Method and pharmaceutical composition for treating Parkinson's syndrome or Parkinson's disease

Abstract

The invention relates to a method and a pharmaceutical composition for treating Parkinson's syndrome or Parkinson's disease, in particular to a pharmaceutical composition, application and a method for treating Parkinson's syndrome or Parkinson's disease by using a peripheral mu-opioid receptor antagonist. According to the pharmaceutical composition, the application and the method, the symptoms, including constipation, of the Parkinson's syndrome or the Parkinson's disease can be remarkably improved, and particularly the constipation which is invalid or refractory to treat by using a universal constipation drug can be remarkably improved.

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field and relates to new uses or methods of use of peripheral μ-opioid receptor antagonists (PAMORAs). Specifically, it relates to pharmaceutical products, uses, and methods of using peripheral μ-opioid receptor antagonists to treat Parkinson's syndrome or Parkinson's disease, and particularly to pharmaceutical products, uses, and methods of using peripheral μ-opioid receptor antagonists to treat constipation in patients with Parkinson's syndrome or Parkinson's disease. Background Technology

[0002] Parkinsonism is a group of neurodegenerative clinical syndromes involving Parkinson's disease (PD), progressive supranuclear palsy (PSP), multiple system atrophy (MSA), Lewy body dementia (DLB), and corticobasal degeneration (CBD), all related to motor function. Among these, Parkinson's disease, which affects the largest number of patients, is currently the fastest-growing neurological disorder worldwide. Improving the quality of life for patients with Parkinson's syndrome is a significant challenge. Parkinson's syndrome is characterized primarily by motor symptoms, but it is also accompanied by non-motor symptoms such as pain and bowel and bladder dysfunction, all of which severely impact the quality of life of patients.

[0003] Several drugs have been approved for the treatment of Parkinson's syndrome. These drugs exert their effects by entering the brain and acting on various receptors and enzymes in the brain (Sivanandy P, Leey TC, Xiang TC, Ling TC, Wey Han SA, Semilan SLA, Hong PK. Systematic Review on Parkinson's Disease Medications, Emphasizing on Three Recently Approved Drugs to Control Parkinson's Symptoms. Int J Environ Res Public Health. 2021 Dec 30; 19(1):364. doi: 10.3390 / ijerph19010364. PMID: 35010624; PMCID: PMC8744877.). On the other hand, various known adverse reactions are believed to stem from side effects after the drug enters the brain (Borovac JA. Sideeffects of a dopamine agonist therapy for Parkinson's disease: a mini-review of clinical pharmacology. Yale J Biol Med. 2016 Mar 24; 89(1): 37-47. PMID:27505015; PMCID: PMC4797835.). Therefore, even if existing drugs can improve Parkinson's syndrome, their side effects will significantly reduce the patient's quality of life. Furthermore, because Parkinson's disease patients often take multiple medications simultaneously to treat the various symptoms caused by Parkinson's disease (Bhagavathula AS, Tesfaye W, Vidyasagar K,Fialova D. Polypharmacy and Hyperpolypharmacy in Older Individuals with Parkinson's Disease: A Systematic Review and Meta-Analysis. Gerontology.2022; 68(10): 1081-1090. doi: 10.1159 / 000521214. Epub 2022 Jan 13. PMID:35026767; PMCID: PMC9677850.), the problem of decreased quality of life caused by drug side effects is even more serious.

[0004] As mentioned above, Parkinson's syndrome is often accompanied by non-motor symptoms such as bowel and bladder abnormalities, with constipation being the most common non-motor symptom. The same applies to Parkinson's disease. According to the prospective cohort study on the association between defecation frequency and Parkinson's disease in Chinese adults (Chinese Journal of Epidemiology, 2020, 41(1): 48-54), 20%–89% of Parkinson's disease patients experience constipation, and the severity of constipation worsens as the disease progresses. Regarding medication, osmotic laxatives are commonly recommended for treating constipation in patients with Parkinson's syndrome or Parkinson's disease, but they are often accompanied by adverse reactions such as diarrhea and bloating. Long-term use may lead to drug tolerance, and some laxatives contain anthraquinone components that are irritating and may cause weakened colonic motility and melanosis coli. Furthermore, 5-HT agonists such as mosapride and cilipride are effective treatments for constipation, but their effectiveness in patients with Parkinson's syndrome or Parkinson's disease remains uncertain.

[0005] Currently, there are no medications available on the market for treating constipation in patients with Parkinson's syndrome or Parkinson's disease, nor are there any methods for treating constipation in patients with Parkinson's syndrome or Parkinson's disease using peripheral μ-opioid receptor antagonists.

[0006] Therefore, there is an unmet medical need for new drugs and methods for treating Parkinson's syndrome or Parkinson's disease that have fewer side effects, are safer, and especially avoid the side effects caused by drugs entering the brain, while simultaneously improving multiple symptoms. Summary of the Invention

[0007] One object of the present invention is to provide a new pharmaceutical composition, use and method for treating patients with Parkinson's syndrome or Parkinson's disease.

[0008] Another object of the present invention is to provide a new pharmaceutical composition, use and method for treating constipation in patients with Parkinson's syndrome or Parkinson's disease.

[0009] In their experiments, the inventors unexpectedly discovered that, in a mouse model of Parkinson's disease, administration of the peripheral μ-opioid receptor antagonists naldemeton-methyl and avimopan significantly improved the symptoms of Parkinson's syndrome. Based on this discovery, the inventors completed this invention, thus achieving the aforementioned objective.

[0010] The invention can be described from different aspects, and the invention described in any of these aspects and in any of their embodiments is independent of each other but related to each other, and together constitutes the content of the invention.

[0011] A first aspect of the present invention provides a method for treating a patient with Parkinson's syndrome or Parkinson's disease, the method comprising the step of administering a therapeutically effective amount of a peripheral μ-opioid receptor antagonist to the patient.

[0012] In some embodiments of this aspect, a method for treating a patient with Parkinson's syndrome or Parkinson's disease is provided, wherein the patient has constipation, the method comprising the step of administering a therapeutically effective amount of a peripheral μ-opioid receptor antagonist to the patient.

[0013] In some embodiments of this aspect, a method for treating motor disorders in a patient with Parkinson's syndrome is provided, the method comprising the step of administering a therapeutically effective amount of a peripheral μ-opioid receptor antagonist to the patient.

[0014] In other embodiments of this aspect, a method for treating constipation in a patient with Parkinson's syndrome is provided, the method comprising the step of administering a therapeutically effective amount of a peripheral μ-opioid receptor antagonist to the patient.

[0015] In a particular embodiment of this aspect, the peripheral μ-opioid receptor antagonist is selected from naldemeton-methyl or a pharmaceutically acceptable salt thereof and avimopan or a pharmaceutically acceptable salt thereof.

[0016] In a specific embodiment of this aspect, a method for treating constipation in a patient with Parkinson's disease is provided, the method comprising administering to the patient a therapeutically effective amount of a peripheral μ-opioid receptor antagonist, wherein the peripheral μ-opioid receptor antagonist is selected from naldemeton-methyl or a pharmaceutically acceptable salt thereof and avimopan or a pharmaceutically acceptable salt thereof. In one specific embodiment, the constipation is functional constipation caused by or associated with Parkinson's disease. In another specific embodiment, the constipation is refractory, recurrent, or refractory constipation caused by or associated with Parkinson's disease and treated with common constipation medications.

[0017] A second aspect of the invention provides a method for treating constipation in a patient with Parkinson's syndrome or Parkinson's disease while treating motor dysfunction in that patient, the method comprising administering a therapeutically effective amount of a peripheral μ-opioid receptor antagonist to the patient.

[0018] In a particular embodiment of this aspect, the peripheral μ-opioid receptor antagonist is selected from naldemeton-methyl or a pharmaceutically acceptable salt thereof and avimopan or a pharmaceutically acceptable salt thereof.

[0019] A third aspect of the invention provides the use of a peripheral μ-opioid receptor antagonist in the preparation of a medicament for treating patients with Parkinson's syndrome or Parkinson's disease.

[0020] In some embodiments of this aspect, the use of a peripheral μ-opioid receptor antagonist in the preparation of a medicament for treating a patient with Parkinson's syndrome or Parkinson's disease, wherein the patient has constipation.

[0021] In some embodiments of this aspect, the use of peripheral μ-opioid receptor antagonists in the preparation of medicaments for treating movement disorders in patients with Parkinson's syndrome is provided.

[0022] In other embodiments of this aspect, the use of a peripheral μ-opioid receptor antagonist in the preparation of a medicament for treating constipation in patients with Parkinson's syndrome is provided.

[0023] In a particular embodiment of this aspect, the peripheral μ-opioid receptor antagonist is selected from naldemeton-methyl or a pharmaceutically acceptable salt thereof and avimopan or a pharmaceutically acceptable salt thereof.

[0024] In a specific embodiment of this aspect, the use of a peripheral μ-opioid receptor antagonist in the preparation of a medicament for treating constipation in patients with Parkinson's disease is provided, wherein the peripheral μ-opioid receptor antagonist is selected from naldemeton-methyl or a pharmaceutically acceptable salt thereof and avimopan or a pharmaceutically acceptable salt thereof. In one specific embodiment, the constipation is functional constipation caused by or associated with Parkinson's disease. In another specific embodiment, the constipation is refractory, recurrent, or refractory constipation caused by or associated with Parkinson's disease and treated with common constipation medications.

[0025] A fourth aspect of the invention provides the use of a peripheral μ-opioid receptor antagonist in the preparation of a medicament for treating constipation in patients with Parkinson's syndrome or Parkinson's disease while treating motor disorders in such patients.

[0026] In a particular embodiment of this aspect, the peripheral μ-opioid receptor antagonist is selected from naldemeton-methyl or a pharmaceutically acceptable salt thereof and avimopan or a pharmaceutically acceptable salt thereof.

[0027] A fifth aspect of the invention provides a pharmaceutical composition comprising a peripheral μ-opioid receptor antagonist and a pharmaceutically acceptable excipient for treating a patient with Parkinson's syndrome or Parkinson's disease.

[0028] In some embodiments of this aspect, a pharmaceutical composition comprising a peripheral μ-opioid receptor antagonist and a pharmaceutically acceptable excipient is provided for treating a patient with Parkinson's syndrome or Parkinson's disease, wherein the patient has constipation.

[0029] In some embodiments of this aspect, a pharmaceutical composition comprising a peripheral μ-opioid receptor antagonist and a pharmaceutically acceptable excipient is provided for treating motor disorders in patients with Parkinson's syndrome.

[0030] In other embodiments of this aspect, a pharmaceutical composition comprising a peripheral μ-opioid receptor antagonist and a pharmaceutically acceptable excipient is provided for treating constipation in patients with Parkinson's syndrome.

[0031] In a particular embodiment of this aspect, the peripheral μ-opioid receptor antagonist is selected from naldemeton-methyl or a pharmaceutically acceptable salt thereof and avimopan or a pharmaceutically acceptable salt thereof.

[0032] In a specific embodiment of this aspect, a pharmaceutical composition comprising a peripheral μ-opioid receptor antagonist and a pharmaceutically acceptable excipient is provided for treating constipation in patients with Parkinson's disease, wherein the peripheral μ-opioid receptor antagonist is selected from naldemeton-methyl or a pharmaceutically acceptable salt thereof and avimopan or a pharmaceutically acceptable salt thereof. In one specific embodiment, the constipation is functional constipation caused by or associated with Parkinson's disease. In another specific embodiment, the constipation is refractory, recurrent, or refractory constipation caused by or associated with Parkinson's disease that is not treated with commonly used constipation medications.

[0033] A sixth aspect of the invention provides a pharmaceutical composition comprising a peripheral μ-opioid receptor antagonist and a pharmaceutically acceptable excipient for treating constipation in patients with Parkinson's syndrome or Parkinson's disease while treating motor dysfunction in such patients.

[0034] In a particular embodiment of this aspect, the peripheral μ-opioid receptor antagonist is selected from naldemeton-methyl or a pharmaceutically acceptable salt thereof and avimopan or a pharmaceutically acceptable salt thereof.

[0035] Based on the research results of this invention, it is anticipated that the pharmaceutical compositions, uses and methods of this invention can be used to treat Parkinson's syndrome, especially Parkinson's disease, effectively improve the symptoms of Parkinson's syndrome patients, including movement disorders and constipation, and delay the progression of Parkinson's syndrome.

[0036] Currently approved Parkinson's disease treatments all exert their effects by entering the brain and acting on various receptors and enzymes, which may have some degree of brain-related side effects. Peripheral μ-opioid receptor antagonists can avoid such side effects. Therefore, the pharmaceutical composition, uses, and methods of the present invention can effectively improve motor disorders in Parkinson's syndrome or Parkinson's disease while also improving constipation and abdominal distension in Parkinson's syndrome patients, and can avoid side effects caused by the drug entering the brain. It has good tolerability and safety, and no adverse events leading to decreased colonic motility or melanosis coli have been reported. Attached Figure Description

[0037] Figure 1 This study demonstrated the effect of naldemeton-methyl tosylate and avimopanol in improving kinetic disorders in mouse models after injection.

[0038] Figure 2 This study demonstrated that naldemeton-methyl tosylate and avimopan increased the frequency of defecation in mouse models after injection.

[0039] Figure 3 This study demonstrated the effect of naldemeton-methyl tosylate and avimopan on increasing the weight of wet feces in mouse models after injection.

[0040] Figure 4 This study demonstrated the effect of naldemeton-toluene and avimopan on increasing the weight of dry feces in mouse models after injection. Detailed Implementation

[0041] To facilitate understanding of this invention, certain terms used herein are defined. The definitions of these terms should be understood in conjunction with the understanding of those skilled in the art regarding the remainder of this specification. Unless otherwise specifically defined herein, all technical and scientific terms used in this invention have the same meaning as commonly understood by those skilled in the art. If the meaning of a term specifically defined herein differs from the commonly understood meaning by those skilled in the art, the meaning specifically defined herein shall prevail.

[0042] Unless the context otherwise requires, the term "constipation in patients with Parkinson's syndrome" as used herein refers to constipation occurring in patients with Parkinson's syndrome. Constipation in patients with Parkinson's disease refers to constipation caused by or associated with Parkinson's disease, also known as Parkinson's disease constipation. According to the Rome IV criteria, constipation in patients with Parkinson's disease is a type of functional constipation (S. Pavan, M. Ballal, A. Prabhu, S. Gorthi, B. Das, A. Mutreja, T. Ramamurthy, A. Pai. Functional Constipation in Parkinson's Disease[abstract]. Mov Disord. 2021; 36 (suppl 1)), characterized by its intractability, recurrence, or refractory nature. This includes constipation that is resistant to or refractory to conventional constipation medications, and is distinct from other types of constipation in clinical practice, such as opioid-induced constipation (Aziz I, Whitehead WE, Palsson OS, Törnblom H, Simrén M. An approach to the diagnosis and management of RomeIV functional disorders of chronic constipation. Expert Rev Gastroenterol Hepatol. 2020 Jan;14(1):39-46.).

[0043] As used in this invention, the term "treatment" refers to eliminating one or more symptoms of the referred disease, reducing its severity, or preventing the occurrence of the referred condition in the treated person. For example, the term "treatment of constipation in a patient with Parkinson's disease" includes reducing the severity of constipation in a patient with Parkinson's disease, increasing the frequency of bowel movements in a patient with Parkinson's disease, and increasing the volume of bowel movements in a patient with Parkinson's disease, or both or all of these. Similarly, the term "treatment of constipation in a patient with Parkinson's syndrome" includes reducing the severity of constipation in a patient with Parkinson's syndrome, increasing the frequency of bowel movements in a patient with Parkinson's syndrome, and increasing the volume of bowel movements in a patient with Parkinson's syndrome, or both or all of these.

[0044] The terms “patient,” “subject,” and “patient” used in this invention have the same meaning and can be used interchangeably in this invention.

[0045] Unless the context otherwise requires, the phrase "therapeuticly effective amount" as used herein, when used to modify peripheral μ-opioid receptor antagonists, refers to the amount of peripheral μ-opioid receptor antagonist administered to a patient to achieve the therapeutic effect. For example, the therapeutic effect may be the elimination of one or more symptoms in a patient with Parkinson's syndrome (e.g., Parkinson's disease), or a reduction in the severity of said symptoms. These symptoms include motor dysfunction and constipation. Therefore, the therapeutic effect includes improving constipation in patients with Parkinson's disease, i.e., reducing the severity of constipation, increasing the frequency of bowel movements, and increasing the volume of stool in patients with Parkinson's disease, or both or all of these.

[0046] The active pharmaceutical ingredient "naldimedin" used in this invention refers to a compound having the following chemical structural formula:

[0047]

[0048] CN101228172B discloses this compound and its preparation method, the entire contents of which are incorporated herein by reference. References to naldemeton in this invention include references to its stereoisomers, metabolites, and prodrugs known in the art as having the same pharmacological activity as naldemeton. References to naldemeton in this invention also include references to solvates of naldemeton or its pharmaceutically acceptable salts, such as hydrates. Furthermore, references to naldemeton in this invention also include references to isotopically labeled naldemeton.

[0049] The pharmaceutically active ingredient "avimopan" used in this invention refers to a compound having the following chemical structural formula:

[0050]

[0051] Its chemical name is [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-1-piperidinyl]methyl]-1-oxo-3-phenylpropyl]amino]acetic acid. U.S. Patent No. 5,250,542 discloses avicomopan and its preparation method, the entire contents of which are incorporated herein by reference. References to avicomopan in this invention include references to its stereoisomers, metabolites, or prodrugs known in the art as having the same pharmacological activity as avicomopan. References to avicomopan in this invention also include references to solvates of avicomopan or its pharmaceutically acceptable salts, such as hydrates. Furthermore, references to avicomopan in this invention also include references to isotopically labeled avicomopan.

[0052] The isotopically labeled sodium demetonide means that, except that one or more of its atoms are replaced by atoms with atomic weights or mass numbers different from those normally found in nature, the isotopically labeled sodium demetonide has the same chemical structure as the sodium demetonide shown above. Examples of applicable isotopes include isotopes of hydrogen, carbon, and nitrogen, for example, but not limited to, those of other types. 2 H, 3 H, 13 C 14 C and 15 N. Those skilled in the art will recognize that isotopically labeled sodium dimethoate can be prepared using methods known in the art by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents.

[0053] Similarly, the isotopically labeled avermorandum means that, except that one or more of its atoms are replaced by atoms with atomic weights or mass numbers different from those normally found in nature, the isotopically labeled avermorandum has the same chemical structure as avermorandum as shown above. Examples of applicable isotopes include isotopes of hydrogen, carbon, and nitrogen, such as, but not limited to, those of other types. 2 H, 3 H, 13 C 14 C and 15 N. Those skilled in the art will recognize that isotopically labeled avimopan can be prepared using methods known in the art by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents.

[0054] The phrase "pharmaceutically acceptable" as used in this invention means that the substance or composition is chemically, physiologically and / or toxicologically compatible with other components contained in the formulation and / or the mammal being treated.

[0055] The pharmaceutically acceptable salts of naldemeton-methyl or avimoran described in this invention include various pharmaceutically acceptable salts, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, hydrogen sulfate, phosphate, formate, acetate, lactate, citrate, tartrate, ascorbate, succinate, maleate, fumarate, gluconate, glucuronide, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, and dihydroxynaphthyl salt.

[0056] According to a first aspect of the invention, a method for treating a patient with Parkinson's syndrome or Parkinson's disease is provided, the method comprising the step of administering to the patient a therapeutically effective amount of a peripheral μ-opioid receptor antagonist, wherein the peripheral μ-opioid receptor antagonist is selected from naldemeton-methyl or a pharmaceutically acceptable salt thereof and avimopan or a pharmaceutically acceptable salt thereof.

[0057] In some implementations, a method for treating a patient with Parkinson's disease is provided, the method comprising administering to the patient a therapeutically effective amount of naldemeton-methyl or a pharmaceutically acceptable salt thereof.

[0058] In some implementations, a method for treating a patient with Parkinson's disease is provided, the method comprising administering to the patient a therapeutically effective amount of avimopan or a pharmaceutically acceptable salt thereof.

[0059] In some implementations, the treatment of a patient's Parkinson's disease includes treating the patient's constipation, such as refractory, recurrent, or constipation that is difficult to treat with common constipation medications.

[0060] In other embodiments, the treatment of a patient with Parkinson's disease includes improving the patient's motor symptoms or improving their motor function.

[0061] According to a second aspect of the invention, a method is provided for treating constipation in a patient with Parkinson's syndrome or Parkinson's disease while treating motor dysfunction in that patient, the method comprising administering to the patient a therapeutically effective amount of a peripheral μ-opioid receptor antagonist, wherein the peripheral μ-opioid receptor antagonist is selected from naldemeton-methyl or a pharmaceutically acceptable salt thereof and avimopan or a pharmaceutically acceptable salt thereof.

[0062] In some embodiments, a method is provided for treating constipation in a patient with Parkinson's disease while treating motor dysfunction, the method comprising administering to the patient a therapeutically effective amount of a peripheral μ-opioid receptor antagonist, wherein the peripheral μ-opioid receptor antagonist is selected from naldemeton-methyl or a pharmaceutically acceptable salt thereof and avimopan or a pharmaceutically acceptable salt thereof.

[0063] In some implementations, a method is provided for treating constipation in a patient with Parkinson's syndrome or Parkinson's disease while treating the patient's motor dysfunction, the method comprising administering to the patient a therapeutically effective amount of naldemeton-methyl or a pharmaceutically acceptable salt thereof.

[0064] In some implementations, a method is provided for treating constipation in a patient with Parkinson's disease while treating motor dysfunction, the method comprising administering to the patient a therapeutically effective amount of naldemeton-methyl or a pharmaceutically acceptable salt thereof.

[0065] In some embodiments, a method is provided for treating constipation in a patient with Parkinson's syndrome or Parkinson's disease while simultaneously treating the patient's motor dysfunction, the method comprising the step of administering to the patient a therapeutically effective amount of avimoran or a pharmaceutically acceptable salt thereof. In some embodiments, a method is provided for treating constipation in a patient with Parkinson's disease while simultaneously treating the patient's motor dysfunction, the method comprising the step of administering to the patient a therapeutically effective amount of avimoran or a pharmaceutically acceptable salt thereof.

[0066] In some implementations, the constipation is refractory, recurrent, or difficult to treat with common constipation medications.

[0067] According to a third aspect of the invention, there is use of a peripheral μ-opioid receptor antagonist in the preparation of a medicament for treating a patient with Parkinson's syndrome or Parkinson's disease, wherein the peripheral μ-opioid receptor antagonist is selected from naldemeton-methyl or a pharmaceutically acceptable salt thereof and avimopan or a pharmaceutically acceptable salt thereof.

[0068] In some implementations, the use of naldemeton-methyl or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a patient’s Parkinson’s disease is provided.

[0069] In some implementations, the use of avimopan or a pharmaceutically acceptable salt thereof is provided in the preparation of a medicament for treating patients with Parkinson's disease.

[0070] In some implementations, the treatment of a patient's Parkinson's disease includes treating the patient's constipation, such as refractory, recurrent, or constipation that is difficult to treat with common constipation medications.

[0071] In other embodiments, the treatment of a patient with Parkinson's disease includes alleviating the patient's motor symptoms or improving their motor function.

[0072] According to a fourth aspect of the invention, there is use of a peripheral μ-opioid receptor antagonist in the preparation of a medicament for treating constipation in a patient with Parkinson's syndrome or Parkinson's disease while treating motor dysfunction in that patient, wherein the peripheral μ-opioid receptor antagonist is selected from naldemeton-methyl or a pharmaceutically acceptable salt thereof and avimopan or a pharmaceutically acceptable salt thereof.

[0073] In some embodiments, the use of a peripheral μ-opioid receptor antagonist in the preparation of a medicament for treating constipation in a patient with Parkinson's disease while treating motor dysfunction, wherein the peripheral μ-opioid receptor antagonist is selected from naldemeton-methyl or a pharmaceutically acceptable salt thereof and avimopan or a pharmaceutically acceptable salt thereof.

[0074] In some embodiments, naldemeton-methyl or a pharmaceutically acceptable salt thereof is provided for use in the preparation of a medicament for treating constipation in patients with Parkinson's syndrome or Parkinson's disease while treating motor disorders in such patients.

[0075] In some embodiments, naldemeton-methyl or a pharmaceutically acceptable salt thereof is provided for use in the preparation of a medicament for treating constipation in patients with Parkinson's disease while treating motor disorders in such patients.

[0076] In some embodiments, the use of avimopan or a pharmaceutically acceptable salt thereof is provided in the preparation of a medicament for treating constipation in patients with Parkinson's syndrome or Parkinson's disease while treating motor disorders in such patients.

[0077] In some embodiments, the use of avimopan or a pharmaceutically acceptable salt thereof is provided in the preparation of a medicament for treating constipation in patients with Parkinson's disease while treating motor disorders in such patients.

[0078] In some implementations, the constipation is refractory, recurrent, or difficult to treat with common constipation medications.

[0079] According to a fifth aspect of the invention, a pharmaceutical composition comprising a peripheral μ-opioid receptor antagonist and a pharmaceutically acceptable excipient is provided for treating a patient with Parkinson's syndrome or Parkinson's disease, wherein the peripheral μ-opioid receptor antagonist is selected from naldemeton-methyl or a pharmaceutically acceptable salt thereof and avimopan or a pharmaceutically acceptable salt thereof.

[0080] In some embodiments, a pharmaceutical composition comprising naldemeton-methyl or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient is provided for treating a patient with Parkinson's disease.

[0081] In some embodiments, a pharmaceutical composition comprising avimopanol or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient is provided for treating a patient with Parkinson's disease.

[0082] In some implementations, the treatment of a patient's Parkinson's disease includes treating the patient's constipation, such as refractory, recurrent, or constipation that is difficult to treat with common constipation medications.

[0083] In other embodiments, the treatment of a patient with Parkinson's disease includes alleviating the patient's motor symptoms or improving their motor function.

[0084] According to a sixth aspect of the invention, a pharmaceutical composition comprising a peripheral μ-opioid receptor antagonist and a pharmaceutically acceptable excipient is provided for treating constipation in a patient with Parkinson's syndrome or Parkinson's disease while treating motor dysfunction in that patient, wherein the peripheral μ-opioid receptor antagonist is selected from naldemeton-methyl or a pharmaceutically acceptable salt thereof and avimopam or a pharmaceutically acceptable salt thereof.

[0085] In some embodiments, a pharmaceutical composition comprising a peripheral μ-opioid receptor antagonist and a pharmaceutically acceptable excipient is provided for treating constipation in a patient with Parkinson's disease while treating motor dysfunction, wherein the peripheral μ-opioid receptor antagonist is selected from naldemeton-methyl or a pharmaceutically acceptable salt thereof and avimopan or a pharmaceutically acceptable salt thereof.

[0086] In some embodiments, a pharmaceutical composition comprising naldemeton-methyl or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient is provided for treating constipation in a patient with Parkinson's syndrome or Parkinson's disease while treating the patient's motor dysfunction.

[0087] In some embodiments, a pharmaceutical composition comprising naldemeton-methyl or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient is provided for treating constipation in a patient with Parkinson's disease while treating the patient's motor dysfunction.

[0088] In some embodiments, a pharmaceutical composition comprising avimopan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient is provided for treating constipation in a patient with Parkinson's syndrome or Parkinson's disease while treating the patient's motor dysfunction.

[0089] In some embodiments, a pharmaceutical composition comprising avimopanol or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient is provided for treating constipation in a patient with Parkinson's disease while treating the patient's motor dysfunction.

[0090] In some implementations, the constipation is refractory, recurrent, or difficult to treat with common constipation medications.

[0091] In particular, the present invention may be represented as one, more, or all of the following embodiments:

[0092] Implementation Scheme 1. A method for treating a patient with Parkinson's syndrome or Parkinson's disease, the method comprising the step of administering a therapeutically effective amount of a peripheral μ-opioid receptor antagonist to the patient.

[0093] Implementation Scheme 2. The method described in Implementation Scheme 1, wherein the patient suffers from constipation.

[0094] Implementation Scheme 3. The method according to Implementation Scheme 1 or 2, wherein the peripheral μ-opioid receptor antagonist is selected from naldemeton-methyl or a pharmaceutically acceptable salt thereof and avimopan or a pharmaceutically acceptable salt thereof.

[0095] Implementation Plan 4. Use of peripheral μ-opioid receptor antagonists in the preparation of medicaments for the treatment of patients with Parkinson's syndrome or Parkinson's disease.

[0096] Implementation Scheme 5. The use described in Implementation Scheme 4, wherein the patient suffers from constipation.

[0097] Implementation Scheme 6. The use according to Implementation Scheme 4 or 5, wherein the peripheral μ-opioid receptor antagonist is selected from naldemeton-methyl or a pharmaceutically acceptable salt thereof and avimopan or a pharmaceutically acceptable salt thereof.

[0098] Implementation Scheme 7. A pharmaceutical composition comprising a peripheral μ-opioid receptor antagonist and a pharmaceutically acceptable excipient for treating a patient with Parkinson's syndrome or Parkinson's disease.

[0099] Implementation Scheme 8. A pharmaceutical composition for use according to Implementation Scheme 7, wherein the patient suffers from constipation.

[0100] Implementation Scheme 9. A pharmaceutical composition for use according to Implementation Scheme 7 or 8, wherein the peripheral μ-opioid receptor antagonist is selected from naldemeton-methyl or a pharmaceutically acceptable salt thereof and avimopan or a pharmaceutically acceptable salt thereof.

[0101] Implementation Scheme 10. A method for treating constipation in a patient with Parkinson's syndrome or Parkinson's disease, the method comprising administering to the patient a therapeutically effective amount of a peripheral μ-opioid receptor antagonist.

[0102] Implementation Scheme 11. The method according to Implementation Scheme 10, wherein the peripheral μ-opioid receptor antagonist is selected from naldemeton-methyl or a pharmaceutically acceptable salt thereof and avimopan or a pharmaceutically acceptable salt thereof.

[0103] Implementation Plan 12. Use of peripheral μ-opioid receptor antagonists in the preparation of medicaments for the treatment of constipation in patients with Parkinson's syndrome or Parkinson's disease.

[0104] Implementation Scheme 13. The use according to Implementation Scheme 12, wherein the peripheral μ-opioid receptor antagonist is selected from naldemeton-methyl or a pharmaceutically acceptable salt thereof and avimopan or a pharmaceutically acceptable salt thereof.

[0105] Implementation Scheme 14. A pharmaceutical composition comprising a peripheral μ-opioid receptor antagonist and a pharmaceutically acceptable excipient for treating constipation in patients with Parkinson's syndrome or Parkinson's disease.

[0106] Implementation Scheme 15. A pharmaceutical composition for use according to Implementation Scheme 14, wherein the peripheral μ-opioid receptor antagonist is selected from naldemeton-methyl or a pharmaceutically acceptable salt thereof and avimopan or a pharmaceutically acceptable salt thereof.

[0107] Implementation Plan 16. Peripheral μ-opioid receptor antagonists, used to treat patients with Parkinson's syndrome or Parkinson's disease.

[0108] Implementation Scheme 17. A peripheral μ-opioid receptor antagonist for use according to Implementation Scheme 16, wherein the patient suffers from constipation.

[0109] Implementation Scheme 18. A peripheral μ-opioid receptor antagonist for use according to Implementation Scheme 16 or 17, wherein the peripheral μ-opioid receptor antagonist is selected from naldemeton-methyl or a pharmaceutically acceptable salt thereof and avimopan or a pharmaceutically acceptable salt thereof.

[0110] Implementation Plan 19. Peripheral μ-opioid receptor antagonists for the treatment of constipation in patients with Parkinson's syndrome or Parkinson's disease.

[0111] Implementation Scheme 20. A peripheral μ-opioid receptor antagonist for use according to Implementation Scheme 19, wherein the peripheral μ-opioid receptor antagonist is selected from naldemeton-methyl or a pharmaceutically acceptable salt thereof and avimopan or a pharmaceutically acceptable salt thereof.

[0112] The pharmaceutical compositions of the present invention can be prepared into dosage forms suitable for patient use using methods known in the art and suitable pharmaceutical excipients. The selection of specific excipients will depend on the route of administration or the type and state of disease for treating a particular patient. For example, pharmaceutically acceptable excipients include diluents, carriers, fillers, binders, wetting agents, disintegrants, absorption enhancers, surfactants, adsorbents, and lubricants, etc., which are conventional in the pharmaceutical field. Flavoring agents, preservatives, and sweeteners may also be added to the pharmaceutical composition if necessary. Methods for preparing suitable pharmaceutical compositions for specific routes of administration are entirely within the knowledge of those skilled in the art.

[0113] The pharmaceutical compositions of the present invention can be formulated into unit dose forms for administration. The dosage form can be a liquid or a solid dosage form. Liquid dosage forms can be solutions, colloids, emulsions, or suspensions, etc. Solid dosage forms can be, for example, tablets, powders, suppositories, granules, or capsules, etc. Other dosage forms include aerosols, implants, patches, or liniments, etc. The term "unit dose form" as used herein refers to a physically dispersed unit suitable for use as a unit dose in human subjects, particularly patients with Parkinson's disease, each unit containing a predetermined amount of the peripheral μ-opioid receptor antagonist of the present invention calculated to produce the desired therapeutic effect.

[0114] The pharmaceutical compositions of the present invention can be administered in any manner and form commonly used in the art. For example, the pharmaceutical compositions of the present invention can be administered via a selection of methods including oral administration, inhalation via spray, rectal administration, nasal administration, vaginal administration, topical administration, and parenteral administration such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intrasternal, intrasternal, or intracranial injection, with oral, intramuscular, intraperitoneal, or intravenous administration being preferred. Oral administration is preferred for patients in need.

[0115] For oral administration, any suitable pharmaceutical excipient commonly used in the preparation of solid dosage forms can be used, and formulation techniques known in the art can be employed to formulate the pharmaceutical compositions of the present invention into solid dosage forms, such as tablets, capsules, and powders. Alternatively, any suitable pharmaceutical excipient commonly used in the preparation of liquid dosage forms can be used, and formulation techniques known in the art can be employed to formulate the pharmaceutical compositions of the present invention into liquid dosage forms, such as solutions, syrups, suspensions, and emulsions.

[0116] For parenteral administration, any suitable excipient commonly used in the preparation of parenteral formulations can be used. The pharmaceutical compositions of the present invention can be formulated into formulations suitable for parenteral administration using formulation techniques known in the art, such as sterile injections, lyophilized powders, transdermal patches, aerosols, oral and nasal inhalers, and suppositories. Parenteral administration routes include intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and local routes.

[0117] In the methods, uses, or pharmaceutical compositions of the present invention, the peripheral μ-opioid receptor antagonist, particularly naldemeton-methyl or a pharmaceutically acceptable salt thereof and acimopam or a pharmaceutically acceptable salt thereof, is administered in a single dose of about 0.01 mg to about 13 mg, preferably about 0.1 mg to about 0.5 mg. It is administered once or twice daily, preferably once daily. Therefore, it is advantageous that the pharmaceutical composition or medicine comprising the peripheral μ-opioid receptor antagonist in unit dose form of the present invention contains 0.01 mg to about 13 mg (e.g., 0.05 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg or 12 mg), preferably about 0.1 mg to about 0.5 mg of the peripheral μ-opioid receptor antagonist, especially naldemeton-methyl or a pharmaceutically acceptable salt thereof and acimopam or a pharmaceutically acceptable salt thereof.

[0118] Based on the results of this invention, it is anticipated that the methods, uses, and pharmaceutical compositions of this invention can effectively treat constipation in patients with Parkinson's syndrome or Parkinson's disease, with good tolerability and safety, without causing adverse events such as decreased colonic motility or melanosis coli, and can improve abdominal distension in patients, thereby improving the quality of life of patients with Parkinson's syndrome or Parkinson's disease.

[0119] Example

[0120] The foregoing description of exemplary compositions, uses, and methods of the present invention is followed by embodiments of the invention, which are for illustrative purposes only and not intended to limit the invention. Unless otherwise specifically stated, all materials used in the present invention are commercially available.

[0121] I. Construction of MPTP-induced mouse Parkinson's disease model and evaluation of drug effects (motor disorder)

[0122] A mouse model of Parkinson's disease was established by intraperitoneal injection of MPTP into mice, and the efficacy of experimental drugs on MPTP-induced motor disorders was studied.

[0123] • Experimental animals: C57BL / 6J mice, 8 weeks old, male.

[0124] ·drug:

[0125] MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), physiological saline, methylcellulose, naldemeton-tosylate, and avimopan.

[0126] Preparation of MTPT solution:

[0127] Weigh out MPTP and add it to physiological saline to prepare a solution of 3 mg / mL. Mix well and store frozen. The dosage is 10 mL / kg.

[0128] Preparation of sodium dimethoate toluenesulfonate solution:

[0129] Weigh out naldemeton-tosylate and place it in a clear test tube. Then add physiological saline containing 0.5% methylcellulose and vortex thoroughly to obtain a 0.01 mg / mL naldemeton-tosylate solution. The dosage is 10 mL / kg.

[0130] Preparation of avimopan solution:

[0131] Weigh acimolam into a clear test tube, then add physiological saline containing 0.5% methylcellulose, and vortex thoroughly to obtain a 0.1 mg / mL acimolam solution. The dosage is 10 mL / kg.

[0132] • Mouse model construction and drug administration:

[0133] A total of 32 mice were randomly divided into 4 groups of 8 mice each.

[0134] From day 1 to day 8, the model group was injected intraperitoneally with 30 mg / kg of MPTP daily.

[0135] From day 1 to day 8, mice in the sham model were injected intraperitoneally with saline solution daily.

[0136] Before the experiment, the mice were allowed one week to adapt to the environment. Each mouse underwent a health check, including an assessment of its fur, limbs and mouthparts, and an examination of its posture and movements for any abnormal signs.

[0137] • Dosage composition (Table 1)

[0138] Group Treatment (injection) Mouse number 1 Dummy modules, media 8 2 Model group, medium 8 3 Model group: Nadecamidine tosylate 0.1 mg / kg body weight 8 4 Model group, avimopan 1 mg / kg body weight 8

[0139] ·Grip strength analysis

[0140] On day 9, mice were administered the drug orally. Grip strength was tested 1 hour after administration.

[0141] In the grip strength test, mice were instructed to grip the metal grid of the grip strength meter with their forelimbs, and then their tails were gently pulled back until the mice could no longer grip the grid. The average grip strength observed in 10 trials was recorded and calculated.

[0142] Statistical analysis

[0143] When the differences were significant, the effects of naldemeton-tosylate and avimopanol on the model were tested using the Kruskal-Wallis test, and then Conover's multiple comparison test was used to compare with vehicles.

[0144] The comparison between the model media group and the sham model group was performed using the two-tailed Mann-Whitney test (###P<0.001). When the difference was significant, the effects of naldemeton-tosylate and avimopanol in the model were first tested by Kruskal-Wallis analysis, and then compared with the model media group by Conover multiple test (*P<0.05,**P<0.01).

[0145] Experimental Results

[0146] According to the dosage and route of administration shown in Table 1, the mice were administered the drugs as described above, and the results are as follows: Figure 1 As shown. Figure 1 As shown in the figure, from a statistical point of view, the grip strength of the model medium group was significantly lower than that of the sham medium group. Moreover, in the model group, the grip strength of the sodium tosylate administration group and the avimopan administration group was also significantly increased compared with the medium group.

[0147] The results showed that the peripheral μ-opioid receptor antagonists naldemeton-methyl and avimopan may improve motor dysfunction in patients with Parkinson's disease.

[0148] II. Construction of MPTP-induced mouse Parkinson's disease model and evaluation of drug effects (constipation)

[0149] A mouse model of Parkinson's disease was established by intraperitoneal injection of MPTP into mice, and the efficacy of the experimental drugs on MPTP-induced intestinal motility inhibition was studied.

[0150] • Experimental animals: C57BL / 6J mice, 8 weeks old, male.

[0151] ·drug:

[0152] MPTP, physiological saline

[0153] Methylcellulose, naldemeton-tosylate, and avimopan.

[0154] Preparation of MTPT solution:

[0155] Weigh out MPTP and add it to physiological saline to prepare a solution of 3 mg / mL. Mix well and store frozen. The dosage is 10 mL / kg.

[0156] Preparation of sodium dimethoate toluenesulfonate solution:

[0157] Weigh out naldemeton-tosylate and place it in a clear test tube. Then add physiological saline containing 0.5% methylcellulose and vortex thoroughly to obtain a 0.01 mg / mL naldemeton-tosylate solution. The dosage is 10 mL / kg.

[0158] Preparation of avimopan solution:

[0159] Weigh acimolam into a clear test tube, then add physiological saline containing 0.5% methylcellulose, and vortex thoroughly to obtain a 0.1 mg / mL acimolam solution. The dosage is 10 mL / kg.

[0160] • Mouse model construction and drug administration:

[0161] A total of 32 mice were randomly divided into 4 groups of 8 mice each.

[0162] From day 1 to day 7, the model group was injected intraperitoneally with 30 mg / kg of MPTP daily.

[0163] From day 1 to day 7, mice in the sham model were injected intraperitoneally with saline solution daily.

[0164] Before the experiment, the mice were allowed one week to adapt to the environment. Each mouse underwent a health check, including an assessment of its fur, limbs and mouthparts, and an examination of its posture and movements for any abnormal signs.

[0165] • Dosage composition (Table 2)

[0166] Group Treatment (injection) Mouse number 1 Dummy modules, media 8 2 Model group, medium 8 3 Model group: Nadecamidine tosylate 0.1 mg / kg body weight 8 4 Model group, avimopan 1 mg / kg body weight 8

[0167] • Stool analysis:

[0168] On day 7, the mice were fasted and deprived of water for 12 hours. On day 8, the mice were allowed to eat and drink for 2 hours. 1.5 hours later, the mice were administered the drug orally. 30 minutes later, each mouse was placed in a clean, individual box for 1 hour, and then returned to its original cage. Feces were collected, counted, and weighed, and then dried overnight at 65°C to assess fecal dry weight.

[0169] Statistical analysis

[0170] The comparison between the model media group and the sham model group was performed using the two-tailed Mann-Whitney test (#P<0.05). When the difference was significant, the effects of naldemeton-tosylate and avimopanol in the model were first tested by Kruskal-Wallis analysis, and then compared with the model media group by Dunn multiple test (*P<0.05, **P<0.01, ***P<0.001).

[0171] Experimental Results

[0172] According to the dosage and route of administration shown in Table 2, the mice were administered the drugs as described above, and the results are as follows: Figure 2-4 As shown, after injection of MPTP, mice had fewer bowel movements and less dry and wet stool weight, indicating signs of constipation.

[0173] like Figure 2 As shown, after administration of naldemeton-tosylate 0.1 mg / kg body weight and avimopane 1 mg / kg body weight, the frequency of bowel movements increased compared to the model media group.

[0174] like Figure 3 As shown, after administration of naldemeton-tosylate 0.1 mg / kg body weight and avimopane 1 mg / kg body weight, the weight of wet stool increased compared to the model media group.

[0175] like Figure 4 As shown, after administration of naldemeton-tosylate 0.1 mg / kg body weight and avimopane 1 mg / kg body weight, the weight of dry stool increased compared to the model media group.

[0176] The above results indicate that administration of naldemeton-tosylate 0.1 mg / kg body weight and avimopan 1 mg / kg body weight increased both the frequency and weight of bowel movements compared to the model mediator group, significantly improving constipation in Parkinson's disease mice. Therefore, naldemeton-tosylate or avimopan can be expected to be used to treat constipation in patients with Parkinson's syndrome or Parkinson's disease.

Claims

1. Use of a peripheral mu opioid receptor antagonist in the manufacture of a medicament for the treatment of Parkinsonism or Parkinson's disease in a patient.

2. Use according to claim 1 wherein the patient also suffers from constipation.

3. Use according to claim 2 wherein the constipation is intractable, recurrent or refractory to commonly used constipation therapies.

4. Use according to any one of claims 1 to 3 wherein the peripheral mu opioid receptor antagonist is selected from naldeimide or a pharmaceutically acceptable salt thereof and aviprimophan or a pharmaceutically acceptable salt thereof.

5. Use of a peripheral mu opioid receptor antagonist in the manufacture of a medicament for the treatment of constipation in a patient being treated for motor symptoms of Parkinsonism or Parkinson's disease.

6. Use according to claim 5 wherein the constipation is intractable, recurrent or refractory to commonly used constipation therapies.

7. Use according to claim 5 or 6 wherein the peripheral mu opioid receptor antagonist is selected from naldeimide or a pharmaceutically acceptable salt thereof and aviprimophan or a pharmaceutically acceptable salt thereof.

8. Use of a peripheral mu opioid receptor antagonist in the manufacture of a medicament for the treatment of constipation in a patient suffering from Parkinsonism or Parkinson's disease.

9. Use according to claim 8 wherein the constipation is intractable, recurrent or refractory to commonly used constipation therapies.

10. Use according to claim 8 or 9 wherein the peripheral mu opioid receptor antagonist is selected from naldeimide or a pharmaceutically acceptable salt thereof and aviprimophan or a pharmaceutically acceptable salt thereof.

11. Use of a peripheral mu opioid receptor antagonist in the manufacture of a medicament for the treatment of constipation caused by Parkinson's disease.

12. Use according to claim 11 wherein the constipation is intractable, recurrent or refractory to commonly used constipation therapies.

13. Use according to claim 11 or 12 wherein the peripheral mu opioid receptor antagonist is selected from naldeimide or a pharmaceutically acceptable salt thereof and aviprimophan or a pharmaceutically acceptable salt thereof.

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