator may cause an increase or decrease in the magnitude of a particular activity of a certain type of molecule compared to the magnitude of activity in the absence of the modulator. For example, a modulator may be an agonist or antagonist of a particular target, these terms as defined herein. For example, in some embodiments, the modulator is an agonist. In some embodiments, the modulator is an antagonist.

[0040] Oral administration: As used herein, the terms “oral administration” and “administered orally” have the meanings understood in the art to refer to the administration of a compound or composition by mouth.

[0041] Parenteral: As used herein, the terms “parenteral administration” and “administered parenterally” have the meaning as understood in the art, usually by injection, and refer to modes of administration other than intestinal and topical administration, including, but not limited to, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, intramuscular, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, and intrasternal injections and infusions.

[0042] Patient or Subject: As used herein, the terms “patient” or “subject” refer to any organism to which the provided composition is administered or may be administered for, for example, experimental, diagnostic, prophylactic, cosmetic, and / or therapeutic purposes. Typical patients or subjects include animals (e.g., mammals, e.g., mice, rats, rabbits, non-human primates, and / or humans). In some embodiments, the patient is human. In some embodiments, the patient or subject suffers from or is susceptible to one or more disorders or conditions. In some embodiments, the patient or subject exhibits one or more symptoms of a disorder or condition. In some embodiments, the patient or subject has been diagnosed with one or more disorders or conditions. In some embodiments, the patient or subject is receiving or has received a particular treatment to diagnose and / or treat a disease, disorder, or condition.

[0043] Pharmaceutical composition: As used herein, the term “pharmaceutical composition” refers to an activator formulated with one or more pharmaceutically acceptable carriers. In some embodiments, the activator is present in a unit dose appropriate for administration in a therapeutic or drug regimen that demonstrates a statistically significant probability of achieving a predetermined therapeutic effect when administered to the relevant population. In some embodiments, pharmaceutical compositions may be specifically formulated for administration in solid or liquid form, including those adapted for: oral administration, e.g., liquid drugs (aqueous or non-aqueous solutions or suspensions), gels, tablets, e.g., for intracheek, sublingual, and systemic absorption, boluses, powders, granules, and pastes for application to the tongue; parenteral administration, e.g., by subcutaneous, intramuscular, intravenous, or epidural injection as sterile solutions or suspensions or sustained-release formulations; topical application, e.g., as creams, ointments, or controlled-release patches or sprays applied to the skin, lungs, or oral cavity; intravaginal or rectal, e.g., as pessaries, creams, or foams; sublingual; intraocular; transdermal; or intranasal, intrapulmonary, and other mucosal surfaces.

[0044] Pharmacologically acceptable: As used herein, the term “pharmaceutically acceptable” means a compound, material, composition, and / or dosage form that, within the bounds of sound medical judgment, is suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic response, or other problems or complications, and that is commensurate with a reasonable benefit-to-risk ratio.

[0045] Pharmacopoeia-acceptable salts: When used herein, the term "pharmacopoeia-acceptable salt" refers to a salt of a compound that is suitable for use in a pharmaceutical context, i.e., a salt that, within the bounds of sound medical judgment, is suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, allergic reactions, etc., and that has a reasonable benefit-to-risk ratio. Pharmacopoeia-acceptable salts are well known in the art. For example, SMBerge et al. describe pharmacopoeia-acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977).

[0046] Preventing or Prevention: As used herein, the terms “preventing” or “prevention,” when used in relation to the onset of a disease, disorder, and / or condition, mean reducing the risk of developing a disease, disorder, and / or condition, and / or delaying the onset of one or more characteristics or symptoms of the disease, disorder, or condition. Prevention may be considered complete if the onset of the disease, disorder, or condition is delayed for a given period of time.

[0047] Small molecules: As used herein, the term “small molecules” means low molecular weight organic and / or inorganic compounds. Generally, “small molecules” are molecules with a size of less than about 5 kilodaltons (kD). In some embodiments, small molecules are less than about 4 kD, less than 3 kD, less than about 2 kD, or less than about 1 kD. In some embodiments, small molecules are less than about 800 daltons (D), less than about 600 D, less than about 500 D, less than about 400 D, less than about 300 D, less than about 200 D, or less than about 100 D. In some embodiments, small molecules are less than about 2000 g / mol, less than about 1500 g / mol, less than about 1000 g / mol, less than about 800 g / mol, or less than about 500 g / mol. In some embodiments, small molecules are not polymers.

[0048] In some embodiments, the small molecule does not contain a polymer portion. In some embodiments, the small molecule is neither a protein nor a polypeptide, and / or does not contain either a protein or a polypeptide (e.g., neither an oligopeptide nor a peptide). In some embodiments, the small molecule is not a polynucleotide, and / or does not contain a polynucleotide (e.g., not an oligonucleotide). In some embodiments, the small molecule is not a polysaccharide, and / or does not contain a polysaccharide (e.g., in some embodiments, the small molecule is not a glycoprotein, proteoglycan, glycolipid, etc.). In some embodiments, the small molecule is not a lipid.

[0049] In some embodiments, the small molecule is a modulator (e.g., an inhibitor or activator). In some embodiments, the small molecule is biologically active. In some embodiments, the small molecule is detectable (e.g., containing at least one detectable moiety). In some embodiments, the small molecule is a therapeutic agent.

[0050] Those skilled in the art will understand, by reading this disclosure, that certain small molecule compounds described herein may be provided and / or available in any of the following forms, for example, crystalline form (e.g., polymorphs, solvates, etc.), salt form, protected form, prodrug form, ester form, isomer form (e.g., optical isomers and / or structural isomers), isotopic form, etc.

[0051] Those skilled in the art will understand that certain small molecule compounds have a structure that can exist in one or more stereoisomer forms. In some embodiments, such small molecules may be available in the form of individual enantiomers, diastereomers, or geometric isomers, or in the form of a mixture of stereoisomers, and in some embodiments, such small molecules may be available in the form of a racemic mixture, according to this disclosure.

[0052] One skilled in the art will understand that a particular small molecule compound may have a structure that can exist in one or more tautomeric forms. In some embodiments, such small molecules may be utilized in accordance with the present disclosure in the form of individual tautomers or in a form that interconverts between tautomeric forms.

[0053] One skilled in the art will understand that a particular small molecule compound may have a structure that permits isotope substitution (e.g., for H 2 H or 3 H, 12 for C 11 C, 13 C, or 14 C, 14 for N 13 N or 15 N, 16 for O 17 O or 18 O, 35 for Cl or 37 for Cl 36 Cl, 19 for F 18 F, 127 for I 131 I, etc.). In some embodiments, such small molecules may be utilized in accordance with the present disclosure in one or more isotopically modified forms or mixtures thereof.

[0054] In some embodiments, reference to a particular small molecule compound may relate to a particular form of the compound. In some embodiments, a particular small molecule compound may be provided and / or utilized in salt form (e.g., in the form of an acid addition salt or a base addition salt, depending on the compound), and in some such embodiments, the salt form may be in the form of a pharmaceutically acceptable salt.

[0055] In some embodiments, if a small molecule compound is naturally occurring or found, the compound may be provided and / or utilized in accordance with this disclosure in a form different from that which is naturally occurring or found. Those skilled in the art will understand that in some embodiments, a preparation of a particular small molecule compound or a particular form of that compound containing that compound in some absolute or relative amount is distinguished from the compound as it would be in the reference preparation or source if it differs from the absolute or relative amount of that compound or form present in the reference preparation (e.g., a primary sample derived from a target source, e.g., a biological or environmental source) in the reference preparation (e.g., in relation to another component of the preparation, including another form of the compound). Therefore, in some embodiments, for example, a preparation of a single stereoisomer of a small molecule compound can be considered a different form of the compound from a racemic mixture of that compound; a particular salt of a small molecule compound can be considered a different form from another salt form of that compound; a preparation containing only one form of the compound containing one stereoisomer of the double bond ((Z) or (E)) can be considered a different form of the compound from one containing the other stereoisomer of the double bond ((E) or (Z)); and a preparation in which one or more atoms are isotopes different from those present in the reference preparation can be considered a different form.

[0056] Treatment: As used herein, the terms “treatment,” “treatment,” or “doing treatment” refer to any method used to reduce, improve, alleviate, inhibit, prevent, delay, reduce the severity thereof, and / or reduce the occurrence thereof, either partially or completely. Treatment may be administered to subjects who are not showing any signs of disease, disorder, and / or condition. In some embodiments, treatment may be administered to subjects showing only early signs of disease, disorder, and / or condition, for example, to reduce the risk of developing pathologies associated with disease, disorder, and / or condition. compound 1 In some embodiments, the present disclosure relates to a compound 1 in an amount greater than 0.15% by weight.

[0057] [ka]

[0058] The present invention provides a composition comprising a pharmaceutically acceptable salt thereof. The applicant discovered that compound 1 ((2s)-2-[(E)-2-[(3,4-dihydroxy-5-nitrophenyl)ethylidene]hydrazine-1-yl]-3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid) is a byproduct of carbidopa and entacapone. Allowing a high content of compound 1 in a carbidopa and entacapone composition extends the shelf life of the composition. Compositions containing carbidopa and entacapone in combination with levodopa are useful therapeutic agents for the treatment of Parkinson's disease.

[0059] To date, two such products offer compositions containing carbidopa, entacapone, and levodopa for treating patients with Parkinson's disease: Lecigon® from Intrance Medical System and Stalevo® from Novartis. However, the administration of levodopa has been observed to present challenges due to the low bioavailability of this drug. It has been found that administering levodopa together with entacapone substantially increases the efficacy of levodopa compared to treatments that do not include entacapone, such as AbbVie's Duopa®, which contains only carbidopa and levodopa.

[0060] Current formulations containing carbidopa and entacapone face a relatively short shelf life of approximately 16 weeks under refrigerated conditions (e.g., 5±3°C) due to the generation of by-products or other impurities. Current regulatory requirements, however, do not permit pharmaceutical compositions for treatment to contain more than 0.15% by weight of any impurities that are not identified in the regulatory documentation and have not been analyzed for safety. The applicant's identification and characterization of Compound 1 offers the opportunity for novel treatments with a longer shelf life, which will ultimately provide patients with greater access to treatment.

[0061] Furthermore, the discovery and characterization of compound 1 provides manufacturers with a reference standard that can be used to qualify compositions containing carbidopa and entacapone. Such compositions may include compound 1 and, optionally, any other suitable solvents, diluents, carriers, etc., to assist in the manufacturer's quality control.

[0062] In some embodiments, the present disclosure relates to compound 1 exceeding 0.15% by weight:

[0063] [ka]

[0064] The present invention provides a composition comprising a pharmaceutically acceptable salt thereof. In some embodiments, the composition contains 1% by weight or more of compound 1. In some embodiments, the composition contains 10% by weight or more of compound 1. In some embodiments, the composition contains 15% by weight or more of compound 1. In some embodiments, the composition contains 20% by weight or more of compound 1. In some embodiments, the composition contains 25% by weight or more of compound 1. In some embodiments, the composition contains 30% by weight or more of compound 1. In some embodiments, the composition contains 35% by weight or more of compound 1. In some embodiments, the composition contains 40% by weight or more of compound 1. In some embodiments, the composition contains 45% by weight or more of compound 1. In some embodiments, the composition contains 50% by weight or more of compound 1. In some embodiments, the composition contains 55% by weight or more of compound 1. In some embodiments, the composition contains 60% by weight or more of compound 1. In some embodiments, the composition contains 65% by weight or more of compound 1. In some embodiments, the composition contains 70% by weight or more of compound 1. In some embodiments, the composition contains 75% by weight or more of compound 1. In some embodiments, the composition contains 80% by weight or more of compound 1. In some embodiments, the composition contains 85% by weight or more of compound 1. In some embodiments, the composition contains 90% by weight or more of compound 1. In some embodiments, the composition contains 95% by weight or more of compound 1. In some embodiments, the composition contains 96% by weight or more of compound 1. In some embodiments, the composition contains 97% by weight or more of compound 1. In some embodiments, the composition contains 98% by weight or more of compound 1. In some embodiments, the composition contains 99% by weight or more of compound 1. In some embodiments, the composition is essentially composed of compound 1.

[0065] In some embodiments, the composition contains less than 10% by weight of an organic solvent. In some embodiments, the composition contains less than 9% by weight of an organic solvent. In some embodiments, the composition contains less than 8% by weight of an organic solvent. In some embodiments, the composition contains less than 7% by weight of an organic solvent. In some embodiments, the composition contains less than 6% by weight of an organic solvent. In some embodiments, the composition contains less than 5% by weight of an organic solvent. In some embodiments, the composition contains less than 4% by weight of an organic solvent. In some embodiments, the composition contains less than 3% by weight of an organic solvent. In some embodiments, the composition contains less than 2% by weight of an organic solvent. In some embodiments, the composition contains less than 1% by weight of an organic solvent.

[0066] In some embodiments, the organic solvent is selected from methanol, dichloromethane, acetone, ethanol, isopropanol, ethyl acetate, acetaldehyde, heptane, and acetaldehyde. In some embodiments, the organic solvent is methanol. In some embodiments, the organic solvent is dichloromethane. In some embodiments, the organic solvent is acetone. In some embodiments, the organic solvent is ethanol. In some embodiments, the organic solvent is isopropanol. In some embodiments, the organic solvent is ethyl acetate. In some embodiments, the organic solvent is acetaldehyde. In some embodiments, the organic solvent is heptane. In some embodiments, the organic solvent is acetaldehyde. In some embodiments, the organic solvent is selected from methanol and dichloromethane.

[0067] In some embodiments, the composition contains less than 10% by weight of an organic solvent selected from methanol and dichloromethane. It is understood that the organic solvent content is determined by any method known to those skilled in the art, including chromatographic methods (e.g., gas chromatography). In some embodiments, the composition contains less than 5% by weight of an organic solvent selected from methanol and dichloromethane. In some embodiments, the composition contains less than 5% by weight of methanol. In some embodiments, the composition contains less than 5% by weight of dichloromethane.

[0068] In some embodiments, the composition contains 4% by weight or less of water. In some embodiments, the composition contains 3% by weight or less of water. In some embodiments, the composition contains 2% by weight or less of water. It is understood that the water content is determined by any method known to those skilled in the art, including, for example, Karl Fischer analysis (e.g., coulometric titration Karl Fischer or volumetric titration Karl Fischer). In some embodiments, the composition contains 1.5% by weight or less of water. In some embodiments, the composition contains 1% by weight or less of water. In some embodiments, the composition contains 0.5% by weight or less of water. Pharmaceutical composition containing compound 1 In some embodiments, the disclosure relates to carbidopa, entacapone, and compound 1 in an amount greater than 0.15% by weight:

[0069] [ka]

[0070] The present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable salt thereof. In some embodiments, carbidopa is carbidopa monohydrate.

[0071] In some embodiments, the pharmaceutical composition further comprises levodopa. In other words, in some embodiments, the pharmaceutical composition comprises carbidopa, entacapone, and compound 1 in an amount greater than 0.15% by weight:

[0072] [ka]

[0073] or a pharmaceutically acceptable salt thereof, as well as levodopa. In some embodiments, carbidopa is carbidopa monohydrate.

[0074] In some embodiments, the pharmaceutical compositions described herein are stored for a specific period before administration to a patient. In some embodiments, the pharmaceutical compositions described herein are stable for a specific period at a specific temperature and pressure. For example, after a specific period and / or at a specific temperature and / or humidity, in some embodiments, the pharmaceutical compositions described herein are stable if the pharmaceutical composition contains 1% or less by weight of impurities. In some embodiments, the pharmaceutical compositions are stable if the pharmaceutical composition contains less than 0.75% or less by weight of impurities. In some embodiments, the pharmaceutical compositions are stable if the pharmaceutical composition contains less than 0.50% or less by weight of impurities. In some embodiments, the pharmaceutical compositions are stable if the pharmaceutical composition contains less than 0.40% or less by weight of impurities. In some embodiments, the pharmaceutical compositions are stable if the pharmaceutical composition contains less than 0.25% or less by weight of impurities. In some embodiments, the pharmaceutical compositions are stable if the pharmaceutical composition contains less than 0.15% or less by weight of impurities. In some embodiments, the pharmaceutical compositions are stable if the pharmaceutical composition contains less than 0.10% or less by weight of impurities. In some embodiments, the pharmaceutical composition is stable if it is substantially free of impurities.

[0075] In some embodiments, the pharmaceutical composition is stable for about 16 weeks or more when stored at about 5°C. In some embodiments, the pharmaceutical composition is stable for about 20 weeks or more when stored at about 5°C. In some embodiments, the pharmaceutical composition is stable for about 25 weeks or more when stored at about 5°C. In some embodiments, the pharmaceutical composition is stable for about 30 weeks or more when stored at about 5°C. In some embodiments, the pharmaceutical composition is stable for about 32 weeks or more when stored at about 5°C.

[0076] In some embodiments, the pharmaceutical composition is stable for about 36 weeks or more when stored at about 5°C. In some embodiments, the pharmaceutical composition is stable for about 40 weeks or more when stored at about 5°C. In some embodiments, the pharmaceutical composition is stable for about 44 weeks or more when stored at about 5°C. In some embodiments, the pharmaceutical composition is stable for about 48 weeks or more when stored at about 5°C. In some embodiments, the pharmaceutical composition is stable for about 52 weeks or more when stored at about 5°C.

[0077] In some embodiments, the pharmaceutical composition is stable for about 16 weeks or more when stored at about 25°C. In some embodiments, the pharmaceutical composition is stable for about 20 weeks or more when stored at about 25°C. In some embodiments, the pharmaceutical composition is stable for about 25 weeks or more when stored at about 25°C. In some embodiments, the pharmaceutical composition is stable for about 30 weeks or more when stored at about 25°C. In some embodiments, the pharmaceutical composition is stable for about 32 weeks or more when stored at about 25°C. In some embodiments, the pharmaceutical composition is stable for about 36 weeks or more when stored at about 25°C. In some embodiments, the pharmaceutical composition is stable for about 40 weeks or more when stored at about 25°C. In some embodiments, the pharmaceutical composition is stable for about 44 weeks or more when stored at about 25°C. In some embodiments, the pharmaceutical composition is stable for about 48 weeks or more when stored at about 25°C. In some embodiments, the pharmaceutical composition is stable for about 52 weeks or more when stored at about 25°C.

[0078] In some embodiments, the pharmaceutical composition contains less than 2% by weight of water after storage at approximately 5°C for 16 weeks or more. In some embodiments, the pharmaceutical composition contains less than 2% by weight of water after storage at approximately 25°C for 16 weeks or more. In some embodiments, the pharmaceutical composition contains less than 3% by weight of water after storage at approximately 5°C for 26 weeks or more. In some embodiments, the pharmaceutical composition contains less than 3% by weight of water after storage at approximately 25°C for 26 weeks or more. In some embodiments, the pharmaceutical composition contains less than 4% by weight of water after storage at approximately 5°C for 52 weeks or more. In some embodiments, the pharmaceutical composition contains less than 4% by weight of water after storage at approximately 25°C for 52 weeks or more. In some embodiments, the pharmaceutical composition contains less than 4.5% by weight of water after storage at approximately 25°C for 52 weeks or more.

[0079] In some embodiments, the pharmaceutical composition is stable for about 16 weeks or more when stored at 5°C ± 3°C. In some embodiments, the pharmaceutical composition is stable for about 20 weeks or more when stored at 5°C ± 3°C. In some embodiments, the pharmaceutical composition is stable for about 25 weeks or more when stored at 5°C ± 3°C. In some embodiments, the pharmaceutical composition is stable for about 30 weeks or more when stored at 5°C ± 3°C. In some embodiments, the pharmaceutical composition is stable for about 32 weeks or more when stored at 5°C ± 3°C.

[0080] In some embodiments, the pharmaceutical composition is stable for approximately 36 weeks or more when stored at 5°C ± 3°C. In some embodiments, the pharmaceutical composition is stable for approximately 40 weeks or more when stored at 5°C ± 3°C. In some embodiments, the pharmaceutical composition is stable for approximately 44 weeks or more when stored at 5°C ± 3°C. In some embodiments, the pharmaceutical composition is stable for approximately 48 weeks or more when stored at 5°C ± 3°C. In some embodiments, the pharmaceutical composition is stable for approximately 52 weeks or more when stored at 5°C ± 3°C.

[0081] In some embodiments, the pharmaceutical composition contains less than 2% by weight of water after storage at 5°C ± 3°C for 16 weeks or more. In some embodiments, the pharmaceutical composition contains less than 2% by weight of water after storage at 25°C ± 2°C for 16 weeks or more. In some embodiments, the pharmaceutical composition contains less than 3% by weight of water after storage at 5°C ± 3°C for 26 weeks or more. In some embodiments, the pharmaceutical composition contains less than 3% by weight of water after storage at 25°C ± 2°C for 26 weeks or more. In some embodiments, the pharmaceutical composition contains less than 4% by weight of water after storage at 5°C ± 3°C for 52 weeks or more. In some embodiments, the pharmaceutical composition contains less than 4% by weight of water after storage at 25°C ± 2°C for 52 weeks or more. In some embodiments, the pharmaceutical composition contains less than 4.5% by weight of water after storage at 25°C ± 2°C for 52 weeks or more.

[0082] In some embodiments, the pharmaceutical composition is stable for 16 hours or more at physiological temperature (e.g., 37°C). In some embodiments, the pharmaceutical composition is stable for 24 hours or more at physiological temperature (e.g., 37°C). In some embodiments, the pharmaceutical composition is stable for 32 hours or more at physiological temperature (e.g., 37°C). In some embodiments, the pharmaceutical composition is stable for 48 hours or more at physiological temperature (e.g., 37°C).

[0083] Existing formulations containing carbidopa and entacapone have had stability issues at room temperature or physiological temperature, and in many cases, they had to be discarded after 16 weeks when stored at 5°C.

[0084] In some embodiments, the pharmaceutical composition contains about 0.1 to 2% by weight of carbidopa. In some embodiments, the pharmaceutical composition contains about 0.1 to 1% by weight of carbidopa. In some embodiments, the pharmaceutical composition contains about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1% by weight of carbidopa. In some embodiments, the pharmaceutical composition contains about 0.5% by weight of carbidopa.

[0085] In some embodiments, the pharmaceutical composition contains about 1 to 7.5% by weight of entacapone. In some embodiments, the pharmaceutical composition contains about 1 to 5% by weight of entacapone. In some embodiments, the pharmaceutical composition contains about 1 to 3% by weight of entacapone. In some embodiments, the pharmaceutical composition contains about 1, 1.5, 2, 2.5, or 3% by weight of entacapone. In some embodiments, the pharmaceutical composition contains about 3% by weight of entacapone.

[0086] In some embodiments, the pharmaceutical composition contains about 1 to 15% by weight of levodopa. In some embodiments, the pharmaceutical composition contains about 1 to 10% by weight of levodopa. In some embodiments, the pharmaceutical composition contains about 1 to 5% by weight of levodopa. In some embodiments, the pharmaceutical composition contains about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5% by weight of levodopa. In some embodiments, the pharmaceutical composition contains about 2% by weight of levodopa.

[0087] In some embodiments, the pharmaceutical composition contains more than 0.15% by weight of compound 1. In some embodiments, the pharmaceutical composition contains about 0.15 to 1.5% by weight of compound 1. In some embodiments, the pharmaceutical composition contains about 0.15 to 1% by weight of compound 1. In some embodiments, the pharmaceutical composition contains about 0.15 to 0.8% by weight of compound 1. In some embodiments, the pharmaceutical composition contains about 0.15 to 0.5% by weight of compound 1. In some embodiments, the pharmaceutical composition contains about 0.15 to 0.4% by weight of compound 1. In some embodiments, the pharmaceutical composition contains about 0.15 to 0.2% by weight of compound 1.

[0088] In some embodiments, the pharmaceutical composition comprises about 1 to 15% by weight of levodopa, about 0.1 to 2% by weight of carbidopa, and about 1 to 7.5% by weight of entacapone. In some embodiments, the pharmaceutical composition comprises about 2% by weight of entacapone, about 0.5% by weight of carbidopa, and about 2% by weight of entacapone.

[0089] In some embodiments, the pharmaceutical composition contains about 12.5 mg to about 50 mg of carbidopa. In some embodiments, the pharmaceutical composition contains about 12.5 mg, 18.75 mg, 25 mg, 31.25 mg, 37.5 mg, or 50 mg of carbidopa. In some embodiments, the pharmaceutical composition contains about 12.5 mg of carbidopa. In some embodiments, the pharmaceutical composition contains about 18.75 mg of carbidopa. In some embodiments, the pharmaceutical composition contains about 25 mg of carbidopa. In some embodiments, the pharmaceutical composition contains about 31.25 mg of carbidopa. In some embodiments, the pharmaceutical composition contains about 37.5 mg of carbidopa. In some embodiments, the pharmaceutical composition contains about 50 mg of carbidopa.

[0090] In some embodiments, the pharmaceutical composition contains about 50 mg to about 200 mg of levodopa. In some embodiments, the pharmaceutical composition contains about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, or about 200 mg of levodopa. In some embodiments, the pharmaceutical composition contains about 50 mg of levodopa. In some embodiments, the pharmaceutical composition contains about 25 mg of levodopa. In some embodiments, the pharmaceutical composition contains about 100 mg of levodopa. In some embodiments, the pharmaceutical composition contains about 125 mg of levodopa. In some embodiments, the pharmaceutical composition contains about 150 mg of levodopa. In some embodiments, the pharmaceutical composition contains about 200 mg of levodopa.

[0091] In some embodiments, the pharmaceutical composition contains about 200 mg of entacapone. In some embodiments, the pharmaceutical composition comprises carbidopa and levodopa in a weight ratio of approximately 1:4.

[0092] In some embodiments, the pharmaceutical composition contains about 12.5 mg of carbidopa, about 50 mg of levodopa, and about 200 mg of entacapone. In some embodiments, the pharmaceutical composition contains about 18.75 mg of carbidopa, about 75 mg of levodopa, and about 200 mg of entacapone. In some embodiments, the pharmaceutical composition contains about 25 mg of carbidopa, about 100 mg of levodopa, and about 200 mg of entacapone. In some embodiments, the pharmaceutical composition contains about 31.25 mg of carbidopa, about 125 mg of levodopa, and about 200 mg of entacapone. In some embodiments, the pharmaceutical composition contains about 37.5 mg of carbidopa, about 150 mg of levodopa, and about 200 mg of entacapone. In some embodiments, the pharmaceutical composition comprises about 50 mg of carbidopa, about 200 mg of levodopa, and about 200 mg of entacapone.

[0093] In some embodiments, the pharmaceutical compositions described herein further comprise one or more pharmaceutical carriers, adjuvants, or vehicles. In certain embodiments, the compositions described herein are formulated for administration to a patient requiring such a composition. In some embodiments, the compositions described herein are formulated for oral administration to a patient. In some embodiments, the compositions described herein are formulated for intragastric (e.g., intra-gastrointestinal) administration to a patient.

[0094] The compositions produced by the methods of this disclosure are administered using any amount and any route of administration that is effective in treating or reducing the severity of the disorders provided herein. The exact amount required will vary from subject to subject, depending on the species, age, and overall condition of the subject, the severity of the infection, the specific drug, and its mode of administration. The compositions described herein are preferably formulated in unit dosage forms for ease of administration and uniformity of dosage.

[0095] The compositions of this disclosure may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, in the cheek, vaginally, intestinally by direct administration into the gastrointestinal tract (i.e., intragastric administration), intraperitoneally, intracisionally, or via an implanted reservoir. In some embodiments, the compositions are administered orally, intraperitoneally, or intravenously.

[0096] The sterile injection forms of the compositions described herein may be aqueous or oily suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersants or wetting agents and suspending agents. The sterile injection preparations may also be sterile injection solutions or suspensions in non-toxic, parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used are, among others, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixing oils are conventionally used as solvents or suspension media.

[0097] For this purpose, any non-irritating fixative oil, including synthetic monoglycerides or diglycerides, can be used. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injection solutions, as are naturally pharmaceutically acceptable oils, such as olive oil or castor oil, in particular their polyoxyethylated versions. These oily solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose, sodium carboxymethylcellulose, or similar dispersants widely used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other widely used surfactants, such as Tween, Span, and other emulsifiers or bioavailability enhancers widely used in the manufacture of pharmaceutically acceptable solids, liquids, or other dosage forms, can also be used for formulation purposes.

[0098] Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable media before use.

[0099] To extend the effects of the compounds of this disclosure, it is often desirable to slow down the absorption of the compounds from subcutaneous or intramuscular injection. This can be achieved by using liquid suspensions of crystalline or amorphous materials with low water solubility. Thus, the rate of absorption of a compound depends on its dissolution rate, which may depend on the size of the crystals and the crystalline form. Alternatively, delaying the absorption of parenterally administered compound forms is achieved by dissolving or suspending the compound in an oily vehicle. Depot formulations for injection are prepared by forming a microcapsule matrix of the compound in a biodegradable polymer such as polylactide-polyglycolide. The rate of compound release can be controlled depending on the ratio of the compound to the polymer and the properties of the specific polymer used. Other examples of biodegradable polymers include poly(orthoesters) and poly(anhydrous). Depot injection formulations are also prepared by encapsulating the compound in liposomes or microemulsions compatible with body tissues.

[0100] In some embodiments, the pharmaceutically acceptable compositions provided are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions described herein are administered without food. In other embodiments, the pharmaceutically acceptable compositions described herein are administered with food. The pharmaceutically acceptable compositions described herein may be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions, or solutions. For tablets for oral use, commonly used carriers include lactose and corn starch. Lubricants, such as magnesium stearate, are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifiers and suspending agents. Certain sweeteners, flavorings, or colorings may also be added, if desired.

[0101] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is provided with at least one inert, pharmaceutically acceptable excipient or carrier, e.g., sodium citrate or dicalcium phosphate, and / or a) fillers or bulking agents, e.g., starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, e.g., carboxymethylcellulose, sodium carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, carbomer, sucrose, and acacia; c) water-retaining agents, e.g., glycerol; d) disintegrants, e.g., agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarding agents. f) an absorption enhancer, e.g., a quaternary ammonium compound, g) a wetting agent, e.g., cetyl alcohol and glycerol monostearate, h) an absorbent, e.g., kaolin and bentonite clay, and / or i) a lubricant, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also include a buffering agent.

[0102] Similar types of solid compositions can also be used as fillers in soft and hard-filled gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells, such as enteric coatings and other coatings well known in the field of pharmaceutical formulations. They may optionally contain emulsifiers and may optionally be compositions that release the active ingredient only to or preferentially to a specific part of the gastrointestinal tract in a delayed manner. Examples of embedding compositions that can be used include polymer substances and waxes. Similar types of solid compositions can also be used as fillers in soft and hard-filled gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0103] The active compound may also be in the form of microcapsules encapsulated with one or more excipients, as described above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells, e.g., enteric coatings, controlled-release coatings, and other coatings well known in the field of pharmaceutical formulations. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, e.g., sucrose, lactose, or starch. Such dosage forms may also include additional substances other than inert diluents, as is common practice, e.g., tableting lubricants and other tableting aids, e.g., magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage form may also include buffering agents. These may optionally contain emulsifiers and may optionally be compositions that release the active ingredient only to or preferentially to a specific part of the gastrointestinal tract in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0104] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid dosage form may contain inert diluents widely used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, as well as mixtures thereof. In addition to inert diluents, the oral composition may also contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances.

[0105] Alternatively, the pharmaceutically acceptable compositions described herein may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore melts in the rectum to release the drug. Examples of such materials include cocoa butter, beeswax, and polyethylene glycol.

[0106] Compositions for rectal and vaginal administration are preferably suppositories, which can be prepared by mixing the compounds described herein with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or suppository wax, which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity to release the active compound.

[0107] The pharmaceutically acceptable compositions described herein may also be administered topically, particularly when the target of treatment includes areas or organs that are readily accessible by topical application, including diseases of the eyes, skin, or lower gastrointestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0108] Topical application to the lower gastrointestinal tract can be achieved with rectal suppositories or suitable enema formulations. Topical transdermal patches may also be used.

[0109] With regard to topical application, the pharmaceutically acceptable compositions provided may be formulated in a preferred ointment containing the active ingredient suspended or dissolved in one or more carriers. Suitable carriers for topical administration of the compounds described herein include, but are not limited to, mineral oil, liquid paraffin, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying waxes, and water. Alternatively, the pharmaceutically acceptable compositions provided may be formulated in a preferred lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0110] For ophthalmic use, the pharmaceutically acceptable composition provided may be formulated as a micronized suspension in isotonic pH-adjusted sterile saline, or preferably as a solution in isotonic pH-adjusted sterile saline, with or without a preservative, such as benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutically acceptable composition may be formulated in an ointment, such as petrolatum.

[0111] The pharmaceutically acceptable compositions described herein may also be administered by intranasal aerosol or inhalation. Such compositions may be prepared according to techniques well known in the field of pharmaceutical formulations and may be prepared as solutions in physiological saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other common solubilizers or dispersants.

[0112] Dosage forms for topical or transdermal administration of the compounds disclosed herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalations, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and, if necessary, any required preservatives or buffers. Ophthalmic formulations, ear drops, and eye drops are also intended to be within the scope of this disclosure. In addition, this disclosure intends for the use of transdermal patches, which have the further advantage of providing controlled delivery of the compound to the body. Such dosage forms can be prepared by dissolving or aliquoting the compound in a suitable culture medium. Absorption enhancers can also be used to increase the flow of the compound throughout the skin. The rate can be controlled by either providing a rate-controlled membrane or by dispersing the compound in a polymer matrix or gel.

[0113] For direct administration into the patient's gastrointestinal tract, an intragastric form such as a gel may be used. The active ingredient is mixed with a pharmaceutically acceptable carrier, along with any other preservatives or buffers that may be required. For example, in some embodiments, the pharmaceutical compositions described herein further comprise one or more pharmaceutically acceptable carriers. In some embodiments, the pharmaceutically acceptable carrier is a polysaccharide. In some embodiments, the polysaccharide is a cellulose derivative. In some embodiments, the polysaccharide is methylcellulose, ethylcellulose, or carboxymethylcellulose or sodium carboxymethylcellulose. In some embodiments, the polysaccharide is methylcellulose. In some embodiments, the polysaccharide is ethylcellulose. In some embodiments, the polysaccharide is or carboxymethylcellulose.

[0114] In some embodiments, the pharmaceutical composition contains about 2-3% by weight of polysaccharide. In some embodiments, the pharmaceutical composition contains about 2-3% by weight of a cellulose derivative. In some embodiments, the pharmaceutical composition contains about 2-3% by weight of methylcellulose, ethylcellulose, or carboxymethylcellulose or sodium carboxymethylcellulose. In some embodiments, the pharmaceutical composition contains about 2-3% by weight of methylcellulose. In some embodiments, the pharmaceutical composition contains about 2-3% by weight of ethylcellulose. In some embodiments, the pharmaceutical composition contains about 2-3% by weight of carboxymethylcellulose.

[0115] In some embodiments, the pharmaceutical composition is in the form of a gel. In some embodiments, the pH of the gel described herein is less than about 5.7. In some embodiments, the pH of the gel described herein is about 4.5 to 5.7. In some embodiments, the pH of the gel described herein is about 4.5 to 5.5. In some embodiments, the pH of the gel described herein is about 5.0.

[0116] In some embodiments, the pharmaceutical composition is a gel having a viscosity of approximately 3000–5000 CPS when measured by Brookfield DVII TRV using a small sample adapter, spindle SC4-28, and solid shaft at an incubation temperature of 50 RPM and 25°C. In some embodiments, the pharmaceutical composition is a gel having a viscosity of approximately 3500–4500 CPS when measured by Brookfield DVII TRV using a small sample adapter, spindle SC4-28, and solid shaft at an incubation temperature of 50 RPM and 25°C. Methods for treating neurodegenerative disorders In some embodiments, this disclosure provides methods for treating diseases, disorders, and conditions using the pharmaceutical compositions described herein. In some embodiments, this disclosure provides methods for treating neurological disorders by administering the pharmaceutical compositions described herein to a patient.

[0117] For example, in some embodiments, the present disclosure relates to a method for treating a neurological disorder comprising carbidopa, entacapone, and compound 1 in an amount greater than 0.15% by weight:

[0118] [ka]

[0119] The present invention provides a method comprising a pharmaceutical composition containing a pharmaceutically acceptable salt thereof. In some embodiments, the neurological disorder is Parkinson's disease. In some embodiments, the Parkinson's disease is progressive Parkinson's disease.

[0120] In some embodiments, the pharmaceutical composition is administered to the patient continuously over a period of about 16 hours. In some embodiments, about 25% of the daily dose of the pharmaceutical composition described herein is administered to the patient in the morning. In some embodiments, the pharmaceutical composition is administered to the patient over a period of 16 hours, where about 25% of the daily dose of the pharmaceutical composition is administered to the patient in the morning, followed by continuous administration of the pharmaceutical composition to the patient over the remainder of the 16-hour administration period.

[0121] In some embodiments, the pharmaceutical composition is administered to the patient once a day. In some embodiments, the pharmaceutical composition is administered directly to the patient's gastrointestinal tract. In some embodiments, the pharmaceutical composition is administered via a PEG-J tube.

[0122] In some embodiments, the pharmaceutical composition is in the form of an oral dosage form. In some embodiments, the oral dosage form is a capsule or a tablet. In some embodiments, the oral dosage form is a capsule. In some embodiments, the oral dosage form is a tablet.

[0123] In some embodiments, the pharmaceutical composition is in the form of an oral dosage form, which is administered to the patient such that the total daily dose of levodopa administered to the patient is 1200 mg or less.

[0124] In some embodiments, this disclosure provides the use of the pharmaceutical compositions described herein for the treatment of neurological disorders similarly described herein. Method for qualifying a composition containing compound 1 This disclosure further provides, in particular, methods for qualifying or evaluating the quality of pharmaceutical compositions. In some embodiments, this disclosure provides a method for characterizing the purity of a pharmaceutical composition comprising levodopa, carbidopa, and entacapone, by comparison of a sample of the pharmaceutical composition with a reference standard, wherein compound 1 in the pharmaceutical composition:

[0125] [ka]

[0126] The present invention provides a method that includes determining the amount of a known compound 1, wherein the reference standard contains a known amount of compound 1.

[0127] In some embodiments, a sample of a pharmaceutical composition is classified as having high purity if the pharmaceutical composition contains less than about 0.15% by weight of compound 1. In some embodiments, a sample of a pharmaceutical composition is classified as having moderate purity if the pharmaceutical composition contains about 0.15 to 1% by weight of compound 1. In some embodiments, a sample of a pharmaceutical composition is classified as having high purity if the pharmaceutical composition contains about 0.5% by weight or less of compound 1. In some embodiments, a sample of a pharmaceutical composition is classified as having high purity if the pharmaceutical composition contains about 0.4% by weight or less of compound 1. In some embodiments, a sample of a pharmaceutical composition is classified as having low purity if the pharmaceutical composition contains about 1% by weight or less of compound 1.

[0128] In some embodiments, the reference standard comprises a composition containing 95% by weight or more of compound 1. In some embodiments, the reference standard comprises a composition containing about 95, 96, 97, 98, 99, or 99.9% by weight of compound 1. In some embodiments, the reference standard comprises a composition essentially consisting of compound 1.

[0129] In some embodiments, this disclosure relates to a known amount of compound 1:

[0130] [ka]

[0131] The present invention provides a method for determining the purity level of a pharmaceutical composition using a reference standard containing a compound 1, the method comprising comparing the amount of compound 1 in the reference standard with the amount of compound 1 in the pharmaceutical composition.

[0132] In some embodiments, the amount of compound 1 in the pharmaceutical composition is evaluated by high-pressure liquid chromatography (HPLC) using a Waters SunFire C18 column, 150 × 4.6 mm, 3.5 μm, UV / Vis detector, mobile phase A being 0.06% trifluoroacetic acid (TFA) in water, and mobile phase B being 0.04% TFA in (80:20 MeOH;H2O). Method for preparing compound 1 In some embodiments, this disclosure relates to compound 1

[0133] [ka]

[0134] A method for producing a composition containing compound 2

[0135] [ka]

[0136] Compound 3

[0137] [ka]

[0138] The present invention provides a method comprising contacting the substance in the presence of an organic solvent and a sulfate. In some embodiments, the sulfate is sodium sulfate, potassium sulfate, magnesium sulfate, calcium sulfate, or ammonium sulfate. In some embodiments, the sulfate is sodium sulfate. In some embodiments, the sulfate is potassium sulfate. In some embodiments, the sulfate is magnesium sulfate. In some embodiments, the sulfate is calcium sulfate. In some embodiments, the sulfate is ammonium sulfate.

[0139] In some embodiments, the organic solvent is methanol, ethanol, propanol, isopropanol, butanol, or ethyl acetate. In some embodiments, the organic solvent is methanol, ethanol, propanol, isopropanol, or butanol. In some embodiments, the organic solvent is methanol. In some embodiments, the organic solvent is ethanol. In some embodiments, the organic solvent is propanol. In some embodiments, the organic solvent is isopropanol. In some embodiments, the organic solvent is butanol. In some embodiments, the organic solvent is ethyl acetate.

[0140] In some embodiments, a method for producing compound 1 further includes suspending compound 1 in an organic solvent and filtering the solid form of compound 1 to provide a composition containing compound 1 that is impurity-free in greater than 90% by weight (i.e., the composition containing compound 1 has any impurities in less than 10% by weight). In some embodiments, the production method described herein provides compound 1 that is impurity-free in greater than 95% by weight. In some embodiments, the production method described herein provides compound 1 that is impurity-free in greater than 99% by weight. In some embodiments, the production method described herein provides compound 1 that is impurity-free in greater than 99.9% by weight. In some embodiments, the production method described herein provides compound 1 that is substantially impurity-free. Exemplary Embodiments The embodiments of the present disclosure described above are intended to be illustrative only, and numerous variations and modifications will be apparent to those skilled in the art. All such variations and modifications are intended to be within the scope of the present invention as defined in any appended claims. 1. Compound 1 exceeding approximately 0.15% by weight:

[0141] [ka]

[0142] A composition comprising a pharmaceutically acceptable salt thereof. 2. The composition according to Embodiment 1, comprising approximately 50% by weight or more of compound 1. 3. The composition according to Embodiment 1 or 2, comprising approximately 75% by weight or more of compound 1. 4. A composition according to any one of Embodiments 1 to 3, comprising approximately 85% by weight or more of compound 1. 5. A composition according to any one of Embodiments 1 to 4, comprising approximately 90% by weight or more of compound 1. 6. A composition according to any one of Embodiments 1 to 5, comprising approximately 95% by weight or more of compound 1. 7. The composition according to any one of Embodiments 1 to 6, wherein the composition contains less than 10% by weight of an organic solvent. 8. The composition according to any one of Embodiments 1 to 7, wherein the composition contains less than 5% by weight of an organic solvent. 9. The composition according to Embodiment 7 or 8, wherein the organic solvent is selected from the group consisting of methanol, dichloromethane, acetone, ethanol, isopropanol, ethyl acetate, acetaldehyde, heptane, and acetaldehyde. 10. The composition according to any one of Embodiments 1 to 9, wherein the composition contains about 2% by weight or less of water. 11. The composition according to any one of Embodiments 1 to 10, wherein the composition contains about 1.5% by weight or less of water. 12. The composition according to Embodiment 10 or 11, wherein the weight of water is determined by Karl Fischer analysis. 13. Carbidopa, entacapone, and compound 1 exceeding 0.15% by weight:

[0143] [ka]

[0144] A pharmaceutical composition comprising a pharmaceutically acceptable salt thereof. 14. The pharmaceutical composition according to Embodiment 13, further comprising levodopa. 15. The pharmaceutical composition according to Embodiment 13 or 14, characterized in that the pharmaceutical composition is stable for 16 weeks or more when stored at approximately 5°C. 16. The pharmaceutical composition according to any one of embodiments 13 to 15, characterized in that the pharmaceutical composition is stable for 16 hours or more at a physiological temperature (e.g., 37°C). 17. A pharmaceutical composition, Approximately 1-15% by weight of Revodopa, Approximately 0.1-2% by weight of carbidopa, and Approximately 1-7.5% by weight of entacapone A pharmaceutical composition according to any one of embodiments 14 to 16, including the following. 18. A pharmaceutical composition is Approximately 2% by weight of Revodopa, Approximately 0.5% by weight of carbidopa, and Approximately 2% by weight of entacapone A pharmaceutical composition according to any one of embodiments 14 to 17, including the following: 19. A pharmaceutical composition according to any one of embodiments 13 to 18, further comprising one or more pharmaceutical carriers. 20. The pharmaceutical composition according to Embodiment 19, wherein one or more pharmaceutical carriers are polysaccharides. 21. The pharmaceutical composition according to Embodiment 20, wherein the polysaccharide is sodium carboxymethylcellulose. 22. The pharmaceutical composition according to Embodiment 20, wherein the pharmaceutical composition contains about 2-3% by weight of sodium carboxymethylcellulose. 23. A pharmaceutical composition according to any one of embodiments 13 to 22, wherein the pharmaceutical composition is in the form of a gel. 24. The pharmaceutical composition according to Embodiment 23, wherein the pH of the gel is less than approximately 5.7. 25. The pharmaceutical composition according to Embodiment 23 or 24, wherein the pH of the gel is approximately 4.5 to approximately 5.5. 26. A pharmaceutical composition according to any one of embodiments 23 to 25, wherein the pH of the gel is approximately 5.0. 27. A pharmaceutical composition according to any one of embodiments 23 to 26, wherein the viscosity of the gel is approximately 3000 to approximately 5000 CPS. 28. A pharmaceutical composition according to any one of embodiments 23 to 27, wherein the viscosity of the gel is approximately 3500 to approximately 4500 CPS. 29. A pharmaceutical composition according to any one of embodiments 23 to 28, wherein the gel is formulated for administration to the gastrointestinal tract. 30. The pharmaceutical composition according to any one of embodiments 13 to 22, wherein the pharmaceutical composition is in the form of an oral dosage form. 31. A method for treating Parkinson's disease (PD) in a patient, comprising administering to the subject a pharmaceutical composition described in any one of Embodiments 13 to 29. 32. The method according to Embodiment 31, wherein the Parkinson's disease is progressive Parkinson's disease. 33. The method according to Embodiment 31 or 32, wherein the pharmaceutical composition is administered to a patient over a 16-hour period. 34. The method according to any one of embodiments 31 to 33, wherein approximately 25% of the total daily dose of the pharmaceutical composition is administered to the patient in the morning. 35. The method according to any one of embodiments 31 to 34, wherein the pharmaceutical composition is administered to a patient once daily. 36. The method according to any one of embodiments 31 to 35, wherein the pharmaceutical composition is administered directly to the gastrointestinal tract. 37. The method according to Embodiment 36, wherein the pharmaceutical composition is administered by a PEG-J tube. 38. A method for treating Parkinson's disease (PD) in a patient, comprising administering to the subject the pharmaceutical composition described in Embodiment 30. 39. The method according to Embodiment 38, wherein the Parkinson's disease is progressive Parkinson's disease. 40. Compound 1

[0145] [ka]

[0146] A method for producing a composition containing compound 2

[0147] [ka]

[0148] Compound 3

[0149] [ka]

[0150] A method comprising contacting the substance in the presence of an organic solvent and a sulfate. 41. The method according to Embodiment 40, wherein the sulfate is sodium sulfate, potassium sulfate, magnesium sulfate, calcium sulfate, or ammonium sulfate. 42. The method according to Embodiment 40 or 41, wherein the sulfate is sodium sulfate. 43. The method according to any one of Embodiments 40 to 42, wherein the organic solvent is methanol, ethanol, propanol, isopropanol, or butanol. 44. The method according to Embodiment 43, wherein the organic solvent is methanol. 45. The method according to any one of Embodiments 40 to 44, further comprising suspending compound 1 in an organic solvent and filtering the solid form of compound 1 to provide a composition containing compound 1 that is impurity-free in a proportion of more than 90% by weight. 46. ​​The method according to Embodiment 45, wherein the composition containing compound 1 is impurity-free in more than 95% by weight. 47. The method according to Embodiment 46, wherein the composition containing compound 1 is impurity-free in a proportion exceeding 99% by weight. 48. The method according to Embodiment 47, wherein the composition containing compound 1 is substantially free of impurities. 49. The method according to any one of embodiments 40 to 48, wherein the organic solvent is dichloromethane. 50. A method for characterizing the purity of a pharmaceutical composition comprising levodopa, carbidopa, and entacapone, wherein the purity of compound 1 in the pharmaceutical composition is determined by comparison of a sample of the pharmaceutical composition with a reference standard.

[0151] [ka]

[0152] A method comprising determining the amount of a reference standard containing a known amount of compound 1. 51. The method according to Embodiment 50, wherein the pharmaceutical composition is characterized as having high purity when the pharmaceutical composition contains less than about 0.15% by weight of compound 1. 52. The method according to Embodiment 50 or 51, wherein the reference standard is a composition containing 95% by weight or more of compound 1. 53. The method according to any one of Embodiments 50 to 52, wherein the purity of the pharmaceutical composition is evaluated by high-pressure liquid chromatography (HPLC) using a Waters SunFire C18 column, 150 × 4.6 mm, 3.5 μm, UV / Vis detector, mobile phase A being 0.06% trifluoroacetic acid (TFA) in water, and mobile phase B being 0.04% TFA in (80:20 MeOH;H2O). 54. Known amount of compound 1:

[0153] [ka]

[0154] A method for determining the purity level of a pharmaceutical composition using a reference standard containing a compound 1, comprising comparing the amount of compound 1 in the reference standard with the amount of compound 1 in the pharmaceutical composition. 55. The method according to Embodiment 54, wherein the purity of the pharmaceutical composition is evaluated by high-pressure liquid chromatography (HPLC) using a Waters SunFire C18 column, 150 × 4.6 mm, 3.5 μm, UV / Vis detector, mobile phase A being 0.06% trifluoroacetic acid (TFA) in water, and mobile phase B being 0.04% TFA in (80:20 MeOH;H2O). [Examples]

[0155] Examples As described in the following examples, in certain exemplary embodiments, the compounds are prepared according to the following general procedure. While the general method illustrates the synthesis of a particular compound in this disclosure, it will be understood that the following general method and other methods known to those skilled in the art may be applied to all compounds and their respective subclasses and species as described herein.

[0156] Example 1 Synthesis of Compound 1 This example provides the synthesis of compound 1.

[0157] [ka]

[0158] 77 g of compound 2 (purchased from Combi-Blocks, CAS number 116313-85-0) (1 equivalent) and 100 g of compound 3 (purchased from Combi-Blocks, CAS number 28860-95-9) (1.05 equivalents) were stirred at room temperature for 1 hour in a flask containing Na2SO4 (1.5 w / w) and methanol (MeOH). Sodium sulfate was purchased from Caledon Laboratories Limited, CAS number 7757-82-6. Methanol (MeOH) was purchased from Caledon Laboratories Limited, CAS number 67-56-1. The resulting mixture was filtered and dried under vacuum to obtain the crude product.

[0159] The crude product was slurryed in dichloromethane (DCM) for 18 hours. Dichloromethane (DCM) was purchased from Caledon Laboratories Limited, CAS number 1975-09-02. The fine solid product was collected, the residual solid was ground with a mortar and pestle, and then resuspended in DCM and stirred overnight. The fine solid was collected, all the fine solids were combined and suspended in DCM and stirred overnight. The resulting mixture was dried in a vacuum oven to obtain compound 1.

[0160] Example 2 Analysis of Compound 1 The purity of compound 1 was determined by HPLC at two wavelengths, 220 nm and 280 nm. Compound 1 was identified using IR and NMR methods. 1 1H NMR, 13 The analysis was performed by 13C NMR. The residual solvents, methanol and dichloromethane (DCM), were determined by gas chromatography (GC). The residual water content was determined by Karl Fischer analysis. Thermogravimetric analysis (TGA) of compound 1 was also performed at a final temperature of 105°C with a retention time of 10 minutes.

[0161] The potency of the composition containing compound 1, corrected with solvent and residual water, was calculated according to Alphora SOP LC038 "Standard Qualification in the QC / AS Laboratory" using the following equation:

[0162]

number

[0163] Details of the analysis are described below: 1. Materials and equipment: Column: Waters SunFire C18 column, 150 x 4.6 mm, 3.5 μm HPLC pumps: Quaternary or binary pumps Detection: UV or diode array detector A data system based on an integrating device or computer. An autosampler equipped with a sample cooling system. Calibrated analytical balance. Class A volumetric flasks and pipettes HPLC vials and caps 2. Reagents and standards: Methanol (MeOH) HPLC grade or equivalent Water (H2O): MilliQ purified or equivalent Trifluoroacetic acid (TFA): HPLC grade or equivalent You may use an equivalent or higher grade. 3. Solution The volume may be scaled up or down to suit the needs of the analysis. 3.1. Mobile phase A (0.06% TFA in water): Transfer 0.6 ml of TFA to a container with 1 L of H2O and mix thoroughly. Degas under vacuum using ultrasonic treatment. 3.2. Mobile phase B: (0.04% TFA in (80:20 MeOH:H2O) Transfer 0.4 mL of TFA to a container containing 800 mL of MeOH and 200 mL of H2O in a 1 L HPLC reservoir. Mix thoroughly. Degas under vacuum by sonication. 3.3 Diluent: 80:20 MeOH / H2O Transfer 160 mL of MeOH and 40 mL of H2O to a 200 mL HPLC reservoir. Mix thoroughly and degas under vacuum by sonication. 3.4 Blank solution: Diluent ECA - Analytical Method - E920H2 - Standard Qualification 4. Instrument parameters Detection device: UV / Vis or diode array detection device Wavelength: Signal A: 280nm, Bandwidth: 4nm, Reference: OFF Signal B: 220nm, Bandwidth: 4nm, Reference: OFF Column: SunFire C18 column (150 x 4.6 mm, 3.5 μm) Mobile phase A: 0.06% TFA in H2O Mobile phase B: 0.04% TFA in (MeOH:H2O,80:20) Gradient, Time, Minutes A% B% 0 100 0 8 85 15 25 0 100 25.1 100 0 30 100 0 Autosampler temperature: 6℃ Column temperature: 40℃ Flow rate: 1.0mL / min Injection volume: 5 μL Electrophoresis time: 30 minutes 5. Purity analysis 5.1 Sample Preparation (Double Strip) • Accurately weigh approximately 10.0 mg of the test sample into a 20 mL volumetric flask. Dilute with the diluent to the final volume and mix thoroughly. (0.5 mg / mL) 5.2 Injection Procedure Number of solution injections Diluent blank 2 Test sample preparation 1 1 Test sample preparation 2 1 Note: If necessary, additional blank injections may be performed until a stable and reproducible baseline is obtained. Additional test sample injections may be added as needed. 5.3 Integral Integrate all peaks greater than 0.05 a / a%, which are not present in the blank solution. ECA - Analytical Method - E920H2 - Standard Qualification 6. Chromatography System Compatibility Requirements 6.1 Injection of blank solution: A stable and reproducible baseline must be observed. The injection of blank solution may be repeated until this condition is met. 6.2 Peak Identification: • The chromatographic profiles of the replicated preparations must be comparable. 7. Calculation 7.1 Individual impurities: • For any impurities of 0.05a / a% or more, report the impurity percentage value to two decimal places. Do not report any impurities below 0.05a / a%. If only one value of 0.05a / a% or more appears, report that value based on a single injection. 7.2 Total impurities (a / a%) • Total impurities (a / a%) = sum of all impurities exceeding 0.05 a / a% 8. Report • Report results at wavelengths of 220nm and 280nm. 8.1. For all detected impurities at a concentration of 0.05a / a% or higher, report the following: • Quantity (a / a%) • Relative retention time Total impurities: a / a% to one decimal place Note: For efficacy assessment, use the purity results obtained from 280 nm. 9. Typical retention times and exemplary chromatograms: 9.1 Typical retention time: Component RT, min Min RRT Compound 1 21.578 1.0 ECA - Analytical Method - E920H2 - Standard Quality Example 3 Stability of the composition containing compound 1 The stability profile of Compound 1 (Eurofins CDMO Alphora Inc. code: E920) was evaluated over 6 months under long-term storage conditions below -20°C, and over 6 months under accelerated conditions of 25±2°C / 60%±5% RH and intermediate storage conditions of 5±3°C. After 6 months of sufficient stability results, additional samples were stored under each storage condition to cover a maximum of 12 months of stability study. The attributes tested included: composition details, purity by HPLC, identification by HPLC, and water content by Karl Fischer (KF) method. This study was conducted in compliance with ICH Q1A(R2) and Alphora Standard Operating Procedure SOP LC027.

[0164] The following test conditions were studied, reflecting the long-term storage conditions for E920. The storage conditions also reflect the packaging configuration, storage, and transportation conditions presented at the time of material manufacture.

[0165] [Table 1]

[0166] Test methods and standards The test attributes included in the release specifications and the test attributes included in the stability tests are listed below. Test attributes and their rationale included in release and stability standards

[0167] [Table 2]

[0168] Exam Schedule The table below outlines the test schedule by condition and time point.

[0169] [Table 3]

[0170] Results: Stability over 3 months was sufficient, and it is expected to remain stable for at least 6 months at -20°C and 25°C / 60% RH.

[0171] [Table 4]

[0172] Example 4 Stability of the composition containing compound 1 The stability profile of Compound 1 (Eurofins CDMO Alphora Inc. code: E920) was evaluated for up to 12 months under long-term storage conditions below -20°C, and for up to 12 months under accelerated storage conditions of 25±2°C / 60%±5% RH and intermediate storage conditions of 5±3°C only. The attributes tested included: composition details, purity by HPLC, identification by HPLC, and water content by Karl Fischer (KF) method. This study was conducted in compliance with ICH Q1A(R2) and Alphora Standard Operating Procedure SOP LC027.

[0173] The following test conditions described below were studied, which reflect the long-term storage conditions of E920. The storage conditions also reflect the packaging configuration, storage, and transportation conditions presented at the time of material production.

[0174]

Table 5

[0175] Test methods and specifications The test attributes included in the release specifications and the test attributes included in the stability tests are listed below. Test attributes and their bases included in the release and stability specifications

[0176]

Table 6

[0177] Test schedule The following table outlines the test schedule for each condition and time point.

[0178]

Table 7

[0179] Results: The stability for 12 months is sufficient, and it is expected to be stable for at least 12 months at -20°C and 25°C / 60% RH.

[0180]

Table 8

[0181]

Table 9

Claims

1. Compound 1 exceeding approximately 0.15% by weight: 【Chemistry 1】 A composition comprising a pharmaceutically acceptable salt thereof.

2. The composition according to claim 1, comprising approximately 50% by weight or more of compound 1.

3. The composition according to claim 1 or 2, comprising approximately 75% by weight or more of compound 1.

4. A composition according to any one of claims 1 to 3, comprising approximately 85% by weight or more of compound 1.

5. A composition according to any one of claims 1 to 4, comprising approximately 90% by weight or more of compound 1.

6. A composition according to any one of claims 1 to 5, comprising approximately 95% by weight or more of compound 1.

7. The composition according to any one of claims 1 to 6, wherein the composition comprises less than 10% by weight of an organic solvent.

8. The composition according to any one of claims 1 to 7, wherein the composition comprises less than 5% by weight of an organic solvent.

9. The composition according to claim 7 or 8, wherein the organic solvent is selected from the group consisting of methanol, dichloromethane, acetone, ethanol, isopropanol, ethyl acetate, acetaldehyde, heptane, and acetaldehyde.

10. The composition according to any one of claims 1 to 9, wherein the composition contains about 4% by weight or less, preferably about 3% or less of water.

11. The composition according to any one of claims 1 to 10, wherein the composition contains about 2% by weight or less of water.

12. The composition according to any one of claims 1 to 11, wherein the composition contains about 1.5% by weight or less of water.

13. The composition according to claim 10 or 12, wherein the weight of water is determined by Karl Fischer analysis.

14. Carbidopa, entacapone, and compound 1 exceeding 0.15% by weight: 【Chemistry 2】 A pharmaceutical composition comprising a pharmaceutically acceptable salt thereof.

15. The pharmaceutical composition according to claim 14, further comprising levodopa.

16. The pharmaceutical composition according to claim 14 or 15, characterized in that the pharmaceutical composition is stable for 16 weeks or more when stored at approximately 5°C.

17. The pharmaceutical composition according to claim 14 or 15, characterized in that the pharmaceutical composition is stable for 16 weeks or more when stored at 5°C ± 3°C.

18. The pharmaceutical composition according to any one of claims 14 to 17, characterized in that the pharmaceutical composition is stable for 16 hours or more at a physiological temperature (for example, 37°C).

19. The aforementioned pharmaceutical composition Approximately 1-15% by weight of levodopa, Approximately 0.1 to 2% by weight of carbidopa, and Approximately 1-7.5% by weight of entacapone A pharmaceutical composition according to any one of claims 15 to 18, comprising:

20. The aforementioned pharmaceutical composition Approximately 2% by weight of levodopa, Approximately 0.5% by weight of carbidopa, and Approximately 2% by weight of entacapone A pharmaceutical composition according to any one of claims 15 to 19, comprising:

21. A pharmaceutical composition according to any one of claims 14 to 20, further comprising one or more pharmaceutical carriers.

22. The pharmaceutical composition according to claim 21, wherein the one or more pharmaceutical carriers are polysaccharides.

23. The pharmaceutical composition according to claim 22, wherein the polysaccharide is sodium carboxymethylcellulose.

24. The pharmaceutical composition according to claim 22, wherein the pharmaceutical composition comprises about 2 to 3% by weight of sodium carboxymethylcellulose.

25. The pharmaceutical composition according to any one of claims 13 to 24, wherein the pharmaceutical composition is in the form of a gel.

26. The pharmaceutical composition according to claim 25, wherein the pH of the gel is less than approximately 5.

7.

27. The pharmaceutical composition according to claim 25 or 26, wherein the pH of the gel is approximately 4.5 to approximately 5.

5.

28. The pharmaceutical composition according to any one of claims 25 to 27, wherein the pH of the gel is approximately 5.

0.

29. The pharmaceutical composition according to any one of claims 25 to 28, wherein the viscosity of the gel is about 3000 to about 5000 CPS.

30. The pharmaceutical composition according to any one of claims 25 to 29, wherein the viscosity of the gel is about 3500 to about 4500 CPS.

31. The pharmaceutical composition according to any one of claims 25 to 30, wherein the gel is formulated for administration to the gastrointestinal tract.

32. The pharmaceutical composition according to any one of claims 14 to 24, wherein the pharmaceutical composition is in the form of an oral dosage form.

33. A method for treating Parkinson's disease (PD) in a patient, comprising administering to the subject a pharmaceutical composition according to any one of claims 14 to 31.

34. The method according to claim 33, wherein the Parkinson's disease is progressive Parkinson's disease.

35. The method according to claim 33 or 34, wherein the pharmaceutical composition is administered to the patient over a period of 16 hours.

36. The method according to any one of claims 33 to 35, wherein approximately 25% of the total daily dose of the pharmaceutical composition is administered to the patient in the morning.

37. The method according to any one of claims 33 to 36, wherein the pharmaceutical composition is administered to the patient once a day.

38. The method according to any one of claims 33 to 37, wherein the pharmaceutical composition is administered directly to the gastrointestinal tract.

39. The method according to claim 38, wherein the pharmaceutical composition is administered by a PEG-J tube.

40. A method for treating Parkinson's disease (PD) in a patient, comprising administering the pharmaceutical composition described in claim 32 to the subject.

41. The method according to claim 40, wherein the Parkinson's disease is progressive Parkinson's disease.

42. Compound 1 【Transformation 3】 A method for producing a composition containing compound 2 【Chemistry 4】 Compound 3 【Transformation 5】 A method comprising contacting the substance in the presence of an organic solvent and a sulfate.

43. The method according to claim 42, wherein the sulfate is sodium sulfate, potassium sulfate, magnesium sulfate, calcium sulfate, or ammonium sulfate.

44. The method according to claim 42 or 43, wherein the sulfate is sodium sulfate.

45. The method according to any one of claims 42 to 44, wherein the organic solvent is methanol, ethanol, propanol, isopropanol, or butanol.

46. The method according to any one of claims 42 to 45, wherein the organic solvent is ethyl acetate.

47. The method according to claim 45, wherein the organic solvent is methanol.

48. The method according to any one of claims 42 to 47, further comprising suspending compound 1 in an organic solvent, filtering the solid form of compound 1, thereby providing a composition containing compound 1 that is impurity-free in a proportion of more than 90% by weight.

49. The method according to claim 48, wherein the composition containing compound 1 is free of impurities in a proportion exceeding 95% by weight.

50. The method according to claim 49, wherein the composition containing compound 1 is free of impurities in a proportion exceeding 99% by weight.

51. The method according to claim 50, wherein the composition containing compound 1 is substantially free of impurities.

52. The method according to any one of claims 42 to 51, wherein the organic solvent is dichloromethane.

53. A method for characterizing the purity of a pharmaceutical composition comprising levodopa, carbidopa, and entacapone, wherein the purity of compound 1 in the pharmaceutical composition is determined by comparison of a sample of the pharmaceutical composition with a reference standard. 【Transformation 6】 A method comprising determining the amount of a reference standard, wherein the reference standard contains a known amount of compound 1.

54. The method according to claim 53, wherein the pharmaceutical composition is characterized as having high purity when the pharmaceutical composition contains less than about 0.15% by weight of compound 1.

55. The method according to claim 53 or 54, wherein the reference standard is a composition comprising 95% by weight or more of compound 1.

56. The purity of the pharmaceutical composition is determined by a Waters SunFire C18 column, 150 × 4.6 mm, 3.5 μm, UV / Vis detector, mobile phase A being 0.06% trifluoroacetic acid (TFA) in water, and (80:20 MeOH;H ２ The method according to any one of claims 53 to 55, wherein the mobile phase B is 0.04% TFA and is evaluated by high-pressure liquid chromatography (HPLC).

57. Known amount of compound 1: 【Transformation 7】 A method for determining the purity level of a pharmaceutical composition using a reference standard containing a compound 1, wherein the method includes comparing the amount of compound 1 in the reference standard with the amount of compound 1 in the pharmaceutical composition.

58. The purity of the pharmaceutical composition is determined by a Waters SunFire C18 column, 150 × 4.6 mm, 3.5 μm, UV / Vis detector, mobile phase A being 0.06% trifluoroacetic acid (TFA) in water, and (80:20 MeOH;H ２ The method according to claim 57, wherein the mobile phase B is 0.04% TFA and is evaluated by high-pressure liquid chromatography (HPLC).

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